WorldWideScience

Sample records for targeting sensitive populations

  1. Target population growth: zero.

    Science.gov (United States)

    2000-02-01

    The Fifth Session of the Fourth National Council of the China Family Planning Association held in Beijing on December 13, 1999, focused on how to control the number of people in China and improve their quality of life. Family planners also explored ways to decrease the number of babies with birth defects and maternal mortality rate. During the meeting, Zhang Weiqing, minister of the State Family Planning Commission, expressed that they are optimistic about keeping the Chinese population under 1.3 billion before the 21st century. He added that top attention should be paid to providing family planning service (sexual and reproductive counseling) for unmarried young people, laid-off workers, and the transient population in urban areas. In Shenzhen, a special economic zone, 854 family planning offices have been established among 2.8 million temporary residents, these agencies, many of which are led by temporary residents themselves. Lastly, Zhang announced that a draft national law on population and family planning has been finished and the law is expected to be enacted in 3 years.

  2. Burst Populations and Detector Sensitivity

    Science.gov (United States)

    Band, David L.

    2003-01-01

    The F(sub T) (peak bolometric photon flux) vs. E(sub p) (peak energy) plane is a powerful tool to compare the burst populations detected by different detectors. Detector sensitivity curves in this plane demonstrate which burst populations the detectors will detect. For example, future CZT-based detectors will show the largest increase in sensitivity for soft bursts, and will be particularly well- suited to study X-ray rich bursts and X-ray Flashes. Identical bursts at different redshifts describe a track in the F(sub T)-E(sub p) plane.

  3. Rabies Vaccination Targets for Stray Dog Populations

    Science.gov (United States)

    Leung, Tiffany; Davis, Stephen A.

    2017-01-01

    The role of stray dogs in the persistence of domestic dog rabies, and whether removal of such dogs is beneficial, remains contentious issues for control programs seeking to eliminate rabies. While a community might reach the WHO vaccination target of 70% for dogs that can be handled, the stray or neighborhood dogs that are too wary of humans to be held are a more problematic population to vaccinate. Here, we present a method to estimate vaccination targets for stray dogs when the dog population is made up of stray, free-roaming, and confined dogs, where the latter two types are considered to have an identifiable owner. The control effort required for stray dogs is determined by the type-reproduction number, T1, the number of stray dogs infected by one rabid stray dog either directly or via any chain of infection involving owned dogs. Like the basic reproduction number R0 for single host populations, T1 determines the vaccination effort required to control the spread of disease when control is targeted at one host type, and there is a mix of host types. The application of T1 to rabies in mixed populations of stray and owned dogs is novel. We show that the outcome is sensitive to the vaccination coverage in the owned dog population, such that if vaccination rates of owned dogs were too low then no control effort targeting stray dogs is able to control or eliminate rabies. The required vaccination level also depends on the composition of the dog population, where a high proportion of either stray or free-roaming dogs implies unrealistically high vaccination levels are required to prevent rabies. We find that the required control effort is less sensitive to continuous culling that increases the death rate of stray dogs than to changes in the carrying capacity of the stray dog population. PMID:28451589

  4. Rabies Vaccination Targets for Stray Dog Populations.

    Science.gov (United States)

    Leung, Tiffany; Davis, Stephen A

    2017-01-01

    The role of stray dogs in the persistence of domestic dog rabies, and whether removal of such dogs is beneficial, remains contentious issues for control programs seeking to eliminate rabies. While a community might reach the WHO vaccination target of 70% for dogs that can be handled, the stray or neighborhood dogs that are too wary of humans to be held are a more problematic population to vaccinate. Here, we present a method to estimate vaccination targets for stray dogs when the dog population is made up of stray, free-roaming, and confined dogs, where the latter two types are considered to have an identifiable owner. The control effort required for stray dogs is determined by the type-reproduction number, T 1 , the number of stray dogs infected by one rabid stray dog either directly or via any chain of infection involving owned dogs. Like the basic reproduction number R 0 for single host populations, T 1 determines the vaccination effort required to control the spread of disease when control is targeted at one host type, and there is a mix of host types. The application of T 1 to rabies in mixed populations of stray and owned dogs is novel. We show that the outcome is sensitive to the vaccination coverage in the owned dog population, such that if vaccination rates of owned dogs were too low then no control effort targeting stray dogs is able to control or eliminate rabies. The required vaccination level also depends on the composition of the dog population, where a high proportion of either stray or free-roaming dogs implies unrealistically high vaccination levels are required to prevent rabies. We find that the required control effort is less sensitive to continuous culling that increases the death rate of stray dogs than to changes in the carrying capacity of the stray dog population.

  5. Temperature targets revisited under climate sensitivity uncertainty

    Science.gov (United States)

    Neubersch, Delf; Roth, Robert; Held, Hermann

    2015-04-01

    While the 2° target has become an official goal of the COP (Conference of the Parties) process recent work has shown that it requires re-interpretation if climate sensitivity uncertainty in combination with anticipated future learning is considered (Schmidt et al., 2011). A strict probabilistic limit as suggested by the Copenhagen diagnosis may lead to conceptual flaws in view of future learning such a negative expected value of information or even ill-posed policy recommendations. Instead Schmidt et al. suggest trading off the probabilistic transgression of a temperature target against mitigation-induced welfare losses and call this procedure cost risk analysis (CRA). Here we spell out CRA for the integrated assessment model MIND and derive necessary conditions for the exact nature of that trade-off. With CRA at hand it is for the first time that the expected value of climate information, for a given temperature target, can meaningfully be assessed. When focusing on a linear risk function as the most conservative of all possible risk functions, we find that 2° target-induced mitigation costs could be reduced by up to 1/3 if the climate response to carbon dioxide emissions were known with certainty, amounting to hundreds of billions of Euros per year (Neubersch et al., 2014). Further benefits of CRA over strictly formulated temperature targets are discussed. References: D. Neubersch, H. Held, A. Otto, Operationalizing climate targets under learning: An application of cost-risk analysis, Climatic Change, 126 (3), 305-318, DOI 10.1007/s10584-014-1223-z (2014). M. G. W. Schmidt, A. Lorenz, H. Held, E. Kriegler, Climate Targets under Uncertainty: Challenges and Remedies, Climatic Change Letters, 104 (3-4), 783-791, DOI 10.1007/s10584-010-9985-4 (2011).

  6. Accounting for Population Variation in Targeted Proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Fujimoto, Grant M.; Monroe, Matthew E.; Rodriguez, Larissa; Wu, Chaochao; MacLean, Brendan; Smith, Richard D.; MacCoss, Michael J.; Payne, Samuel H.

    2014-01-03

    Individual proteomes typically differ from the reference human proteome at ~10,000 single amino acid variants. When viewed at the population scale, this individual variation results in a wide variety of protein sequences. In targeted proteomics experiments, such variability would confound accurate protein quantification. To facilitate researchers in identifying target peptides with high variability within the human population we have created the Population Variation plug-in for Skyline, which provides easy access to the polymorphisms stored in dbSNP. Given a set of peptides, the tool reports minor allele frequency for common polymorphisms. We highlight the importance of considering genetic variation by applying the tool to public datasets.

  7. Culture-sensitive campaign targets hepatitis awareness.

    Science.gov (United States)

    MacDougall, D S

    1998-07-01

    A new U.S. public service announcement (PSA) campaign is attempting to reach those at greatest risk of contracting viral hepatitis. The campaign incorporates a culturally diverse outreach initiative targeting African Americans, Hispanics, gay men, and others at increased risk for infection. The campaign design recognizes the unique and various factors that put these groups at risk for exposure. Radio and television will be used primarily to target African-Americans because of their high use of these media. Magazines and other publications with high African American readership will also be used as message deliverers, as will church leaders and others recognized as trusted sources. Hispanics will be approached through messages on Spanish-speaking television and radio programs, through strategic alliances that will be developed with community leaders, and through outreach programs that will be created to produce and disseminate culturally and linguistically appropriate hepatitis education materials. Gay men will be reached using mainstream media, the internet, and outreach programs that target community centers, bars, health clubs, and gay pride festivals. Tables provide data on the diagnosis of viral hepatitis, the recommended prophylaxis for hepatitis A (HAV) and hepatitis B (HBV), and vaccine guidelines for HAV and HBV.

  8. Rabies Vaccination Targets for Stray Dog Populations

    OpenAIRE

    Leung, Tiffany; Davis, Stephen A.

    2017-01-01

    The role of stray dogs in the persistence of domestic dog rabies, and whether removal of such dogs is beneficial, remains contentious issues for control programs seeking to eliminate rabies. While a community might reach the WHO vaccination target of 70% for dogs that can be handled, the stray or neighborhood dogs that are too wary of humans to be held are a more problematic population to vaccinate. Here, we present a method to estimate vaccination targets for stray dogs when the dog populati...

  9. Targeted drug delivery using temperature-sensitive liposomes

    International Nuclear Information System (INIS)

    Magin, R.L.; Niesman, M.R.

    1984-01-01

    Liposomes are receiving considerable attention as vehicles for selective drug delivery. One method of targeting liposomal contents involves the combination of local hyperthermia with temperature-sensitive liposomes. Such liposomes have been used to increase the uptake of methotrexate and cis-platinum into locally heated mouse tumors. However, additional information is needed on the mechanism of liposome drug release and the physiologic deposition of liposomes in vivo before clinical trails are begun. Current research is directed at studying the encapsulation and release of water soluble drugs from temperature-sensitive liposomes. The influence of liposome size, structure, and composition on the rapid release in plasma of cytosine arabinoside, cis-platinum, and the radiation sensitizer SR-2508 are described. These results demonstrate potential applications for temperature-sensitive liposomes in selective drug delivery

  10. Beyond the Mean: Sensitivities of the Variance of Population Growth.

    Science.gov (United States)

    Trotter, Meredith V; Krishna-Kumar, Siddharth; Tuljapurkar, Shripad

    2013-03-01

    Populations in variable environments are described by both a mean growth rate and a variance of stochastic population growth. Increasing variance will increase the width of confidence bounds around estimates of population size, growth, probability of and time to quasi-extinction. However, traditional sensitivity analyses of stochastic matrix models only consider the sensitivity of the mean growth rate. We derive an exact method for calculating the sensitivity of the variance in population growth to changes in demographic parameters. Sensitivities of the variance also allow a new sensitivity calculation for the cumulative probability of quasi-extinction. We apply this new analysis tool to an empirical dataset on at-risk polar bears to demonstrate its utility in conservation biology We find that in many cases a change in life history parameters will increase both the mean and variance of population growth of polar bears. This counterintuitive behaviour of the variance complicates predictions about overall population impacts of management interventions. Sensitivity calculations for cumulative extinction risk factor in changes to both mean and variance, providing a highly useful quantitative tool for conservation management. The mean stochastic growth rate and its sensitivities do not fully describe the dynamics of population growth. The use of variance sensitivities gives a more complete understanding of population dynamics and facilitates the calculation of new sensitivities for extinction processes.

  11. The sensitivity analysis of population projections

    NARCIS (Netherlands)

    Caswell, H.; Sánchez Gassen, N.

    2015-01-01

    Background Population projections using the cohort component method can be written as time-varying matrix population models. The matrices are parameterized by schedules of mortality, fertility, immigration, and emigration over the duration of the projection. A variety of dependent variables are

  12. Microenvironment around tumors and their radiation sensitivity. The possibility of molecular target for radiation sensitization

    Energy Technology Data Exchange (ETDEWEB)

    Akimoto, Tetsuo; Ishikawa, Hitoshi [Gunma Univ., Maebashi (Japan). School of Medicine; Mitsuhashi, Norio [Tokyo Women' s Medical Coll. (Japan)

    2001-12-01

    There have been scarce studies concerning the effect of microenvironment around tumors on their radiation sensitivity and this review describes the influence of environmental factors of cell adhesion, growth factors, cytokines, hypoxia and angiogenesis on the sensitivity and response to radiation and on the signal transduction to consider the possibility of molecular target for radiation sensitization. Cell-cell adhesion and cell-matrix interaction in response to radiation may have a role in inducing apoptotic process like anti-apoptotic or pro-apoptotic one. Growth factors and cytokines can affect the tumor response to radiation in more extent than p53 gene status since apoptosis induction is not always an indication of radiation sensitivity in many tumors clinically encountered. Radiation sensitivity is low in tumor cells under hypoxic conditions and it is important to know the relationship between those hypoxic cell response and angiogenesis by factors like HIF (hypoxia-inducible factor)-1. Molecular targets for radiation sensitization are now under development and both basic and clinical studies are important for future application of those sensitizing agents for the radiotherapy of tumors. (K.H.)

  13. Microenvironment around tumors and their radiation sensitivity. The possibility of molecular target for radiation sensitization

    International Nuclear Information System (INIS)

    Akimoto, Tetsuo; Ishikawa, Hitoshi

    2001-01-01

    There have been scarce studies concerning the effect of microenvironment around tumors on their radiation sensitivity and this review describes the influence of environmental factors of cell adhesion, growth factors, cytokines, hypoxia and angiogenesis on the sensitivity and response to radiation and on the signal transduction to consider the possibility of molecular target for radiation sensitization. Cell-cell adhesion and cell-matrix interaction in response to radiation may have a role in inducing apoptotic process like anti-apoptotic or pro-apoptotic one. Growth factors and cytokines can affect the tumor response to radiation in more extent than p53 gene status since apoptosis induction is not always an indication of radiation sensitivity in many tumors clinically encountered. Radiation sensitivity is low in tumor cells under hypoxic conditions and it is important to know the relationship between those hypoxic cell response and angiogenesis by factors like HIF (hypoxia-inducible factor)-1. Molecular targets for radiation sensitization are now under development and both basic and clinical studies are important for future application of those sensitizing agents for the radiotherapy of tumors. (K.H.)

  14. Synchronous Sounds Enhance Visual Sensitivity without Reducing Target Uncertainty

    Directory of Open Access Journals (Sweden)

    Yi-Chuan Chen

    2011-10-01

    Full Text Available We examined the crossmodal effect of the presentation of a simultaneous sound on visual detection and discrimination sensitivity using the equivalent noise paradigm (Dosher & Lu, 1998. In each trial, a tilted Gabor patch was presented in either the first or second of two intervals consisting of dynamic 2D white noise with one of seven possible contrast levels. The results revealed that the sensitivity of participants' visual detection and discrimination performance were both enhanced by the presentation of a simultaneous sound, though only close to the noise level at which participants' target contrast thresholds started to increase with the increasing noise contrast. A further analysis of the psychometric function at this noise level revealed that the increase in sensitivity could not be explained by the reduction of participants' uncertainty regarding the onset time of the visual target. We suggest that this crossmodal facilitatory effect may be accounted for by perceptual enhancement elicited by a simultaneously-presented sound, and that the crossmodal facilitation was easier to observe when the visual system encountered a level of noise that happened to be close to the level of internal noise embedded within the system.

  15. Population growth changes targets for immunization.

    Science.gov (United States)

    Tuljapurkar, S; John, A M

    1995-01-01

    The faster the rate of population growth in developing countries, the less likely it is that current protocols for immunization against measles, rubella, and mumps will eradicate these childhood diseases. Standard protocols (timing, percentage of children to be immunized) do not take into account the rapid rates of population growth in developing countries (3.0% per year on average in sub-Saharan Africa and 2.0% in the rest of Africa, in Latin America, and in Asia, excluding China). Most public health planning models in this area were created based on static infant populations. The World Health Organization advises vaccinating at least 85% of children aged 6 to 9 months, a 3-month immunization window during which maternal antibodies are low (so the vaccination takes) and herd immunity is high (the probability that a child will encounter the disease is low because most children have been immunized). In practice, the immunization window in developing countries is 1 year or more. More susceptible children are present than assumed by the models. A larger number of susceptible babies are added each year during rapid population growth. As the age range for immunization widens, a higher percentage of children must be vaccinated to eradicate disease (chart). The proportion of each birth cohort that must be immunized rises as the population growth rate increases. At zero population growth, 94% must be vaccinated; at population growth rates greater than 3%, 98% must be vaccinated.

  16. Amphibian Population Sensitivity to Environmental and ...

    Science.gov (United States)

    Anticipating chronic effects of contaminant exposure on amphibian species is complicated both by toxicological and ecological uncertainty. Data for both chemical exposures and amphibian vital rates, including altered growth, are sparse. Developmental plasticity in amphibians further complicates evaluation of chemical impacts as metamorphosis is also influenced by other biotic and abiotic stressors, such as temperature, hydroperiod, predation, and conspecific density. Determining the effect of delayed tadpole development on survival through metamorphosis and subsequent recruitment must include possible effects of pond drying accelerating metamorphosis near the end of the larval stage. This model considers the combined influence of delayed onset of metamorphosis in a cohort as well as accelerated metamorphosis toward the end of the hydroperiod and determines the net influence of counteracting forces on tadpole development and survival. Amphibian populations with greater initial density dependence have less capacity for developmental plasticity and are therefore more vulnerable to delayed development and reduced hydroperiod. The consequential reduction in larval survival has a relatively greater impact on species with a shorter lifespan, allowing for fewer breeding seasons during which to successfully produce offspring. In response to risk assessment approaches that consider only survival and reproductive endpoints in population evaluation, we calculate conta

  17. Trastuzumab Sensitizes Ovarian Cancer Cells to EGFR-targeted Therapeutics

    Directory of Open Access Journals (Sweden)

    Wilken Jason A

    2010-03-01

    Full Text Available Abstract Background Early studies have demonstrated comparable levels of HER2/ErbB2 expression in both breast and ovarian cancer. Trastuzumab (Herceptin, a therapeutic monoclonal antibody directed against HER2, is FDA-approved for the treatment of both early and late stage breast cancer. However, clinical studies of trastuzumab in epithelial ovarian cancer (EOC patients have not met the same level of success. Surprisingly, however, no reports have examined either the basis for primary trastuzumab resistance in ovarian cancer or potential ways of salvaging trastuzumab as a potential ovarian cancer therapeutic. Methods An in vitro model of primary trastuzumab-resistant ovarian cancer was created by long-term culture of HER2-positive ovarian carcinoma-derived cell lines with trastuzumab. Trastuzumab treated vs. untreated parental cells were compared for HER receptor expression, trastuzumab sensitivity, and sensitivity to other HER-targeted therapeutics. Results In contrast to widely held assumptions, here we show that ovarian cancer cells that are not growth inhibited by trastuzumab are still responsive to trastuzumab. Specifically, we show that responsiveness to alternative HER-targeted inhibitors, such as gefitinib and cetuximab, is dramatically potentiated by long-term trastuzumab treatment of ovarian cancer cells. HER2-positive ovarian carcinoma-derived cells are, therefore, not "unresponsive" to trastuzumab as previously assumed, even when they not growth inhibited by this drug. Conclusions Given the recent success of EGFR-targeted therapeutics for the treatment of other solid tumors, and the well-established safety profile of trastuzumab, results presented here provide a rationale for re-evaluation of trastuzumab as an experimental ovarian cancer therapeutic, either in concert with, or perhaps as a "primer" for EGFR-targeted therapeutics.

  18. Targeting population heterogeneity for optimal cell factories

    DEFF Research Database (Denmark)

    Heins, Anna-Lena; Carlqvist, Magnus; Helmark, S.

    the heterogeneity level of the population. To further investigate these phenomena and gain a deeper understanding of population heterogeneity, Saccharomyces cerevisiae growth reporter strains based on the expression of green fluorescent protein (GFP) were constructed which enabled us to perform single cell level......, substrates, and pH are typically observed in many industrial scale fermentation processes. Consequently, the microbial cells experience rapid changes in environmental conditions as they circulate throughout the reactor, which might pose stress on the cells and affect their metabolism and consequently affect...

  19. Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization

    International Nuclear Information System (INIS)

    Sekhar, Konjeti R.; Benamar, Mouadh; Venkateswaran, Amudhan; Sasi, Soumya; Penthala, Narsimha R.; Crooks, Peter A.; Hann, Stephen R.; Geng, Ling; Balusu, Ramesh; Abbas, Tarek; Freeman, Michael L.

    2014-01-01

    Purpose: To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization. Methods and Materials: Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts. Results: Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts. Conclusions: These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity

  20. Setting population targets for mammals using body mass as a predictor of population persistence.

    Science.gov (United States)

    Hilbers, Jelle P; Santini, Luca; Visconti, Piero; Schipper, Aafke M; Pinto, Cecilia; Rondinini, Carlo; Huijbregts, Mark A J

    2017-04-01

    Conservation planning and biodiversity assessments need quantitative targets to optimize planning options and assess the adequacy of current species protection. However, targets aiming at persistence require population-specific data, which limit their use in favor of fixed and nonspecific targets, likely leading to unequal distribution of conservation efforts among species. We devised a method to derive equitable population targets; that is, quantitative targets of population size that ensure equal probabilities of persistence across a set of species and that can be easily inferred from species-specific traits. In our method, we used models of population dynamics across a range of life-history traits related to species' body mass to estimate minimum viable population targets. We applied our method to a range of body masses of mammals, from 2 g to 3825 kg. The minimum viable population targets decreased asymptotically with increasing body mass and were on the same order of magnitude as minimum viable population estimates from species- and context-specific studies. Our approach provides a compromise between pragmatic, nonspecific population targets and detailed context-specific estimates of population viability for which only limited data are available. It enables a first estimation of species-specific population targets based on a readily available trait and thus allows setting equitable targets for population persistence in large-scale and multispecies conservation assessments and planning. © 2016 The Authors. Conservation Biology published by Wiley Periodicals, Inc. on behalf of Society for Conservation Biology.

  1. Target and Non-Target Site Mechanisms Developed by Glyphosate-Resistant Hairy beggarticks (Bidens pilosa L. Populations from Mexico

    Directory of Open Access Journals (Sweden)

    Ricardo Alcántara-de la Cruz

    2016-10-01

    Full Text Available In 2014 hairy beggarticks (Bidens pilosa L. has been identified as being glyphosate-resistant in citrus orchards from Mexico. The target and non-target site mechanisms involved in the response to glyphosate of two resistant populations (R1 and R2 and one susceptible (S were studied. Experiments of dose-response, shikimic acid accumulation, uptake-translocation, enzyme activity and EPSPS gene sequencing were carried out in each population. The R1 and R2 populations were 20.4 and 2.8-fold less glyphosate sensitive, respectively, than the S population. The resistant populations showed a lesser shikimic acid accumulation than the S population. In the latter one, 24.9% of 14C-glyphosate was translocated to the roots at 96 h after treatment; in the R1 and R2 populations only 12.9 and 15.5%, respectively, was translocated. Qualitative results confirmed the reduced 14C-glyphosate translocation in the resistant populations. The EPSPS enzyme activity of the S population was 128.4 and 8.5-fold higher than the R1 and R2 populations of glyphosate-treated plants, respectively. A single (Pro-106-Ser, and a double (Thr-102-Ile followed by Pro-106-Ser mutations were identified in the EPSPS2 gene conferred high resistance in R1 population. Target-site mutations associated with a reduced translocation were responsible for the higher glyphosate resistance in the R1 population. The low-intermediate resistance of the R2 population was mediated by reduced translocation. This is the first glyphosate resistance case confirmed in hairy beggarticks in the world.

  2. Target and Non-target Site Mechanisms Developed by Glyphosate-Resistant Hairy beggarticks (Bidens pilosa L.) Populations from Mexico.

    Science.gov (United States)

    Alcántara-de la Cruz, Ricardo; Fernández-Moreno, Pablo T; Ozuna, Carmen V; Rojano-Delgado, Antonia M; Cruz-Hipolito, Hugo E; Domínguez-Valenzuela, José A; Barro, Francisco; De Prado, Rafael

    2016-01-01

    In 2014 hairy beggarticks ( Bidens pilosa L.) has been identified as being glyphosate-resistant in citrus orchards from Mexico. The target and non-target site mechanisms involved in the response to glyphosate of two resistant populations (R1 and R2) and one susceptible (S) were studied. Experiments of dose-response, shikimic acid accumulation, uptake-translocation, enzyme activity and 5-enolpyruvyl shikimate-3-phosphate synthase (EPSPS) gene sequencing were carried out in each population. The R1 and R2 populations were 20.4 and 2.8-fold less glyphosate sensitive, respectively, than the S population. The resistant populations showed a lesser shikimic acid accumulation than the S population. In the latter one, 24.9% of 14 C-glyphosate was translocated to the roots at 96 h after treatment; in the R1 and R2 populations only 12.9 and 15.5%, respectively, was translocated. Qualitative results confirmed the reduced 14 C-glyphosate translocation in the resistant populations. The EPSPS enzyme activity of the S population was 128.4 and 8.5-fold higher than the R1 and R2 populations of glyphosate-treated plants, respectively. A single (Pro-106-Ser), and a double (Thr-102-Ile followed by Pro-106-Ser) mutations were identified in the EPSPS2 gene conferred high resistance in R1 population. Target-site mutations associated with a reduced translocation were responsible for the higher glyphosate resistance in the R1 population. The low-intermediate resistance of the R2 population was mediated by reduced translocation. This is the first glyphosate resistance case confirmed in hairy beggarticks in the world.

  3. Predicting the sensitivity of populations from individual exposure to chemicals: the role of ecological interactions.

    Science.gov (United States)

    Gabsi, Faten; Schäffer, Andreas; Preuss, Thomas G

    2014-07-01

    Population responses to chemical stress exposure are influenced by nonchemical, environmental processes such as species interactions. A realistic quantification of chemical toxicity to populations calls for the use of methodologies that integrate these multiple stress effects. The authors used an individual-based model for Daphnia magna as a virtual laboratory to determine the influence of ecological interactions on population sensitivity to chemicals with different modes of action on individuals. In the model, hypothetical chemical toxicity targeted different vital individual-level processes: reproduction, survival, feeding rate, or somatic growth rate. As for species interactions, predatory and competition effects on daphnid populations were implemented following a worst-case approach. The population abundance was simulated at different food levels and exposure scenarios, assuming exposure to chemical stress solely or in combination with either competition or predation. The chemical always targeted one vital endpoint. Equal toxicity-inhibition levels differently affected the population abundance with and without species interactions. In addition, population responses to chemicals were highly sensitive to the environmental stressor (predator or competitor) and to the food level. Results show that population resilience cannot be attributed to chemical stress only. Accounting for the relevant ecological interactions would reduce uncertainties when extrapolating effects of chemicals from individuals to the population level. Validated population models should be used for a more realistic risk assessment of chemicals. © 2014 SETAC.

  4. Sensitivity analysis of effective population size to demographic parameters in house sparrow populations.

    Science.gov (United States)

    Stubberud, Marlene Waege; Myhre, Ane Marlene; Holand, Håkon; Kvalnes, Thomas; Ringsby, Thor Harald; Saether, Bernt-Erik; Jensen, Henrik

    2017-05-01

    The ratio between the effective and the census population size, Ne/N, is an important measure of the long-term viability and sustainability of a population. Understanding which demographic processes that affect Ne/N most will improve our understanding of how genetic drift and the probability of fixation of alleles is affected by demography. This knowledge may also be of vital importance in management of endangered populations and species. Here, we use data from 13 natural populations of house sparrow (Passer domesticus) in Norway to calculate the demographic parameters that determine Ne/N. Using the global variance-based Sobol' method for the sensitivity analyses, we found that Ne/N was most sensitive to demographic variance, especially among older individuals. Furthermore, the individual reproductive values (that determine the demographic variance) were most sensitive to variation in fecundity. Our results draw attention to the applicability of sensitivity analyses in population management and conservation. For population management aiming to reduce the loss of genetic variation, a sensitivity analysis may indicate the demographic parameters towards which resources should be focused. The result of such an analysis may depend on the life history and mating system of the population or species under consideration, because the vital rates and sex-age classes that Ne/N is most sensitive to may change accordingly. © 2017 John Wiley & Sons Ltd.

  5. Time Sensitive Targeting: Overcoming the Intelligence Gap in Interagency Operations

    National Research Council Canada - National Science Library

    Hewitt, Mark

    2003-01-01

    The Central Intelligence Agency's attack on a group of terrorists in Yemen epitomized the agency's short-notice capability to detect, track, and destroy a highly mobile and fleeting target of opportunity. The U.S...

  6. Radio-sensitivity of spruce population progeny in Bulgaria

    International Nuclear Information System (INIS)

    Aleksandrov, A.

    1976-01-01

    The radio-sensitivity of Picea abies (L.) Karst populations was investigated by comparing the effect of acute irradiation with different Co-60 rates on seed germination and the survival of the seedlings obtained from them. Spruce stands in the Rila, Pirin and Rhodopes, the Balkan, Vitosha and Ossogovo mountains have been studied at 1000 to 2000 m alt. into 200-300 m intervals. The seed material collected from them by individual trees, altitude belts and mountains has been irradiated with 200 krad, 500 krad, 1000 krad, 1500 krad and 7500 krad. The germination capacity of the seeds was calculated in technical germination, absolute germination, germination energy and seed dormancy, while the post-irradiation effect was established in accordance with the survival rate of the seedlings for one- and two-year periods in greenhouses on a sand substrate. Radio-sensitivity of every spruce population depended on its vitality and Vigour. The spruce population in the Rhodope Mountains exhibits highest radio-hardiness, followed by those in the Rila, Central Balkan, Pirin, Vitosha and Ossogovo mountains. Irradiation with 200 krad, and in certain cases with 500 krad, showed a stimulation effect on germination of spruce seeds and the survival rate of the seedlings. LD-50 for spruce seeds, taking into account one- and two-year-old seedlings, was within the 500 to 1000 krad range. (author)

  7. Prevalence of fragrance sensitivity in the American population.

    Science.gov (United States)

    Caress, Stanley M; Steinemann, Anne C

    2009-03-01

    This study determined the percentages of individuals who report adverse effects from exposure to fragranced products in the U.S. population and in subpopulations of those with asthma or chemical sensitivity. Data were collected through telephone interviews from two geographically weighted, random samples of the continental U.S. in two surveys during 2002-2003 and 2005-2006 (1,057 and 1,058 cases, respectively). Respondents were asked if they find being next to someone wearing a scented product irritating or appealing; if they have headaches, breathing difficulties, or other problems when exposed to air fresheners or deodorizers; and if they are irritated by the scent from laundry products, fabric softeners, or dryer sheets that are vented outside. Results aggregated from both surveys found that 30.5% of the general population reported scented products on others irritating, 19% reported adverse health effects from air fresheners, and 10.9% reported irritation by scented laundry products vented outside. This study reveals that a considerable percentage of the U.S. population reports adverse health effects or irritation from fragranced products, with higher percentages among those with asthma and chemical sensitivity.

  8. The population program shifts to 'high-scenario' targets.

    Science.gov (United States)

    Aragon-choudury, P

    1986-01-01

    The Philippine Population Program would like to achieve a replacement level of 1 daughter per childbearing woman by the year 2000 to reduce the population growth rate to 2% by 1992. Laing projected that high performance by the National Population Program would mean continued increase of sterilization prevalence at an average 1978-1983 rate. Strategies have been adopted to strengthen information-education-communication efforts, to attain higher contraceptive prevalence rates and use-effectiveness, to develop manpower, to achieve self-reliance, and to effect better program coordination, monitoring, research use. Effective service delivery will be a key to achieving the high-scenario targets. Effective use of natural family planning (NFP), will help in achieving the high-scenario goals. Apart from the heavy demand on NFP follow-up, need for prompt delivery of supplies, and lack of doctors and nurses, other factors may impede the high-scenario targets. Saniel believes that program workers should be allowed to insert IUDs and to dispense pills. Under the cost-recovery and cost-sharing schemes of the high-scenario targets, only sterilization will be done for free. It might affect the campaign for increased acceptors, but the start for self-reliance must happen now.

  9. Price-related sensitivities of greenhouse gas intensity targets

    International Nuclear Information System (INIS)

    Muller, Benito; Muller-Furstenberger, Georg

    2003-12-01

    Greenhouse gas intensities are an appealing tool to foster abatement without imposing constraints on economic growth. This paper shows, however, that the computation of intensities is subject to some significant statistical and conceptual problems which relate to the inflation proofing of GDP growth. It is shown that the choice of price-index, the updating of quantity weights and the choice of base year prices can have a significant impact upon the commitment of intensity targets

  10. PAHs sensitivity of picophytoplankton populations in the Red Sea

    KAUST Repository

    Kottuparambil, Sreejith

    2018-04-25

    In this study, we investigated the in situ responses of Red Sea picophytoplankton, the dominant phytoplankton group in the oligotrophic ocean, to two toxic polycyclic aromatic hydrocarbons (PAHs), phenanthrene and pyrene. The experiments were conducted across a latitudinal gradient of the Saudi Arabian Red Sea, an area sensitive to oil pollution. We observed significant adverse effects on the growth and abundance of the picocyanobacteria Synechococcus and picoeukaryotes, at all stations sampled. Prochlorococcus, which was abundant only at one of the stations, also appeared to be affected. Pyrene was found to be more toxic to phytoplankton at all stations. In general, picoeukaryotes exhibited higher sensitivity to PAHs than Synechococcus. Populations in the highly oligotrophic Northern region of the Red Sea were more tolerant to PAHs, presumably influenced by the natural selection of more resistant strains of phytoplankton due to the prolonged exposure to PAHs. Toxicity threshold values estimated here are higher than those reported for picophytoplankton from other oligotrophic marine waters and exceed by far the natural levels of PAHs in many oceans. Our findings reveal a possible adaptation of picophytoplankton populations to oil-related contaminants, which may clearly influence their spatial distribution patterns in the Red Sea.

  11. Detectability counts when assessing populations for biodiversity targets.

    Directory of Open Access Journals (Sweden)

    Silviu O Petrovan

    Full Text Available Efficient, practical and accurate estimates of population parameters are a necessary basis for effective conservation action to meet biodiversity targets. The brown hare is representative of many European farmland species: historically widespread and abundant but having undergone rapid declines as a result of agricultural intensification. As a priority species in the UK Biodiversity Action Plan, it has national targets for population increase that are part of wider national environmental indicators. Previous research has indicated that brown hare declines have been greatest in pastural landscapes and that gains might be made by focussing conservation effort there. We therefore used hares in pastural landscapes to examine how basic changes in survey methodology can affect the precision of population density estimates and related these to national targets for biodiversity conservation in the UK. Line transects for hares carried out at night resulted in higher numbers of detections, had better-fitting detection functions and provided more robust density estimates with lower effort than those during the day, due primarily to the increased probability of detection of hares at night and the nature of hare responses to the observer. Hare spring densities varied widely within a single region, with a pooled mean of 20.6 hares km(-2, significantly higher than the reported national average of hares in pastures of 3.3 hares km(-2. The high number of encounters allowed us to resolve hare densities at site, season and year scales. We demonstrate how survey conduct can impact on data quantity and quality with implications for setting and monitoring biodiversity targets. Our case study of the brown hare provides evidence that for wildlife species with low detectability, large scale volunteer-based monitoring programmes, either species specific or generalist, might be more successfully and efficiently carried out by a small number of trained personnel able to

  12. Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis.

    Science.gov (United States)

    Tang, An; Hallouch, Oussama; Chernyak, Victoria; Kamaya, Aya; Sirlin, Claude B

    2018-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer mortality worldwide. Incidence rates of liver cancer vary widely between geographic regions and are highest in Eastern Asia and sub-Saharan Africa. In the United States, the incidence of HCC has increased since the 1980s. HCC detection at an early stage through surveillance and curative therapy has considerably improved the 5-year survival. Therefore, medical societies advocate systematic screening and surveillance of target populations at particularly high risk for developing HCC to facilitate early-stage detection. Risk factors for HCC include cirrhosis, chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), excess alcohol consumption, non-alcoholic fatty liver disease, family history of HCC, obesity, type 2 diabetes mellitus, and smoking. Medical societies utilize risk estimates to define target patient populations in which imaging surveillance is recommended (risk above threshold) or in which the benefits of surveillance are uncertain (risk unknown or below threshold). All medical societies currently recommend screening and surveillance in patients with cirrhosis and subsets of patients with chronic HBV; some societies also include patients with stage 3 fibrosis due to HCV as well as additional groups. Thus, target population definitions vary between regions, reflecting cultural, demographic, economic, healthcare priority, and biological differences. The Liver Imaging Reporting and Data System (LI-RADS) defines different patient populations for surveillance and for diagnosis and staging. We also discuss general trends pertaining to geographic region, age, gender, ethnicity, impact of surveillance on survival, mortality, and future trends.

  13. Ultrasound-sensitive nanoparticle aggregates for targeted drug delivery.

    Science.gov (United States)

    Papa, Anne-Laure; Korin, Netanel; Kanapathipillai, Mathumai; Mammoto, Akiko; Mammoto, Tadanori; Jiang, Amanda; Mannix, Robert; Uzun, Oktay; Johnson, Christopher; Bhatta, Deen; Cuneo, Garry; Ingber, Donald E

    2017-09-01

    Here we describe injectable, ultrasound (US)-responsive, nanoparticle aggregates (NPAs) that disintegrate into slow-release, nanoscale, drug delivery systems, which can be targeted to selective sites by applying low-energy US locally. We show that, unlike microbubble based drug carriers which may suffer from stability problems, the properties of mechanical activated NPAs, composed of polymer nanoparticles, can be tuned by properly adjusting the polymer molecular weight, the size of the nanoparticle precursors as well as the percentage of excipient utilized to hold the NPA together. We then apply this concept to practice by fabricating NPAs composed of nanoparticles loaded with Doxorubicin (Dox) and tested their ability to treat tumors via ultrasound activation. Mouse studies demonstrated significantly increased efficiency of tumor targeting of the US-activated NPAs compared to PLGA nanoparticle controls (with or without US applied) or intact NPAs. Importantly, when the Dox-loaded NPAs were injected and exposed to US energy locally, this increased ability to concentrate nanoparticles at the tumor site resulted in a significantly greater reduction in tumor volume compared to tumors treated with a 20-fold higher dose of the free drug. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Sensitive optical biosensors for unlabeled targets: A review

    International Nuclear Information System (INIS)

    Fan Xudong; White, Ian M.; Shopova, Siyka I.; Zhu Hongying; Suter, Jonathan D.; Sun Yuze

    2008-01-01

    This article reviews the recent progress in optical biosensors that use the label-free detection protocol, in which biomolecules are unlabeled or unmodified, and are detected in their natural forms. In particular, it will focus on the optical biosensors that utilize the refractive index change as the sensing transduction signal. Various optical label-free biosensing platforms will be introduced, including, but not limited to, surface plasmon resonance, interferometers, waveguides, fiber gratings, ring resonators, and photonic crystals. Emphasis will be given to the description of optical structures and their respective sensing mechanisms. Examples of detecting various types of biomolecules will be presented. Wherever possible, the sensing performance of each optical structure will be evaluated and compared in terms of sensitivity and detection limit

  15. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  16. Genes contributing to pain sensitivity in the normal population

    DEFF Research Database (Denmark)

    Williams, Frances M.K.; Scollen, Serena; Cao, Dandan

    2012-01-01

    Sensitivity to pain varies considerably between individuals and is known to be heritable. Increased sensitivity to experimental pain is a risk factor for developing chronic pain, a common and debilitating but poorly understood symptom. To understand mechanisms underlying pain sensitivity and to s...

  17. EFFECTIVELY SELECTING A TARGET POPULATION FOR A FUTURE COMPARATIVE STUDY.

    Science.gov (United States)

    Zhao, Lihui; Tian, Lu; Cai, Tianxi; Claggett, Brian; Wei, L J

    2013-01-01

    When comparing a new treatment with a control in a randomized clinical study, the treatment effect is generally assessed by evaluating a summary measure over a specific study population. The success of the trial heavily depends on the choice of such a population. In this paper, we show a systematic, effective way to identify a promising population, for which the new treatment is expected to have a desired benefit, utilizing the data from a current study involving similar comparator treatments. Specifically, using the existing data, we first create a parametric scoring system as a function of multiple multiple baseline covariates to estimate subject-specific treatment differences. Based on this scoring system, we specify a desired level of treatment difference and obtain a subgroup of patients, defined as those whose estimated scores exceed this threshold. An empirically calibrated threshold-specific treatment difference curve across a range of score values is constructed. The subpopulation of patients satisfying any given level of treatment benefit can then be identified accordingly. To avoid bias due to overoptimism, we utilize a cross-training-evaluation method for implementing the above two-step procedure. We then show how to select the best scoring system among all competing models. Furthermore, for cases in which only a single pre-specified working model is involved, inference procedures are proposed for the average treatment difference over a range of score values using the entire data set, and are justified theoretically and numerically. Lastly, the proposals are illustrated with the data from two clinical trials in treating HIV and cardiovascular diseases. Note that if we are not interested in designing a new study for comparing similar treatments, the new procedure can also be quite useful for the management of future patients, so that treatment may be targeted towards those who would receive nontrivial benefits to compensate for the risk or cost of the

  18. Characterizing sensitivity of longwave infrared hyperspectral target detection with respect to signature mismatch and dimensionality reduction

    Science.gov (United States)

    Meola, Joseph

    2017-05-01

    Hyperspectral target detection typically relies upon libraries of material reflectance and emissivity signatures. Application to real-world, airborne data requires estimation of atmospheric properties in order to convert reflectance/emissivity signatures to the sensor data domain. In the longwave infrared, an additional nuisance parameter of surface temperature exists that further complicates the signature conversion process. A significant amount of work has been done in atmospheric compensation and temperature-emissivity-separation techniques. This work examines the sensitivity of target detection performance for various materials with respect to target signature mismatch introduced from atmospheric compensation error or target temperature mismatch. Additionally, the impact of dimensionality reduction via principal components analysis is assessed.

  19. Tedizolid population pharmacokinetics, exposure response, and target attainment.

    Science.gov (United States)

    Flanagan, S; Passarell, J; Lu, Q; Fiedler-Kelly, J; Ludwig, E; Prokocimer, P

    2014-11-01

    Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, and linear elimination described the PK data well. Variability was small (clearance, 31% coefficient of variation; volume, 13.4% coefficient of variation), and absolute bioavailability was high (86%). No clinically significant covariate effects on tedizolid PK were found. Based on phase 3 data evaluating 200-mg once-daily tedizolid for acute bacterial skin and skin structure infections (ABSSSI), no relationships were seen between various efficacy outcomes and estimated tedizolid exposure; the estimated exposure range (free-drug area under the concentration-time curve over 24 h at steady state [AUCss(0-24)], 7 to 50 μg · h/ml) in these patients was modest. Safety data modeling, using once-daily doses of up to 400 mg, showed a small increase in the probability of an adverse event with increasing model-estimated tedizolid exposure; no such relationship was observed when specifically evaluating the 200-mg dose. There were no trends in neutrophil or platelet counts with increasing tedizolid exposure. Target attainment simulations for 200-mg tedizolid indicated a 98.31% probability of attaining the target measure (AUC for the free, unbound fraction of a drug [fAUC]/MIC = 3) against a Staphylococcus aureus strain for which the MIC was ≤0.5 μg/ml. These findings support 200-mg tedizolid once daily as the optimum dose for treatment of ABSSSI. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  20. Sensitizing Black Adult and Youth Consumers to Targeted Food Marketing Tactics in Their Environments.

    Science.gov (United States)

    Isselmann DiSantis, Katherine; Kumanyika, Shiriki; Carter-Edwards, Lori; Rohm Young, Deborah; Grier, Sonya A; Lassiter, Vikki

    2017-10-29

    Food marketing environments of Black American consumers are heavily affected by ethnically-targeted marketing of sugar sweetened beverages, fast foods, and other products that may contribute to caloric overconsumption. This qualitative study assessed Black consumers' responses to targeted marketing. Black adults (2 mixed gender groups; total n = 30) and youth (2 gender specific groups; total n = 35) from two U.S. communities participated before and after a sensitization procedure-a critical practice used to understand social justice concerns. Pre-sensitization focus groups elicited responses to scenarios about various targeted marketing tactics. Participants were then given an informational booklet about targeted marketing to Black Americans, and all returned for the second (post-sensitization) focus group one week later. Conventional qualitative content analysis of transcripts identified several salient themes: seeing the marketer's perspective ("it's about demand"; "consumers choose"), respect for community ("marketers are setting us up for failure"; "making wrong assumptions"), and food environments as a social justice issue ("no one is watching the door"; "I didn't realize"). Effects of sensitization were reflected in participants' stated reactions to the information in the booklet, and also in the relative occurrence of marketer-oriented themes and social justice-oriented themes, respectively, less and more after sensitization.

  1. Sensitizing Black Adult and Youth Consumers to Targeted Food Marketing Tactics in Their Environments

    Science.gov (United States)

    Isselmann DiSantis, Katherine; Kumanyika, Shiriki; Rohm Young, Deborah; Grier, Sonya A.; Lassiter, Vikki

    2017-01-01

    Food marketing environments of Black American consumers are heavily affected by ethnically-targeted marketing of sugar sweetened beverages, fast foods, and other products that may contribute to caloric overconsumption. This qualitative study assessed Black consumers’ responses to targeted marketing. Black adults (2 mixed gender groups; total n = 30) and youth (2 gender specific groups; total n = 35) from two U.S. communities participated before and after a sensitization procedure—a critical practice used to understand social justice concerns. Pre-sensitization focus groups elicited responses to scenarios about various targeted marketing tactics. Participants were then given an informational booklet about targeted marketing to Black Americans, and all returned for the second (post-sensitization) focus group one week later. Conventional qualitative content analysis of transcripts identified several salient themes: seeing the marketer’s perspective (“it’s about demand”; “consumers choose”), respect for community (“marketers are setting us up for failure”; “making wrong assumptions”), and food environments as a social justice issue (“no one is watching the door”; “I didn’t realize”). Effects of sensitization were reflected in participants’ stated reactions to the information in the booklet, and also in the relative occurrence of marketer-oriented themes and social justice-oriented themes, respectively, less and more after sensitization. PMID:29109377

  2. Sensitizing Black Adult and Youth Consumers to Targeted Food Marketing Tactics in Their Environments

    Directory of Open Access Journals (Sweden)

    Katherine Isselmann DiSantis

    2017-10-01

    Full Text Available Food marketing environments of Black American consumers are heavily affected by ethnically-targeted marketing of sugar sweetened beverages, fast foods, and other products that may contribute to caloric overconsumption. This qualitative study assessed Black consumers’ responses to targeted marketing. Black adults (2 mixed gender groups; total n = 30 and youth (2 gender specific groups; total n = 35 from two U.S. communities participated before and after a sensitization procedure—a critical practice used to understand social justice concerns. Pre-sensitization focus groups elicited responses to scenarios about various targeted marketing tactics. Participants were then given an informational booklet about targeted marketing to Black Americans, and all returned for the second (post-sensitization focus group one week later. Conventional qualitative content analysis of transcripts identified several salient themes: seeing the marketer’s perspective (“it’s about demand”; “consumers choose”, respect for community (“marketers are setting us up for failure”; “making wrong assumptions”, and food environments as a social justice issue (“no one is watching the door”; “I didn’t realize”. Effects of sensitization were reflected in participants’ stated reactions to the information in the booklet, and also in the relative occurrence of marketer-oriented themes and social justice-oriented themes, respectively, less and more after sensitization.

  3. Single-cell analysis of targeted transcriptome predicts drug sensitivity of single cells within human myeloma tumors.

    Science.gov (United States)

    Mitra, A K; Mukherjee, U K; Harding, T; Jang, J S; Stessman, H; Li, Y; Abyzov, A; Jen, J; Kumar, S; Rajkumar, V; Van Ness, B

    2016-05-01

    Multiple myeloma (MM) is characterized by significant genetic diversity at subclonal levels that have a defining role in the heterogeneity of tumor progression, clinical aggressiveness and drug sensitivity. Although genome profiling studies have demonstrated heterogeneity in subclonal architecture that may ultimately lead to relapse, a gene expression-based prediction program that can identify, distinguish and quantify drug response in sub-populations within a bulk population of myeloma cells is lacking. In this study, we performed targeted transcriptome analysis on 528 pre-treatment single cells from 11 myeloma cell lines and 418 single cells from 8 drug-naïve MM patients, followed by intensive bioinformatics and statistical analysis for prediction of proteasome inhibitor sensitivity in individual cells. Using our previously reported drug response gene expression profile signature at the single-cell level, we developed an R Statistical analysis package available at https://github.com/bvnlabSCATTome, SCATTome (single-cell analysis of targeted transcriptome), that restructures the data obtained from Fluidigm single-cell quantitative real-time-PCR analysis run, filters missing data, performs scaling of filtered data, builds classification models and predicts drug response of individual cells based on targeted transcriptome using an assortment of machine learning methods. Application of SCATT should contribute to clinically relevant analysis of intratumor heterogeneity, and better inform drug choices based on subclonal cellular responses.

  4. Non-target-site resistance to ALS-inhibiting herbicides in a Sagittaria trifolia L. population.

    Science.gov (United States)

    Zhao, Bochui; Fu, Danni; Yu, Yang; Huang, Chengtian; Yan, Kecheng; Li, Pingsheng; Shafi, Jamil; Zhu, He; Wei, Songhong; Ji, Mingshan

    2017-08-01

    Sagittaria trifolia L. is one of the most competitive weeds in rice fields in northeastern China. The continuous use of acetolactate synthase (ALS)-inhibitors has led to the evolution of herbicide resistant S. trifolia. A subpopulation BC1, which was derived from the L1 population, was analyzed using DNA sequencing and ALS enzyme activity assays and levels of resistance to five ALS-inhibiting herbicides was determined. DNA sequencing and ALS enzyme assays revealed no amino acid substitutions and no significant differences in enzyme sensitivity between susceptible and resistant populations. Whole-plant dose-response experiments showed that the BC1 population exhibited different levels of resistance (resistance ratios ranging from 2.14 to 51.53) to five ALS herbicides, and the addition of malathion (P450 inhibitor) to bensulfuron-methyl, penoxsulam and bispyribac-sodium strongly reduced the dry weight accumulation of the BC1 population compared with the effects of the three herbicides alone. The results of the present study demonstrated that the BC1 population has evolved non-target-site resistance to ALS-inhibiting herbicides. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Peroxisomal Targeting as a Sensitive Tool to Detect Protein-Small RNA Interactions through in Vivo Piggybacking

    Directory of Open Access Journals (Sweden)

    Marco Incarbone

    2018-02-01

    Full Text Available Peroxisomes are organelles that play key roles in eukaryotic metabolism. Their protein complement is entirely imported from the cytoplasm thanks to a unique pathway that is able to translocate folded proteins and protein complexes across the peroxisomal membrane. The import of molecules bound to a protein targeted to peroxisomes is an active process known as ‘piggybacking’ and we have recently shown that P15, a virus-encoded protein possessing a peroxisomal targeting sequence, is able to piggyback siRNAs into peroxisomes. Here, we extend this observation by analyzing the small RNA repertoire found in peroxisomes of P15-expressing plants. A direct comparison with the P15-associated small RNA retrieved during immunoprecipitation (IP experiments, revealed that in vivo piggybacking coupled to peroxisome isolation could be a more sensitive means to determine the various small RNA species bound by a given protein. This increased sensitivity of peroxisome isolation as opposed to IP experiments was also striking when we analyzed the small RNA population bound by the Tomato bushy stunt virus-encoded P19, one of the best characterized viral suppressors of RNA silencing (VSR, artificially targeted to peroxisomes. These results support that peroxisomal targeting should be considered as a novel/alternative experimental approach to assess in vivo interactions that allows detection of labile binding events. The advantages and limitations of this approach are discussed.

  6. Interpreting adjoint and ensemble sensitivity toward the development of optimal observation targeting strategies

    Energy Technology Data Exchange (ETDEWEB)

    Ancell, B.C.; Hakim, G.J. [Univ. of Washington, Seattle, WA (United States)

    2007-12-15

    Two general methods, adjoint or singular vector methods, and ensemble-based methods, have been previously investigated to identify locations where observations would have a significant positive impact on a numerical weather model forecast. In this paper, we perform a basic comparison of targeting regions chosen to reduce the expected variance of a chosen forecast response function within an ensemble Kalman filter (EnKF) based on both an adjoint method and an ensemble method. Ensemble sensitivity is defined by linear regressions of a chosen forecast response function onto the model initial-time state variables, and is used to calculate variance reduction fields to provide targeting guidance for the ensemble-based method. Adjoint sensitivity is used to provide targeting guidance for the adjoint-based method. 90 ensemble forecasts are considered over a 24-hour forecast period, and the response function is chosen to represent the sea-level pressure at a single point in the Pacific Northwest United States. Targeting by ensemble guidance is shown to be a function of ensemble sensitivity and both the initial-time model state and observation variance. We find that large areas of variance reduction exist away from regions of large ensemble sensitivity, adjoint sensitivity, and the initial-time variance of the model state. For hypothetical aircraft observations, ensemble guidance is superior to adjoint guidance for 850 hPa temperature observations in a single case. This advantage increases as the number of flight tracks increases. In all cases, as more flight tracks are considered, diminishing returns on response function variance reduction are realized. Implications of these results for the development of targeting strategies are discussed. (orig.)

  7. Differential Sensitivity of Specific Neuronal Populations of the Rat Hypothalamus to Prolactin Action

    Science.gov (United States)

    Sapsford, Tony J.; Kokay, Ilona C.; Östberg, Lovisa; Bridges, Robert S.; Grattan, David R.

    2014-01-01

    Prolactin stimulates dopamine release from neuroendocrine dopaminergic (NEDA) neurons in the hypothalamic arcuate nucleus (ARC) to maintain low levels of serum prolactin. Elevated prolactin levels during pregnancy and lactation may mediate actions in other hypothalamic regions such as the paraventricular nucleus (PVN) and rostral preoptic area (rPOA). We predicted that NEDA neurons would be more sensitive prolactin targets than neurons in other regions because they are required to regulate basal prolactin secretion. Moreover, differences in the accessibility of the ARC to prolactin in blood may influence the responsiveness of this population. Therefore, we compared prolactin-induced signaling in different hypothalamic neuronal populations following either systemic or intracerebroventricular (icv) prolactin administration. Phosphorylation of the signal transduction factor, STAT5 (pSTAT5), was used to identify prolactin-responsive neurons. In response to systemic prolactin, pSTAT5-labeled cells were widely observed in the ARC but absent from the rPOA and PVN. Many of these responsive cells in the ARC were identified as NEDA neurons. The lowest icv prolactin dose (10 ng) induced pSTAT5 in the ARC, but with higher doses (>500 ng) pSTAT5 was detected in numerous regions, including the rPOA and PVN. NEDA neurons were maximally labeled with nuclear pSTAT5 in response to 500 ng prolactin and appeared to be more sensitive than dopaminergic neurons in the rPOA. Subpopulations of oxytocin neurons in the hypothalamus were also found to be differentially sensitive to prolactin. These data suggest that differences in the accessibility of the arcuate nucleus to prolactin, together with intrinsic differences in the NEDA neurons, may facilitate homeostatic feedback regulation of prolactin release. PMID:21953590

  8. Rapid and Sensitive Detection of BLAD in Cattle Population

    Directory of Open Access Journals (Sweden)

    Daniela Elena Ilie

    2014-05-01

    Full Text Available Bovine leukocyte adhesion deficiency (BLAD is an autosomal recessive disorder with negative impact on dairy cattle breeding. The molecular basis of BLAD is a single point mutation (A→G, resulting in a single amino acid substitution (aspartic acid → glycine at amino acid 128 in the adhesion molecule CD18. The object of this study was to establish a fast and sensitive molecular genotyping assay to detect BLAD carriers using high-resolution melting (HRM curve analysis. We tested animals with known genotypes for BLAD that were previously confirmed by PCR-RFLP method, and then examined the sensitivity of mutation detection using PCR followed by HRM curve analysis. BLAD carriers were readily detectable using HRM assay. Thus, the PCR-HRM genotyping method is a rapid, easily interpretable, reliable and cost-effective assay for BLAD mutant allele detection. This assay can be useful in cattle genotyping and genetic selection.

  9. Allergic contact sensitization in an adult Danish population

    DEFF Research Database (Denmark)

    Nielsen, N H; Linneberg, A; Menné, T

    2001-01-01

    In 1990 and 1998 15-41-year-old people were patch-tested in 2 cross-sectional studies of random samples of the population in the western part of Copenhagen County, Denmark. In 1990, 290 subjects and in 1998, 469 subjects were patch-tested. The participation rates were 69% and 51%, respectively. C...

  10. Target range-sensitive neurons in the auditory cortex of the mustache bat.

    Science.gov (United States)

    O'Neill, W E; Suga, N

    1979-01-05

    Echolocating bats determine distance to targets by the time delay between their emitted biosonar pulses and the returning echoes. By varying the delay between synthetic pulses and echoes in stimulus pairs at various repetition rates and durations, neurons have been found in the auditory cortex of the mustache bat (Pteronotus parnellii rubiginosus) which are sensitive to target range during the search, approach, and terminal phases of prey capture or landing. Two classes of range-sensitive neurons were found: (i) tracking neurons, whose best delay for response to an echo following the emitted pulse becomes shorter and narrower as the bat closes in on the target, and (ii) range-tuned neurons, whose best delay is constant, and which respond to the target only when it is within a certain narrow fixed range. Range-tuned neurons are specialized for processing echoes only during a particular period of the search, approach, or terminal phases of echolocation, and they provide support for a theory of ranging in bats that incorporates groups of neurons with a spectrum of preferred echo delays to detect target distance.

  11. Influence of Cellular and Molecular Factors on Membrane Target Sensitivity to Insecticides.

    Science.gov (United States)

    Raymond, Valérie; Goven, Delphine; Benzidane, Yassine; List, Olivier; Lapied, Bruno

    2017-01-01

    The effective control of insect pests is based on the use of insecticides. Most of these compounds act on molecular targets in the insect nervous system. However, the largescale deployment of insecticide treatment has led to the development of resistance, which decreases insecticide efficacy. Although the resistance mechanisms are largely studied today, this review aims to point out new insights on the less-known cellular and molecular factors involved in the modulation of the sensitivity of the targets to insecticides. This review will focus on the phosphorylation/dephosphorylation process, the post-transcriptional events such as editing and alternative splicing and the influence of the association with auxiliary proteins of the receptors and/or ion channels targeted by insecticides. In addition, the involvement of calcium-dependent signaling pathways in the modulation of the sensitivity of the target to insecticides will also be considered and discussed. Finally, this review will insist on different strategies proposed to optimize the efficacy of insecticide treatment while reducing doses to decrease side effects on environment and on non-target organisms by combining two different chemical insecticides or a given active ingredient associated with biological and/or chemical synergistic agents. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity". Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  12. Radiation-sensitive genetically susceptible pediatric sub-populations

    Energy Technology Data Exchange (ETDEWEB)

    Kleinerman, Ruth A. [National Cancer Institute, NIH, DHHS, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Rockville, MD (United States)

    2009-02-15

    Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation. (orig.)

  13. Target distance-dependent variation of hearing sensitivity during echolocation in a false killer whale.

    Science.gov (United States)

    Supin, Alexander Ya; Nachtigall, Paul E; Breese, Marlee

    2010-06-01

    Evidence of varying hearing sensitivity according to the target distance was obtained in a false killer whale Pseudorca crassidens during echolocation. Auditory evoked potentials (AEPs) triggered by echolocation clicks were recorded. The target distance varied from 1 to 6 m. The records contained AEPs to the self-heard emitted click and AEPs to the echoes. Mean level of echolocation clicks depended on distance (the longer the distance, the higher the click level), however, the effect of click level on AEP amplitude was eliminated by extracting AEPs to clicks of certain particular levels. The amplitude of the echo-provoked AEP was almost independent of distance, however, the amplitude of the AEP to the emitted click, did depend on distance within a range from 1 to 4 m: the longer the distance, the higher the amplitude. The latter result is interpreted as confirmational evidence that the animal is capable of varying hearing sensitivity according to target distance. The variation of hearing sensitivity may help to compensate for the echo attenuation with distance; as a secondary effect, this variation manifested itself in a variation of the amplitude of the AEP to emitted clicks.

  14. Acid-sensitive polymeric vector targeting to hepatocarcinoma cells via glycyrrhetinic acid receptor-mediated endocytosis.

    Science.gov (United States)

    Yan, Tingsheng; Cheng, Jinju; Liu, Zongjun; Cheng, Feng; Wei, Xinjing; Huang, Yudong; He, Jinmei

    2018-06-01

    Liver cancer is one of the top death causing cancers, traditional treatments have not settled for the requirement of patients. In this work, a smart acid-responsive micelle based on glycyrrhetinic acid modified chitosan-polyethyleneimine-4-Hydrazinobenzoic acid-doxorubicin (GA-CS-PEI-HBA-DOX) was synthesized for targeted delivery of DOX to liver cancer. A dual pH-sensitive and receptor-mediated strategy has been exploited to enhance the delivery efficiency. The micelle possesses positive charges under pH 6.8 and can be turned into negative charges above pH 7.0, which help to be accumulated in tumor tissues (pH 6.0-7.0). In the intracellular environment (pH 4.5-6.5) of tumor cells, the pH-sensitive hydrazone bonds between DOX and GA-CS-PEI-HBA would break and release as much as 90.3% of the encapsulated payloads in 48 h. In addition, GA was modified to improve the targeting abilities. The micelles exhibited high lethality to HepG2 cells while showed much lower cytotoxicity to HUVEC cells. With high drug-loading capacity and the targeted release ability, the GA-CS-PEI-HBA-DOX micelle might be employed as a promising candidate for targeted cancer treatment. Copyright © 2018. Published by Elsevier B.V.

  15. Genome Target Evaluator (GTEvaluator: A workflow exploiting genome dataset to measure the sensitivity and specificity of genetic markers.

    Directory of Open Access Journals (Sweden)

    Arnaud Felten

    Full Text Available Most of the bacterial typing methods used to discriminate isolates in medical or food safety microbiology are based on genetic markers used as targets in PCR or hybridization experiments. These DNA typing methods are important tools for studying prevalence and epidemiology, for conducting surveillance, investigations and control of biological hazard sources. In that perspective, it is crucial to insure that the chosen genetic markers have the greatest specificity and sensitivity. The wealth of whole-genome sequences available for many bacterial species offers the opportunity to evaluate the performance of these genetic markers. In the present study, we have developed GTEvaluator, a bioinformatics workflow which ranks genetic markers depending on their sensitivity and specificity towards groups of well-defined genomes. GTEvaluator identifies the most performant genetic markers to target individuals among a population. The individuals (i.e. a group of genomes within a collection are defined by any kind of particular phenotypic or biological properties inside a related population (i.e. collection of genomes. The performance of the genetic markers is computed by a distance value which takes into account both sensitivity and specificity. In this study we report two examples of GTEvaluator application. In the first example Bacillus phenotypic markers were evaluated for their capacity to distinguish B. cereus from B. thuringiensis. In the second experiment, GTEvaluator measured the performance of genetic markers dedicated to the molecular serotyping of Salmonella enterica. In one in silico experiment it was possible to test 64 markers onto 134 genomes corresponding to 14 different serotypes.

  16. The elimination of contraceptive acceptor targets and the evolution of population policy in India.

    Science.gov (United States)

    Donaldson, Peter J

    2002-03-01

    In 1966 the government of India announced a new national population policy that eliminated numerical targets for new contraceptive acceptors. This paper examines the history of target setting in India and factors that led to the elimination of targets. The analysis is based on published and unpublished reports on India's population policy and the family planning programme and interviews with senior Indian and foreign officials and population specialists. Five factors are identified as playing a role in the evolution from target setting to a target-free policy:(1) the research of India's academics; (2) the work of women's health advocates; (3) the support of officials in the state bureaucracy who approved the target-free approach; (4) the influence of the donors to India's family planning programme, especially the World Bank; and (5) the International Conference on Population and Development.

  17. Sensitivity to stress in the bivalve Macoma balthica from the most northern (Arctic) to the most southern (French) populations: low sensitivity in Arctic populations because of genetic adaptations?

    NARCIS (Netherlands)

    Hummel, H.; Bogaards, R.H.; Bek, T.; Polishchuk, L.; Amiard-Triquet, C.; Bachelet, G.; Desprez, M.; Strelkov, P.P.; Sukhotin, A.A.; Naumov, A.; Dahle, S.; Denisenko, S.; Gantsevich, M.; Sokolov, K.; De Wolf, L.

    1997-01-01

    The stress sensitivity, determined in copper exposure experiments and in survival in air tests, and the genetic structure, measured by means of isoenzyme electrophoresis, were assessed in populations of the Baltic clam Macoma balthica (L.) from its southern to its northern distribution limit, in

  18. A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren.

    Science.gov (United States)

    Bjerg, Anders; Winberg, Anna; Berthold, Malin; Mattsson, Lars; Borres, Magnus P; Rönmark, Eva

    2015-09-01

    Animal sensitization is a major determinant of asthma in children. Component-resolved studies of unselected pediatric populations are lacking. The aim was to describe sensitization to animal components and the association with asthma and rhinitis in animal-sensitized schoolchildren. A random sample of 696 children (11-12 years) from a Swedish population-based cohort was tested for sensitization to cat, dog, and horse dander using ImmunoCAP. Sera from animal-sensitized children were further analyzed by microarray including three allergen components from cat, four from dog, and two from horse. The parents completed an expanded ISAAC questionnaire. Of 259 animal-sensitized children (≥0.1 kUA /l), 51% were sensitized to all three, 23% to two, and 25% to one species. Current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. This association was seen already at moderate-level sensitization (1-15 ISU) to Fel d 4, at which level most children were sensitized to Fel d 1, as well. In dog-sensitized children, the majority was sensitized to more than one dog component, and co-sensitization to Can f 5 and Can f 1/f 2 conferred the greatest risk for asthma. Sensitization to the highly cross-reactive serum albumins was uncommon and not associated with asthma. Among schoolchildren in northern Sweden, where mite allergy is uncommon, furry animals were the primary perennial sensitizers. Asthma was associated with higher levels of component sensitization, and sensitization to more than one component from the same animal conferred the greatest risk. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence.

    Science.gov (United States)

    Verplaetse, Terril L; Weinberger, Andrea H; Smith, Philip H; Cosgrove, Kelly P; Mineur, Yann S; Picciotto, Marina R; Mazure, Carolyn M; McKee, Sherry A

    2015-04-01

    Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Divergence in androgen sensitivity contributes to population differences in sexual dimorphism of electrocommunication behavior.

    Science.gov (United States)

    Ho, Winnie W; Rack, Jessie M; Smith, G Troy

    2013-01-01

    Weakly-electric fish (Apteronotidae) produce highly diverse electrocommunication signals. Electric organ discharges (EODs) vary across species, sexes, and in the magnitude and direction of their sexual dimorphism. Gonadal steroid hormones can modulate EODs, and differences in androgen sensitivity are hypothesized to underlie variation in the degree of sexual dimorphism across species. In this study, we asked whether variation in androgen sensitivity explained variation in sexual dimorphism of EODs within species, at the population level. We examined two populations of black ghost knifefish (Apteronotus albifrons), one from the Orinoco and the other from the Amazon River Basin. EOD frequency (EODf) and chirp rates were measured to characterize diversity in sexual dimorphism across populations. The magnitude of sexual dimorphism in EODf differed significantly across populations, and was more pronounced in the Orinoco population than in the Amazon population. Chirp rates were sexually monomorphic in both populations. 11-Ketotestosterone (11-kT) was administered over a two-week period to assess population differences in sensitivity to androgens. 11-kT masculinized EODf significantly more in the population with the greater degree of sexual dimorphism. 11-kT had no effect on the sexually monomorphic chirping rates. We conclude that population divergence in androgen sensitivity contributes to variation in sexual dimorphism of EODf in A. albifrons. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Tedizolid Population Pharmacokinetics, Exposure Response, and Target Attainment

    OpenAIRE

    Flanagan, S.; Passarell, J.; Lu, Q.; Fiedler-Kelly, J.; Ludwig, E.; Prokocimer, P.

    2014-01-01

    Tedizolid phosphate is a novel antibacterial prodrug that is rapidly and extensively converted to its active moiety, tedizolid. We developed a population pharmacokinetics (PK) model for tedizolid using pooled data from seven densely and sparsely sampled clinical trials evaluating oral and intravenous tedizolid. Model-derived exposure estimates were evaluated for relationships to select efficacy and safety outcomes. A two-compartment model with sigmoidal absorption, absolute bioavailability, a...

  2. Advancing the sensitivity of selected reaction monitoring-based targeted quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Tujin; Su, Dian; Liu, Tao; Tang, Keqi; Camp, David G.; Qian, Weijun; Smith, Richard D.

    2012-04-01

    Selected reaction monitoring (SRM)—also known as multiple reaction monitoring (MRM)—has emerged as a promising high-throughput targeted protein quantification technology for candidate biomarker verification and systems biology applications. A major bottleneck for current SRM technology, however, is insufficient sensitivity for e.g., detecting low-abundance biomarkers likely present at the pg/mL to low ng/mL range in human blood plasma or serum, or extremely low-abundance signaling proteins in the cells or tissues. Herein we review recent advances in methods and technologies, including front-end immunoaffinity depletion, fractionation, selective enrichment of target proteins/peptides or their posttranslational modifications (PTMs), as well as advances in MS instrumentation, which have significantly enhanced the overall sensitivity of SRM assays and enabled the detection of low-abundance proteins at low to sub- ng/mL level in human blood plasma or serum. General perspectives on the potential of achieving sufficient sensitivity for detection of pg/mL level proteins in plasma are also discussed.

  3. Multilevel Interventions Targeting Obesity: Research Recommendations for Vulnerable Populations.

    Science.gov (United States)

    Stevens, June; Pratt, Charlotte; Boyington, Josephine; Nelson, Cheryl; Truesdale, Kimberly P; Ward, Dianne S; Lytle, Leslie; Sherwood, Nancy E; Robinson, Thomas N; Moore, Shirley; Barkin, Shari; Cheung, Ying Kuen; Murray, David M

    2017-01-01

    The origins of obesity are complex and multifaceted. To be successful, an intervention aiming to prevent or treat obesity may need to address multiple layers of biological, social, and environmental influences. NIH recognizes the importance of identifying effective strategies to combat obesity, particularly in high-risk and disadvantaged populations with heightened susceptibility to obesity and subsequent metabolic sequelae. To move this work forward, the National Heart, Lung, and Blood Institute, in collaboration with the NIH Office of Behavioral and Social Science Research and NIH Office of Disease Prevention convened a working group to inform research on multilevel obesity interventions in vulnerable populations. The working group reviewed relevant aspects of intervention planning, recruitment, retention, implementation, evaluation, and analysis, and then made recommendations. Recruitment and retention techniques used in multilevel research must be culturally appropriate and suited to both individuals and organizations. Adequate time and resources for preliminary work are essential. Collaborative projects can benefit from complementary areas of expertise and shared investigations rigorously pretesting specific aspects of approaches. Study designs need to accommodate the social and environmental levels under study, and include appropriate attention given to statistical power. Projects should monitor implementation in the multiple venues and include a priori estimation of the magnitude of change expected within and across levels. The complexity and challenges of delivering interventions at several levels of the social-ecologic model require careful planning and implementation, but hold promise for successful reduction of obesity in vulnerable populations. Copyright © 2016. Published by Elsevier Inc.

  4. The prevalence and morbidity of sensitization to fragrance mix I in the general population

    DEFF Research Database (Denmark)

    Thyssen, J P; Linneberg, A; Menné, T

    2009-01-01

    BACKGROUND: The prevalence of sensitization to fragrance mix (FM) I and Myroxylon pereirae (MP, balsam of Peru) has decreased in recent years among Danish women with dermatitis. OBJECTIVES: This study investigated whether the decrease could be confirmed among women in the general population...... supported a recent decrease in the prevalence of FM I and MP sensitization in Denmark. The study also showed that fragrance sensitization was associated with self-reported cosmetic dermatitis and use of health care related to cosmetic dermatitis....

  5. Sensitization and allergy to Cannabis sativa leaves in a population of tomato (Lycopersicon esculentum)-sensitized patients.

    Science.gov (United States)

    de Larramendi, Carlos Hernando; Carnés, Jerónimo; García-Abujeta, José Luís; García-Endrino, Ana; Muñoz-Palomino, Elena; Huertas, Angel Julio; Fernández-Caldas, Enrique; Ferrer, Angel

    2008-01-01

    Cases of allergy to Cannabis sativa have occasionally been reported, but both the allergenic profile and eventual cross-reactivity pattern remain unknown. To analyze the allergenic profile of a population of patients from Spain sensitized to C. sativa and to characterize the C. sativa leaf extract. A total of 32 subjects were enrolled in the study: group A, 10 individuals sensitized to tomato, reporting reactions by contact or inhalation to Cannabis; group B, 14 individuals sensitized to tomato, without reactions to Cannabis; group C, 8 individuals not sensitized to tomato and without reactions to Cannabis. Sensitivity to Cannabis, tomato and peach peel, Platanus hybrida and Artemisia vulgaris pollen extracts was measured by skin tests and specific IgE. Individual immunoblots and inhibition experiments with a pool of sera were conducted. All tomato-sensitized subjects (and 1 negative) had positive skin tests to C. sativa leaves and hashish. Specific IgE to C. sativa and peach peel was more common than to tomato. Immunoblot experiments showed 2 prominent bands of 10 and 14 kDa and 2 weakly recognized bands of 30 and 45 kDa. Tomato, peach and A. vulgaris extracts inhibited most of the bands present in C. sativa. P. hybrida inhibited only the high-molecular-weight bands. Sensitization to C. sativa with or without symptoms is frequent among patients in Spain sensitized to tomato. C. sativa leaves are a potential allergenic source and their allergens may cross-react with other allergenic sources from plants (fruit peels and pollen). (c) 2008 S. Karger AG, Basel

  6. Diagnosis of canine leptospirosis by a highly sensitive FRET-PCR targeting the lig genes.

    Directory of Open Access Journals (Sweden)

    Chuanling Xu

    Full Text Available Canine leptospirosis is underdiagnosed due to its wide spectrum of clinical presentations and the lack of a rapid and sensitive test for the accurate diagnosis of acute and chronic infections. In this study, we developed a highly sensitive and specific fluorescence resonance energy transfer (FRET-PCR to detect common pathogenic leptospires in dogs, including Leptospira interrogans serovars Autumnalis, Canicola, Copenhageni (Icterohaemorrhagiae serogroup and Pomona, and Leptospira kirschneri serovar Grippotyphosa. This PCR targets the lig genes, exclusively found in the pathogenic Leptospira species but not in saprophytic species (L. biflexa. A robust, high-stringency step-down real-time platform was coupled to the highly specific detection of leptospiral DNA by fluorescently labeled FRET probes. This enabled the detection of a single copy of the lig gene in a PCR containing DNA from up to 50 µL canine blood or 400 µL urine. Sensitivity determination by use of limiting serial dilutions of extracted leptospiral DNA indicated that the lig FRET-PCR we established was almost 100-fold more sensitive than the widely accepted lipL32 SYBR assay and 10-fold more sensitive than a 16S rRNA TaqMan assay. Application of this method to 207 dogs with potential leptospiral infection enabled us to diagnose three cases of canine leptospirosis characterized by low amounts of leptospiral DNA in body fluids. Detection of canine leptospirosis with the lig FRET-PCR was more sensitive with the lig FRET-PCR than with the 16S rRNA TaqMan PCR, which detected only 2 of the 3 cases, and the lipL32 SYBR PCR, which detected none of the 3 dogs with leptospirosis.

  7. In Vitro Drug Sensitivity Tests to Predict Molecular Target Drug Responses in Surgically Resected Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Ryohei Miyazaki

    Full Text Available Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs and anaplastic lymphoma kinase (ALK inhibitors have dramatically changed the strategy of medical treatment of lung cancer. Patients should be screened for the presence of the EGFR mutation or echinoderm microtubule-associated protein-like 4 (EML4-ALK fusion gene prior to chemotherapy to predict their clinical response. The succinate dehydrogenase inhibition (SDI test and collagen gel droplet embedded culture drug sensitivity test (CD-DST are established in vitro drug sensitivity tests, which may predict the sensitivity of patients to cytotoxic anticancer drugs. We applied in vitro drug sensitivity tests for cyclopedic prediction of clinical responses to different molecular targeting drugs.The growth inhibitory effects of erlotinib and crizotinib were confirmed for lung cancer cell lines using SDI and CD-DST. The sensitivity of 35 cases of surgically resected lung cancer to erlotinib was examined using SDI or CD-DST, and compared with EGFR mutation status.HCC827 (Exon19: E746-A750 del and H3122 (EML4-ALK cells were inhibited by lower concentrations of erlotinib and crizotinib, respectively than A549, H460, and H1975 (L858R+T790M cells were. The viability of the surgically resected lung cancer was 60.0 ± 9.8 and 86.8 ± 13.9% in EGFR-mutants vs. wild types in the SDI (p = 0.0003. The cell viability was 33.5 ± 21.2 and 79.0 ± 18.6% in EGFR mutants vs. wild-type cases (p = 0.026 in CD-DST.In vitro drug sensitivity evaluated by either SDI or CD-DST correlated with EGFR gene status. Therefore, SDI and CD-DST may be useful predictors of potential clinical responses to the molecular anticancer drugs, cyclopedically.

  8. A pilot study to delimit tsetse target populations in Zimbabwe.

    Directory of Open Access Journals (Sweden)

    Gerald Chikowore

    2017-05-01

    Full Text Available Tsetse (Glossina sensu stricto are cyclical vectors of human and animal trypanosomoses, that are presently targeted by the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC coordinated by the African Union. In order to achieve effective control of tsetse, there is need to produce elaborate plans to guide intervention programmes. A model intended to aid in the planning of intervention programmes and assist a fuller understanding of tsetse distribution was applied, in a pilot study in the Masoka area, Mid-Zambezi valley in Zimbabwe, and targeting two savannah species, Glossina morsitans morsitans and Glossina pallidipes.The field study was conducted between March and December 2015 in 105 sites following a standardized grid sampling frame. Presence data were used to study habitat suitability of both species based on climatic and environmental data derived from MODIS and SPOT 5 satellite images. Factors influencing distribution were studied using an Ecological Niche Factor Analysis (ENFA whilst habitat suitability was predicted using a Maximum Entropy (MaxEnt model at a spatial resolution of 250 m. Area Under the Curve (AUC, an indicator of model performance, was 0.89 for G. m. morsitans and 0.96 for G. pallidipes. We then used the predicted suitable areas to calculate the probability that flies were really absent from the grid cells where they were not captured during the study based on a probability model using a risk threshold of 0.05. Apart from grid cells where G. m. morsitans and G. pallidipes were captured, there was a high probability of presence in an additional 128 km2 and 144 km2 respectively.The modelling process promised to be useful in optimizing the outputs of presence/absence surveys, allowing the definition of tsetse infested areas with improved accuracy. The methodology proposed here can be extended to all the tsetse infested parts of Zimbabwe and may also be useful for other PATTEC national initiatives in other

  9. Comparative sensitivity of three populations of the cladoceran Moinodaphnia macleayi to acute and chronic uranium exposure.

    Science.gov (United States)

    Semaan, M; Holdway, D A; van Dam, R A

    2001-10-01

    Assessment of differences in the response of three different populations of the tropical cladoceran Moinodaphnia macleayi to uranium exposure was evaluated. The populations tested included a laboratory stock (maintained for 10 years), a wild population collected from Bowerbird Billabong (an uncontaminated environment), and a population collected from Djalkmara Billabong (a relatively contaminated environment with elevated levels of uranium), located on the Ranger uranium mine site, Jabiru East, NT, Australia. Chronic and acute toxicity of uranium was determined for all three populations. The no-observed-effect-concentration (NOEC; reproduction) and lowest observed-effect-concentration (LOEC; reproduction) for uranium ranged between 8-31 micrograms L-1 and 20-49 micrograms L-1, respectively, for all three populations. The 48 h EC50 (immobilization-lethality) for uranium ranged between 160-390 micrograms L-1 for all three populations. There was little difference in the response of the three populations of M. macleayi to acute and chronic uranium exposure, although the response of the laboratory population to chronic uranium exposure appeared more variable than the "wild" populations. There was no apparent tolerance in the population of M. macleayi obtained from Djalkmara Billabong when exposed to elevated levels of uranium. M. macleayi was significantly more sensitive to uranium exposure than other species previously tested. It was concluded that the sensitivity of the laboratory population (to uranium) is still representative of natural M. macleayi populations.

  10. A fission-fragment-sensitive target for X-ray spectroscopy in neutron-induced fission

    CERN Document Server

    Ethvignot, T; Giot, L; Casoli, P; Nelson, R O

    2002-01-01

    A fission-fragment-sensitive detector built for low-energy photon spectroscopy applications at the WNR 'white' neutron source at Los Alamos is described. The detector consists of eight layers of thin photovoltaic cells, onto which 1 mg/cm sup 2 of pure sup 2 sup 3 sup 8 U is deposited. The detector serves as an active target to select fission events from background and other reaction channels. The fairly small thickness of the detector with respect to transmission of 20-50 keV photons permits the measurement of prompt fission-fragment X-rays. Results with the GEANIE photon spectrometer are presented.

  11. A Unique "Angiotensin-Sensitive" Neuronal Population Coordinates Neuroendocrine, Cardiovascular, and Behavioral Responses to Stress.

    Science.gov (United States)

    de Kloet, Annette D; Wang, Lei; Pitra, Soledad; Hiller, Helmut; Smith, Justin A; Tan, Yalun; Nguyen, Dani; Cahill, Karlena M; Sumners, Colin; Stern, Javier E; Krause, Eric G

    2017-03-29

    rouse psychological, cardiovascular, and metabolic impairments. As a consequence, there is an urgent need for the development of novel therapeutic approaches to prevent or dampen deleterious aspects of "stress." While the renin-angiotensin system has received some attention in this regard, the neural mechanisms by which this endocrine system may impact stress-related pathologies and consequently serve as targets for therapeutic intervention are not clear. The present studies provide substantial insight in this regard. That is, they reveal that a distinct population of angiotensin-sensitive neurons is integral to the coordination of stress responses. The implication is that this neuronal phenotype may serve as a target for stress-related disease. Copyright © 2017 the authors 0270-6474/17/373479-13$15.00/0.

  12. Intraregional and inter-regional variability of herbicide sensitivity in common arable weed populations

    DEFF Research Database (Denmark)

    de Mol, Friederike; Gerowitt, Bärbel; Kaczmarek, Sylwia

    2015-01-01

    The question on intraregional versus inter-regional variability in herbicide sensitivity for weed populations is of major importance, both in extrapolation of model parameters and in herbicide zonal approval procedures. We hypothesised that inter-regional variability in herbicide sensitivity...... for field populations would be the same as intraregional variability for regions with similar climatic conditions. Seeds of field weed populations were collected in a Danish, German and Polish region. Herbicide sensitivity was tested in dose–response experiments in the glasshouse with flufenacet...... and iodosulfuron (Apera spica-venti), florasulam and tribenuron (Tripleurospermum inodorum), diflufenican, diflufenican + flurtamone and pendimethalin (Viola arvensis). ED50 values and variance components of the ED50 values were estimated to describe the influence of region, year and population. The regions...

  13. The sensitivity of real-time PCR amplification targeting invasive Salmonella serovars in biological specimens

    Directory of Open Access Journals (Sweden)

    Chau Tran

    2010-05-01

    Full Text Available Abstract Background PCR amplification for the detection of pathogens in biological material is generally considered a rapid and informative diagnostic technique. Invasive Salmonella serovars, which cause enteric fever, can be commonly cultured from the blood of infected patients. Yet, the isolation of invasive Salmonella serovars from blood is protracted and potentially insensitive. Methods We developed and optimised a novel multiplex three colour real-time PCR assay to detect specific target sequences in the genomes of Salmonella serovars Typhi and Paratyphi A. We performed the assay on DNA extracted from blood and bone marrow samples from culture positive and negative enteric fever patients. Results The assay was validated and demonstrated a high level of specificity and reproducibility under experimental conditions. All bone marrow samples tested positive for Salmonella, however, the sensitivity on blood samples was limited. The assay demonstrated an overall specificity of 100% (75/75 and sensitivity of 53.9% (69/128 on all biological samples. We then tested the PCR detection limit by performing bacterial counts after inoculation into blood culture bottles. Conclusions Our findings corroborate previous clinical findings, whereby the bacterial load of S. Typhi in peripheral blood is low, often below detection by culture and, consequently, below detection by PCR. Whilst the assay may be utilised for environmental sampling or on differing biological samples, our data suggest that PCR performed directly on blood samples may be an unsuitable methodology and a potentially unachievable target for the routine diagnosis of enteric fever.

  14. Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons: a sensitive target for ethanol.

    Science.gov (United States)

    Maguire, Edward P; Mitchell, Elizabeth A; Greig, Scott J; Corteen, Nicole; Balfour, David J K; Swinny, Jerome D; Lambert, Jeremy J; Belelli, Delia

    2014-04-01

    Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory 'phasic' post-synaptic currents mediated primarily by synaptic GABAA receptors (GABAAR) and, to a lesser extent, by synaptic glycine receptors (GlyR). In addition to such phasic transmission mediated by the vesicular release of neurotransmitter, the activity of certain neurons may be governed by a 'tonic' conductance resulting from ambient GABA activating extrasynaptic GABAARs. However, for DR neurons extrasynaptic GABAARs exert only a limited influence. By contrast, we report that unusually the GlyR antagonist strychnine reveals a large tonic conductance mediated by extrasynaptic GlyRs, which dominates DR inhibition. In agreement, for DR neurons strychnine increases their input resistance, induces membrane depolarization, and consequently augments their excitability. Importantly, this glycinergic conductance is greatly enhanced in a strychnine-sensitive fashion, by behaviorally relevant ethanol concentrations, by drugs used for the treatment of alcohol withdrawal, and by taurine, an ingredient of certain 'energy drinks' often imbibed with ethanol. These findings identify extrasynaptic GlyRs as critical regulators of DR excitability and a novel molecular target for ethanol.

  15. Assessing pest control using changes in instantaneous rate of population increase: treated targets and stable fly populations case study.

    Science.gov (United States)

    Beresford, D V; Sutcliffe, J F

    2010-06-01

    The instantaneous rate of population increase was used to assess the ability of attractive targets coated with permethrin to control stable fly populations on 3 dairy farms in south central Ontario, Canada. Two attractive targets were deployed over 10 wk in 2001 at each of 6 dairy farms. Three farms were outfitted with 2 untreated targets and 3 were outfitted with 2 targets treated with permethrin [Ectiban-impregnated Coroplast (Ectiban: Schering-Plough Canada Inc., Pointe-Claire, Québec, Canada; Coroplast: Great Pacific Enterprises Inc., Granby, Québec, Canada)]. Population growth rate was measured in terms of degree-days above a 10 degrees C developmental threshold (r(DD10)). The r(DD10) at the 3 treated dairy farms were significantly lower than r(DD10) at the 3 neighboring untreated dairy farms (mean r(DD10): treated=0.0088, untreated=0.013), but not in the previous year when targets were not installed (mean r(DD10): treated=0.012, untreated=0.015). This supports a long-term approach to management that lowers population growth rates in those regions where stable fly numbers increase exponentially from spring until winter, by shortening the period of economic impact of this pest. 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  16. MiR-216b increases cisplatin sensitivity in ovarian cancer cells by targeting PARP1.

    Science.gov (United States)

    Liu, Y; Niu, Z; Lin, X; Tian, Y

    2017-05-01

    Cisplatin resistance hinders the efficacy of chemotherapy in ovarian cancer. MicroRNAs (miRs) have been implicated in drug resistance in anti-cancer chemotherapy. We compared the expression profiles of miRs between cisplatin-resistant and cisplatin-sensitive ovarian cancer cells, and found that miR-216b was significantly downregulated in cisplatin-resistant ovarian cancer cells. To investigate its molecular mechanism, we performed cell viability and apoptosis assays in cisplatin-resistant ovarian cells, and found that miR-216b reduced cell viability and promoted apoptosis. Although 4 potential targets were obtained through bioinformatics, only the mRNA level of poly(ADP-ribose) polymerase (PARP)-1 was significantly regulated by miR-216b. Disruption of the complementary binding sequence of miR-216b on the 3'-untranslated region (3'-UTR) of the PARP1 led to the loss of miR-216b targeting. Spearman's correlation coefficient of the levels of miR-216b and PARP1 mRNA from 51 human ovarian cancer specimens also showed a significantly negative correlation between them. Importantly, the improved cisplatin sensitivity induced by miR-216b was markedly reversed by PARP1 overexpression. Tumor formation assay in nude mice further provided an evidence on the suppressive role of miR-216b in tumor growth. Taken together, this study demonstrated that a new miRNA, miR-216b, was involved in cisplatin resistance in ovarian cancer, which could be regarded as a potential sensitizer in cisplatin chemotherapy.

  17. MicroRNA-224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1.

    Science.gov (United States)

    Geng, Shuo; Gu, Lina; Ju, Fang; Zhang, Hepeng; Wang, Yiwen; Tang, Han; Bi, ZhengGang; Yang, Chenglin

    2016-09-01

    Osteosarcoma is the most common primary bone tumour in children and adolescents. Accumulating evidence has shown that microRNAs (miRNAs) participate in the development of almost all types of cancer. Here, we investigated the role of miR-224 in the development and progression of osteosarcoma. We demonstrated that miR-224 was down-regulated in osteosarcoma cell lines and tissues. Lower miR-224 levels were correlated with shorter survivalin osteosarcoma patients. Furthermore, overexpression of miR-224 suppressed osteosarcoma cell proliferation, migration and invasion and contributed to the increased sensitivity of MG-63 cells to cisplatin. We identified Rac1 as a direct target gene of miR-224 in osteosarcoma. Rac1 expression was up-regulated in the osteosarcoma cell lines and tissues, and there was an inverse correlation between Rac1 and miR-224 expression in osteosarcoma tissues. Furthermore, rescuing Rac1 expression decreased the sensitivity of miR-224-overexpressing MG-63 cells to cisplatin. We also demonstrated that ectopic expression of Rac1 promoted the proliferation, migration and invasion of miR-224-overexpressing MG-63 cells. These data suggest that miR-224 plays a tumour suppressor role in the development of osteosarcoma and is related to the sensitivity of osteosarcoma to cisplatin. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  18. Optical supermicrosensor responses for simple recognition and sensitive removal of Cu (II) Ion target.

    Science.gov (United States)

    El-Safty, Sherif A; Ismail, Adel A; Shahat, Ahmed

    2011-02-15

    The field of optical chemosensor technology demands a simple yet general design for fast, sensitive, selective, inexpensive, and specific recognition of a broad range of toxic metal ions. The suitable accommodation of chromogenic receptors onto ordered porous carriers have led to selective and sensitive chemosensors of target species. In this study, we offer real evidence on the potential use of two- and three-dimensional (2D and 3D) ordered supermicroporous monoliths as selective shape and size carriers for immobilizing the chromogenic probe. Among all the chemosensors, 3D supermicropore has exhibited easy accessibility of target ions, such as ion transports and high affinity responses of receptor-metal analyte binding events. This leads to an optical color signal that is easily generated and transduced even at trace levels of Cu(II) target ions. The supermicrosensors have shown the ability to create Cu(II) ion-sensing responses up to nanomolar concentrations (∼10(-9) mol/dm(3)) with rapid response time (in the order of seconds). Supermicrosensors have the ability to create easily modified sensing systems with multiple regeneration/reuse cycles of sensing systems of Cu(II) analytes. The simple treatment using ClO(4)(-) anion as a stripping agent has removed effectively the Cu(II) ions and formed a "metal-free" probe surface. The supermicrosensors have exhibited the specificity behavior permitting Cu(II) ion-selective determination in real-life samples, such as in wastewater, despite the presence of active component species. Extensive analytical results indicate that the use of the supermicrosensor as Cu(II) ion strips for field screening can be a time- and cost-alternative tool to current effective laboratory assays. Copyright © 2010 Elsevier B.V. All rights reserved.

  19. Permanent Genetic Access to Transiently Active Neurons via TRAP: Targeted Recombination in Active Populations

    OpenAIRE

    Guenthner, Casey J.; Miyamichi, Kazunari; Yang, Helen H.; Heller, H. Craig; Luo, Liqun

    2013-01-01

    Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed a new approach, Targeted Recombination in Active Populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreERT2 is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that expr...

  20. MicroRNA-221 and -222 Regulate Radiation Sensitivity by Targeting the PTEN Pathway

    International Nuclear Information System (INIS)

    Zhang Chunzhi; Kang Chunsheng; Wang Ping; Cao Yongzhen; Lv Zhonghong; Yu Shizhu; Wang Guangxiu; Zhang Anling; Jia Zhifan; Han Lei; Yang Chunying; Ishiyama, Hiromichi; Teh, Bin S.; Xu Bo; Pu Peiyu

    2011-01-01

    Purpose: MicroRNAs (miRNAs) are noncoding RNAs inhibiting expression of numerous target genes by posttranscriptional regulation. miRNA-221 and miRNA-222 (miRNA-221/-222) expression is elevated in radioresistant tumor cell lines; however, it is not known whether and how miRNAs control cellular responses to ionizing irradiation. Methods and Materials: We used bioinformatic analyses, luciferase reporter assay, and genetic knockdown and biochemical assays to characterize the regulation pathways of miRNA-221/-222 in response to radiation treatment. Results: We identified the PTEN gene as a target of miRNA-221/-222. Furthermore, we found that knocking down miRNA-221/-222 by antisense oligonucleotides upregulated PTEN expression. Upregulated PTEN expression suppressed AKT activity and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in tumor cells. Conclusions: miRNA-221/-222 control radiation sensitivity by regulating the PTEN/AKT pathway and can be explored as novel targets for radiosensitization.

  1. UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma.

    Science.gov (United States)

    Zhang, Bo; Zhang, Yujie; Liao, Ziwei; Jiang, Ting; Zhao, Jingjing; Tuo, Yanyan; She, Xiaojian; Shen, Shun; Chen, Jun; Zhang, Qizhi; Jiang, Xinguo; Hu, Yu; Pang, Zhiqing

    2015-01-01

    Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.

  2. Road-traffic noise: annoyance, risk perception, and noise sensitivity in the Finnish adult population.

    Science.gov (United States)

    Okokon, Enembe Oku; Turunen, Anu W; Ung-Lanki, Sari; Vartiainen, Anna-Kaisa; Tiittanen, Pekka; Lanki, Timo

    2015-05-26

    Exposure to road-traffic noise commonly engenders annoyance, the extent of which is determined by factors not fully understood. Our aim was to estimate the prevalence and determinants of road-traffic noise annoyance and noise sensitivity in the Finnish adult population, while comparing the perceptions of road-traffic noise to exhausts as environmental health problems. Using a questionnaire that yielded responses from 1112 randomly selected adult Finnish respondents, we estimated road-traffic noise- and exhausts-related perceived exposures, health-risk perceptions, and self-reported annoyance on five-point scales, while noise sensitivity estimates were based on four questions. Determinants of noise annoyance and sensitivity were investigated using multivariate binary logistic regression and linear regression models, respectively. High or extreme noise annoyance was reported by 17% of respondents. Noise sensitivity scores approximated a Gaussian distribution. Road-traffic noise and exhausts were, respectively, considered high or extreme population-health risks by 22% and 27% of respondents. Knowledge of health risks from traffic noise, OR: 2.04 (1.09-3.82) and noise sensitivity, OR: 1.07 (1.00-1.14) were positively associated with annoyance. Knowledge of health risks (proad-traffic noise, and perceive it to be a significant health risk, almost comparable to traffic exhausts. There is no distinct noise-sensitive population subgroup. Knowledge of health risks of road-traffic noise, and attitudinal variables are associated with noise annoyance and sensitivity.

  3. Quasi-extinction risk and population targets for the Eastern, migratory population of monarch butterflies (Danaus plexippus)

    Science.gov (United States)

    Semmens, Brice X.; Semmens, Darius J.; Thogmartin, Wayne E.; Wiederholt, Ruscena; Lopez-Hoffman, Laura; Diffendorfer, James E.; Pleasants, John M.; Oberhauser, Karen S.; Taylor, Orley R.

    2016-01-01

    The Eastern, migratory population of monarch butterflies (Danaus plexippus), an iconic North American insect, has declined by ~80% over the last decade. The monarch’s multi-generational migration between overwintering grounds in central Mexico and the summer breeding grounds in the northern U.S. and southern Canada is celebrated in all three countries and creates shared management responsibilities across North America. Here we present a novel Bayesian multivariate auto-regressive state-space model to assess quasi-extinction risk and aid in the establishment of a target population size for monarch conservation planning. We find that, given a range of plausible quasi-extinction thresholds, the population has a substantial probability of quasi-extinction, from 11–57% over 20 years, although uncertainty in these estimates is large. Exceptionally high population stochasticity, declining numbers, and a small current population size act in concert to drive this risk. An approximately 5-fold increase of the monarch population size (relative to the winter of 2014–15) is necessary to halve the current risk of quasi-extinction across all thresholds considered. Conserving the monarch migration thus requires active management to reverse population declines, and the establishment of an ambitious target population size goal to buffer against future environmentally driven variability.

  4. Using target population specification, effect size, and reach to estimate and compare the population impact of two PTSD preventive interventions.

    Science.gov (United States)

    Zatzick, Douglas F; Koepsell, Thomas; Rivara, Frederick P

    2009-01-01

    The population impact of a preventive intervention depends on two factors: what proportion of the full population at risk receives the intervention and how large a reduction in risk occurs among those who receive it. We sought to illustrate how information from a cognitive behavioral psychotherapy (CBT) trial and stepped collaborative care (CC) trial could be used to estimate the population impact of two contrasting approaches to PTSD prevention. We first specified trauma center target populations represented by participants in each trial. Patient characteristics were compared, as were effect size and reach indices and population-level reductions in PTSD incidence. The CBT trial demonstrated a larger effect size (50% PTSD prevention), but minimal reach (27/10,000), while the CC trial demonstrated a smaller effect size (7% PTSD prevention) but greater reach (1762/10,000). Modeling of the population impact suggested that a 9.5-fold greater cumulative reduction in the incidence of PTSD would result from the dissemination of the CC broad reach prevention strategy. A reciprocal relationship between effect size and reach was evident in these two trials. By specifying a target population, effect size and reach could be combined to project the overall population impact of each PTSD prevention approach.

  5. A sensitive membrane-targeted biosensor for monitoring changes in intracellular chloride in neuronal processes.

    Science.gov (United States)

    Watts, Spencer D; Suchland, Katherine L; Amara, Susan G; Ingram, Susan L

    2012-01-01

    Regulation of chloride gradients is a major mechanism by which excitability is regulated in neurons. Disruption of these gradients is implicated in various diseases, including cystic fibrosis, neuropathic pain and epilepsy. Relatively few studies have addressed chloride regulation in neuronal processes because probes capable of detecting changes in small compartments over a physiological range are limited. In this study, a palmitoylation sequence was added to a variant of the yellow fluorescent protein previously described as a sensitive chloride indicator (YFPQS) to target the protein to the plasma membrane (mbYFPQS) of cultured midbrain neurons. The reporter partitions to the cytoplasmic face of the cellular membranes, including the plasma membrane throughout the neurons and fluorescence is stable over 30-40 min of repeated excitation showing less than 10% decrease in mbYFPQS fluorescence compared to baseline. The mbYFPQS has similar chloride sensitivity (k(50) =  41 mM) but has a shifted pKa compared to the unpalmitoylated YFPQS variant (cytYFPQS) that remains in the cytoplasm when expressed in midbrain neurons. Changes in mbYFPQS fluorescence were induced by the GABA(A) agonist muscimol and were similar in the soma and processes of the midbrain neurons. Amphetamine also increased mbYFPQS fluorescence in a subpopulation of cultured midbrain neurons that was reversed by the selective dopamine transporter (DAT) inhibitor, GBR12909, indicating that mbYFPQS is sensitive enough to detect endogenous DAT activity in midbrain dopamine (DA) neurons. The mbYFPQS biosensor is a sensitive tool to study modulation of intracellular chloride levels in neuronal processes and is particularly advantageous for simultaneous whole-cell patch clamp and live-cell imaging experiments.

  6. Cartography of Emergency Department Visits for Asthma – Targeting High-Morbidity Populations

    Directory of Open Access Journals (Sweden)

    Pierre Lajoie

    2004-01-01

    Full Text Available BACKGROUND: Asthma education should be offered with priority to populations with the highest asthma-related morbidity. In the present study, the aim was to identify populations with high-morbidity for asthma from the Quebec Health Insurance Board Registry, a large administrative database, to help the Quebec Asthma and Chronic Obstructive Pulmonary Disease Network target its interventions.

  7. Global sensitivity analysis applied to drying models for one or a population of granules

    DEFF Research Database (Denmark)

    Mortier, Severine Therese F. C.; Gernaey, Krist; Thomas, De Beer

    2014-01-01

    sensitivity in a broad parameter space, is performed to detect the most sensitive factors in two models, that is, one for drying of a single granule and one for the drying of a population of granules [using population balance model (PBM)], which was extended by including the gas velocity as extra input...... performance impacts drying behavior, the latter is informative with respect to the variables that primarily need to be controlled during continuous operation. In addition, several GSA techniques are analyzed and compared with respect to the correct conclusion and computational load. (c) 2014 American...

  8. Sensitivity of population smoke exposure to fire locations in Equatorial Asia

    Science.gov (United States)

    Kim, Patrick S.; Jacob, Daniel J.; Mickley, Loretta J.; Koplitz, Shannon N.; Marlier, Miriam E.; DeFries, Ruth S.; Myers, Samuel S.; Chew, Boon Ning; Mao, Yuhao H.

    2015-02-01

    High smoke concentrations in Equatorial Asia, primarily from land conversion to oil palm plantations, affect a densely populated region and represent a serious but poorly quantified air quality concern. Continued expansion of the oil palm industry is expected but the resulting population exposure to smoke is highly dependent on where this expansion takes place. We use the adjoint of the GEOS-Chem chemical transport model to map the sensitivity of smoke concentrations in major Equatorial Asian cities, and for the population-weighted region, to the locations of the fires. We find that fires in southern Sumatra are particularly detrimental, and that a land management policy protecting peatswamp forests in Southeast Sumatra would be of great air quality benefit. Our adjoint sensitivities can be used to immediately infer population exposure to smoke for any future fire emission scenario.

  9. Voltage-sensitive styryl dyes as singlet oxygen targets on the surface of bilayer lipid membrane.

    Science.gov (United States)

    Sokolov, V S; Gavrilchik, A N; Kulagina, A O; Meshkov, I N; Pohl, P; Gorbunova, Yu G

    2016-08-01

    Photosensitizers are widely used as photodynamic therapeutic agents killing cancer cells by photooxidation of their components. Development of new effective photosensitive molecules requires profound knowledge of possible targets for reactive oxygen species, especially for its singlet form. Here we studied photooxidation of voltage-sensitive styryl dyes (di-4-ANEPPS, di-8-ANEPPS, RH-421 and RH-237) by singlet oxygen on the surface of bilayer lipid membranes commonly used as cell membrane models. Oxidation was induced by irradiation of a photosensitizer (aluminum phthalocyanine tetrasulfonate) and monitored by the change of dipole potential on the surface of the membrane. We studied the drop of the dipole potential both in the case when the dye molecules were adsorbed on the same side of the lipid bilayer as the photosensitizer (cis-configuration) and in the case when they were adsorbed on the opposite side (trans-configuration). Based on a simple model, we determined the rate of oxidation of the dyes from the kinetics of change of the potential during and after irradiation. This rate is proportional to steady-state concentration of singlet oxygen in the membrane under irradiation. Comparison of the oxidation rates of various dyes reveals that compounds of ANEPPS series are more sensitive to singlet oxygen than RH type dyes, indicating that naphthalene group is primarily responsible for their oxidation. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Reproductive value, sensitivity, and nonlinearity: Population-management heuristics derived from classical demography

    OpenAIRE

    Karsten R.; Teismann H.; Vogels A.

    2013-01-01

    In classical demographic theory, reproductive value and stable age distribution are proportional to the sensitivities of the asymptotic population size to changes in mortality and maternity, respectively. In this note we point out that analogous relationships hold if the maternity function is allowed to depend on the population density. The relevant formulae can essentially be obtained by replacing the growth rate ("Lotka'sr") with zero. These facts may be used to derive heuristics for popula...

  11. Point-of-care detection of extracellular vesicles: Sensitivity optimization and multiple-target detection.

    Science.gov (United States)

    Oliveira-Rodríguez, Myriam; Serrano-Pertierra, Esther; García, Agustín Costa; López-Martín, Soraya; Yañez-Mo, María; Cernuda-Morollón, Eva; Blanco-López, M C

    2017-01-15

    Extracellular vesicles (EVs) are membrane-bound nanovesicles delivered by different cellular lineages under physiological and pathological conditions. Although these vesicles have shown relevance as biomarkers for a number of diseases, their isolation and detection still has several technical drawbacks, mainly related with problems of sensitivity and time-consumed. Here, we reported a rapid and multiple-targeted lateral flow immunoassay (LFIA) system for the detection of EVs isolated from human plasma. A range of different labels (colloidal gold, carbon black and magnetic nanoparticles) was compared as detection probe in LFIA, being gold nanoparticles that showed better results. Using this platform, we demonstrated that improvements may be carried out by incorporating additional capture lines with different antibodies. The device exhibited a limit of detection (LOD) of 3.4×10 6 EVs/µL when anti-CD81 and anti-CD9 were selected as capture antibodies in a multiple-targeted format, and anti-CD63 labeled with gold nanoparticles was used as detection probe. This LFIA, coupled to EVs isolation kits, could become a rapid and useful tool for the point-of-care detection of EVs, with a total analysis time of two hours. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    International Nuclear Information System (INIS)

    Androic, Ilija; Krämer, Andrea; Yan, Ruilan; Rödel, Franz; Gätje, Regine; Kaufmann, Manfred; Strebhardt, Klaus; Yuan, Juping

    2008-01-01

    Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy

  13. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    Directory of Open Access Journals (Sweden)

    Strebhardt Klaus

    2008-12-01

    Full Text Available Abstract Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1, is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.

  14. Social identity and support for counteracting tobacco company marketing that targets vulnerable populations.

    Science.gov (United States)

    Baig, Sabeeh A; Pepper, Jessica K; Morgan, Jennifer C; Brewer, Noel T

    2017-06-01

    Tobacco companies use advertising to target vulnerable populations, including youth, racial/ethnic minorities, and sexual minorities. We sought to examine how personal identity affects support for population-specific anti-smoking advertisements that could serve as countermeasures to industry marketing practices. In 2014-2015, we surveyed probability phone samples of adults and adolescents (n = 6,139) and an online convenience sample of adults (n = 4,137) in the United States. We experimentally varied the description of tobacco industry marketing practices (no description, general, or specific to a target group). The four prevention target groups were teens; African Americans; Latinos; and gays, lesbians, and bisexuals (GLBs). Participants were either members or non-members of their prevention target group. Support was highest for anti-smoking advertisements targeting teens, moderate for Latinos and African Americans, and lowest for GLBs. In-group members expressed higher support than out-group members when anti-smoking advertisements targeted African Americans, Latinos, and GLBs (all p marketing practices did not have an effect. Results were similar across the phone and online studies. Our findings suggest that the public strongly supports advertisements to prevent smoking among teens, but support for similar efforts among other vulnerable populations is comparatively low. Anti-smoking campaigns for vulnerable populations may benefit from a greater understanding of the role of social identity in shaping public support for such campaigns. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. The prevalence of allergic contact sensitization in a general population in Tromsø, Norway.

    Science.gov (United States)

    Dotterud, Lars Kåre

    2007-09-01

    This study investigated the prevalence of contact sensitization in a general adult population and the relationship between the history of metal dermatitis and sensitization to metal allergens. A cross-sectional population study using patch tests and a questionnaire was conducted among adults in Tromsø, Northern Norway. A random sample of 830 participants aged 18-75 years were invited to participate in the patch testing and completed a 1-page self-administered questionnaire. Of the adults, 531 (64%) were actually TRUE tested (using a standardized, ready-to-apply patch test system) and completed the self-administered questionnaire about ear piercing, metal reactions, skin reactions to different allergens, atopic dermatitis, eczema, cooking equipment and diet. The study showed that nickel (19.2%; women 31.1% and men 5.0%), fragrance mix (3.4%) and cobalt (1.7%) were the most prevalent allergens causing contact sensitization. For all other allergens, less than 1.1% tested positive. Eighty-four (45.2%) subjects with a positive history of metal dermatitis had negative patch tests. Contact sensitization was found frequently in this general adult population, especially to nickel and perfumes with a predominance among females. An eczematous reaction caused by cheap earrings seemed to be the best indicator for metal sensitivity.

  16. Differences in sensitivity to the fungal pathogen Batrachochytrium dendrobatidis among amphibian populations

    Science.gov (United States)

    Paul W. Bradley; Stephanie S. Gervasi; Jessica Hua; Rickey D. Cothran; Rick A. Relyea; Deanna H. Olson; Andrew R. Blaustein

    2015-01-01

    Contributing to the worldwide biodiversity crisis are emerging infectious diseases, which can lead to extirpations and extinctions of hosts. For example, the infectious fungal pathogen Batrachochytrium dendrobatidis (Bd) is associated with worldwide amphibian population declines and extinctions. Sensitivity to Bd varies with species, season, and life stage. However,...

  17. Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, A.R.; Dorlo, T.P.C.; Gruppen, M.P.; De Boer, A.; De Vries, P.J.

    2015-01-01

    Aim The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Methods Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were

  18. Population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome

    NARCIS (Netherlands)

    Kreeftmeijer-Vegter, A. R.; Dorlo, T. P. C.; Gruppen, M. P.; de Boer, A. [=Anthonius; de Vries, P. J.

    2015-01-01

    The aim was to investigate the population pharmacokinetics of levamisole in children with steroid-sensitive nephrotic syndrome. Non-linear mixed effects modelling was performed on samples collected during a randomized controlled trial. Samples were collected from children who were receiving 2.5 mg

  19. Evaluating fungicide sensitivity of regional Blumeria graminis f.sp. tritici populations in the United States

    Science.gov (United States)

    Blumeria graminis f.sp. tritici (Bgt), cause of wheat powdery mildew, has a high likelihood of developing fungicide resistance because of the large quantity of spores produced along with the mixed mode of reproduction. Additionally, once reduced sensitivity appears in a population it can influence n...

  20. Diversity of dietary habits in the population as important factor of the regional radioecological sensitivity

    International Nuclear Information System (INIS)

    Travnikova, I.; Bruk, G.; Shutov, V.

    2001-01-01

    The assessment of the ways and regularities of internal dose formation in the population is impossible without the determination of food consumption habits for the population residing in contaminated areas. Food habits of peoples inhabiting the former Soviet Union differ both due to historical reasons and to religious traditions. Variation of food consumption is an important factor of radio-ecological sensitivity of the population. We try to show this on the example of south-west districts of the Bryansk region contaminated as a result of the Chernobyl accident. In these regions, a set of countermeasures has been applied that strongly deformed traditional food consumption. (orig.)

  1. Reproductive value, sensitivity, and nonlinearity: population-management heuristics derived from classical demography.

    Science.gov (United States)

    Karsten, Richard; Teismann, Holger; Vogels, Angela

    2013-05-01

    In classical demographic theory, reproductive value and stable age distribution are proportional to the sensitivities of the asymptotic population size to changes in mortality and maternity, respectively. In this note we point out that analogous relationships hold if the maternity function is allowed to depend on the population density. The relevant formulae can essentially be obtained by replacing the growth rate ("Lotka's r") with zero. These facts may be used to derive heuristics for population management (pest control). Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Components of Population Vulnerability and Their Relationship With Climate-Sensitive Health Threats.

    Science.gov (United States)

    English, P B; Richardson, M J

    2016-03-01

    Climate change is increasingly being framed as risks that will impact the poorest and most vulnerable communities among us. This has led to more efforts to estimate climate change risks across populations and in the context of human health and health equity. We describe the public health dimensions of climate vulnerability-exposure, population sensitivity, and adaptive capacity-and explore how these dimensions can modify population health impacts and their distribution. An overview of health disparities associated with specific climate risks is presented, and we offer potential solutions grounded in equitable urban development and improved characterization of climate vulnerabilities.

  3. The costs of HIV prevention for different target populations in Mumbai, Thane and Bangalore.

    Science.gov (United States)

    Chandrashekar, Sudha; Vassall, Anna; Reddy, Bhaskar; Shetty, Govindraj; Vickerman, Peter; Alary, Michel

    2011-12-29

    Avahan, the India AIDS Initiative, delivers HIV prevention services to high-risk populations at scale. Although the broad costs of such HIV interventions are known, to-date there has been little data available on the comparative costs of reaching different target groups, including female sex workers (FSWs), replace with 'high risk men who have sex with men (HR-MSM) and trans-genders. Costs are estimated for the first three years of Avahan scale up differentiated by typology of female sex workers (brothel, street, home, lodge based, bar based), HR-MSM and transgenders in urban districts in India: Mumbai and Thane in Maharashtra and Bangalore in Karnataka. Financial and economic costs were collected prospectively from a provider perspective. Outputs were measured using data collected by the Avahan programme. Costs are presented in US$2008. Costs were found to vary substantially by target group. Non-governmental organisations (NGOs) working with transgender populations had a higher mean cost (US $116) per person reached compared to those dealing primarily with FSWs (US $75-96) and MSWs (US $90) by the end of year three of the programme in Mumbai. The mean cost of delivering the intervention to HR-MSMs (US $42) was higher than delivering it to FSWs (US $37) in Bangalore. The package of services delivered to each target group was similar, and our results suggest that cost variation is related to the target population size, the intensity of the programme (in terms of number of contacts made per year) and a number of specific issues related to each target group. Based on our data policy makers and program managers need to consider the ease of accessing high risk population when planning and budgeting for HIV prevention services for these populations and avoid funding programmes on the basis of target population size alone.

  4. Varied sensitivity to therapy of HIV-1 strains in CD4+ lymphocyte sub-populations upon ART initiation

    Directory of Open Access Journals (Sweden)

    Paxton William A

    2010-12-01

    Full Text Available Abstract Background Although antiretroviral therapy (ART has proven its success against HIV-1, the long lifespan of infected cells and viral latency prevent eradication. In this study we analyzed the sensitivity to ART of HIV-1 strains in naïve, central memory and effector memory CD4+ lymphocyte subsets. Methods From five patients cellular HIV-1 infection levels were quantified before and after initiation of therapy (2-5 weeks. Through sequencing the C2V3 region of the HIV-1 gp120 envelope, we studied the effect of short-term therapy on virus variants derived from naïve, central memory and effector memory CD4+ lymphocyte subsets. Results During short-term ART, HIV-1 infection levels declined in all lymphocyte subsets but not as much as RNA levels in serum. Virus diversity in the naïve and central memory lymphocyte populations remained unchanged, whilst diversity decreased in serum and the effector memory lymphocytes. ART differentially affected the virus populations co-circulating in one individual harboring a dual HIV-1 infection. Changes in V3 charge were found in all individuals after ART initiation with increases within the effector memory subset and decreases found in the naïve cell population. Conclusions During early ART virus diversity is affected mainly in the serum and effector memory cell compartments. Differential alterations in V3 charge were observed between effector memory and naïve populations. While certain cell populations can be targeted preferentially during early ART, some virus strains demonstrate varied sensitivity to therapy, as shown from studying two strains within a dual HIV-1 infected individual.

  5. Clinical Sensitivity of Cystic Fibrosis Mutation Panels in a Diverse Population.

    Science.gov (United States)

    Hughes, Erin E; Stevens, Colleen F; Saavedra-Matiz, Carlos A; Tavakoli, Norma P; Krein, Lea M; Parker, April; Zhang, Zhen; Maloney, Breanne; Vogel, Beth; DeCelie-Germana, Joan; Kier, Catherine; Anbar, Ran D; Berdella, Maria N; Comber, Paul G; Dozor, Allen J; Goetz, Danielle M; Guida, Louis; Kattan, Meyer; Ting, Andrew; Voter, Karen Z; van Roey, Patrick; Caggana, Michele; Kay, Denise M

    2016-02-01

    Infants are screened for cystic fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the US FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002 to 2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and zero or one mutation were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG) to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially available panels, and could be considered for NBS, clinical, or research laboratories conducting CF screening. © 2015 WILEY PERIODICALS, INC.

  6. Folate-receptor-targeted NIR-sensitive polydopamine nanoparticles for chemo-photothermal cancer therapy

    Science.gov (United States)

    Li, Hao; Jin, Zhen; Cho, Sunghoon; Jeon, Mi Jeong; Du Nguyen, Van; Park, Jong-Oh; Park, Sukho

    2017-10-01

    We propose the use of folate-receptor-targeted, near-infrared-sensitive polydopamine nanoparticles (NPs) for chemo-photothermal cancer therapy as an enhanced type of drug-delivery system which can be synthesized by in situ polymerization and conjugation with folic acid. The NPs consist of a Fe3O4/Au core, coated polydopamine, conjugated folic acid, and loaded anti-cancer drug (doxorubicin). The proposed multifunctional NPs show many advantages for therapeutic applications such as good biocompatibility and easy bioconjugation. The polydopamine coating of the NPs show a higher photothermal effect and thus more effective cancer killing compared to Fe3O4/Au nanoparticles at the same intensity as near-infrared laser irradiation. In addition, the conjugation of folic acid was shown to enhance cancer cellular uptake efficiency via the folate receptor and thus improve chemotherapeutic efficiency. Through in vitro cancer cell treatment testing, the proposed multifunctional NPs showed advanced photothermal and chemotherapeutic performance. Based on these enhanced anti-cancer properties, we expect that the proposed multifunctional NPs can be used as a drug-delivery system in cancer therapy.

  7. A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

    Science.gov (United States)

    Giordano, Courtney R; Mueller, Kelly L; Terlecky, Laura J; Krentz, Kendra A; Bollig-Fischer, Aliccia; Terlecky, Stanley R; Boerner, Julie L

    2012-10-01

    Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. Copyright © 2012. Published by Elsevier Inc.

  8. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin.

    Science.gov (United States)

    Elf, S; Lin, R; Xia, S; Pan, Y; Shan, C; Wu, S; Lonial, S; Gaddh, M; Arellano, M L; Khoury, H J; Khuri, F R; Lee, B H; Boggon, T J; Fan, J; Chen, J

    2017-01-12

    The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small-molecule 6PGD inhibitors Physcion and its derivative S3, shows anticancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase, exhibit non-immune hemolytic anemia upon exposure to aspirin and various antimalarial drugs. Inspired by these clinical observations, we examined the anticancer potential of combined treatment with 6PGD inhibitors and antimalarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to antimalarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel antileukemia treatment without inducing hemolysis.

  9. Anxiety sensitivity and working memory capacity: Risk factors and targets for health behavior promotion.

    Science.gov (United States)

    Otto, Michael W; Eastman, Abraham; Lo, Stephen; Hearon, Bridget A; Bickel, Warren K; Zvolensky, Michael; Smits, Jasper A J; Doan, Stacey N

    2016-11-01

    Understanding the nature and influence of specific risk profiles is increasingly important for health behavior promotion. The purpose of this article is to document the value of two factors-anxiety sensitivity (AS) and working memory capacity (WMC)-for enhancing risk for the initiation and/or maintenance of a range of negative health behaviors. AS is a distress-related risk factor that potentiates avoidance/coping motivations for negative health behaviors. Stress provides the conditions for negative somatic and affective states, and AS amplifies the aversiveness of these experiences and correspondingly hinders adaptive functioning. In contrast, low WMC is hypothesized to exert its effect by decreasing the capacity to filter out current temptations, attenuating a focus on longer-term goals and impairing the application of relevant coping skills at times of stress. In this review, we provide conceptual models for the separate roles of high AS and low WMC in negative health behaviors, review the influence of these factors on specific health behavior exemplars (eating behaviors/obesity, physical activity, smoking, alcohol use, and sleep promotion), provide preliminary evidence for their value as independent treatment targets for health-behavior promotion, and encourage specific research directions in relation to these variables. Copyright © 2016. Published by Elsevier Ltd.

  10. Targeting MYC sensitizes malignant mesothelioma cells to PAK blockage-induced cytotoxicity.

    Science.gov (United States)

    Tan, Yinfei; Sementino, Eleonora; Chernoff, Jonathan; Testa, Joseph R

    2017-01-01

    Clinical management of malignant mesothelioma (MM) is very challenging due to marked resistance of this tumor to chemotherapy. Various mechanisms lead to a less than ideal drug concentration inside of MM cells, diminishing cytotoxicity. Consequently, single cytotoxic drugs achieve very modest response rates in MM patients, and combination regimens using standard and novel therapies have achieved only limited improvement in overall survival. Here, we demonstrate that MYC has either proliferative or pro-survival effects in MM cells during normal or stressed conditions, respectively. A MYC inhibitor 10058-F4 reduced MM cell proliferation via down regulation of cyclin D. Under serum starvation conditions, MM cells became quiescent, and the addition of MYC inhibitors triggered apoptosis in the resting MM cells. We also found that high concentrations of the PAK inhibitor PF3758309 killed MM cells, but the drug had only cytostatic effects at lower concentrations. These quiescent cells underwent apoptosis upon pharmacological inhibition of MYC. A novel MYC inhibitor KJ-Pyr-9 and a newer PAK inhibitor, FRAX597, also demonstrated marked cytotoxic cooperativity. Collectively, these findings demonstrate that targeting of MYC can sensitize MM cells and provide rationale for inhibition of MYC and PAK as a novel combinatory regimen for the treatment of this otherwise therapy-resistant, clinically incurable malignancy.

  11. Identification of transporters associated with Etoposide sensitivity of stomach cancer cell lines and methotrexate sensitivity of breast cancer cell lines by quantitative targeted absolute proteomics.

    Science.gov (United States)

    Obuchi, Wataru; Ohtsuki, Sumio; Uchida, Yasuo; Ohmine, Ken; Yamori, Takao; Terasaki, Tetsuya

    2013-02-01

    Membrane transporter proteins may influence the sensitivity of cancer cells to anticancer drugs that can be recognized as substrates. The purpose of this study was to identify proteins that play a key role in the drug sensitivity of stomach and breast cancer cell lines by measuring the absolute protein expression levels of multiple transporters and other membrane proteins and examining their correlation to drug sensitivity. Absolute protein expression levels of 90 membrane proteins were examined by quantitative targeted absolute proteomics using liquid chromatography-linked tandem mass spectrometry. Among them, 11 and 14 membrane proteins, including transporters, were present in quantifiable amounts in membrane fraction of stomach cancer and breast cancer cell lines, respectively. In stomach cancer cell lines, the protein expression level of multidrug resistance-associated protein 1 (MRP1) was inversely correlated with etoposide sensitivity. MK571, an MRP inhibitor, increased both the cell-to-medium ratio of etoposide and the etoposide sensitivity of MRP1-expressing stomach cancer cell lines. In breast cancer cell lines, the protein expression level of reduced folate carrier 1 (RFC1) was directly correlated with methotrexate (MTX) sensitivity. Initial uptake rate and steady-state cell-to-medium ratio of [(3)H]MTX were correlated with both RFC1 expression level and MTX sensitivity. These results suggest that MRP1 modulates the etoposide sensitivity of stomach cancer cell lines and RFC1 modulates the MTX sensitivity of breast cancer cell lines. Our results indicate that absolute quantification of multiple membrane proteins could be a useful strategy for identification of candidate proteins involved in drug sensitivity.

  12. Enzyme-free amplification for sensitive electrochemical detection of DNA via target-catalyzed hairpin assembly assisted current change.

    Science.gov (United States)

    Qian, Yong; Wang, Chunyan; Gao, Fenglei

    2014-12-01

    An isothermal, enzyme-free and sensitive method for electrochemical detection of DNA is proposed based on target catalyzed hairpin assembly and for signal amplification. Molecular beacon 1 (MB1) contains a ferrocene (Fc) tag, which was immobilized on the gold electrode as recognition probe to hybridize with target DNA. Then, molecular beacon 2 hybridized with the opened MB1, allowing the target to be displaced. The displaced target again triggered the next round of strand exchange reaction resulting in many Fc far away from the GE to achieve signal amplification for sensitive DNA detection. The current signal amplification strategy is relatively simple and inexpensive owing to avoid the use of any kind of enzyme or sophisticated equipment. It can achieve a sensitivity of 42 fM with a wide linear dynamic range from 10(-13) to 10(-9)M and discriminate mismatched DNA from perfect matched target DNA with a high selectivity. The proposed method showed excellent specificity, high sensitivity and low detection limit, and could be applied in analysis of real samples. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Range position and climate sensitivity: The structure of among-population demographic responses to climatic variation.

    Science.gov (United States)

    Amburgey, Staci M; Miller, David A W; Campbell Grant, Evan H; Rittenhouse, Tracy A G; Benard, Michael F; Richardson, Jonathan L; Urban, Mark C; Hughson, Ward; Brand, Adrianne B; Davis, Christopher J; Hardin, Carmen R; Paton, Peter W C; Raithel, Christopher J; Relyea, Rick A; Scott, A Floyd; Skelly, David K; Skidds, Dennis E; Smith, Charles K; Werner, Earl E

    2018-01-01

    Species' distributions will respond to climate change based on the relationship between local demographic processes and climate and how this relationship varies based on range position. A rarely tested demographic prediction is that populations at the extremes of a species' climate envelope (e.g., populations in areas with the highest mean annual temperature) will be most sensitive to local shifts in climate (i.e., warming). We tested this prediction using a dynamic species distribution model linking demographic rates to variation in temperature and precipitation for wood frogs (Lithobates sylvaticus) in North America. Using long-term monitoring data from 746 populations in 27 study areas, we determined how climatic variation affected population growth rates and how these relationships varied with respect to long-term climate. Some models supported the predicted pattern, with negative effects of extreme summer temperatures in hotter areas and positive effects on recruitment for summer water availability in drier areas. We also found evidence of interacting temperature and precipitation influencing population size, such as extreme heat having less of a negative effect in wetter areas. Other results were contrary to predictions, such as positive effects of summer water availability in wetter parts of the range and positive responses to winter warming especially in milder areas. In general, we found wood frogs were more sensitive to changes in temperature or temperature interacting with precipitation than to changes in precipitation alone. Our results suggest that sensitivity to changes in climate cannot be predicted simply by knowing locations within the species' climate envelope. Many climate processes did not affect population growth rates in the predicted direction based on range position. Processes such as species-interactions, local adaptation, and interactions with the physical landscape likely affect the responses we observed. Our work highlights the need to

  14. Range position and climate sensitivity: The structure of among-population demographic responses to climatic variation

    Science.gov (United States)

    Amburgey, Staci M.; Miller, David A. W.; Grant, Evan H. Campbell; Rittenhouse, Tracy A. G.; Benard, Michael F.; Richardson, Jonathan L.; Urban, Mark C.; Hughson, Ward; Brand, Adrianne B,; Davis, Christopher J.; Hardin, Carmen R.; Paton, Peter W. C.; Raithel, Christopher J.; Relyea, Rick A.; Scott, A. Floyd; Skelly, David K.; Skidds, Dennis E.; Smith, Charles K.; Werner, Earl E.

    2018-01-01

    Species’ distributions will respond to climate change based on the relationship between local demographic processes and climate and how this relationship varies based on range position. A rarely tested demographic prediction is that populations at the extremes of a species’ climate envelope (e.g., populations in areas with the highest mean annual temperature) will be most sensitive to local shifts in climate (i.e., warming). We tested this prediction using a dynamic species distribution model linking demographic rates to variation in temperature and precipitation for wood frogs (Lithobates sylvaticus) in North America. Using long-term monitoring data from 746 populations in 27 study areas, we determined how climatic variation affected population growth rates and how these relationships varied with respect to long-term climate. Some models supported the predicted pattern, with negative effects of extreme summer temperatures in hotter areas and positive effects on recruitment for summer water availability in drier areas. We also found evidence of interacting temperature and precipitation influencing population size, such as extreme heat having less of a negative effect in wetter areas. Other results were contrary to predictions, such as positive effects of summer water availability in wetter parts of the range and positive responses to winter warming especially in milder areas. In general, we found wood frogs were more sensitive to changes in temperature or temperature interacting with precipitation than to changes in precipitation alone. Our results suggest that sensitivity to changes in climate cannot be predicted simply by knowing locations within the species’ climate envelope. Many climate processes did not affect population growth rates in the predicted direction based on range position. Processes such as species-interactions, local adaptation, and interactions with the physical landscape likely affect the responses we observed. Our work highlights the

  15. Comparing methods of targeting obesity interventions in populations: An agent-based simulation.

    Science.gov (United States)

    Beheshti, Rahmatollah; Jalalpour, Mehdi; Glass, Thomas A

    2017-12-01

    Social networks as well as neighborhood environments have been shown to effect obesity-related behaviors including energy intake and physical activity. Accordingly, harnessing social networks to improve targeting of obesity interventions may be promising to the extent this leads to social multiplier effects and wider diffusion of intervention impact on populations. However, the literature evaluating network-based interventions has been inconsistent. Computational methods like agent-based models (ABM) provide researchers with tools to experiment in a simulated environment. We develop an ABM to compare conventional targeting methods (random selection, based on individual obesity risk, and vulnerable areas) with network-based targeting methods. We adapt a previously published and validated model of network diffusion of obesity-related behavior. We then build social networks among agents using a more realistic approach. We calibrate our model first against national-level data. Our results show that network-based targeting may lead to greater population impact. We also present a new targeting method that outperforms other methods in terms of intervention effectiveness at the population level.

  16. Ocular morbidities in a targeted high-risk urban population in Benin ...

    African Journals Online (AJOL)

    Ocular morbidities in a targeted high-risk urban population in Benin City, Edo State. RO Momoh, CU Ukponmwan, AI Osahon, MO Uhumwangho, VW Okeigbemen, OA Dawodu, AE Omoti, OT Edema, MJ Erameh, OJ Olubor, MU Olowolayeimo, JC Ezechila ...

  17. Association between high-sensitive troponin I and coronary artery calcification in a Danish general population

    DEFF Research Database (Denmark)

    Olson, Fredrik; Engborg, Jonathan; Grønhøj, Mette H.

    2016-01-01

    BACKGROUND: High-sensitive troponin I (hs-TnI) is an individual predictor of future cardiovascular disease (CVD). However, the relationship between hs-TnI and coronary artery calcification (CAC) as determined by computed tomography (CT) has not previously been investigated in a general population....... METHODS: 1173 randomized, middle-aged subjects without known CVD underwent a non-contrast cardiac-CT scan for CAC determination. Hs-TnI was detected using ARCHITECT STAT High Sensitive Troponin-I immunoassay. Total 10-year cardiovascular mortality risk was estimated using HeartScore. The relationship.......695 (p population without previously known CVD. This is a step towards understanding hs-TnI as a risk marker for CVD....

  18. Sensitivity of Anopheles gambiae population dynamics to meteo-hydrological variability: a mechanistic approach

    Directory of Open Access Journals (Sweden)

    Gilioli Gianni

    2011-10-01

    Full Text Available Abstract Background Mechanistic models play an important role in many biological disciplines, and they can effectively contribute to evaluate the spatial-temporal evolution of mosquito populations, in the light of the increasing knowledge of the crucial driving role on vector dynamics played by meteo-climatic features as well as other physical-biological characteristics of the landscape. Methods In malaria eco-epidemiology landscape components (atmosphere, water bodies, land use interact with the epidemiological system (interacting populations of vector, human, and parasite. In the background of the eco-epidemiological approach, a mosquito population model is here proposed to evaluate the sensitivity of An. gambiae s.s. population to some peculiar thermal-pluviometric scenarios. The scenarios are obtained perturbing meteorological time series data referred to four Kenyan sites (Nairobi, Nyabondo, Kibwesi, and Malindi representing four different eco-epidemiological settings. Results Simulations highlight a strong dependence of mosquito population abundance on temperature variation with well-defined site-specific patterns. The upper extreme of thermal perturbation interval (+ 3°C gives rise to an increase in adult population abundance at Nairobi (+111% and Nyabondo (+61%, and a decrease at Kibwezi (-2% and Malindi (-36%. At the lower extreme perturbation (-3°C is observed a reduction in both immature and adult mosquito population in three sites (Nairobi -74%, Nyabondo -66%, Kibwezi -39%, and an increase in Malindi (+11%. A coherent non-linear pattern of population variation emerges. The maximum rate of variation is +30% population abundance for +1°C of temperature change, but also almost null and negative values are obtained. Mosquitoes are less sensitive to rainfall and both adults and immature populations display a positive quasi-linear response pattern to rainfall variation. Conclusions The non-linear temperature-dependent response is in

  19. Biological evaluation and molecular docking of Rhein as a multi-targeted radiotherapy sensitization agent of nasopharyngeal carcinoma

    Science.gov (United States)

    Su, Zhengying; Tian, Wei; Li, Jing; Wang, Chunmiao; Pan, Zhiyu; Li, Danrong; Hou, Huaxin

    2017-11-01

    Radiation resistance of nasopharyngeal carcinoma (NPC) is a joint effect caused by complex molecular mechanisms. The development of multi-target radiotherapy sensitization agents offered a promising method for the treatment of NPC. In this work, the probability of Rhein to be a multi-target radiotherapy sensitization agent was explored through computer aid virtual screening by inverse docking study. In order to validate the accuracy of the computational results, radiotherapy sensitization of Rhein to NPC cells and its effects on the expression of target proteins were evaluated separately by CCK8 assay and Western blotting analysis. Our result demonstrated that Rhein possessed strong binding affinity with RAC1 and HSP90. No cytotoxic concentration of Rhein had radiosensitization effect on nasopharyngeal carcinoma CNE1 cells. After treatment with Rhein and 2Gy radiation, the expression of RAC1 upregulated and the expression of HSP90 down-regulated in cells. Based on the above data, Rhein is likely to become an attractive lead compound for the future design of multi-target radiotherapy sensitization agents.

  20. The effects of nongenetic memory on population level sensitivity to stress

    Science.gov (United States)

    Adams, Rhys; Nevozhay, Dmitry; van Itallie, Elizabeth; Bennett, Matthew; Balazsi, Gabor

    2011-03-01

    While gene expression is often thought of as a unidirectional determinant of cellular fitness, recent studies have shown how growth retardation due to protein expression can affect gene expression levels in single cells. We developed two yeast strains carrying a drug resistance protein under the control of different synthetic gene constructs, one of which was monostable, while the other was bistable. The gene expression of these cell populations was tuned using a molecular inducer so that their respective means and noises were identical, while their nongenetic memory properties were different. We tested the sensitivity of these two cell population distributions to the antibiotic zeocin. We found that the gene expression distributions of bistable cell populations were sensitive to stressful environments, while the gene expression distribution of monostable cells were nearly unchanged by stress. We conclude that cell populations with high nongenetic memory are more adaptable to their environment. This work was funded by the National Institutes of Health through the NIH Director's New Innovator Award Program, 1-DP2- OD006481-01.

  1. Auditory evoked potentials (AEP) methods for population-level assessment of hearing sensitivity in bottlenose dolphins

    Science.gov (United States)

    Houser, Dorian; Finneran, James

    2005-04-01

    A portable system for recording auditory evoked potentials (AEP) was developed to rapidly assess the hearing sensitivity of dolphins in air. The system utilizes a transducer embedded in a silicone suction cup to deliver amplitude modulated tones to the dolphin through the lower jaw. Frequencies tested range from 10-150 kHz and testing of both ears is completed within 90 min. AEP-determined thresholds from one subject were benchmarked against that subject's direct field behavioral audiogram to quantify variation between the two methods. To date, AEP audiograms have been obtained from over 30 bottlenose dolphins. Considerable individual variation in frequency-specific hearing sensitivity was observed. Some high-frequency hearing loss was observed in relatively young (early 20s) and old (35+ years) animals; conversely, age was not necessarily related to hearing loss as several animals greater than 40 years of age had good hearing sensitivity across the range of tested frequencies. Profound hearing loss typically occurred at higher frequencies. Decline in sensitivity was rapid in all cases and began between 50-60 kHz. Increased sample size of hearing sensitivity in dolphins suggest that the use of audiometric functions from single animals as representative of population level audiometry might be misleading.

  2. Population sensitivities of animals to chronic ionizing radiation-model predictions from mice to elephant.

    Science.gov (United States)

    Sazykina, Tatiana G

    2018-02-01

    Model predictions of population response to chronic ionizing radiation (endpoint 'morbidity') were made for 11 species of warm-blooded animals, differing in body mass and lifespan - from mice to elephant. Predictions were made also for 3 bird species (duck, pigeon, and house sparrow). Calculations were based on analytical solutions of the mathematical model, simulating a population response to low-LET ionizing radiation in an ecosystem with a limiting resource (Sazykina, Kryshev, 2016). Model parameters for different species were taken from biological and radioecological databases; allometric relationships were employed for estimating some parameter values. As a threshold of decreased health status in exposed populations ('health threshold'), a 10% reduction in self-repairing capacity of organisms was suggested, associated with a decline in ability to sustain environmental stresses. Results of the modeling demonstrate a general increase of population vulnerability to ionizing radiation in animal species of larger size and longevity. Populations of small widespread species (mice, house sparrow; body mass 20-50 g), which are characterized by intensive metabolism and short lifespan, have calculated 'health thresholds' at dose rates about 6.5-7.5 mGy day -1 . Widespread animals with body mass 200-500 g (rat, common pigeon) - demonstrate 'health threshold' values at 4-5 mGy day -1 . For populations of animals with body mass 2-5 kg (rabbit, fox, raccoon), the indicators of 10% health decrease are in the range 2-3.4 mGy day -1 . For animals with body mass 40-100 kg (wolf, sheep, wild boar), thresholds are within 0.5-0.8 mGy day -1 ; for herbivorous animals with body mass 200-300 kg (deer, horse) - 0.5-0.6 mGy day -1 . The lowest health threshold was estimated for elephant (body mass around 5000 kg) - 0.1 mGy day -1 . According to the model results, the differences in population sensitivities of warm-blooded animal species to ionizing radiation are generally

  3. Adolescent women as a key target population for community nutrition education programs in Indonesia.

    Science.gov (United States)

    Savage, Amy; Februhartanty, Judhiastuty; Worsley, Anthony

    2017-05-01

    Adolescence is a critical life-stage that sets the foundation for health in adulthood. Adolescent women are a unique population and should be targeted as such for nutrition promotion activities. Using Indonesia as a case study, this qualitative study aimed to identify existing nutrition promotion programs aimed at adolescent girls, how best to target this population and effective recommendations to inform nutrition education program design for this important group. Semi-structured interviews and questionnaires were conducted with ten key informants working in public health in Indonesia. Interview transcripts were analysed and coded to identify key themes. No existing nutrition education programs targeting adolescent women in Indonesia were identified. Several strategies apply to nutrition programs for adolescent girls: 1) nutrition promotion messages that are relevant to the lifestyles and interests of adolescent women; 2) technology-based interventions show promise, however, they need to be appropriately targeted to sub-groups; 3) school remains an important setting; and 4) early marriage is an important issue affecting nutritional status and engagement of adolescent girls. The informants recommended that: 1) more research is needed about the underlying motivations for behaviour change among adolescent women and ways to effectively implement the identified engagement strategies; 2) adolescent girls should be included in program design to improve its suitability and uptake; and 3) government budget and policy support is crucial to success. Adolescent women are an important population group and more research is required to identify the optimal forms of engagement to improve nutrition programs for them.

  4. Controlling range expansion in habitat networks by adaptively targeting source populations.

    Science.gov (United States)

    Hock, Karlo; Wolff, Nicholas H; Beeden, Roger; Hoey, Jessica; Condie, Scott A; Anthony, Kenneth R N; Possingham, Hugh P; Mumby, Peter J

    2016-08-01

    Controlling the spread of invasive species, pests, and pathogens is often logistically limited to interventions that target specific locations at specific periods. However, in complex, highly connected systems, such as marine environments connected by ocean currents, populations spread dynamically in both space and time via transient connectivity links. This results in nondeterministic future distributions of species in which local populations emerge dynamically and concurrently over a large area. The challenge, therefore, is to choose intervention locations that will maximize the effectiveness of the control efforts. We propose a novel method to manage dynamic species invasions and outbreaks that identifies the intervention locations most likely to curtail population expansion by selectively targeting local populations most likely to expand their future range. Critically, at any point during the development of the invasion or outbreak, the method identifies the local intervention that maximizes the long-term benefit across the ecosystem by restricting species' potential to spread. In so doing, the method adaptively selects the intervention targets under dynamically changing circumstances. To illustrate the effectiveness of the method we applied it to controlling the spread of crown-of-thorns starfish (Acanthaster sp.) outbreaks across Australia's Great Barrier Reef. Application of our method resulted in an 18-fold relative improvement in management outcomes compared with a random targeting of reefs in putative starfish control scenarios. Although we focused on applying the method to reducing the spread of an unwanted species, it can also be used to facilitate the spread of desirable species through connectivity networks. For example, the method could be used to select those fragments of habitat most likely to rebuild a population if they were sufficiently well protected. © 2016 Society for Conservation Biology.

  5. Estimated Prevalence of the Target Population for Brain-Computer Interface Neurotechnology in the Netherlands.

    Science.gov (United States)

    Pels, Elmar G M; Aarnoutse, Erik J; Ramsey, Nick F; Vansteensel, Mariska J

    2017-07-01

    People who suffer from paralysis have difficulties participating in society. Particularly burdensome is the locked-in syndrome (LIS). LIS patients are not able to move and speak but are cognitively healthy. They rely on assistive technology to interact with the world and may benefit from neurotechnological advances. Optimal research and design of such aids requires a well-defined target population. However, the LIS population is poorly characterized and the number of patients in this condition is unknown. Here we estimated and described the LIS patient population in the Netherlands to define the target population for assistive (neuro)technology. We asked physicians in the Netherlands if they had patients suffering from severe paralysis and communication problems in their files. Physicians responding affirmatively were asked to fill out a questionnaire on the patients' status. We sent out 9570 letters to general practitioners (GPs), who reported 83 patients. After first screening, the GPs of 46 patients received the questionnaire. Based on the responses, 26 patients were classified as having LIS. Extrapolation of these numbers resulted in a prevalence of 0.73 patients per 100 000 inhabitants. Notable results from the questionnaire were the percentage of patients with neuromuscular disease (>50%) and living at home (>70%). We revealed an etiologically diverse group of LIS patients. The functioning and needs of these patients were, however, similar and many relied on assistive technology. By characterizing the LIS population, our study may contribute to optimal development of assistive (neuro)technology.

  6. Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin.

    Directory of Open Access Journals (Sweden)

    Jennifer H E Baker

    Full Text Available Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels.

  7. Smaller Fixation Target Size Is Associated with More Stable Fixation and Less Variance in Threshold Sensitivity.

    Directory of Open Access Journals (Sweden)

    Kazunori Hirasawa

    Full Text Available The aims of this randomized observational case control study were to quantify fixation behavior during standard automated perimetry (SAP with different fixation targets and to evaluate the relationship between fixation behavior and threshold variability at each test point in healthy young participants experienced with perimetry. SAP was performed on the right eyes of 29 participants using the Octopus 900 perimeter, program 32, dynamic strategy. The fixation targets of Point, Cross, and Ring were used for SAP. Fixation behavior was recorded using a wearable eye-tracking glass. All participants underwent SAP twice with each fixation target in a random fashion. Fixation behavior was quantified by calculating the bivariate contour ellipse area (BCEA and the frequency of deviation from the fixation target. The BCEAs (deg2 of Point, Cross, and Ring targets were 1.11, 1.46, and 2.02, respectively. In all cases, BCEA increased significantly with increasing fixation target size (p < 0.05. The logarithmic value of BCEA demonstrated the same tendency (p < 0.05. A positive correlation was identified between fixation behavior and threshold variability for the Point and Cross targets (ρ = 0.413-0.534, p < 0.05. Fixation behavior increased with increasing fixation target size. Moreover, a larger fixation behavior tended to be associated with a higher threshold variability. A small fixation target is recommended during the visual field test.

  8. Qualitative methods to ensure acceptability of behavioral and social interventions to the target population.

    Science.gov (United States)

    Ayala, Guadalupe X; Elder, John P

    2011-01-01

    This paper introduces qualitative methods for assessing the acceptability of an intervention. Acceptability refers to determining how well an intervention will be received by the target population and the extent to which the new intervention or its might meet the needs of the target population an d organizational setting. In this paper, we focus on two common qualitative methods for conducting acceptability research and their advantages and disadvantages: focus groups and interviews. We provide examples from our own research and other studies to demonstrate the use of these methods for conducting acceptability research and how one might adapt this approach for oral health research. We present emerging methods for conducting acceptability research, including the use of community-based participatory research, as well as the utility of conducting acceptability research for assessing the appropriateness of measures in intervention research.

  9. Enhancing Exercise Responsiveness across Prediabetes Phenotypes by Targeting Insulin Sensitivity with Nutrition

    OpenAIRE

    Gaitan, Julian M.; Weltman, Arthur; Malin, Steven K.

    2017-01-01

    Exercise is a cornerstone therapy for chronic diseases related to multiorgan insulin resistance. However, not all individuals show the anticipated improvement in insulin sensitivity following exercise and these individuals are considered exercise resistant. Caloric restriction is an approach to enhance the effect of exercise on increasing peripheral and hepatic insulin sensitivity, as replenishing expended calories blunts these benefits. Alternatively, restricting carbohydrate intake, indepen...

  10. Performance of autofocusing schemes for single target and populated scenes behind unknown walls

    Science.gov (United States)

    Ahmad, Fauzia; Amin, Moeness G.

    2007-04-01

    The quality and reliability of through-the-wall radar imagery is governed, among other things, by the knowledge of the wall characteristics. Ambiguity in wall characteristics has a two-fold effect. It smears and blurs the image, and also shifts the imaged target positions. Higher order standardized moments have been shown to be suitable measures of the degree of smearing and blurriness of through-the-wall images. These moments can be used to tune the wall variables to achieve autofocusing. It is noted that the solution to the autofocusing problem is not unique, and there exist several assumed wall characteristics, in addition to the exact, that lead to similar focused images. In this paper, we analyze the dependency of the estimated autofocusing wall parameters on the imaged scene, specifically target density and location, in the presence of single uniform wall. We consider single and multiple target cases with different scene complexity and population. Supporting simulation results are also provided.

  11. [A population-targeted approach to connect prevention, care and welfare: visualising the trend].

    Science.gov (United States)

    Lemmens, L C; Drewes, H W; Lette, M; Baan, C A

    2017-01-01

    To map initiatives in the Netherlands using a population-targeted approach to link prevention, care and welfare. Descriptive investigation, based on conversations and structured interviews. We searched for initiatives in which providers in the areas of prevention, care and welfare together with health insurers and/or local authorities attempted to provide the 'triple aim': improving the health of the population and the quality of care, and managing costs. We found potential initiatives on the basis of interviews with key figures, project databases and congress programmes. We looked for additional information on websites and via contact persons to gather additional information to determine whether the initiative met the inclusion criteria. An initiative should link prevention, care and welfare with a minimum of three players actively pursuing a population-targeted goal through multiple interventions for a non-disease specific and district-transcending population. We described the goal, organisational structure, parties involved, activities and funding on the basis of interviews conducted in the period August-December 2015 with the managers of the initiatives included. We found 19 initiatives which met the criteria where there was experimentation with organisational forms, levels of participation, interventions and funding. It was noticeable that the interventions mostly concerned medical care. There was a lack of insight into the 'triple aim', mostly because data exchange between parties is generally difficult. There is an increasing number of initiatives that follow a population-targeted approach. Although the different parties strive to connect the three domains, they are still searching for an optimal collaboration, organisational form, data exchange and financing.

  12. Gene targeting associated with the radiation sensitivity in squamous cell carcinoma by using microarray analysis

    International Nuclear Information System (INIS)

    Nimura, Yoshinori; Kumagai, Ken; Kouzu, Yoshinao; Higo, Morihiro; Kato, Yoshikuni; Seki, Naohiko; Yamada, Shigeru

    2005-01-01

    In order to identify a set of genes related to radiation sensitivity of squamous cell carcinoma (SCC) and establish a predictive method, we compared expression profiles of radio-sensitive/radio-resistant SCC cell lines, using the in-house cDNA microarray consisting of 2,201 human genes derived from full-length enriched SCC cDNA libraries and the Human oligo chip 30 K (Hitachi Software Engineering). Surviving fractions (SF) after irradiation of heavy iron were calculated by colony formation assay. Three pairs (TE2-TE13, YES5-YES6, and HSC3-HSC2), sensitive (SF1 0.6), were selected for the microarray analysis. The results of cDNA microarray analysis showed that 20 genes in resistant cell lines and 5 genes in sensitive cell lines were up regulated more than 1.5-fold compared with sensitive and resistant cell lines respectively. Fourteen out of 25 genes were confirmed the gene expression profiles by real-time polymerase chain reaction (PCR). Twenty-seven genes identified by Human oligo chip 30 K are candidate for the markers to distinguish radio-sensitive from radio-resistant. These results suggest that the isolated 27 genes are the candidates that might be used as specific molecular markers to predict radiation sensitivity. (author)

  13. Target-triggered transcription machinery for ultra-selective and sensitive fluorescence detection of nucleoside triphosphates in one minute.

    Science.gov (United States)

    Dong, Jiantong; Wu, Tongbo; Xiao, Yu; Chen, Lu; Xu, Lei; Li, Mengyuan; Zhao, Meiping

    2018-02-15

    Nucleoside triphosphates (NTPs) play important roles in living organisms. However, no fluorescent assays are currently available to simply and rapidly detect multiple NTPs with satisfactory selectivity, sensitivity and low cost. Here we demonstrate for the first time a target-triggered in-vitro transcription machinery for ultra-selective, sensitive and instant fluorescence detection of multiple NTPs. The machinery assembles RNA polymerase, DNA template and non-target NTPs to convert the target NTP into equivalent RNA signal sequences which are monitored by the fluorescence enhancement of molecular beacon. The machinery offers excellent selectivity for the target NTP against NDP, NMP and dNTP. Notably, to accelerate the kinetics of the machinery while maintain its high specificity, we investigated the sequence of DNA templates systematically and established a set of guidelines for the design of the optimum DNA templates, which allowed for instant detection of the target NTP at fmol level in less than 1min. Furthermore, the machinery could be transformed into logic gates to study the coeffects of two NTPs in biosynthesis and real-time monitoring systems to reflect the distribution of NTP in nucleotide pools. These results provide very useful and low-cost tools for both biochemical tests and point-of-care analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Conditioned Pain Modulation and Pressure Pain Sensitivity in the Adult Danish General Population

    DEFF Research Database (Denmark)

    Skovbjerg, Sine; Jørgensen, Torben; Arendt-Nielsen, Lars

    2017-01-01

    Increased pressure pain sensitivity and impaired descending pain control have been associated with chronic pain, but knowledge on the variability in the adult general population is lacking. Pressure pain thresholds (PPTs) and descending pain control assessed using conditioned pain modulation (CPM......) were recorded in a randomly selected sample (n = 2,199, 53% female) of the Danish adult general population aged 18 to 70 years. PPTs were recorded over the tibialis anterior muscle and the upper trapezius muscle. CPM was defined as the difference between PPT assessments before and during conditioning...... was associated with lower PPTs (P CPM potency was lower in female compared with male participants (P ≤ .003), whereas no association with age was found. Higher level of education (P ≤ .05), premature withdrawal from the cold pressor test...

  15. Design and construction of a position-sensitive rotating implantation target system with beta-gamma discrimination capabilities

    CERN Document Server

    Famiano, M A; Nishimura, S; Tanihata, I

    2003-01-01

    A rotating implantation target system has been designed for use at the RIKEN projectile fragment separator. While the original design is for the study of short beta-decay lifetimes, the versatility of the device is also noted. The ability of the position-sensitive detector system to distinguish beta and gamma rays is studied, and the correlation of implantation position to beam position for purposes of particle identification is also described. Future improvements and experiments are planned and described briefly. The target detector system represents a simple, inexpensive, yet efficient way of conducting online implantation experiments where particle identification and rapid measurements are desired.

  16. An Improved Compressive Sensing and Received Signal Strength-Based Target Localization Algorithm with Unknown Target Population for Wireless Local Area Networks

    Directory of Open Access Journals (Sweden)

    Jun Yan

    2017-05-01

    Full Text Available In this paper a two-phase compressive sensing (CS and received signal strength (RSS-based target localization approach is proposed to improve position accuracy by dealing with the unknown target population and the effect of grid dimensions on position error. In the coarse localization phase, by formulating target localization as a sparse signal recovery problem, grids with recovery vector components greater than a threshold are chosen as the candidate target grids. In the fine localization phase, by partitioning each candidate grid, the target position in a grid is iteratively refined by using the minimum residual error rule and the least-squares technique. When all the candidate target grids are iteratively partitioned and the measurement matrix is updated, the recovery vector is re-estimated. Threshold-based detection is employed again to determine the target grids and hence the target population. As a consequence, both the target population and the position estimation accuracy can be significantly improved. Simulation results demonstrate that the proposed approach achieves the best accuracy among all the algorithms compared.

  17. Sensitivity of Population Size Estimation for Violating Parametric Assumptions in Log-linear Models

    Directory of Open Access Journals (Sweden)

    Gerritse Susanna C.

    2015-09-01

    Full Text Available An important quality aspect of censuses is the degree of coverage of the population. When administrative registers are available undercoverage can be estimated via capture-recapture methodology. The standard approach uses the log-linear model that relies on the assumption that being in the first register is independent of being in the second register. In models using covariates, this assumption of independence is relaxed into independence conditional on covariates. In this article we describe, in a general setting, how sensitivity analyses can be carried out to assess the robustness of the population size estimate. We make use of log-linear Poisson regression using an offset, to simulate departure from the model. This approach can be extended to the case where we have covariates observed in both registers, and to a model with covariates observed in only one register. The robustness of the population size estimate is a function of implied coverage: as implied coverage is low the robustness is low. We conclude that it is important for researchers to investigate and report the estimated robustness of their population size estimate for quality reasons. Extensions are made to log-linear modeling in case of more than two registers and the multiplier method

  18. Association between biomarkers of inflammation and insulin sensitivity index among Mongolian population

    International Nuclear Information System (INIS)

    Wang Ke; Wei Xiaolin; Bu Xiaoqing; Tang Lingyan; Zhang Yonghong; Lu Hongmin; Zhao Li

    2012-01-01

    Objective: To explore the association between the biomarkers of inflammation including C-reactive protein (CRP), soluble E-selectin (sE-selectin) and soluble inter-cellular adhesion molecule-l (sICAM-1) and insulin sensitivity index (ISI) in Mongolian population. Methods: Mongolian residents aged 20 and above were served as study subjects. Demographic characteristics and lifestyle risk factors were investigated by the questionnaire, and their body height, weight and blood pressure were measured, and blood lipids, blood glucose, insulin and inflammatory markers etc, were examined for all subjects. Multivariate logistic regression analysis were used to estimate the association between the biomarkers of inflammation and insulin sensitivity index. Results: Among the Mongolian residents, the risk of decreased ISI (ISI≤0.0130) was significantly increased (P<0.05) with increased CRP. Compared to lowest quartile of CRP and sE-selectin, odds ratio (95% confidence interval) of decreased ISI associated with highest quartile of CRP and sE-selectin were 1.324 (0.990∼1.771) and 1.986 (1.486∼2.654), respectively. However, there was no significant association between increased sICAM-1 and decreased ISI. Conclusion: Increased C-reactive protein and sE-selectin were associated with decreased ISI among Mongolian population. (authors)

  19. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT--relationship to newly identified mitochondrial pyruvate carrier proteins.

    Directory of Open Access Journals (Sweden)

    Jerry R Colca

    Full Text Available Thiazolidinedione (TZD insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44 and BRP44 Like (BRP44L, which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.

  20. Tyramide Signal Amplification for Antibody-overlay Lectin Microarray: A Strategy to Improve the Sensitivity of Targeted Glycan Profiling

    Science.gov (United States)

    Meany, Danni L.; Hackler, Laszlo; Zhang, Hui; Chan, Daniel W.

    2011-01-01

    Antibody-overlay lectin microarray (ALM) has been used for targeted glycan profiling to identify disease-related protein glycoforms. In this context, high sensitivity is desired because it allows for the identification of disease-related glycoforms that are often present at low concentration. We describe a new Tyramide Signal Amplification (TSA) for Antibody-overlay Lectin Microarray procedure for sensitive profiling of glycosylation patterns. We demonstrated that TSA increased the sensitivity of the microarray over 100 times for glycan profiling using the model protein Prostate Specific Antigen (PSA). The glycan profile of PSA enriched from LNCAP cells, obtained at a sub-nanogram level with the aid of TSA, was consistent with the previous reports. We also established the glycan profile of Prostate Specific Membrane Antigen (PSMA) using the TSA and ALM. Thus, the Tyramide Signal Amplification for Antibody-overlay Lectin Microarray is a sensitive, rapid, comprehensive, and high-throughput method for targeted glycan profiling and can potentially be used for the identification of disease-related protein glycoforms. PMID:21133419

  1. Evolutionary control: Targeted change of allele frequencies in natural populations using externally directed evolution.

    Science.gov (United States)

    Shafiey, Hassan; Gossmann, Toni I; Waxman, David

    2017-04-21

    Random processes in biology, in particular random genetic drift, often make it difficult to predict the fate of a particular mutation in a population. Using principles of theoretical population genetics, we present a form of biological control that ensures a focal allele's frequency, at a given locus, achieves a prescribed probability distribution at a given time. This control is in the form of an additional evolutionary force that acts on a population. We provide the mathematical framework that determines the additional force. Our analysis indicates that generally the additional force depends on the frequency of the focal allele, and it may also depend on the time. We argue that translating this additional force into an externally controlled process, which has the possibility of being implemented in a number of different ways corresponding to selection, migration, mutation, or a combination of these, may provide a flexible instrument for targeted change of traits of interest in natural populations. This framework may be applied, or used as an informed form of guidance, in a variety of different biological scenarios including: yield and pesticide optimisation in crop production, biofermentation, the local regulation of human-associated natural populations, such as parasitic animals, or bacterial communities in hospitals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.

    Science.gov (United States)

    Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

    2016-12-02

    Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Fabrication of thermo-sensitive complex micelles for reversible cell targeting.

    Science.gov (United States)

    Wu, Yukun; Yang, Chengling; Lai, Quanyong; Zhang, Qian; Wang, Wei; Yuan, Zhi

    2015-11-01

    To ideally solve the contradiction between enhanced cellular uptake and prolonged blood circulation, reversible targeting polymeric micelles based on the expanding and shrinking behavior of a temperature-responsive polymer were developed. The micelle contained a hydrophobic PCL core and a mixed shell consisting of poly(N-isopropylacrylamide) (PNIPAAm) and biotin-terminated poly(ethylene glycol) (Biotin-PEG), and its targeting ability could be switched on/off by temperature. The cellular uptake of the complex polymeric micelles was studied. The results from a quantitative enzyme-linked immunosorbent assay (ELISA) indicated that the surface biotin content increased by as much as 11.6-fold when the temperature increased above the lower critical solution temperature (LCST). More importantly, the ELISA confirmed that biotin-mediated targeting on the surface was reversibly switched on and off for at least five cycles. In addition, the results from quantitative flow cytometry and confocal spectroscopy indicated that the cellular uptake of the targeted micelles at temperatures above the LCST was much higher than that at temperatures below the LCST. This complex polymeric micelle with reversible targeting property could be a promising alternative for drug delivery.

  4. Incorporating uncertainty of management costs in sensitivity analyses of matrix population models.

    Science.gov (United States)

    Salomon, Yacov; McCarthy, Michael A; Taylor, Peter; Wintle, Brendan A

    2013-02-01

    The importance of accounting for economic costs when making environmental-management decisions subject to resource constraints has been increasingly recognized in recent years. In contrast, uncertainty associated with such costs has often been ignored. We developed a method, on the basis of economic theory, that accounts for the uncertainty in population-management decisions. We considered the case where, rather than taking fixed values, model parameters are random variables that represent the situation when parameters are not precisely known. Hence, the outcome is not precisely known either. Instead of maximizing the expected outcome, we maximized the probability of obtaining an outcome above a threshold of acceptability. We derived explicit analytical expressions for the optimal allocation and its associated probability, as a function of the threshold of acceptability, where the model parameters were distributed according to normal and uniform distributions. To illustrate our approach we revisited a previous study that incorporated cost-efficiency analyses in management decisions that were based on perturbation analyses of matrix population models. Incorporating derivations from this study into our framework, we extended the model to address potential uncertainties. We then applied these results to 2 case studies: management of a Koala (Phascolarctos cinereus) population and conservation of an olive ridley sea turtle (Lepidochelys olivacea) population. For low aspirations, that is, when the threshold of acceptability is relatively low, the optimal strategy was obtained by diversifying the allocation of funds. Conversely, for high aspirations, the budget was directed toward management actions with the highest potential effect on the population. The exact optimal allocation was sensitive to the choice of uncertainty model. Our results highlight the importance of accounting for uncertainty when making decisions and suggest that more effort should be placed on

  5. Allergic sensitization prevalence in a children and adolescent population of northeastern Greece region.

    Science.gov (United States)

    Katotomichelakis, Michael; Danielides, Gerasimos; Iliou, Theodoros; Anastassopoulos, George; Nikolaidis, Christos; Kirodymos, Efthimios; Giotakis, Evangelos; Constantinidis, Theodoros C

    2016-10-01

    To evaluate the prevalence of allergic sensitization in a childhood and adolescent population, to explore age- and gender-specific variations and finally to discover co-sensitivities among allergens. A two-stage cross-sectional survey among school-aged children. The two stages of the study involved enrollment of schools and then skin prick testing (SPT) within schools. A total of 675 school children were included in the study. Of those, 231 were diagnosed with allergic rhinitis (AR), according to the medical history as provided by parental-completed questionnaires and positive SPT results. The antigen panel consisted of common allergens and more specifically house dust mites-HDM (Dermatophagoides farinae and Dermatophagoides pteronyssinus), grass mix, trees (olive, cypress and pine), weeds (Parietaria spp.), cat and dog epithelium and moulds (Alternaria spp., Cladosporium spp.). The SPT sensitivity was graded according to SPT-USA Standards. The overall prevalence rate of AR was 34.22%. In total, 93 school children (40.3%) were mono- and 138 (59.7%) were poly-sensitized. Overall, the most prevalent sensitizations in decreasing order were to HDM (59.74%), to grasses (48.9%), to Alternaria (34.6%) and to olive (14.71%). There were no age- and sex-specific differences, except for Alternaria mould that showed a significant prevalence among primary school-aged children and predominance in the female gender, by contrast to grass pollen allergy that was predominant to males. A 32% of SPT-positive individuals were not aware of their allergy, with no statistically significant differences between ages. Co-sensitivities were detected for grass pollens and pine and olive trees, for Alternaria and Cladosporium moulds, for cypress and pine trees, and finally for dog and cat danders. Given data among school-aged children should be a baseline from which to monitor disease trends and is considered important for the optimal management of AR patients. Copyright © 2016 Elsevier

  6. Targeting of slug sensitizes anaplastic thyroid carcinoma SW1736 cells to doxorubicin via PUMA upregulation.

    Science.gov (United States)

    Dong, Anbing; Jiao, Xuelong; Chen, Dong; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers and often shows resistance to multimodal therapeutic approaches. It has been shown that the transcriptional repressor Slug inhibits the chemotherapeutic agent-induced apoptosis of cancer cells. We evaluated whether targeting of Slug could augment doxorubicin (DOX)-induced apoptosis of ATC cells. We also determined changes in PUMA (p53-upregulated modulator of apoptosis) expression levels to identify possible mechanisms of their combined actions. Methods SW1736 cells were transfected with Slug siRNA or/and PUMA siRNA and then exposed to DOX (0.1, 1, and 5 mM) for selected times. Scrambled siRNA was used as a control. The effects on cell viability were determined via MTT assay. Apoptosis was assessed using TUNEL assays and annexin V staining, and was confirmed by flow cytometry analyses. Slug and PUMA levels were determined using western blotting and immunofluorescence analyses. We used a subcutaneous implanted tumor model of SW1736 cells in nude mice to assess the effects of Slug silencing in combination with DOX on tumor development. Apoptosis was assessed via TUNEL assay. Results Targeting of Slug using siRNA combined with DOX led to lower cell viability than treatment with DOX alone in SW1736 cells. TUNEL and flow cytometry analyses showed that targeting of Slug enhanced DOX-induced apoptosis of SW1736 cells. In addition, targeting of Slug increased PUMA expression, and targeting of PUMA restored the chemoresistance of SW1736/Slug siRNA cells to DOX. Conclusions Knockdown of Slug enhanced the antitumor activity of DOX in SW1736 cells via induction of PUMA upregulation. Our results suggest that targeting of Slug has good potential for the development of new therapeutic strategies for ATC.

  7. Emergence of target waves in paced populations of cyclically competing species

    International Nuclear Information System (INIS)

    Jiang Luoluo; Zhou Tao; Wang Binghong; Perc, Matjaz; Huang Xin

    2009-01-01

    We investigate the emergence of target waves in a cyclic predator-prey model incorporating a periodic current of the three competing species in a small area situated at the center of a square lattice. The periodic current acts as a pacemaker, trying to impose its rhythm on the overall spatiotemporal evolution of the three species. We show that the pacemaker is able to nucleate target waves that eventually spread across the whole population, whereby three routes leading to this phenomenon can be distinguished depending on the mobility of the three species and the oscillation period of the localized current. First, target waves can emerge due to the synchronization between the periodic current and oscillations of the density of the three species on the spatial grid. The second route is similar to the first, the difference being that the synchronization sets in only intermittently. Finally, the third route toward target waves is realized when the frequency of the pacemaker is much higher than that characterizing the oscillations of the overall density of the three species. By considering the mobility and frequency of the current as variable parameters, we thus provide insights into the mechanisms of pattern formation resulting from the interplay between local and global dynamics in systems governed by cyclically competing species.

  8. Anxiety sensitivity and working memory capacity: Risk factors and targets for health behavior promotion

    NARCIS (Netherlands)

    Otto, M.W.; Eastman, A.; Lo, S.; Hearon, B.A.; Bickel, W.K.; Zvolensky, M.J.; Smits, J.A.J.; Doan, S.N.

    2016-01-01

    Understanding the nature and influence of specific risk profiles is increasingly important for health behavior promotion. The purpose of this article is to document the value of two factors - anxiety sensitivity (AS) and working memory capacity (WMC) - for enhancing risk for the initiation and/or

  9. Developing and testing ScrollQuest: A video game targeting rejection sensitivity in adolescents

    NARCIS (Netherlands)

    Tuijnman, A.; Granic, I.; Whitkin, J.; Engels, R.C.M.E.

    2017-01-01

    Depression affects a large proportion of adolescents and current interventions only have moderate effects. With the potential of video games for emotional and mental health in mind, we developed a video game for rejection sensitivity, which is a major risk factor for depression. A process of

  10. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  11. GM biofortified crops: potential effects on targeting the micronutrient intake gap in human populations.

    Science.gov (United States)

    De Steur, Hans; Mehta, Saurabh; Gellynck, Xavier; Finkelstein, Julia L

    2017-04-01

    Genetic engineering has been successfully applied to increase micronutrient content in staple crops. Nutrition evidence is key to ensure scale-up and successful implementation. Unlike conventional plant breeding efforts, research on the efficacy or effectiveness of GM biofortified crops on nutritional status in human populations is lacking. This review reports on the potential role of GM biofortified crops in closing the micronutrient gap - increasing the dietary intake of micronutrients in human populations. To date, one clinical trial in the United States reported a high bio-conversion rate of β-carotene in Golden Rice, and potential effects of GM biofortified crop consumption on dietary intake and nutritional outcomes are promising. However, further research needs to confirm the ex ante assessments in target regions. Copyright © 2017. Published by Elsevier Ltd.

  12. Prospects for immunocontraception in feral horse population control: exploring novel targets for an equine fertility vaccine.

    Science.gov (United States)

    Swegen, Aleona; Aitken, R John

    2016-06-01

    Feral horses populate vast land areas and often induce significant ecological and economic damage throughout the landscape. Non-lethal population control methods are considered favourable in light of animal welfare, social and ethical considerations; however, no single effective, safe and species-specific contraceptive agent is currently available for use in free-ranging wild and feral horses. This review explores aspects of equine reproductive physiology that may provide avenues for the development of specific and long-lasting immunocontraceptive vaccines and some of the novel strategies that may be employed to facilitate appropriate antigen discovery in future research. Potential antigen targets pertaining to spermatozoa, the ovary and oocyte, as well as the early conceptus and its associated factors, are reviewed in the context of their suitability for immunocontraceptive vaccine development.

  13. A national population study of the prevalence of multiple chemical sensitivity.

    Science.gov (United States)

    Caress, Stanley M; Steinemann, Anne C

    2004-06-01

    The authors conducted a telephone survey of 1054 randomly selected individuals within the continental United States to determine the prevalence of chemical hypersensitivity and the medical diagnosis of multiple chemical sensitivity (MCS) in the American population. The etiology and symptomatology of MCS also were investigated. Results produced a 95% confidence level and a +/-3% margin of error. The authors found that 11.2% of Americans reported an unusual hypersensitivity to common chemical products such as perfume, fresh paint, pesticides, and other petrochemical-based substances, and 2.5% reported they had been medically diagnosed with MCS. Additionally, 31.1% of those sampled reported adverse reactions to fragranced products, and 17.6% experienced breathing difficulties and other health problems when exposed to air fresheners. Although chemical hypersensitivity was more common in women, it affected individuals in all demographic groups studied.

  14. Targeting of slug sensitizes anaplastic thyroid carcinoma SW1736 cells to doxorubicin via PUMA upregulation

    OpenAIRE

    Dong, Anbing; Jiao, Xuelong; Chen, Dong; Hao, Fengyun; Zhang, Kejun

    2016-01-01

    Objective: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers and often shows resistance to multimodal therapeutic approaches. It has been shown that the transcriptional repressor Slug inhibits the chemotherapeutic agent-induced apoptosis of cancer cells. We evaluated whether targeting of Slug could augment doxorubicin (DOX)-induced apoptosis of ATC cells. We also determined changes in PUMA (p53-upregulated modulator of apoptosis) expression levels to identify poss...

  15. Versatile redox-sensitive pullulan nanoparticles for enhanced liver targeting and efficient cancer therapy.

    Science.gov (United States)

    Huang, Liping; Chaurasiya, Birendra; Wu, Dawei; Wang, Huimin; Du, Yunai; Tu, Jiasheng; Webster, Thomas J; Sun, Chunmeng

    2018-02-02

    A reversibly disulfide-crosslinked pullulan nanoparticle with folic acid (FA) decoration (FA-Pull-LA CLNPs) was fabricated for dual-targeted and reduction-responsive anti-tumoral liver drug delivery based on the specific affinity of pullulan and FA to overexpress asialoglycoprtein receptors (ASGPR) and folate receptors (FR), respectively. Paclitaxel (PTX)-loaded FA-Pull-LA nanoparticles (NPs) with satisfactory size, polydispersity index (PDI), and zeta potential exhibited much faster PTX release in the presence of 10mM glutathione (GSH) rather than physiological conditions. In vitro cellular assays confirmed the dual targetability and endosomal accumulation of FA-Pull-LA NPs. In SMMC-7721 tumor-bearing mice, FA-Pull-LA-PTX CLNPs showed the strongest anti-tumor efficiency as well as the lowest toxicity among all three groups. Conclusively, the present study implied that reversibly crosslinked FA-Pull-LA NPs with dual-targeting capacity provided a stable and intelligent platform for efficient liver cancer therapy, which should be further studied for a wide range of anti-cancer applications. Copyright © 2018. Published by Elsevier Inc.

  16. Specific isolation of disseminated cancer cells: a new method permitting sensitive detection of target molecules of diagnostic and therapeutic value.

    Science.gov (United States)

    Tveito, Siri; Maelandsmo, Gunhild M; Hoifodt, Hanne K; Rasmussen, Heidi; Fodstad, Oystein

    2007-01-01

    Molecular studies of rare cells, such as circulating cancer cells, require efficient pre-enrichment steps to obtain a pure population of target cells for further characterization. We have developed a two-step approach, starting with immunomagnetic enrichment, followed by specific isolation of individual, easily identifiable bead-rosetted target cells using a new semi-automated CellPick system. With this procedure, 1-50 live target cells can now be isolated. As a model system, we spiked a small number of tumor cells into millions of normal mononuclear cells (MNCs). Efficient isolation of pure target cells was obtained by use of the CellPick system, and the nature of isolated, bead-rosetted cells was verified by use of FISH. Single breast cancer cells were picked directly into an RNA preserving lysis buffer, reverse transcribed, and PCR amplified with two cDNA specific primer sets. With the isolated cells we consistently obtained both ubiquitously expressed and tumor cell specific PCR products. We also performed a successful mutation analysis of single cells using PCR and cycling temperature capillary electrophoresis (CTCE). This may have significant clinical implications in cancer and in other diseases, e.g. in characterizing micrometastatic cancer cells in blood and lymph nodes to help identifying patients who most likely will respond to therapies like tyrosine kinase inhibitors and compounds targeting specific mutations. By use of the CellPick system it is possible to specifically isolate bead-rosetted or otherwise labelled target cells from a heterogeneous cell population for further molecular characterization.

  17. Permanent genetic access to transiently active neurons via TRAP: targeted recombination in active populations.

    Science.gov (United States)

    Guenthner, Casey J; Miyamichi, Kazunari; Yang, Helen H; Heller, H Craig; Luo, Liqun

    2013-06-05

    Targeting genetically encoded tools for neural circuit dissection to relevant cellular populations is a major challenge in neurobiology. We developed an approach, targeted recombination in active populations (TRAP), to obtain genetic access to neurons that were activated by defined stimuli. This method utilizes mice in which the tamoxifen-dependent recombinase CreER(T2) is expressed in an activity-dependent manner from the loci of the immediate early genes Arc and Fos. Active cells that express CreER(T2) can only undergo recombination when tamoxifen is present, allowing genetic access to neurons that are active during a time window of less than 12 hr. We show that TRAP can provide selective access to neurons activated by specific somatosensory, visual, and auditory stimuli and by experience in a novel environment. When combined with tools for labeling, tracing, recording, and manipulating neurons, TRAP offers a powerful approach for understanding how the brain processes information and generates behavior. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Taxi Drivers: A Target Population for the Prevention of Transmissible Disease?

    Science.gov (United States)

    Limper, Heather M; Burns, Jennifer L; Alexander, Kenneth A

    2016-04-01

    We set out to assess the feasibility and uptake of an on-site influenza vaccination campaign targeting taxi drivers in airport taxicab lots in Chicago, Illinois. Influenza vaccine was provided by the Chicago Department of Public Health as this event aligned with ongoing efforts to provide influenza vaccinations throughout the city. Clinicians and clinic support staff were volunteers recruited from the University of Chicago Medicine and incorporated nursing staff, physicians, physician residents, and administrative support. Together, this allowed for a cost-effective approach to provide free influenza vaccines to the primarily uninsured taxi driver population. During these events, 545 taxi drivers received influenza vaccine in 2012 while 354 drivers were immunized in 2013. Nearly all drivers reported uninsured or under-insured status. The ability to use volunteers and healthcare organization's desires to meet the needs of the community, in collaboration with often under-staffed but highly dedicated local health departments have the potential to offer valuable public health services to underserved members of the community. Educational initiatives targeting vaccine hesitancy and misinformation may be necessary to improve immunization coverage among this population.

  19. National survey on sports injuries in the Netherlands: target populations for sports injury prevention programs.

    Science.gov (United States)

    Schmikli, Sandor L; Backx, Frank J G; Kemler, Helena J; van Mechelen, Willem

    2009-03-01

    To define target populations for sports injury prevention programs. A computer-assisted telephone survey on sports injuries and sports participation during 2000-2005 using a 3-month recall period. Data obtained from a representative sample of Dutch citizens. Fifty-eight thousand four hundred five Dutch citizens aged older than 3 years. Age, gender, and type of sports were used to distinguish subgroups with a substantial contribution to sports injuries. The absolute number of sports injuries, the incidence of sports injuries per 10,000 hours, the severity, and costs of sports injuries. Sports participation was associated with 1.5 million injuries per year and 10 injuries per 10,000 hours; of these, 50% had to be treated medically. Two-thirds of all medically treated sports injuries were associated with 9 sports (representing 18 subpopulations, all younger than 55 years): outdoor soccer (males 4-54 years and females 4-17 years), indoor soccer (males 18-34 years), tennis (males/females 35-54 years), volleyball (females 18-54 years), field hockey (males 18-34 years and females 4-17 years), running/jogging (males/females 35-54 years), gymnastics (males/females 4-17 years), skiing/snowboarding (males 4-17 years and females 18-34 years), and equestrian sports (females 18-34 years). These groups showed more than average injury rates and covered two-thirds of all direct and indirect costs (euro 400 million). The survey identified the most important (sports-, age-, and gender-specific) target populations for injury prevention programs in the Netherlands. Sports participants aged older than 55 years were excluded from these target groups because of their limited contribution to the total sports injury problem.

  20. Ages and stages questionnaires: adaptation to an Arabic speaking population and cultural sensitivity.

    Science.gov (United States)

    Charafeddine, Lama; Sinno, Durriyah; Ammous, Farah; Yassin, Walid; Al-Shaar, Laila; Mikati, Mohamad A

    2013-09-01

    Early detection of developmental delay is essential to initiate early intervention. The Ages and Stages Questionnaires (ASQ) correlate well with physician's assessment and have high predictive value. No such tool exists in Arabic. Translate and test the applicability and reliability of Arabic translated Ages and Stages Questionnaires (A-ASQ) in an Arabic speaking population. 733 healthy children were assessed. ASQ-II for 10 age groups (4-60 months) were translated to Arabic, back translations and cultural adaptation were performed. Test-retest reliability and internal consistency were evaluated using Pearson Correlation Coefficient (CC) and Cronbach's alpha (Cα). Mean scores per domain were compared to US normative scores using t-test. A-ASQ, after culturally relevant adaptations, was easily administered for 4-36 months age groups but not for 4-5 year old due to numerous cultural differences in the later. For the 4-36 month age groups Pearson CC ranged from 0.345 to 0.833. The internal consistency coefficients Cα scores ranged from 0.111 to 0.816. Significant differences were found in the mean domain scores of all age groups between Lebanese and US normative sample (p-value age groups. It proved to be culturally sensitive, which should be taken into consideration when adapting such tool to non-western populations. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  1. Coral population trajectories, increased disturbance and management intervention: A sensitivity analysis

    KAUST Repository

    Riegl, Bernhard

    2013-03-07

    Coral reefs distant from human population were sampled in the Red Sea and one-third showed degradation by predator outbreaks (crown-of-thorns-starfish=COTS observed in all regions in all years) or bleaching (1998, 2010). Models were built to assess future trajectories. They assumed variable coral types (slow/fast growing), disturbance frequencies (5,10,20years), mortality (equal or not), and connectivity (un/connected to un/disturbed community). Known disturbances were used to parameterize models. Present and future disturbances were estimated from remote-sensing chlorophyll and temperature data. Simulations and sensitivity analysis suggest community resilience at >20-year disturbance frequency, but degradation at higher frequency. Trajectories move from fast-grower to slow-grower dominance at intermediate disturbance frequency, then again to fast-grower dominance. A similar succession was observed in the field: Acropora to Porites to Stylophora/Pocillopora dominance on shallow reefs, and a transition from large poritids to small faviids on deep reefs. Synthesis and application: Even distant reefs are impacted by global changes. COTS impacts and bleaching were key driver of coral degradation, coral population decline could be reduced if these outbreaks and bleaching susceptibility were managed by maintaining water quality and by other interventions. Just leaving reefs alone, seems no longer a satisfactory option. 2013 The Authors. Ecology and Evolution.

  2. Prevalence of contact allergy in the general population: Sensitization to metals with a focus on nickel sulfate, the EDEN Fragrance Study Group

    NARCIS (Netherlands)

    Schuttelaar, M.-L.; Ofenloch, R.; Bruze, M.; Cazzaniga, S.; Elsner, P.; Gonçalo, M.; Naldi, L.; Svensson, Å.; Diepgen, T.

    2016-01-01

    Sensitization to metals is assessed mostly in clinical populations. Studies in the general population are scarce. Our objective was to determine the prevalence of metal sensitization in the general population and to determine risk factors for nickel sensitization. In five European countries (the

  3. Sensitivity Analysis for Assessing Effects of Tree Population Dynamics on Soil Bioturbation

    Science.gov (United States)

    Martin, Y. E.; Johnson, E. A.

    2012-12-01

    Bioturbation due to tree root throw is thought to be an important process in soil production and soil mixing. Despite progress in our understanding of root throw processes, the tree population dynamics affecting the occurrence and timing of root throw events remain much less well explained. Unfortunately, research about forest dynamics is not always undertaken from the perspective of those interested in tree death, tree topple and associated root throw. As a result, the necessary field data about tree population dynamics is often unavailable for many locations. The acquisition of such data would allow for improved interpretation of root throw observations and for incorporation within numerical models of tree root throw occurrence. The present study uses our earlier tree population dynamics model calibrated for subalpine forests in the Canadian Rockies to test the sensitivity of forest parameters within the model that determine tree death, tree topple, root throw and soil bioturbation. Crown wildfire disturbance is the primary driver of tree population dynamics, with wind throw being mainly of local importance. The recruitment and mortality of trees during multiple generations of forest determine the number of live trees on the landscape at any given time. Tree death may occur due to competition/thinning of trees between wildfire events or as a result of the wildfire itself. Unless trees die due to sudden wind throw events (as mentioned above, this is only of local significance in our study area), they remain standing for some time period after tree death and before tree topple; these trees are referred to as standing dead trees. The duration of this time window and several other factors influence if a tree breaks at its base or upheaves a relatively intact root plate with attached sediment. Our field research has also suggested that a minimum dbh is required before a root plate is large enough to upheave notable amounts of sediment. Modelling results in this study

  4. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. | Office of Cancer Genomics

    Science.gov (United States)

    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition.

  5. Mannosylated dextran nanoparticles: A pH-sensitive system engineered for immunomodulation through mannose targeting

    KAUST Repository

    Cui, Lina

    2011-05-18

    Biotherapeutic delivery is a rapidly growing field in need of new materials that are easy to modify, are biocompatible, and provide for triggered release of their encapsulated cargo. Herein, we report on a particulate system made of a polysaccharide-based pH-sensitive material that can be efficiently modified to display mannose-based ligands of cellsurface receptors. These ligands are beneficial for antigen delivery, as they enhance internalization and activation of APCs, and are thus capable of modulating immune responses. When compared to unmodified particles or particles modified with a nonspecific sugar residue used in the delivery of antigens to dendritic cells (DCs), themannosylated particles exhibited enhanced antigen presentation in the context of major histocompatibility complex (MHC) class I molecules. This represents the first demonstration of a mannosylated particulate system that enables enhancedMHC I antigen presentation by DCs in vitro. Our readily functionalized pH-sensitive material may also open new avenues in the development of optimally modulated vaccine delivery systems. © 2011 American Chemical Society.

  6. High-sensitivity C-reactive protein predicts target organ damage in Chinese patients with metabolic syndrome

    DEFF Research Database (Denmark)

    Zhao, Zhigang; Nie, Hai; He, Hongbo

    2007-01-01

    with metabolic syndrome. A total of 1082 consecutive patients of Chinese origin were screened for the presence of metabolic syndrome according to the National Cholesterol Education Program's Adult Treatment Panel III. High-sensitivity C-reactive protein and target organ damage, including cardiac hypertrophy......, carotid intima-media thickness, and renal impairment, were investigated. The median (25th and 75th percentiles) of high-sensitivity C-reactive protein in 619 patients with metabolic syndrome was 2.42 mg/L (0.75 and 3.66 mg/L) compared with 1.13 mg/L (0.51 and 2.46 mg/L) among 463 control subjects (P ...). There was a progressive increase in high-sensitivity C-reactive protein level with the number of components of the metabolic syndrome. Stratification of patients with metabolic syndrome into 3 groups according to their high-sensitivity C-reactive protein concentrations (3.0 mg/L) showed that the subjects...

  7. The contribution of common rpsL mutations in Escherichia coli to sensitivity to ribosome targeting antibiotics.

    Science.gov (United States)

    Pelchovich, Gidi; Schreiber, Rachel; Zhuravlev, Alina; Gophna, Uri

    2013-12-01

    Point mutations in the rpsL gene encoding ribosomal protein S12 can generate resistance to streptomycin, resulting in rapid emergence of resistance to this antibiotic during treatment. In this work, we demonstrate that while spontaneous rpsL mutants in Escherichia coli are resistant to streptomycin, they are more sensitive to the ribosome-targeting antibiotics chloramphenicol, tetracycline and erythromycin. Moreover, combinations of these antibiotics, even in low concentrations were enough to achieve complete growth inhibition of both wild type and rpsL mutant strains. Thus, combining ribosome-targeting drugs can be used as a new treatment strategy that may be effective against streptomycin-resistant ribosome mutants. Copyright © 2013 Elsevier GmbH. All rights reserved.

  8. MegaGTA: a sensitive and accurate metagenomic gene-targeted assembler using iterative de Bruijn graphs

    OpenAIRE

    Li, Dinghua; Huang, Yukun; Leung, Chi-Ming; Luo, Ruibang; Ting, Hing-Fung; Lam, Tak-Wah

    2017-01-01

    Background The recent release of the gene-targeted metagenomics assembler Xander has demonstrated that using the trained Hidden Markov Model (HMM) to guide the traversal of de Bruijn graph gives obvious advantage over other assembly methods. Xander, as a pilot study, indeed has a lot of room for improvement. Apart from its slow speed, Xander uses only 1 k-mer size for graph construction and whatever choice of k will compromise either sensitivity or accuracy. Xander uses a Bloom-filter represe...

  9. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

    Science.gov (United States)

    Panayotopoulou, Effrosini G; Müller, Anna-Katharina; Börries, Melanie; Busch, Hauke; Hu, Guohong; Lev, Sima

    2017-07-11

    Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

  10. pH-sensitive Au-BSA-DOX-FA nanocomposites for combined CT imaging and targeted drug delivery.

    Science.gov (United States)

    Huang, He; Yang, Da-Peng; Liu, Minghuan; Wang, Xiangsheng; Zhang, Zhiyong; Zhou, Guangdong; Liu, Wei; Cao, Yilin; Zhang, Wen Jie; Wang, Xiansong

    2017-01-01

    Albumin-based nanoparticles (NPs) as a drug delivery system have attracted much attention owing to their nontoxicity, non-immunogenicity, great stability and ability to bind to many therapeutic drugs. Herein, bovine serum albumin (BSA) was utilized as a template to prepare Au-BSA core/shell NPs. The outer layer BSA was subsequently conjugated with cis -aconityl doxorubicin (DOX) and folic acid (FA) to create Au-BSA-DOX-FA nanocomposites. A list of characterizations was undertaken to identify the successful conjugation of drug molecules and targeted agents. In vitro cytotoxicity using a cell counting kit-8 (CCK-8) assay indicated that Au-BSA NPs did not display obvious cytotoxicity to MGC-803 and GES-1 cells in the concentration range of 0-100 μg/mL, which can therefore be used as a safe drug delivery carrier. Furthermore, compared with free DOX, Au-BSA-DOX-FA nanocomposites exhibited a pH-sensitive drug release ability and superior antitumor activity in a drug concentration-dependent manner. In vivo computed tomography (CT) imaging experiments showed that Au-BSA-DOX-FA nanocomposites could be used as an efficient and durable CT contrast agent for targeted CT imaging of the folate receptor (FR) overexpressed in cancer tissues. In vivo antitumor experiments demonstrated that Au-BSA-DOX-FA nanocomposites have selective antitumor activity effects on FR-overexpressing tumors and no adverse effects on normal tissues and organs. In conclusion, the Au-BSA-DOX-FA nanocomposite exhibits selective targeting activity, X-ray attenuation activity and pH-sensitive drug release activity. Therefore, it can enhance CT imaging and improve the targeting therapeutic efficacy of FR-overexpressing gastric cancers. Our findings suggest that Au-BSA-DOX-FA nanocomposite is a novel drug delivery carrier and a promising candidate for cancer theranostic applications.

  11. pH-sensitive Au–BSA–DOX–FA nanocomposites for combined CT imaging and targeted drug delivery

    Science.gov (United States)

    Huang, He; Yang, Da-Peng; Liu, Minghuan; Wang, Xiangsheng; Zhang, Zhiyong; Zhou, Guangdong; Liu, Wei; Cao, Yilin; Zhang, Wen Jie; Wang, Xiansong

    2017-01-01

    Albumin-based nanoparticles (NPs) as a drug delivery system have attracted much attention owing to their nontoxicity, non-immunogenicity, great stability and ability to bind to many therapeutic drugs. Herein, bovine serum albumin (BSA) was utilized as a template to prepare Au–BSA core/shell NPs. The outer layer BSA was subsequently conjugated with cis-aconityl doxorubicin (DOX) and folic acid (FA) to create Au–BSA–DOX–FA nanocomposites. A list of characterizations was undertaken to identify the successful conjugation of drug molecules and targeted agents. In vitro cytotoxicity using a cell counting kit-8 (CCK-8) assay indicated that Au–BSA NPs did not display obvious cytotoxicity to MGC-803 and GES-1 cells in the concentration range of 0–100 μg/mL, which can therefore be used as a safe drug delivery carrier. Furthermore, compared with free DOX, Au–BSA–DOX–FA nanocomposites exhibited a pH-sensitive drug release ability and superior antitumor activity in a drug concentration-dependent manner. In vivo computed tomography (CT) imaging experiments showed that Au–BSA–DOX–FA nanocomposites could be used as an efficient and durable CT contrast agent for targeted CT imaging of the folate receptor (FR) overexpressed in cancer tissues. In vivo antitumor experiments demonstrated that Au–BSA–DOX–FA nanocomposites have selective antitumor activity effects on FR-overexpressing tumors and no adverse effects on normal tissues and organs. In conclusion, the Au–BSA–DOX–FA nanocomposite exhibits selective targeting activity, X-ray attenuation activity and pH-sensitive drug release activity. Therefore, it can enhance CT imaging and improve the targeting therapeutic efficacy of FR-overexpressing gastric cancers. Our findings suggest that Au–BSA–DOX–FA nanocomposite is a novel drug delivery carrier and a promising candidate for cancer theranostic applications. PMID:28435261

  12. Targeting miR-21 enhances the sensitivity of human colon cancer HT-29 cells to chemoradiotherapy in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Jun; Lei, Wan; Fu, Jian-Chun; Zhang, Ling; Li, Jun-He; Xiong, Jian-Ping, E-mail: jpxiong@medmail.com.cn

    2014-01-17

    Highlight: •MiR-21 plays a significant role in 5-FU resistance. •This role might be attributed to targeting of hMSH2 as well as TP and DPD via miR-21 targeted hMSH2. •Indirectly targeted TP and DPD to influence 5-FU chemotherapy sensitivity. -- Abstract: 5-Fluorouracil (5-FU) is a classic chemotherapeutic drug that has been widely used for colorectal cancer treatment, but colorectal cancer cells are often resistant to primary or acquired 5-FU therapy. Several studies have shown that miR-21 is significantly elevated in colorectal cancer. This suggests that this miRNA might play a role in this resistance. In this study, we investigated this possibility and the possible mechanism underlying this role. We showed that forced expression of miR-21 significantly inhibited apoptosis, enhanced cell proliferation, invasion, and colony formation ability, promoted G1/S cell cycle transition and increased the resistance of tumor cells to 5-FU and X radiation in HT-29 colon cancer cells. Furthermore, knockdown of miR-21 reversed these effects on HT-29 cells and increased the sensitivity of HT-29/5-FU to 5-FU chemotherapy. Finally, we showed that miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

  13. Ensemble-sensitivity Analysis Based Observation Targeting for Mesoscale Convection Forecasts and Factors Influencing Observation-Impact Prediction

    Science.gov (United States)

    Hill, A.; Weiss, C.; Ancell, B. C.

    2017-12-01

    The basic premise of observation targeting is that additional observations, when gathered and assimilated with a numerical weather prediction (NWP) model, will produce a more accurate forecast related to a specific phenomenon. Ensemble-sensitivity analysis (ESA; Ancell and Hakim 2007; Torn and Hakim 2008) is a tool capable of accurately estimating the proper location of targeted observations in areas that have initial model uncertainty and large error growth, as well as predicting the reduction of forecast variance due to the assimilated observation. ESA relates an ensemble of NWP model forecasts, specifically an ensemble of scalar forecast metrics, linearly to earlier model states. A thorough investigation is presented to determine how different factors of the forecast process are impacting our ability to successfully target new observations for mesoscale convection forecasts. Our primary goals for this work are to determine: (1) If targeted observations hold more positive impact over non-targeted (i.e. randomly chosen) observations; (2) If there are lead-time constraints to targeting for convection; (3) How inflation, localization, and the assimilation filter influence impact prediction and realized results; (4) If there exist differences between targeted observations at the surface versus aloft; and (5) how physics errors and nonlinearity may augment observation impacts.Ten cases of dryline-initiated convection between 2011 to 2013 are simulated within a simplified OSSE framework and presented here. Ensemble simulations are produced from a cycling system that utilizes the Weather Research and Forecasting (WRF) model v3.8.1 within the Data Assimilation Research Testbed (DART). A "truth" (nature) simulation is produced by supplying a 3-km WRF run with GFS analyses and integrating the model forward 90 hours, from the beginning of ensemble initialization through the end of the forecast. Target locations for surface and radiosonde observations are computed 6, 12, and

  14. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity.

    Science.gov (United States)

    Wang, Yiguo; Inoue, Hiroshi; Ravnskjaer, Kim; Viste, Kristin; Miller, Nina; Liu, Yi; Hedrick, Susan; Vera, Liliana; Montminy, Marc

    2010-02-16

    Under fasting conditions, increases in circulating concentrations of pancreatic glucagon maintain glucose homeostasis through induction of gluconeogenic genes by the CREB coactivator CRTC2. Hepatic CRTC2 activity is elevated in obesity, although the extent to which this cofactor contributes to attendant increases in insulin resistance is unclear. Here we show that mice with a knockout of the CRTC2 gene have decreased circulating glucose concentrations during fasting, due to attenuation of the gluconeogenic program. CRTC2 was found to stimulate hepatic gene expression in part through an N-terminal CREB binding domain that enhanced CREB occupancy over relevant promoters in response to glucagon. Deletion of sequences encoding the CREB binding domain in CRTC2 (-/-) mice lowered circulating blood glucose concentrations and improved insulin sensitivity in the context of diet-induced obesity. Our results suggest that small molecules that attenuate the CREB-CRTC2 pathway may provide therapeutic benefit to individuals with type 2 diabetes.

  15. pH-sensitive micelles for targeted drug delivery prepared using a novel membrane contactor method.

    Science.gov (United States)

    Laouini, Abdallah; Koutroumanis, Konstantinos P; Charcosset, Catherine; Georgiadou, Stella; Fessi, Hatem; Holdich, Richard G; Vladisavljević, Goran T

    2013-09-25

    A novel membrane contactor method was used to produce size-controlled poly(ethylene glycol)-b-polycaprolactone (PEG-PCL) copolymer micelles composed of diblock copolymers with different average molecular weights, Mn (9200 or 10,400 Da) and hydrophilic fractions, f (0.67 or 0.59). By injecting 570 L m(-2) h(-1) of the organic phase (a 1 mg mL(-1) solution of PEG-PCL in tetrahydrofuran) through a microengineered nickel membrane with a hexagonal pore array and 200 μm pore spacing into deionized water agitated at 700 rpm, the micelle size linearly increased from 92 nm for a 5-μm pore size to 165 nm for a 40-μm pore size. The micelle size was finely tuned by the agitation rate, transmembrane flux and aqueous to organic phase ratio. An encapsulation efficiency of 89% and a drug loading of ~75% (w/w) were achieved when a hydrophobic drug (vitamin E) was entrapped within the micelles, as determined by ultracentrifugation method. The drug-loaded micelles had a mean size of 146 ± 7 nm, a polydispersity index of 0.09 ± 0.01, and a ζ potential of -19.5 ± 0.2 mV. When drug-loaded micelles where stored for 50 h, a pH sensitive drug release was achieved and a maximum amount of vitamin E (23%) was released at the pH of 1.9. When a pH-sensitive hydrazone bond was incorporated between PEG and PCL blocks, no significant change in micelle size was observed at the same micellization conditions.

  16. Target-induced structure switching of hairpin aptamers for label-free and sensitive fluorescent detection of ATP via exonuclease-catalyzed target recycling amplification.

    Science.gov (United States)

    Xu, Yunying; Xu, Jin; Xiang, Yun; Yuan, Ruo; Chai, Yaqin

    2014-01-15

    In this work, we described the development of a new label-free, simple and sensitive fluorescent ATP sensing platform based on exonuclease III (Exo III)-catalyzed target recycling (ECTR) amplification and SYBR Green I indicator. The hairpin aptamer probes underwent conformational structure switching and re-configuration in the presence of ATP, which led to catalytic cleavage of the re-configured aptamers by Exo III to release ATP and to initiate the ECTR process. Such ECTR process resulted in the digestion of a significant number of the hairpin aptamer probes, leading to much less intercalation of SYBR Green I to the hairpin stems and drastic suppression of the fluorescence emission for sensitive ATP detection down to the low nanomolar level. Due to the highly specific affinity bindings between aptamers and ATP, the developed method exhibited excellent selectivity toward ATP against other analogous molecules. Besides, our ATP sensing approach used un-modified aptamer probes and could be performed in a "mix-and-detect" fashion in homogenous solutions. All these distinct advantages of the developed method thus made it hold great potential for the development of simple and robust sensing strategies for the detection of other small molecules. © 2013 Elsevier B.V. All rights reserved.

  17. Reproductive value, the stable stage distribution, and the sensitivity of the population growth rate to changes in vital rates

    Directory of Open Access Journals (Sweden)

    Hal Caswell

    2010-09-01

    Full Text Available The population growth rate, or intrinsic rate of increase, measures the potential rate of growth of a population with specified and fixed vital rates.The sensitivity of population growth rate to changes in the vital rates can be written in terms of the stable stage or age distribution and the reproductive value distribution. If the vital rate measures the rate of production of one type of individual by another, then the sensitivity of growth rate is proportional to the reproductive value of the destination type and the representation in the stable stage distribution of the source type. This formal relationship exists in three forms: one limited to age-classified populations, a second that applies to stage- or age-classified populations, and a third that uses matrix calculus. Each uses a different set of formal demographic techniques; together they provide a relationship that beautifully cuts across different types of demographic models.

  18. Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing: a population-based study

    Science.gov (United States)

    2014-01-01

    Background Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia. Methods We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls. Results Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls. Conclusions We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis. PMID:24956927

  19. Identifying water price and population criteria for meeting future urban water demand targets

    Science.gov (United States)

    Ashoori, Negin; Dzombak, David A.; Small, Mitchell J.

    2017-12-01

    Predictive models for urban water demand can help identify the set of factors that must be satisfied in order to meet future targets for water demand. Some of the explanatory variables used in such models, such as service area population and changing temperature and rainfall rates, are outside the immediate control of water planners and managers. Others, such as water pricing and the intensity of voluntary water conservation efforts, are subject to decisions and programs implemented by the water utility. In order to understand this relationship, a multiple regression model fit to 44 years of monthly demand data (1970-2014) for Los Angeles, California was applied to predict possible future demand through 2050 under alternative scenarios for the explanatory variables: population, price, voluntary conservation efforts, and temperature and precipitation outcomes predicted by four global climate models with two CO2 emission scenarios. Future residential water demand in Los Angeles is projected to be largely driven by price and population rather than climate change and conservation. A median projection for the year 2050 indicates that residential water demand in Los Angeles will increase by approximately 36 percent, to a level of 620 million m3 per year. The Monte Carlo simulations of the fitted model for water demand were then used to find the set of conditions in the future for which water demand is predicted to be above or below the Los Angeles Department of Water and Power 2035 goal to reduce residential water demand by 25%. Results indicate that increases in price can not ensure that the 2035 water demand target can be met when population increases. Los Angeles must rely on furthering their conservation initiatives and increasing their use of stormwater capture, recycled water, and expanding their groundwater storage. The forecasting approach developed in this study can be utilized by other cities to understand the future of water demand in water-stressed areas

  20. Radio-sensitization of WRN helicase deficient cancer cells by targeting homologous recombination pathway

    International Nuclear Information System (INIS)

    Gupta, Pooja; Saha, Bhaskar; Patro, Birija Sankar; Chattopadhyay, Subrata

    2016-01-01

    Ionizing radiation (IR) induced DNA double-strand breaks (DSBs) are primarily repaired by non-homologous end joining (NHEJ). However, it is well established that a subset DSBs which are accumulated in IR-induced G2 phase are dependent on homologous recombination (HR). DNA repair deficient tumor cells have been shown to accumulate high levels of DNA damage. Consequently, these cells become hyperdependent on DNA damage response pathways, including the CHK1-kinase-mediated HR-repair. These observations suggest that DNA repair deficient tumors should exhibit increased radio-sensitivity under HR inhibition. Genetic defects leading to functional loss of werner (WRN) protein is associated with genomic instability and increased cancer incidence. WRN function is known to be abrogated in several human cancer cells due to hypermethylation of CpGisland-promoter and transcriptional silencing of WRN gene. In the current investigation, using isogenic pairs of cell lines differing only in the WRN function, we showed that WRN-deficient cell lines were hyper-radiosensitive to CHK1 pharmacologic inhibition. Here, we found that unrepaired DSB was drastically increased in WRN-deficient cells vis-à-vis WRN-proficient cells in response to IR and CHK1 inhibitor (CHK1i). Our results revealed a marginal role of NHEJ pathway accountable for the radio-sensitivity of WRN-deficient cells. Interestingly, silencing CTIP, a HR protein required for RAD51 loading, significantly abrogated the CHK1i-mediated radiosensitivity in WRN-deficient cells. Silencing of WRN or CTIP individually led to no significant difference in the extent of DNA end resection, as required during HR pathway. Imperatively, our results revealed that WRN and CTIP together play a complementary role in executing DNA end resection during HR-mediated repair of IR induced DSBs. Altogether, our data indicated that inhibition of IR-induced HR pathway at RAD51 loading, but not at DSB end resection, make the WRN-deficient cancer cells

  1. A geranyl acetophenone targeting cysteinyl leukotriene synthesis prevents allergic airway inflammation in ovalbumin-sensitized mice

    International Nuclear Information System (INIS)

    Ismail, Norazren; Jambari, Nuzul Nurahya; Zareen, Seema; Akhtar, Mohamad Nadeem; Shaari, Khozirah; Zamri-Saad, Mohamad; Tham, Chau Ling; Sulaiman, Mohd Roslan; Lajis, Nordin Hj; Israf, Daud Ahmad

    2012-01-01

    Asthma is associated with increased pulmonary inflammation and airway hyperresponsiveness. The current use of corticosteroids in the management of asthma has recently raised issues regarding safety and lack of responsiveness in 5–10% of asthmatic individuals. The aim of the present study was to investigate the therapeutic effect of a non-steroidal small molecule that has cysteinyl leukotriene (cysLT) inhibitory activity, upon attenuation of allergic lung inflammation in an acute murine model. Mice were sensitized with ovalbumin (OVA) and treated with several intraperitoneal doses (100, 20, 2 and 0.2 mg/kg) of 2,4,6,-trihydroxy-3-geranylacetophenone (tHGA). Bronchoalveolar lavage was performed, blood and lung samples were obtained and respiratory function was measured. OVA sensitization increased pulmonary inflammation and pulmonary allergic inflammation was significantly reduced at doses of 100, 20 and 2 mg/kg with no effect at the lowest dose of 0.2 mg/kg. The beneficial effects in the lung were associated with reduced eosinophilic infiltration and reduced secretion of Th2 cytokines and cysLTs. Peripheral blood reduction of total IgE was also a prominent feature. Treatment with tHGA significantly attenuated altered airway hyperresponsiveness as measured by the enhanced pause (Penh) response to incremental doses of methacholine. These data demonstrate that tHGA, a synthetic non-steroidal small molecule, can prevent acute allergic inflammation. This proof of concept opens further avenues of research and development of tHGA as an additional option to the current armamentarium of anti-asthma therapeutics. -- Highlights: ► Safer and effective anti-asthmatic drugs are in great demand. ► tHGA is a new 5-LO/cysLT inhibitor that inhibits allergic asthma in mice. ► tHGA is a natural compound that can be synthesized. ► Doses as low as 2 mg/kg alleviate lung pathology in experimental asthma. ► tHGA is a potential drug lead for the treatment of allergic asthma.

  2. JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

    Science.gov (United States)

    McKenney, Anna Sophia; Somasundara, Amritha Varshini Hanasoge; Spitzer, Barbara; Intlekofer, Andrew M.; Ahn, Jihae; Shank, Kaitlyn; Rapaport, Franck T.; Patel, Minal A.; Papalexi, Efthymia; Shih, Alan H.; Chiu, April; Freinkman, Elizaveta; Akbay, Esra A.; Steadman, Mya; Nagaraja, Raj; Yen, Katharine; Teruya-Feldstein, Julie; Wong, Kwok-Kin; Rampal, Raajit; Thompson, Craig B.

    2018-01-01

    Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617F and mutant IDH1R132H or Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617F Idh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mut and IDH2mut mutations. Taken together, these data suggest that combined JAK and IDH inhibition may offer a therapeutic advantage in this high-risk MPN subtype. PMID:29355841

  3. Ultrasound sensitive eLiposomes containing doxorubicin for drug targeting therapy.

    Science.gov (United States)

    Lin, Chung-Yin; Javadi, Marjan; Belnap, David M; Barrow, Jeffery R; Pitt, William G

    2014-01-01

    This study describes a novel nanocarrier of emulsion liposomes (eLiposomes) composed of a perfluoropentane nanodroplet within the aqueous interior of a DPPC liposome, along with the anticancer drug doxorubicin (Dox). The eLiposome containing Dox (eLipoDox) displayed good release of Dox upon insonation with low intensity ultrasound at 20-kHz, 1.0-MHz and 3.0-MHz. More release occurs in vitro at 20-kHz than at the higher frequencies. Controlled delivery was demonstrated by applying ultrasound (US) to HeLa tumor cells in vitro. The confocal images of Dox release to cells indicate that eLipoDox is an effective carrier of chemotherapeutic agent, and releases Dox to the cell cytosol upon insonation. This novel drug delivery system promises to provide more effective US therapy and tumor treatment and has the potential to reduce the side effects of cardiotoxicity caused by Dox. In this paper, an ultrasound-sensitive doxorubicine-carrying nanoliposome delivery system is reported. Doxorubicin release as a result of ultrasound exposure is clearly demonstrated, paving the way to potential clinical applications with the aim of reducing the systemic toxicity and enhanced local delivery of this compound. © 2013.

  4. New Conotoxin SO-3 Targeting N-type Voltage-Sensitive Calcium Channels

    Directory of Open Access Journals (Sweden)

    Lei Wen

    2006-04-01

    Full Text Available Selective blockers of the N-type voltage-sensitive calcium (CaV channels are useful in the management of severe chronic pain. Here, the structure and function characteristics of a novel N-type CaV channel blocker, SO-3, are reviewed. SO-3 is a 25-amino acid conopeptide originally derived from the venom of Conus striatus, and contains the same 4-loop, 6-cysteine framework (C-C-CC-C-C as O-superfamily conotoxins. The synthetic SO-3 has high analgesic activity similar to ω-conotoxin MVIIA (MVIIA, a selective N-type CaV channel blocker approved in the USA and Europe for the alleviation of persistent pain states. In electrophysiological studies, SO-3 shows more selectivity towards the N-type CaV channels than MVIIA. The dissimilarity between SO-3 and MVIIA in the primary and tertiary structures is further discussed in an attempt to illustrate the difference in selectivity of SO-3 and MVIIA towards N-type CaV channels.

  5. Global sensitivity analysis for complex ecological models: a case study of riparian cottonwood population dynamics.

    Science.gov (United States)

    Harper, Elizabeth B; Stella, John C; Fremier, Alexander K

    2011-06-01

    Mechanism-based ecological models are a valuable tool for understanding the drivers of complex ecological systems and for making informed resource-management decisions. However, inaccurate conclusions can be drawn from models with a large degree of uncertainty around multiple parameter estimates if uncertainty is ignored. This is especially true in nonlinear systems with multiple interacting variables. We addressed these issues for a mechanism-based, demographic model of Populus fremontii (Fremont cottonwood), the dominant riparian tree species along southwestern U.S. rivers. Many cottonwood populations have declined following widespread floodplain conversion and flow regulation. As a result, accurate predictive models are needed to analyze effects of future climate change and water management decisions. To quantify effects of parameter uncertainty, we developed an analytical approach that combines global sensitivity analysis (GSA) with classification and regression trees (CART) and Random Forest, a bootstrapping CART method. We used GSA to quantify the interacting effects of the full range of uncertainty around all parameter estimates, Random Forest to rank parameters according to their total effect on model predictions, and CART to identify higher-order interactions. GSA simulations yielded a wide range of predictions, including annual germination frequency of 10-100%, annual first-year survival frequency of 0-50%, and patch occupancy of 0-100%. This variance was explained primarily by complex interactions among abiotic parameters including capillary fringe height, stage-discharge relationship, and floodplain accretion rate, which interacted with biotic factors to affect survival. Model precision was primarily influenced by well-studied parameter estimates with minimal associated uncertainty and was virtually unaffected by parameter estimates for which there are no available empirical data and thus a large degree of uncertainty. Therefore, research to improve

  6. Enhanced Sensitivity for Selected Reaction Monitoring Mass Spectrometry-based Targeted Proteomics Using a Dual Stage Electrodynamic Ion Funnel Interface*

    Science.gov (United States)

    Hossain, Mahmud; Kaleta, David T.; Robinson, Errol W.; Liu, Tao; Zhao, Rui; Page, Jason S.; Kelly, Ryan T.; Moore, Ronald J.; Tang, Keqi; Camp, David G.; Qian, Wei-Jun; Smith, Richard D.

    2011-01-01

    Selected reaction monitoring mass spectrometry (SRM-MS) is playing an increasing role in quantitative proteomics and biomarker discovery studies as a method for high throughput candidate quantification and verification. Although SRM-MS offers advantages in sensitivity and quantification compared with other MS-based techniques, current SRM technologies are still challenged by detection and quantification of low abundance proteins (e.g. present at ∼10 ng/ml or lower levels in blood plasma). Here we report enhanced detection sensitivity and reproducibility for SRM-based targeted proteomics by coupling a nanospray ionization multicapillary inlet/dual electrodynamic ion funnel interface to a commercial triple quadrupole mass spectrometer. Because of the increased efficiency in ion transmission, significant enhancements in overall signal intensities and improved limits of detection were observed with the new interface compared with the original interface for SRM measurements of tryptic peptides from proteins spiked into non-depleted mouse plasma over a range of concentrations. Overall, average SRM peak intensities were increased by ∼70-fold. The average level of detection for peptides also improved by ∼10-fold with notably improved reproducibility of peptide measurements as indicated by the reduced coefficients of variance. The ability to detect proteins ranging from 40 to 80 ng/ml within mouse plasma was demonstrated for all spiked proteins without the application of front-end immunoaffinity depletion and fractionation. This significant improvement in detection sensitivity for low abundance proteins in complex matrices is expected to enhance a broad range of SRM-MS applications including targeted protein and metabolite validation. PMID:20410378

  7. Let-7d increases ovarian cancer cell sensitivity to a genistein analog by targeting c-Myc.

    Science.gov (United States)

    Ning, Ying-Xia; Luo, Xin; Xu, Meng; Feng, Xin; Wang, Jian

    2017-09-26

    c-Myc is a key oncogenic transcription factor that participates in tumor pathogenesis. In this study, we found that levels of c-Myc mRNA and protein were higher in early ovarian cancer tissues than normal ovary samples. Increased c-Myc levels correlated positively with clinical stage I (Ia+b/Ic) in ovarian cancer patients. Patients with higher nuclear c-Myc expression had shorter overall survival times than patients with low c-Myc expression. Knocking down c-Myc sensitized ovarian cancer cells to 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), a novel synthetic genistein analogue that suppressed PI3K/AKT signaling in vitro and in vivo . Finally, c-Myc was confirmed to be a direct target of let-7d, and let-7d-induced suppression of c-Myc increased the DFOG-sensitivity of ovarian cancer cells. These results indicate that nuclear c-Myc expression is an unfavorable factor in early ovarian cancer, and that let-7d increases ovarian cancer cell sensitivity to DFOG by suppressing c-Myc and PI3K/AKT signaling.

  8. DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine.

    Directory of Open Access Journals (Sweden)

    Fang Liu

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1 is a key negative regulator of mitogen activated protein kinases (MAPKs. Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK and p38 mitogen activated protein kinase (p38 MAPK, key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.

  9. Sensitivity to TOP2 targeting chemotherapeutics is regulated by Oct1 and FILIP1L.

    Directory of Open Access Journals (Sweden)

    Huarui Lu

    Full Text Available Topoisomerase II (TOP2 targeting drugs like doxorubicin and etoposide are frontline chemotherapeutics for a wide variety of solid and hematological malignancies, including breast and ovarian adenocarcinomas, lung cancers, soft tissue sarcomas, leukemias and lymphomas. These agents cause a block in DNA replication leading to a pronounced DNA damage response and initiation of apoptotic programs. Resistance to these agents is common, however, and elucidation of the mechanisms causing resistance to therapy could shed light on strategies to reduce the frequency of ineffective treatments. To explore these mechanisms, we utilized an unbiased shRNA screen to identify genes that regulate cell death in response to doxorubicin treatment. We identified the Filamin A interacting protein 1-like (FILIP1L gene as a crucial mediator of apoptosis triggered by doxorubicin. FILIP1L shares significant similarity with bacterial SbcC, an ATPase involved in DNA repair. FILIP1L was originally described as DOC1, or "down-regulated in ovarian cancer" and has since been shown to be downregulated in a wide variety of human tumors. FILIP1L levels increase markedly through transcriptional mechanisms following treatment with doxorubicin and other TOP2 poisons, including etoposide and mitoxantrone, but not by the TOP2 catalytic inhibitors merbarone or dexrazoxane (ICRF187, or by UV irradiation. This induction requires the action of the OCT1 transcription factor, which relocalizes to the FILIP1L promoter and facilitates its expression following doxorubicin treatment. Our findings suggest that the FILIP1L expression status in tumors may influence the response to anti-TOP2 chemotherapeutics.

  10. Targeting MCL-1 sensitizes human esophageal squamous cell carcinoma cells to cisplatin-induced apoptosis.

    Science.gov (United States)

    Yu, Xinfang; Li, Wei; Xia, Zhenkun; Xie, Li; Ma, Xiaolong; Liang, Qi; Liu, Lijun; Wang, Jian; Zhou, Xinmin; Yang, Yifeng; Liu, Haidan

    2017-06-28

    Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in China and is an exceptionally drug-resistant tumor with a 5-year survival rate less than 15%. Cisplatin is the most commonly used conventional chemotherapeutic drug for the treatment of ESCC, but some patients have a poor response to cisplatin-based chemotherapy. New strategies that could enhance chemosensitivity to cisplatin are needed. We used reverse transcription-RCR (RT-PCR), immunoblot, immunohistochemical (IHC) staining, anchorage-dependent and -independent growth assays, co-immunoprecipitation (Co-IP) assay, RNA interference and in vivo tumor growth assay to study the expression of MCL-1 in ESCCs and the response of ESCC cells to cisplatin. The present study showed that MCL-1 expression was significantly increased in ESCC tissues compared to normal adjacent tissues and was associated with depth of invasion and lymph node metastasis. Knockdown of MCL-1 produced significant chemosensitization to cisplatin in association with caspase-3 activation and PARP cleavage in KYSE150 and KYSE510 cells. The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage. The current study suggests that MCL-1 contributes to the development of ESCC and is a promising therapeutic target for chemosensitization of ESCC cells to cisplatin. This might provide a scientific basis for developing effective approaches to treat the subset of ESCCs patients with MCL-1 overexpression.

  11. A system dynamics optimization framework to achieve population desired of average weight target

    Science.gov (United States)

    Abidin, Norhaslinda Zainal; Zulkepli, Jafri Haji; Zaibidi, Nerda Zura

    2017-11-01

    Obesity is becoming a serious problem in Malaysia as it has been rated as the highest among Asian countries. The aim of the paper is to propose a system dynamics (SD) optimization framework to achieve population desired weight target based on the changes in physical activity behavior and its association to weight and obesity. The system dynamics approach of stocks and flows diagram was used to quantitatively model the impact of both behavior on the population's weight and obesity trends. This work seems to bring this idea together and highlighting the interdependence of the various aspects of eating and physical activity behavior on the complex of human weight regulation system. The model was used as an experimentation vehicle to investigate the impacts of changes in physical activity on weight and prevalence of obesity implications. This framework paper provides evidence on the usefulness of SD optimization as a strategic decision making approach to assist in decision making related to obesity prevention. SD applied in this research is relatively new in Malaysia and has a high potential to apply to any feedback models that address the behavior cause to obesity.

  12. Many Mobile Health Apps Target High-Need, High-Cost Populations, But Gaps Remain.

    Science.gov (United States)

    Singh, Karandeep; Drouin, Kaitlin; Newmark, Lisa P; Lee, JaeHo; Faxvaag, Arild; Rozenblum, Ronen; Pabo, Erika A; Landman, Adam; Klinger, Elissa; Bates, David W

    2016-12-01

    With rising smartphone ownership, mobile health applications (mHealth apps) have the potential to support high-need, high-cost populations in managing their health. While the number of available mHealth apps has grown substantially, no clear strategy has emerged on how providers should evaluate and recommend such apps to patients. Key stakeholders, including medical professional societies, insurers, and policy makers, have largely avoided formally recommending apps, which forces patients to obtain recommendations from other sources. To help stakeholders overcome barriers to reviewing and recommending apps, we evaluated 137 patient-facing mHealth apps-those intended for use by patients to manage their health-that were highly rated by consumers and recommended by experts and that targeted high-need, high-cost populations. We found that there is a wide variety of apps in the marketplace but that few apps address the needs of the patients who could benefit the most. We also found that consumers' ratings were poor indications of apps' clinical utility or usability and that most apps did not respond appropriately when a user entered potentially dangerous health information. Going forward, data privacy and security will continue to be major concerns in the dissemination of mHealth apps. Project HOPE—The People-to-People Health Foundation, Inc.

  13. miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Lu-Ying; Deng, Jun; Xiang, Xiao-Jun; Zhang, Ling; Yu, Feng; Chen, Jun; Sun, Zhe; Feng, Miao; Xiong, Jian-Ping, E-mail: jpxiong@medmail.com.cn

    2015-02-06

    Highlights: • miR-320 plays a significant role in chemoresistance. • This role might be attribute to targeting FOXM1. • The Wnt/β-catenin pathway also involves in this chemotherapy sensitivity. - Abstract: miR-320 expression level is found to be down-regulated in human colon cancer. To date, however, its underlying mechanisms in the chemo-resistance remain largely unknown. In this study, we demonstrated that ectopic expression of miR-320 led to inhibit HCT-116 cell proliferation, invasion and hypersensitivity to 5-Fu and Oxaliplatin. Also, knockdown of miR-320 reversed these effects in HT-29 cells. Furthermore, we identified an oncogene, FOXM1, as a direct target of miR-320. In addition, miR-320 could inactive the activity of Wnt/β-catenin pathway. Finally, we found that miR-320 and FOXM1 protein had a negative correlation in colon cancer tissues and adjacent normal tissues. These findings implied that miR-320–FOXM1 axis may overcome chemo-resistance of colon cancer cells and provide a new therapeutic target for the treatment of colon cancer.

  14. Population genomics: laying the groundwork for genetic disease modeling and targeting.

    Science.gov (United States)

    Gulcher, J; Stefansson, K

    1998-08-01

    The family has proven the most appropriate unit with which to study Mendelian diseases. There are, however, certain limitations on the use of the family as a fundamental unit in the study of common diseases, most of which are complex genetic diseases. The groups that are most likely to yield the genetics of complex diseases are isolated populations with strong founder effects. Therefore, access to such populations is proving to be a precious resource in the work on the genetics of common diseases. The Icelandic population is an excellent population for the study of the genetics of common diseases; it is genetically homogeneous, with founder effects for many traits, and the genealogy of the entire nation is well documented back to the founding days. Furthermore, the nature of the Icelandic national health care system facilitates the assignment of phenotypes in the search for disease genes. Decode Genetics has begun to study of the genetics of 20 of the most common diseases in the Western parts of the world. The company has placed the groundwork for the construction of an encrypted database with information on the health care of the entire nation, genealogy of the entire nation, genotyping information with high density of markers on a large part of the nation (including typing for known disease genes), and resource use in the Icelandic health care system. The plan is to build the database with approval of participating individuals as well as Icelandic government and health care officials. The database will be used to model health care as viewed in the context of genetic predisposition to the development of disease. The database will also be used in the search for drug targets in complex diseases and in the solution of pharmacogenomic problems. Basing the company in Iceland directly benefits the population in terms of employment and return on investment as well as providing the health care system with an information resource which may be used in preventive medicine

  15. Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation.

    Directory of Open Access Journals (Sweden)

    Pallavi Srivastava

    Full Text Available High linear energy transfer (LET radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase is an enzyme which plays important role in the non-homologous end joining (NHEJ DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi

  16. Targeting DNA repair with PNKP inhibition sensitizes radioresistant prostate cancer cells to high LET radiation.

    Science.gov (United States)

    Srivastava, Pallavi; Sarma, Asitikantha; Chaturvedi, Chandra Mohini

    2018-01-01

    High linear energy transfer (LET) radiation or heavy ion such as carbon ion radiation is used as a method for advanced radiotherapy in the treatment of cancer. It has many advantages over the conventional photon based radiotherapy using Co-60 gamma or high energy X-rays from a Linear Accelerator. However, charged particle therapy is very costly. One way to reduce the cost as well as irradiation effects on normal cells is to reduce the dose of radiation by enhancing the radiation sensitivity through the use of a radiomodulator. PNKP (polynucleotide kinase/phosphatase) is an enzyme which plays important role in the non-homologous end joining (NHEJ) DNA repair pathway. It is expected that inhibition of PNKP activity may enhance the efficacy of the charged particle irradiation in the radioresistant prostate cancer cell line PC-3. To test this hypothesis, we investigated cellular radiosensitivity by clonogenic cell survival assay in PC-3 cells.12Carbon ion beam of62 MeVenergy (equivalent 5.16 MeV/nucleon) and with an entrance LET of 287 kev/μm was used for the present study. Apoptotic parameters such as nuclear fragmentation and caspase-3 activity were measured by DAPI staining, nuclear ladder assay and colorimetric caspase-3method. Cell cycle arrest was determined by FACS analysis. Cell death was enhanced when carbon ion irradiation is combined with PNKPi (PNKP inhibitor) to treat cells as compared to that seen for PNKPi untreated cells. A low concentration (10μM) of PNKPi effectively radiosensitized the PC-3 cells in terms of reduction of dose in achieving the same survival fraction. PC-3 cells underwent significant apoptosis and cell cycle arrest too was enhanced at G2/M phase when carbon ion irradiation was combined with PNKPi treatment. Our findings suggest that combined treatment of carbon ion irradiation and PNKP inhibition could enhance cellular radiosensitivity in a radioresistant prostate cancer cell line PC-3. The synergistic effect of PNKPi and carbon ion

  17. Sensitive targeted multiple protein quantification based on elemental detection of Quantum Dots

    Energy Technology Data Exchange (ETDEWEB)

    Montoro Bustos, Antonio R.; Garcia-Cortes, Marta [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); González-Iglesias, Hector [Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernandez-Vega, Avenida Doctores Fernández-Vega, 34, Oviedo 33012 (Spain); Ruiz Encinar, Jorge, E-mail: ruizjorge@uniovi.es [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); Costa-Fernández, José M. [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain); Coca-Prados, Miguel [Fundación de Investigación Oftalmológica, Instituto Oftalmológico Fernandez-Vega, Avenida Doctores Fernández-Vega, 34, Oviedo 33012 (Spain); Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06510 (United States); Sanz-Medel, Alfredo, E-mail: asm@uniovi.es [Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, Oviedo 33006 (Spain)

    2015-06-16

    Highlights: • Novel generic platform for multiparametric quantification of proteins. • QDs labeling and ICP-MS detection allow significant analytical signal amplification. • ICP-MS mass balances information provided an internal validation of the immunoassay. • Multiparametric determination of 5 proteins in human serum samples. • ICP-MS reduced matrix effects as compared to other conventional detection techniques. - Abstract: A generic strategy based on the use of CdSe/ZnS Quantum Dots (QDs) as elemental labels for protein quantification, using immunoassays with elemental mass spectrometry (ICP-MS), detection is presented. In this strategy, streptavidin modified QDs (QDs-SA) are bioconjugated to a biotinylated secondary antibody (b-Ab{sub 2}). After a multi-technique characterization of the synthesized generic platform (QDs-SA-b-Ab{sub 2}) it was applied to the sequential quantification of five proteins (transferrin, complement C3, apolipoprotein A1, transthyretin and apolipoprotein A4) at different concentration levels in human serum samples. It is shown how this generic strategy does only require the appropriate unlabeled primary antibody for each protein to be detected. Therefore, it introduces a way out to the need for the cumbersome and specific bioconjugation of the QDs to the corresponding specific recognition antibody for every target analyte (protein). Results obtained were validated with those obtained using UV–vis spectrophotometry and commercial ELISA Kits. As expected, ICP-MS offered one order of magnitude lower DL (0.23 fmol absolute for transferrin) than the classical spectrophotometric detection (3.2 fmol absolute). ICP-MS precision and detection limits, however turned out to be compromised by procedural blanks. The full analytical performance of the ICP-MS-based immunoassay proposed was assessed for detection of transferrin (Tf), present at the low ng mL{sup −1} range in a complex “model” synthetic matrix, where the total protein

  18. Impact of Targeted Tuberculosis Vaccination Among a Mining Population in South Africa: A Model-Based Study.

    Science.gov (United States)

    Shrestha, Sourya; Chihota, Violet; White, Richard G; Grant, Alison D; Churchyard, Gavin J; Dowdy, David W

    2017-12-15

    Optimizing the use of new tools, such as vaccines, may play a crucial role in reaching global targets for tuberculosis (TB) control. Some of the most promising candidate vaccines target adults, although high-coverage mass vaccinations may be logistically more challenging among this population than among children. Vaccine-delivery strategies that target high-risk groups or settings might yield proportionally greater impact than do those that target the general population. We developed an individual-based TB transmission model representing a hypothetical population consisting of people who worked in South African gold mines or lived in associated labor-sending communities. We simulated the implementation of a postinfection adult vaccine with 60% efficacy and a mean effect duration of 10 years. We then compared the impact of a mine-targeted vaccination strategy, in which miners were vaccinated while in the mines, with that of a community-targeted strategy, in which random individuals within the labor-sending communities were vaccinated. Mine-targeted vaccination averted an estimated 0.37 TB cases per vaccine dose compared with 0.25 for community-targeted vaccination, for a relative efficacy of 1.46 (95% range, 1.13-1.91). The added benefit of mine-targeted vaccination primarily reflected the disproportionate demographic burden of TB among the population of adult males as a whole. As novel vaccines for TB are developed, venue-based vaccine delivery that targets high-risk demographic groups may improve both vaccine feasibility and the impact on transmission. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Broad Resistance to ACCase Inhibiting Herbicides in a Ryegrass Population Is Due Only to a Cysteine to Arginine Mutation in the Target Enzyme

    Science.gov (United States)

    Kaundun, Shiv Shankhar; Hutchings, Sarah-Jane; Dale, Richard Paul; McIndoe, Eddie

    2012-01-01

    Background The design of sustainable weed management strategies requires a good understanding of the mechanisms by which weeds evolve resistance to herbicides. Here we have conducted a study on the mechanism of resistance to ACCase inhibiting herbicides in a Lolium multiflorum population (RG3) from the UK. Methodology/Principal Findings Analysis of plant phenotypes and genotypes showed that all the RG3 plants (72%) that contained the cysteine to arginine mutation at ACCase codon position 2088 were resistant to ACCase inhibiting herbicides. Whole plant dose response tests on predetermined wild and mutant 2088 genotypes from RG3 and a standard sensitive population indicated that the C2088R mutation is the only factor conferring resistance to all ten ACCase herbicides tested. The associated resistance indices ranged from 13 for clethodim to over 358 for diclofop-methyl. Clethodim, the most potent herbicide was significantly affected even when applied on small mutant plants at the peri-emergence and one leaf stages. Conclusion/Significance This study establishes the clear and unambiguous importance of the C2088R target site mutation in conferring broad resistance to ten commonly used ACCase inhibiting herbicides. It also demonstrates that low levels “creeping”, multigenic, non target site resistance, is not always selected before single gene target site resistance appears in grass weed populations subjected to herbicide selection pressure. PMID:22768118

  20. Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment

    Directory of Open Access Journals (Sweden)

    Pan C

    2018-02-01

    Full Text Available Changqie Pan,1–3,* Yuqing Liu,2,3,* Minyu Zhou,1 Wensheng Wang,4 Min Shi,1 Malcolm Xing,2,3,5 Wangjun Liao11Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China; 2Department of Mechanical Engineering, 3Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada; 4The Imaging Center, 999 Brain Hospital, Guangzhou, China; 5Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada*These authors contributed equally to this work Abstract: A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate nanoparticles with a supermagnetic core and folic acid (FA conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@IONPs] to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical (1H nuclear magnetic resonance and physical (morphology and supermagnetic characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs, and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone

  1. The impact of targeting repetitive BamHI-W sequences on the sensitivity and precision of EBV DNA quantification.

    Directory of Open Access Journals (Sweden)

    Armen Sanosyan

    Full Text Available Viral load monitoring and early Epstein-Barr virus (EBV DNA detection are essential in routine laboratory testing, especially in preemptive management of Post-transplant Lymphoproliferative Disorder. Targeting the repetitive BamHI-W sequence was shown to increase the sensitivity of EBV DNA quantification, but the variability of BamHI-W reiterations was suggested to be a source of quantification bias. We aimed to assess the extent of variability associated with BamHI-W PCR and its impact on the sensitivity of EBV DNA quantification using the 1st WHO international standard, EBV strains and clinical samples.Repetitive BamHI-W- and LMP2 single- sequences were amplified by in-house qPCRs and BXLF-1 sequence by a commercial assay (EBV R-gene™, BioMerieux. Linearity and limits of detection of in-house methods were assessed. The impact of repeated versus single target sequences on EBV DNA quantification precision was tested on B95.8 and Raji cell lines, possessing 11 and 7 copies of the BamHI-W sequence, respectively, and on clinical samples.BamHI-W qPCR demonstrated a lower limit of detection compared to LMP2 qPCR (2.33 log10 versus 3.08 log10 IU/mL; P = 0.0002. BamHI-W qPCR underestimated the EBV DNA load on Raji strain which contained fewer BamHI-W copies than the WHO standard derived from the B95.8 EBV strain (mean bias: - 0.21 log10; 95% CI, -0.54 to 0.12. Comparison of BamHI-W qPCR versus LMP2 and BXLF-1 qPCR showed an acceptable variability between EBV DNA levels in clinical samples with the mean bias being within 0.5 log10 IU/mL EBV DNA, whereas a better quantitative concordance was observed between LMP2 and BXLF-1 assays.Targeting BamHI-W resulted to a higher sensitivity compared to LMP2 but the variable reiterations of BamHI-W segment are associated with higher quantification variability. BamHI-W can be considered for clinical and therapeutic monitoring to detect an early EBV DNA and a dynamic change in viral load.

  2. The impact of targeting repetitive BamHI-W sequences on the sensitivity and precision of EBV DNA quantification.

    Science.gov (United States)

    Sanosyan, Armen; Fayd'herbe de Maudave, Alexis; Bollore, Karine; Zimmermann, Valérie; Foulongne, Vincent; Van de Perre, Philippe; Tuaillon, Edouard

    2017-01-01

    Viral load monitoring and early Epstein-Barr virus (EBV) DNA detection are essential in routine laboratory testing, especially in preemptive management of Post-transplant Lymphoproliferative Disorder. Targeting the repetitive BamHI-W sequence was shown to increase the sensitivity of EBV DNA quantification, but the variability of BamHI-W reiterations was suggested to be a source of quantification bias. We aimed to assess the extent of variability associated with BamHI-W PCR and its impact on the sensitivity of EBV DNA quantification using the 1st WHO international standard, EBV strains and clinical samples. Repetitive BamHI-W- and LMP2 single- sequences were amplified by in-house qPCRs and BXLF-1 sequence by a commercial assay (EBV R-gene™, BioMerieux). Linearity and limits of detection of in-house methods were assessed. The impact of repeated versus single target sequences on EBV DNA quantification precision was tested on B95.8 and Raji cell lines, possessing 11 and 7 copies of the BamHI-W sequence, respectively, and on clinical samples. BamHI-W qPCR demonstrated a lower limit of detection compared to LMP2 qPCR (2.33 log10 versus 3.08 log10 IU/mL; P = 0.0002). BamHI-W qPCR underestimated the EBV DNA load on Raji strain which contained fewer BamHI-W copies than the WHO standard derived from the B95.8 EBV strain (mean bias: - 0.21 log10; 95% CI, -0.54 to 0.12). Comparison of BamHI-W qPCR versus LMP2 and BXLF-1 qPCR showed an acceptable variability between EBV DNA levels in clinical samples with the mean bias being within 0.5 log10 IU/mL EBV DNA, whereas a better quantitative concordance was observed between LMP2 and BXLF-1 assays. Targeting BamHI-W resulted to a higher sensitivity compared to LMP2 but the variable reiterations of BamHI-W segment are associated with higher quantification variability. BamHI-W can be considered for clinical and therapeutic monitoring to detect an early EBV DNA and a dynamic change in viral load.

  3. MegaGTA: a sensitive and accurate metagenomic gene-targeted assembler using iterative de Bruijn graphs.

    Science.gov (United States)

    Li, Dinghua; Huang, Yukun; Leung, Chi-Ming; Luo, Ruibang; Ting, Hing-Fung; Lam, Tak-Wah

    2017-10-16

    The recent release of the gene-targeted metagenomics assembler Xander has demonstrated that using the trained Hidden Markov Model (HMM) to guide the traversal of de Bruijn graph gives obvious advantage over other assembly methods. Xander, as a pilot study, indeed has a lot of room for improvement. Apart from its slow speed, Xander uses only 1 k-mer size for graph construction and whatever choice of k will compromise either sensitivity or accuracy. Xander uses a Bloom-filter representation of de Bruijn graph to achieve a lower memory footprint. Bloom filters bring in false positives, and it is not clear how this would impact the quality of assembly. Xander does not keep track of the multiplicity of k-mers, which would have been an effective way to differentiate between erroneous k-mers and correct k-mers. In this paper, we present a new gene-targeted assembler MegaGTA, which attempts to improve Xander in different aspects. Quality-wise, it utilizes iterative de Bruijn graphs to take full advantage of multiple k-mer sizes to make the best of both sensitivity and accuracy. Computation-wise, it employs succinct de Bruijn graphs (SdBG) to achieve low memory footprint and high speed (the latter is benefited from a highly efficient parallel algorithm for constructing SdBG). Unlike Bloom filters, an SdBG is an exact representation of a de Bruijn graph. It enables MegaGTA to avoid false-positive contigs and to easily incorporate the multiplicity of k-mers for building better HMM model. We have compared MegaGTA and Xander on an HMP-defined mock metagenomic dataset, and showed that MegaGTA excelled in both sensitivity and accuracy. On a large rhizosphere soil metagenomic sample (327Gbp), MegaGTA produced 9.7-19.3% more contigs than Xander, and these contigs were assigned to 10-25% more gene references. In our experiments, MegaGTA, depending on the number of k-mers used, is two to ten times faster than Xander. MegaGTA improves on the algorithm of Xander and achieves higher

  4. Association of cytokines in individuals sensitive and insensitive to dust mites in a Brazilian population.

    Science.gov (United States)

    Caniatti, Marcela Caleffi da Costa Lima; Marchioro, Ariella Andrade; Guilherme, Ana Lúcia Falavigna; Tsuneto, Luiza Tamie

    2014-01-01

    Allergic reaction to dust mites is a relatively common condition among children, triggering cutaneous and respiratory responses that have a great impact on the health of this population. Anaphylactic hypersensitivity is characterized by an exacerbated response involving the production of regulatory cytokines responsible for stimulating the production of IgE antibodies. To investigate an association of variants in cytokine genes (IL1A-889, IL1B-511, +3962, IL1R1970, IL1RA11100, IL4RA+1902, IL12-1188, IFNG+874, TGFB1 codon 10, codon 25, TNFA-308, -238, IL2-330, +166, IL4-1098, -590, -33, IL6-174, nt565, and IL10-1082, -819, -592) between patients sensitive to dust mites and a control group. A total of 254 patients were grouped as atopic and non-atopic according to sensitivity as evaluated by the Prick Test and to cytokine genotyping by the polymerase chain reaction-sequence specific primers (PCR-SSP) method using the Cytokine Genotyping Kit. A comparison between individuals allergic to Dermatophagoides farinae, Dermatophagoides pteronyssinus, and Blomia tropicalis and a non-atopic control group showed significant differences between allele and genotype frequencies in the regulatory regions of cytokine genes, with important evidence for IL4-590 in T/C (10.2% vs. 43.1%, odd ratio [OR] = 0.15, p = 5.2 10-8, pc = 0.0000011, and 95% confidence interval [95%CI] = 0.07-0.32) and T/T genotypes (42.9% vs. 13.8%, OR = 4.69, p = 2.5 10-6, pc = 0.000055, and 95%CI = 2.42-9.09). Other associations were observed in the pro-inflammatory cytokines IL1A-889 (T/T, C, and T) and IL2-330 (G/T and T/T) and the anti-inflammatory cytokines IL4RA+1902 (A and G), IL4-590 (T/C, T/T, C, and T), and IL10-592 (A/A, C/A, A, and C). Our results suggest a possible association between single nucleotide polymorphisms (SNPs) in cytokine genes and hypersensitivity to dust mites.

  5. pH-sensitive Au–BSA–DOX–FA nanocomposites for combined CT imaging and targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Huang H

    2017-04-01

    Full Text Available He Huang,1 Da-Peng Yang,2 Minghuan Liu,2 Xiangsheng Wang,1 Zhiyong Zhang,1 Guangdong Zhou,1 Wei Liu,1 Yilin Cao,1 Wen Jie Zhang,1 Xiansong Wang1 1Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, National Tissue Engineering Center of China, Shanghai, 2College of Chemical Engineering and Materials Science, Quanzhou Normal University, Quanzhou, People’s Republic of China Abstract: Albumin-based nanoparticles (NPs as a drug delivery system have attracted much attention owing to their nontoxicity, non-immunogenicity, great stability and ability to bind to many therapeutic drugs. Herein, bovine serum albumin (BSA was utilized as a template to prepare Au–BSA core/shell NPs. The outer layer BSA was subsequently conjugated with cis-aconityl doxorubicin (DOX and folic acid (FA to create Au–BSA–DOX–FA nanocomposites. A list of characterizations was undertaken to identify the successful conjugation of drug molecules and targeted agents. In vitro cytotoxicity using a cell counting kit-8 (CCK-8 assay indicated that Au–BSA NPs did not display obvious cytotoxicity to MGC-803 and GES-1 cells in the concentration range of 0–100 µg/mL, which can therefore be used as a safe drug delivery carrier. Furthermore, compared with free DOX, Au–BSA–DOX–FA nanocomposites exhibited a pH-sensitive drug release ability and superior antitumor activity in a drug concentration-dependent manner. In vivo computed tomography (CT imaging experiments showed that Au–BSA–DOX–FA nanocomposites could be used as an efficient and durable CT contrast agent for targeted CT imaging of the folate receptor (FR overexpressed in cancer tissues. In vivo antitumor experiments demonstrated that Au–BSA–DOX–FA nanocomposites have selective antitumor activity effects on FR-overexpressing tumors and no adverse effects on normal tissues and

  6. Prevalence and sensitization of atopic allergy and coeliac disease in the Northern Sweden Population Health Study

    Directory of Open Access Journals (Sweden)

    Stefan Enroth

    2013-08-01

    Full Text Available Background. Atopic allergy is effected by a number of environmental exposures, such as dry air and time spent outdoors, but there are few estimates of the prevalence in populations from sub-arctic areas. Objective. To determine the prevalence and severity of symptoms of food, inhalation and skin-related allergens and coeliac disease (CD in the sub-arctic region of Sweden. To study the correlation between self-reported allergy and allergy test results. To estimate the heritability of these estimates. Study design. The study was conducted in Karesuando and Soppero in Northern Sweden as part of the Northern Sweden Population Health Study (n=1,068. We used a questionnaire for self-reported allergy and CD status and measured inhalation-related allergens using Phadiatop, food-related allergens using the F×5 assay and IgA and IgG antibodies against tissue transglutaminase (anti-tTG to indicate prevalence of CD. Results. The prevalence of self-reported allergy was very high, with 42.3% reporting mild to severe allergy. Inhalation-related allergy was reported in 26.7%, food-related allergy in 24.9% and skin-related allergy in 2.4% of the participants. Of inhalation-related allergy, 11.0% reported reactions against fur and 14.6% against pollen/grass. Among food-related reactions, 14.9% reported milk (protein and lactose as the cause. The IgE measurements showed that 18.4% had elevated values for inhalation allergens and 11.7% for food allergens. Self-reported allergies and symptoms were positively correlated (p<0.01 with age- and sex-corrected inhalation allergens. Allergy prevalence was inversely correlated with age and number of hours spent outdoors. High levels of IgA and IgG anti-tTG antibodies, CD-related allergens, were found in 1.4 and 0.6% of participants, respectively. All allergens were found to be significantly (p<3e–10 heritable, with estimated heritabilities ranging from 0.34 (F×5 to 0.65 (IgA. Conclusions. Self-reported allergy

  7. Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment.

    Science.gov (United States)

    Pan, Changqie; Liu, Yuqing; Zhou, Minyu; Wang, Wensheng; Shi, Min; Xing, Malcolm; Liao, Wangjun

    2018-01-01

    A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical ( 1 H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

  8. Budesonide loaded nanoparticles with pH-sensitive coating for improved mucosal targeting in mouse models of inflammatory bowel diseases.

    Science.gov (United States)

    Ali, H; Weigmann, B; Neurath, M F; Collnot, E M; Windbergs, M; Lehr, C-M

    2014-06-10

    The purpose of this study was to investigate the therapeutic potential of budesonide loaded nanocarriers for the treatment of inflammatory bowel disease (IBD). First, budesonide was encapsulated in poly(lactic-co-glycolic) acid (PLGA) nanoparticles by an oil in water (O/W) emulsion technique. A second batch of the same nanoparticles was additionally coated with a pH-sensitive methyl-methacrylate-copolymer. The particle sizes of the plain and the coated PLGA were 200±10.1nm and ~240±14.7nm, respectively. As could be shown in vitro, the pH-sensitive coating prevented premature drug release at acidic pH and only releases the drug at neutral to slightly alkaline pH. The efficacy of both coated and plain nanoparticle formulations was assessed in different acute and chronic colitis mouse models, also in comparison to an aqueous solution of the drug. The dose was always the same (0.168mg/kg). It was found that delivery by coated PLGA nanoparticles alleviated the induced colitis significantly better than by plain PLGA particles, which was already more effective than treatment with the same dose of the free drug. These data further corroborate the potential of polymeric nanocarriers for targeted drug delivery to the inflamed intestinal mucosa, and that this concept can still be further improved regarding the oral route of administration by implementing pH-dependent drug release characteristics. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Structure-based, targeted deglycosylation of HIV-1 gp120 and effects on neutralization sensitivity and antibody recognition

    International Nuclear Information System (INIS)

    Koch, Markus; Pancera, Marie; Kwong, Peter D.; Kolchinsky, Peter; Grundner, Christoph; Wang Liping; Hendrickson, Wayne A.; Sodroski, Joseph; Wyatt, Richard

    2003-01-01

    The human immunodeficiency virus (HIV-1) exterior envelope glycoprotein, gp120, mediates receptor binding and is the major target for neutralizing antibodies. Primary HIV-1 isolates are characteristically more resistant to broadly neutralizing antibodies, although the structural basis for this resistance remains obscure. Most broadly neutralizing antibodies are directed against functionally conserved gp120 regions involved in binding to either the primary virus receptor, CD4, or the viral coreceptor molecules that normally function as chemokine receptors. These antibodies are known as CD4 binding site (CD4BS) and CD4-induced (CD4i) antibodies, respectively. Inspection of the gp120 crystal structure reveals that although the receptor-binding regions lack glycosylation, sugar moieties lie proximal to both receptor-binding sites on gp120 and thus in proximity to both the CD4BS and the CD4i epitopes. In this study, guided by the X-ray crystal structure of gp120, we deleted four N-linked glycosylation sites that flank the receptor-binding regions. We examined the effects of selected changes on the sensitivity of two prototypic HIV-1 primary isolates to neutralization by antibodies. Surprisingly, removal of a single N-linked glycosylation site at the base of the gp120 third variable region (V3 loop) increased the sensitivity of the primary viruses to neutralization by CD4BS antibodies. Envelope glycoprotein oligomers on the cell surface derived from the V3 glycan-deficient virus were better recognized by a CD4BS antibody and a V3 loop antibody than were the wild-type glycoproteins. Absence of all four glycosylation sites rendered a primary isolate sensitive to CD4i antibody-mediated neutralization. Thus, carbohydrates that flank receptor-binding regions on gp120 protect primary HIV-1 isolates from antibody-mediated neutralization

  10. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

    Science.gov (United States)

    Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

    2016-01-01

    Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations. PMID:27806319

  11. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin.

    Science.gov (United States)

    Chisholm, Cristine L; Wang, Haitao; Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

    2016-12-20

    Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations.

  12. The Intercultural Sensitivity of Chilean Teachers Serving an Immigrant Population in Schools

    Directory of Open Access Journals (Sweden)

    Karla Morales

    2017-01-01

    Full Text Available The objective of this article is to evaluate the intercultural sensitivity of teachers working in culturally diverse classrooms, and to analyse differences in intercultural sensitivity based on the gender, age, training (advanced training courses, and intercultural experience of the teachers. A quantitative approach with a comparative descriptive design was chosen. The Intercultural Sensitivity Scale was used, composed of 24 statements, which were responded to by 50 teachers. The results show that teachers possess moderate intercultural sensitivity and that the highest rated competencies are trust and attention to communication.

  13. Design and evaluation of novel pH-sensitive ureido-conjugated chitosan/TPP nanoparticles targeted to Helicobacter pylori.

    Science.gov (United States)

    Jing, Zi-Wei; Jia, Yi-Yang; Wan, Ning; Luo, Min; Huan, Meng-Lei; Kang, Tai-Bin; Zhou, Si-Yuan; Zhang, Bang-Le

    2016-04-01

    The covalently modified ureido-conjugated chitosan/TPP multifunctional nanoparticles have been developed as targeted nanomedicine delivery system for eradication of Helicobacter pylori. H. pylori can specifically express the urea transport protein on its membrane to transport urea into cytoplasm for urease to produce ammonia, which protects the bacterium in the acid milieu of stomach. The clinical applicability of topical antimicrobial agent is needed to eradicate H. pylori in the infected fundal area. In this study, we designed and synthesized two ureido-conjugated chitosan derivatives UCCs-1 and UCCs-2 for preparation of multifunctional nanoparticles. The process was optimized in order to prepare UCCs/TPP nanoparticles for encapsulation of amoxicillin. The results showed that the amoxicillin-UCCs/TPP nanoparticles exhibited favorable pH-sensitive characteristics, which could procrastinate the release of amoxicillin at gastric acids and enable the drug to deliver and target to H. pylori at its survival region effectively. Compared with unmodified amoxicillin-chitosan/TPP nanoparticles, a more specific and effective H. pylori growth inhibition was observed for amoxicillin-UCCs/TPP nanoparticles. Drug uptake analysis tested by flow cytometry and confocal laser scanning microscopy verified that the uptake of FITC-UCCs-2/TPP nanoparticles was associated with urea transport protein on the membrane of H. pylori and reduced with the addition of urea as competitive transport substrate. These findings suggest that the multifunctional amoxicillin-loaded nanoparticles have great potential for effective therapy of H. pylori infection. They may also serve as pharmacologically effective nanocarriers for oral targeted delivery of other therapeutic drugs to treat H. pylori. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Methodological approaches to planar and volumetric scintigraphic imaging of small volume targets with high spatial resolution and sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Mejia, J.; Galvis-Alonso, O.Y. [Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil). Faculdade de Medicina. Dept. de Biologia Molecular], e-mail: mejia_famerp@yahoo.com.br; Braga, J. [Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil). Div. de Astrofisica; Correa, R. [Instituto Nacional de Pesquisas Espaciais (INPE), Sao Jose dos Campos, SP (Brazil). Div. de Ciencia Espacial e Atmosferica; Leite, J.P. [Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil). Dept. de Neurologia, Psiquiatria e Psicologia Medica; Simoes, M.V. [Faculdade de Medicina de Sao Jose do Rio Preto (FAMERP), SP (Brazil). Dept. de Clinica Medica

    2009-08-15

    Single-photon emission computed tomography (SPECT) is a non-invasive imaging technique, which provides information reporting the functional states of tissues. SPECT imaging has been used as a diagnostic tool in several human disorders and can be used in animal models of diseases for physiopathological, genomic and drug discovery studies. However, most of the experimental models used in research involve rodents, which are at least one order of magnitude smaller in linear dimensions than man. Consequently, images of targets obtained with conventional gamma-cameras and collimators have poor spatial resolution and statistical quality. We review the methodological approaches developed in recent years in order to obtain images of small targets with good spatial resolution and sensitivity. Multi pinhole, coded mask- and slit-based collimators are presented as alternative approaches to improve image quality. In combination with appropriate decoding algorithms, these collimators permit a significant reduction of the time needed to register the projections used to make 3-D representations of the volumetric distribution of target's radiotracers. Simultaneously, they can be used to minimize artifacts and blurring arising when single pinhole collimators are used. Representation images are presented, which illustrate the use of these collimators. We also comment on the use of coded masks to attain tomographic resolution with a single projection, as discussed by some investigators since their introduction to obtain near-field images. We conclude this review by showing that the use of appropriate hardware and software tools adapted to conventional gamma-cameras can be of great help in obtaining relevant functional information in experiments using small animals. (author)

  15. Methodological approaches to planar and volumetric scintigraphic imaging of small volume targets with high spatial resolution and sensitivity

    International Nuclear Information System (INIS)

    Mejia, J.; Galvis-Alonso, O.Y.; Braga, J.; Correa, R.; Leite, J.P.; Simoes, M.V.

    2009-01-01

    Single-photon emission computed tomography (SPECT) is a non-invasive imaging technique, which provides information reporting the functional states of tissues. SPECT imaging has been used as a diagnostic tool in several human disorders and can be used in animal models of diseases for physiopathological, genomic and drug discovery studies. However, most of the experimental models used in research involve rodents, which are at least one order of magnitude smaller in linear dimensions than man. Consequently, images of targets obtained with conventional gamma-cameras and collimators have poor spatial resolution and statistical quality. We review the methodological approaches developed in recent years in order to obtain images of small targets with good spatial resolution and sensitivity. Multi pinhole, coded mask- and slit-based collimators are presented as alternative approaches to improve image quality. In combination with appropriate decoding algorithms, these collimators permit a significant reduction of the time needed to register the projections used to make 3-D representations of the volumetric distribution of target's radiotracers. Simultaneously, they can be used to minimize artifacts and blurring arising when single pinhole collimators are used. Representation images are presented, which illustrate the use of these collimators. We also comment on the use of coded masks to attain tomographic resolution with a single projection, as discussed by some investigators since their introduction to obtain near-field images. We conclude this review by showing that the use of appropriate hardware and software tools adapted to conventional gamma-cameras can be of great help in obtaining relevant functional information in experiments using small animals. (author)

  16. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability.

    Science.gov (United States)

    Harford-Wright, Elizabeth; Bidère, Nicolas; Gavard, Julie

    2016-10-11

    Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM.

  17. Microbial population index and community structure in saline-alkaline soil using gene targeted metagenomics.

    Science.gov (United States)

    Keshri, Jitendra; Mishra, Avinash; Jha, Bhavanath

    2013-03-30

    Population indices of bacteria and archaea were investigated from saline-alkaline soil and a possible microbe-environment pattern was established using gene targeted metagenomics. Clone libraries were constructed using 16S rRNA and functional gene(s) involved in carbon fixation (cbbL), nitrogen fixation (nifH), ammonia oxidation (amoA) and sulfur metabolism (apsA). Molecular phylogeny revealed the dominance of Actinobacteria, Firmicutes and Proteobacteria along with archaeal members of Halobacteraceae. The library consisted of novel bacterial (20%) and archaeal (38%) genera showing ≤95% similarity to previously retrieved sequences. Phylogenetic analysis indicated ability of inhabitant to survive in stress condition. The 16S rRNA gene libraries contained novel gene sequences and were distantly homologous with cultured bacteria. Functional gene libraries were found unique and most of the clones were distantly related to Proteobacteria, while clones of nifH gene library also showed homology with Cyanobacteria and Firmicutes. Quantitative real-time PCR exhibited that bacterial abundance was two orders of magnitude higher than archaeal. The gene(s) quantification indicated the size of the functional guilds harboring relevant key genes. The study provides insights on microbial ecology and different metabolic interactions occurring in saline-alkaline soil, possessing phylogenetically diverse groups of bacteria and archaea, which may be explored further for gene cataloging and metabolic profiling. Copyright © 2012 Elsevier GmbH. All rights reserved.

  18. Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

    Directory of Open Access Journals (Sweden)

    Gao W

    2017-02-01

    Full Text Available Wei Gao,1 Guihua Ye,1 Xiaochuan Duan,1 Xiaoying Yang,1 Victor C Yang1,2 1Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics, School of Pharmacy, Tianjin Medical University, Tianjin, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA Abstract: The emergence of drug resistance is partially associated with overproduction of transferrin receptor (TfR. To overcome multidrug resistance (MDR and achieve tumor target delivery, we designed a novel biodegradable pH-sensitive micellar system modified with HAIYPRH, a TfR ligand (7pep. First, the polymers poly(l-histidine-coupled polyethylene glycol-2000 (PHIS-PEG2000 and 7pep-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (7pep-DSPE-PEG2000 were synthesized, and the mixed micelles were prepared by blending of PHIS-PEG2000 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG2000 or 7pep-DSPE-PEG2000 (7-pep HD micelles. The micelles exhibited good size uniformity, high encapsulation efficiency, and a low critical micelle concentration. By changing the polymer ratio in the micellar formulation, the pH response range was specially tailored to pH ~6.0. When loaded with antitumor drug doxorubicin (DOX, the micelle showed an acid pH-triggering drug release profile. The cellular uptake and cytotoxicity study demonstrated that 7-pep HD micelles could significantly enhance the intracellular level and antitumor efficacy of DOX in multidrug-resistant cells (MCF-7/Adr, which attributed to the synergistic effect of poly(l-histidine-triggered endolysosom escape and TfR-mediated endocytosis. Most importantly, the in vivo imaging study confirmed the targetability of 7-pep HD micelles to MDR tumor. These findings indicated that 7-pep HD micelles would be a promising drug delivery system in the treatment of drug

  19. A mitochondrial-targeted antioxidant improves myofilament Ca2+ sensitivity during prolonged low frequency force depression at low PO2.

    Science.gov (United States)

    Gandra, Paulo G; Shiah, Amy A; Nogueira, Leonardo; Hogan, Michael C

    2018-03-15

    Skeletal muscle contractile activity is associated with an enhanced reactive oxygen species (ROS) generation. At very low PO2, ROS generation by mitochondria can be elevated in intact cells. An elevated intracellular oxidant activity may affect muscle force development and recovery from fatigue. We treated intact single muscle fibres with a mitochondrial antioxidant and stimulated the fibres to contract at a low extracellular PO2 that is similar to the intracellular PO2 that is observed during moderate to intense exercise in vivo. The mitochondrial antioxidant prevented a sustained decrease in the myofibrillar Ca 2+ sensitivity and improved muscle submaximal force development after fatigue at low extracellular PO2. Skeletal muscle can develop a prolonged low frequency-stimulation force depression (PLFFD) following fatigue-inducing contractions. Increased levels of reactive oxygen species (ROS) have been implicated in the development of PLFFD. During exercise the skeletal muscle intracellular PO2 decreases to relatively low levels, and can be further decreased when there is an impairment in O 2 diffusion or availability, such as in certain chronic diseases and during exercise at high altitude. Since ROS generation by mitochondria is elevated at very low PO2 in cells, we tested the hypothesis that treatment of muscle fibres with a mitochondrial-targeted antioxidant at a very low, near hypoxic, PO2 can attenuate PLFFD. We treated intact single fibres from mice with the mitochondrial-specific antioxidant SS31, and measured force development and intracellular [Ca 2+ ] 30 min after fatigue at an extracellular PO2 of ∼5 Torr. After 30 min following the end of the fatiguing contractions, fibres treated with SS31 showed significantly less impairment in force development compared to untreated fibres at submaximal frequencies of stimulation. The cytosolic peak [Ca 2+ ] transients (peak [Ca 2+ ] c ) were equally decreased in both groups compared to pre-fatigue values. The

  20. [Sensitization to three house dust mites in a children allergic population of cuba].

    Science.gov (United States)

    Reyes-Zamora, Mary Carmen; Labrada-Rosado, Alexis; Mateo-Morejón, Maytee; López-Chacón, Alejandro

    2012-01-01

    Allergic diseases constitute a worldwide health problem and mites are among the main etiological agents. To characterize the sensitization to the mites Dermatophagoides pteronyssinus, Dermatophagoides siboney, and Blomia tropicalis, by skin tests in a children allergic sample from Cuba. This is a descriptive transversal investigation that included 103 allergic children, with ages ranging from 3 to 15 years, who underwent skin prick tests with D. pteronyssinus, D. siboney, and B. tropicalis allergenic extracts. For the analysis of the results, sex, place of residence and degree of exposure to house dust were considered. The greater sensitization was to D. pteronyssinus (36,9%), followed by D. siboney (35%) and B. tropicalis (33%). The greater geometric mean of the wheal diameter was 5,14 mm for D. pteronyssinus (IC95%: 4.52-5.76 mm); 4.82 mm for D. siboney (IC95%: 4.22-5.43 mm) and 4.25 mm for B. tropicalis (IC95%: 3.93-4.58 mm). Fifty six children (54.3%) were not sensitive to none of the three mites. In 45.7% we found sensitization at least to one mite, and 21.4% were sensitive to the three mites. There were no significant differences (p >0.05) in the sensitization according to sex, place of residence and degree of exposure to house dust. The percentage of sensitive patients with rhinitis plus asthma was more significant (p mites. There was a different pattern of sensitization with mites in relation to gender. Patients with asthma plus rhinitis showed more sensitization concerning the number and intensity of the skin tests.

  1. Prevalence and genetic diversity of Trichomonas vaginalis clinical isolates in a targeted population in Xinxiang City, Henan Province, China.

    Science.gov (United States)

    Zhang, Zhenchao; Kang, Lixia; Wang, Weijuan; Zhao, Xin; Li, Yuhua; Xie, Qing; Wang, Shuai; He, Tong; Li, Han; Xiao, Tingwei; Chen, Yunchao; Zuo, Suqiong; Kong, Lingmin; Li, Pengju; Li, Xiangrui

    2018-03-02

    Trichomonas vaginalis (TV) is a protozoan parasite that causes trichomoniasis, a sexually transmitted disease, worldwide. In this study, we investigated the prevalence and genetic characterization of T. vaginalis and contrasted the most prevalent strains of T. vaginalis isolated from Xinxiang City, Henan Province, China. In Xinxiang from September 2015 to September 2017, a total of 267 (1.64%, 95% confidence interval, CI: 1.45-1.85) clinical T. vaginalis-positive samples from vaginal secretions were observed by wet mount microscopy from 16,294 women with some clinical symptoms of trichomoniasis. We found that trichomoniasis frequently occurred in the 21- to 40-year-old age group and in winter. After the 267 clinical T. vaginalis positive samples were cultured, 68 isolates of T. vaginalis were harvested and identified as genotype E (58.82%), H (17.65%), mixed 1 (17.65%) and mixed 2 (5.88%) using a sensitive and reliable polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) typing method on the actin gene. The phylogenetic diversity analysis showed that the genotype E samples fell within a separate clade compared to the other T. vaginalis isolates, while the samples of the genotype H separated into two clades. Our results demonstrate a notable gene polymorphism of clinical isolates from the targeted population and provide insight into the performance of these genetic markers in the molecular epidemiology of trichomoniasis. However, further studies are needed to clarify the association between a certain genotype and the pathogenicity of T. vaginalis.

  2. Network analysis of translocated Takahe populations to identify disease surveillance targets.

    Science.gov (United States)

    Grange, Zoë L; VAN Andel, Mary; French, Nigel P; Gartrell, Brett D

    2014-04-01

    network in 2011. Likewise, the wild Murchison Mountains population was consistently the sink of the network. Other nodes, such as the offshore islands and the wildlife hospital, varied in importance over time. Common network descriptors and measures of centrality identified key locations for targeting disease surveillance. The visual representation of movements of animals in a population that this technique provides can aid decision makers when they evaluate translocation proposals or attempt to control a disease outbreak. © 2014 Society for Conservation Biology.

  3. Non-allergic cutaneous reactions in airborne chemical sensitivity--a population based study

    DEFF Research Database (Denmark)

    Berg, Nikolaj Drimer; Linneberg, Allan; Thyssen, Jacob Pontoppidan

    2011-01-01

    the relationship between cutaneous reactions from patch testing and self-reported severity of chemical sensitivity to common airborne chemicals. A total of 3460 individuals participating in a general health examination, Health 2006, were patch tested with allergens from the European standard series and screened...... for chemical sensitivity with a standardised questionnaire dividing the participants into four severity groups of chemical sensitivity. Both allergic and non-allergic cutaneous reactions--defined as irritative, follicular, or doubtful allergic reactions--were analysed in relationship with severity of chemical...... most severe groups of self-reported sensitivity to airborne chemicals. When adjusting for confounding, associations were weakened, and only non-allergic cutaneous reactions were significantly associated with individuals most severely affected by inhalation of airborne chemicals (odds ratio = 2.5, p = 0...

  4. Challenges and strategies for conducting sensitive research with an Arab American population.

    Science.gov (United States)

    Timraz, Shahrazad M; Alhasanat, Dalia I; Albdour, Maha M; Lewin, Linda; Giurgescu, Carmen; Kavanaugh, Karen

    2017-02-01

    Recruiting minority groups such as Arab Americans (Ar-Am) for research studies has been challenging. To date no studies were found that explicitly addressed challenges to recruit Ar-Am for sensitive research. The purpose of this article is to present the challenges across three pilot studies that involved Ar-Am samples and the strategies that were implemented to overcome these challenges. The challenges faced with conducting studies with Ar-Am included difficulty for participants to express emotions, influence of male/female authority to consent for the study, lack of trust to disclose sensitive information, language barrier, and slow recruitment. Having bilingual female recruiters of Arabic descent, engaging the women's family members in the consent process, and addressing the sensitive topics in culturally appropriate language were effective strategies to overcome these challenges. These strategies might be helpful for other researchers who recruit Ar-Am for sensitive research. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Multifunctional pH-sensitive magnetic nanoparticles for simultaneous imaging, sensing and targeted intracellular anticancer drug delivery

    International Nuclear Information System (INIS)

    Banerjee, Shashwat S; Chen, D-H

    2008-01-01

    A novel multifunctional magnetic nanocarrier was fabricated for synchronous cancer therapy and sensing. The nanocarrier, programed to display a response to environmental stimuli (pH value), was synthesized by coupling doxorubicin (DOX) to adipic dihydrazide-grafted gum arabic modified magnetic nanoparticles (ADH-GAMNP) via the hydrolytically degradable pH-sensitive hydrazone bond. The resultant nanocarrier, DOX-ADH-GAMNP, had a mean diameter of 13.8 nm and the amount of DOX coupled was about 6.52 mg g -1 . Also, it exhibited pH triggered release of DOX in an acidic environment (pH 5.0) but was relatively stable at physiological pH (pH 7.4). Furthermore, both GAMNP and DOX were found to possess fluorescence properties when excited in the near-infrared region due to the two-photon absorption mechanism. The coupling of DOX to GAMNP resulted in a reversible self-quenching of fluorescence through the fluorescence resonant energy transfer (FRET) between the donor GAMNP and acceptor DOX. The release of DOX from DOX-ADH-GAMNP when exposed to acidic media indicated the recovery of fluorescence from both GAMNP and DOX. The change in the fluorescence intensity of DOX-ADH-GAMNP on the release of DOX can act as a potential sensor to sense the delivery of the drug. The analysis of zeta potential and plasmon absorbance in different pH conditions also confirmed the pH sensitivity of the product. This multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.

  6. Targeted deposition of antibodies on a multiplex CMOS microarray and optimization of a sensitive immunoassay using electrochemical detection.

    Directory of Open Access Journals (Sweden)

    John Cooper

    2010-03-01

    Full Text Available The CombiMatrix ElectraSense microarray is a highly multiplex, complementary metal oxide semiconductor with 12,544 electrodes that are individually addressable. This platform is commercially available as a custom DNA microarray; and, in this configuration, it has also been used to tether antibodies (Abs specifically on electrodes using complementary DNA sequences conjugated to the Abs.An empirical method is described for developing and optimizing immunoassays on the CombiMatrix ElectraSense microarray based upon targeted deposition of polypyrrole (Ppy and capture Ab. This process was automated using instrumentation that can selectively apply a potential or current to individual electrodes and also measure current generated at the electrodes by an enzyme-enhanced electrochemical (ECD reaction. By designating groups of electrodes on the array for different Ppy deposition conditions, we determined that the sensitivity and specificity of a sandwich immunoassay for staphylococcal enterotoxin B (SEB is influenced by the application of different voltages or currents and the application time. The sandwich immunoassay used a capture Ab adsorbed to the Ppy and a reporter Ab labeled for fluorescence detection or ECD, and results from these methods of detection were different.Using Ppy deposition conditions for optimum results, the lower limit of detection for SEB using the ECD assay was between 0.003 and 0.01 pg/ml, which represents an order of magnitude improvement over a conventional enzyme-linked immunosorbant assay. In the absence of understanding the variables and complexities that affect assay performance, this highly multiplexed electrode array provided a rapid, high throughput, and empirical approach for developing a sensitive immunoassay.

  7. Allergen sensitivity (mites, insects, and pets) in a Puerto Rican population.

    Science.gov (United States)

    Nazario, Sylvette; Zaragoza, Rafael; Velázquez, Vylma; Ramos-Valencia, Gilberto; Acantilado, Carmen; Rodríguez, Ray; Rivera, Angel M; Alvarez, María M; López-Almodóvar, Carlos; López-Malpica, Fernando

    2012-03-01

    The people of Puerto Rico have one of the highest asthma prevalence and morbidity rates in the U.S.A. Limited information is available on the most common allergy sensitivities among island residents. The aims of the study were to determine the most common inhalant allergen sensitivities among a convenience sample in Puerto Rico and determine as well their relationship to an asthma or a rhinitis diagnosis. In August of 2008, we evaluated a cohort of subjects visiting ambulatory clinics offering health screening; the clinics were located in two of the island's biggest cities: Guaynabo in the north and Ponce in the south. Subjects over three years of age (or their parents) visiting the clinics answered a survey on asthma and rhinitis and were skin tested for reactivity to common aeroallergens. The survey included 395 subjects with a mean age of 29 years. Thirty-six percent reported a history of asthma, of whom 83% (30% of the total participants) reported still having asthma, and 76% reported having rhinitis. Sixty-five percent of the subjects were sensitive to at least one antigen. Subjects sensitive to mites were 53% more likely to have suffered from asthma than were non-mite-sensitized subjects (OR = 1.53, p insects. Mite sensitivity was associated with rhinitis and asthma. Sensitivity to animal dander as well as to mosquitoes was associated to with rhinitis. Further studies are warranted to explore the relevance of allergen sensitivity in terms of asthma and rhinitis prevalence and morbidity among residents of Puerto Rico.

  8. Methodological approaches to planar and volumetric scintigraphic imaging of small volume targets with high spatial resolution and sensitivity

    Directory of Open Access Journals (Sweden)

    J. Mejia

    2009-08-01

    Full Text Available Single-photon emission computed tomography (SPECT is a non-invasive imaging technique, which provides information reporting the functional states of tissues. SPECT imaging has been used as a diagnostic tool in several human disorders and can be used in animal models of diseases for physiopathological, genomic and drug discovery studies. However, most of the experimental models used in research involve rodents, which are at least one order of magnitude smaller in linear dimensions than man. Consequently, images of targets obtained with conventional gamma-cameras and collimators have poor spatial resolution and statistical quality. We review the methodological approaches developed in recent years in order to obtain images of small targets with good spatial resolution and sensitivity. Multipinhole, coded mask- and slit-based collimators are presented as alternative approaches to improve image quality. In combination with appropriate decoding algorithms, these collimators permit a significant reduction of the time needed to register the projections used to make 3-D representations of the volumetric distribution of target’s radiotracers. Simultaneously, they can be used to minimize artifacts and blurring arising when single pinhole collimators are used. Representation images are presented, which illustrate the use of these collimators. We also comment on the use of coded masks to attain tomographic resolution with a single projection, as discussed by some investigators since their introduction to obtain near-field images. We conclude this review by showing that the use of appropriate hardware and software tools adapted to conventional gamma-cameras can be of great help in obtaining relevant functional information in experiments using small animals.

  9. Local Populations ofArabidopsis thalianaShow Clear Relationship between Photoperiodic Sensitivity of Flowering Time and Altitude.

    Science.gov (United States)

    Lewandowska-Sabat, Anna M; Fjellheim, Siri; Olsen, Jorunn E; Rognli, Odd A

    2017-01-01

    Adaptation of plants to local conditions that vary substantially within their geographic range is essential for seasonal timing of flowering, a major determinant of plant reproductive success. This study investigates photoperiodic responses in natural populations of Arabidopsis thaliana from high northern latitudes and their significance for local adaptation. Thirty lineages from ten local A. thaliana populations, representing different locations across an altitudinal gradient (2-850 m a.s.l.) in Norway, were grown under uniform controlled conditions, and used to screen for responses to five different photoperiods. We studied relationships between variation in photoperiodic sensitivity of flowering time, altitude, and climatic factors associated with the sites of origin. We found that variation in response to photoperiod is significantly correlated with altitude and climatic variables associated with the sites of origin of the populations. Populations originating from lower altitudes showed stronger photoperiodic sensitivity than populations from higher altitudes. Our results indicate that the altitudinal climatic gradient generates clinal variation in adaptive traits in A. thaliana .

  10. Encoding of Naturalistic Optic Flow by a Population of Blowfly Motion-Sensitive Neurons

    NARCIS (Netherlands)

    Karmeier, K.; Hateren, J.H. van; Kern, R.; Egelhaaf, M.

    In sensory systems information is encoded by the activity of populations of neurons. To analyze the coding properties of neuronal populations sensory stimuli have usually been used that were much simpler than those encountered in real life. It has been possible only recently to stimulate visual

  11. Non-allergic cutaneous reactions in airborne chemical sensitivity--a population based study.

    Science.gov (United States)

    Berg, Nikolaj Drimer; Linneberg, Allan; Thyssen, Jacob Pontoppidan; Dirksen, Asger; Elberling, Jesper

    2011-06-01

    Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. The aetiology is unknown, but chemical related respiratory symptoms have been found associated with positive patch test. The purpose of this study was to investigate the relationship between cutaneous reactions from patch testing and self-reported severity of chemical sensitivity to common airborne chemicals. A total of 3460 individuals participating in a general health examination, Health 2006, were patch tested with allergens from the European standard series and screened for chemical sensitivity with a standardised questionnaire dividing the participants into four severity groups of chemical sensitivity. Both allergic and non-allergic cutaneous reactions--defined as irritative, follicular, or doubtful allergic reactions--were analysed in relationship with severity of chemical sensitivity. Associations were controlled for the possible confounding effects of sex, age, asthma, eczema, atopic dermatitis, psychological and social factors, and smoking habits. In unadjusted analyses we found associations between allergic and non-allergic cutaneous reactions on patch testing and the two most severe groups of self-reported sensitivity to airborne chemicals. When adjusting for confounding, associations were weakened, and only non-allergic cutaneous reactions were significantly associated with individuals most severely affected by inhalation of airborne chemicals (odds ratio = 2.5, p = 0.006). Our results suggest that individuals with self-reported chemical sensitivity show increased non-allergic cutaneous reactions based on day 2 readings of patch tests. Copyright © 2011 Elsevier GmbH. All rights reserved.

  12. Nef decreases HIV-1 sensitivity to neutralizing antibodies that target the membrane-proximal external region of TMgp41.

    Directory of Open Access Journals (Sweden)

    Rachel P J Lai

    2011-12-01

    Full Text Available Primate lentivirus nef is required for sustained virus replication in vivo and accelerated progression to AIDS. While exploring the mechanism by which Nef increases the infectivity of cell-free virions, we investigated a functional link between Nef and Env. Since we failed to detect an effect of Nef on the quantity of virion-associated Env, we searched for qualitative changes by examining whether Nef alters HIV-1 sensitivity to agents that target distinct features of Env. Nef conferred as much as 50-fold resistance to 2F5 and 4E10, two potent neutralizing monoclonal antibodies (nAbs that target the membrane proximal external region (MPER of TMgp41. In contrast, Nef had no effect on HIV-1 neutralization by MPER-specific nAb Z13e1, by the peptide inhibitor T20, nor by a panel of nAbs and other reagents targeting gp120. Resistance to neutralization by 2F5 and 4E10 was observed with Nef from a diverse range of HIV-1 and SIV isolates, as well as with HIV-1 virions bearing Env from CCR5- and CXCR4-tropic viruses, clade B and C viruses, or primary isolates. Functional analysis of a panel of Nef mutants revealed that this activity requires Nef myristoylation but that it is genetically separable from other Nef functions such as the ability to enhance virus infectivity and to downregulate CD4. Glycosylated-Gag from MoMLV substituted for Nef in conferring resistance to 2F5 and 4E10, indicating that this activity is conserved in a retrovirus that does not encode Nef. Given the reported membrane-dependence of MPER-recognition by 2F5 and 4E10, in contrast to the membrane-independence of Z13e1, the data here is consistent with a model in which Nef alters MPER recognition in the context of the virion membrane. Indeed, Nef and Glycosylated-Gag decreased the efficiency of virion capture by 2F5 and 4E10, but not by other nAbs. These studies demonstrate that Nef protects lentiviruses from one of the most broadly-acting classes of neutralizing antibodies. This newly

  13. Folate-targeted polymeric micelles loaded with ultrasmall superparamagnetic iron oxide: combined small size and high MRI sensitivity

    Directory of Open Access Journals (Sweden)

    Hong GB

    2012-06-01

    Full Text Available Guo-bin Hong,1,2 Jing-xing Zhou,2 Ren-xu Yuan31Department of Radiology, Fifth Affiliated Hospital, Zhuhai, 2Department of Radiology, Sun Yat-sen Memorial Hospital, Guangzhou, 3School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, ChinaAbstract: Targeted delivery of contrast agents is a highly desirable strategy for enhancing diagnostic efficiency and reducing side effects and toxicity. Water-soluble and tumor-targeting superparamagnetic iron oxide nanoparticles (SPIONs were synthesized by loading hydrophobic SPIONs into micelles assembled from an amphiphilic block copolymer poly(ethylene glycol-poly(ε-caprolactone (PEG-PCL bearing folate in the distal ends of PEG chains. Compared to the water-soluble SPIONs obtained by small molecular surfactant coating, ultrasmall SPION encapsulation with PEG-PCL micelles (PEG-PCL-SPIONs simultaneously increases transverse (r2 and decreases longitudinal (r1 magnetic resonance (MR relaxivities of water proton in micelle solution, leading to a notably high r2/r1 ratio up to 78, which makes the PEG-PCL-SPIONs a highly sensitive MR imaging (MRI T2 contrast agent. The mean size of folate-attached SPION micelles (Fa-PEG-PCL-SPIONs is 44 ± 3 nm on average, ideal for in vivo MRI applications in which long circulation is greatly determined by small particle size and is highly desirable. Prussian blue staining of BEL-7402 cells over-expressing folate receptors, after incubation with micelle-containing medium, demonstrated that folate functionalization of the magnetic particles significantly enhanced their cell uptake. The potential of Fa-PEG-PCL-SPIONs as a potent MRI probe for in vivo tumor detection was assessed. At 3 hours after intravenous injection of the Fa-PEG-PCL-SPION solution into mice bearing subcutaneous xenografts of human BEL-7402 hepatoma, a 41.2% signal intensity decrease was detected in the T2-weighted MR images of the tumor, indicating the efficient accumulation of Fa

  14. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  15. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  16. Parameterization and Sensitivity Analysis of a Complex Simulation Model for Mosquito Population Dynamics, Dengue Transmission, and Their Control

    Science.gov (United States)

    Ellis, Alicia M.; Garcia, Andres J.; Focks, Dana A.; Morrison, Amy C.; Scott, Thomas W.

    2011-01-01

    Models can be useful tools for understanding the dynamics and control of mosquito-borne disease. More detailed models may be more realistic and better suited for understanding local disease dynamics; however, evaluating model suitability, accuracy, and performance becomes increasingly difficult with greater model complexity. Sensitivity analysis is a technique that permits exploration of complex models by evaluating the sensitivity of the model to changes in parameters. Here, we present results of sensitivity analyses of two interrelated complex simulation models of mosquito population dynamics and dengue transmission. We found that dengue transmission may be influenced most by survival in each life stage of the mosquito, mosquito biting behavior, and duration of the infectious period in humans. The importance of these biological processes for vector-borne disease models and the overwhelming lack of knowledge about them make acquisition of relevant field data on these biological processes a top research priority. PMID:21813844

  17. Serum, plasma, and dried blood spot high sensitivity C-reactive protein enzyme immunoassay for population research

    OpenAIRE

    Brindle, Eleanor; Fujita, Masako; Shofer, Jane; O’Connor, Kathleen A.

    2010-01-01

    C-reactive protein (CRP) is used as a biomarker of morbidity and mortality risk in studies of population health, and is essential to interpretation of several micronutrient biomarkers. There is thus need for a robust high sensitivity CRP (hsCRP) measurement method for large-scale, non-clinical studies. We developed an efficient, inexpensive assay suitable for quantifying CRP across the physiological range using any blood specimen type. The ELISA uses readily available monoclonal antibodies to...

  18. A computational framework for testing arrhythmia marker sensitivities to model parameters in functionally calibrated populations of atrial cells

    Science.gov (United States)

    Vagos, Márcia R.; Arevalo, Hermenegild; de Oliveira, Bernardo Lino; Sundnes, Joakim; Maleckar, Mary M.

    2017-09-01

    Models of cardiac cell electrophysiology are complex non-linear systems which can be used to gain insight into mechanisms of cardiac dynamics in both healthy and pathological conditions. However, the complexity of cardiac models can make mechanistic insight difficult. Moreover, these are typically fitted to averaged experimental data which do not incorporate the variability in observations. Recently, building populations of models to incorporate inter- and intra-subject variability in simulations has been combined with sensitivity analysis (SA) to uncover novel ionic mechanisms and potentially clarify arrhythmogenic behaviors. We used the Koivumäki human atrial cell model to create two populations, representing normal Sinus Rhythm (nSR) and chronic Atrial Fibrillation (cAF), by varying 22 key model parameters. In each population, 14 biomarkers related to the action potential and dynamic restitution were extracted. Populations were calibrated based on distributions of biomarkers to obtain reasonable physiological behavior, and subjected to SA to quantify correlations between model parameters and pro-arrhythmia markers. The two populations showed distinct behaviors under steady state and dynamic pacing. The nSR population revealed greater variability, and more unstable dynamic restitution, as compared to the cAF population, suggesting that simulated cAF remodeling rendered cells more stable to parameter variation and rate adaptation. SA revealed that the biomarkers depended mainly on five ionic currents, with noted differences in sensitivities to these between nSR and cAF. Also, parameters could be selected to produce a model variant with no alternans and unaltered action potential morphology, highlighting that unstable dynamical behavior may be driven by specific cell parameter settings. These results ultimately suggest that arrhythmia maintenance in cAF may not be due to instability in cell membrane excitability, but rather due to tissue-level effects which

  19. Evaluation of paediatric nursing-sensitive outcomes in an Australian population using linked administrative hospital data.

    Science.gov (United States)

    Wilson, Sally; Bremner, Alexandra P; Hauck, Yvonne; Finn, Judith

    2013-10-08

    Research into nursing-sensitive outcomes using administrative health data has focussed on hospitalised adults. However, we developed algorithms for the identification of 13 paediatric nursing-sensitive outcomes, which we seek to examine for clinical utility. The aims were to determine the rates of paediatric nursing-sensitive outcomes in a Western Australian hospital and ascertain sociodemographic and clinical characteristics associated with a greater risk of developing nursing-sensitive outcomes in hospitalised children. A retrospective cohort study used linked administrative data of all Western Australian children ≤18 years admitted to the only tertiary paediatric hospital in Perth between 1999 and 2009. Rates per 1,000 hospital separations and per 10,000 patient days were calculated for the following nursing-sensitive outcomes: lower respiratory tract infection (LRTI), gastrointestinal (GI) infection, pneumonia, sepsis, arrest/shock/respiratory failure, central nervous system complication, central venous line infection, infectious disease, pressure ulcer, failure to rescue, surgical wound infection, physiologic/metabolic derangement, and postoperative cardiopulmonary complications. Poisson multiple regression models were fitted to estimate rate ratios (RR) and 95% confidence intervals (CI) for suspected risk factors. Linked records of 129,719 hospital separations were analysed. Rates ranged from 0.5/1,000 for pressure ulcer to 14.0/1,000 hospital separations for GI infections. Age was significantly associated with the risk of a nursing-sensitive outcome: compared with adolescents, toddlers had greater risk of GI infection (RR 9.89; 95% CI 6.24, 15.69); infants had 7.74 times greater risk of LRTI (95% CI 5.11, 11.75), while neonates had lower risks for sepsis (RR 0.26; 95% CI 0.08, 0.90) and physiologic/metabolic derangement (RR 0.12; 95% CI 0.04, 0.35). The risk of surgical wound infection was 7.78 times greater (95% CI 5.10, 11.86) for emergency admissions

  20. Target-site mutations conferring resistance to glyphosate in feathertop Rhodes grass (Chloris virgata) populations in Australia.

    Science.gov (United States)

    Ngo, The D; Krishnan, Mahima; Boutsalis, Peter; Gill, Gurjeet; Preston, Christopher

    2018-05-01

    Chloris virgata is a warm-season, C 4 , annual grass weed affecting field crops in northern Australia that has become an emerging weed in southern Australia. Four populations with suspected resistance to glyphosate were collected in South Australia, Queensland and New South Wales, Australia, and compared with one susceptible (S) population to confirm glyphosate resistance and elucidate possible mechanisms of resistance. Based on the rate of glyphosate required to kill 50% of treated plants (LD 50 ), glyphosate resistance (GR) was confirmed in four populations of C. virgata (V12, V14.2, V14.16 and V15). GR plants were 2-9.7-fold more resistant and accumulated less shikimate after glyphosate treatment than S plants. GR and S plants did not differ in glyphosate absorption and translocation. Target-site EPSPS mutations corresponding to Pro-106-Leu (V14.2) and Pro-106-Ser (V15, V14.16 and V12) substitutions were found in GR populations. The population with Pro-106-Leu substitution was 2.9-4.9-fold more resistant than the three other populations with Pro-106-Ser substitution. This report confirms glyphosate resistance in C. virgata and shows that target-site EPSPS mutations confer resistance to glyphosate in this species. The evolution of glyphosate resistance in C. virgata highlights the need to identify alternative control tactics. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  1. A retrospective population-based cohort study identifying target areas for prevention of acute lower respiratory infections in children

    Directory of Open Access Journals (Sweden)

    Richmond Peter

    2010-12-01

    Full Text Available Abstract Background Acute lower respiratory infections (ALRI are a major cause of hospitalisation in young children. Many factors can lead to increased risk of ALRI in children and predispose a child to hospitalisation, but population attributable fractions for different risk factors and how these fractions differ between Indigenous and non-Indigenous children is unknown. This study investigates population attributable fractions of known infant and maternal risk factors for ALRI to inform prevention strategies that target high-risk groups or particular risk factors. Methods A retrospective population-based data linkage study of 245,249 singleton births in Western Australia. Population attributable fractions of known maternal and infant risk factors for hospitalisation with ALRI between 1996 and 2005 were calculated using multiple logistic regression. Results The overall ALRI hospitalisation rate was 16.1/1,000 person-years for non-Aboriginal children and 93.0/1,000 for Aboriginal children. Male gender, being born in autumn, gestational age Conclusions The population attributable fractions estimated in this study should help in guiding public health interventions to prevent ALRI. A key risk factor for all children is maternal smoking during pregnancy, and multiple previous pregnancies and autumnal births are important high-risk groups. Specific key target areas are reducing elective caesareans in non-Aboriginal women and reducing teenage pregnancies and improving access to services and living conditions for the Aboriginal population.

  2. Sensitivity Analysis for Studying Impacts of Aging on Population Toxicokinetics and Toxicodynamics

    Science.gov (United States)

    Assessing the impacts of toxicant exposures upon susceptible populations such as the elderly requires adequate characterization of prior long-term exposures, reductions in various organ functions, and potential intake of multiple drugs. Additionally, significant uncertainties and...

  3. Non-allergic cutaneous reactions in airborne chemical sensitivity--a population based study

    DEFF Research Database (Denmark)

    Berg, Nikolaj Drimer; Linneberg, Allan; Thyssen, Jacob Pontoppidan

    2011-01-01

    Multiple chemical sensitivity (MCS) is characterised by adverse effects due to exposure to low levels of chemical substances. The aetiology is unknown, but chemical related respiratory symptoms have been found associated with positive patch test. The purpose of this study was to investigate the r...

  4. Detecting the presence of target-site resistance to neonicotinoids and pyrethroids in Italian populations of Myzus persicae.

    Science.gov (United States)

    Panini, Michela; Dradi, Davide; Marani, Gabriele; Butturini, Alda; Mazzoni, Emanuele

    2014-06-01

    Myzus persicae is a key pest of peach, which in commercial orchards is mainly controlled by chemical treatments. Neonicotinoids represent the main control strategy, but resistance monitoring programmes in Southern Europe have shown the widespread presence of populations highly resistant to this insecticide class in peach orchards. Moreover, in Italy reports of neonicotinoid application failures are increasing. This work describes the status of the main target-site mutations associated with neonicotinoid and pyrethroid resistance in Italian populations collected in 2012. R81T mutation linked with neonicotinoid resistance was found in 65% of analysed aphids (35.5% with a homozygous resistant genotype). For the first time, R81T was found in samples collected from herbaceous hosts. Bioassays on a few genotyped populations also revealed the involvement of P450-based metabolic resistance. Only a few individuals without kdr (L1014F) and s-kdr (M918T) target-site mutations were collected. A new single nucleotide polymorphism in the s-kdr locus producing M918L substitution was found. Target-site resistance to neonicotinoids is common in specialised peach-growing areas, and it is spreading in other Italian regions and on herbaceous hosts. The high frequency of target-site mutations and data obtained from bioassays confirm the presence of multiple resistance mechanisms and suggest the importance of coordinated control strategies. © 2013 Society of Chemical Industry.

  5. Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases.

    Science.gov (United States)

    Varela, Miguel A; Curtis, Helen J; Douglas, Andrew G L; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew J A

    2016-02-01

    Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.

  6. Synthesis and in vitro experiments of carcinoma vascular endothelial targeting polymeric nano-micelles combining small particle size and supermagnetic sensitivity.

    Science.gov (United States)

    Zhang, Yi; Pan, Jielin; Xu, Qilan; Li, Hao; Wang, Jianhao; Zhang, Chao; Hong, Guobin

    2018-01-01

    Objective: To construct carcinoma vascular endothelial-targeted polymeric nanomicelles with high magnetic resonance imaging (MRI) sensitivity and to evaluate their biological safety and in vitro tumor-targeting effect, and to monitor their feasibility using clinical MRI scanner. Method: Amphiphilic block copolymer, poly(ethylene glycol)- b -poly(ε-caprolactone) (PEG-PCL) was synthesized via the ring-opening polymerization of ε-caprolactone (CL) initiated by poly(ethylene glycol) (PEG), in which cyclic pentapeptide Arg-Gly-Asp (cRGD) was conjugated with the terminal of hydrophilic PEG block. During the self-assembly of PEG-PCL micelles, superparamagnetic γ-Fe 2 O 3 nanoparticles (11 nm) was loaded into the hydrophobic core. The cRGD-terminated γ-Fe 2 O 3 -loaded polymeric micelles targeting to carcinoma vascular endothelial cells, were characterized in particle size, morphology, loading efficiency and so on, especially high MRI sensitivity in vitro. Normal hepatic vascular endothelial cells (ED25) were incubated with the resulting micelles for assessing their safety. Human hepatic carcinoma vascular endothelial cells (T3A) were cultured with the resulting micelles to assess the micelle uptake using Prussian blue staining and the cell signal intensity using MRI. Results: All the polymeric micelles exhibited ultra-small particle sizes with approximately 50 nm, high relaxation rate, and low toxicity even at high iron concentrations. More blue-stained iron particles were present in the targeting group than the non-targeting and competitive inhibition groups. In vitro MRI showed T 2 WI and T 2 relaxation times were significantly lower in the targeting group than in the other two groups. Conclusion: γ-Fe 2 O 3 -loaded PEG-PCL micelles not only possess ultra-small size and high superparamagnetic sensitivity, also can be actively targeted to carcinoma vascular endothelial cells by tumor-targeted cRGD. It appears to be a promising contrast agent for tumor-targeted

  7. The RIPASA score is sensitive and specific for the diagnosis of acute appendicitis in a western population.

    Science.gov (United States)

    Malik, Muhammad Usman; Connelly, Tara M; Awan, Faisal; Pretorius, Frederik; Fiuza-Castineira, Constantino; El Faedy, Osama; Balfe, Paul

    2017-04-01

    The definitive diagnosis of acute appendicitis (AA) requires histopathological examination. Various clinical diagnostic scoring systems attempt to reduce negative appendectomy rates. The most commonly used in Western Europe and the USA is the Alvarado score. The Raja Isteri Pengiran Anak Saleha appendicitis (RIPASA) score achieves better sensitivity and specificity in Asian and Middle Eastern populations. We aimed to determine the diagnostic accuracy of the RIPASA score in Irish patients with AA. All patients who presented to our institution with right iliac fossa pain and clinically suspected AA between January 1 and December 31, 2015, were indentified from our hospital inpatient enquiry database and retrospectively studied. Operating theatre records and histology reports confirmed those who underwent a non-elective operative procedure and the presence or absence of AA. SPSS version 22 was used for statistical analysis. Standard deviation is provided where appropriate. Two hundred eight patients were included in the study (106/51% male, mean age 22.7 ± 9.2 years). One hundred thirty-five (64.9%) had histologically confirmed AA (mean symptom duration = 36.19 ± 15.90 h). At a score ≥7.5, the previously determined score most likely associated with AA in Eastern populations, the RIPASA scoring system demonstrated a sensitivity of 85.39%, specificity of 69.86%, positive predictive value of 84.06%, negative predictive value of 72.86% and diagnostic accuracy of 80% in our cohort. The RIPASA score is a useful tool to aid in the diagnosis of acute appendicitis in the Irish population. A score of ≥7.5 provides sensitivity and specificity exceeding that previously documented for the Alvarado score in Western populations. WHAT DOES THIS PAPER ADD TO THE LITERATURE?: This is the first study evaluating the utility of the RIPASA score in predicting acute appendicitis in a Western population. At a value of 7.5, a cut-off score suggestive of appendicitis in the

  8. MicroRNA-106a targets autophagy and enhances sensitivity of lung cancer cells to Src inhibitors.

    Science.gov (United States)

    Rothschild, Sacha I; Gautschi, Oliver; Batliner, Jasmin; Gugger, Mathias; Fey, Martin F; Tschan, Mario P

    2017-05-01

    Src tyrosine kinase inhibitors (TKIs) significantly inhibit cell migration and invasion in lung cancer cell lines with minor cytotoxic effects. In clinical trials, however, they show modest activity in combination with chemotherapeutic agents. Possible resistance mechanisms include the induction of cytoprotective autophagy upon Src inhibition. Autophagy is a cellular recycling process that allows cell survival in response to a variety of stress stimuli including responses to various treatments. We screened autophagic activity in A549, H460, and H1299 NSCLC cell lines treated with two different Src-TKIs (saracatinib, dasatinib) or shRNA targeting SRC. The autophagy response was determined by LC3B-I to -II conversion, increased ULK1 epxression and increased GFP-LC3B dot formation. Autophagy was inhibited by pharmacological (bafilomycin A, chloroquine) or genetic (ULK1 shRNA) means. Expression of miR-106a and miR-20b was analyzed by qPCR, and we used different lentivral vectors for ectopic expression of either miR-106a mimetics, anti-sense miR-106a or different miR-106a-363 cluster constructs. In the current study we found that Src-TKIs induce autophagy in lung adenocarcinoma cell lines and that a combination of autophagy and Src tyrosine kinase inhibition results in cell death. Moreover, Src-TKI induced autophagy depends on the induction of the key autophagy kinase ULK1. This ULK1 upregulation is caused by downregulation of the ULK1-targeting microRNA-106a. An inverse correlation of miR-106a and ULK1 expression was seen in lung adenocarcinoma. Accordingly, ectopic expression of miR-106a in combination with Src-TKI treatment resulted in significant cell death as compared to control transduced cells. Autophagy protects lung adenocarcinoma cells from Src-TKIs via a newly identified miR-106a-ULK1 signaling pathway. The combined inhibition of Src and ULK1/autophagy might represent a promising treatment option for future clinical trials. Lastly, our data might challenge

  9. Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles

    Czech Academy of Sciences Publication Activity Database

    Ergen, C.; Heymann, F.; Al Rawashdeh, W.; Gremse, F.; Bartneck, M.; Panzer, U.; Pola, Robert; Pechar, Michal; Storm, G.; Mohr, N.; Barz, M.; Zentel, R.; Kiessling, F.; Trautwein, C.; Lammers, T.; Tacke, F.

    2017-01-01

    Roč. 114, January (2017), s. 106-120 ISSN 0142-9612 Institutional support: RVO:61389013 Keywords : targeted delivery * nanomedicine * macrophages Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 8.402, year: 2016

  10. Local and Systemic Changes in Pain Sensitivity After 4 Weeks of Calf Muscle Stretching in a Nonpainful Population: A Randomized Trial.

    Science.gov (United States)

    Bartholdy, Cecilie; Zangger, Graziella; Hansen, Lisbeth; Ginnerup-Nielsen, Elisabeth; Bliddal, Henning; Henriksen, Marius

    2016-07-01

    Stretching is often used in clinical practice for a variety of purposes, including pain therapy. The possible mechanism behind the effect of stretching remains to be clarified. To investigate whether 4 weeks of unilateral stretching of the calf muscles would affect local and central pain sensitivity. This study was a randomized assessor-blinded clinical study. Healthy participants (age 18 to 40) were included and randomized. Participants in the intervention group were instructed to perform 2 stretching exercises targeting the calf muscles; 3 times 30 seconds, 7 days a week for 4 weeks on the dominant leg. Participants in the control group were instructed not to do any stretching for 4 weeks. Pressure pain threshold (PPT) and temporal summation (TS) of pressure pain were measured on the stretched calf, the contra-lateral calf, and contra-lateral lower arm using a computerized cuff algometer. Analyses of variance on the per-protocol population (defined as participants that adhered to the protocol) were used to assess group differences in the changes from baseline. Forty healthy volunteers were included, of which 34 participants adhered to the protocol (15 intervention group/19 control group). No statistically significant group differences in the changes from baseline were found regarding PPT and TS measurements for the stretched calf, the contra-lateral calf, and the arm. Four weeks of regular stretching of the calf muscles does not affect pressure pain sensitivity, suggesting that pressure pain sensitivity is unaffected by stretching in a healthy population. The mechanisms underlying any benefits of regular stretching remain to be explained. © 2015 World Institute of Pain.

  11. MsrA Overexpression Targeted to the Mitochondria, but Not Cytosol, Preserves Insulin Sensitivity in Diet-Induced Obese Mice.

    Directory of Open Access Journals (Sweden)

    JennaLynn Hunnicut

    Full Text Available There is growing evidence that oxidative stress plays an integral role in the processes by which obesity causes type 2 diabetes. We previously identified that mice lacking the protein oxidation repair enzyme methionine sulfoxide reductase A (MsrA are particularly prone to obesity-induced insulin resistance suggesting an unrecognized role for this protein in metabolic regulation. The goals of this study were to test whether increasing the expression of MsrA in mice can protect against obesity-induced metabolic dysfunction and to elucidate the potential underlying mechanisms. Mice with increased levels of MsrA in the mitochondria (TgMito MsrA or in the cytosol (TgCyto MsrA were fed a high fat/high sugar diet and parameters of glucose homeostasis were monitored. Mitochondrial content, markers of mitochondrial proteostasis and mitochondrial energy utilization were assessed. TgMito MsrA, but not TgCyto MsrA, mice remain insulin sensitive after high fat feeding, though these mice are not protected from obesity. This metabolically healthy obese phenotype of TgMito MsrA mice is not associated with changes in mitochondrial number or biogenesis or with a reduction of proteostatic stress in the mitochondria. However, our data suggest that increased mitochondrial MsrA can alter metabolic homeostasis under diet-induced obesity by activating AMPK signaling, thereby defining a potential mechanism by which this genetic alteration can prevent insulin resistance without affecting obesity. Our data suggest that identification of targets that maintain and regulate the integrity of the mitochondrial proteome, particular against oxidative damage, may play essential roles in the protection against metabolic disease.

  12. Targeting helicase-dependent amplification products with an electrochemical genosensor for reliable and sensitive screening of genetically modified organisms.

    Science.gov (United States)

    Moura-Melo, Suely; Miranda-Castro, Rebeca; de-Los-Santos-Álvarez, Noemí; Miranda-Ordieres, Arturo J; Dos Santos Junior, J Ribeiro; da Silva Fonseca, Rosana A; Lobo-Castañón, Maria Jesús

    2015-08-18

    Cultivation of genetically modified organisms (GMOs) and their use in food and feed is constantly expanding; thus, the question of informing consumers about their presence in food has proven of significant interest. The development of sensitive, rapid, robust, and reliable methods for the detection of GMOs is crucial for proper food labeling. In response, we have experimentally characterized the helicase-dependent isothermal amplification (HDA) and sequence-specific detection of a transgene from the Cauliflower Mosaic Virus 35S Promoter (CaMV35S), inserted into most transgenic plants. HDA is one of the simplest approaches for DNA amplification, emulating the bacterial replication machinery, and resembling PCR but under isothermal conditions. However, it usually suffers from a lack of selectivity, which is due to the accumulation of spurious amplification products. To improve the selectivity of HDA, which makes the detection of amplification products more reliable, we have developed an electrochemical platform targeting the central sequence of HDA copies of the transgene. A binary monolayer architecture is built onto a thin gold film where, upon the formation of perfect nucleic acid duplexes with the amplification products, these are enzyme-labeled and electrochemically transduced. The resulting combined system increases genosensor detectability up to 10(6)-fold, allowing Yes/No detection of GMOs with a limit of detection of ∼30 copies of the CaMV35S genomic DNA. A set of general utility rules in the design of genosensors for detection of HDA amplicons, which may assist in the development of point-of-care tests, is also included. The method provides a versatile tool for detecting nucleic acids with extremely low abundance not only for food safety control but also in the diagnostics and environmental control areas.

  13. Sensitive populations, especially children, are the measure of all things in scientific risk assessment

    OpenAIRE

    German Federal Institute for Risk Assessment

    2016-01-01

    Children are considered to be especially sensitive to potentially harmful substances. This is taken into account in the assessment of the health risks of pesticidal active ingredients and in the setting of health-based limit values. For this purpose, toxicological limit values such as the ADI (Acceptable Daily Intake of a substance) and the ARfD (Acute Reference Dose), which are established by international panels of experts, are compared to the exposure of children. This also applies to the ...

  14. Predicting global population connectivity and targeting conservation action for snow leopard across its range

    Science.gov (United States)

    Philip Riordan; Samuel A. Cushman; David Mallon; Kun Shi; Joelene Hughes

    2016-01-01

    Movements of individuals within and among populations help to maintain genetic variability and population viability. Therefore, understanding landscape connectivity is vital for effective species conservation. The snow leopard is endemic to mountainous areas of central Asia and occurs within 12 countries. We assess potential connectivity across the species’...

  15. Bortezomib sensitivity of acute myeloid leukemia CD34(+) cells can be enhanced by targeting the persisting activity of NF-kappa B and the accumulation of MCL-1

    NARCIS (Netherlands)

    Bosman, Matthieu Cornelis Johannes; Schuringa, Jan Jacob; Quax, Wilhelmus Johannes; Vellenga, Edo

    Sustained NF-kappa B activation is often observed in acute myeloid leukemia (AML); therefore, proteasome inhibition has been proposed to efficiently target AML cells. In this study, we questioned whether leukemic stem cell-enriched CD34(+) cells are sensitive to the proteasome inhibitor bortezomib.

  16. Strand Invasion Based Amplification (SIBA®): a novel isothermal DNA amplification technology demonstrating high specificity and sensitivity for a single molecule of target analyte.

    Science.gov (United States)

    Hoser, Mark J; Mansukoski, Hannu K; Morrical, Scott W; Eboigbodin, Kevin E

    2014-01-01

    Isothermal nucleic acid amplification technologies offer significant advantages over polymerase chain reaction (PCR) in that they do not require thermal cycling or sophisticated laboratory equipment. However, non-target-dependent amplification has limited the sensitivity of isothermal technologies and complex probes are usually required to distinguish between non-specific and target-dependent amplification. Here, we report a novel isothermal nucleic acid amplification technology, Strand Invasion Based Amplification (SIBA). SIBA technology is resistant to non-specific amplification, is able to detect a single molecule of target analyte, and does not require target-specific probes. The technology relies on the recombinase-dependent insertion of an invasion oligonucleotide (IO) into the double-stranded target nucleic acid. The duplex regions peripheral to the IO insertion site dissociate, thereby enabling target-specific primers to bind. A polymerase then extends the primers onto the target nucleic acid leading to exponential amplification of the target. The primers are not substrates for the recombinase and are, therefore unable to extend the target template in the absence of the IO. The inclusion of 2'-O-methyl RNA to the IO ensures that it is not extendible and that it does not take part in the extension of the target template. These characteristics ensure that the technology is resistant to non-specific amplification since primer dimers or mis-priming are unable to exponentially amplify. Consequently, SIBA is highly specific and able to distinguish closely-related species with single molecule sensitivity in the absence of complex probes or sophisticated laboratory equipment. Here, we describe this technology in detail and demonstrate its use for the detection of Salmonella.

  17. Strand Invasion Based Amplification (SIBA®: a novel isothermal DNA amplification technology demonstrating high specificity and sensitivity for a single molecule of target analyte.

    Directory of Open Access Journals (Sweden)

    Mark J Hoser

    Full Text Available Isothermal nucleic acid amplification technologies offer significant advantages over polymerase chain reaction (PCR in that they do not require thermal cycling or sophisticated laboratory equipment. However, non-target-dependent amplification has limited the sensitivity of isothermal technologies and complex probes are usually required to distinguish between non-specific and target-dependent amplification. Here, we report a novel isothermal nucleic acid amplification technology, Strand Invasion Based Amplification (SIBA. SIBA technology is resistant to non-specific amplification, is able to detect a single molecule of target analyte, and does not require target-specific probes. The technology relies on the recombinase-dependent insertion of an invasion oligonucleotide (IO into the double-stranded target nucleic acid. The duplex regions peripheral to the IO insertion site dissociate, thereby enabling target-specific primers to bind. A polymerase then extends the primers onto the target nucleic acid leading to exponential amplification of the target. The primers are not substrates for the recombinase and are, therefore unable to extend the target template in the absence of the IO. The inclusion of 2'-O-methyl RNA to the IO ensures that it is not extendible and that it does not take part in the extension of the target template. These characteristics ensure that the technology is resistant to non-specific amplification since primer dimers or mis-priming are unable to exponentially amplify. Consequently, SIBA is highly specific and able to distinguish closely-related species with single molecule sensitivity in the absence of complex probes or sophisticated laboratory equipment. Here, we describe this technology in detail and demonstrate its use for the detection of Salmonella.

  18. Identification of target risk groups for population-based Clostridium difficile infection prevention strategies using a population attributable risk approach.

    Science.gov (United States)

    Oh, Sung-Hee; Kang, Hye-Young

    2018-01-01

    We aimed to determine risk factors associated with Clostridium difficile infection (CDI) and assess the contributions of these factors on CDI burden. We conducted a 1:4 matched case-control study using a national claims dataset. Cases were incident CDI without a history of CDI in the previous 84 days, and were age- and sex-matched with control patients. We ascertained exposure, defined as a history of morbidities and drug use within 90 days. The population attributable risk (PAR) percent for risk factors was estimated using odds ratios (ORs) obtained from the case-control study. Overall, the strongest CDI-associated risk factors, which have significant contributions to the CDI burden as well, were the experience of gastroenteritis (OR=5.08, PAR%=17.09%) and use of antibiotics (OR=1.69, PAR%=19.00%), followed by the experiences of female pelvic infection, irritable bowel syndrome, inflammatory bowel disease, and pneumonia, and use of proton-pump inhibitors (OR=1.52-2.37, PAR%=1.95-2.90). The control of risk factors that had strong association with CDI and affected large proportions of total CDI cases would be beneficial for CDI prevention. We suggest performing CDI testing for symptomatic patients with gastroenteritis and implementing antibiotics stewardship. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  19. Apportioning bacterial carbon source utilization in soil using 14 C isotope analysis of FISH-targeted bacterial populations sorted by fluorescence activated cell sorting (FACS): 14 C-FISH-FACS.

    Science.gov (United States)

    Gougoulias, Christos; Meade, Andrew; Shaw, Liz J

    2018-02-19

    An unresolved need in microbial ecology is methodology to enable quantitative analysis of in situ microbial substrate carbon use at the population level. Here, we evaluated if a novel combination of radiocarbon-labelled substrate tracing, fluorescence in situ hybridisation (FISH) and fluorescence-activated cell sorting (FACS) to sort the FISH-targeted population for quantification of incorporated radioactivity ( 14 C-FISH-FACS) can address this need. Our test scenario used FISH probe PSE1284 targeting Pseudomonas spp. (and some Burkholderia spp.) and salicylic acid added to rhizosphere soil. We examined salicylic acid- 14 C fate (mineralized, cell-incorporated, extractable and non-extractable) and mass balance (0-24 h) and show that the PSE1284 population captured ∼ 50% of the Nycodenz extracted biomass 14 C. Analysis of the taxonomic distribution of the salicylic acid biodegradation trait suggested that PSE1284 population success was not due to conservation of this trait but due to competitiveness for the added carbon. Adding 50KBq of 14 C sample -1 enabled detection of 14 C in the sorted population at ∼ 60-600 times background; a sensitivity which demonstrates potential extension to analysis of rarer/less active populations. Given its sensitivity and compatibility with obtaining a C mass balance, 14 C-FISH-FACS allows quantitative dissection of C flow within the microbial biomass that has hitherto not been achieved. © 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.

  20. Influenza-vaccination: an inventory of strategies to reach the target population and optimise vaccination uptake.

    NARCIS (Netherlands)

    Kroneman, M.; Paget, J.

    2002-01-01

    Background: Influenza continues to be a considerable health problem of the populations in Europe. Complications of influenza are especially present in elderly patients and patients with chronic conditions such as cardiovascular disorders and respiratory disorders. Vaccination is an effective

  1. Prevalence of Self-Reported Gluten Sensitivity and Adherence to a Gluten-Free Diet in Argentinian Adult Population

    Science.gov (United States)

    Cabrera-Chávez, Francisco; Dezar, Gimena V. A.; Islas-Zamorano, Anna P.; Espinoza-Alderete, Jesús G.; Vergara-Jiménez, Marcela J.; Magaña-Ordorica, Dalia; Ontiveros, Noé

    2017-01-01

    Background: Previous studies suggest that the prevalence of wheat/gluten sensitivity and adherence to a gluten-free diet (GFD) are high in Latin population despite a poor diagnosis of celiac disease. However, these prevalence rates still remain unknown in most Latin American countries. Methods: A cross-sectional survey study was conducted in Santa Fe, Argentina. Results: The estimated self-reported prevalence rates were (95% Confidence Interval [CI]): self-reported gluten sensitivity (SR-GS) 7.61% (6.2–9.2), SR-GS currently following a GFD 1.82% (1.2–2.7), celiac disease 0.58% (0.3–1.2), wheat allergy 0.33% (0.12–0.84), self-reported non-celiac gluten sensitivity (SR-NCGS) 6.28% (5.1–7.8), SR-NCGS currently following a GFD 0.91% (0.5–1.6), and adherence to a GFD 6.37% (5.1–7.9). SR-GS was more common in women (6.0%; p < 0.001) and associated with irritable bowel syndrome (p < 0.001). Among the GFD followers, 71.4% were doing it for reasons other than health-related benefits and 50.6% without medical/dietitian advice. In the non-SR-GS group, the main motivations for following a GFD were weight control and the perception that a GFD is healthier. Conclusion: In Argentina, gluten sensitivity is commonly reported and it seems that physicians/gastroenterologists are aware of celiac disease diagnosis. Trustable information about the benefits and potential consequences of following a GFD should be given to the general population. PMID:28117706

  2. Prevalence of Self-Reported Gluten Sensitivity and Adherence to a Gluten-Free Diet in Argentinian Adult Population

    Directory of Open Access Journals (Sweden)

    Francisco Cabrera-Chávez

    2017-01-01

    Full Text Available Background: Previous studies suggest that the prevalence of wheat/gluten sensitivity and adherence to a gluten-free diet (GFD are high in Latin population despite a poor diagnosis of celiac disease. However, these prevalence rates still remain unknown in most Latin American countries. Methods: A cross-sectional survey study was conducted in Santa Fe, Argentina. Results: The estimated self-reported prevalence rates were (95% Confidence Interval [CI]: self-reported gluten sensitivity (SR-GS 7.61% (6.2–9.2, SR-GS currently following a GFD 1.82% (1.2–2.7, celiac disease 0.58% (0.3–1.2, wheat allergy 0.33% (0.12–0.84, self-reported non-celiac gluten sensitivity (SR-NCGS 6.28% (5.1–7.8, SR-NCGS currently following a GFD 0.91% (0.5–1.6, and adherence to a GFD 6.37% (5.1–7.9. SR-GS was more common in women (6.0%; p < 0.001 and associated with irritable bowel syndrome (p < 0.001. Among the GFD followers, 71.4% were doing it for reasons other than health-related benefits and 50.6% without medical/dietitian advice. In the non-SR-GS group, the main motivations for following a GFD were weight control and the perception that a GFD is healthier. Conclusion: In Argentina, gluten sensitivity is commonly reported and it seems that physicians/gastroenterologists are aware of celiac disease diagnosis. Trustable information about the benefits and potential consequences of following a GFD should be given to the general population.

  3. Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles

    NARCIS (Netherlands)

    Ergen, Can; Heymann, Felix; Al Rawashdeh, Wa'el; Gremse, Felix; Bartneck, Matthias; Panzer, Ulf; Pola, Robert; Pechar, Michal; Storm, G; Mohr, Nicole; Barz, Matthias; Zentel, Rudolf; Kiessling, Fabian; Trautwein, Christian; Lammers, Twan; Tacke, Frank

    2017-01-01

    Identifying intended or accidental cellular targets for drug delivery systems is highly relevant for evaluating therapeutic and toxic effects. However, limited knowledge exists on the distribution of nano- and micrometer-sized carrier systems at the cellular level in different organs. We

  4. Anaplastic Lymphoma Kinase Rearrangement in Digestive Tract Cancer: Implication for Targeted Therapy in Chinese Population.

    Directory of Open Access Journals (Sweden)

    Jianming Ying

    Full Text Available Anaplastic lymphoma kinase (ALK rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Tissue microarray (TMA was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH, real-time polymerase chain reaction (qRT-PCR, target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.Among the tested cases, 2 (0.44% CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1. One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.The incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.

  5. Gradient simulation experiments for targeting population heterogeneity in continuous Saccharomyces cerevisiae fermentation

    DEFF Research Database (Denmark)

    Heins, Anna-Lena; Lencastre Fernandes, Rita; Lundin, L.

    of population heterogeneity, a Saccharomyces cerevisiae growth reporter strain based on the expression of green fluorescent protein (GFP) was constructed which allows to perform single cell analysis, and thereby created the possibility to map population heterogeneity. A factorial design experiment of the growth...... experience rapid changes in environmental conditions as they circulate throughout the reactor, which might pose stress on the cells, affect their metabolism and consequently affect the level of heterogeneity of the population. To further investigate these phenomena and gain a deeper understanding...... of the growth rate reporter strain was performed and the physiological changes were analysed on a single cell level. From the simulation experiment it could be demonstrated that glucose had a clear influence on subpopulation distribution....

  6. Sensitivity of condition indices to changing density in a white-tailed deer population

    Science.gov (United States)

    Sams, M.G.; Lochmiller, R.L.; Qualls, C.W.; Leslie, David M.

    1998-01-01

    The ways in which comprehensive condition profiles, incorporating morphometric, histologic, physiologic, and diet quality indices, responded to changes in density of a white-tailed deer (Odocoileus virginianus) population were examined. Changes in these condition indices were monitored in a northeastern Oklahoma deer herd as density declined from peaks of 80 and 72 deer/km2 in 1989 and 1990 (high-density) to lows of 39 and 41 deer/km2 in 1991 and 1992 (reduced-density), respectively. Compared to a reference population (6 deer/km2), deer sampled during high-density exhibited classic signs of nutritional stress such as low body and visceral organ masses (except elevated adrenal gland mass), low fecal nitrogen levels, reduced concentrations of serum albumin, elevated serum creatinine concentrations, and a high prevalence of parasitic infections. Although density declined by one half over the 4-yr study, gross indices of condition (in particular body mass and size) remained largely unchanged. However, selected organ masses, serum albumin and non-protein nitrogen constituents, and fecal nitrogen indices reflected improvements in nutritional status with reductions in density. Many commonly used indices of deer condition (fat reserves, hematocrit, total serum protein, and blood urea nitrogen) were not responsive to fluctuations in density. ?? Wildlife Disease Association 1998.

  7. Targeting population heterogeneity in Saccharomyces cerevisiae batch fermentation for optimal cell factories

    DEFF Research Database (Denmark)

    Heins, Anna-Lena; Lencastre Fernandes, Rita; Lundin, L.

    and affect their metabolism and consequently affect the heterogeneity level of the population. To further investigate these phenomena and gain a deeper understanding of population heterogeneity, Saccharomyces cerevisiae growth reporter strains based on the expression of green fluorescent protein (GFP) were......)). Significant gradients of e.g. dissolved oxygen, substrates, and pH are typically observed in many industrial scale fermentation processes. Consequently, the microbial cells experience rapid changes in environmental conditions as they circulate throughout the reactor, which might pose stress on the cells...

  8. Target recycling amplification for label-free and sensitive colorimetric detection of adenosine triphosphate based on un-modified aptamers and DNAzymes.

    Science.gov (United States)

    Gong, Xue; Li, Jinfu; Zhou, Wenjiao; Xiang, Yun; Yuan, Ruo; Chai, Yaqin

    2014-05-30

    Based on target recycling amplification, the development of a new label-free, simple and sensitive colorimetric detection method for ATP by using un-modified aptamers and DNAzymes is described. The association of the model target molecules (ATP) with the corresponding aptamers of the dsDNA probes leads to the release of the G-quadruplex sequences. The ATP-bound aptamers can be further degraded by Exonuclease III to release ATP, which can again bind the aptamers of the dsDNA probes to initiate the target recycling amplification process. Due to this target recycling amplification, the amount of the released G-quadruplex sequences is significantly enhanced. Subsequently, these G-quadruplex sequences bind hemin to form numerous peroxidase mimicking DNAzymes, which cause substantially intensified color change of the probe solution for highly sensitive colorimetric detection of ATP down to the sub-nanomolar (0.33nM) level. Our method is highly selective toward ATP against other control molecules and can be performed in one single homogeneous solution, which makes our sensing approach hold great potential for sensitive colorimetric detection of other small molecules and proteins. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Most at-risk populations: contextualising HIV prevention programmes targeting marginalised groups in Zanzibar, Tanzania.

    Science.gov (United States)

    Ahmed, Naheed

    2014-09-01

    According to a 2009 UNAIDS report the HIV/AIDS prevalence rate in Zanzibar, Tanzania, is low in the general population (0.6%), but high among vulnerable groups, specifically sex workers (10.8%), injecting drug users (15.1%), and men who have sex with men (12.3%). In response to this concentrated epidemic, the Government of Zanzibar, international and local non-profit organisations have focused their prevention activities on these marginal populations. Although these efforts are beneficial in terms of disseminating information about HIV/AIDS and referring clients to health clinics, they fail to address how the socio-economic status of these groups places them at a greater risk for contracting and dying from the virus. Furthermore, there is an absence of qualitative research on these populations which is needed to understand the challenges these groups face and to improve the effectiveness of interventions. Through interviews with employees of government agencies and non-profit organisations, medical professionals, vulnerable populations and HIV/AIDS patients, this paper used a political economy of health and syndemic framework to examine how local realities inform and challenge HIV/AIDS programmes in Zanzibar.

  10. Contact sensitization to cosmetic series of allergens in a general population in Beijing.

    Science.gov (United States)

    Zhao, Jian; Li, Lin-Feng

    2014-03-01

    Cosmetic allergic contact dermatitis (CACD) due to common cosmetic allergens in standard series has been extensively studied; however, the prevalence of contact allergy to other cosmetic allergens other than those in standard series is largely unknown. In this study, the frequency of contact sensitization to a European cosmetic series of allergens (Chemotechnique Diagnostics, Vellinge, Sweden) in healthy university student volunteers were detected in Beijing. Of 201 students studied, fifty-eight exhibited positive results, and 9 of them reported had cosmetics related dermatitis previously. The total positivity rate was not correlated to gender. The leading allergens were thimerosal (19.4%), shellac (3.0%), cocamidopropyl betaine (2.0%), hexamethylenetetramine (1.5%), dodecyl gallate (1.5%), hexahydro-1,3,5-tris-(2-hydroxyethyl)triazine (1.0%) and methyldibromo glutaronitrile (1.0%). The positivity rate of thimerosal patch test in men (9.8%) was lower than that of women (23.6%, P cosmetic allergens in men and women (P > 0.05, Chi square test). These results suggested that some cosmetic-related contact allergies may be missed by just testing patients with the European standard series or T.R.U.E. test system only, we recommend shellac, cocamidopropyl betaine, hexamethylenetetramine and dodecyl gallate as the additionally candidates for patch testing in patients with suspected CACD. © 2014 Wiley Periodicals, Inc.

  11. Effects of intra- and interspecific competition on the sensitivity of Daphnia magna populations to the fungicide carbendazim.

    Science.gov (United States)

    Del Arco, Ana Isabel; Rico, Andreu; van den Brink, Paul J

    2015-08-01

    The ecological risk assessment of pesticides is generally based on toxicity data obtained from single-species laboratory experiments and does not take into account ecological interactions such as competition or predation. Intraspecific and interspecific competition are expected to result in additional stress and might increase the sensitivity of aquatic populations to pesticide contamination. To test this hypothesis, the effects of the fungicide carbendazim were assessed on the population dynamics of the micro-crustacean Daphnia magna under different levels of intraspecific and interspecific competition for an algal food resource, using the rotifer Brachionus calyciflorus as competing species. The experiments were performed in glass jars with three different carbendazim concentrations (i.e., 50, 100 and 150 µg/L), and had a duration of 25 days, with a 4-day pre-treatment period in which competition was allowed to take place and a 21-day exposure period. The endpoints evaluated were D. magna total population abundance and population structure. Results of these experiments show that competition stress on its own had a significant influence on shaping D. magna population's structure, however, a different response was observed in the intraspecific and interspecific competition experiments. The use of a 4-day pre-treatment period in the intraspecific experiment already led to an absence of interactive effects due to the quick abundance confluence between the different intraspecific treatments, thus not allowing the observation of interactive effects between competition and carbendazim stress. Results of the interspecific competition experiment showed that rotifers were quickly outcompeted by D. magna and that D. magna even profited from the rotifer presence through exploitative competition, which alleviated the original stress caused by the algal resource limitation. These experiments suggest that competition interactions play an important role in defining population

  12. The contribution of age structure to cell population responses to targeted therapeutics.

    Science.gov (United States)

    Gabriel, Pierre; Garbett, Shawn P; Quaranta, Vito; Tyson, Darren R; Webb, Glenn F

    2012-10-21

    Cells grown in culture act as a model system for analyzing the effects of anticancer compounds, which may affect cell behavior in a cell cycle position-dependent manner. Cell synchronization techniques have been generally employed to minimize the variation in cell cycle position. However, synchronization techniques are cumbersome and imprecise and the agents used to synchronize the cells potentially have other unknown effects on the cells. An alternative approach is to determine the age structure in the population and account for the cell cycle positional effects post hoc. Here we provide a formalism to use quantifiable lifespans from live cell microscopy experiments to parameterize an age-structured model of cell population response. Copyright © 2012 Elsevier Ltd. All rights reserved.

  13. Neurochemical differences between target-specific populations of rat dorsal raphe projection neurons.

    Science.gov (United States)

    Prouty, Eric W; Chandler, Daniel J; Waterhouse, Barry D

    2017-11-15

    Serotonin (5-HT)-containing neurons in the dorsal raphe (DR) nucleus project throughout the forebrain and are implicated in many physiological processes and neuropsychiatric disorders. Diversity among these neurons has been characterized in terms of their neurochemistry and anatomical organization, but a clear sense of whether these attributes align with specific brain functions or terminal fields is lacking. DR 5-HT neurons can co-express additional neuroactive substances, increasing the potential for individualized regulation of target circuits. The goal of this study was to link DR neurons to a specific functional role by characterizing cells according to both their neurotransmitter expression and efferent connectivity; specifically, cells projecting to the medial prefrontal cortex (mPFC), a region implicated in cognition, emotion, and responses to stress. Following retrograde tracer injection, brainstem sections from Sprague-Dawley rats were immunohistochemically stained for markers of serotonin, glutamate, GABA, and nitric oxide (NO). 98% of the mPFC-projecting serotonergic neurons co-expressed the marker for glutamate, while the markers for NO and GABA were observed in 60% and less than 1% of those neurons, respectively. To identify potential target-specific differences in co-transmitter expression, we also characterized DR neurons projecting to a visual sensory structure, the lateral geniculate nucleus (LGN). The proportion of serotonergic neurons co-expressing NO was greater amongst cells targeting the mPFC vs LGN (60% vs 22%). The established role of 5-HT in affective disorders and the emerging role of NO in stress signaling suggest that the impact of 5-HT/NO co-localization in DR neurons that regulate mPFC circuit function may be clinically relevant. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. [Which zoonoses should the general population be more awareness of ? Qualitative research targeted at veterinarians].

    Science.gov (United States)

    Horiguchi, Itsuko; Ishikawa, Naoko; Feng, Qiaolian; Kigawa, Mika; Marui, Eiji

    2011-09-01

    The purpose of this study was to determine which zoonoses should the general population be more aware of. We conducted qualitative research (Delphi method) on thirty veterinarians who were selected from the whole country. Twenty-four diseases were selected. The reasons for their selection were classified into three categories: "Amount of knowledge, attitude and behavior", "Clinicoepidemiologic characteristics" and "Social characteristics". More than half of the top ten zoonoses are those that are not transmitted from humans to humans, with rabies in the first place, avian influenza (with its high pathogenicity) in the second place and psittacosis in the third place. From the top ten diseases, it is considered that the prevention of animal-to-human transmission should be emphasized. In addition, from the reasons for the selection, it is suggested that it is necessary to review social characteristics, such as the inadequacy of quarantine and the insufficiencies of legal systems. As for the zoonoses that are transmitted from humans to humans, it will be indispensable in the future to widely spread information on zoonoses and enlighten the general population about them. It is thought that this survey can be a basis for selecting a zoonosis that should be given priority in enlightening the general population.

  15. Sensitivity of oral fluids for detecting influenza A virus in populations of vaccinated and non‐vaccinated pigs

    Science.gov (United States)

    Romagosa, Anna; Gramer, Marie; Joo, Han Soo; Torremorell, Montserrat

    2011-01-01

    Please cite this paper as: Romagosa et al. (2011) Sensitivity of oral fluids for detecting influenza A virus in populations of vaccinated and non‐vaccinated pigs. Influenza and Other Respiratory Viruses. Background/objective  We evaluated the sensitivity of PCR on oral fluids in detecting influenza virus in vaccinated and non‐vaccinated pigs. Methods  Three‐week‐old influenza‐free pigs were divided into three groups: (i) control, non‐vaccinated, (ii) vaccinated with a commercial, heterologous vaccine, and (iii) vaccinated with an experimental, homologous vaccine. After vaccination, an influenza‐infected pig was placed in contact with each of the groups. Individual nasal swabs and pen oral fluids were collected daily. Viral RNA was tested for the presence of influenza by RRT‐PCR and virus isolation attempted from oral fluids. A pen was considered positive if at least one nasal swab was positive. Results  Based on nasal swab results, 43·8% of pens were detected positive but only 35% based on oral fluids. Overall sensitivity of oral fluids was 80%, and virus was isolated from 51% of RRT‐PCR‐positive oral fluids. The kappa coefficient for agreement (ĸ) between oral fluids and nasal swabs was 0·82. Among groups, ĸ was 1 (95% CI, 1–1), 0·74 (95% CI, 0·55–0·92), and 0·76 (95% CI, 0·5–1) for control, heterologous, and homologous‐vaccinated groups, respectively. There was less agreement when within pen prevalence was 10% or less. Probability of detecting influenza virus in oral fluids was 99% when within pen prevalence was higher than 18% and decreased to 69% when prevalence was 9%. Conclusions  Results indicated that pen‐based collection of oral fluids is a sensitive method to detect influenza even when within pen prevalence is low and when pigs have been vaccinated and highlight the potential use of oral fluids for influenza surveillance. PMID:21777397

  16. A distribution-based method for assessing the differences between clinical trial target populations and patient populations in electronic health records.

    Science.gov (United States)

    Weng, C; Li, Y; Ryan, P; Zhang, Y; Liu, F; Gao, J; Bigger, J T; Hripcsak, G

    2014-01-01

    To improve the transparency of clinical trial generalizability and to illustrate the method using Type 2 diabetes as an example. Our data included 1,761 diabetes clinical trials and the electronic health records (EHR) of 26,120 patients with Type 2 diabetes who visited Columbia University Medical Center of New-York Presbyterian Hospital. The two populations were compared using the Generalizability Index for Study Traits (GIST) on the earliest diagnosis age and the mean hemoglobin A1c (HbA1c) values. Greater than 70% of Type 2 diabetes studies allow patients with HbA1c measures between 7 and 10.5, but less than 40% of studies allow HbA1c10.5. In the real-world population, only 38% of patients had HbA1c between 7 and 10.5, with 12% having values above the range and 52% having HbA1cpatients >80 or patients were 80. The GIST for age was 0.75. We contribute a scalable method to profile and compare aggregated clinical trial target populations with EHR patient populations. We demonstrate that Type 2 diabetes studies are more generalizable with regard to age than they are with regard to HbA1c. We found that the generalizability of age increased from Phase 1 to Phase 3 while the generalizability of HbA1c decreased during those same phases. This method can generalize to other medical conditions and other continuous or binary variables. We envision the potential use of EHR data for examining the generalizability of clinical trials and for defining population-representative clinical trial eligibility criteria.

  17. Local and Systemic Changes in Pain Sensitivity After 4 Weeks of Calf Muscle Stretching in a Nonpainful Population

    DEFF Research Database (Denmark)

    Bartholdy, Cecilie; Zangger, Graziella; Hansen, Lisbeth

    2016-01-01

    BACKGROUND: Stretching is often used in clinical practice for a variety of purposes, including pain therapy. The possible mechanism behind the effect of stretching remains to be clarified. AIM: To investigate whether 4 weeks of unilateral stretching of the calf muscles would affect local...... and central pain sensitivity. METHOD: This study was a randomized assessor-blinded clinical study. Healthy participants (age 18 to 40) were included and randomized. Participants in the intervention group were instructed to perform 2 stretching exercises targeting the calf muscles; 3 times 30 seconds, 7 days...... intervention group/19 control group). No statistically significant group differences in the changes from baseline were found regarding PPT and TS measurements for the stretched calf, the contra-lateral calf, and the arm. CONCLUSION: Four weeks of regular stretching of the calf muscles does not affect pressure...

  18. Target population involvement in urban ciclovias: a preliminary evaluation of St. Louis open streets.

    Science.gov (United States)

    Hipp, J Aaron; Eyler, Amy A; Kuhlberg, Jill A

    2013-12-01

    Ciclovias are active street events when roads are open to walkers, cyclists, and families and closed to automobiles. Over 70 cities in the USA have implemented ciclovias to promote physical activity. The authors evaluated four events during 2010 to determine what activities participants perform and who is attending. For two ciclovia events in St. Louis, Missouri, observation reports of activities, gender, and age of 1,452 participants were collected, and 82 adults were interviewed via direct approach. The survey covered six domains: physical activity, travel to event, sense of community, marketing, economic impact, and demographics. Each event occurred within the city, along multiple streets. Domains were selected from Ciclovia Recreativa developed by Ciclovia Bogota, Pan American Health Organization, and CDC. Additional questions addressed city-specific goals and matched similar evaluations in other cities. Over 50 % of participants met CDC-defined weekly minute thresholds for physical activity. Participants, primarily (>80 %) middle class, college educated, and white, were not representative of the majority minority city population, which has high rates of poverty, and low percentage of college graduates. Cities must work with residents to increase low-income minority population participation in ciclovia-based physical activity.

  19. Future Freshwater Stress on Small Islands: Population, Aridity and Global Warming Targets

    Science.gov (United States)

    Karnauskas, K. B.; Schleussner, C. F.; Donnelly, J. P.; Anchukaitis, K. J.

    2017-12-01

    Small island developing states (SIDS) face multiple threats from anthropogenic climate change, including potential changes in freshwater resource availability. Future freshwater stress, including geographic and seasonal variability, has important implications for climate change adaptation scenarios for vulnerable human populations living on islands across the world ocean. Due to a mismatch in spatial scale between SIDS landforms and the horizontal resolution of global climate models (GCMs), SIDS are mostly unaccounted for in GCMs that are used to make future projections of global climate change and its regional impacts. Specific approaches are required to address this gap between broad-scale model projections and regional, policy-relevant outcomes. Here we apply a recently developed methodology to project future changes in aridity in combination with population projections associated with different shared socioeconomic pathways (SSPs) to evaluate overall changes in freshwater stress in SIDS at warming levels of 1.5°C and 2°C above pre-industrial levels. By accounting for evaporative demand a posteriori, we reveal a robust yet spatially variable tendency towards increasing aridity for 16 million people living on islands by mid-century. Although about half of the islands are projected to experience increased rainfall—predominantly in the deep tropics—projected changes in evaporation are more uniform, shifting the global distribution of changes in island freshwater balance towards greater aridity. In many cases, the magnitude of projected drying is comparable to the amplitude of the estimated observed interannual variability, with important consequences for extreme events. While we find that future population growth will dominate changes in projected freshwater stress especially towards the end of the century, projected changes in aridity are found to compound freshwater stress for the vast majority of SIDS. Particularly across the Caribbean region, a

  20. Characterization of the rate and temperature sensitivities of bacterial remineralization of dissolved organic phosphorus by natural populations

    Directory of Open Access Journals (Sweden)

    Angelicque E. White

    2012-08-01

    Full Text Available Production, transformation, and degradation are the principal components of the cycling of dissolved organic matter (DOM in marine systems. Heterotrophic Bacteria (and Archaea play a large part in this cycling via enzymatic decomposition and intracellular transformations of organic material to inorganic carbon (C, nitrogen (N , and phosphorus (P. The rate and magnitude of inorganic nutrient regeneration from DOM is related to the elemental composition and lability of DOM substrates as well as the nutritional needs of the mediating organisms. While many previous efforts have focused on C and N cycling of DOM, less is known in regards to the controls of organic P utilization and remineralization by natural populations of bacteria. In order to constrain the relative time scales and degradation of select dissolved organic P (DOP compounds we have conducted a series of experiments focused on (1 assessment of the short-term lability of a range of DOP compounds, (2 characterization of labile DOP remineralization rates and (3 examination of temperature sensitivities of labile DOP remineralization for varying bacterial populations. Results reinforce previous findings of monoester and polyphosphate lability and the relative recalcitrance of a model phosphonate: 2-aminoethylphosphonate. High resolution time-series of P monoester remineralization indicates decay constants on the order of 0.67-7.04 d-1 for bacterial populations isolated from coastal and open ocean surface waters. The variability of these rates is predictably related to incubation temperature and initial concentrations of heterotrophic bacteria. Additional controls on DOP hydrolysis included seasonal shifts in bacterial populations and the physiological state of bacteria at the initiation of DOP addition experiments. Composite results indicate that bacterial hydrolysis of P-monoesters exceeds bacterial P demand and thus DOP remineralization efficiency may control P availability to autotrophs.

  1. Stepwise targeted drug delivery to liver cancer cells for enhanced therapeutic efficacy by galactose-grafted, ultra-pH-sensitive micelles.

    Science.gov (United States)

    Yan, Guoqing; Wang, Jun; Hu, Liefeng; Wang, Xin; Yang, Guanqing; Fu, Shengxiang; Cheng, Xu; Zhang, Panpan; Tang, Rupei

    2017-03-15

    To promote drug accumulation and cell-killing ability at tumor tissue, we have prepared a stepwise targeted drug delivery system that can remain stealthy and long-circulating in the blood vessels, improve drug retention at extracellular stimuli, enhance cellular uptake through special targeting ligands, and then achieve rapid drug release to improve toxicity to tumor cells at intracellular stimuli. Herein, galactose-grafted, ultra-pH-sensitive drug carriers (POEAd-g-LA-DOX micelles), which could respond to both extracellular and intracellular pH, and combine with galactose-receptors in cell membrane, were constructed by a facile method, therefore achieving: (i) remaining stable at pH 7.4; (ii) responding to tumoral extracellular pH following gradually larger nanoparticles (NPs); (iii) conjugating receptors in the cell membrane of liver cancer through surface galactose-ligands of micelles; (iv) being sensitive to tumoral intracellular pH following further swelling for rapid drug release. In vitro cytotoxicity and cellular uptake measurement showed that POEAd-g-LA20-DOX micelle was more easily internalized and more toxic effect on tumor cells than free DOX. Moreover, in vivo biodistribution and tumor inhibition examinations demonstrated that POEAd-g-LA20-DOX formulation had more superior efficacy to significantly enhance drug accumulation in tumor, and then restrain tumor growth while decreasing drug concentration in heart. Chemotherapeutic efficacy is limited by poor tumor selectivity, which also causes severe toxicity in normal tissues and organs, although many targeted drug delivery systems have been developed by passive targeting strategies or active targeting strategies with specific targeting ligands in recent years. Herein, galactose-grafted, ultra-pH-sensitive, ortho ester-based drug carriers, which can respond to both extracellular and intracellular pH, and target to galactose-receptors in cell membrane, have been successfully constructed by facile method

  2. Target-site resistance to pyrethroids in European populations of pollen beetle, Meligethes aeneus F

    DEFF Research Database (Denmark)

    Nauen, Ralf; Zimmer, Christoph T; Andrews, Melanie

    2012-01-01

    detected a single nucleotide change that results in an amino acid substitution (L1014F) within the domain IIS6 region of the channel protein. The L1014F mutation, often termed kdr, has been found in several other insect pests and is known to confer moderate levels of resistance to pyrethroids. We developed......Pollen beetle, Meligethes aeneus F. (Coleoptera: Nitidulidae) is a major univoltine pest of oilseed rape in many European countries. Winter oilseed rape is cultivated on several million hectares in Europe and the continuous use of pyrethroid insecticides to control pollen beetle populations has...... resulted in high selection pressure and subsequent development of resistance. Resistance to pyrethroid insecticides in this pest is now widespread and the levels of resistance are often sufficient to result in field control failures at recommended application rates. Recently, metabolic resistance mediated...

  3. Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population.

    Science.gov (United States)

    Tatlisumak, Turgut; Putaala, Jukka; Innilä, Markus; Enzinger, Christian; Metso, Tiina M; Curtze, Sami; von Sarnowski, Bettina; Amaral-Silva, Alexandre; Jungehulsing, Gerhard Jan; Tanislav, Christian; Thijs, Vincent; Rolfs, Arndt; Norrving, Bo; Fazekas, Franz; Suomalainen, Anu; Kolodny, Edwin H

    2016-02-01

    Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (≤165 cm for males; ≤155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A>G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A>G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.

  4. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam; Ardell, Jeffrey L

    2016-11-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. Copyright © 2016 the American Physiological Society.

  5. PSCC: sensitive and reliable population-scale copy number variation detection method based on low coverage sequencing.

    Directory of Open Access Journals (Sweden)

    Xuchao Li

    Full Text Available BACKGROUND: Copy number variations (CNVs represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS we have developed an effective population-scale CNV calling (PSCC method. METHODOLOGY/PRINCIPAL FINDINGS: In our novel method, two-step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100% and 98.6%/100% sensitivity and specificity for over 300 kb CNV calling in the condition of LCS (∼2× and ultra LCS (∼0.2×, respectively. Finally, we applied this novel method to analyze 34 clinical samples with an average of 2× LCS. In the final results, all the 31 pathogenic CNVs identified by aCGH were successfully detected. In addition, the performance comparison revealed that our method had significant advantages over existing methods using ultra LCS. CONCLUSIONS/SIGNIFICANCE: Our study showed that PSCC can sensitively and reliably detect CNVs using low coverage or even ultra-low coverage data through population-scale sequencing.

  6. Assessing multi-taxa sensitivity to the human footprint, habitat fragmentation and loss by exploring alternative scenarios of dispersal ability and population size: A simulation approach

    Science.gov (United States)

    Brian K. Hand; Samuel A. Cushman; Erin L. Landguth; John Lucotch

    2014-01-01

    Quantifying the effects of landscape change on population connectivity is compounded by uncertainties about population size and distribution and a limited understanding of dispersal ability for most species. In addition, the effects of anthropogenic landscape change and sensitivity to regional climatic conditions interact to strongly affect habitat...

  7. Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release.

    Science.gov (United States)

    Kern, Aurelie; Zhou, Chensheng W; Jia, Feng; Xu, Qiaobing; Hu, Linden T

    2016-08-31

    The incidence of Lyme disease has continued to rise despite attempts to control its spread. Vaccination of zoonotic reservoirs of human pathogens has been successfully used to decrease the incidence of rabies in raccoons and foxes. We have previously reported on the efficacy of a vaccinia virus vectored vaccine to reduce carriage of Borrelia burgdorferi in reservoir mice and ticks. One potential drawback to vaccinia virus vectored vaccines is the risk of accidental infection of humans. To reduce this risk, we developed a process to encapsulate vaccinia virus with a pH-sensitive polymer that inactivates the virus until it is ingested and dissolved by stomach acids. We demonstrate that the vaccine is inactive both in vitro and in vivo until it is released from the polymer. Once released from the polymer by contact with an acidic pH solution, the virus regains infectivity. Vaccination with coated vaccinia virus confers protection against B. burgdorferi infection and reduction in acquisition of the pathogen by naïve feeding ticks. Copyright © 2016. Published by Elsevier Ltd.

  8. Two rhodamine lactam modulated lysosome-targetable fluorescence probes for sensitively and selectively monitoring subcellular organelle pH change

    International Nuclear Information System (INIS)

    Li, Hongmei; Wang, Cuiling; She, Mengyao; Zhu, Yuelu; Zhang, Jidong; Yang, Zheng; Liu, Ping; Wang, Yaoyu; Li, Jianli

    2015-01-01

    Be a powerful technique for convenient detection of pH change in living cells, especially at subcellular level, fluorescent probes has attracted more and more attention. In this work, we designed and synthesized three rhodamine lactam modulated fluorescent probes RS1, RS2 and RS3, which all respond sensitively toward weak acidity (pH range 4–6) via the photophysical property in buffer solution without interference from the other metal ions, and they also show ideal pKa values and excellent reversibility. Particularly, by changing the lone pair electrons distribution of lactam-N atom with different conjugations, RS2 and RS3 exhibit high quantum yield, negligible cytotoxicity and excellent permeability. They are suitable to stain selectively lysosomes of tumor cells and monitor its pH changes sensitively via optical molecular imaging. The above findings suggest that the probes we designed could act as ideal and easy method for investigating the pivotal role of H + in lysosomes and are potential pH detectors in disease diagnosis through direct intracellular imaging. - Highlights: • Two probes for sensitively and selectively monitoring weak acidic pH change. • The pKa of the probes was highly suitable for staining lysosomes in tumor cells. • The properties of those probes were changed by different conjugate system. • These probes have negligible cytotoxicity and good sensitivity in vivo.

  9. [Interval cancers and episode sensitivity in population-based screening programmes for colorectal cancer: a systematic review].

    Science.gov (United States)

    Domènech, Xènia; Garcia, Montse; Benito, Llúcia; Binefa, Gemma; Vidal, Carmen; Milà, Núria; Moreno, Víctor

    2015-01-01

    To describe interval cancers (IC) and the sensitivity of colorectal cancer (CRC) screening programmes. A systematic review of the literature was conducted through a MEDLINE (PubMed) search. The search strategy combined the terms 'interval cancer', 'false negative', 'mass screening', 'screening' 'early detection of cancer', 'colorectal cancer' and 'bowel cancer'. Inclusion criteria consisted of population-based screening programmes, original articles written in English or Spanish and publication dates between 1999/01/01 and 2015/02/28. A narrative synthesis of the included articles was performed detailing the characteristics of the screening programmes, the IC rate, and the information sources used in each study. Thirteen articles were included. The episode sensitivity of CRC screening programmes ranged from 42.2% to 65.3% in programmes using the guaiac test and between 59.1% and 87.0% with the immunochemical test. We found a higher proportion of women who were diagnosed with IC and these lesions were mainly located in the proximal colon. There is wide variability in the IC rate in CRC programmes. To ensure comparability between programmes, there is a need for consensus on the working definition of IC and the methods used for their identification and quantification. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  10. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J. Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam

    2016-01-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. PMID:27591222

  11. Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models

    Directory of Open Access Journals (Sweden)

    Andre Cassell

    2012-11-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC is characterized by overexpression of the epidermal growth factor receptor (EGFR where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473, phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

  12. Targeting pro-apoptotic trail receptors sensitizes HeLa cervical cancer cells to irradiation-induced apoptosis

    NARCIS (Netherlands)

    Maduro, John H.; de Vries, Elisabeth G. E.; Meersma, Gert-Jan; Hougardy, Brigitte M. T.; van der Zee, Ate G. J.; De Jong, Steven

    2008-01-01

    Purpose: To investigate the potential of irradiation in combination with drugs targeting the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor (DR)4 and DR5 and their mechanism of action in a cervical cancer cell line. Methods and Materials: Recombinant human TRAIL

  13. Targeting TORC1/2 enhances sensitivity to EGFR inhibitors in head and neck cancer preclinical models.

    Science.gov (United States)

    Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

    2012-11-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC.

  14. Targeting TORC1/2 Enhances Sensitivity to EGFR Inhibitors in Head and Neck Cancer Preclinical Models1

    Science.gov (United States)

    Cassell, Andre; Freilino, Maria L; Lee, Jessica; Barr, Sharon; Wang, Lin; Panahandeh, Mary C; Thomas, Sufi M; Grandis, Jennifer R

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is characterized by overexpression of the epidermal growth factor receptor (EGFR) where treatments targeting EGFR have met with limited clinical success. Elucidation of the key downstream-pathways that remain activated in the setting of EGFR blockade may reveal new therapeutic targets. The present study was undertaken to test the hypothesis that inhibition of the mammalian target of rapamycin (mTOR) complex would enhance the effects of EGFR blockade in HNSCC preclinical models. Treatment of HNSCC cell lines with the newly developed TORC1/TORC2 inhibitor OSI-027/ASP4876 resulted in dose-dependent inhibition of proliferation with abrogation of phosphorylation of known downstream targets including phospho-AKT (Ser473), phospho-4E-BP1, phospho-p70s6K, and phospho-PRAS40. Furthermore, combined treatment with OSI-027 and erlotinib resulted in enhanced biochemical effects and synergistic growth inhibition in vitro. Treatment of mice bearing HNSCC xenografts with a combination of the Food and Drug Administration (FDA)-approved EGFR inhibitor cetuximab and OSI-027 demonstrated a significant reduction of tumor volumes compared with either treatment alone. These findings suggest that TORC1/TORC2 inhibition in conjunction with EGFR blockade represents a plausible therapeutic strategy for HNSCC. PMID:23226094

  15. Upregulation of miR-146a increases cisplatin sensitivity of the non-small cell lung cancer A549 cell line by targeting JNK-2.

    Science.gov (United States)

    Pang, Linrong; Lu, Jinger; Huang, Jia; Xu, Caihong; Li, Hui; Yuan, Guangbo; Cheng, Xiaochun; Chen, Jun

    2017-12-01

    The aim of the present study was to investigate the effects of microRNA (miR-)146a on the cisplatin sensitivity of the non-small cell lung cancer (NSCLC) A549 cell line and study the underlying molecular mechanism. The differences in expression of miRNAs between A549 and A549/cisplatin (A549/DDP) cells were determined, and miR-146a was selected to study its effect on cisplatin sensitivity of A549/DDP cells. miR-146a mimic and inhibitor transient transfection systems were constructed using vectors, and A549/DDP cells were infected with miR-146a mimic and inhibitor to investigate growth, apoptosis and migration. The directed target of miR-146a was determined and the underlying molecular mechanism was validated in the present study. The results of the present study demonstrated that miR-146a was downregulated in NSCLC A549/DDP cells, compared with A549 cells. The overexpression of miR-146a induced apoptosis and inhibited the growth and invasion of A549/DDP cells, which resulted in increased cisplatin sensitivity in NSCLC cells. The JNK2 gene was determined as the direct target of miR-146a, and may be activated by the overexpression of miR-146a. Additionally, JNK2 activated the expression of p53 and inhibited B cell lymphoma 2. The upregulation of miR-146a increased cisplatin sensitivity of the A549 cell line by targeting JNK2, which may provide a novel method for treating NSCLC cisplatin resistance.

  16. Long-Gradient Separations Coupled with Selected Reaction Monitoring for Highly Sensitive, Large Scale Targeted Protein Quantification in a Single Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Tujin; Fillmore, Thomas L.; Gao, Yuqian; Zhao, Rui; He, Jintang; Schepmoes, Athena A.; Nicora, Carrie D.; Wu, Chaochao; Chambers, Justin L.; Moore, Ronald J.; Kagan, Jacob; Srivastava, Sudhir; Liu, Alvin Y.; Rodland, Karin D.; Liu, Tao; Camp, David G.; Smith, Richard D.; Qian, Weijun

    2013-10-01

    Long-gradient separations coupled to tandem MS were recently demonstrated to provide a deep proteome coverage for global proteomics; however, such long-gradient separations have not been explored for targeted proteomics. Herein, we investigate the potential performance of the long-gradient separations coupled with selected reaction monitoring (LG-SRM) for targeted protein quantification. Direct comparison of LG-SRM (5 h gradient) and conventional LC-SRM (45 min gradient) showed that the long-gradient separations significantly reduced background interference levels and provided an 8- to 100-fold improvement in LOQ for target proteins in human female serum. Based on at least one surrogate peptide per protein, an LOQ of 10 ng/mL was achieved for the two spiked proteins in non-depleted human serum. The LG-SRM detection of seven out of eight endogenous plasma proteins expressed at ng/mL or sub-ng/mL levels in clinical patient sera was also demonstrated. A correlation coefficient of >0.99 was observed for the results of LG-SRM and ELISA measurements for prostate-specific antigen (PSA) in selected patient sera. Further enhancement of LG-SRM sensitivity was achieved by applying front-end IgY14 immunoaffinity depletion. Besides improved sensitivity, LG-SRM offers at least 3 times higher multiplexing capacity than conventional LC-SRM due to ~3-fold increase in average peak widths for a 300-min gradient compared to a 45-min gradient. Therefore, LG-SRM holds great potential for bridging the gap between global and targeted proteomics due to its advantages in both sensitivity and multiplexing capacity.

  17. Membrane fatty acid composition of different target populations: Importance of baseline on supplementation

    Directory of Open Access Journals (Sweden)

    Veronica Silva

    2015-09-01

    Full Text Available Omega-3 fatty acids (n-3 FA supplementation has been widely used regardless the initial FA composition of the studied population. In this work we compared the red blood cell FA (RBC-FA composition in healthy and different diseased populations at baseline and show how this affects the incorporation of n-3 FA supplementation in ICU-trauma patients. Blood was drawn from Healthy (H, n = 22, Psoriasis (P, n = 13, Cancer(C, n = 81, Geriatric (G, n = 49, Social-phobia (SP, n = 27 and ICU-trauma (T, n = 40 patients before n-3 FA supplementation. For the T group blood was also drawn 8 days after receiving a formula with 4.1 g/L EPA and 5.5 g/L GLA (Oxepa, Abbott. RBC-FA was assessed by gas chromatography and the percentage of each FA was calculated in relation to the total identified FAs. Baseline RBC-FA profile was significantly different between groups (p < 0.0001 with subjects in the healthy group having higher n-3 FA status. H and SP showed the highest content in total n-3 FA (11.89 ± 0.22% H vs 7.45 ± 0.26% T and EPA (1.61 ± 0.03% H vs 0.41 ± 0.13% P. DHA was higher in C and H than in the other groups (6.15 ± 0.15% C vs 4.32 ± 0.11% T. ARA was highest in C (16.04 ± 0.20% C vs 14.85 ± 0.22% H and comparable in the rest of the groups. The n-6/n-3 ratio was lowest for H and highest for T (2.75 ± 0.07 vs 4.96 ± 0.13. Moreover, we showed that for the T group, the treatment-associated changes in the n-3 content are dependent on the initial n-3 FA status, since a negative correlation between the baseline omega 3 index (EPA + DHA and its change after supplementation was found (p = 0.002, r2 = 0.219. We conclude that RBC-FA profile should be evaluated and considered individually for each patient or groups before generalized supplementation schemes, strengthening the concept of personalized medicine.

  18. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression

    International Nuclear Information System (INIS)

    Paschall, Amy V; Bielawska, Alicja; Liu, Kebin; Zimmerman, Mary A; Torres, Christina M; Yang, Dafeng; Chen, May R; Li, Xia; Bieberich, Erhard; Bai, Aiping; Bielawski, Jacek

    2014-01-01

    Ceramide is a bioeffector that mediates various cellular processes, including apoptosis. However, the mechanism underlying ceramide function in apoptosis is apparently cell type-dependent and is not well-understood. We aimed at identifying molecular targets of ceramide in metastatic human colon and breast cancer cells, and determining the efficacy of ceramide analog in suppression of colon and breast cancer metastasis. The activity of and mechanism underlying ceramide as a cytotoxic agent, and as a sensitizer for Fas-mediated apoptosis was analyzed in human cell lines established from primary or metastatic colon and breast cancers. The efficacy of ceramide analog LCL85 in suppression of metastasis was examined in preclinical mouse tumor models. Exposure of human colon carcinoma cells to ceramide analog LCL85 results in apoptosis in a dose-dependent manner. Interestingly, a sublethal dose of LCL85 increased C16 ceramide content and overcame tumor cell resistance to Fas-mediated apoptosis. Subsequently, treatment of tumor cells with exogenous C16 ceramide resulted in increased tumor cell sensitivity to Fas-mediated apoptosis. LCL85 resembles Smac mimetic BV6 in sensitization of colon carcinoma cells to Fas-mediated apoptosis by inducing proteasomal degradation of cIAP1 and xIAP proteins. LCL85 also decreased xIAP1 and cIAP1 protein levels and sensitized metastatic human breast cancer cells to Fas-mediated apoptosis. Silencing xIAP and cIAP1 with specific siRNAs significantly increased the metastatic human colon carcinoma cell sensitivity to Fas-mediated apoptosis, suggesting that IAP proteins mediate apoptosis resistance in metastatic human colon carcinoma cells and ceramide induces IAP protein degradation to sensitize the tumor cells to apoptosis induction. Consistent with its apoptosis sensitization activity, subtoxic doses of LCL85 suppressed colon carcinoma cell metastatic potential in an experimental lung metastasis mouse model, as well as breast cancer growth

  19. Spatial and population drivers of persistent cholera transmission in rural Bangladesh: Implications for vaccine and intervention targeting.

    Science.gov (United States)

    Nazia, Nushrat; Ali, Mohammad; Jakariya, Md; Nahar, Quamrun; Yunus, Mohammad; Emch, Michael

    2018-02-01

    We identify high risk clusters and measure their persistence in time and analyze spatial and population drivers of small area incidence over time. The geographically linked population and cholera surveillance data in Matlab, Bangladesh for a 10-year period were used. Individual level data were aggregated by local 250 × 250 m communities. A retrospective space-time scan statistic was applied to detect high risk clusters. Generalized estimating equations were used to identify risk factors for cholera. We identified 10 high risk clusters, the largest of which was in the southern part of the study area where a smaller river flows into a large river. There is persistence of local spatial patterns of cholera and the patterns are related to both the population composition and ongoing spatial diffusion from nearby areas over time. This information suggests that targeting interventions to high risk areas would help eliminate locally persistent endemic areas. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA.

    Science.gov (United States)

    Zhang, Qing-An; Yang, Xu-Hai; Chen, Dong; Yan, Xiang; Jing, Fu-Chun; Liu, Hong-Qian; Zhang, Ronghua

    2018-01-01

    miR-34 was deregulated in tumor tissues compared with corresponding noncancerous tissue samples. Furthermore, miR-34 may contribute to cancer-stromal interaction associated with cancer progression. However, whether miR-34 could decrease chemoresistance of cancer cells to chemotherapeutic agent remains unclear. In our study, we examined whether overexpression of miR-34 could sensitize gemcitabine -mediated apoptosis in human pancreatic cancer PANC-1 cells. We found that miR-34 markedly induced gemcitabine -mediated apoptosis in PANC-1 cells. miR-34 induced down-regulation of Slug expression and upregulation of p53 up-regulated modulator of apoptosis (PUMA) expression. The over-expression of Slug or downregulation of PUMA by Slug cDNA or PUMA siRNA transfection markedly blocked miR-34-induced gemcitabine sensitization. Furthermore, miR-34 induced PUMA expression by downregulation of Slug. Taken together, our study demonstrates that miR-34 enhances sensitization against gemcitabine-mediated apoptosis through the down-regulation of Slug expression, and up-regulation of Slug-dependent PUMA expression.

  1. Ammonium tetrathiomolybdate treatment targets the copper transporter ATP7A and enhances sensitivity of breast cancer to cisplatin

    OpenAIRE

    Chisholm, Cristine L.; Wang, Haitao; Wong, Ada Hang-Heng; Vazquez-Ortiz, Guelaguetza; Chen, Weiping; Xu, Xiaoling; Deng, Chu-Xia

    2016-01-01

    Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) ...

  2. MicroRNA-9 functions as a tumor suppressor and enhances radio-sensitivity in radio-resistant A549 cells by targeting neuropilin 1.

    Science.gov (United States)

    Xiong, Kai; Shao, Li Hong; Zhang, Hai Qin; Jin, Linlin; Wei, Wei; Dong, Zhuo; Zhu, Yue Quan; Wu, Ning; Jin, Shun Zi; Xue, Li Xiang

    2018-03-01

    Radiotherapy is commonly used to treat lung cancer but may not kill all cancer cells, which may be attributed to the radiotherapy resistance that often occurs in non-small cell lung cancer (NSCLC). At present, the molecular mechanism of radio-resistance remains unclear. Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF), was demonstrated to be associated with radio-resistance of NSCLC cells via the VEGF-phosphoinositide 3-kinase-nuclear factor-κB pathway in our previous study. It was hypothesized that certain microRNAs (miRs) may serve crucial functions in radio-sensitivity by regulating NRP1. Bioinformatics predicted that NRP1 was a potential target of miR-9, and this was validated by luciferase reporter assays. Functionally, miR-9-transfected A549 cells exhibited a decreased proliferation rate, increased apoptosis rate and attenuated migratory and invasive abilities. Additionally, a high expression of miR-9 also significantly enhanced the radio-sensitivity of A549 cells in vitro and in vivo . These data improve understanding of the mechanisms of cell radio-resistance, and suggest that miR-9 may be a molecular target for the prediction of radio-sensitivity in NSCLC.

  3. [Experience of knowledge translation in the ITSAL (immigration, work and health) research project with representatives of the target population].

    Science.gov (United States)

    Ronda, Elena; López-Jacob, M José; Paredes-Carbonell, Joan J; López, Pilar; Boix, Pere; García, Ana M

    2014-01-01

    This article describes the experience of knowledge translation between researchers of the ITSAL (immigration, work and health) project and representatives of organizations working with immigrants to discuss the results obtained in the project and future research lines. A meeting was held, attended by three researchers and 18 representatives from 11 institutions. Following a presentation of the methodology and results of the project, the participants discussed the results presented and research areas of interest, thus confirming matches between the two sides and obtaining proposals of interest for the ITSAL project. We understand the process described as an approach to social validation of some of the main results of this project. This experience has allowed us to open a channel of communication with the target population of the study, in line with the necessary two-way interaction between researchers and users. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

  4. Support for National Health Insurance Seven Years Into Massachusetts Healthcare Reform: Views of Populations Targeted by the Reform.

    Science.gov (United States)

    Saluja, Sonali; Zallman, Leah; Nardin, Rachel; Bor, David; Woolhandler, Steffie; Himmelstein, David U; McCormick, Danny

    2016-01-01

    Before the Affordable Care Act (ACA), many surveys showed majority support for national health insurance (NHI), also known as single payer; however, little is currently known about views of the ACA's targeted population. Massachusetts residents have had seven years of experience with state health care reform that became the model for the ACA. We surveyed 1,151 adults visiting safety-net emergency departments in Massachusetts in late 2013 on their preference for NHI or the Massachusetts reform and on their experiences with insurance. Most of the patients surveyed were low-income and non-white. The majority of patients (72.0%) preferred NHI to the Massachusetts reform. Support for NHI among those with public insurance, commercial insurance, and no insurance was 68.9%, 70.3%, and 86.3%, respectively (p reform, a reappraisal of the ACA's ability to meet the needs of underserved patients is warranted. © The Author(s) 2015.

  5. A versatile and highly sensitive homogeneous electrochemical strategy based on the split aptamer binding-induced DNA three-way junction and exonuclease III-assisted target recycling.

    Science.gov (United States)

    Hou, Ting; Li, Wei; Zhang, Lianfang; Li, Feng

    2015-08-21

    Herein, a highly sensitive and versatile homogeneous electrochemical biosensing strategy is proposed, based on the split aptamer-incorporated DNA three-way junction and the exonuclease (Exo) III-assisted target recycling. The aptamer of adenosine triphosphate (ATP, chosen as the model analyte) is split into two fragments and embedded in single-stranded DNA1 and DNA2, respectively. ATP specifically binds with the split aptamers, bringing DNA1 and DNA2 close to each other, thus inducing the DNA three-way junction formation through the partial hybridization among DNA1, DNA2 and the methylene blue-labelled MB-DNA. Subsequently, MB-DNA is specifically digested by Exo III, releasing a MB-labelled mononucleotide, as well as a DNA1-ATP-DNA2 complex, which acts as the recycled target and hybridizes with another intact MB-DNA to initiate the subsequent cycling cleavage process. As a result, large amounts of MB-labelled mononucleotides are released, generating a significantly amplified electrochemical signal toward the ATP assay. To the best of our knowledge, it is the first example to successfully incorporate split aptamers into DNA three-way junctions and to be adopted in a homogeneous electrochemical assay. In addition to high sensitivity, this strategy also exhibits the advantages of simplicity and convenience, because it is carried out in a homogeneous solution, and sophisticated electrode modification processes are avoided. By simply changing the sequences of the split aptamer fragments, this versatile strategy can be easily adopted to assay a large spectrum of targets. Due to its advantages of high sensitivity, excellent selectivity, versatility and simple operation, the as-proposed approach has great potential to be applied in biochemical research and clinical practices.

  6. Sleep disturbances and severe stress as glial activators: key targets for treating central sensitization in chronic pain patients?

    Science.gov (United States)

    Nijs, Jo; Loggia, Marco L; Polli, Andrea; Moens, Maarten; Huysmans, Eva; Goudman, Lisa; Meeus, Mira; Vanderweeën, Luc; Ickmans, Kelly; Clauw, Daniel

    2017-08-01

    The mechanism of sensitization of the central nervous system partly explains the chronic pain experience in many patients, but the etiological mechanisms of this central nervous system dysfunction are poorly understood. Recently, an increasing number of studies suggest that aberrant glial activation takes part in the establishment and/or maintenance of central sensitization. Areas covered: This review focused on preclinical work and mostly on the neurobiochemistry studied in animals, with limited human studies available. Glial overactivation results in a low-grade neuroinflammatory state, characterized by high levels of BDNF, IL-1β, TNF-α, which in turn increases the excitability of the central nervous system neurons through mechanisms like long-term potentiation and increased synaptic efficiency. Aberrant glial activity in chronic pain might have been triggered by severe stress exposure, and/or sleeping disturbances, each of which are established initiating factors for chronic pain development. Expert opinion: Potential treatment avenues include several pharmacological options for diminishing glial activity, as well as conservative interventions like sleep management, stress management and exercise therapy. Pharmacological options include propentofylline, minocycline, β -adrenergic receptor antagonists, and cannabidiol. Before translating these findings from basic science to clinical settings, more human studies exploring the outlined mechanisms in chronic pain patients are needed.

  7. Differential effects of drugs targeting cancer stem cell (CSC and non-CSC populations on lung primary tumors and metastasis.

    Directory of Open Access Journals (Sweden)

    Leyre Larzabal

    Full Text Available Cancer stem cells (CSCs are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05, whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05. Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster

  8. Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.

    Science.gov (United States)

    Kalsner, Louisa; Twachtman-Bassett, Jennifer; Tokarski, Kristin; Stanley, Christine; Dumont-Mathieu, Thyde; Cotney, Justin; Chamberlain, Stormy

    2017-12-21

    Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well. We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database. We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database. The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that

  9. A Sensitive in Vitro High-Throughput Screen To Identify Pan-filoviral Replication Inhibitors Targeting the VP35–NP Interface

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Gai; Nash, Peter J.; Johnson, Britney; Pietzsch, Colette; Ilagan, Ma. Xenia G.; Bukreyev, Alexander; Basler, Christopher F.; Bowlin, Terry L.; Moir, Donald T.; Leung, Daisy W.; Amarasinghe, Gaya K. (WU-MED); (GSU); (Texas-MED); (Microbiotix)

    2017-01-24

    The 2014 Ebola outbreak in West Africa, the largest outbreak on record, highlighted the need for novel approaches to therapeutics targeting Ebola virus (EBOV). Within the EBOV replication complex, the interaction between polymerase cofactor, viral protein 35 (VP35), and nucleoprotein (NP) is critical for viral RNA synthesis. We recently identified a peptide at the N-terminus of VP35 (termed NPBP) that is sufficient for interaction with NP and suppresses EBOV replication, suggesting that the NPBP binding pocket can serve as a potential drug target. Here we describe the development and validation of a sensitive high-throughput screen (HTS) using a fluorescence polarization assay. Initial hits from this HTS include the FDA-approved compound tolcapone, whose potency against EBOV infection was validated in a nonfluorescent secondary assay. High conservation of the NP–VP35 interface among filoviruses suggests that this assay has the capacity to identify pan-filoviral inhibitors for development as antivirals.

  10. [MiR-18a Can Regulate Chemotherapy Sensitivity of Leukemia Cell HL-60 to VP-16 and VCR by Targeting ATM].

    Science.gov (United States)

    Xiao, Yue; Hu, Rong

    2015-08-01

    To investigate the regulatory effects of miR-18a on chemotherapeutic sensitivity of leukemia cell HL-60 to VP-16 and VCR, and explore its molecular mechamism. The HL-60 PC DNA3.1-miR-18A cell line with stably overexpressing miR-18a was constructed and their sensitivity to VP-16 and VCR was detected. The luciferase reporter vector of ATM 3'UTR region was constructed and the targeting effect of miR-18a on ATM was identified. The expression level of ATM in HL-60 cells overexpressing miR-18a was detected by Western blot. The seusitivity of HL-60 cells with knockdown of ATM to VP-16 and VCR was detected by CCK-8 method. The ATM expression level in HL-60 cells with stably overexpression miR-18a after transfection of miR-18a inhibitor was detected by using Western blot and the sensitivity changes of these HL-60 cells to VP-16 and BCR were detected. After overexpression of miR-18a, the viability of HL-60 cells treated with VP-16 and VCR of same concentration decreased; the detectiion of luciferase activity showed that the miR-18a could inhitit activity of luciferase reporter vector of ATM; the expression level of ATM in HL-60 cells was down-regulated after transfection with miR-18a; the cell viability decreased when HL-60 cells were treated with VP-16 and VCR after knockdown of ATM; the expression level of ATM was up-regulated and the cell viability decreased when HL-60 cells were treated with VP-16 and VCR after transfection with miR-18a inhibitor. The miR-18a can regulated the sensitivity of leukemia HL-60 cells to VP-16 and VCR by targeting ATM.

  11. Receptor-targeted lentiviral vectors are exceptionally sensitive toward the biophysical properties of the displayed single-chain Fv.

    Science.gov (United States)

    Friedel, Thorsten; Hanisch, Lydia J; Muth, Anke; Honegger, Annemarie; Abken, Hinrich; Plückthun, Andreas; Buchholz, Christian J; Schneider, Irene C

    2015-04-01

    An increasing number of applications require the expression of single-chain variable fragments (scFv) fusion proteins in mammalian cells at the cell surface membrane. Here we assessed the CD30-specific scFv HRS3, which is used in immunotherapy, for its ability to retarget lentiviral vectors (LVs) to CD30 and to mediate selective gene transfer into CD30-positive cells. Fused to the C-terminus of the type-II transmembrane protein hemagglutinin (H) of measles virus and expressed in LV packaging cells, gene transfer mediated by the released LV particles was inefficient. A series of point mutations in the scFv framework regions addressing its biophysical properties, which substantially improved production and increased the melting temperature without impairing its kinetic binding behavior to CD30, also improved the performance of LV particles. Gene transfer into CD30-positive cells increased ∼100-fold due to improved transport of the H-scFv protein to the plasma membrane. Concomitantly, LV particle aggregation and syncytia formation in packaging cells were substantially reduced. The data suggest that syncytia formation can be triggered by trans-cellular dimerization of H-scFv proteins displayed on adjacent cells. Taken together, we show that the biophysical properties of the targeting ligand have a decisive role for the gene transfer efficiency of receptor-targeted LVs. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Perceived Stress, Multimorbidity, and Risk for Hospitalizations for Ambulatory Care-sensitive Conditions: A Population-based Cohort Study.

    Science.gov (United States)

    Prior, Anders; Vestergaard, Mogens; Davydow, Dimitry S; Larsen, Karen K; Ribe, Anette R; Fenger-Grøn, Morten

    2017-02-01

    Psychiatric disorders are associated with an increased risk for ambulatory care-sensitive condition (ACSC)-related hospitalizations, but it remains unknown whether this holds for individuals with nonsyndromic stress that is more prevalent in the general population. To determine whether perceived stress is associated with ACSC-related hospitalizations and rehospitalizations, and posthospitalization 30-day mortality. Population-based cohort study with 118,410 participants from the Danish National Health Survey 2010, which included data on Cohen's Perceived Stress Scale, followed from 2010 to 2014, combined with individual-level national register data on hospitalizations and mortality. Multimorbidity was assessed using health register information on diagnoses and drug prescriptions within 39 condition categories. Being in the highest perceived stress quintile was associated with a 2.13-times higher ACSC-related hospitalization risk (95% CI, 1.91, 2.38) versus being in the lowest stress quintile after adjusting for age, sex, follow-up time, and predisposing conditions. The associated risk attenuated to 1.48 (95% CI, 1.32, 1.67) after fully adjusting for multimorbidity and socioeconomic factors. Individuals with above reference stress levels experienced 1703 excess ACSC-related hospitalizations (18% of all). A dose-response relationship was observed between perceived stress and the ACSC-related hospitalization rate regardless of multimorbidity status. Being in the highest stress quintile was associated with a 1.26-times insignificantly increased adjusted risk (95% CI, 0.79, 2.00) for ACSC rehospitalizations and a 1.43-times increased adjusted risk (95% CI, 1.13, 1.81) of mortality within 30 days of admission. Elevated perceived stress levels are associated with increased risk for ACSC-related hospitalization and poor short-term prognosis.

  13. Relevance of risk predictions derived from a chronic species sensitivity distribution with cadmium to aquatic populations and ecosystems

    Science.gov (United States)

    Mebane, C.A.

    2010-01-01

    Criteria to protect aquatic life are intended to protect diverse ecosystems, but in practice are usually developed from compilations of single-species toxicity tests using standard test organisms that were tested in laboratory environments. Species sensitivity distributions (SSDs) developed from these compilations are extrapolated to set aquatic ecosystem criteria. The protectiveness of the approach was critically reviewed with a chronic SSD for cadmium comprising 27 species within 21 genera. Within the data set, one genus had lower cadmium effects concentrations than the SSD fifth percentile-based criterion, so in theory this genus, the amphipod Hyalella, could be lost or at least allowed some level of harm by this criteria approach. However, population matrix modeling projected only slightly increased extinction risks for a temperate Hyalella population under scenarios similar to the SSD fifth percentile criterion. The criterion value was further compared to cadmium effects concentrations in ecosystem experiments and field studies. Generally, few adverse effects were inferred from ecosystem experiments at concentrations less than the SSD fifth percentile criterion. Exceptions were behavioral impairments in simplified food web studies. No adverse effects were apparent in field studies under conditions that seldom exceeded the criterion. At concentrations greater than the SSD fifth percentile, the magnitudes of adverse effects in the field studies were roughly proportional to the laboratory-based fraction of species with adverse effects in the SSD. Overall, the modeling and field validation comparisons of the chronic criterion values generally supported the relevance and protectiveness of the SSD fifth percentile approach with cadmium. ?? 2009 Society for Risk Analysis.

  14. Multiplex Real-Time PCR Assay Targeting Eight Parasites Customized to the Korean Population: Potential Use for Detection in Diarrheal Stool Samples from Gastroenteritis Patients.

    Directory of Open Access Journals (Sweden)

    Eun Jeong Won

    Full Text Available Intestinal parasitic diseases occur worldwide and can cause diarrhea or gastroenteritis; however, their diagnosis is quite difficult, especially in low-endemism countries. We developed a multiplex real-time PCR assay for detection of eight intestinal parasites and prospectively evaluated it for patients with gastroenteritis. The assay targeted Cryptosporidium parvum, Giardia lamblia, Entamoeba histolytica, Blastocystis hominis, Dientamoeba fragilis, Clonorchis sinensis, Metagonimus yokogawai, and Gymnophalloides seoi. Performance characteristics were evaluated based on recovery after DNA extraction, analytical sensitivity, specificity, reproducibility, cross-reactivity, and interference characteristics. Clinical performance was validated against microscopy on 123 diarrheal samples. The assay demonstrated strong correlations between DNA concentrations and Ct values (R2, 0.9924-0.9998, and had a high PCR efficiency (83.3%-109.5%. Polymerase chain reactions detected as few as 10-30 copies of genomic DNA, and coefficient of variance was 0-7%. There was no cross-reactivity to the other 54 microorganisms tested. Interference occurred only in presence of high concentrations of erythrocytes or leukocytes. This assay had a higher correct identification rate (100.0% vs. 90.2% and lower incorrect ID rate (0.0% vs. 9.8% when compared to microscopy. Overall, this assay showed a higher sensitivity (100.0%; 95% confidence interval [CI] of 80.5-100.0 than microscopy (29.4%; 95% CI 10.31-55.96, and the specificity levels were comparable for both methods (100.0%; 95% CI 96.58-100.0. This newly developed multiplex real-time PCR assay offers a potential use for detecting intestinal parasitic pathogens customized to the Korean population.

  15. The Gene-Lifestyle Interaction on Leptin Sensitivity and Lipid Metabolism in Adults: A Population Based Study

    Directory of Open Access Journals (Sweden)

    Harry Freitag Luglio

    2017-07-01

    Full Text Available Background: Obesity has been associated with leptin resistance and this might be caused by genetic factors. The aim of this study was to investigate the gene-lifestyle interaction between −866G/A UCP2 (uncoupling protein 2 gene polymorphism, dietary intake and leptin in a population based study. Methods: This is a cross sectional study conducted in adults living at urban area of Yogyakarta, Indonesia. Data of adiposity, lifestyle, triglyceride, high density lipoprotein (HDL cholesterol, leptin and UCP2 gene polymorphism were obtained in 380 men and female adults. Results: UCP2 gene polymorphism was not significantly associated with adiposity, leptin, triglyceride, HDL cholesterol, dietary intake and physical activity (all p > 0.05. Leptin was lower in overweight subjects with AA + GA genotypes than those with GG genotype counterparts (p = 0.029. In subjects with AA + GA genotypes there was a negative correlation between leptin concentration (r = −0.324; p < 0.0001 and total energy intake and this correlation was not seen in GG genotype (r = −0.111; p = 0.188. Conclusions: In summary, we showed how genetic variation in −866G/A UCP2 affected individual response to leptin production. AA + GA genotype had a better leptin sensitivity shown by its response in dietary intake and body mass index (BMI and this explained the protective effect of A allele to obesity.

  16. The Gene-Lifestyle Interaction on Leptin Sensitivity and Lipid Metabolism in Adults: A Population Based Study.

    Science.gov (United States)

    Luglio, Harry Freitag; Sulistyoningrum, Dian Caturini; Huriyati, Emy; Lee, Yi Yi; Wan Muda, Wan Abdul Manan

    2017-07-07

    Obesity has been associated with leptin resistance and this might be caused by genetic factors. The aim of this study was to investigate the gene-lifestyle interaction between -866G/A UCP2 (uncoupling protein 2) gene polymorphism, dietary intake and leptin in a population based study. This is a cross sectional study conducted in adults living at urban area of Yogyakarta, Indonesia. Data of adiposity, lifestyle, triglyceride, high density lipoprotein (HDL) cholesterol, leptin and UCP2 gene polymorphism were obtained in 380 men and female adults. UCP2 gene polymorphism was not significantly associated with adiposity, leptin, triglyceride, HDL cholesterol, dietary intake and physical activity (all p > 0.05). Leptin was lower in overweight subjects with AA + GA genotypes than those with GG genotype counterparts ( p = 0.029). In subjects with AA + GA genotypes there was a negative correlation between leptin concentration ( r = -0.324; p correlation was not seen in GG genotype ( r = -0.111; p = 0.188). In summary, we showed how genetic variation in -866G/A UCP2 affected individual response to leptin production. AA + GA genotype had a better leptin sensitivity shown by its response in dietary intake and body mass index (BMI) and this explained the protective effect of A allele to obesity.

  17. Aconitase is a sensitive and critical target of oxygen poisoning in cultured mammalian cells and in rat lungs.

    Science.gov (United States)

    Gardner, P R; Nguyen, D D; White, C W

    1994-01-01

    The effect of hyperoxia on activity of the superoxide-sensitive citric acid cycle enzyme aconitase was measured in cultured human epithelial-like A549 cells and in rat lungs. Rapid and progressive loss of > 80% of the aconitase activity in A549 cells was seen during a 24-hr exposure to a PO2 of 600 mmHg (1 mmHg = 133 Pa). Inhibition of mitochondrial respiratory capacity correlated with loss of aconitase activity in A549 cells exposed to hyperoxia, and this effect could be mimicked by fluoroacetate (or fluorocitrate), a metabolic poison of aconitase. Exposure of rats to an atmospheric PO2 of 760 mmHg or 635 mmHg for 24 hr caused respective 73% and 61% decreases in total lung aconitase activity. We propose that early inactivation of aconitase and inhibition of the energy-producing and biosynthetic reactions of the citric acid cycle contribute to the sequelae of lung damage and edema seen during exposure to hyperoxia. Images PMID:7991614

  18. Enzyme sensitive smart inulin-dehydropeptide conjugate self-assembles into nanostructures useful for targeted delivery of ornidazole.

    Science.gov (United States)

    Shivhare, Kriti; Garg, Charu; Priyam, Ayushi; Gupta, Alka; Sharma, Ashwani Kumar; Kumar, Pradeep

    2018-01-01

    Molecular self-assembly of biodegradable amphiphilic polymers allows rational design of biocompatible nanomaterials for drug delivery. Use of substituted polysaccharides for such applications offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. The present work focuses on the synthesis, characterization and potential biomedical applications of self-assembled polysaccharide-based materials. We demonstrated that the synthesized amphiphilic inulin self-assembled in aqueous medium into nanostructures with average size in the range of 146-486nm and encapsulated hydrophobic therapeutic molecule, ornidazole. Hydrophophic dehydropeptide was conjugated with inulin via a biocompatible ester linkage. Dehydrophenylalanine, an unusual amino acid, was incorporated in the peptide to make it stable at a broader range of pH as well as against proteases. The resulting core-shell type of nanostructures could encapsulate ornidazole in the hydrophobic core and released it in a controlled fashion. By taking the advantage of inulin, which gets degraded in the colon by colonic bacteria, the effect of enzyme, inulinase, present in the microflora of the large intestine, on inulin-peptide degradation followed by drug release has been studied. Altogether, small peptide conjugated to inulin offers novel scaffold for the future design of nanostructures with potential applications in the field of targeted drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. A new double-antibody sandwich ELISA targeting Plasmodium falciparum aldolase to evaluate anti-malarial drug sensitivity

    Directory of Open Access Journals (Sweden)

    Brun Reto

    2009-10-01

    Full Text Available Abstract Background The standard in vitro test to assess anti-malarial activity of chemical compounds is the [3H]hypoxanthine incorporation assay. It is a radioactivity-based method to measure DNA replication of Plasmodium in red blood cells. The method is highly reproducible, however, the handling of radioactive material is costly, hazardous and requires the availability of appropriate technology and trained staff. Several other ways to evaluate in vitro anti-malarial activity do exist, all with their own assets and limitations. Methods The newly developed double-antibody sandwich ELISA described here is based on the properties of a non-overlapping pair of monoclonal antibodies directed against Plasmodium falciparum aldolase. This glycolytic enzyme possesses some unique nucleotide sequences compared to the human isoenzymes and has been highly conserved through evolution. Out of twenty possibilities, the most sensitive antibody pair was selected and used to quantitatively detect parasite aldolase in infected blood lysates. Results A total of 34 compounds with anti-malarial activity were tested side-by-side by ELISA and the [3H]hypoxanthine incorporation assay. The novel ELISA provided IC50s closely paralleling those from the radioactivity-based assay (R = 0.99, p Conclusion The newly developed ELISA presents several advantages over the comparative method, the [3H]hypoxanthine incorporation assay. The assay is highly reproducible, less hazardous (involves no radioactivity and requires little and cheap technical equipment. Relatively unskilled personnel can conduct this user-friendly assay. All this makes it attractive to be employed in resource-poor laboratories.

  20. ATP-sensitive potassium channel: a novel target for protection against UV-induced human skin cell damage.

    Science.gov (United States)

    Cao, Cong; Healey, Sarah; Amaral, Ashley; Lee-Couture, Avery; Wan, Shu; Kouttab, Nicola; Chu, Wenming; Wan, Yinsheng

    2007-07-01

    Ultraviolet radiation (UV) induces cell damages leading to skin photoaging and skin cancer. ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to exert significant myocardial preservation and neuroprotection in vitro and in vivo, and yet the potential role of those KCOs in protection against UV-induced skin cell damage is unknown. We investigated the effects of pinacidil and diazoxide, two classical KCOs, on UV-induced cell death using cultured human keratinocytes (HaCat cells). Here, we demonstrated for the first time that Kir 6.1, Kir 6.2 and SUR2 subunits of K(ATP) channels are functionally expressed in HaCaT cells and both non-selective K(ATP) channel opener pinacidil and mitoK(ATP) (mitochondrial K(ATP)) channel opener diazoxide attenuated UV-induced keratinocytes cell death. The protective effects were abolished by both non-selective K(ATP) channel blocker glibenclamide and selective mitoK(ATP) channel blocker 5-hydroxydecanoate (5-HD). Also, activation of K(ATP) channel with pinacidil or diazoxide resulted in suppressive effects on UV-induced MAPK activation and reactive oxygen species (ROS) production. Unexpectedly, we found that the level of intracellular ROS was slightly elevated in HaCaT cells when treated with pinacidil or diazoxide alone. Furthermore, UV-induced mitochondrial membrane potential loss, cytochrome c release and ultimately apoptotic cell death were also inhibited by preconditioning with pinacidil and diazoxide, and their effects were reversed by glibenclamide and 5-HD. Taken together, we contend that mitoK(ATP) is likely to contribute the protection against UV-induced keratinocytes cell damage. Our findings suggest that K(ATP) openers such as pinacidil and diazoxide may be utilized to prevent from UV-induced skin aging.

  1. New treatment strategy against advanced rectal cancer. Enzyme-targeting and radio-sensitization treatment under parallel use of TS-1

    International Nuclear Information System (INIS)

    Obata, Shiro; Yamanishi, Mikio; Katsumi, Shingo

    2015-01-01

    Preoperative chemoradiotherapy was applied to two cases of advanced rectal cancer. In addition, radiation sensitizers were injected to the lesion endoscopically at a pace of twice a week in order to enhance therapeutic effects (so-called enzyme-targeting and radio-sensitization treatment: KORTUC [Kochi Oxydol Radio-sensitization Treatment for Unresectable Carcinomas]). The flattening of the lesion shape was observed for both cases in a short period of time, then, Mile's and lateral lymphnode dissection was performed. The remnant of lesion was not pointed out in postoperative pathological specimens for both cases, and histological judgment after the treatment was ranked as Grade 3. In light of the better-than-expected results, this hospital is preparing for clinical trials, and planning to carefully accumulate the cases. As one of the curative treatment strategies against advanced rectal cancer, the authors are willing to make this KORTUC more objectively reliable as a safe and minimally invasive therapy. (A.O.)

  2. The addition of a pH-sensitive gel improves microemulsion stability for the targeted removal of colonic ammonia

    Directory of Open Access Journals (Sweden)

    Zhang Wen-Jun

    2011-05-01

    Full Text Available Abstract Background We prepared an oral W/O microemulsion for the removal of colonic ammonia (ME-RCA. The effect of this microemulsion was influenced by the digestion process in the gastrointestinal tract. In this paper, we aim to show that stability was improved by using a microemulsion-based gel for the removal of colonic ammonia (MBG-RCA. Methods MBG-RCA was prepared by adding sodium alginate to the ME-RCA. MBG-RCA and ME-RCA were passed through a simulated gastrointestinal environment, and the amount of colonic ammonia present was then determined by titration with a standard solution of hydrochloric acid. The pH of the gastrointestinal fluid was measured using a pH test paper and the size and form of the microemulsions were examined under the microscope. 18 healthy rats were randomly divided into three groups, fasted for 24 hours and allowed to drink normally. Three-way pipes were placed at the gastroduodenal junction in Group I, and at the terminal ileum in Group II. After the intragastric administration of ME-RCA, the stomach contents in Group I, the effluent from the terminal ileum in Group II and discharge from the anus in Group III were collected. The pH values of the gastrointestinal juice were measured by the pH test paper and those of the colon were determined by a universal indicator. These animal experiments were also used to test the effect of MBG-RCA. Results MBG-RCA showed a better removal rate of artificial colonic ammonia than ME-RCA (P Conclusions MBG-RCA was more stable in the gastrointestinal tract and more effective at removing colonic ammonia when a higher concentration of ammonia was present. This made it possible to achieve the targeted removal of colonic ammonia and is a promising method to prevent hepatic encephalopathy (HE in future studies.

  3. Tailor-Made Temperature-Sensitive Micelle for Targeted and On-Demand Release of Anticancer Drugs.

    Science.gov (United States)

    Panja, S; Dey, G; Bharti, R; Kumari, K; Maiti, T K; Mandal, M; Chattopadhyay, S

    2016-05-18

    The design of nanomedicines from the tuned architecture polymer is a leading object of immense research in recent years. Here, smart thermoresponsive micelles were prepared from novel architecture four-arm star block copolymers, namely, pentaerythritol polycaprolactone-b-poly(N-isopropylacrylamide) and pentaerythritol polycaprolactone-b-poly(N-vinylcaprolactam). The polymers were synthesized and tagged with folic acid (FA) to render them as efficient cancer cell targeting cargos. FA-conjugated block copolymers were self-assembled to a nearly spherical (ranging from 15 to 170 nm) polymeric micelle (FA-PM) with a sufficiently lower range of critical micelle concentration (0.59 × 10(-2) to 1.52 × 10(-2) mg/mL) suitable for performing as an efficient drug carrier. The blocks show lower critical solution temperature (LCST) ranging from 30 to 39 °C with high DOX-loading content (24.3%, w/w) as compared to that reported for a linear polymer in the contemporary literature. The temperature-induced reduction in size (57%) of the FA-PM enables a high rate of DOX release (78.57% after 24 h) at a temperature above LCST. The DOX release rate has also been tuned by on-demand administration of temperature. The in vitro biocompatibilities of the blank and DOX-loaded FA-PMs have been studied by the MTT assay. The cellular uptake study proves selective internalization of the FA-PM into cancerous cells (C6 glioma) compared that into normal cells (HaCaT). In vivo administration of the DOX-loaded FA-PMs into the C6 glioma rat tumor model resulted in significant accumulation in tumor sites, which drastically inhibited the tumor volume by ∼83.9% with respect to control without any significant systemic toxicity.

  4. Dimeric DNA Aptamer Complexes for High-capacity–targeted Drug Delivery Using pH-sensitive Covalent Linkages

    Directory of Open Access Journals (Sweden)

    Olcay Boyacioglu

    2013-01-01

    Full Text Available Treatment with doxorubicin (Dox results in serious systemic toxicities that limit effectiveness for cancer treatment and cause long-term health issues for cancer patients. We identified a new DNA aptamer to prostate-specific membrane antigen (PSMA using fixed sequences to promote Dox binding and developed dimeric aptamer complexes (DACs for specific delivery of Dox to PSMA+ cancer cells. DACs are stable under physiological conditions and are internalized specifically into PSMA+ C4-2 cells with minimal uptake into PSMA-null PC3 cells. Cellular internalization of DAC was demonstrated by confocal microscopy and flow cytometry. Covalent modification of DAC with Dox (DAC-D resulted in a complex with stoichiometry ~4:1. Dox was covalently bound in DAC-D using a reversible linker that promotes covalent attachment of Dox to genomic DNA following cell internalization. Dox was released from the DAC-D under physiological conditions with a half-life of 8 hours, sufficient for in vivo targeting. DAC-D was used to selectively deliver Dox to C4-2 cells with endosomal release and nuclear localization of Dox. DAC-D was selectively cytotoxic to C4-2 cells with similar cytotoxicity as the molar equivalent of free-Dox. In contrast, DAC-D displayed minimal cytotoxicity to PC3 cells, demonstrating the complex displays a high degree of selectivity for PSMA+ cells. DAC-D displays specificity and stability features that may be useful for improved delivery of Dox selectively to malignant tissue in vivo.

  5. Cy5 maleimide labelling for sensitive detection of free thiols in native protein extracts: identification of seed proteins targeted by barley thioredoxin h isoforms

    DEFF Research Database (Denmark)

    Maeda, K.; Finnie, Christine; Svensson, Birte

    2004-01-01

    Barley thioredoxin h isoforms HvTrxh1 and HvTrxh2 differ in temporal and spatial distribution and in kinetic properties. Target proteins of HvTrxh1 and HvTrxh2 were identified in mature seeds and in seeds after 72 h of germination. Improvement of the established method for identification of thior......Barley thioredoxin h isoforms HvTrxh1 and HvTrxh2 differ in temporal and spatial distribution and in kinetic properties. Target proteins of HvTrxh1 and HvTrxh2 were identified in mature seeds and in seeds after 72 h of germination. Improvement of the established method for identification...... of thioredoxin-targeted proteins based on two-dimensional electrophoresis and fluorescence labelling of thiol groups was achieved by application of a highly sensitive Cy5 maleimide dye and large-format two-dimensional gels, resulting in a 10-fold increase in the observed number of labelled protein spots...

  6. The addition of a pH-sensitive gel improves microemulsion stability for the targeted removal of colonic ammonia.

    Science.gov (United States)

    Wang, Ai-Hong; Duan, Zhi-Jun; Tian, Ge; Lu, Dan; Zhang, Wen-Jun; He, Gao-Hong; Fang, Gui-Hua

    2011-05-10

    higher concentration of ammonia was present. This made it possible to achieve the targeted removal of colonic ammonia and is a promising method to prevent hepatic encephalopathy (HE) in future studies.

  7. The NuSTAR extragalactic survey: a first sensitive look at the high-energy cosmic x-ray background population

    DEFF Research Database (Denmark)

    Alexander, D. M.; Stern, D.; Del Moro, A.

    2013-01-01

    We report on the first 10 identifications of sources serendipitously detected by the Nuclear Spectroscopic Telescope Array ( NuSTAR ) to provide the first sensitive census of the cosmic X-ray background source population at ≳ 10 keV. We find that these NuSTAR -detected sources are ≈ 100 times fai...

  8. Association of Repeatedly Measured High-Sensitivity-Assayed Troponin I with Cardiovascular Disease Events in a General Population from the MORGAM/BiomarCaRE Study

    DEFF Research Database (Denmark)

    Hughes, Maria F; Ojeda, Francisco; Saarela, Olli

    2017-01-01

    BACKGROUND: High-sensitivity troponin I (hs-cTnI) concentrations reflect myocardial stress. The role of hs-cTnI in predicting long-term changes in the risk of cardiovascular disease (CVD) in general populations is not clearly defined. METHODS: We investigated whether the change in 3 repeated meas...

  9. Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli.

    Science.gov (United States)

    Züger, Daniela; Forster, Karoline; Lutz, Thomas A; Riediger, Thomas

    2013-03-15

    The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of

  10. Analysis of the common deletions in the mitochondrial DNA is a sensitive biomarker detecting direct and non-targeted cellular effects of low dose ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Schilling-Toth, Boglarka; Sandor, Nikolett; Kis, Eniko [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary); Kadhim, Munira [Genomic Instability Research Group, School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Safrany, Geza, E-mail: safrany.geza@osski.hu [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary); Hegyesi, Hargita [Department of Molecular and Tumor Radiobiology, Frederic Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna u 5, H-1221 Budapest (Hungary)

    2011-11-01

    One of the key issues of current radiation research is the biological effect of low doses. Unfortunately, low dose science is hampered by the unavailability of easily performable, reliable and sensitive quantitative biomarkers suitable detecting low frequency alterations in irradiated cells. We applied a quantitative real time polymerase chain reaction (qRT-PCR) based protocol detecting common deletions (CD) in the mitochondrial genome to assess direct and non-targeted effects of radiation in human fibroblasts. In directly irradiated (IR) cells CD increased with dose and was higher in radiosensitive cells. Investigating conditioned medium-mediated bystander effects we demonstrated that low and high (0.1 and 2 Gy) doses induced similar levels of bystander responses and found individual differences in human fibroblasts. The bystander response was not related to the radiosensitivity of the cells. The importance of signal sending donor and signal receiving target cells was investigated by placing conditioned medium from a bystander response positive cell line (F11-hTERT) to bystander negative cells (S1-hTERT) and vice versa. The data indicated that signal sending cells are more important in the medium-mediated bystander effect than recipients. Finally, we followed long term effects in immortalized radiation sensitive (S1-hTERT) and normal (F11-hTERT) fibroblasts up to 63 days after IR. In F11-hTERT cells CD level was increased until 35 days after IR then reduced back to control level by day 49. In S1-hTERT cells the increased CD level was also normalized by day 42, however a second wave of increased CD incidence appeared by day 49 which was maintained up to day 63 after IR. This second CD wave might be the indication of radiation-induced instability in the mitochondrial genome of S1-hTERT cells. The data demonstrated that measuring CD in mtDNA by qRT-PCR is a reliable and sensitive biomarker to estimate radiation-induced direct and non-targeted effects.

  11. An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Ding Y

    2015-10-01

    Full Text Available Yuan Ding,1,* Dan Sun,1,* Gui-Ling Wang,1 Hong-Ge Yang,1 Hai-Feng Xu,1 Jian-Hua Chen,2 Ying Xie,1,3 Zhi-Qiang Wang4 1Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing, 2School of Medicine, Jianghan University, Wuhan, 3State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People’s Republic of China; 4Department of Chemistry and Biochemistry, Kent State University Geauga, Burton, OH, USA *These authors contributed equally to this work Abstract: Cell-penetrating peptides (CPPs as small molecular transporters with abilities of cell penetrating, internalization, and endosomal escape have potential prospect in drug delivery systems. However, a bottleneck hampering their application is the poor specificity for cells. By utilizing the function of hydration shell of polyethylene glycol (PEG and acid sensitivity of hydrazone bond, we constructed a kind of CPP-modified pH-sensitive PEGylated liposomes (CPPL to improve the selectivity of these peptides for tumor targeting. In CPPL, CPP was directly attached to liposome surfaces via coupling with stearate (STR to avoid the hindrance of PEG as a linker on the penetrating efficiency of CPP. A PEG derivative by conjugating PEG with STR via acid-degradable hydrazone bond (PEG2000-Hz-STR, PHS was synthesized. High-performance liquid chromatography and flow cytometry demonstrated that PHS was stable at normal neutral conditions and PEG could be completely cleaved from liposome surface to expose CPP under acidic environments in tumor. An optimal CPP density on liposomes was screened to guaranty a maximum targeting efficiency on tumor cells as well as not being captured by normal cells that consequently lead to a long circulation in blood. In vitro and in vivo studies indicated, in 4 mol% CPP of lipid modified system, that CPP exerted higher efficiency on internalizing the liposomes into

  12. Population.

    Science.gov (United States)

    International Planned Parenthood Federation, London (England).

    In an effort to help meet the growing interest and concern about the problems created by the rapid growth of population, The International Planned Parenthood Federation has prepared this booklet with the aim of assisting the study of the history and future trends of population growth and its impact on individual and family welfare, national,…

  13. Population Connectivity Measures of Fishery-Targeted Coral Reef Species to Inform Marine Reserve Network Design in Fiji.

    Science.gov (United States)

    Eastwood, Erin K; López, Elora H; Drew, Joshua A

    2016-01-25

    Coral reef fish serve as food sources to coastal communities worldwide, yet are vulnerable to mounting anthropogenic pressures like overfishing and climate change. Marine reserve networks have become important tools for mitigating these pressures, and one of the most critical factors in determining their spatial design is the degree of connectivity among different populations of species prioritized for protection. To help inform the spatial design of an expanded reserve network in Fiji, we used rapidly evolving mitochondrial genes to investigate connectivity patterns of three coral reef species targeted by fisheries in Fiji: Epinephelus merra (Serranidae), Halichoeres trimaculatus (Labridae), and Holothuria atra (Holothuriidae). The two fish species, E. merra and Ha. trimaculatus, exhibited low genetic structuring and high amounts of gene flow, whereas the sea cucumber Ho. atra displayed high genetic partitioning and predominantly westward gene flow. The idiosyncratic patterns observed among these species indicate that patterns of connectivity in Fiji are likely determined by a combination of oceanographic and ecological characteristics. Our data indicate that in the cases of species with high connectivity, other factors such as representation or political availability may dictate where reserves are placed. In low connectivity species, ensuring upstream and downstream connections is critical.

  14. Mothers and not genes determine inherited differences in cadmium sensitivities within unexposed populations of the freshwater crustacean Gammarus fossarum.

    Science.gov (United States)

    Vigneron, Amandine; Geffard, Olivier; Quéau, Hervé; Chaumot, Arnaud

    2016-02-01

    Deciphering evolutionary processes occurring within contaminated populations is important for the ecological risk assessment of toxic chemicals. Whereas increased tolerance to contaminants is well documented in aquatic animal populations, whether such phenotypic changes occur through genetic adaptation is still debated. In that sense, several studies with the freshwater crustacean Gammarus concluded in a weak potential for genetic adaptation to cadmium (Cd), while others reported inheritable increased tolerance in Cd-contaminated populations. Using quantitative genetics and selection experiments, this study sought to further assess the potential of Gammarus populations to genetically adapt to Cd. By combining the control of the reproductive cycle of this species in the laboratory and protocols of individual Cd exposure, we conducted half-sib analyses to establish the genetic and environmental sources of variance in Cd sensitivity of neonates. Prior to experiments, computations allowed optimizing the experimental design in order to increase the power to detect additive genetic variance. The main findings are the existence of strong between-brood variability along with weak heritability of Cd sensitivity within Gammarus populations. This study also revealed a significant maternal effect on individual Cd sensitivity. This sheds new light on the importance of maternal influence in microevolutionary processes occurring in contaminated environments.

  15. Age-specific interval breast cancers in Japan. Estimation of the proper sensitivity of screening using a population-based cancer registry

    International Nuclear Information System (INIS)

    Suzuki, Akihiko; Kuriyama, Shinichi; Kawai, Masaaki

    2008-01-01

    The age-specific sensitivity of a screening program was investigated using a population-based cancer registry as a source of false-negative cancer cases. A population-based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population-based cancer registry to estimate the number of false-negative cases of screening program. Among 112071 women screened by mammography combined with CBE, the number of detected cancers, false-negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false-negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population-based cancer registry was much lower than that in women 50-59 and 60-69 years of age (40-49: 18, 71.4%, 50-59: 19, 85.8%, 60-69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population-based cancer registry for detecting false-negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age. (author)

  16. Communication Strategies Must Be Tailored to a Medication's Targeted Population: Lessons from the Case of BiDil

    Science.gov (United States)

    Hawkins-Taylor, Chamika; Carlson, Angeline M

    2013-01-01

    Background The American population's diversity continues to grow, and its racial and ethnic mixes are changing. The US healthcare system must confront this changing reality. The introduction of isosorbide dinitrate/hydralazine hydrochloride (BiDil) to the US marketplace was a move toward recognizing these changing consumer needs. BiDil was approved specifically as a secondary treatment for heart failure in African-American patients. It remains the first and only drug approved by the US Food and Drug Administration for a race-based indication. To ensure commercial success, a drug must be made “visible” to healthcare providers and to consumers. Objectives To describe and analyze the case of BiDil and its potential implications for drugs developed for targeted populations to help them avoid a similar fate of market withdrawal because of commercial considerations. Method This analysis is based on 12 comprehensive interviews with 5 clinical investigators, 1 minority healthcare provider, and 5 pharmaceutical representatives, as well as a review of the literature. Overall, 12 one-hour semistructured interviews were conducted. Of the 11 interviewees, 10 were interviewed once and 1 was interviewed once early in the process and then had a second interview by the end of the study. When the 12 scheduled interviews were completed, the recordings were transcribed and subjected to analysis through the use of a readily available computer software package, using concepts and themes collected from the literature and the interviewees' responses. Results The interviewees lacked consensus regarding the unique nature of BiDil. The clinical researchers considered it innovative in identifying that taking the 2 drugs together produced the greatest clinical effect in African-American patients with heart failure. For them, BiDil represented an innovation in the emerging field of personalized medicine. However, they were dismayed to see that these beliefs were challenged by the medical

  17. Communication Strategies Must Be Tailored to a Medication's Targeted Population: Lessons from the Case of BiDil.

    Science.gov (United States)

    Hawkins-Taylor, Chamika; Carlson, Angeline M

    2013-09-01

    The American population's diversity continues to grow, and its racial and ethnic mixes are changing. The US healthcare system must confront this changing reality. The introduction of isosorbide dinitrate/hydralazine hydrochloride (BiDil) to the US marketplace was a move toward recognizing these changing consumer needs. BiDil was approved specifically as a secondary treatment for heart failure in African-American patients. It remains the first and only drug approved by the US Food and Drug Administration for a race-based indication. To ensure commercial success, a drug must be made "visible" to healthcare providers and to consumers. To describe and analyze the case of BiDil and its potential implications for drugs developed for targeted populations to help them avoid a similar fate of market withdrawal because of commercial considerations. This analysis is based on 12 comprehensive interviews with 5 clinical investigators, 1 minority healthcare provider, and 5 pharmaceutical representatives, as well as a review of the literature. Overall, 12 one-hour semistructured interviews were conducted. Of the 11 interviewees, 10 were interviewed once and 1 was interviewed once early in the process and then had a second interview by the end of the study. When the 12 scheduled interviews were completed, the recordings were transcribed and subjected to analysis through the use of a readily available computer software package, using concepts and themes collected from the literature and the interviewees' responses. The interviewees lacked consensus regarding the unique nature of BiDil. The clinical researchers considered it innovative in identifying that taking the 2 drugs together produced the greatest clinical effect in African-American patients with heart failure. For them, BiDil represented an innovation in the emerging field of personalized medicine. However, they were dismayed to see that these beliefs were challenged by the medical community and their physician colleagues

  18. Contact sensitization to fragrances in the general population: a Koch's approach may reveal the burden of disease

    DEFF Research Database (Denmark)

    Thyssen, J P; Menné, T; Linneberg, A

    2009-01-01

    BACKGROUND: Contact sensitization to fragrance mix (FM) I and Myroxylon pereirae (MP) is common among European patients with dermatitis. Recently, FM II was included in the European baseline series as an additional marker of fragrance sensitization. OBJECTIVES: This literature review aims to asse...

  19. Sensitivity to peer evaluation and its genetic and environmental determinants : Findings from a population-based twin study

    NARCIS (Netherlands)

    Klippel, Annelie; Reininghaus, Ulrich; Viechtbauer, Wolfgang; Decoster, Jeroen; Delespaul, Philippe; Derom, Catherine; de Hert, Marc; Jacobs, Nele; Menne-Lothmann, Claudia; Rutten, Bart P.; Thiery, Evert; Van Os, Jim J.; van Winkel, Ruud; Myin-Germeys, Inez; Wichers, Maria

    2018-01-01

    Purpose. Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. Methods. A sample of 354 healthy

  20. Establishment of a sensitive system for analysis of human vaginal microbiota on the basis of rRNA-targeted reverse transcription-quantitative PCR.

    Science.gov (United States)

    Kurakawa, Takashi; Ogata, Kiyohito; Tsuji, Hirokazu; Kado, Yukiko; Takahashi, Takuya; Kida, Yumi; Ito, Masahiro; Okada, Nobuhiko; Nomoto, Koji

    2015-04-01

    Ten specific primer sets, for Lactobacillus gasseri, Lactobacillus crispatus, Atopobium vaginae, Gardnerella vaginalis, Mobiluncus curtisii, Chlamydia trachomatis/muridarum, Bifidobacterium longum subsp. longum, Bifidobacterium longum subsp. infantis, Bifidobacterium adolescentis, and Bifidobacterium angulatum, were developed for quantitative analysis of vaginal microbiota. rRNA-targeted reverse transcription-quantitative PCR (RT-qPCR) analysis of the vaginal samples from 12 healthy Japanese volunteers using the new primer sets together with 25 existing primer sets revealed the diversity of their vaginal microbiota: Lactobacilli such as L. crispatus, L. gasseri, Lactobacillus jensenii, Lactobacillus iners, and Lactobacillus vaginalis, as the major populations at 10(7) cells/ml vaginal fluid, were followed by facultative anaerobes such as Streptococcus and strict anaerobes at lower population levels of 10(4) cells/ml or less. Certain bacterial vaginosis (BV)-related bacteria, such as G. vaginalis, A. vaginae, M. curtisii, and Prevotella, were also detected in some subjects. Especially in one subject, both G. vaginalis and A. vaginae were detected at high population levels of 10(8.8) and 10(8.9) cells/ml vaginal fluid, suggesting that she is an asymptomatic BV patient. These results suggest that the RT-qPCR system is effective for accurate analysis of major vaginal commensals and diagnosis of several vaginal infections. Copyright © 2015 Elsevier B.V. All rights reserved.

  1. Income level and chronic ambulatory care sensitive conditions in adults: a multicity population-based study in Italy.

    Science.gov (United States)

    Agabiti, Nera; Pirani, Monica; Schifano, Patrizia; Cesaroni, Giulia; Davoli, Marina; Bisanti, Luigi; Caranci, Nicola; Costa, Giuseppe; Forastiere, Francesco; Marinacci, Chiara; Russo, Antonio; Spadea, Teresa; Perucci, Carlo A

    2009-12-11

    A relationship between quality of primary health care and preventable hospitalizations has been described in the US, especially among the elderly. In Europe, there has been a recent increase in the evaluation of Ambulatory Care Sensitive Conditions (ACSC) as an indicator of health care quality, but evidence is still limited. The aim of this study was to determine whether income level is associated with higher hospitalization rates for ACSC in adults in a country with universal health care coverage. From the hospital registries in four Italian cities (Turin, Milan, Bologna, Rome), we identified 9384 hospital admissions for six chronic conditions (diabetes, hypertension, congestive heart failure, angina pectoris, chronic obstructive pulmonary disease, and asthma) among 20-64 year-olds in 2000. Case definition was based on the ICD-9-CM coding algorithm suggested by the Agency for Health Research and Quality - Prevention Quality Indicators. An area-based (census block) income index was used for each individual. All hospitalization rates were directly standardised for gender and age using the Italian population. Poisson regression analysis was performed to assess the relationship between income level (quintiles) and hospitalization rates (RR, 95% CI) separately for the selected conditions controlling for age, gender and city of residence. Overall, the ACSC age-standardized rate was 26.1 per 10.000 inhabitants. All conditions showed a statistically significant socioeconomic gradient, with low income people being more likely to be hospitalized than their well off counterparts. The association was particularly strong for chronic obstructive pulmonary disease (level V low income vs. level I high income RR = 4.23 95%CI 3.37-5.31) and for congestive heart failure (RR = 3.78, 95% CI = 3.09-4.62). With the exception of asthma, males were more vulnerable to ACSC hospitalizations than females. The risks were higher among 45-64 year olds than in younger people. The socioeconomic

  2. Effects of Withania somnifera and Tinospora cordifolia extracts on the side population phenotype of human epithelial cancer cells: toward targeting multidrug resistance in cancer.

    Science.gov (United States)

    Maliyakkal, Naseer; Appadath Beeran, Asmy; Balaji, Sai A; Udupa, Nayanabhirama; Ranganath Pai, Sreedhara; Rangarajan, Annapoorni

    2015-03-01

    Recent reports suggest the existence of a subpopulation of stem-like cancer cells, termed as cancer stem cells (CSCs), which bear functional and phenotypic resemblance with the adult, tissue-resident stem cells. Side population (SP) assay based on differential efflux of Hoechst 33342 has been effectively used for the isolation of CSCs. The drug resistance properties of SP cells are typically due to the increased expression of ABC transporters leading to drug efflux. Conventionally used chemotherapeutic drugs may often leads to an enrichment of SP, revealing their inability to target the drug-resistant SP and CSCs. Thus, identification of agents that can reduce the SP phenotype is currently in vogue in cancer therapeutics. Withania somnifera (WS) and Tinospora cordifolia (TC) have been used in Ayurveda for treating various diseases, including cancer. In the current study, we have investigated the effects of ethanolic (ET) extracts of WS and TC on the cancer SP phenotype. Interestingly, we found significant decrease in SP on treatment with TC-ET, but not with WS-ET. The SP-inhibitory TC-ET was further fractionated into petroleum ether (TC-PET), dichloromethane (TC-DCM), and n-butyl alcohol (TC-nBT) fractions using bioactivity-guided fractionation. Our data revealed that TC-PET and TC-DCM, but not TC-nBT, significantly inhibited SP in a dose-dependent manner. Furthermore, flow cytometry-based functional assays revealed that TC-PET and TC-DCM significantly inhibited ABC-B1 and ABC-G2 transporters and sensitized cancer cells toward chemotherapeutic drug-mediated cytotoxicity. Thus, the TC-PET and TC-DCM may harbor phytochemicals with the potential to reverse the drug-resistant phenotype, thus improving the efficacy of cancer chemotherapy. © The Author(s) 2014.

  3. Reaction rate sensitivity of 44Ti production in massive stars and implications of a thick target yield measurement of 40Ca(alpha,gamma)44Ti

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, R D; Sheets, S A; Burke, J T; Scielzo, N D; Rauscher, T; Norman, E B; Tumey, S; Brown, T A; Grant, P G; Hurst, A M; Phair, L; Stoyer, M A; Wooddy, T; Fisker, J L; Bleuel, D

    2010-02-16

    We evaluate two dominant nuclear reaction rates and their uncertainties that affect {sup 44}Ti production in explosive nucleosynthesis. Experimentally we develop thick-target yields for the {sup 40}Ca({alpha},{gamma}){sup 44}Ti reaction at E{sub {alpha}} = 4.13, 4.54, and 5.36 MeV using {gamma}-ray spectroscopy. At the highest beam energy, we also performed an activation measurement which agrees with the thick target result. From the measured yields a stellar reaction rate was developed that is smaller than current statistical-model calculations and recent experimental results, which would suggest lower {sup 44}Ti production in scenarios for the {alpha}-rich freeze out. Special attention has been paid to assessing realistic uncertainties of stellar reaction rates produced from a combination of experimental and theoretical cross sections. With such methods, we also develop a re-evaluation of the {sup 44}Ti({alpha},p){sup 47}V reaction rate. Using these two rates we carry out a sensitivity survey of {sup 44}Ti synthesis in eight expansions representing peak temperature and density conditions drawn from a suite of recent supernova explosion models. Our results suggest that the current uncertainty in these two reaction rates could lead to as large an uncertainty in {sup 44}Ti synthesis as that produced by different treatments of stellar physics.

  4. REACTION RATE SENSITIVITY OF 44Ti PRODUCTION IN MASSIVE STARS AND IMPLICATIONS OF A THICK TARGET YIELD MEASUREMENT OF 40Ca(α, γ)44Ti

    International Nuclear Information System (INIS)

    Hoffman, R. D.; Sheets, S. A.; Burke, J. T.; Scielzo, N. D.; Norman, E. B.; Tumey, S.; Brown, T. A.; Grant, P. G.; Hurst, A. M.; Stoyer, M. A.; Wooddy, T.; Fisker, J. L.; Bleuel, D.; Rauscher, T.; Phair, L.

    2010-01-01

    We evaluate two dominant nuclear reaction rates and their uncertainties that affect 44 Ti production in explosive nucleosynthesis. Experimentally we develop thick target yields for the 40 Ca(α, γ) 44 Ti reaction at E α = 4.13, 4.54, and 5.36 MeV using γ-ray spectroscopy. At the highest beam energy, we also performed an activation measurement which agrees with the thick target result. From the measured yields a stellar reaction rate was developed that is smaller than current statistical-model calculations and recent experimental results, which would suggest lower 44 Ti production in scenarios for the α-rich freezeout. Special attention has been paid to assessing realistic uncertainties of stellar reaction rates produced from a combination of experimental and theoretical cross sections. With such methods, we also develop a re-evaluation of the 44 Ti(α, p) 47 V reaction rate. Using these two rates we carry out a sensitivity survey of 44 Ti synthesis in eight expansions representing peak temperature and density conditions drawn from a suite of recent supernova explosion models. Our results suggest that the current uncertainty in these two reaction rates could lead to as large an uncertainty in 44 Ti synthesis as that produced by different treatments of stellar physics.

  5. Targeted Delivery of Doxorubicin via CD147-Mediated ROS/pH Dual-Sensitive Nanomicelles for the Efficient Therapy of Hepatocellular Carcinoma.

    Science.gov (United States)

    Qu, Chenxi; Li, Jizhao; Zhou, Yejuan; Yang, Shudi; Chen, Weiliang; Li, Fang; You, Bengang; Liu, Yang; Zhang, Xuenong

    2018-02-23

    Low accumulation in tumor sites and slow intracellular drug release remain as the obstacles for nanoparticles to achieve effective delivery of chemotherapeutic drugs. In this study, multifunctional micelles were designed to deliver doxorubicin (Dox) to tumor sites to provide more efficient therapy against hepatic carcinoma. The micelles were based on pH-responsive carboxymethyl chitosan (CMCh) modified with a reactive oxygen species (ROS)-responsive segment phenylboronic acid pinacol ester (BAPE) and an active targeted ligand CD147 monoclonal antibody. The Dox-loaded micelles provided rapid and complete drug release in pH 5.3 incubation conditions with 1 mM H 2 O 2 . In addition, an in vitro cell uptake study revealed that CD147 modification significantly enhanced cellular internalization due to the high affinity to CD147 receptors, which are overexpressed on tumor cells. An in vivo study revealed that CD147-modified micellar formulations exhibited high accumulation in tumor sites and markedly enhanced antiproliferation effects with fewer side effects than other formulations. In conclusion, this CD147 receptor targeted delivery system with ROS/pH dual sensitivity provides a promising strategy for the treatment of hepatic carcinoma.

  6. Highly Sensitive Matrix-Independent Quantification of Major Food Allergens Peanut and Soy by Competitive Real-Time PCR Targeting Mitochondrial DNA.

    Science.gov (United States)

    Ladenburger, Eva-Maria; Dehmer, Markus; Grünberg, Ruben; Waiblinger, Hans-Ulrich; Stoll, Dieter; Bergemann, Jörg

    2018-01-01

    The development of two competitive real-time PCR assays for the quantitative detection of trace amounts of two major food allergens, peanut and soybean, is reported. In order to achieve very low detection levels for both allergens, we established PCR primers and probes targeting mitochondrial DNA sequences. We were able to demonstrate that this approach led to an increase in detection sensitivity in the range of at least 1 order of magnitude compared with published assays targeting nuclear DNA. Furthermore, we generated corresponding competitor molecules, which were used as internal standards to compete with matrix effects that are evident during DNA extraction and PCR amplification in heterogeneous analytical matrixes like food. According to the recently described competitive quantitative PCR method published by Holzhauser et al. (2014), we performed threshold calibration against milk powder spiked with 10 ppm peanut and soy. Matrix-independent quantitative determination of peanut and soy could be demonstrated for three different calibrated food matrix standards in a range between 1 and 100 ppm. The data presented indicate that both assay concepts are powerful analytical tools for the quantitative detection of trace amounts of peanut and soy in commercial food products.

  7. Improving food environments and tackling obesity: A realist systematic review of the policy success of regulatory interventions targeting population nutrition.

    Science.gov (United States)

    Sisnowski, Jana; Street, Jackie M; Merlin, Tracy

    2017-01-01

    This systematic review (PROSPERO: CRD42015025276) employs a realist approach to investigate the effect of "real-world" policies targeting different aspects of the food environment that shape individual and collective nutrition. We were interested in assessing intermediate outcomes along the assumed causal pathway to "policy success", in addition to the final outcome of changed consumption patterns. We performed a search of 16 databases through October 2015, with no initial restriction by language. We included all publications that reported the effect of statutory provisions aimed at reducing the consumption of energy-dense foods and beverages in the general population. We allowed all methodological approaches that contained some measure of comparison, including studies of implementation progress. We reviewed included studies using the appraisal tools for pre-post and observational studies developed by the National Heart, Lung, and Blood Institute. Given the considerable heterogeneity in interventions assessed, study designs employed, and outcome measures reported, we opted for a narrative synthesis of results. Results drawn from 36 peer-reviewed articles and grey literature reports demonstrated that isolated regulatory interventions can improve intermediate outcomes, but fail to affect consumption at clinically significant levels. The included literature covered six different types of interventions, with 19 studies reporting on calorie posting on chain restaurant menus. The large majority of the identified interventions were conducted in the US. Early results from recent taxation measures were published after the review cut-off date but these suggested more favorable effects on consumption levels. Nevertheless, the evidence assessed in this review suggests that current policies are generally falling short of anticipated health impacts.

  8. A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis.

    Science.gov (United States)

    McLaren, Zoë M; Schnippel, Kathryn; Sharp, Alana

    2016-01-01

    Identifying those infected with tuberculosis (TB) is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context. We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing. Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p strategy. Targeting active case finding to key populations at higher risk of infection or poor clinical outcomes may prove more cost effective than broad efforts. However, these results should increase caution in

  9. Estimating the Public Health Impact of Setting Targets at the European Level for the Reduction of Zoonotic Salmonella in Certain Poultry Populations

    Directory of Open Access Journals (Sweden)

    Marta Hugas

    2013-10-01

    Full Text Available In the European Union (EU, targets are being set for the reduction of certain zoonotic Salmonella serovars in different animal populations, including poultry populations, within the framework of Regulation (EC No. 2160/2003 on the control of zoonoses. For a three-year transitional period, the EU targets were to cover only Salmonella Enteritidis and S. Typhimurium (and in addition S. Hadar, S. Infantis and S. Virchow for breeding flocks of Gallus gallus. Before the end of that transitional period, the revision of the EU targets was to be considered, including the potentially addition of other serovars with public health significance to the permanent EU targets. This review article aims at providing an overview of the assessments carried out by the Scientific Panel on Biological Hazards of the European Food Safety Authority in the field of setting targets for Salmonella in poultry populations (breeding flocks of Gallus gallus, laying flocks of Gallus gallus, broiler flocks of Gallus gallus and flocks of breeding and fattening turkeys and their impact in subsequent changes in EU legislation.

  10. Sensitivity to Peer Evaluation and Its Genetic and Environmental Determinants: Findings from a Population-Based Twin Study.

    Science.gov (United States)

    Klippel, Annelie; Reininghaus, Ulrich; Viechtbauer, Wolfgang; Decoster, Jeroen; Delespaul, Philippe; Derom, Cathérine; de Hert, Marc; Jacobs, Nele; Menne-Lothmann, Claudia; Rutten, Bart; Thiery, Evert; van Os, Jim; van Winkel, Ruud; Myin-Germeys, Inez; Wichers, Marieke

    2018-02-23

    Adolescents and young adults are highly focused on peer evaluation, but little is known about sources of their differential sensitivity. We examined to what extent sensitivity to peer evaluation is influenced by interacting environmental and genetic factors. A sample of 354 healthy adolescent twin pairs (n = 708) took part in a structured, laboratory task in which they were exposed to peer evaluation. The proportion of the variance in sensitivity to peer evaluation due to genetic and environmental factors was estimated, as was the association with specific a priori environmental risk factors. Differences in sensitivity to peer evaluation between adolescents were explained mainly by non-shared environmental influences. The results on shared environmental influences were not conclusive. No impact of latent genetic factors or gene-environment interactions was found. Adolescents with lower self-rated positions on the social ladder or who reported to have been bullied more severely showed significantly stronger responses to peer evaluation. Not genes, but subjective social status and past experience of being bullied seem to impact sensitivity to peer evaluation. This suggests that altered response to peer evaluation is the outcome of cumulative sensitization to social interactions.

  11. Development of a rapid, sensitive TaqMan real-time RT-PCR assay for the detection of Rose rosette virus using multiple gene targets.

    Science.gov (United States)

    Babu, Binoy; Jeyaprakash, Ayyamperumal; Jones, Debra; Schubert, Timothy S; Baker, Carlye; Washburn, Brian K; Miller, Steven H; Poduch, Kristina; Knox, Gary W; Ochoa-Corona, Francisco M; Paret, Mathews L

    2016-09-01

    Rose rosette virus (RRV), belonging to the genus Emaravirus, is a highly destructive pathogen that causes rose rosette disease. The disease is a major concern for the rose industry in the U.S. due to the lack of highly sensitive methods for early detection of RRV. This is critical, as early identification of the infected plants and eradication is necessary in minimizing the risks associated with the spread of the disease. A highly reliable, specific and sensitive detection assay is thus required to test and confirm the presence of RRV in suspected plant samples. In this study a TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was developed for the detection of RRV from infected roses, utilizing multiple gene targets. Four pairs of primers and probes; two of them (RRV_2-1 and RRV_2-2) based on the consensus sequences of the glycoprotein gene (RNA2) and the other two (RRV_3-2 and RRV_3-5) based on the nucleocapsid gene (RNA3) were designed. The specificity of the primers and probes was evaluated against other representative viruses infecting roses, belonging to the genera Alfamovirus, Cucumovirus, Ilarvirus, Nepovirus, Tobamovirus, and Tospovirus and one Emaravirus (Wheat mosaic virus). Dilution assays using the in vitro transcripts (spiked with total RNA from healthy plants, and non-spiked) showed that all the primers and probes are highly sensitive in consistently detecting RRV with a detection limit of 1 fg. Testing of the infected plants over a period of time (three times in monthly intervals) indicated high reproducibility, with the primer/probe RRV_3-5 showing 100% positive detection, while RRV_2-1, RRV_2-2 and RRV_3-2 showed 90% positive detection. The developed real-time RT-PCR assay is reliable, highly sensitive, and can be easily used in diagnostic laboratories for testing and confirmation of RRV. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Impaired baroreflex sensitivity and the risks of new-onset ambulatory hypertension, in an elderly population-based study.

    Science.gov (United States)

    Dauphinot, Virginie; Kossovsky, Michel P; Gueyffier, François; Pichot, Vincent; Gosse, Philippe; Roche, Frédéric; Barthélémy, Jean-Claude

    2013-10-09

    Impairment of the autonomic nervous system activity may be involved in the development of hypertension. Yet the prognostic values of heart rate variability and baroreflex sensitivity in the risk of new-onset ambulatory hypertension have not been investigated. We sought to assess the relationship between heart rate variability and baroreflex sensitivity parameters and ambulatory hypertension in a community-dwelling elderly cohort. Normotensive subjects were selected from the PROOF study cohort, including 1011 subjects aged 65 years at baseline. The autonomic nervous system activity was assessed through 24-hour heart rate variability and 15-minute spontaneous baroreflex sensitivity at baseline. Incident hypertension was defined with the 24-hour, day-time and night-time ambulatory blood pressure measurements and antihypertensive treatment use, at two-years of follow-up. At baseline, 13.7% of subjects developed day-time hypertension, 18.2% developed night-time hypertension and 13.6% developed 24-hour hypertension. Reduced baroreflex sensitivity at baseline was associated with onset of hypertension after adjustment for blood pressure level, C-reactive protein levels and depression score (OR = 0.45 [0.23-0.86]). Indices of heart rate variability were not associated with hypertension onset. Baroreflex sensitivity may represent an intermediate goal for prevention of ambulatory hypertension at early stage. © 2013.

  13. Sensitivity Analysis of Population in The Generation of Hazardous and Non-Harzardous Wastes, and Gas from Dumpsites of Ogbomosoland in Nigeria

    Directory of Open Access Journals (Sweden)

    Samson O. Ojoawo

    2013-01-01

    Full Text Available This paper applies the principles of system dynamics modeling in studying the pattern of population changes and the corresponding non-hazardous wastes and gas being generated from the dumpsites of Ogbomosoland, Nigeria. The five (5 Local government Areas (LGAs of Ogbomosoland were categorized as Urban (Ogbomoso North and Ogbomoso South and Rural (Oriire, Ogo Oluwa and Suurulere based on the size, population of residents, consumption pattern and socio-economic activities of the area. A sensitivity analysis of the simulated variables i.e the population, wastes and gas, was performed by employing the developed model results. Findings showed that the wastes and gas increased with the increased population in the 1000 years period. Also, gas production exceeds wastes generation rates for the rural LGAs in all cases. After a 25 years benchmark, when the simulated population of the urban and rural LGAs are respectively 303,411 and 344,735, the rates of waste generation are 3.33x106 and 6.22 x106 m 3 , while the corresponding rates of gas production is 2.44x103 and 6.47x103 m 3 in same order. The study concludes that wastes and gas generation from dumpsites are highly sensitive to population growth. It also concluded that the rate of gas generation is higher in organic wastes of the rural LGAs. The maximum population permissible in the model is 300,000 thus design of full-fledge landfills is recommended to replace the existing dumpsites in the study area.

  14. miR-15a/16 Enhances Radiation Sensitivity of Non-Small Cell Lung Cancer Cells by Targeting the TLR1/NF-κB Signaling Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lan, Fengming [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China); Radiation Oncology Department, Tianjin Hospital, Tianjin (China); Yue, Xiao [Tianjin Huanhu Hospital, Tianjin Neurosurgery Institute, Tianjin (China); Ren, Gang; Li, Hongqi; Ping, Li; Wang, Yingjie [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China); Xia, Tingyi, E-mail: xiatingyi1959@163.com [Radiation Oncology Department, PLA Airforce General Hospital, Beijing (China)

    2015-01-01

    Purpose: Many miRNAs have been identified as essential issues and core determining factors in tumor radiation. Recent reports have demonstrated that miRNAs and Toll-like receptors could exert reciprocal effects to control cancer development in various ways. However, a novel role of miR-15a/16 in enhancing radiation sensitivity by directly targeting TLR1 has not been reported, to our knowledge. Methods and Materials: Bioinformatic analyses, luciferase reporter assay, biochemical assays, and subcutaneous tumor establishment were used to characterize the signaling pathways of miRNA-15a/16 in response to radiation treatment. Results: First, an inverse correlation between the expression of miR-15a/16 and TLR1 protein was revealed in non-small cell lung cancer (NSCLC) and normal lung tissues. Next, we corroborated that miR-15a/16 specifically bound to TLR1 3′UTR and inhibited the expression of TLR1 in H358 and A549 cells. Furthermore, miR-15a/16 downregulated the activity of the NF-κB signaling pathway through TLR1. In addition, overexpression of miR-15a/16 inhibited survival capability and increased radiation-induced apoptosis, resulting in enhancement of radiosensitivity in H358 and A549 cells. Finally, subcutaneous tumor bearing NSCLC cells in a nude mice model was established, and the results showed that combined groups (miR-15a/16 + radiation) inhibited tumor growth more significantly than did radiation alone. Conclusions: We mainly elucidate that miRNA-15a/16 can enhance radiation sensitivity by regulating the TLR1/NF-κB signaling pathway and act as a potential therapeutic approach to overcome radioresistance for lung cancer treatment.

  15. SYBR Green real-time PCR-RFLP assay targeting the plasmodium cytochrome B gene--a highly sensitive molecular tool for malaria parasite detection and species determination.

    Directory of Open Access Journals (Sweden)

    Weiping Xu

    Full Text Available A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale for parasite detection and species determination with DNA extracted from dried blood spots collected on filter paper. The performance of cytb-qPCR was first compared against four reference PCR methods using serially diluted Plasmodium samples. The detection limit of the cytb-qPCR was 1 parasite/μl (p/μl for P. falciparum and P. ovale, and 2 p/μl for P. vivax and P. malariae, while the reference PCRs had detection limits of 0.5-10 p/μl. The ability of the PCR methods to detect low-density Plasmodium infections was then assessed using 2977 filter paper samples collected during a cross-sectional survey in Zanzibar, a malaria pre-elimination setting in sub-Saharan Africa. Field samples were defined as 'final positive' if positive in at least two of the five PCR methods. Cytb-qPCR preformed equal to or better than the reference PCRs with a sensitivity of 100% (65/65; 95%CI 94.5-100% and a specificity of 99.9% (2910/2912; 95%CI 99.7-100% when compared against 'final positive' samples. The results indicate that the cytb-qPCR may represent an opportunity for improved molecular surveillance of low-density Plasmodium infections in malaria pre-elimination settings.

  16. SYBR Green real-time PCR-RFLP assay targeting the plasmodium cytochrome B gene--a highly sensitive molecular tool for malaria parasite detection and species determination.

    Science.gov (United States)

    Xu, Weiping; Morris, Ulrika; Aydin-Schmidt, Berit; Msellem, Mwinyi I; Shakely, Delér; Petzold, Max; Björkman, Anders; Mårtensson, Andreas

    2015-01-01

    A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR) targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale) for parasite detection and species determination with DNA extracted from dried blood spots collected on filter paper. The performance of cytb-qPCR was first compared against four reference PCR methods using serially diluted Plasmodium samples. The detection limit of the cytb-qPCR was 1 parasite/μl (p/μl) for P. falciparum and P. ovale, and 2 p/μl for P. vivax and P. malariae, while the reference PCRs had detection limits of 0.5-10 p/μl. The ability of the PCR methods to detect low-density Plasmodium infections was then assessed using 2977 filter paper samples collected during a cross-sectional survey in Zanzibar, a malaria pre-elimination setting in sub-Saharan Africa. Field samples were defined as 'final positive' if positive in at least two of the five PCR methods. Cytb-qPCR preformed equal to or better than the reference PCRs with a sensitivity of 100% (65/65; 95%CI 94.5-100%) and a specificity of 99.9% (2910/2912; 95%CI 99.7-100%) when compared against 'final positive' samples. The results indicate that the cytb-qPCR may represent an opportunity for improved molecular surveillance of low-density Plasmodium infections in malaria pre-elimination settings.

  17. SYBR Green Real-Time PCR-RFLP Assay Targeting the Plasmodium Cytochrome B Gene – A Highly Sensitive Molecular Tool for Malaria Parasite Detection and Species Determination

    Science.gov (United States)

    Xu, Weiping; Morris, Ulrika; Aydin-Schmidt, Berit; Msellem, Mwinyi I.; Shakely, Delér; Petzold, Max; Björkman, Anders; Mårtensson, Andreas

    2015-01-01

    A prerequisite for reliable detection of low-density Plasmodium infections in malaria pre-elimination settings is the availability of ultra-sensitive and high-throughput molecular tools. We developed a SYBR Green real-time PCR restriction fragment length polymorphism assay (cytb-qPCR) targeting the cytochrome b gene of the four major human Plasmodium species (P. falciparum, P. vivax, P. malariae, and P. ovale) for parasite detection and species determination with DNA extracted from dried blood spots collected on filter paper. The performance of cytb-qPCR was first compared against four reference PCR methods using serially diluted Plasmodium samples. The detection limit of the cytb-qPCR was 1 parasite/μl (p/μl) for P. falciparum and P. ovale, and 2 p/μl for P. vivax and P. malariae, while the reference PCRs had detection limits of 0.5–10 p/μl. The ability of the PCR methods to detect low-density Plasmodium infections was then assessed using 2977 filter paper samples collected during a cross-sectional survey in Zanzibar, a malaria pre-elimination setting in sub-Saharan Africa. Field samples were defined as ‘final positive’ if positive in at least two of the five PCR methods. Cytb-qPCR preformed equal to or better than the reference PCRs with a sensitivity of 100% (65/65; 95%CI 94.5–100%) and a specificity of 99.9% (2910/2912; 95%CI 99.7–100%) when compared against ‘final positive’ samples. The results indicate that the cytb-qPCR may represent an opportunity for improved molecular surveillance of low-density Plasmodium infections in malaria pre-elimination settings. PMID:25774805

  18. Fast, sensitive, and selective gas chromatography tandem mass spectrometry method for the target analysis of chemical secretions from femoral glands in lizards.

    Science.gov (United States)

    Sáiz, Jorge; García-Roa, Roberto; Martín, José; Gómara, Belén

    2017-09-08

    Chemical signaling is a widespread mode of communication among living organisms that is used to establish social organization, territoriality and/or for mate choice. In lizards, femoral and precloacal glands are important sources of chemical signals. These glands protrude chemical secretions used to mark territories and also, to provide valuable information from the bearer to other individuals. Ecologists have studied these chemical secretions for decades in order to increase the knowledge of chemical communication in lizards. Although several studies have focused on the chemical analysis of these secretions, there is a lack of faster, more sensitive and more selective analytical methodologies for their study. In this work a new GC coupled to tandem triple quadrupole MS (GC-QqQ (MS/MS)) methodology is developed and proposed for the target study of 12 relevant compounds often found in lizard secretions (i.e. 1-hexadecanol, palmitic acid, 1-octadecanol, oleic acid, stearic acid, 1-tetracosanol, squalene, cholesta-3,5-diene, α-tocopherol, cholesterol, ergosterol and campesterol). The method baseline-separated the analytes in less than 7min, with instrumental limits of detection ranging from 0.04 to 6.0ng/mL. It was possible to identify differences in the composition of the samples from the lizards analyzed, which depended on the species, the habitat occupied and the diet of the individuals. Moreover, α-tocopherol has been determined for the first time in a lizard species, which was thought to lack its expression in chemical secretions. Globally, the methodology has been proven to be a valuable alternative to other published methods with important improvements in terms of analysis time, sensitivity, and selectivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Inhibition of Mammalian Target of Rapamycin Complex 1 Attenuates Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats.

    Science.gov (United States)

    Kumar, Vikash; Wollner, Clayton; Kurth, Theresa; Bukowy, John D; Cowley, Allen W

    2017-10-01

    The goal of the present study was to explore the protective effects of mTORC1 (mammalian target of rapamycin complex 1) inhibition by rapamycin on salt-induced hypertension and kidney injury in Dahl salt-sensitive (SS) rats. We have previously demonstrated that H 2 O 2 is elevated in the kidneys of SS rats. The present study showed a significant upregulation of renal mTORC1 activity in the SS rats fed a 4.0% NaCl for 3 days. In addition, renal interstitial infusion of H 2 O 2 into salt-resistant Sprague Dawley rats for 3 days was also found to stimulate mTORC1 activity independent of a rise of arterial blood pressure. Together, these data indicate that the salt-induced increases of renal H 2 O 2 in SS rats activated the mTORC1 pathway. Daily administration of rapamycin (IP, 1.5 mg/kg per day) for 21 days reduced salt-induced hypertension from 176.0±9.0 to 153.0±12.0 mm Hg in SS rats but had no effect on blood pressure salt sensitivity in Sprague Dawley treated rats. Compared with vehicle, rapamycin reduced albumin excretion rate in SS rats from 190.0±35.0 to 37.0±5.0 mg/d and reduced the renal infiltration of T lymphocytes (CD3 + ) and macrophages (ED1 + ) in the cortex and medulla. Renal hypertrophy and cell proliferation were also reduced in rapamycin-treated SS rats. We conclude that enhancement of intrarenal H 2 O 2 with a 4.0% NaCl diet stimulates the mTORC1 pathway that is necessary for the full development of the salt-induced hypertension and kidney injury in the SS rat. © 2017 American Heart Association, Inc.

  20. Expression of amphetamine sensitization is associated with recruitment of a reactive neuronal population in the nucleus accumbens core

    NARCIS (Netherlands)

    Nordquist, R.E.; Vanderschuren, L.J.M.J.; Jonker, A.J.; Bergsma, M.; de Vries, T.J.; Pennartz, C.M.A.; Voorn, P.

    2008-01-01

    Rationale: Repeated exposure to psychostimulant drugs causes a long-lasting increase in the psychomotor and reinforcing effects of these drugs and an array of neuroadaptations. One such alteration is a hypersensitivity of striatal activity such that a low dose of amphetamine in sensitized animals

  1. Characterisation of novel target promoters for the dexamethasone-inducible/tetracycline-repressible regulator TGV using luciferase and isopentenyl transferase as sensitive reporter genes.

    Science.gov (United States)

    Böhner, S; Gatz, C

    2001-02-01

    The chimeric transcriptional activator TGV mediates dexamethasone (dx)-inducible and tetracycline (tc)-repressible transgene expression in tobacco (dx-on/ tc-off system). The expression profiles of four different synthetic target promoters, comprising multiple TGV binding sites upstream of a core promoter, were characterised using the sensitive luciferase assay. Induction factors of over 1,000 were measured in roots and leaves of over 30% of the transgenic plants, irrespective of the promoter used. Promoters PTF and PTax, which carry the -48 to +1 region of the Cauliflower Mosaic Virus 35S promoter, showed higher expression levels in both the uninduced and induced states than PTop10 and PTFM, which harbour several point mutations in this region. Moreover, PTax expressed higher background activities than PTF, indicating that the sequence of the synthetic regulatory region can influence background levels. The usefulness of the dx-on/tc-off system for experiments addressing gene function was demonstrated by using it to control the expression of isopentenyl transferase. This enzyme catalyses the rate-limiting step in cytokinin biosynthesis and causes phenotypic effects even at low expression levels. Only dx-induced transgenic plants displayed phenotypic alterations indicative for increased cytokinin synthesis (e.g. outgrowth of lateral buds). Simultaneous treatment of selected buds with the antiinducer tc suppressed bud growth. This result suggests that cytokinins cannot serve as mobile signals to elicit the release of apical dominance in tissues compromised for enhanced cytokinin synthesis.

  2. Applications of the epidemiological modelling outputs for targeted mental health planning in conflict-affected populations: the Syria case-study.

    Science.gov (United States)

    Charlson, F J; Lee, Y Y; Diminic, S; Whiteford, H

    2016-01-01

    Epidemiological models are frequently utilised to ascertain disease prevalence in a population; however, these estimates can have wider practical applications for informing targeted scale-up and optimisation of mental health services. We explore potential applications for a conflict-affected population, Syria. We use prevalence estimates of major depression and post-traumatic stress disorder (PTSD) in conflict-affected populations as inputs for subsequent estimations. We use Global Burden of Disease (GBD) methodology to estimate years lived with a disability (YLDs) for depression and PTSD in Syrian populations. Human resource (HR) requirements to scale-up recommended packages of care for PTSD and depression in Syria over a 15-year period were modelled using the World Health Organisation mhGAP costing tool. Associated avertable burden was estimated using health benefit analyses. The total number of cases of PTSD in Syria was estimated at approximately 2.2 million, and approximately 1.1 million for depression. An age-standardised major depression rate of 13.4 (95% UI 9.8-17.5) YLDs per 1000 Syrian population is estimated compared with the GBD 2010 global age-standardised YLD rate of 9.2 (95% UI 7.0-11.8). HR requirements to support a linear scale-up of services in Syria using the mhGAP costing tool demonstrates a steady increase from 0.3 FTE in at baseline to 7.6 FTE per 100 000 population after scale-up. Linear scale-up over 15 years could see 7-9% of disease burden being averted. Epidemiological estimates of mental disorders are key inputs into determining disease burden and guiding optimal mental health service delivery and can be used in target populations such as conflict-affected populations.

  3. Links between maternal postpartum depressive symptoms, maternal distress, infant gender and sensitivity in a high-risk population

    Directory of Open Access Journals (Sweden)

    Eickhorst Andreas

    2011-03-01

    Full Text Available Abstract Background Maternal postpartum depression has an impact on mother-infant interaction. Mothers with depression display less positive affect and sensitivity in interaction with their infants compared to non-depressed mothers. Depressed women also show more signs of distress and difficulties adjusting to their role as mothers than non-depressed women. In addition, depressive mothers are reported to be affectively more negative with their sons than with daughters. Methods A non-clinical sample of 106 mother-infant dyads at psychosocial risk (poverty, alcohol or drug abuse, lack of social support, teenage mothers and maternal psychic disorder was investigated with EPDS (maternal postpartum depressive symptoms, the CARE-Index (maternal sensitivity in a dyadic context and PSI-SF (maternal distress. The baseline data were collected when the babies had reached 19 weeks of age. Results A hierarchical regression analysis yielded a highly significant relation between the PSI-SF subscale "parental distress" and the EPDS total score, accounting for 55% of the variance in the EPDS. The other variables did not significantly predict the severity of depressive symptoms. A two-way ANOVA with "infant gender" and "maternal postpartum depressive symptoms" showed no interaction effect on maternal sensitivity. Conclusions Depressive symptoms and maternal sensitivity were not linked. It is likely that we could not find any relation between both variables due to different measuring methods (self-reporting and observation. Maternal distress was strongly related to maternal depressive symptoms, probably due to the generally increased burden in the sample, and contributed to 55% of the variance of postpartum depressive symptoms.

  4. Donor-specific cell-based assays in studying sensitivity to low-dose radiation: a population-based perspective

    Directory of Open Access Journals (Sweden)

    Dora eIl'yasova

    2014-11-01

    Full Text Available Currently, a linear no-threshold model is used to estimate health risks associated with exposure to low-dose radiation, a prevalent exposure in the general population, because the direct estimation from epidemiological studies suffers from uncertainty. This model has been criticized based on unique biology of low-dose radiation. Whether the departure from linearity is toward increased or decreased risk is intensely debated. We present an approach based on individual radiosensitivity testing and discuss how individual radiosensitivity can be assessed with the goal to develop a quantifiable measure of cellular response that can be conducted via high-throughput population testing.

  5. Assessing Coverage of Population-Based and Targeted Fortification Programs with the Use of the Fortification Assessment Coverage Toolkit (FACT): Background, Toolkit Development, and Supplement Overview.

    Science.gov (United States)

    Friesen, Valerie M; Aaron, Grant J; Myatt, Mark; Neufeld, Lynnette M

    2017-05-01

    Food fortification is a widely used approach to increase micronutrient intake in the diet. High coverage is essential for achieving impact. Data on coverage is limited in many countries, and tools to assess coverage of fortification programs have not been standardized. In 2013, the Global Alliance for Improved Nutrition developed the Fortification Assessment Coverage Toolkit (FACT) to carry out coverage assessments in both population-based (i.e., staple foods and/or condiments) and targeted (e.g., infant and young child) fortification programs. The toolkit was designed to generate evidence on program coverage and the use of fortified foods to provide timely and programmatically relevant information for decision making. This supplement presents results from FACT surveys that assessed the coverage of population-based and targeted food fortification programs across 14 countries. It then discusses the policy and program implications of the findings for the potential for impact and program improvement.

  6. Effects of temperature, genetic variation and species competition on the sensitivity of algae populations to the antibiotic enrofloxacin.

    Science.gov (United States)

    Rico, Andreu; Zhao, Wenkai; Gillissen, Frits; Lürling, Miquel; Van den Brink, Paul J

    2018-02-01

    Primary producers are amongst the most sensitive organisms to antibiotic pollution in aquatic ecosystems. To date, there is little information on how different environmental conditions may affect their sensitivity to antibiotics. In this study we assessed how temperature, genetic variation and species competition may affect the sensitivity of the cyanobacterium Microcystis aeruginosa and the green-algae Scenedesmus obliquus to the antibiotic enrofloxacin. First, we performed single-species tests to assess the toxicity of enrofloxacin under different temperature conditions (20°C and 30°C) and to assess the sensitivity of different species strains using a standard temperature (20°C). Next, we investigated how enrofloxacin contamination may affect the competition between M. aeruginosa and S. obliquus. A competition experiment was performed following a full factorial design with different competition treatments, defined as density ratios (i.e. initial bio-volume of 25/75%, 10/90% and 1/99% of S. obliquus/M. aeruginosa, respectively), one 100% S. obliquus treatment and one 100% M. aeruginosa treatment, and four different enrofloxacin concentrations (i.e. control, 0.01, 0.05 and 0.10mg/L). Growth inhibition based on cell number, bio-volume, chlorophyll-a concentration as well as photosynthetic activity were used as evaluation endpoints in the single-species tests, while growth inhibition based on measured chlorophyll-a was primarily used in the competition experiment. M. aeruginosa photosynthetic activity was found to be the most sensitive endpoint to enrofloxacin (EC50-72h =0.02mg/L), followed by growth inhibition based on cell number. S. obliquus was found to be slightly more sensitive at 20°C than at 30°C (EC50-72h cell number growth inhibition of 38 and 41mg/L, respectively), whereas an opposite trend was observed for M. aeruginosa (0.047 and 0.037mg/L, respectively). Differences in EC50-72h values between algal strains of the same species were within a factor

  7. An application of population size estimation to official statistics : Sensitivity of model assumptions and the effect of implied coverage

    NARCIS (Netherlands)

    Gerritse, S.C.

    2016-01-01

    Official Statistics bureaus are periodically asked to give an estimate of their country's population, which can be defined by the number of usual residents. A person is considered a usual resident when they have lived in the Netherlands for longer than a year, or if they have the intention to reside

  8. Nasal carriage of methicillin-resistant and methicillin-sensitive strains of Staphylococcus sciuri in the Indonesian population

    NARCIS (Netherlands)

    J.A. Severin (Juliëtte); E.S. Lestari (Endang Sri); K. Kuntaman (Kuntaman); M. Pastink (Martijn); S.V. Snijders (Susan); N. Lemmens-den Toom (Nicole); D. Horst-Kreft (Deborah); U. Hadi (Usman); D.O. Duerink (Offra); W.H.F. Goessens (Wil); A.C. Fluit (Ad); W.J.B. van Wamel (Willem); A.F. van Belkum (Alex); H.A. Verbrugh (Henri)

    2010-01-01

    textabstractStaphylococcus sciuri strains were unexpectedly cultured from healthy persons and patients from Indonesia during a population-based survey on nasal Staphylococcus aureus carriage. Fifty-one S. sciuri isolates were further characterized. The S. aureus mecA gene was detected by PCR in 22

  9. Nasal carriage of methicillin-resistant and methicillin-sensitive strains of Staphylococcus sciuri in the Indonesian population.

    NARCIS (Netherlands)

    Severin, J.A.; Lestari, E.S.; Kuntaman, K.; Pastink, M.; Snijders, S.V.; Lemmens-den Toom, N.; Horst-Kreft, D.; Hadi, U.; Duerink, D.O.; Goessens, W.H.F.; Fluit, A.C.; Wamel, W. van; Belkum, A. van; Verbrugh, H.A.; Gyssens, I.C.J.; et al.,

    2010-01-01

    Staphylococcus sciuri strains were unexpectedly cultured from healthy persons and patients from Indonesia during a population-based survey on nasal Staphylococcus aureus carriage. Fifty-one S. sciuri isolates were further characterized. The S. aureus mecA gene was detected by PCR in 22 isolates

  10. Defining a target population at high risk of long-term foster care: barriers to permanency for families of children with serious emotional disturbances.

    Science.gov (United States)

    Akin, Becci A; Bryson, Stephanie A; McDonald, Tom; Walker, Sheila

    2012-01-01

    Long-term foster care (LTFC) is an enduring problem that lacks evidence of effective strategies for practice or policy. This article describes initial activities of a statewide project of the national Permanency Innovations Initiative. The authors sought to: (1) verify the relevance of children's mental health as a predictor of LTFC, (2) describe critical barriers encountered by parents of children with serious emotional disturbances, and (3) identify systems barriers that hinder permanency for this target population.

  11. MicroRNA-223 Enhances Radiation Sensitivity of U87MG Cells In Vitro and In Vivo by Targeting Ataxia Telangiectasia Mutated

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Liping; Zhu, Ji [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zaorsky, Nicholas G. [Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Deng, Yun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Wu, Xingzhong [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Yong [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Liu, Fangqi; Cai, Guoxiang; Gu, Weilie [Department of Colorectal Cancer, Fudan University, Shanghai Cancer Center, Shanghai (China); Shen, Lijun [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China); Zhang, Zhen, E-mail: zhenzhang6@hotmail.com [Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai (China)

    2014-03-15

    Purpose: Ataxia telangiectasia mutated (ATM) protein is important in the DNA damage response because it repairs radiation-induced damage in cancers. We examined the effect of microRNA-223 (miR-223), a regulator of ATM expression, on radiation sensitivity of cancer cells. Methods and Materials: Human embryonic kidney 293 T (293T) cells were infected with pLL3.7-miR-223 plasmid to generate the pLL3.7-miR-223 and -empty virus (EV) lentivirus (miR-223 and EV). A dual luciferase assay in which the reporter contained wild-type 3′ untranslated region (UTR) of ATM was performed. U87MG cells were infected with miR-223 or EV to establish the overexpressed stable cell lines (U87-223 or U87-EV, respectively). Cells were irradiated in vitro, and dose enhancement ratios at 2 Gy (DER{sub 2}) were calculated. Hind legs of BALB/c athymic mice were injected with U87-223 or U87-EV cells; after 2 weeks, half of the tumors were irradiated. Tumor volumes were tracked for a total of 5 weeks. Results: The dual luciferase reporter assay showed a significant reduction in luciferase activity of 293T cells cotransfected with miR-223 and the ATM 3′UTR compared to that in EV control. Overexpression of miR-223 in U87MG cells showed that ATM expression was significantly downregulated in the U87-223 cells compared to that in U87-EV (ATM/β-actin mRNA 1.0 vs 1.5, P<.05). U87-223 cells were hypersensitive to radiation compared to U87-EV cells in vitro (DER{sub 2} = 1.32, P<.01). Mice injected with miR-223-expressing tumors had almost the same tumors after 3 weeks (1.5 cm{sup 3} vs 1.7 cm{sup 3}). However, irradiation significantly decreased tumor size in miR-223-expressing tumors compared to those in controls (0.033 cm{sup 3} vs 0.829 cm{sup 3}). Conclusions: miR-223 overexpression downregulates ATM expression and sensitizes U87 cells to radiation in vitro and in vivo. MicroRNA-223 may be a novel cancer-targeting therapy, although its cancer- and patient-specific roles are

  12. Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands.

    Science.gov (United States)

    de Haas, Masja; Thurik, Florentine F; van der Ploeg, Catharina P B; Veldhuisen, Barbera; Hirschberg, Hoang; Soussan, Aicha Ait; Woortmeijer, Heleen; Abbink, Frithjofna; Page-Christiaens, Godelieve C M L; Scheffer, Peter G; Ellen van der Schoot, C

    2016-11-07

     To determine the accuracy of non-invasive fetal testing for the RHD gene in week 27 of pregnancy as part of an antenatal screening programme to restrict anti-D immunoglobulin use to women carrying a child positive for RHD DESIGN:  Prospectively monitoring of fetal RHD testing accuracy compared with serological cord blood typing on introduction of the test. Fetal RHD testing was performed with a duplex real time quantitative polymerase chain reaction, with cell-free fetal DNA isolated from 1 mL of maternal plasma The study period was between 4 July 2011 and 7 October 2012. The proportion of women participating in screening was determined.  Nationwide screening programme, the Netherlands. Tests are performed in a centralised setting.  25 789 RhD negative pregnant women.  Sensitivity, specificity, false negative rate, and false positive rate of fetal RHD testing compared with serological cord blood typing; proportion of technical failures; and compliance to the screening programme.  A fetal RHD test result and serological cord blood result were available for 25 789 pregnancies. Sensitivity for detection of fetal RHD was 99.94% (95% confidence interval 99.89% to 99.97%) and specificity was 97.74% (97.43% to 98.02%). Nine false negative results for fetal RHD testing were registered (0.03%, 95% confidence interval 0.01% to 0.06%). In two cases these were due to technical failures. False positive fetal RHD testing results were registered for 225 samples (0.87%, 0.76% to 0.99%). Weak RhD expression was shown in 22 of these cases, justifying anti-D immunoglobulin use. The negative and positive predictive values were 99.91% (95% confidence interval 99.82% to 99.95%) and 98.60% (98.40% to 98.77%), respectively. More than 98% of the women participated in the screening programme.  Fetal RHD testing in week 27 of pregnancy as part of a national antenatal screening programme is highly reliable and can be used to target both antenatal and postnatal anti

  13. Future Premature Mortality Due to O3, Secondary Inorganic Aerosols and Primary PM in Europe — Sensitivity to Changes in Climate, Anthropogenic Emissions, Population and Building Stock

    Directory of Open Access Journals (Sweden)

    Camilla Geels

    2015-03-01

    Full Text Available Air pollution is an important environmental factor associated with health impacts in Europe and considerable resources are used to reduce exposure to air pollution through emission reductions. These reductions will have non-linear effects on exposure due, e.g., to interactions between climate and atmospheric chemistry. By using an integrated assessment model, we quantify the effect of changes in climate, emissions and population demography on exposure and health impacts in Europe. The sensitivity to the changes is assessed by investigating the differences between the decades 2000–2009, 2050–2059 and 2080–2089. We focus on the number of premature deaths related to atmospheric ozone, Secondary Inorganic Aerosols and primary PM. For the Nordic region we furthermore include a projection on how population exposure might develop due to changes in building stock with increased energy efficiency. Reductions in emissions cause a large significant decrease in mortality, while climate effects on chemistry and emissions only affects premature mortality by a few percent. Changes in population demography lead to a larger relative increase in chronic mortality than the relative increase in population. Finally, the projected changes in building stock and infiltration rates in the Nordic indicate that this factor may be very important for assessments of population exposure in the future.

  14. Advancing forensic RNA typing: On non-target secretions, a nasal mucosa marker, a differential co-extraction protocol and the sensitivity of DNA and RNA profiling.

    Science.gov (United States)

    van den Berge, Margreet; Bhoelai, Bryan; Harteveld, Joyce; Matai, Anuska; Sijen, Titia

    2016-01-01

    The forensic identification of human body fluids and tissues by means of messenger RNA (mRNA) profiling is a long studied methodology that is increasingly applied to casework samples. Previously, we have described an mRNA multiplex system that targets blood, saliva, semen, menstrual secretion, vaginal mucosa and skin (Lindenbergh et al. and van den Berge et al.). In this study we consider various topics to improve this mRNA profiling system or its use and adapt the method accordingly. Bodily secretions that may be encountered at a crime scene whilst not targeted by the multiplex-id est nasal mucosa, sweat, tears, faeces and urine-were examined for false positive signals. The results prompted us to identify a nasal mucosa marker that allows the discrimination of nasal mucosa from saliva or vaginal mucosa and nosebleed blood from peripheral blood. An updated version of the multiplex was prepared to which the nasal mucosa marker was added and in which markers for semen, vaginal mucosa and blood were replaced. Lactobacillus markers were regarded unsuitable as replacement for vaginal mucosa mRNA markers because of background signals on penile swabs that appeared devoid of female DNA. Furthermore, we provide approaches to deal with highly unbalanced mixtures. First, a differential extraction protocol was incorporated into a co-extraction protocol to allow DNA and RNA analysis of separated non-sperm and sperm fractions. In a second approach, besides the standard multiplex, a customized multiplex is used which excludes markers for prevailing cell types. This allows the use of lower cDNA inputs for the prevailing cell types and higher inputs for cell types that appear masked. Additionally, we assessed the relation between the percentage of alleles or markers detected in DNA or RNA profiles when decreasing sample amounts are analysed. While blood, saliva, semen and menstrual secretion show the trend that DNA profiling is more sensitive than RNA profiling, the reverse is seen

  15. The sensitivity of breeding songbirds to changes in seasonal timing is linked to population change but cannot be directly attributed to the effects of trophic asynchrony on productivity.

    Science.gov (United States)

    Franks, Samantha E; Pearce-Higgins, James W; Atkinson, Sian; Bell, James R; Botham, Marc S; Brereton, Tom M; Harrington, Richard; Leech, David I

    2018-03-01

    A consequence of climate change has been an advance in the timing of seasonal events. Differences in the rate of advance between trophic levels may result in predators becoming mismatched with prey availability, reducing fitness and potentially driving population declines. Such "trophic asynchrony" is hypothesized to have contributed to recent population declines of long-distance migratory birds in particular. Using spatially extensive survey data from 1983 to 2010 to estimate variation in spring phenology from 280 plant and insect species and the egg-laying phenology of 21 British songbird species, we explored the effects of trophic asynchrony on avian population trends and potential underlying demographic mechanisms. Species which advanced their laying dates least over the last three decades, and were therefore at greatest risk of asynchrony, exhibited the most negative population trends. We expressed asynchrony as the annual variation in bird phenology relative to spring phenology, and related asynchrony to annual avian productivity. In warmer springs, birds were more asynchronous, but productivity was only marginally reduced; long-distance migrants, short-distance migrants and resident bird species all exhibited effects of similar magnitude. Long-term population, but not productivity, declines were greatest among those species whose annual productivity was most greatly reduced by asynchrony. This suggests that population change is not mechanistically driven by the negative effects of asynchrony on productivity. The apparent effects of asynchrony on population trends are therefore either more likely to be strongly expressed via other demographic pathways, or alternatively, are a surrogate for species' sensitivity to other environmental pressures which are the ultimate cause of decline. © 2017 John Wiley & Sons Ltd.

  16. Developmental exposure to PBDE 99 and PCB affects estrogen sensitivity of target genes in rat brain regions and female sexual behavior

    Energy Technology Data Exchange (ETDEWEB)

    Lichtensteiger, W.; Faass, O.; Ceccatelli, R.; Schlumpf, M. [Zurich Univ. (Switzerland). Inst. of Pharmacology and Toxicology

    2004-09-15

    We recently reported effects of PBDE99 (2,2',4,4'5-pentabromoBDE) on sexual differentiation processes in rat reproductive organs and central nervous system. These studies were prompted by reports on an increase of PBDE levels in human milk, an indicator of the body burden of pregnant women and of potential exposure of the nursing infant, during the last decade. Even higher human adipose tissue and milk levels were reported for North America. PBDE99 is present in human and animal samples and exhibits developmental neurotoxicity in mice. The developing brain is subject to the organizing action of estradiol locally formed from circulating testosterone, and thus represents a target for endocrine active chemicals. One molecular mechanism by which chemicals may interfere with sexual brain differentiation, may be a change in the expression of sex hormone (estrogen)-regulated genes. Such effects may manifest themselves in mRNA expression levels, or in the sensitivity of the genes to estrogen. In order to detect alterations of the latter, more subtle parameter, we have conducted experiments in developmentally chemical-exposed rat offspring that were gonadectomized in adulthood and injected with a challenge dose of estradiol. Effects of PBDE99 were compared with those of a commercial PCB mixture, Aroclor 1254, which had previously been found to influence sexual brain differentiation. We analyzed the expression of estrogen-regulated genes in ventromedial hypothalamus (VMH) and medial preoptic area (MPO), two brain regions that are part of a network involved in the integration of environmental cues, sexual behavior and gonadal function. Since prominent changes were observed in VMH which is particularly important for female sexual behavior, the study was completed by a behavioral analysis.

  17. Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population.

    Directory of Open Access Journals (Sweden)

    Agnieszka Paziewska

    Full Text Available Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to create DNA pools for a genome wide association study (GWAS. GWAS findings were validated with individual HLA tag single nucleotide polymorphism (SNP typing of 473 patients and 714 healthy controls. Association analysis using four HLA-tagging SNPs showed that, as was found in other populations, positive predicting genotypes (HLA-DQ2.5/DQ2.5, HLA-DQ2.5/DQ2.2, and HLA-DQ2.5/DQ8 were found at higher frequencies in CD patients than in healthy control individuals in the Polish population. Both CD-associated SNPs discovered by GWAS were found in the CD susceptibility region, confirming the previously-determined association of the major histocompatibility (MHC region with CD pathogenesis. The two most significant SNPs from the GWAS were rs9272346 (HLA-dependent; localized within 1 Kb of DQA1 and rs3130484 (HLA-independent; mapped to MSH5. Specificity of CD prediction using the four HLA-tagging SNPs achieved 92.9%, but sensitivity was only 45.5%. However, when a testing combination of the HLA-tagging SNPs and the MSH5 SNP was used, specificity decreased to 80%, and sensitivity increased to 74%. This study confirmed that improvement of CD risk prediction sensitivity could be achieved by including non-HLA SNPs alongside HLA SNPs in genetic testing.

  18. Novel CD44 receptor targeting multifunctional “nano-eggs” based on double pH-sensitive nanoparticles for co-delivery of curcumin and paclitaxel to cancer cells and cancer stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Daquan, E-mail: cdq1981@126.com [Peking University, School of Pharmaceutical Sciences, Health Science Center (China); Wang, Guohua [China Academy of Chinese Medical Sciences, Institute of Chinese Materia Madica (China); Song, Weiguo [Shouguang Fukang Pharmceutial Co., Ltd. (China); Zhang, Qiang, E-mail: zqdodo@bjmu.edu.cn [Peking University, School of Pharmaceutical Sciences, Health Science Center (China)

    2015-10-15

    Most anticancer drugs cannot kill cancer stem cells (CSCs) effectively, which lead to the failure of anticancer chemotherapy, such as relapse and metastasis. In this study, we prepared a multifunctional oligosaccharides of hyaluronan (oHA) conjugates, oHA-histidine-menthone 1,2-glycerol ketal (oHM). The oHM conjugates possess pH-sensitive menthone 1,2-glycerol ketal (MGK) as hydrophobic moieties and oHA as the target of CD44 receptor. Anticancer drugs, curcumin(Cur) and paclitaxel(PTX), were loaded into oHM micelles via self-assembly. Then, oHM micelles were mineralized through controlled deposition of inorganic calcium and phosphate ions on the nanoparticular shell via a sequential addition method to fabricate the “nano-eggs.” The formed nano-eggs had a smaller size (120.6 ± 4.5 nm) than oHM micelles (158.6 ± 6.4 nm), indicating that mineralization made the appearance of compact nanoparticles. Interestingly, when the nano-eggs were put into the acidic conditions (pH 6.5), their outer shell(inorganic minerals) will be destroyed with the larger size, while the “nano-eggs” were stable under pH 7.4. For both nano-eggs and oHM micelles, the Cur and PTX were released in a sustained manner depending on the pH of the solution. However, the nano-eggs showed much lower released than the oHM micelles due to the dissolution of the inorganic minerals and pH-sensitive ketal at mildly acidic environments (pH 6.5). In vivo study, the nano-eggs could get to the tumor site more effectively than oHM micelles. CSCs were sorted by a side population assay from MDA-MB-231 breast cancer cell lines over-expressing CD44 receptors. Antitumor activity was also evaluated on MDA-MB-231 xenografts in nude mice. The antitumor efficacy indicated that nano-eggs with co-delivery of Cur and PTX produced the strongest antitumor efficacy, and nano-eggs showed strong activity against cancer stem cells. These double pH-sensitive nano-eggs may provide a promising strategy for drug

  19. A Novel W1999S Mutation and Non-Target Site Resistance Impact on Acetyl-CoA Carboxylase Inhibiting Herbicides to Varying Degrees in a UK Lolium multiflorum Population

    Science.gov (United States)

    Kaundun, Shiv Shankhar; Bailly, Geraldine C.; Dale, Richard P.; Hutchings, Sarah-Jane; McIndoe, Eddie

    2013-01-01

    Background Acetyl-CoA carboxylase (ACCase) inhibiting herbicides are important products for the post-emergence control of grass weed species in small grain cereal crops. However, the appearance of resistance to ACCase herbicides over time has resulted in limited options for effective weed control of key species such as Lolium spp. In this study, we have used an integrated biological and molecular biology approach to investigate the mechanism of resistance to ACCase herbicides in a Lolium multiflorum Lam. from the UK (UK21). Methodology/Principal Findings The study revealed a novel tryptophan to serine mutation at ACCase codon position 1999 impacting on ACCase inhibiting herbicides to varying degrees. The W1999S mutation confers dominant resistance to pinoxaden and partially recessive resistance to cycloxydim and sethoxydim. On the other hand, plants containing the W1999S mutation were sensitive to clethodim and tepraloxydim. Additionally population UK21 is characterised by other resistance mechanisms, very likely non non-target site based, affecting several aryloxyphenoxyproprionate (FOP) herbicides but not the practical field rate of pinoxaden. The positive identification of wild type tryptophan and mutant serine alleles at ACCase position 1999 could be readily achieved with an original DNA based derived cleaved amplified polymorphic sequence (dCAPS) assay that uses the same PCR product but two different enzymes for positively identifying the wild type tryptophan and mutant serine alleles identified here. Conclusion/Significance This paper highlights intrinsic differences between ACCase inhibiting herbicides that could be exploited for controlling ryegrass populations such as UK21 characterised by compound-specific target site and non-target site resistance. PMID:23469130

  20. Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells

    Science.gov (United States)

    Sokolosky, Melissa; Chappell, William H; Stadelman, Kristin; Abrams, Stephen L; Davis, Nicole M; Steelman, Linda S; McCubrey, James A

    2014-01-01

    doxorubicin and tamoxifen, but sensitizes the cells to mTORC1 blockade by rapamycin. Therefore GSK-3β is a key regulatory molecule in sensitivity of breast cancer cells to chemo-, hormonal, and targeted therapy. PMID:24407515

  1. Development of a bone-targeted pH-sensitive liposomal formulation containing doxorubicin: physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis

    Directory of Open Access Journals (Sweden)

    Ferreira DS

    2016-08-01

    assessed in bone metastasis-bearing animals.Results: Liposomes presented suitable diameter (~170 nm, DOX encapsulation (~2 mg/mL, controlled release, and good plasma and serum stability. The existence of interactions between DOX and the lipid bilayer was proved through differential scanning calorimetry and small-angle X-ray scattering. DOX release was faster when the pH was in the range of a tumor than at physiological pH. The bone-targeted formulation showed a strong affinity for hydroxyapatite. The encapsulation of DOX did not interfere in its intrinsic cytotoxicity against the MDA-MB-231 cell line. Biodistribution studies demonstrated high affinity of this formulation for tumors and reduction of uptake in the heart.Conclusion: These results suggest that bone-targeted pH-sensitive liposomes containing DOX can be an interesting strategy for selectively delivering this drug into bone-tumor sites, increasing its activity, and reducing DOX-related toxicity. Keywords: hydroxyapatite-targeted formulations, bisphosphonates, pH-responsive nanostructures, bone-tumor treatment

  2. No Vegetative and Fecundity Fitness Cost Associated with Acetyl-Coenzyme A Carboxylase Non-target-site Resistance in a Black-Grass (Alopecurus myosuroides Huds Population

    Directory of Open Access Journals (Sweden)

    Eshagh Keshtkar

    2017-11-01

    Full Text Available Attention should be devoted to weeds evolving herbicide resistance with non-target-site resistance (NTSR mechanism due to their unpredictable resistance patterns. Quantification of fitness cost can be used in NTSR management strategies to determine the long-term fate of resistant plants in weed populations. To our knowledge, this is the first report evaluating potential fecundity and vegetative fitness of a NTSR black-grass (Alopecurus myosuroides Huds, the most important herbicide resistant weed in Europe, with controlled genetic background. The susceptible (S and NTSR sub-populations were identified and isolated from a fenoxaprop-P-ethyl resistant population by a plant cloning technique. Using a target-neighborhood design, competitive responses of S and NTSR black-grass sub-populations to increasing density of winter wheat were quantified for 2 years in greenhouse and 1 year in field. Fitness traits including potential seed production, vegetative biomass and tiller number of both sub-populations significantly decreased with increasing density of winter wheat. More importantly, no statistically significant differences were found in fitness traits between S and NTSR sub-populations either grown alone (no competition or in competition with winter wheat. According to the results, the NTSR black-grass is probably to persist in field even in the cessation of fenoxaprop-P-ethyl. So, effective herbicide resistant management strategies are strongly suggested to prevent and stop the spread of the NTSR black-grass, otherwise NTSR loci conferring resistance to a range of herbicides in black-grass will persist in the gene pool even in the absence of herbicide application. Consequently, herbicide as an effective tool for control of black-grass will gradually be lost in fields infested by NTSR black-grass.

  3. The ultra-sensitive Nodewalk technique identifies stochastic from virtual, population-based enhancer hubs regulating MYC in 3D: Implications for the fitness of cancer cells

    KAUST Repository

    Sumida, Noriyuki

    2018-03-27

    The relationship between stochastic transcriptional bursts and dynamic 3D chromatin states is not well understood due to poor sensitivity and/or resolution of current chromatin structure-based assays. Consequently, it is not well established if enhancers operate individually and/or in clusters to coordinate gene transcription. In the current study, we introduce Nodewalk, which uniquely combines high sensitivity with high resolution to enable the analysis of chromatin networks in minute input material. The >10,000-fold increase in sensitivity over other many-to-all competing methods uncovered that active chromatin hubs identified in large input material, corresponding to 10 000 cells, flanking the MYC locus are primarily virtual. Thus, the close agreement between chromatin interactomes generated from aliquots corresponding to less than 10 cells with randomly re-sampled interactomes, we find that numerous distal enhancers positioned within flanking topologically associating domains (TADs) converge on MYC in largely mutually exclusive manners. Moreover, when comparing with several enhancer baits, the assignment of the MYC locus as the node with the highest dynamic importance index, indicates that it is MYC targeting its enhancers, rather than vice versa. Dynamic changes in the configuration of the boundary between TADs flanking MYC underlie numerous stochastic encounters with a diverse set of enhancers to depict the plasticity of its transcriptional regulation. Such an arrangement might increase the fitness of the cancer cell by increasing the probability of MYC transcription in response to a wide range of environmental cues encountered by the cell during the neoplastic process.

  4. Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort

    Science.gov (United States)

    Daniels, Benjamin; Lord, Sarah J; Kiely, Belinda E; Houssami, Nehmat; Haywood, Philip; Lu, Christine Y; Ward, Robyn L; Pearson, Sallie-Anne

    2017-01-01

    Background The management of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has changed dramatically with the introduction and widespread use of HER2-targeted therapies. However, there is relatively limited real-world information on patterns of use, effectiveness and safety in whole of population cohorts. The research programme detailed in this protocol will generate evidence on the prescribing patterns, safety monitoring and outcomes of patients with BC treated with HER2-targeted therapies in Australia. Methods/design Our ongoing research programme will involve a series of retrospective cohort studies that include every patient accessing Commonwealth-funded HER2-targeted therapies for the treatment of early BC and advanced BC in Australia. At the time of writing, our cohorts consist of 11 406 patients with early BC and 5631 with advanced BC who accessed trastuzumab and lapatinib between 2001 and 2014. Pertuzumab and trastuzumab emtansine were publicly funded for metastatic BC in 2015, and future data updates will include patients accessing these medicines. We will use dispensing claims for cancer and other medicines, medical service claims and demographics data for each patient accessing HER2-targeted therapies to undertake this research. Ethics and dissemination Ethics approval has been granted by the Population Health Service Research Ethics Committee and data access approval has been granted by the Australian Department of Human Services (DHS) External Review Evaluation Committee. Our findings will be reported in peer-reviewed publications, conference presentations and policy forums. By providing detailed information on the use and outcomes associated with HER2-targeted therapies in a national cohort treated in routine clinical care, our research programme will better inform clinicians and patients about the real-world use of these treatments and will assist third-party payers to better understand the use and economic costs of these

  5. Sex and age differences in the achievement of control targets in patients with type 2 diabetes: results from a population-based study in a South European region.

    Science.gov (United States)

    Cambra, K; Galbete, A; Forga, L; Lecea, O; Ariz, M J; Moreno-Iribas, C; Aizpuru, F; Ibañez, B

    2016-10-12

    We aimed to determine the degree to which control targets of glycaemia and cardiovascular risk factors were achieved among patients with type 2 diabetes and to investigate sex- and age-related differences in this population. This cross-sectional, population-based study was conducted in Spain. Glycated hemoglobin (HbA1c), blood pressure, LDL-c, HDL-c, triglycerides, BMI, and smoking history were obtained from electronic clinical primary care records (n = 32,638 cases). The proportions of patients who met control targets were determined according to sex and age groups. Comparisons between groups were conducted with t-tests for continuous variables, tests for trends in proportions for categorical and ordinal variables, and Pearson's chi-square tests and binary logistic regression models for categorical variables. The overall proportions of patients with type 2 diabetes who met the target objectives for HbA1c (<7 %, 53 mmol/mol), blood pressure (130/80 mmHg), and LDL-cholesterol (100 mg/dl) were 60, 40 and 41 %, respectively. Women were less likely than men to meet the control targets of HbA1c (59 vs 61 %), LDL (35 vs 45 %), and HDL (58 vs 78 %). Patients under 65 years of age presented poorer control than older age groups. Only a minority of patients with type 2 diabetes met the composite target objectives for glycemic control, blood pressure, and LDL. There are differential gaps in the control results of female patients and younger patients, which should prompt improvements in case management and care. There is room for further improvement in the cardiometabolic control of patients with type 2 diabetes.

  6. Regulatory function of a novel population of mouse autoantigen-specific Foxp3 regulatory T cells depends on IFN-gamma, NO, and contact with target cells.

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    Cyndi Chen

    Full Text Available BACKGROUND: Both naturally arising Foxp3(+ and antigen-induced Foxp3(- regulatory T cells (Treg play a critical role in regulating immune responses, as well as in preventing autoimmune diseases and graft rejection. It is known that antigen-specific Treg are more potent than polyclonal Treg in suppressing pathogenic immune responses that cause autoimmunity and inflammation. However, difficulty in identifying and isolating a sufficient number of antigen-specific Treg has limited their use in research to elucidate the mechanisms underlying their regulatory function and their potential role in therapy. METHODOLOGY/PRINCIPAL FINDINGS: Using a novel class II MHC tetramer, we have isolated a population of CD4(+ Foxp3(- T cells specific for the autoantigen glutamic acid decarboxylase p286-300 peptide (NR286 T cells from diabetes-resistant non-obese resistant (NOR mice. These Foxp3(- NR286 T cells functioned as Treg that were able to suppress target T cell proliferation in vitro and inhibit type 1 diabetes in animals. Unexpected results from mechanistic studies in vitro showed that their regulatory function was dependent on not only IFN-gamma and nitric oxide, but also on cell contact with target cells. In addition, separating NR286 Treg from target T cells in transwell assays abolished both production of NO and suppression of target T cells, regardless of whether IFN-gamma was produced in cell cultures. Therefore, production of NO, not IFN-gamma, was cell contact dependent, suggesting that NO may function downstream of IFN-gamma in mediating regulatory function of NR286 Treg. CONCLUSIONS/SIGNIFICANCE: These studies identified a unique population of autoantigen-specific Foxp3(- Treg that can exert their regulatory function dependent on not only IFN-gamma and NO but also cell contact with target cells.

  7. The usefulness of “corrected” body mass index vs. self-reported body mass index: comparing the population distributions, sensitivity, specificity, and predictive utility of three correction equations using Canadian population-based data

    Science.gov (United States)

    2014-01-01

    Background National data on body mass index (BMI), computed from self-reported height and weight, is readily available for many populations including the Canadian population. Because self-reported weight is found to be systematically under-reported, it has been proposed that the bias in self-reported BMI can be corrected using equations derived from data sets which include both self-reported and measured height and weight. Such correction equations have been developed and adopted. We aim to evaluate the usefulness (i.e., distributional similarity; sensitivity and specificity; and predictive utility vis-à-vis disease outcomes) of existing and new correction equations in population-based research. Methods The Canadian Community Health Surveys from 2005 and 2008 include both measured and self-reported values of height and weight, which allows for construction and evaluation of correction equations. We focused on adults age 18–65, and compared three correction equations (two correcting weight only, and one correcting BMI) against self-reported and measured BMI. We first compared population distributions of BMI. Second, we compared the sensitivity and specificity of self-reported BMI and corrected BMI against measured BMI. Third, we compared the self-reported and corrected BMI in terms of association with health outcomes using logistic regression. Results All corrections outperformed self-report when estimating the full BMI distribution; the weight-only correction outperformed the BMI-only correction for females in the 23–28 kg/m2 BMI range. In terms of sensitivity/specificity, when estimating obesity prevalence, corrected values of BMI (from any equation) were superior to self-report. In terms of modelling BMI-disease outcome associations, findings were mixed, with no correction proving consistently superior to self-report. Conclusions If researchers are interested in modelling the full population distribution of BMI, or estimating the prevalence of obesity in a

  8. Highly sensitive stool DNA testing of Fusobacterium nucleatum as a marker for detection of colorectal tumours in a Japanese population.

    Science.gov (United States)

    Suehiro, Yutaka; Sakai, Kouhei; Nishioka, Mitsuaki; Hashimoto, Shinichi; Takami, Taro; Higaki, Shingo; Shindo, Yoshitaro; Hazama, Shoichi; Oka, Masaaki; Nagano, Hiroaki; Sakaida, Isao; Yamasaki, Takahiro

    2017-01-01

    Background Accumulating evidence shows an over-abundance of Fusobacterium nucleatum in colorectal tumour tissues. Although stool DNA testing of Fusobacterium nucleatum might be a potential marker for the detection of colorectal tumours, the difficulty in detecting Fusobacterium nucleatum in stool by conventional methods prevented further explorations. Therefore, we developed a droplet digital polymerase chain reaction (PCR) assay for detecting Fusobacterium nucleatum in stool and investigated its clinical utility in the management of colorectal tumours in a Japanese population. Methods Feces were collected from 60 healthy subjects (control group) and from 11 patients with colorectal non-advanced adenomas (non-advanced adenoma group), 19 patients with colorectal advanced adenoma/carcinoma in situ (advanced adenoma/carcinoma in situ (CIS) group) and 158 patients with colorectal cancer of stages I to IV (colorectal cancer group). Absolute copy numbers of Fusobacterium nucleatum were measured by droplet digital PCR. Results The median copy number of Fusobacterium nucleatum was 17.5 in the control group, 311 in the non-advanced adenoma group, 122 in the advanced adenoma/CIS group, and 317 in the colorectal cancer group. In comparison with that in the control group, the Fusobacterium nucleatum level was significantly higher in the non-advanced adenoma group, the advanced adenoma/CIS group and the colorectal cancer group. Conclusions This study illustrates the potential of stool DNA testing of Fusobacterium nucleatum by droplet digital PCR to detect individuals with colorectal tumours in a Japanese population.

  9. A Data-Driven Evaluation of the Stop TB Global Partnership Strategy of Targeting Key Populations at Greater Risk for Tuberculosis.

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    Zoë M McLaren

    Full Text Available Identifying those infected with tuberculosis (TB is an important component of any strategy for reducing TB transmission and population prevalence. The Stop TB Global Partnership recently launched an initiative with a focus on key populations at greater risk for TB infection or poor clinical outcomes, due to housing and working conditions, incarceration, low household income, malnutrition, co-morbidities, exposure to tobacco and silica dust, or barriers to accessing medical care. To achieve operational targets, the global health community needs effective, low cost, and large-scale strategies for identifying key populations. Using South Africa as a test case, we assess the feasibility and effectiveness of targeting active case finding to populations with TB risk factors identified from regularly collected sources of data. Our approach is applicable to all countries with TB testing and census data. It allows countries to tailor their outreach activities to the particular risk factors of greatest significance in their national context.We use a national database of TB test results to estimate municipality-level TB infection prevalence, and link it to Census data to measure population risk factors for TB including rates of urban households, informal settlements, household income, unemployment, and mobile phone ownership. To examine the relationship between TB prevalence and risk factors, we perform linear regression analysis and plot the set of population characteristics against TB prevalence and TB testing rate by municipality. We overlay lines of best fit and smoothed curves of best fit from locally weighted scatter plot smoothing.Higher TB prevalence is statistically significantly associated with more urban municipalities (slope coefficient β1 = 0.129, p < 0.0001, R2 = 0.133, lower mobile phone access (β1 = -0.053, p < 0.001, R2 = 0.089, lower unemployment rates (β1 = -0.020, p = 0.003, R2 = 0.048, and a lower proportion of low-income households

  10. Xenobiotic Sensor- and Metabolism-Related Gene Variants in Environmental Sensitivity-Related Illnesses: A Survey on the Italian Population

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    Daniela Caccamo

    2013-01-01

    Full Text Available In the environmental sensitivity-related illnesses (SRIs, multiple chemical sensitivity (MCS, chronic fatigue syndrome (FCS, and fibromyalgia (FM, the search for genetic polymorphisms of phase I/II xenobiotic-metabolizing enzymes as suitable diagnostic biomarkers produced so far inconclusive results, due to patient heterogeneity, geographic/ethnic differences in genetic backgrounds, and different methodological approaches. Here, we compared the frequency of gene polymorphisms of selected cytochrome P450 (CYP metabolizing enzymes and, for the first time, the frequency of the xenobiotic sensor Aryl hydrocarbon receptor (AHR in the three cohorts of 156 diagnosed MCS, 94 suspected MCS, and 80 FM/FCS patients versus 113 healthy controls. We found significantly higher frequency of polymorphisms CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2D6*4 and CYP2D6*41 in patients compared with controls. This confirms that these genetic variants represent a genetic risk factor for SRI. Moreover, the compound heterozygosity for CYP2C9*2 and *3 variants was useful to discriminate between either MCS or FM/CFS versus SMCS, while the PM *41/*41 genotype discriminated between MCS and either SMCS or FM/CFS. The compound heterozygosity for CYP2C9 *1/*3 and CYP2D6 *1/*4 differentiated MCS and SMCS cases from FM/CFS ones. Interestingly, despite the distribution of the AHR Arg554Lys variant did not result significantly different between SRI cases and controls, it resulted useful for the discrimination between MCS and SMCS cases when considered within haplotypes in combination with CYP2C19 *1/*2 and CYP2D6 *1/*4. Results allowed us to propose the genotyping for these specific CYP variants, together with the AHR Arg554Lys variant, as reliable, cost-effective genetic parameters to be included in the still undefined biomarkers' panel for laboratory diagnosis of the main types of environmental-borne SRI.

  11. Application of Ensemble Sensitivity Analysis to Observation Targeting for Short-term Wind Speed Forecasting in the Tehachapi Region Winter Season

    Energy Technology Data Exchange (ETDEWEB)

    Zack, John [AWS Truepower, LLC, Albany, NY (United States); Natenberg, Eddie [AWS Truepower, LLC, Albany, NY (United States); Young, Steve [AWS Truepower, LLC, Albany, NY (United States); Van Knowe, Glenn [AWS Truepower, LLC, Albany, NY (United States); Waight, Ken [AWS Truepower, LLC, Albany, NY (United States); Manobainco, John [AWS Truepower, LLC, Albany, NY (United States); Kamath, Chandrika [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2010-10-20

    This study extends the wind power forecast sensitivity work done by Zack et al. (2010a, b) in two prior research efforts. Zack et al. (2010a, b) investigated the relative predictive value and optimal combination of different variables/locations from correlated sensitivity patterns. Their work involved developing the Multiple Observation Optimization Algorithm (MOOA) and applying the algorithm to the results obtained from the Ensemble Sensitivity Analysis (ESA) method (Ancell and Hakim 2007; Torn and Hakim 2008).

  12. Variation of radiation-sensitivity of neural stem and progenitor cell populations within the developing mouse brain

    International Nuclear Information System (INIS)

    Etienne, Olivier; Roque, Telma; Haton, Celine; Boussin, Francois D.

    2012-01-01

    We investigated the DNA damage response (DDR) of fetal neural stem and progenitor cells (NSPC), since exposure to ionizing radiation can severely impair the brain development. We compared apoptosis induction in the dorsal tel-encephalon and the lateral ganglionic eminences (LGE) of mouse embryos after an in utero irradiation. We used two thymidine analogs, together with the physical position of nuclei within brain structures, to determine the fate of irradiated NSPC. NSPC did not activate an apparent protein 21(p21)- dependent G1/S checkpoint within the LGE as their counterparts within the dorsal tel-encephalon. However, the levels of radiation induced apoptosis differed between the two tel-encephalic regions, due to the high radiation sensitivity of intermediate progenitors of the LGE. Besides radial glial cells, that function as neural stem cells, were more resistant and were reoriented toward self-renewing within hours following irradiation. The lack of the p21-dependent-cell cycle arrest at the G1/S transition appears to be a general feature of NSPC in the developing brain. However, we found variation of radiation response in function of the types of NSPC. Factors involved in DDR and those involved in the regulation of neurogenesis are intricately linked in determining the cell fate after irradiations. (authors)

  13. Integration of sensitivity and bifurcation analysis to detect critical processes in a model combining signalling and cell population dynamics

    Science.gov (United States)

    Nikolov, S.; Lai, X.; Liebal, U. W.; Wolkenhauer, O.; Vera, J.

    2010-01-01

    In this article we present and test a strategy to integrate, in a sequential manner, sensitivity analysis, bifurcation analysis and predictive simulations. Our strategy uses some of these methods in a coordinated way such that information, generated in one step, feeds into the definition of further analyses and helps refining the structure of the mathematical model. The aim of the method is to help in the designing of more informative predictive simulations, which focus on critical model parameters and the biological effects of their modulation. We tested our methodology with a multilevel model, accounting for the effect of erythropoietin (Epo)-mediated JAK2-STAT5 signalling in erythropoiesis. Our analysis revealed that time-delays associated with the proliferation-differentiation process are critical to induce pathological sustained oscillations, whereas the modulation of time-delays related to intracellular signalling and hypoxia-controlled physiological dynamics is not enough to induce self-oscillations in the system. Furthermore, our results suggest that the system is able to compensate (through the physiological-level feedback loop on hypoxia) the partial impairment of intracellular signalling processes (downregulation or overexpression of Epo receptor complex and STAT5), but cannot control impairment in some critical physiological-level processes, which provoke the emergence of pathological oscillations.

  14. Association of polymorphism in TP53 gene with susceptibility and radiation sensitivity of non-small-cell-lung cancer in Chinese population

    International Nuclear Information System (INIS)

    Shao Guoguang; Liu Linlin; Xu Chuanjie

    2005-01-01

    Objective: To study the association of polymorphism in TP53 gene with the susceptibility and radiation sensitivity of non-small-cell-lung cancer (NSCLC) of the population in the North of China. Methods: Using RFLP-PCR assays, TP53 genotypes were detected by amplifying DNA fragments with sequence specific primers and digested by FnuD II enzyme in 88 patients with NSCLC as well as 112 healthy controls. Results: The C/C allele frequency was significantly higher in NSCLC patients than that in the healthy controls (χ 2 =5.65, P=0.017). The C/C genotype frequency was significantly higher in NSCLC patients than that of the healthy controls (χ 2 =9.33, P=0.0023). The risk of C/C homozygotes in NSCLC patients was about 2.7 times against G/G homozygotes with odds ratio of 2.43(95% CI=1.32-4.51). Conclusion: In the population in the North of China, TP53 C/C genotype is closely associated with the susceptibility of NSCLC. There is no significant relationship between the polymorphism in TP53 gene and radiation sensitivity in NSCLC. (authors)

  15. Association of glomerular filtration rate with high-sensitivity cardiac troponin T in a community-based population study in Beijing.

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    Fan Wang

    Full Text Available BACKGROUND: Reduced renal function is an independent risk factor for cardiovascular disease mortality, and persistently elevated cardiac troponin T (cTnT is frequently observed in patients with end-stage renal disease. In the general population the relationship between renal function and cTnT levels may not be clear because of the low sensitivity of the assay. In this study, we investigated the level of cTnT using a highly sensitive assay (hs-cTnT and evaluated the association of estimated glomerular filtration rate (eGFR with detectable hs-cTnT levels in a community-based population. METHODS: The serum hs-cTnT levels were measured in 1365 community dwelling population aged ≥45 years in Beijing, China. eGFR was determined by the Chinese modifying modification of diet in renal disease (C-MDRD equation. RESULTS: With the highly sensitive assay, cTnT levels were detectable (≥3pg/mL in 744 subjects (54.5%. The result showed that eGFR was associated with Log hs-cTnT (r = -0.14, P20% and other prognostic indicators, moderate to severe reduced eGFR was independently associated with detectable hs-cTnT, whereas normal to mildly reduced eGFR was not independently associated with detectable hs-cTnT. In addition, after adjustment for other risk factors, the high predicted Framingham CHD risk was associated with detectable hs-cTnT in the subjects with different quartile levels of eGFR. CONCLUSION: The levels of hs-cTnT are detectable in a community-based Chinese population and low eGFR is associated with detectable hs-cTnT. Moreover, eGFR and high predicted Framingham CHD risk are associated with detectable hs-cTnT in subjects with moderate-to-severe reduced renal function.

  16. Small interfering RNA targeting S100A4 sensitizes non-small-cell lung cancer cells (A549) to radiation treatment.

    Science.gov (United States)

    Qi, Ruixue; Qiao, Tiankui; Zhuang, Xibing

    2016-01-01

    This study aimed to investigate the impact of S100A4-small interfering RNA (S100A4-siRNA) on apoptosis and enhanced radiosensitivity in non-small-cell lung cancer (A549) cells. We also explored the mechanisms of radiosensitization and identified a new target to enhance radiosensitivity and gene therapy for non-small-cell lung cancer. RNA interference is a powerful tool for gene silencing. In this study, we constructed an effective siRNA to knock down S100A4. A549 cells were randomly divided into three groups: blank, negative control, and S100A4-siRNA. To investigate the effect of S100A4-siRNA, the expression of S100A4, E-cadherin, and p53 proteins and their messenger RNA (mRNA) was detected by Western blot and quantitative real-time polymerase chain reaction. Transwell chambers were used to assess cell invasion. Cell cycle and apoptosis were analyzed by flow cytometry. Radiosensitivity was determined by colony formation ability. Our results demonstrate that S100A4-siRNA effectively silenced the S100A4 gene. When siRNA against S100A4 was used, S100A4 protein expression was downregulated, whereas the expressions of E-cadherin and p53 were upregulated. In addition, a clear reduction in S100A4 mRNA levels was noted compared with the blank and negative control groups, whereas E-cadherin and p53 mRNA levels increased. Transfection with S100A4-siRNA significantly reduced the invasiveness of A549 cells. S100A4 silencing induced immediate G2/M arrest in cell cycle studies and increased apoptosis rates in A549 cells. In clonogenic assays, we used a multitarget, single-hit model to detect radiosensitivity after S100A4 knockdown. All parameters (D0, Dq, α, β) indicated that the downregulation of S100A4 enhanced radiosensitivity in A549 cells. Furthermore, S100A4-siRNA upregulated p53 expression, suggesting that S100A4 may promote A549 cell proliferation, invasion, and metastasis by regulating the expression of other proteins. Therefore, siRNA-directed S100A4 knockdown may

  17. Sex difference in the association of metabolic syndrome with high sensitivity C-reactive protein in a Taiwanese population

    Directory of Open Access Journals (Sweden)

    Lin Wen-Yuan

    2010-07-01

    Full Text Available Abstract Background Although sex differences have been reported for associations between components of metabolic syndrome and inflammation, the question of whether there is an effect modification by sex in the association between inflammation and metabolic syndrome has not been investigated in detail. Therefore, the aim of this study was to compare associations of high sensitivity C-creative protein (hs-CRP with metabolic syndrome and its components between men and women. Methods A total of 1,305 subjects aged 40 years and over were recruited in 2004 in a metropolitan city in Taiwan. The biochemical indices, such as hs-CRP, fasting glucose levels, lipid profiles, urinary albumin, urinary creatinine and anthropometric indices, were measured. Metabolic syndrome was defined using the American Heart Association and the National Heart, lung and Blood Institute (AHA/NHLBI definition. The relationship between metabolic syndrome and hs-CRP was examined using multivariate logistic regression analysis. Results After adjustment for age and lifestyle factors including smoking, and alcohol intake, elevated concentrations of hs-CRP showed a stronger association with metabolic syndrome in women (odds ratio comparing tertile extremes 4.80 [95% CI: 3.31-6.97] than in men (2.30 [1.65-3.21]. The p value for the sex interaction was 0.002. All components were more strongly associated with metabolic syndrome in women than in men, and all sex interactions were significant except for hypertension. Conclusions Our data suggest that inflammatory processes may be of particular importance in the pathogenesis of metabolic syndrome in women.

  18. The timing and targeting of treatment in influenza pandemics influences the emergence of resistance in structured populations.

    Science.gov (United States)

    Althouse, Benjamin M; Patterson-Lomba, Oscar; Goerg, Georg M; Hébert-Dufresne, Laurent

    2013-01-01

    Antiviral resistance in influenza is rampant and has the possibility of causing major morbidity and mortality. Previous models have identified treatment regimes to minimize total infections and keep resistance low. However, the bulk of these studies have ignored stochasticity and heterogeneous contact structures. Here we develop a network model of influenza transmission with treatment and resistance, and present both standard mean-field approximations as well as simulated dynamics. We find differences in the final epidemic sizes for identical transmission parameters (bistability) leading to different optimal treatment timing depending on the number initially infected. We also find, contrary to previous results, that treatment targeted by number of contacts per individual (node degree) gives rise to more resistance at lower levels of treatment than non-targeted treatment. Finally we highlight important differences between the two methods of analysis (mean-field versus stochastic simulations), and show where traditional mean-field approximations fail. Our results have important implications not only for the timing and distribution of influenza chemotherapy, but also for mathematical epidemiological modeling in general. Antiviral resistance in influenza may carry large consequences for pandemic mitigation efforts, and models ignoring contact heterogeneity and stochasticity may provide misleading policy recommendations.

  19. The timing and targeting of treatment in influenza pandemics influences the emergence of resistance in structured populations.

    Directory of Open Access Journals (Sweden)

    Benjamin M Althouse

    Full Text Available Antiviral resistance in influenza is rampant and has the possibility of causing major morbidity and mortality. Previous models have identified treatment regimes to minimize total infections and keep resistance low. However, the bulk of these studies have ignored stochasticity and heterogeneous contact structures. Here we develop a network model of influenza transmission with treatment and resistance, and present both standard mean-field approximations as well as simulated dynamics. We find differences in the final epidemic sizes for identical transmission parameters (bistability leading to different optimal treatment timing depending on the number initially infected. We also find, contrary to previous results, that treatment targeted by number of contacts per individual (node degree gives rise to more resistance at lower levels of treatment than non-targeted treatment. Finally we highlight important differences between the two methods of analysis (mean-field versus stochastic simulations, and show where traditional mean-field approximations fail. Our results have important implications not only for the timing and distribution of influenza chemotherapy, but also for mathematical epidemiological modeling in general. Antiviral resistance in influenza may carry large consequences for pandemic mitigation efforts, and models ignoring contact heterogeneity and stochasticity may provide misleading policy recommendations.

  20. Incidence and predictors of target lesion failure in a multiethnic Asian population receiving the SYNERGY coronary stent: A prospective all-comers registry.

    Science.gov (United States)

    Ananthakrishna, Rajiv; Kristanto, William; Liu, Li; Chan, Siew-Pang; Loh, Poay Huan; Tay, Edgar L; Chan, Koo Hui; Chan, Mark Y; Lee, Chi-Hang; Low, Adrian F; Tan, Huay Cheem; Loh, Joshua P

    2018-03-07

    To evaluate the target lesion failure (TLF) rate of the SYNERGY stent in all-comers, multiethnic Asian population. Currently, most drug eluting stents deliver anti-proliferative drugs from a durable polymer which is associated with a risk of late stent thrombosis. The novel everolimus-eluting, platinum chromium SYNERGY stent is coated with a bioabsorbable abluminal polymer that resolves within 4 months. This was a prospective, single center registry of consecutive patients treated with the SYNERGY stent between December 2012 and April 2015. The primary outcome was the incidence of TLF, defined as the combination of cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization (TLR) at 1 year. A total of 807 patients received the SYNERGY stent during the study period. One-year clinical outcome data was available for 765 patients (94.8%) and were considered for statistical analysis. The mean age was 60.7 ± 10.8 years, and 83.4% were males. Patients with acute myocardial infarction consisted of 50.3% (ST-segment elevation myocardial infarction: 23.0%, Non-ST-segment elevation myocardial infarction: 27.3%) of the study population. The treated lesions were complex (ACC/AHA type B2/C: 72.7%). The primary end point of TLF at 1 year was 5.8%. Rates of cardiac mortality, target vessel myocardial infarction, and TLR were 4.2, 1.0, and 1.3%, respectively, at 1 year. Predictors of the incidence and time to early TLF were female gender, Malay ethnicity, diabetes mellitus, acute myocardial infarction at presentation, a prior history of coronary artery bypass surgery and the presence of lesion calcification. The incidence of definite stent thrombosis was 0.4% at 1 year. In this registry, the use of the SYNERGY stent was associated with low rates of TLF at 1 year. © 2018 Wiley Periodicals, Inc.

  1. Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury

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    Kathleen M. Keefe

    2017-03-01

    Full Text Available Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI. We focus on nerve growth factor (NGF, brain derived neurotrophic factor (BDNF, and neurotrophin-3 (NT-3, and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord.

  2. Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury.

    Science.gov (United States)

    Keefe, Kathleen M; Sheikh, Imran S; Smith, George M

    2017-03-03

    Neurotrophins are a family of proteins that regulate neuronal survival, synaptic function, and neurotransmitter release, and elicit the plasticity and growth of axons within the adult central and peripheral nervous system. Since the 1950s, these factors have been extensively studied in traumatic injury models. Here we review several members of the classical family of neurotrophins, the receptors they bind to, and their contribution to axonal regeneration and sprouting of sensory and motor pathways after spinal cord injury (SCI). We focus on nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), and their effects on populations of neurons within diverse spinal tracts. Understanding the cellular targets of neurotrophins and the responsiveness of specific neuronal populations will allow for the most efficient treatment strategies in the injured spinal cord.

  3. Model-based global sensitivity analysis as applied to identification of anti-cancer drug targets and biomarkers of drug resistance in the ErbB2/3 network

    Science.gov (United States)

    Lebedeva, Galina; Sorokin, Anatoly; Faratian, Dana; Mullen, Peter; Goltsov, Alexey; Langdon, Simon P.; Harrison, David J.; Goryanin, Igor

    2012-01-01

    High levels of variability in cancer-related cellular signalling networks and a lack of parameter identifiability in large-scale network models hamper translation of the results of modelling studies into the process of anti-cancer drug development. Recently global sensitivity analysis (GSA) has been recognised as a useful technique, capable of addressing the uncertainty of the model parameters and generating valid predictions on parametric sensitivities. Here we propose a novel implementation of model-based GSA specially designed to explore how multi-parametric network perturbations affect signal propagation through cancer-related networks. We use area-under-the-curve for time course of changes in phosphorylation of proteins as a characteristic for sensitivity analysis and rank network parameters with regard to their impact on the level of key cancer-related outputs, separating strong inhibitory from stimulatory effects. This allows interpretation of the results in terms which can incorporate the effects of potential anti-cancer drugs on targets and the associated biological markers of cancer. To illustrate the method we applied it to an ErbB signalling network model and explored the sensitivity profile of its key model readout, phosphorylated Akt, in the absence and presence of the ErbB2 inhibitor pertuzumab. The method successfully identified the parameters associated with elevation or suppression of Akt phosphorylation in the ErbB2/3 network. From analysis and comparison of the sensitivity profiles of pAkt in the absence and presence of targeted drugs we derived predictions of drug targets, cancer-related biomarkers and generated hypotheses for combinatorial therapy. Several key predictions have been confirmed in experiments using human ovarian carcinoma cell lines. We also compared GSA-derived predictions with the results of local sensitivity analysis and discuss the applicability of both methods. We propose that the developed GSA procedure can serve as a

  4. A randomized study of telephonic care support in populations at risk for musculoskeletal preference-sensitive surgeries

    Directory of Open Access Journals (Sweden)

    Veroff David R

    2013-02-01

    Full Text Available Abstract Background The rate of elective surgeries varies dramatically by geography in the United States. For many of these surgeries, there is not clear evidence of their relative merits over alternate treatment choices and there are significant tradeoffs in short- and long-term risks and benefits of selecting one treatment option over another. Conditions and symptoms for which there is this lack of a single clear evidence-based treatment choice present great opportunities for patient and provider collaboration on decision making; back pain and joint osteoarthritis are two such ailments. A number of decision aids are in active use to encourage this shared decision-making process. Decision aids have been assessed in formal studies that demonstrate increases in patient knowledge, increases in patient-provider engagement, and reduction in surgery rates. These studies have not widely demonstrated the added benefit of health coaching in support of shared decision making nor have they commonly provided strong evidence of cost reductions. In order to add to this evidence base, we undertook a comparative study testing the relative impact on health utilization and costs of active outreach through interactive voice response technology to encourage health coaching in support of shared decision making in comparison to mailed outreach or no outreach. This study focused on individuals with back pain or joint pain. Methods We conducted four waves of stratified randomized comparisons for individuals with risk for back, hip, or knee surgery who did not have claims-based evidence of one or more of five chronic conditions and were eligible for population care management services within three large regional health plans in the United States. An interactive voice response (IVR form of outreach that included the capability for individuals to directly connect with health coaches telephonically, known as AutoDialog®, was compared to a control (mailed outreach or

  5. IMPaCT Back study protocol. Implementation of subgrouping for targeted treatment systems for low back pain patients in primary care: a prospective population-based sequential comparison

    Directory of Open Access Journals (Sweden)

    Foster Nadine E

    2010-08-01

    Full Text Available Abstract Background Prognostic assessment tools to identify subgroups of patients at risk of persistent low back pain who may benefit from targeted treatments have been developed and validated in primary care. The IMPaCT Back study is investigating the effects of introducing and supporting a subgrouping for targeted treatment system in primary care. Methods/Design A prospective, population-based, quality improvement study in one Primary Care Trust in England with a before and after design. Phases 1 and 3 collect data on current practice, attitudes and behaviour of health care practitioners, patients' outcomes and health care costs. Phase 2 introduces and supports the subgrouping for targeted treatment system, via a multi-component, quality improvement intervention that includes educational courses and outreach visits led by opinion leaders, audit/feedback, mentoring and organisational support to embed the subgrouping tools within IT and clinical management systems. We aim to recruit 1000 low back pain patients aged 18 years and over consulting 7 GP practices within one Primary Care Trust in England, UK. The study includes GPs in participating practices and physiotherapists in associated services. The primary objective is to determine the effect of the subgrouping for targeted treatment system on back pain related disability and catastrophising at 2 and 6 months, comparing data from phase 1 with phase 3. Key secondary objectives are to determine the impact on: a GPs' and physiotherapists' attitudes and behaviour regarding low back pain; b The process of care that patients receive; c The cost-effectiveness and sustainability of the new clinical system. Discussion This paper details the rationale, design, methods, planned analysis and operational aspects of the IMPaCT Back study. We aim to determine whether the new subgrouping for targeted treatment system is implemented and sustained in primary care, and evaluate its impact on clinical decision

  6. Empirical and targeted therapy of candidemia with fluconazole versus echinocandins: a propensity score-derived analysis of a population-based, multicentre prospective cohort.

    Science.gov (United States)

    López-Cortés, L E; Almirante, B; Cuenca-Estrella, M; Garnacho-Montero, J; Padilla, B; Puig-Asensio, M; Ruiz-Camps, I; Rodríguez-Baño, J

    2016-08-01

    We compared the clinical efficacy of fluconazole and echinocandins in the treatment of candidemia in real practice. The CANDIPOP study is a prospective, population-based cohort study on candidemia carried out between May 2010 and April 2011 in 29 Spanish hospitals. Using strict inclusion criteria, we separately compared the impact of empirical and targeted therapy with fluconazole or echinocandins on 30-day mortality. Cox regression, including a propensity score (PS) for receiving echinocandins, stratified analysis on the PS quartiles and PS-based matched analyses, were performed. The empirical and targeted therapy cohorts comprised 316 and 421 cases, respectively; 30-day mortality was 18.7% with fluconazole and 33.9% with echinocandins (p 0.02) in the empirical therapy group and 19.8% with fluconazole and 27.7% with echinocandins (p 0.06) in the targeted therapy group. Multivariate Cox regression analysis including PS showed that empirical therapy with fluconazole was associated with better prognosis (adjusted hazard ratio 0.38; 95% confidence interval 0.17-0.81; p 0.01); no differences were found within each PS quartile or in cases matched according to PS. Targeted therapy with fluconazole did not show a significant association with mortality in the Cox regression analysis (adjusted hazard ratio 0.77; 95% confidence interval 0.41-1.46; p 0.63), in the PS quartiles or in PS-matched cases. The results were similar among patients with severe sepsis and septic shock. Empirical or targeted treatment with fluconazole was not associated with increased 30-day mortality compared to echinocandins among adults with candidemia. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  7. Life histories predict genetic diversity and population structure within three species of octopus targeted by small-scale fisheries in Northwest Mexico

    Science.gov (United States)

    Ceballos-Vázquez, Bertha P.; Arellano-Martínez, Marcial; García-Rodríguez, Francisco J.; Culver, Melanie; Reyes-Bonilla, Hector

    2018-01-01

    The fishery for octopus in Northwest Mexico has increased to over 2,000 tons annually, but to date the specific composition of the catch has been ignored. With at least three main species targeted by artisanal fisheries in the region with distinct life histories, the lack of basic biological information about the distribution, metapopulation size and structure of each species could impede effective fisheries management to avoid overexploitation. We tested if different life histories of three species of octopus could help predict observed patterns of genetic diversity, population dynamics, structure and connectivity and how this information could be relevant to the sustainable management of the fishery. We sequenced two mitochondrial genes and genotyped seven nuclear microsatellite loci to identify the distribution of each species in 20 locations from the Gulf of California and the west coast of the Baja California peninsula. We tested five hypotheses derived from population genetic theory based on differences in the fecundity and dispersal potential for each species. We discovered that Octopus bimaculoides with low fecundity and direct development (without a planktonic phase) had lower average effective population size and genetic diversity, but higher levels of kinship, population structure, and richness of private alleles, than the other two species. These features indicated limited dispersal and high local recruitment. In contrast, O. bimaculatus and O. hubbsorum with higher fecundity and planktonic phase as paralarvae had higher effective population size and genetic diversity, and overall lower kinship and population structure than O. bimaculoides. These observations supported higher levels of gene flow over a larger geographical scale. O. bimaculatus with the longest planktonic paralarval duration and therefore larger dispersal potential had differences in the calculated parameters possibly associated with increased connectivity. We propose O

  8. Sensitivity and prognostic value of positron emission tomography with F-18-fluorodeoxyglucose and sensitivity of immunoscintigraphy in patients with medullary thyroid carcinoma treated with anticarcinoembryonic antigen-targeted radioimmunotherapy.

    Science.gov (United States)

    Oudoux, Aurore; Salaun, Pierre-Yves; Bournaud, Claire; Campion, Loïc; Ansquer, Catherine; Rousseau, Caroline; Bardet, Stéphane; Borson-Chazot, Françoise; Vuillez, Jean-Philippe; Murat, Arnaud; Mirallié, Eric; Barbet, Jacques; Goldenberg, David M; Chatal, Jean-François; Kraeber-Bodéré, Françoise

    2007-12-01

    Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging. Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC. We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT). INTERVENTIONS/MAIN OUTCOME MEASURES: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated. A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21-8.50) and 1.52 yr (range 0.09-6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06-13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively. These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.

  9. Wolbachia-based population control strategy targeting Culex quinquefasciatus mosquitoes proves efficient under semi-field conditions.

    Science.gov (United States)

    Atyame, Célestine M; Cattel, Julien; Lebon, Cyrille; Flores, Olivier; Dehecq, Jean-Sébastien; Weill, Mylène; Gouagna, Louis Clément; Tortosa, Pablo

    2015-01-01

    In mosquitoes, the maternally inherited bacterial Wolbachia induce a form of embryonic lethality called cytoplasmic incompatibility (CI). This property can be used to reduce the density of mosquito field populations through inundative releases of incompatible males in order to sterilize females (Incompatible Insect Technique, or IIT, strategy). We have previously constructed the LR[wPip(Is)] line representing a good candidate for controlling field populations of the Culex quinquefasciatus mosquito in the islands of the south-western Indian Ocean. The main purpose of the present study was to fill the gap between laboratory experiments and field implementation, i.e. assessing mating competitiveness of these incompatible males under semi-field conditions. In a first set of experiments, we analyzed crossing relationships between LR[wPip(Is)] males and La Réunion field females collected as larvae in 19 distinct localities throughout the island. This investigation revealed total embryonic mortality, confirming the strong sterilizing capacity of LR[wPip(Is)] males. Subsequently, mating competitiveness of LR[wPip(Is)] males was assessed under semi-field conditions in the presence of field males and females from La Réunion. Confrontations were carried out in April and December using different ratios of LR[wPip(Is)] to field males. The results indicated that the LR[wPip(Is)] males successfully compete with field males in mating with field females, displaying even higher competitiveness than field males in April. Our results support the implementation of small-scale field tests in order to assess the feasibility of IIT against Cx. quinquefasciatus in the islands of southwestern Indian Ocean where this mosquito species is a proven competent vector for human pathogens.

  10. Identification of population at risk for future Clostridium difficile infection following hospital discharge to be targeted for vaccine trials.

    Science.gov (United States)

    Baggs, James; Yousey-Hindes, Kimberly; Ashley, Elizabeth Dodds; Meek, James; Dumyati, Ghinwa; Cohen, Jessica; Wise, Matthew E; McDonald, L Clifford; Lessa, Fernanda C

    2015-11-17

    Efforts to develop a Clostridium difficile vaccine are underway; identification of patients at risk for C. difficile infection (CDI) is critical to inform vaccine trials. We identified groups at high risk of CDI ≥ 2 8 days after hospital discharge. Hospital discharge data and pharmacy data from two large academic centers, in New York and Connecticut, were linked to active population-based CDI surveillance data from the Emerging Infections Program (EIP). Adult residents of the EIP surveillance area were included if they had an inpatient stay at a study hospital without prior history of CDI. The primary outcome was CDI by either toxin or molecular assay ≥ 28 days after an index hospitalization. Important predictors of CDI ≥ 28 days post discharge were initially identified through a Cox proportional hazards model (stepwise backward selection) using a derivation cohort; final model parameters were used to develop a risk score evaluated in the validation cohort. Of the 35,186 index hospitalizations, 288 (0.82%) had CDI ≥ 28 days post discharge. After parameter selection, age, number of hospitalizations in the prior 90 days, admission diagnosis, and the use of 3rd/4th generation cephalosporin, clindamycin or fluoroquinolone antibiotic classes remained in the model. Using the validation cohort, the risk score was predictive (p<0.001) with a c-score of 0.75. Based on the distribution of scores in the derivation cohort, we divided the patients into low and high risk groups. In the high risk group, 1.6% experienced CDI ≥ 28 days post discharge compared to 0.3% among our low risk group. Our study identified specific parameters for a risk score that can be applied at discharge to identify a patient population whose risk of CDI ≥ 28 days following an acute care hospitalization was 5 times greater than other patients. Published by Elsevier Ltd.

  11. Improved physiologically based pharmacokinetic model for oral exposures to chromium in mice, rats, and humans to address temporal variation and sensitive populations.

    Science.gov (United States)

    Kirman, C R; Suh, M; Proctor, D M; Hays, S M

    2017-06-15

    A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Culture-sensitive adaptation and validation of the community-oriented program for the control of rheumatic diseases methodology for rheumatic disease in Latin American indigenous populations.

    Science.gov (United States)

    Peláez-Ballestas, Ingris; Granados, Ysabel; Silvestre, Adriana; Alvarez-Nemegyei, José; Valls, Evart; Quintana, Rosana; Figuera, Yemina; Santiago, Flor Julian; Goñi, Mario; González, Rosa; Santana, Natalia; Nieto, Romina; Brito, Irais; García, Imelda; Barrios, Maria Cecilia; Marcano, Manuel; Loyola-Sánchez, Adalberto; Stekman, Ivan; Jorfen, Marisa; Goycochea-Robles, Maria Victoria; Midauar, Fadua; Chacón, Rosa; Martin, Maria Celeste; Pons-Estel, Bernardo A

    2014-09-01

    The purpose of the study is to validate a culturally sensitive adaptation of the community-oriented program for the control of rheumatic diseases (COPCORD) methodology in several Latin American indigenous populations. The COPCORD Spanish questionnaire was translated and back-translated into seven indigenous languages: Warao, Kariña and Chaima (Venezuela), Mixteco, Maya-Yucateco and Raramuri (Mexico) and Qom (Argentina). The questionnaire was administered to almost 100 subjects in each community with the assistance of bilingual translators. Individuals with pain, stiffness or swelling in any part of the body in the previous 7 days and/or at any point in life were evaluated by physicians to confirm a diagnosis according to criteria for rheumatic diseases. Overall, individuals did not understand the use of a 0-10 visual analog scale for pain intensity and severity grading and preferred a Likert scale comprising four items for pain intensity (no pain, minimal pain, strong pain, and intense pain). They were unable to discriminate between pain intensity and pain severity, so only pain intensity was included. For validation, 702 subjects (286 male, 416 female, mean age 42.7 ± 18.3 years) were interviewed in their own language. In the last 7 days, 198 (28.2 %) subjects reported having musculoskeletal pain, and 90 (45.4 %) of these had intense pain. Compared with the physician-confirmed diagnosis, the COPCORD questionnaire had 73.8 % sensitivity, 72.9 % specificity, a positive likelihood ratio of 2.7 and area under the receiver operating characteristic curve of 0.73. The COPCORD questionnaire is a valid screening tool for rheumatic diseases in indigenous Latin American populations.

  13. Dual targeting strategy of magnetic nanoparticle-loaded and RGD peptide-activated stimuli-sensitive polymeric micelles for delivery of paclitaxel

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Meng Meng [Tsinghua University, Department of Chemical Engineering (China); Kang, Yoon Joong [Jungwon University, Department of Biomedical Science (Korea, Republic of); Sohn, Youngjoo [Kyung Hee University, Department of Anatomy, College of Korean Medicine (Korea, Republic of); Kim, Do Kyung, E-mail: eurokorean@gmail.com, E-mail: dokyung@konyang.ac.kr [Konyang University, Industry Cooperation Foundation (Korea, Republic of)

    2015-06-15

    A double targeting strategy of anti-neoplastic agent paclitaxel (PTX) was developed by incorporating magnetic nanoparticles and RGD peptide for enhanced cell cytotoxicity effect at lower dosage. A dual targeting mechanism including magnetic targeting and RGD ligand-specific targeting enhanced the overall cytotoxicity and reduced the effective dosage of PTX to achieve enhanced and sustained release of PTX in vitro. We addressed the issues of water-insolubility of oleic acid (OA)-stabilized SPIONs and low incorporation efficiency of hydrophobic PTX with SPION nanocarriers by using an amphiphilic polymer poly[(N-isopropylacrylamide-r-acrylamide)-b-l-lactic acid] (PNAL) as micelle-forming materials. A targeting moiety, GGGGRGD peptide, a RGD sequence-containing peptide with a short linker, is attached to the surface of PNAL-SPIONs via a homo-crosslinker. Confocal microscopy image analysis revealed that the cellular uptake was increased from (1.5 ± 0.5 % (PNAL) to 11.7 ± 0.8 % (RGD-PNAL-SPIONs) at 6 h incubation, once both RGD peptide and magnetic force attraction were incorporated into the carriers. Such multi-targeting nanocarriers showed promising potential in cancer-oriented diagnosis and therapy.

  14. Using Social Media and Targeted Snowball Sampling to Survey a Hard-to-reach Population: A Case Study

    Directory of Open Access Journals (Sweden)

    Gary Dusek

    2015-08-01

    Full Text Available Response rates to the academic surveys used in quantitative research are decreasing and have been for several decades among both individuals and organizations. Given this trend, providing doctoral students an opportunity to complete their dissertations in a timely and cost effective manner may necessitate identifying more innovative and relevant ways to collect data while maintaining appropriate research standards and rigor. The case of a research study is presented which describes the data collection process used to survey a hard-to-reach population. It details the use of social media, in this case LinkedIn, to facilitate the distribution of the web-based survey. A roadmap to illustrate how this data collection process unfolded is presented, as well as several “lessons learned” during this journey. An explanation of the considerations that impacted the sampling design is provided. The goal of this case study is to provide researchers, including doctoral students, with realistic expectations and an awareness of the benefits and risks associated with the use of this method of data collection.

  15. A moving target--incorporating knowledge of the spatial ecology of fish into the assessment and management of freshwater fish populations.

    Science.gov (United States)

    Cooke, Steven J; Martins, Eduardo G; Struthers, Daniel P; Gutowsky, Lee F G; Power, Michael; Doka, Susan E; Dettmers, John M; Crook, David A; Lucas, Martyn C; Holbrook, Christopher M; Krueger, Charles C

    2016-04-01

    Freshwater fish move vertically and horizontally through the aquatic landscape for a variety of reasons, such as to find and exploit patchy resources or to locate essential habitats (e.g., for spawning). Inherent challenges exist with the assessment of fish populations because they are moving targets. We submit that quantifying and describing the spatial ecology of fish and their habitat is an important component of freshwater fishery assessment and management. With a growing number of tools available for studying the spatial ecology of fishes (e.g., telemetry, population genetics, hydroacoustics, otolith microchemistry, stable isotope analysis), new knowledge can now be generated and incorporated into biological assessment and fishery management. For example, knowing when, where, and how to deploy assessment gears is essential to inform, refine, or calibrate assessment protocols. Such information is also useful for quantifying or avoiding bycatch of imperiled species. Knowledge of habitat connectivity and usage can identify critically important migration corridors and habitats and can be used to improve our understanding of variables that influence spatial structuring of fish populations. Similarly, demographic processes are partly driven by the behavior of fish and mediated by environmental drivers. Information on these processes is critical to the development and application of realistic population dynamics models. Collectively, biological assessment, when informed by knowledge of spatial ecology, can provide managers with the ability to understand how and when fish and their habitats may be exposed to different threats. Naturally, this knowledge helps to better evaluate or develop strategies to protect the long-term viability of fishery production. Failure to understand the spatial ecology of fishes and to incorporate spatiotemporal data can bias population assessments and forecasts and potentially lead to ineffective or counterproductive management actions.

  16. Radioecological sensitivity

    International Nuclear Information System (INIS)

    Howard, Brenda J.; Strand, Per; Assimakopoulos, Panayotis

    2003-01-01

    After the release of radionuclide into the environment it is important to be able to readily identify major routes of radiation exposure, the most highly exposed individuals or populations and the geographical areas of most concern. Radioecological sensitivity can be broadly defined as the extent to which an ecosystem contributes to an enhanced radiation exposure to Man and biota. Radioecological sensitivity analysis integrates current knowledge on pathways, spatially attributes the underlying processes determining transfer and thereby identifies the most radioecologically sensitive areas leading to high radiation exposure. This identifies where high exposure may occur and why. A framework for the estimation of radioecological sensitivity with respect to humans is proposed and the various indicators by which it can be considered have been identified. These are (1) aggregated transfer coefficients (Tag), (2) action (and critical) loads, (3) fluxes and (4) individual exposure of humans. The importance of spatial and temporal consideration of all these outputs is emphasized. Information on the extent of radionuclide transfer and exposure to humans at different spatial scales is needed to reflect the spatial differences which can occur. Single values for large areas, such as countries, can often mask large variation within the country. Similarly, the relative importance of different pathways can change with time and therefore assessments of radiological sensitivity are needed over different time periods after contamination. Radioecological sensitivity analysis can be used in radiation protection, nuclear safety and emergency preparedness when there is a need to identify areas that have the potential of being of particular concern from a risk perspective. Prior identification of radioecologically sensitive areas and exposed individuals improve the focus of emergency preparedness and planning, and contribute to environmental impact assessment for future facilities. The

  17. Systematic analysis of off-target effects in an RNAi screen reveals microRNAs affecting sensitivity to TRAIL-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Enright Anton J

    2010-03-01

    Full Text Available Abstract Background RNA inhibition by siRNAs is a frequently used approach to identify genes required for specific biological processes. However RNAi screening using siRNAs is hampered by non-specific or off target effects of the siRNAs, making it difficult to separate genuine hits from false positives. It is thought that many of the off-target effects seen in RNAi experiments are due to siRNAs acting as microRNAs (miRNAs, causing a reduction in gene expression of unintended targets via matches to the 6 or 7 nt 'seed' sequence. We have conducted a careful examination of off-target effects during an siRNA screen for novel regulators of the TRAIL apoptosis induction pathway(s. Results We identified 3 hexamers and 3 heptamer seed sequences that appeared multiple times in the top twenty siRNAs in the TRAIL apoptosis screen. Using a novel statistical enrichment approach, we systematically identified a further 17 hexamer and 13 heptamer seed sequences enriched in high scoring siRNAs. The presence of one of these seeds sequences (which could explain 6 of 8 confirmed off-target effects is sufficient to elicit a phenotype. Three of these seed sequences appear in the human miRNAs miR-26a, miR-145 and miR-384. Transfection of mimics of these miRNAs protects several cell types from TRAIL-induced cell death. Conclusions We have demonstrated a role for miR-26a, miR-145 and miR-26a in TRAIL-induced apoptosis. Further these results show that RNAi screening enriches for siRNAs with relevant off-target effects. Some of these effects can be identified by the over-representation of certain seed sequences in high-scoring siRNAs and we demonstrate the usefulness of such systematic analysis of enriched seed sequences.

  18. High-sensitivity troponin-T as a prognostic marker after out-of-hospital cardiac arrest - A targeted temperature management (TTM) trial substudy

    NARCIS (Netherlands)

    Gilje, Patrik; Koul, Sasha; Thomsen, Jakob Hartvig; Devaux, Yvan; Friberg, Hans; Kuiper, Michael; Horn, Janneke; Nielsen, Niklas; Pellis, Tomasso; Stammet, Pascal; Wise, Matthew P.; Kjaergaard, Jesper; Hassager, Christian; Erlinge, David

    2016-01-01

    Predicting outcome of unconscious patients after successful resuscitation is challenging and better prognostic markers are highly needed. Ischemic heart disease is a common cause of out-of-hospital cardiac arrest (OHCA). Whether or not high-sensitivity troponin T (hs-TnT) is a prognostic marker

  19. From population genomics to conservation and management: a workflow for targeted analysis of markers identified using genome-wide approaches in Atlantic salmon Salmo salar.

    Science.gov (United States)

    Aykanat, T; Lindqvist, M; Pritchard, V L; Primmer, C R

    2016-12-01

    A genotyping assay for the Ion Torrent Ion PGM platform was developed for fast and cost-effective targeted genotyping of key single nucleotide polymorphisms (SNPs) earlier identified using a genome-wide SNP array in Atlantic salmon Salmo salar. The method comprised a simple primer design step for multiplex-polymerase chain reaction (PCR), followed by two rounds of Ion Torrent Ion PGM sequencing to empirically evaluate marker efficiency in large multiplexes and to optimise or exclude them when necessary. Of 282 primer pairs initially tested, 217 were successfully amplified, indicating good amplification success (>75%). These markers included the sdy partial gene product to determine genetic sex, as well as three additional modules comprising SNPs for assessing neutral genetic variation (N SNP = 150), examining functional genetic variation associated with sea age at maturity (N SNP = 5), and for performing genetic subpopulation assignment (N SNP = 61). The assay was primarily developed to monitor long-term genetic changes in S. salar from the Teno River, but modules are likely suitable for application in a wide range of S. salar populations. Furthermore, the fast and versatile assay development pipeline offers a strategy for developing targeted sequencing assays in any species. © 2016 The Fisheries Society of the British Isles.

  20. Effects of the Degree of Obesity on Achieving Target Blood Pressure and Metabolic Deterioration in Obese Individuals: A Population-Based Study

    Directory of Open Access Journals (Sweden)

    Serkan Ozturk

    2013-11-01

    Full Text Available Background/Aims: This study aimed to evaluate the severity of obesity and its impact on achieving target blood pressure and metabolic derangement in obese individuals. Methods: This cross-sectional and population-based study was conducted between January and December 2012. A total of 1837 consecutive obese patients admitted to our outpatient clinic were enrolled. The anthropometric and blood pressure measurements, bioelectrical impedance fat analysis, blood sample analysis, impaired glucose status, metabolic syndrome, and insulin resistance of 1265 obese patients were compared between groups of patients separated by severity of obesity. Results: Only approximately one-third of patients with previous hypertension achieved normal blood pressure. In addition, the majority of patients without previous hypertension had higher blood pressure at the end of the study compared with baseline. The percent of patients with an impaired fasting blood glucose ≥100 mg/dL was 38.5%. The frequency of impaired glucose tolerance was 39.1% in the patients who underwent OGTT Body mass index (BMI was associated with impaired blood glucose, hypertension, insulin resistance, and the development of metabolic syndrome. The incidences of metabolic syndrome, insulin resistance, impaired glucose tolerance, and uncontrolled blood pressure were significantly different between groups of differing obesity severity (ppp=0.041, and pConclusion: The severity of obesity was associated with the failure to achieve target blood pressure and metabolic syndrome. Based on our data, blood pressure and metabolic parameters in obese patients should be monitored frequently and treated with caution.

  1. Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases.

    Science.gov (United States)

    Chandran, Parwathy; Kavalakatt, Anu; Malarvizhi, Giridharan Loghanathan; Vasanthakumari, Divya Rani Vikraman Nair; Retnakumari, Archana Payickattu; Sidharthan, Neeraj; Pavithran, Keechilat; Nair, Shantikumar; Koyakutty, Manzoor

    2014-05-01

    Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n=9), including refractory and relapsed cases, and three representative cell lines expressing CD34(+)/CD38(-) stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having ~100nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML. Through the use of a protein-vorinostat agent, exceptional single-agent activity was demonstrated against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. The studied epigenetics targeted nanomedicine approach is a promising therapeutic strategy against various French-American-British classes of acute myeloid leukemia. © 2014 Elsevier Inc. All rights reserved.

  2. Comparative Effectiveness of Initial Surgery vs Initial Systemic Therapy for Metastatic Kidney Cancer in the Targeted Therapy Era: Analysis of a Population-based Cohort.

    Science.gov (United States)

    Macleod, Liam C; Odisho, Anobel Y; Tykodi, Scott S; Holt, Sarah K; Harper, Jonathan D; Gore, John L

    2018-03-01

    To use econometric methods to assess comparative overall survival of patients with metastatic renal cell carcinoma (mRCC) managed with initial cytoreductive nephrectomy (CN) vs initial systemic therapy. Randomized data demonstrate improved survival for CN preceding cytokine-based therapy in mRCC. This benefit may be attenuated in the contemporary mRCC era given more effective systemic therapies. Patients over age 65 with mRCC from the Surveillance, Epidemiology, and End Results registries linked with Medicare claims from 2006 to 2011 were categorized by initial treatment. We applied sequential survival analysis methods to assess the association between initial CN and overall survival (OS) including Cox proportional hazards models, propensity scoring, and instrumental variable analysis to account for measured and unmeasured selection bias. Of 537 patients analyzed, 190 had initial CN followed by targeted therapy and 347 had initial targeted therapy. Median OS in the initial CN group was 17.4 months (interquartile range 9.8-32.0), compared with 9.2 months (interquartile range 4.3-18.0) for initial targeted therapy. Cox proportional hazards analysis revealed initial CN was associated with improved OS (hazard ratio 0.50, 95% confidence interval [CI] 0.38-0.65). Propensity matching demonstrated a survival advantage for initial CN of 5.8 months (95% CI 1.9-9.7). Accounting for unmeasured confounding with instrumental variable analysis demonstrated a trend toward improved survival with initial CN (hazard ratio 0.29 [95% CI 0.08-1.00]). Initial CN is associated with improved survival compared with initial systemic therapy in a contemporary population-based mRCC cohort. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Influence of socioeconomic and demographic status on spirometry testing in patients initiating medication targeting obstructive lung disease: a population-based cohort study

    Science.gov (United States)

    2013-01-01

    Background Socioeconomic status is known to influence the prevalence, severity and mortality of obstructive lung diseases, but it is uncertain whether it affects the use of diagnostic spirometry in patients initiating treatment for these conditions. The objective of this paper was to examine a possible association between education, income, labour market affiliation, cohabitation status and having spirometry performed when initiating medication targeting obstructive pulmonary disease. Methods We conducted a population-based cohort study. Danish national registers were linked, retrieving data on prescriptions, spirometry testing, socioeconomic and demographic variables in all first time users of medication targeting obstructive lung disease in 2008. Results A total of 37,734 persons were included and approximately half of the cohort had spirometry performed. Among medication users under 65 years of age, being unemployed was significantly associated with reduced odds of having spirometry performed, the strongest association was seen in men (OR = 0.82, CI = 0.73-0.91). Medium income was associated with increased odds of having spirometry performed in men (OR = 1.18, CI = 1.06-1.30) and high educational level (>12 years) was associated with reduced odds of having spirometry performed in women (OR = 0.86, CI = 0.78-0.94). Cohabitation status was not associated with having spirometry performed. Among medication users over 65 years of age, living alone was associated with reduced odds of having spirometry performed among men (OR = 0.78, CI = 0.69-0.88). Conclusion Social inequity in spirometry testing among patients initiating medication targeting obstructive lung disease was confirmed in this study. Increased focus on spirometry testing among elderly men living alone, among the unemployed and among women with higher education is required when initiating medication. PMID:23768408

  4. Influence of socioeconomic and demographic status on spirometry testing in patients initiating medication targeting obstructive lung disease: a population-based cohort study.

    Science.gov (United States)

    Koefoed, Mette M; Søndergaard, Jens; Christensen, René dePont; Jarbøl, Dorte E

    2013-06-14

    Socioeconomic status is known to influence the prevalence, severity and mortality of obstructive lung diseases, but it is uncertain whether it affects the use of diagnostic spirometry in patients initiating treatment for these conditions. The objective of this paper was to examine a possible association between education, income, labour market affiliation, cohabitation status and having spirometry performed when initiating medication targeting obstructive pulmonary disease. We conducted a population-based cohort study. Danish national registers were linked, retrieving data on prescriptions, spirometry testing, socioeconomic and demographic variables in all first time users of medication targeting obstructive lung disease in 2008. A total of 37,734 persons were included and approximately half of the cohort had spirometry performed. Among medication users under 65 years of age, being unemployed was significantly associated with reduced odds of having spirometry performed, the strongest association was seen in men (OR = 0.82, CI = 0.73-0.91). Medium income was associated with increased odds of having spirometry performed in men (OR =1.18, CI = 1.06-1.30) and high educational level (>12 years) was associated with reduced odds of having spirometry performed in women (OR = 0.86, CI = 0.78-0.94). Cohabitation status was not associated with having spirometry performed. Among medication users over 65 years of age, living alone was associated with reduced odds of having spirometry performed among men (OR = 0.78, CI = 0.69-0.88). Social inequity in spirometry testing among patients initiating medication targeting obstructive lung disease was confirmed in this study. Increased focus on spirometry testing among elderly men living alone, among the unemployed and among women with higher education is required when initiating medication.

  5. Effectiveness of influenza vaccine against laboratory-confirmed influenza, in the late 2011–2012 season in Spain, among population targeted for vaccination

    Science.gov (United States)

    2013-01-01

    Background In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using the observational study cycEVA conducted in the frame of the existing Spanish Influenza Sentinel Surveillance System. The objective of the study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza-like illness (ILI) among the target groups for vaccination in Spain in the 2011–2012 season. We also studied influenza VE in the early (weeks 52/2011-7/2012) and late (weeks 8-14/2012) phases of the epidemic and according to time since vaccination. Methods Medically attended patients with ILI were systematically swabbed to collect information on exposure, laboratory outcome and confounding factors. Patients belonging to target groups for vaccination and who were swabbed 4 months, respectively, since vaccination. A decrease in VE with time since vaccination was only observed in individuals aged ≥ 65 years. Regarding the phase of the season, decreasing point estimates were only observed in the early phase, whereas very low or null estimates were obtained in the late phase for the shortest time interval. Conclusions The 2011–2012 influenza vaccine showed a low-to-moderate protective effect against medically attended, laboratory-confirmed influenza in the target groups for vaccination, in a late season and with a limited match between the vaccine and circulating strains. The suggested decrease in influenza VE with time since vaccination was mostly observed in the elderly population. The decreasing protective effect of the vaccine in the late part of the season could be related to waning vaccine protection because no viral changes were identified throughout the season. PMID:24053661

  6. Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice

    OpenAIRE

    Wei, Zhikui; Lei, Xia; Petersen, Pia S.; Aja, Susan; Wong, G. William

    2014-01-01

    Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in ...

  7. Evaluating the Population Impact on Racial/Ethnic Disparities in HIV in Adulthood of Intervening on Specific Targets: A Conceptual and Methodological Framework.

    Science.gov (United States)

    Howe, Chanelle J; Dulin-Keita, Akilah; Cole, Stephen R; Hogan, Joseph W; Lau, Bryan; Moore, Richard D; Mathews, W Christopher; Crane, Heidi M; Drozd, Daniel R; Geng, Elvin; Boswell, Stephen L; Napravnik, Sonia; Eron, Joseph J; Mugavero, Michael J

    2018-02-01

    Reducing racial/ethnic disparities in human immunodeficiency virus (HIV) disease is a high priority. Reductions in HIV racial/ethnic disparities can potentially be achieved by intervening on important intermediate factors. The potential population impact of intervening on intermediates can be evaluated using observational data when certain conditions are met. However, using standard stratification-based approaches commonly employed in the observational HIV literature to estimate the potential population impact in this setting may yield results that do not accurately estimate quantities of interest. Here we describe a useful conceptual and methodological framework for using observational data to appropriately evaluate the impact on HIV racial/ethnic disparities of interventions. This framework reframes relevant scientific questions in terms of a controlled direct effect and estimates a corresponding proportion eliminated. We review methods and conditions sufficient for accurate estimation within the proposed framework. We use the framework to analyze data on 2,329 participants in the CFAR [Centers for AIDS Research] Network of Integrated Clinical Systems (2008-2014) to evaluate the potential impact of universal prescription of and ≥95% adherence to antiretroviral therapy on racial disparities in HIV virological suppression. We encourage the use of the described framework to appropriately evaluate the potential impact of targeted interventions in addressing HIV racial/ethnic disparities using observational data. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Meat and Seafood Consumption in Relation to Plasma Metabolic Profiles in a Chinese Population: A Combined Untargeted and Targeted Metabolomics Study.

    Science.gov (United States)

    Lu, Yonghai; Zou, Li; Su, Jin; Tai, E Shyong; Whitton, Clare; Dam, Rob M van; Ong, Choon Nam

    2017-06-30

    We examined the relationship between different patterns of meat and seafood consumption and plasma metabolic profiles in an Asian population. We selected 270 ethnic Chinese men and women from the Singapore Prospective Study Program based on their dietary habits assessed with a validated food frequency questionnaire. Participants were divided into four subgroups: high meat and high seafood ( n = 60), high meat and low seafood ( n = 64), low meat and high seafood ( n = 60), and low meat and low seafood ( n = 86) consumers. Plasma metabolites were measured using both targeted and untargeted mass spectroscopy-based analyses. A total of 42 metabolites differed significantly by dietary group. Higher concentrations of essential amino acids, polyunsaturated fatty acids, and d-glucose were found in high meat and/or seafood consumers as compared with the group with a low consumption of these animal foods. Red meat, poultry, fish, shellfish, soy products, and dairy were each correlated with at least one differential metabolite ( r = -0.308 to 0.448). Some observations, such as the correlation between fish and 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), confirmed previous studies. Other observations, such as the correlation between shellfish and phosphatidylethanolamine (p36:4), were novel. We also observed significant correlations between plasma metabolites and clinical characteristics, such as CMPF with fasting blood glucose ( r = 0.401). These findings demonstrate a significant influence of meat and seafood consumption on metabolic profiles in the Asian population.

  9. Optimizing Sample Size to Assess the Genetic Diversity in Common Vetch (Vicia sativa L. Populations Using Start Codon Targeted (SCoT Markers

    Directory of Open Access Journals (Sweden)

    Xutian Chai

    2017-03-01

    Full Text Available Common vetch (Vicia sativa subsp. sativa L. is a self-pollinating annual forage legume with worldwide importance. Here, we investigate the optimal number of individuals that may represent the genetic diversity of a single population, using Start Codon Targeted (SCoT markers. Two cultivated varieties and two wild accessions were evaluated using five SCoT primers, also testing different sampling sizes: 1, 2, 3, 5, 8, 10, 20, 30, 40, 50, and 60 individuals. The results showed that the number of alleles and the Polymorphism Information Content (PIC were different among the four accessions. Cluster analysis by Unweighted Pair Group Method with Arithmetic Mean (UPGMA and STRUCTURE placed the 240 individuals into four distinct clusters. The Expected Heterozygosity (HE and PIC increased along with an increase in sampling size from 1 to 10 plants but did not change significantly when the sample sizes exceeded 10 individuals. At least 90% of the genetic variation in the four germplasms was represented when the sample size was 10. Finally, we concluded that 10 individuals could effectively represent the genetic diversity of one vetch population based on the SCoT markers. This study provides theoretical support for genetic diversity, cultivar identification, evolution, and marker-assisted selection breeding in common vetch.

  10. Is there any association of serum high-sensitivity C-reactive protein with various risk factors for metabolic syndrome in a healthy adult population of karachi, pakistan?

    Science.gov (United States)

    Riaz, Mussarat; Fawwad, Asher; Hydrie, M Zafar Iqbal; Basit, Abdul; Shera, A Samad

    2011-06-01

    The aim of this study was to discover the association of serum high-sensitivity C-reactive protein (hsCRP) with various risk factors for metabolic syndrome in an urban population of Karachi, Pakistan. In this cross-sectional study, 337 healthy adults (108 males and 229 females, mean age 40.7 ± 14.2 years) participated. The subjects were randomly selected in Lyari Town in Karachi using a geographical imaging system (GIS). Their demographic, anthropometric [body mass index (BMI), hip and waist circumferences, waist-to-hip circumference ratio (W-HR), and biochemical (fasting blood glucose, fasting insulin, fasting lipid profile, and hsCRP)] parameters were recorded. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. Correlation of CRP and fasting insulin levels with various parameters of metabolic syndrome were calculated using Pearson correlation. Median CRP levels were found to be higher in females 0.81 (0.20-1.38) compared with males 0.77 (0.19-1.35). Metabolic syndrome was diagnosed in 108 (31.12%) subjects. No significant difference between CRP levels in the metabolic syndrome-positive and metabolic syndrome-negative groups was observed. Similarly, no correlation was observed between hsCRP and fasting insulin levels, insulin resistance, and other parameters of MS. There is lack of correlation between hsCRP levels and various risk factors for metabolic syndrome in our urban population. Further large-scale prospective studies are needed to confirm these findings.

  11. Low effect-site concentration of propofol target-controlled infusion reduces the risk of hypotension during endoscopy in a Taiwanese population.

    Science.gov (United States)

    Hsu, Wen-Hung; Wang, Sophie S W; Shih, Hsiang-Yao; Wu, Meng-Chieh; Chen, Yi-Yu; Kuo, Fu-Chen; Yang, Hui-Ying; Chiu, Shun-Li; Chu, Koung-Shing; Cheng, Kuang-I; Wu, Deng-Chyang; Lu, I-Cheng

    2013-03-01

    Target-controlled infusion (TCI) of propofol is an effective way of delivering propofol during endoscopy. However, the ideal effect-site concentration (Ce) of propofol has not yet been defined in an Asian population. This study aimed to determine the ideal Ce of propofol in painless gastrointestinal endoscopy in a Taiwanese population. A total of 121 consecutive patients undergoing diagnostic endoscopy were recruited for this study. The endoscopic procedure was carried out within 1 h. TCI of propofol was utilized during the procedure. All patients received the same regimen to induce conscious sedation, including a bolus of midazolam (0.04 mg/kg) and fentanyl (0.5 μg/kg). The Ce of propofol was calculated using the Schneider model. Patients were randomly assigned to either the low Ce group (1.5-2.5 μg/mL) or high Ce group (3.0-4.0 μg/mL). Their cardiovascular and respiratory events were monitored during the procedure and the patients' post-procedure satisfaction was evaluated. The mean requirement for propofol was 232.02 mg in the low Ce group and 329.56 mg in the high Ce group, respectively (P hypotension were observed in the high Ce group (P = 0.026). The post-procedure satisfaction rate between the two groups was comparable. A low Ce of propofol TCI (1.5-2.5 μg/mL) achieved adequate anesthesia, reduced the risk of hypotension, and attained a high satisfaction rate in a Taiwanese population undergoing diagnostic painless endoscopy. © 2012 The Authors. Journal of Digestive Diseases © 2012 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  12. A facile, sensitive, and highly specific trinitrophenol assay based on target-induced synergetic effects of acid induction and electron transfer towards DNA-templated copper nanoclusters.

    Science.gov (United States)

    Li, Haiyin; Chang, Jiafu; Hou, Ting; Ge, Lei; Li, Feng

    2016-11-01

    Reliable, selective and sensitive approaches for trinitrophenol (TNP) detection are highly desirable with respect to national security and environmental protection. Herein, a simple and novel fluorescent strategy for highly sensitive and specific TNP assay has been successfully developed, which is based on the quenching of the fluorescent poly(thymine)-templated copper nanoclusters (DNA-CuNCs), through the synergetic effects of acid induction and electron transfer. Upon the addition of TNP, donor-acceptor complexes between the electron-deficient nitro-groups in TNP and the electron-donating DNA templates are formed, resulting in the close proximity between TNP and CuNCs. Moreover, the acidity of TNP contributes to the pH decrease of the system. These factors combine to dramatically quench the fluorescence of DNA-CuNCs, providing a "signal-off" strategy for TNP sensing. The as-proposed strategy demonstrates high sensitivity for TNP assay, and a detection limit of 0.03μM is obtained, which is lower than those reported by using organic fluorescent materials. More significantly, this approach shows outstanding selectivity over a number of TNP analogues, such as 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), 2,4-dinitrophenol (DNP), 3-nitrophenol (NP), nitrobenzene (NB), phenol (BP), and toluene (BT). Compared with previous studies, this method does not need complex DNA sequence design, fluorescent dye labeling, or sophisticated organic reactions, rendering the strategy with additional advantages of simplicity and cost-effectiveness. In addition, the as-proposed strategy has been adopted for the detection of TNP in natural water samples, indicating its great potential to be applied in the fields of public safety and environmental monitoring. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study.

    Science.gov (United States)

    Wei, Xiaoming; Dai, Yi; Yu, Ping; Qu, Ning; Lan, Zhangzhang; Hong, Xiafei; Sun, Yan; Yang, Guanghui; Xie, Shuqi; Shi, Quan; Zhou, Hanlin; Zhu, Qian; Chu, Yuxing; Yao, Fengxia; Wang, Jinming; He, Jingni; Yang, Yun; Liang, Yu; Yang, Yi; Qi, Ming; Yang, Ling; Wang, Wei; Wu, Haitao; Duan, Jing; Shen, Cheng; Wang, Jun; Cui, Liying; Yi, Xin

    2014-01-01

    Duchenne and Becker muscular dystrophies (DMD/BMD) are the most commonly inherited neuromuscular disease. However, accurate and convenient molecular diagnosis cannot be achieved easily because of the enormous size of the dystrophin gene and complex causative mutation spectrum. Such traditional methods as multiplex ligation-dependent probe amplification plus Sanger sequencing require multiple steps to fulfill the diagnosis of DMD/BMD. Here, we introduce a new single-step method for the genetic analysis of DMD patients and female carriers in real clinical settings and demonstrate the validation of its accuracy. A total of 89 patients, 18 female carriers and 245 non-DMD patients were evaluated using our targeted NGS approaches. Compared with traditional methods, our new method yielded 99.99% specificity and 98.96% sensitivity for copy number variations detection and 100% accuracy for the identification of single-nucleotide variation mutations. Additionally, this method is able to detect partial deletions/duplications, thus offering precise personal DMD gene information for gene therapy. We detected novel partial deletions of exons in nine samples for which the breakpoints were located within exonic regions. The results proved that our new method is suitable for routine clinical practice, with shorter turnaround time, higher accuracy, and better insight into comprehensive genetic information (detailed breakpoints) for ensuing gene therapy.

  14. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population.

    Science.gov (United States)

    Belanger, Moria H; Dolman, Lena; Arcand, Suzanna L; Shen, Zhen; Chong, George; Mes-Masson, Anne-Marie; Provencher, Diane; Tonin, Patricia N

    2015-03-27

    The frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients varies depending on histological subtype and population investigated. The six most commonly recurring BRCA1 and BRCA2 mutations previously identified in a founder French Canadian population were investigated in 439 histologically defined ovarian, fallopian tube and primary peritoneal cancer cases that were ascertained at one hospital servicing French Canadians. To further assess the frequency of BRCA1/BRCA2 mutations, a defined subgroup of 116 cases were investigated for all mutations previously reported in this population. A PCR-based assay was used to screen 439 ovarian, fallopian tube or extra-ovarian cancers comprised of serous, high grade endometrioid and mixed cell adenocarcinomas with serous components for specific BRCA1: C4446T and 2953delGTAinsC and BRCA2: 8765delAG, G6085T, 3398del5 and E3002K mutations. A multiplex bead-array-based Luminex assay was used to evaluate 19 specific mutations that have ever been reported in French Canadians, which included the six mutations assayed by PCR, in 116 cases representing all women ascertained within a defined 3-year window. A targeted analysis of six mutations identified 34/439 (7.7%) mutation carriers and at least two mutation carriers for each mutation screened were found. The BRCA1:C4446T mutation was the most frequently identified variant (15/34, 44.1%) among mutation-positive cases. The expanded mutation screen that also included 13 additional variants identified 19/116 (16.4%) mutation carriers, where C4446T was the most common variant (8/19, 42.1%) identified among mutation-positive carriers in this subgroup. Mutations were identified in women with serous, endometrioid, mixed cell, and undifferentiated adenocarcinomas. Within this subgroup there were 73 high-grade (G3) serous ovarian carcinomas, the most common subtype, with mutations identified in 19.2% (n = 14) serous cases. Our results reaffirm that specific BRCA1 and BRCA2

  15. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV: consequences of deficient interferon-dependent antiviral defense

    Directory of Open Access Journals (Sweden)

    Hubbard Gene B

    2011-01-01

    Full Text Available Abstract Background Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. Methods The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors Results We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The

  16. Ginsenoside Rg3 sensitizes human non-small cell lung cancer cells to γ-radiation by targeting the nuclear factor-κB pathway.

    Science.gov (United States)

    Wang, Lei; Li, Xiankui; Song, Yi-Min; Wang, Bin; Zhang, Fu-Rui; Yang, Rui; Wang, Hua-Qi; Zhang, Guo-Jun

    2015-07-01

    At present, it is elusive how non-small cell lung cancer (NSCLC) develops resistance to γ-radiation; however, the transcription factor nuclear factor-κB (NF-κB) and NF-κB-regulated gene products have been proposed as mediators. Ginsenoside Rg3 is a steroidal saponin, which was isolated from Panax ginseng. Ginsenoside Rg3 possesses high pharmacological activity and has previously been shown to suppress NF-κB activation in various types of tumor cell. Therefore, the present study aimed to determine whether Rg3 could suppress NF-κB activation in NSCLC cells and sensitize NSCLC to γ-radiation, using an NSCLC cell line and NSCLC xenograft. A clone formation assay and lung tumor xenograft experiment were used to assess the radiosensitizing effects of ginsenoside Rg3. NF-κB/inhibitor of NF-κB (IκB) modulation was ascertained using an electrophoretic mobility shift assay and western blot analysis. NF-κB-regulated gene products were monitored by western blot analysis. The present study demonstrated that ginsenoside Rg3 was able to sensitize A549 and H1299 lung carcinoma cells to γ-radiation and significantly enhance the efficacy of radiation therapy in C57BL/6 mice bearing a Lewis lung carcinoma cell xenograft tumor. Furthermore, ginsenoside Rg3 suppressed NF-κB activation, phosphorylation of IκB protein and expression of NF-κB-regulated gene products (cyclin D1, c-myc, B-cell lymphoma 2, cyclooxygenase-2, matrix metalloproteinase-9 and vascular endothelial growth factor), a number of which were induced by radiation therapy and mediate radioresistance. In conclusion, the results of the present study suggested that ginsenoside Rg3 may potentiate the antitumor effects of radiation therapy in NSCLC by suppressing NF-κB activity and NF-κB-regulated gene products, leading to the inhibition of tumor progression.

  17. Tc(V)-DMS tumor localization mechanism: a pH-sensitive Tc(V)-DMS-enhanced target/nontarget ratio by glucose-mediated acidosis

    International Nuclear Information System (INIS)

    Horiuchi, Kazuko; Saji, Hideo; Yokoyama, Akira

    1998-01-01

    Since the conception of the pentavalent technetium polynuclear complex of dimercaptosuccinic acid, Tc(V)-DMS, a great number of papers published on its clinical applicability forced us to question ''how tumor tissue appropriates the Tc(V)-DMS.'' Preliminary in vitro studies with Ehrlich ascites tumor cells (EATC) indicated the pH-sensitive character of this tumor agent. From this finding and the well-established notion that malignant tumors are more acidic than normal tissue, the in vivo correlation of Tc(V)-DMS accumulation in tumor tissue with its tissue acidification was considered of interest. The systemic lowering of tumor tissue pH by the stimulation of aerobic glycolysis has been well reported. In the present paper, the response of Tc(V)-DMS tumor accumulation to acidification induced by the glucose administration was explored in EATC-bearing mice. Measurement of tumor tissue pH was carried out by direct microelectrode technique and by histochemical umbelliferone technique in tumor tissue excised from EATC bearing mice. The regional acidity distribution is correlated with the regional radioactivity distribution registered by autoradiography. Evidence related to the pH sensitiveness of Tc(V)-DMS in response to glycolytic acidification was gathered; the pH measurement and the in vivo biodistribution of the double-tracer macroautoradiography with C-14 deoxyglucose (C-14-DG) demonstrated that the regional tissue distribution of Tc(V)-DMS was superimposed to that of C-14-DG. The glucose interventional modality offers the premier foundation for the interpretation of Tc(V)-DMS accumulation in diagnostic studies of malignant tumors

  18. Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma

    International Nuclear Information System (INIS)

    Gu, Ling; Xie, Liping; Zuo, Chuan; Ma, Zhigui; Zhang, Yanle; Zhu, Yiping; Gao, Ju

    2015-01-01

    Increasing evidence indicates that rapamycin could be used as a potential glucocorticoid (GC) sensitizer in lymphoblastic malignancies via genetic prevention of 4E-BP1 phosphorylation. Interestingly, we found that combined rapamycin with dexamethasone can effectively reverse GC resistance in 4E-BP1 null lymphoma cells. In this study, we investigated the potential link between mTOR/p70S6K signaling pathway, glycolysis, autophagy and GC resistance. Antitumor effects of the combination of rapamycin and dexamethasone were evaluated on cell viability by MTT assay and in vivo studies, on cell cycle and apoptosis by flow cytometry, on autophagy by western blot, MDC staining and transmission electron microscopy and on cell signaling by western blot. Moreover, to test whether inhibiting glycolysis is the core mechanism in rapamycin restoring GC sensitivity, we took glycolysis inhibitor 2-deoxyglucose to replace rapamycin and then evaluated the antitumor effects in vitro. Raji cells are resistant to rapamycin (IC 50 > 1000 nM) or dexamethasone (IC 50 > 100 μM) treatment alone. The combination of rapamycin and dexamethasone synergistically inhibited the viability of Raji cells in vitro and in vivo by inducing caspase-dependent and -independent cell death and G 0 /G 1 cell cycle arrest. These effects were achieved by the inhibition of mTOR/p70S6K signaling pathway, which led to the inhibition of glycolysis and the induction of autophagy. Pretreatment with pan-caspase inhibitor z-VAD-fmk or autophagy inhibitor 3-MA failed to protect the cells from combined treatment-induced death. Glycolysis inhibitor combined with dexamethasone produced a similar antitumor effects in vitro. Inhibition of mTOR/p70S6K/glycolysis signaling pathway is the key point of therapy in reversing GC resistant in Burkitt lymphoma patients. The online version of this article (doi:10.1186/s12885-015-1535-z) contains supplementary material, which is available to authorized users

  19. Sleeping Beauty Transposition of Chimeric Antigen Receptors Targeting Receptor Tyrosine Kinase-Like Orphan Receptor-1 (ROR1 into Diverse Memory T-Cell Populations.

    Directory of Open Access Journals (Sweden)

    Drew C Deniger

    Full Text Available T cells modified with chimeric antigen receptors (CARs targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B cells and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1 is expressed on sub-populations of B-cell malignancies and solid tumors, but not by healthy B cells or normal post-partum tissues. Thus, adoptive transfer of T cells specific for ROR1 has potential to eliminate tumor cells and spare healthy tissues. To test this hypothesis, we developed CARs targeting ROR1 in order to generate T cells specific for malignant cells. Two Sleeping Beauty transposons were constructed with 2nd generation ROR1-specific CARs signaling through CD3ζ and either CD28 (designated ROR1RCD28 or CD137 (designated ROR1RCD137 and were introduced into T cells. We selected for T cells expressing CAR through co-culture with γ-irradiated activating and propagating cells (AaPC, which co-expressed ROR1 and co-stimulatory molecules. Numeric expansion over one month of co-culture on AaPC in presence of soluble interleukin (IL-2 and IL-21 occurred and resulted in a diverse memory phenotype of CAR+ T cells as measured by non-enzymatic digital array (NanoString and multi-panel flow cytometry. Such T cells produced interferon-γ and had specific cytotoxic activity against ROR1+ tumors. Moreover, such cells could eliminate ROR1+ tumor xenografts, especially T cells expressing ROR1RCD137. Clinical trials will investigate the ability of ROR1-specific CAR+ T cells to specifically eliminate tumor cells while maintaining normal B-cell repertoire.

  20. The Clinical Course of Patients with PSA≥100 Ng/mL: Insight Into a Potential Population for Targeted PSA Screening.

    Science.gov (United States)

    Leung, Andrew K; Hugar, Lee; Patil, Dattatraya; Wong, Lisa; Carthon, Bradley; Carney, Kenneth; Birdsong, George; Moses, Kelvin A; Master, Viraj A

    2018-04-12

    To characterize men presenting to a tertiary care safety-net hospital with prostate-specific antigen (PSA) values ≥100 ng/mL and identify a potential population for targeted PSA screening. Retrospective review of 100 randomly selected patients out of 204 total who presented to Grady Memorial Hospital from 2004-2011 with initial PSA≥100 ng/mL was performed. Demographics, disease characteristics, and survival status were obtained via the Tumor Registry and a combination of electronic medical records and older paper charts, with missing data from paper charts excluded on analyses. Sixty-five patients were newly diagnosed with PCa on presentation and 35 were previously diagnosed. Median PSA at presentation was 405.5 ng/mL (min 100, max 7805), 81% had metastatic disease, and 94% were Gleason≥7. Median CAPRA score was 8. Median age at presentation was 67.4 years (min 40.8, max 90.6). Eighty-nine percent of patients were African-American (AA), 24% lived alone, 12% were homeless or incarcerated, 51% were insured by Medicare/Medicaid, and 47% were uninsured. Only 1% had HIV, 19% had diabetes, and 13% had chronic kidney disease. Of the 65 newly diagnosed patients, only 23% had ever been screened and 9% previously biopsied. Median time from presentation to death was 17.8 months (min 0.16, max 107.1). Among men presenting with PSA≥100ng/ml at a safety-net hospital, the majority were AA, of lower socioeconomic status, and had metastatic disease. Uniform absence of PCa screening may expose greater numbers of at-risk men to similar outcomes. Discussion is needed regarding targeted PSA screening in higher-risk, vulnerable patients. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. How to improve opportunistic screening by using EMRs and other data. The prevalence of undetected diabetes mellitus in target population in Croatia.

    Science.gov (United States)

    Vrca Botica, M; Carkaxhiu, L; Kern, J; Pavlić Renar, I; Botica, I; Zelić, I; Iliev, D; Vrca, A

    2017-04-01

    Opportunistic screening for type 2 diabetes (T2D) has not been adopted as part of routine practice. The aim of the study was to investigate the yield of opportunistic target screening for T2D in Croatia and to evaluate the process of screening by using data from electronic medical record. We conducted opportunistic screening in 23 general practitioners (GPs) in a population of 13,344 patients aged 45-70 years. First, after excluding patients with T2D, patients with risk factors for T2D were derived from the electronic medical record and GP's assessment during the preconsultation phase. Second, those with data about normoglycemia in past three years were excluded. Remaining patients started the consultation phase during their usual visit, when they were offered capillary fasting plasma glucose testing in the next consultation. Prevalence of T2D was 10.9% (new 1.4%). A total of 5568 (46.1%) patients had risks and 2849 (51.2%) had data about normoglycemia in the last three years. Using those data, number needed to invite to screening (NNI) was reduced to half: from 46.1% to 22.5%. One hundred eighty-four patients were screened positive for T2D in two capillary fasting plasma glucose tests (yield 9.8%). Number needed to screen (NNS) in order to detect one T2D was 10.3 patients. Among risks for T2D, overweight was the best predictive factor for undiagnosed T2D (odds ratio [OR]: 2.11, confidence interval [CI]:1.41-3.15, P overweight patients with a family history in fold were 2.5 times more likely to have T2D (OR: 2.54, CI 1.78-.61, P < .001). To