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Sample records for factor mechanistic implications

  1. Ferritin Diversity: Mechanistic Studies, Disease Implications, and Materials Chemistry

    NASA Astrophysics Data System (ADS)

    Hilton, Robert J.

    2011-07-01

    The study of ferritin includes a rich history of discoveries and scientific progress. Initially, the composition of ferritin was determined. Soon, it was shown that ferritin is a spherical, hollow protein. Eventually, over several decades of research, the structure and some function of this interesting protein was elucidated. However, the ferritin field was not completely satisfied. Today, for example, researchers are interested in refining the details of ferritin function, in discovering the role of ferritin in a variety of diseases, and in using ferritin for materials chemistry applications. The work presented in this dissertation highlights the progress that we have made in each of these three areas: (1) Mechanistic studies: The buffer used during horse spleen ferritin iron loading significantly influences the mineralization process and the quantity of iron deposited in ferritin. The ferrihydrite core of ferritin is crystalline and ordered when iron is loaded into ferritin in the presence of imidazole buffer. On the other hand, when iron is loaded into ferritin in the presence of MOPS buffer, the ferrihydrite core is less crystalline and less ordered, and a smaller amount of total iron is loaded in ferritin. We also show that iron can be released from the ferritin core in a non-reductive manner. The rate of Fe3+ release from horse spleen ferritin was measured using the Fe3+-specific chelator desferoxamine. We show that iron release occurs by three kinetic events. (2) Disease studies: In order to better understand iron disruption during disease states, we performed in vitro assays that mimicked chronic kidney disease. We tested the hypothesis that elevated levels of serum phosphate interrupted normal iron binding by transferrin and ferritin. Results show that phosphate competes for iron, forming an iron(III)-phosphate complex that is inaccessible to either transferrin or ferritin. Ferritin samples separated from the iron(III)-phosphate complex shows that as the

  2. Mechanistic duality of transcription factor function in phytochrome signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The phytochrome (phy) family of sensory photoreceptors (phyA–E in Arabidopsis) elicit changes in gene expression after light-induced migration to the nucleus, where they interact with basic helix–loop–helix transcription factors, such as phytochrome-interacting factor 3 (PIF3). The mechanism by whic...

  3. Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications

    PubMed Central

    Wikström, Mårten; Hummer, Gerhard

    2012-01-01

    Complex I (NADH-ubiquinone oxidoreductase) in the respiratory chain of mitochondria and several bacteria functions as a redox-driven proton pump that contributes to the generation of the protonmotive force across the inner mitochondrial or bacterial membrane and thus to the aerobic synthesis of ATP. The stoichiometry of proton translocation is thought to be 4 H+ per NADH oxidized (2 e-). Here we show that a H+/2 e- ratio of 3 appears more likely on the basis of the recently determined H+/ATP ratio of the mitochondrial F1Fo-ATP synthase of animal mitochondria and of a set of carefully determined ATP/2 e- ratios for different segments of the mitochondrial respiratory chain. This lower H+/2 e- ratio of 3 is independently supported by thermodynamic analyses of experiments with both mitochondria and submitochondrial particles. A reduced H+/2 e- stoichiometry of 3 has important mechanistic implications for this proton pump. In a rough mechanistic model, we suggest a concerted proton translocation mechanism in the three homologous and tightly packed antiporter-like subunits L, M, and N of the proton-translocating membrane domain of complex I. PMID:22392981

  4. Pollution and skin: from epidemiological and mechanistic studies to clinical implications.

    PubMed

    Krutmann, Jean; Liu, Wei; Li, Li; Pan, Xiaochuan; Crawford, Martha; Sore, Gabrielle; Seite, Sophie

    2014-12-01

    In recent years, the health effects associated with air pollution have been intensively studied. Most studies focus on air pollution effects on the lung and the cardiovascular system. More recently, however, epidemiological and mechanistic studies suggest that air pollution is also affecting skin integrity. This state-of-the-art review focuses on this latter aspect; it was developed with the collaboration of European and Chinese board of experts with specific interests in environmental health, clinical and basic research in dermatology and cosmetic dermatology. A literature review limited to pollution and health effects and (sensitive) skin was performed using PubMed. Review and original articles were chosen. We summarize the existing scientific evidence that air pollution exerts detrimental effects on human skin, discuss potential clinical implications and suggest specific and unspecific cosmetic protective measures.

  5. A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females.

    PubMed

    O'Dell, Laura E; Torres, Oscar V

    2014-01-01

    Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

  6. Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications

    PubMed Central

    O’Connell, Malaney; Shubhashish, Sarkar

    2016-01-01

    Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation. The unopposed activation of Wnt/β-catenin pathways, either due to loss of APC function or up-regulation of related stimulatory pathways, results in unopposed hyperproliferation of colonic crypts, considered the single most important risk factor for colon carcinogenesis. Hypermethylation of CpG islands within the promoters of specific genes can potentially inactivate DNA repair genes and/or critical tumor suppressor genes. Recently, CpG methylation of the 5’ promoter of human (h) DCLK1 gene was reported in many human epithelial cancers, including colorectal cancers (CRCs), resulting in the loss of expression of the canonical long isoform of DCLK1 (DCLK1-L) in hCRCs. Instead, a shorter isoform of DCLK1 (DCLK1-S) was discovered to be expressed in hCRCs, from an alternate β promoter of DCLKL1-gene; the clinical and biological implications of these novel findings, in relation to recent publications is discussed. PMID:27777940

  7. Epigenetic regulation of human DCLK-1 gene during colon-carcinogenesis: clinical and mechanistic implications.

    PubMed

    Singh, Pomila; O'Connell, Malaney; Shubhashish, Sarkar

    2016-01-01

    Colorectal carcinogenesis is a multi-step process. While ~25% of colorectal cancers (CRCs) arise in patients with a family history (genetic predisposition), ~75% of CRCs are due to age-associated accumulation of epigenetic alterations which can result in the suppression of key tumor suppressor genes leading to mutations and activation of oncogenic pathways. Sporadic colon-carcinogenesis is facilitated by many molecular pathways of genomic instability which include chromosomal instability (CIN), micro-satellite instability (MSI) and CpG island methylator phenotype (CIMP), leading towards loss of homeostasis and onset of neoplastic transformation. The unopposed activation of Wnt/β-catenin pathways, either due to loss of APC function or up-regulation of related stimulatory pathways, results in unopposed hyperproliferation of colonic crypts, considered the single most important risk factor for colon carcinogenesis. Hypermethylation of CpG islands within the promoters of specific genes can potentially inactivate DNA repair genes and/or critical tumor suppressor genes. Recently, CpG methylation of the 5' promoter of human (h) DCLK1 gene was reported in many human epithelial cancers, including colorectal cancers (CRCs), resulting in the loss of expression of the canonical long isoform of DCLK1 (DCLK1-L) in hCRCs. Instead, a shorter isoform of DCLK1 (DCLK1-S) was discovered to be expressed in hCRCs, from an alternate β promoter of DCLKL1-gene; the clinical and biological implications of these novel findings, in relation to recent publications is discussed.

  8. Calcium Regulation of Hemorrhagic Fever Virus Budding: Mechanistic Implications for Host-Oriented Therapeutic Intervention

    PubMed Central

    Han, Ziying; Madara, Jonathan J.; Herbert, Andrew; Prugar, Laura I.; Ruthel, Gordon; Lu, Jianhong; Liu, Yuliang; Liu, Wenbo; Liu, Xiaohong; Wrobel, Jay E.; Reitz, Allen B.; Dye, John M.; Harty, Ronald N.; Freedman, Bruce D.

    2015-01-01

    Hemorrhagic fever viruses, including the filoviruses (Ebola and Marburg) and arenaviruses (Lassa and Junín viruses), are serious human pathogens for which there are currently no FDA approved therapeutics or vaccines. Importantly, transmission of these viruses, and specifically late steps of budding, critically depend upon host cell machinery. Consequently, strategies which target these mechanisms represent potential targets for broad spectrum host oriented therapeutics. An important cellular signal implicated previously in EBOV budding is calcium. Indeed, host cell calcium signals are increasingly being recognized to play a role in steps of entry, replication, and transmission for a range of viruses, but if and how filoviruses and arenaviruses mobilize calcium and the precise stage of virus transmission regulated by calcium have not been defined. Here we demonstrate that expression of matrix proteins from both filoviruses and arenaviruses triggers an increase in host cytoplasmic Ca2+ concentration by a mechanism that requires host Orai1 channels. Furthermore, we demonstrate that Orai1 regulates both VLP and infectious filovirus and arenavirus production and spread. Notably, suppression of the protein that triggers Orai activation (Stromal Interaction Molecule 1, STIM1) and genetic inactivation or pharmacological blockade of Orai1 channels inhibits VLP and infectious virus egress. These findings are highly significant as they expand our understanding of host mechanisms that may broadly control enveloped RNA virus budding, and they establish Orai and STIM1 as novel targets for broad-spectrum host-oriented therapeutics to combat these emerging BSL-4 pathogens and potentially other enveloped RNA viruses that bud via similar mechanisms. PMID:26513362

  9. Solvent isotope effects on alkane formation by cyanobacterial aldehyde deformylating oxygenase and their mechanistic implications.

    PubMed

    Waugh, Matthew W; Marsh, E Neil G

    2014-09-02

    The reaction catalyzed by cyanobacterial aldehyde deformylating oxygenase is of interest both because of its potential application to the production of biofuels and because of the highly unusual nature of the deformylation reaction it catalyzes. Whereas the proton in the product alkane derives ultimately from the solvent, the identity of the proton donor in the active site remains unclear. To investigate the proton transfer step, solvent isotope effect (SIE) studies were undertaken. The rate of alkane formation was found to be maximal at pH 6.8 and to be the same in D2O or H2O within experimental error, implying that proton transfer is not a kinetically significant step. However, when the ratio of protium to deuterium in the product alkane was measured as a function of the mole fraction of D2O, a (D2O)SIEobs of 2.19 ± 0.02 was observed. The SIE was invariant with the mole fraction of D2O, indicating the involvement of a single protic site in the reaction. We interpret this SIE as most likely arising from a reactant state equilibrium isotope effect on a proton donor with an inverse fractionation factor, for which Φ = 0.45. These observations are consistent with an iron-bound water molecule being the proton donor to the alkane in the reaction.

  10. Mechanistic heterogeneity in site recognition by the structurally homologous DNA-binding domains of the ETS family transcription factors Ets-1 and PU.1.

    PubMed

    Wang, Shuo; Linde, Miles H; Munde, Manoj; Carvalho, Victor D; Wilson, W David; Poon, Gregory M K

    2014-08-01

    ETS family transcription factors regulate diverse genes through binding at cognate DNA sites that overlap substantially in sequence. The DNA-binding domains of ETS proteins (ETS domains) are highly conserved structurally yet share limited amino acid homology. To define the mechanistic implications of sequence diversity within the ETS family, we characterized the thermodynamics and kinetics of DNA site recognition by the ETS domains of Ets-1 and PU.1, which represent the extremes in amino acid divergence among ETS proteins. Even though the two ETS domains bind their optimal sites with similar affinities under physiologic conditions, their nature of site recognition differs strikingly in terms of the role of hydration and counter ion release. The data suggest two distinct mechanisms wherein Ets-1 follows a "dry" mechanism that rapidly parses sites through electrostatic interactions and direct protein-DNA contacts, whereas PU.1 utilizes hydration to interrogate sequence-specific sites and form a long-lived complex relative to the Ets-1 counterpart. The kinetic persistence of the high affinity PU.1 · DNA complex may be relevant to an emerging role of PU.1, but not Ets-1, as a pioneer transcription factor in vivo. In addition, PU.1 activity is critical to the development and function of macrophages and lymphocytes, which present osmotically variable environments, and hydration-dependent specificity may represent an important regulatory mechanism in vivo, a hypothesis that finds support in gene expression profiles of primary murine macrophages.

  11. Mechanistic Heterogeneity in Site Recognition by the Structurally Homologous DNA-binding Domains of the ETS Family Transcription Factors Ets-1 and PU.1*

    PubMed Central

    Wang, Shuo; Linde, Miles H.; Munde, Manoj; Carvalho, Victor D.; Wilson, W. David; Poon, Gregory M. K.

    2014-01-01

    ETS family transcription factors regulate diverse genes through binding at cognate DNA sites that overlap substantially in sequence. The DNA-binding domains of ETS proteins (ETS domains) are highly conserved structurally yet share limited amino acid homology. To define the mechanistic implications of sequence diversity within the ETS family, we characterized the thermodynamics and kinetics of DNA site recognition by the ETS domains of Ets-1 and PU.1, which represent the extremes in amino acid divergence among ETS proteins. Even though the two ETS domains bind their optimal sites with similar affinities under physiologic conditions, their nature of site recognition differs strikingly in terms of the role of hydration and counter ion release. The data suggest two distinct mechanisms wherein Ets-1 follows a “dry” mechanism that rapidly parses sites through electrostatic interactions and direct protein-DNA contacts, whereas PU.1 utilizes hydration to interrogate sequence-specific sites and form a long-lived complex relative to the Ets-1 counterpart. The kinetic persistence of the high affinity PU.1·DNA complex may be relevant to an emerging role of PU.1, but not Ets-1, as a pioneer transcription factor in vivo. In addition, PU.1 activity is critical to the development and function of macrophages and lymphocytes, which present osmotically variable environments, and hydration-dependent specificity may represent an important regulatory mechanism in vivo, a hypothesis that finds support in gene expression profiles of primary murine macrophages. PMID:24952944

  12. Childhood Obesity as a Risk Factor for Bone Fracture: A Mechanistic Study

    PubMed Central

    Kim, Jong-Eun; Hsieh, Min-Heng; Soni, Bharat K.; Zayzafoon, Majd; Allison, David B.

    2013-01-01

    Objective To investigate the risk of bone fracture sustained by obese children exposed to falls. We hypothesized that the bone fracture risk of obese children would be greater than that of their nonobese counterparts. Design and Methods We developed finite element-based computational models for children that reflected various levels of obesity by varying body mass and the thickness of the subcutaneous adipose tissue layer. The models took account of both the momentum effect of variation of body mass and the cushion effect of variation of soft tissue thickness and examined these two contradictory effects on pelvic bone fracture risk through a set of sideways fall simulations with a range of impact speeds. Results The critical impact speed that yielded pelvic bone fracture decreased as the levels of obesity increased, which meant that the momentum effect of a greater body mass took precedence over the cushion effect of the soft tissue layer. Conclusions The result suggests that obese children have a greater risk of pelvic bone fracture than do their nonobese counterparts in sideways falls. A further implication is that current child safety devices, systems, and regulations will need to be revisited as the prevalence of child obesity increases. PMID:23512354

  13. Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

    PubMed

    Benson, Neil

    2015-08-01

    Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way.

  14. Concurrent esterification and N-acetylation of amino acids with orthoesters: A useful reaction with interesting mechanistic implications

    PubMed Central

    Gibson, Sarah; Romero, Dickie; Jacobs, Hollie K.; Gopalan, Aravamudan S.

    2010-01-01

    The concurrent esterification and N-acetylation of amino acids has been studied with triethyl orthoacetate (TEOA) and triethyl orthoformate (TEOF). In a surprising finding, only one equivalent of TEOA in refluxing toluene was necessary to convert L-proline and L-phenylalanine to the corresponding N-acetyl ethyl esters in good yield. The same transformation using TEOF was not effective. Stereochemical outcome and stoichiometric studies as well as structural variation of the amino acids in this reaction provided unexpected mechanistic insight. PMID:21286246

  15. Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

    PubMed Central

    Nagaraja, Sridevi; Reifman, Jaques; Mitrophanov, Alexander Y.

    2015-01-01

    Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation. PMID:26633296

  16. Physiological constraints on organismal response to global warming: Mechanistic insights from clinally varying populations and implications for assessing endangerment.

    PubMed

    Bernardo, Joseph; Spotila, James R

    2006-03-22

    Recent syntheses indicate that global warming affects diverse biological processes, but also highlight the potential for some species to adapt behaviourally or evolutionarily to rapid climate change. Far less attention has addressed the alternative, that organisms lacking this ability may face extinction, a fate projected to befall one-quarter of global biodiversity. This conclusion is controversial, in part because there exist few mechanistic studies that show how climate change could precipitate extinction. We provide a concrete, mechanistic example of warming as a stressor of organisms that are closely adapted to cool climates from a comparative analysis of organismal tolerance among clinally varying populations along a natural thermal gradient. We found that two montane salamanders exhibit significant metabolic depression at temperatures within the natural thermal range experienced by low and middle elevation populations. Moreover, the magnitude of depression was inversely related to native elevation, suggesting that low elevation populations are already living near the limit of their physiological tolerances. If this finding generally applies to other montane specialists, the prognosis for biodiversity loss in typically diverse montane systems is sobering. We propose that indices of warming-induced stress tolerance may provide a critical new tool for quantitative assessments of endangerment due to anthropogenic climate change across diverse species.

  17. Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis

    PubMed Central

    Khanam Irin, Afroza; Tom Kodamullil, Alpha; Gündel, Michaela; Hofmann-Apitius, Martin

    2015-01-01

    Neurodegenerative as well as autoimmune diseases have unclear aetiologies, but an increasing number of evidences report for a combination of genetic and epigenetic alterations that predispose for the development of disease. This review examines the major milestones in epigenetics research in the context of diseases and various computational approaches developed in the last decades to unravel new epigenetic modifications. However, there are limited studies that systematically link genetic and epigenetic alterations of DNA to the aetiology of diseases. In this work, we demonstrate how disease-related epigenetic knowledge can be systematically captured and integrated with heterogeneous information into a functional context using Biological Expression Language (BEL). This novel methodology, based on BEL, enables us to integrate epigenetic modifications such as DNA methylation or acetylation of histones into a specific disease network. As an example, we depict the integration of epigenetic and genetic factors in a functional context specific to Parkinson's disease (PD) and Multiple Sclerosis (MS). PMID:26636108

  18. Mechanistic insights into protonation state as a critical factor in hFPPS enzyme inhibition

    NASA Astrophysics Data System (ADS)

    Fernández, David; Ortega-Castro, Joaquin; Mariño, Laura; Perelló, Joan; Frau, Juan

    2015-07-01

    Zoledronate and risedronate are the most powerful available nitrogen-containing bisphosphonates used in the treatment of bone-resorption disorders. Knowledge about inhibition mechanisms of these molecules is based on available crystallographic structures of human farnesyl pyrophosphate synthase (hFPPS). However, there is a lack of information explaining the inhibition potency of these two molecules compared to the natural substrate, dimethylallyl pyrophosphate. We carried out a molecular dynamics study that shown: (1) that NBPs potency is related to higher electrostatic interactions with the metallic cluster of the active site than to the natural substrate, and (2) the protonation of the R2 side chain is a critical factor to stabilize the NBPs into a closely irreversible ternary complex with the hFPPS.

  19. Mechanistic peptidomics: factors that dictate specificity in the formation of endogenous peptides in human milk.

    PubMed

    Guerrero, Andres; Dallas, David C; Contreras, Stephanie; Chee, Sabrina; Parker, Evan A; Sun, Xin; Dimapasoc, Lauren; Barile, Daniela; German, J Bruce; Lebrilla, Carlito B

    2014-12-01

    An extensive mass spectrometry analysis of the human milk peptidome has revealed almost 700 endogenous peptides from 30 different proteins. Two in-house computational tools were created and used to visualize and interpret the data through both alignment of the peptide quasi-molecular ion intensities and estimation of the differential enzyme participation. These results reveal that the endogenous proteolytic activity in the mammary gland is remarkably specific and well conserved. Certain proteins-not necessarily the most abundant ones-are digested by the proteases present in milk, yielding endogenous peptides from selected regions. Our results strongly suggest that factors such as the presence of specific proteases, the position and concentration of cleavage sites, and, more important, the intrinsic disorder of segments of the protein drive this proteolytic specificity in the mammary gland. As a consequence of this selective hydrolysis, proteins that typically need to be cleaved at specific positions in order to exert their activity are properly digested, and bioactive peptides encoded in certain protein sequences are released. Proteins that must remain intact in order to maintain their activity in the mammary gland or in the neonatal gastrointestinal tract are unaffected by the hydrolytic environment present in milk. These results provide insight into the intrinsic structural mechanisms that facilitate the selectivity of the endogenous milk protease activity and might be useful to those studying the peptidomes of other biofluids.

  20. Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications.

    PubMed

    Rexer, Brent N; Arteaga, Carlos L

    2013-07-01

    The combination of a PI3K inhibitor with trastuzumab has been shown to be effective at overcoming trastuzumab resistance in models of HER2(+) breast cancer by inhibiting HER2-PI3K-FOXO-survivin signaling. In this review the potential clinical implications of these findings are discussed.

  1. Distinct properties of semiquinone species detected at the ubiquinol oxidation Qo site of cytochrome bc1 and their mechanistic implications

    PubMed Central

    Sarewicz, Marcin

    2016-01-01

    The two-electron ubiquinol oxidation or ubiquinone reduction typically involves semiquinone (SQ) intermediates. Natural engineering of ubiquinone binding sites of bioenergetic enzymes secures that SQ is sufficiently stabilized, so that it does not leave the site to membranous environment before full oxidation/reduction is completed. The ubiquinol oxidation Qo site of cytochrome bc1 (mitochondrial complex III, cytochrome b6f in plants) has been considered an exception with catalytic reactions assumed to involve highly unstable SQ or not to involve any SQ intermediate. This view seemed consistent with long-standing difficulty in detecting any reaction intermediates at the Qo site. New perspective on this issue is now offered by recent, independent reports on detection of SQ in this site. Each of the described SQs seems to have different spectroscopic properties leaving space for various interpretations and mechanistic considerations. Here, we comparatively reflect on those properties and their consequences on the SQ stabilization, the involvement of SQ in catalytic reactions, including proton transfers, and the reactivity of SQ with oxygen associated with superoxide generation activity of the Qo site. PMID:27194483

  2. A mechanistic model to study the thermal ecology of a southeastern pacific dominant intertidal mussel and implications for climate change.

    PubMed

    Finke, G R; Bozinovic, F; Navarrete, S A

    2009-01-01

    Developing mechanistic models to predict an organism's body temperature facilitates the study of physiological stresses caused by extreme climatic conditions the species might have faced in the past or making predictions about changes to come in the near future. Because the models combine empirical observation of different climatic variables with essential morphological attributes of the species, it is possible to examine specific aspects of predicted climatic changes. Here, we develop a model for the competitively dominant intertidal mussel Perumytilus purpuratus that estimates body temperature on the basis of meteorological and tidal data with an average difference (+/-SE) of 0.410 degrees +/- 0.0315 degrees C in comparison with a field-deployed temperature logger. Modeled body temperatures of P. purpuratus in central Chile regularly exceeded 30 degrees C in summer months, and values as high as 38 degrees C were found. These results suggest that the temperatures reached by mussels in the intertidal zone in central Chile are not sufficiently high to induce significant mortality on adults of this species; however, because body temperatures >40 degrees C can be lethal for this species, sublethal effects on physiological performance warrant further investigation. Body temperatures of mussels increased sigmoidally with increasing tidal height. Body temperatures of individuals from approximately 70% of the tidal range leveled off and did not increase any further with increasing tidal height. Finally, body size played an important role in determining body temperature. A hypothetical 5-cm-long mussel (only 1 cm longer than mussels found in nature) did reach potentially lethal body temperatures, suggesting that the biophysical environment may play a role in limiting the size of this small species.

  3. Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.

    PubMed

    Lo Surdo, Paola; Bottomley, Matthew J; Calzetta, Alessandra; Settembre, Ethan C; Cirillo, Agostino; Pandit, Shilpa; Ni, Yan G; Hubbard, Brian; Sitlani, Ayesha; Carfí, Andrea

    2011-12-01

    The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.

  4. Involvement in Denitrification is Beneficial to the Biofilm Lifestyle of Comamonas testosteroni: A Mechanistic Study and Its Environmental Implications.

    PubMed

    Wu, Yichao; Shukal, Sudha; Mukherjee, Manisha; Cao, Bin

    2015-10-06

    Comamonas is one of the most abundant microorganisms in biofilm communities driving wastewater treatment. Little has been known about the role of this group of organisms and their biofilm mode of life. In this study, using Comamonas testosteroni as a model organism, we demonstrated the involvement of Comamonas biofilms in denitrification under bulk aerobic conditions and elucidated the influence of nitrate respiration on its biofilm lifestyle. Our results showed that C. testosteroni could use nitrate as the sole electron acceptor for anaerobic growth. Under bulk aerobic condition, biofilms of C. testosteroni were capable of reducing nitrate, and intriguingly, nitrate reduction significantly enhanced viability of the biofilm-cells and reduced cell detachment from the biofilms. Nitrate respiration was further shown to play an essential role in maintaining high cell viability in the biofilms. RNA-seq analysis, quantitative polymerase chain reaction, and liquid chromatography-mass spectrometry revealed a higher level of bis(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) in cells respiring on nitrate than those grown aerobically (1.3 × 10(-4) fmol/cell vs 7.9 × 10(-6) fmol/cell; P < 0.01). C-di-GMP is one universal signaling molecule that regulates the biofilm mode of life, and a higher c-di-GMP concentration reduces cell detachment from biofilms. Taking these factors together, this study reveals that nitrate reduction occurs in mature biofilms of C. testosteroni under bulk aerobic conditions, and the respiratory reduction of nitrate is beneficial to the biofilm lifestyle by providing more metabolic energy to maintain high viability and a higher level of c-di-GMP to reduce cell detachment.

  5. Mechanistic, mathematical model to predict the dynamics of tissue genesis in bone defects via mechanical feedback and mediation of biochemical factors.

    PubMed

    Moore, Shannon R; Saidel, Gerald M; Knothe, Ulf; Knothe Tate, Melissa L

    2014-06-01

    The link between mechanics and biology in the generation and the adaptation of bone has been well studied in context of skeletal development and fracture healing. Yet, the prediction of tissue genesis within - and the spatiotemporal healing of - postnatal defects, necessitates a quantitative evaluation of mechano-biological interactions using experimental and clinical parameters. To address this current gap in knowledge, this study aims to develop a mechanistic mathematical model of tissue genesis using bone morphogenetic protein (BMP) to represent of a class of factors that may coordinate bone healing. Specifically, we developed a mechanistic, mathematical model to predict the dynamics of tissue genesis by periosteal progenitor cells within a long bone defect surrounded by periosteum and stabilized via an intramedullary nail. The emergent material properties and mechanical environment associated with nascent tissue genesis influence the strain stimulus sensed by progenitor cells within the periosteum. Using a mechanical finite element model, periosteal surface strains are predicted as a function of emergent, nascent tissue properties. Strains are then input to a mechanistic mathematical model, where mechanical regulation of BMP-2 production mediates rates of cellular proliferation, differentiation and tissue production, to predict healing outcomes. A parametric approach enables the spatial and temporal prediction of endochondral tissue regeneration, assessed as areas of cartilage and mineralized bone, as functions of radial distance from the periosteum and time. Comparing model results to histological outcomes from two previous studies of periosteum-mediated bone regeneration in a common ovine model, it was shown that mechanistic models incorporating mechanical feedback successfully predict patterns (spatial) and trends (temporal) of bone tissue regeneration. The novel model framework presented here integrates a mechanistic feedback system based on the

  6. Hard Tick Factors Implicated in Pathogen Transmission

    PubMed Central

    Liu, Xiang Ye; Bonnet, Sarah I.

    2014-01-01

    Ticks are the most common arthropod vector, after mosquitoes, and are capable of transmitting the greatest variety of pathogens. For both humans and animals, the worldwide emergence or re-emergence of tick-borne disease is becoming increasingly problematic. Despite being such an important issue, our knowledge of pathogen transmission by ticks is incomplete. Several recent studies, reviewed here, have reported that the expression of some tick factors can be modulated in response to pathogen infection, and that some of these factors can impact on the pathogenic life cycle. Delineating the specific tick factors required for tick-borne pathogen transmission should lead to new strategies in the disruption of pathogen life cycles to combat emerging tick-borne disease. PMID:24498444

  7. Mechanistic Approach to Understanding the Toxicity of the Azole Fungicide Triadimefon to a Nontarget Aquatic Insect and Implications for Exposure Assessment

    EPA Science Inventory

    We utilized mechanistic and stereoselective based in vitro metabolism assays and sublethal exposures of triadimefon to gain insight into the extent of carbonyl reduction and the toxic mode of action of triadimefon with black fly (Diptera: Simuliidae) larvae.

  8. Minimum-noise production of translation factor eIF4G maps to a mechanistically determined optimal rate control window for protein synthesis

    PubMed Central

    Meng, Xiang; Firczuk, Helena; Pietroni, Paola; Westbrook, Richard; Dacheux, Estelle; Mendes, Pedro; McCarthy, John E.G.

    2017-01-01

    Gene expression noise influences organism evolution and fitness. The mechanisms determining the relationship between stochasticity and the functional role of translation machinery components are critical to viability. eIF4G is an essential translation factor that exerts strong control over protein synthesis. We observe an asymmetric, approximately bell-shaped, relationship between the average intracellular abundance of eIF4G and rates of cell population growth and global mRNA translation, with peak rates occurring at normal physiological abundance. This relationship fits a computational model in which eIF4G is at the core of a multi-component–complex assembly pathway. This model also correctly predicts a plateau-like response of translation to super-physiological increases in abundance of the other cap-complex factors, eIF4E and eIF4A. Engineered changes in eIF4G abundance amplify noise, demonstrating that minimum stochasticity coincides with physiological abundance of this factor. Noise is not increased when eIF4E is overproduced. Plasmid-mediated synthesis of eIF4G imposes increased global gene expression stochasticity and reduced viability because the intrinsic noise for this factor influences total cellular gene noise. The naturally evolved eIF4G gene expression noise minimum maps within the optimal activity zone dictated by eIF4G's mechanistic role. Rate control and noise are therefore interdependent and have co-evolved to share an optimal physiological abundance point. PMID:27928055

  9. Antimalarial bicyclic peroxides belonging to the G-factor family: mechanistic aspects of their formation and iron (II) induced reduction.

    PubMed

    Ruiz, Jeremy; Azema, Joelle; Payrastre, Corinne; Baltas, Michel; Tuccio, Beatrice; Vial, Henri; Andre-Barres, Christiane

    2014-01-01

    Artemisinin and its derivatives are peroxide-containing compounds targeting P. falciparum. We review here structural analogues of bicyclic peroxides belonging to the G factors family presenting antimalarial properties. They were synthesised under Mannich type conditions, followed by an autoxidation step resulting exclusively in the peroxide. As the electron transfer from haem or free iron to the peroxide is the first step in the mode of action of artemisinin-like compounds, the redox properties of some endoperoxides were studied by electrochemistry allowing the evaluation of the reduction standard potentials. The Fe(II) induced reduction was also investigated and the reactivity of the C-centered radical intermediate formed was linked to the antimalarial activity. These bicyclic peroxides both with various hybrid molecules containing the endoperoxide framework were evaluated in vitro against Plasmodium falciparum. They exhibited moderate to good activities.

  10. Structural and mechanistic insights into nuclear transport and delivery of the critical pluripotency factor Oct4 to DNA.

    PubMed

    Okuyama, Takahide; Yamagishi, Ryosuke; Shimada, Jiro; Ikeda, Masaaki; Maruoka, Yayoi; Kaneko, Hiroki

    2017-02-06

    Oct4 is a master regulator of the induction and maintenance of cellular pluripotency, and has crucial roles in early stages of differentiation. It is the only factor that cannot be substituted by other members of the same protein family to induce pluripotency. However, although Oct4 nuclear transport and delivery to target DNA are critical events for reprogramming to pluripotency, little is known about the molecular mechanism. Oct4 is imported to the nucleus by the classical nuclear transport mechanism, which requires importin α as an adaptor to bind the nuclear localization signal (NLS). Although there are structures of complexes of the NLS of transcription factors (TFs) in complex with importin α, there are no structures available for complexes involving intact TFs. We have therefore modeled the structure of the complex of the whole Oct4 POU domain and importin α2 using protein-protein docking and molecular dynamics. The model explains how the Ebola virus VP24 protein has a negative effect on the nuclear import of STAT1 by importin α but not on Oct4, and how Nup 50 facilitates cargo release from importin α. The model demonstrates the structural differences between the Oct4 importin α bound and DNA bound crystal states. We propose that the "expanded linker" between the two DNA-binding domains of Oct4 is an intrinsically disordered region and that its conformational changes have a key role in the recognition/binding to both DNA and importin α. Moreover, we propose that this structural change enables efficient delivery to DNA after release from importin α.

  11. Mechanistic insights into elastin degradation by pseudolysin, the major virulence factor of the opportunistic pathogen Pseudomonas aeruginosa.

    PubMed

    Yang, Jie; Zhao, Hui-Lin; Ran, Li-Yuan; Li, Chun-Yang; Zhang, Xi-Ying; Su, Hai-Nan; Shi, Mei; Zhou, Bai-Cheng; Chen, Xiu-Lan; Zhang, Yu-Zhong

    2015-04-23

    Pseudolysin is the most abundant protease secreted by Pseudomonas aeruginosa and is the major extracellular virulence factor of this opportunistic human pathogen. Pseudolysin destroys human tissues by solubilizing elastin. However, the mechanisms by which pseudolysin binds to and degrades elastin remain elusive. In this study, we investigated the mechanism of action of pseudolysin on elastin binding and degradation by biochemical assay, microscopy and site-directed mutagenesis. Pseudolysin bound to bovine elastin fibers and preferred to attack peptide bonds with hydrophobic residues at the P1 and P1' positions in the hydrophobic domains of elastin. The time-course degradation processes of both bovine elastin fibers and cross-linked human tropoelastin by pseudolysin were further investigated by microscopy. Altogether, the results indicate that elastin degradation by pseudolysin began with the hydrophobic domains on the fiber surface, followed by the progressive disassembly of macroscopic elastin fibers into primary structural elements. Moreover, our site-directed mutational results indicate that five hydrophobic residues in the S1-S1' sub-sites played key roles in the binding of pseudolysin to elastin. This study sheds lights on the pathogenesis of P. aeruginosa infection.

  12. The Role of Parathyroid Hormone-Related Protein (PTHrP) in Osteoblast Response to Microgravity: Mechanistic Implications for Osteoporosis Development

    PubMed Central

    Camirand, Anne; Goltzman, David; Gupta, Ajay; Kaouass, Mohammadi; Panda, Dibyendu; Karaplis, Andrew

    2016-01-01

    Prolonged skeletal unloading through bedrest results in bone loss similar to that observed in elderly osteoporotic patients, but with an accelerated timeframe. This rapid effect on weight-bearing bones is also observed in astronauts who can lose up to 2% of their bone mass per month spent in Space. Despite the important implications for Spaceflight travelers and bedridden patients, the exact mechanisms involved in disuse osteoporosis have not been elucidated. Parathyroid hormone-related protein (PTHrP) regulates many physiological processes including skeletal development, and has been proposed as a mechanosensor. To investigate the role of PTHrP in microgravity-induced bone loss, trabecular and calvarial osteoblasts (TOs and COs) from Pthrp +/+ and -/- mice were subjected to actual Spaceflight for 6 days (Foton M3 satellite). Pthrp +/+, +/- and -/- osteoblasts were also exposed to simulated microgravity for periods varying from 6 days to 6 weeks. While COs displayed little change in viability in 0g, viability of all TOs rapidly decreased in inverse proportion to PTHrP expression levels. Furthermore, Pthrp+/+ TOs displayed a sharp viability decline after 2 weeks at 0g. Microarray analysis of Pthrp+/+ TOs after 6 days in simulated 0g revealed expression changes in genes encoding prolactins, apoptosis/survival molecules, bone metabolism and extra-cellular matrix composition proteins, chemokines, insulin-like growth factor family members and Wnt-related signalling molecules. 88% of 0g-induced expression changes in Pthrp+/+ cells overlapped those caused by Pthrp ablation in normal gravity, and pulsatile treatment with PTHrP1-36 not only reversed a large proportion of 0g-induced effects in Pthrp+/+ TOs but maintained viability over 6-week exposure to microgravity. Our results confirm PTHrP efficacy as an anabolic agent to prevent microgravity-induced cell death in TOs. PMID:27463808

  13. Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

    PubMed

    Brownstein, Catherine A; Kleiman, Robin J; Engle, Elizabeth C; Towne, Meghan C; D'Angelo, Eugene J; Yu, Timothy W; Beggs, Alan H; Picker, Jonathan; Fogler, Jason M; Carroll, Devon; Schmitt, Rachel C O; Wolff, Robert R; Shen, Yiping; Lip, Va; Bilguvar, Kaya; Kim, April; Tembulkar, Sahil; O'Donnell, Kyle; Gonzalez-Heydrich, Joseph

    2016-05-01

    Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis.

  14. [Associated factors and clinical implications of post transplant renal anemia].

    PubMed

    Freiberg, Mónica; Chiurchiu, Carlos; Capra, Raúl; Eckhardt, Andrea; De La Fuente, Jorge; Douthat, Walter; De Arteaga, Javier; Massari, Pablo U

    2013-01-01

    A considerable percentage of patients exhibit anemia post kidney transplant. Its origin is multifactorial and the main causes involved depend on the post transplant period considered. We studied in a group of 134 consecutive patients the associated factors and the clinical implications of "late anemia" (6 months post transplant). Multiple regression analysis showed that post transplant oliguria and acute rejection episodes were significantly associated with anemia. Graft survival at 36 months was significantly reduced in the anemic group (83 % versus 96%, p < 0.01). No differences in patients survival or rate of cardiovascular events were observed. We concluded that anemia at 6 months post transplant is independently and significantly associated with events that reduced functioning renal mass and kidney survival.

  15. Hepatocyte growth factor (HGF) and hemodialysis: physiopathology and clinical implications.

    PubMed

    Libetta, Carmelo; Esposito, Pasquale; Martinelli, Claudia; Grosjean, Fabrizio; Gregorini, Marilena; Rampino, Teresa; Dal Canton, Antonio

    2016-06-01

    Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.

  16. ATP-binding site of adenylate kinase: mechanistic implications of its homology with ras-encoded p21, F1-ATPase, and other nucleotide-binding proteins.

    PubMed

    Fry, D C; Kuby, S A; Mildvan, A S

    1986-02-01

    The MgATP binding site of adenylate kinase, located by a combination of NMR and x-ray diffraction, is near three protein segments, five to seven amino acids in length, that are homologous in sequence to segments found in other nucleotide-binding phosphotransferases, such as myosin and F1-ATPase, ras p21 and transducin GTPases, and cAMP-dependent and src protein kinases, suggesting equivalent mechanistic roles of these segments in all of these proteins. Segment 1 is a glycine-rich flexible loop that, on adenylate kinase, may control access to the ATP-binding site by changing its conformation. Segment 2 is an alpha-helix containing two hydrophobic residues that interact with the adenine-ribose moiety of ATP, and a lysine that may bind to the beta- and gamma-phosphates of ATP. Segment 3 is a hydrophobic strand of parallel beta-pleated sheet, terminated by a carboxylate, that flanks the triphosphate binding site. The various reported mutations of ras p21 that convert it to a transforming agent all appear to involve segment 1, and such substitutions may alter the properties of p21 by hindering a conformational change at this segment. In F1-ATPase, the flexible loop may, by its position, control both the accessibility and the ATP/ADP equilibrium constant on the enzyme.

  17. Hydration effects on skin microstructure as probed by high-resolution cryo-scanning electron microscopy and mechanistic implications to enhanced transcutaneous delivery of biomacromolecules.

    PubMed

    Tan, Grace; Xu, Peng; Lawson, Louise B; He, Jibao; Freytag, Lucia C; Clements, John D; John, Vijay T

    2010-02-01

    Although hydration is long known to improve the permeability of skin, penetration of macromolecules such as proteins is limited and the understanding of enhanced transport is based on empirical observations. This study uses high-resolution cryo-scanning electron microscopy to visualize microstructural changes in the stratum corneum (SC) and enable a mechanistic interpretation of biomacromolecule penetration through highly hydrated porcine skin. Swollen corneocytes, separation of lipid bilayers in the SC intercellular space to form cisternae, and networks of spherical particulates are observed in porcine skin tissue hydrated for a period of 4-10 h. This is explained through compaction of skin lipids when hydrated, a reversal in the conformational transition from unilamellar liposomes in lamellar granules to lamellae between keratinocytes when the SC skin barrier is initially established. Confocal microscopy studies show distinct enhancement in penetration of fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) through skin hydrated for 4-10 h, and limited penetration of FITC-BSA once skin is restored to its natively hydrated structure when exposed to the environment for 2-3 h. These results demonstrate the effectiveness of a 4-10 h hydration period to enhance transcutaneous penetration of large biomacromolecules without permanently damaging the skin.

  18. ATP-binding site of adenylate kinase: mechanistic implications of its homology with ras-encoded p21, F1-ATPase, and other nucleotide-binding proteins.

    PubMed Central

    Fry, D C; Kuby, S A; Mildvan, A S

    1986-01-01

    The MgATP binding site of adenylate kinase, located by a combination of NMR and x-ray diffraction, is near three protein segments, five to seven amino acids in length, that are homologous in sequence to segments found in other nucleotide-binding phosphotransferases, such as myosin and F1-ATPase, ras p21 and transducin GTPases, and cAMP-dependent and src protein kinases, suggesting equivalent mechanistic roles of these segments in all of these proteins. Segment 1 is a glycine-rich flexible loop that, on adenylate kinase, may control access to the ATP-binding site by changing its conformation. Segment 2 is an alpha-helix containing two hydrophobic residues that interact with the adenine-ribose moiety of ATP, and a lysine that may bind to the beta- and gamma-phosphates of ATP. Segment 3 is a hydrophobic strand of parallel beta-pleated sheet, terminated by a carboxylate, that flanks the triphosphate binding site. The various reported mutations of ras p21 that convert it to a transforming agent all appear to involve segment 1, and such substitutions may alter the properties of p21 by hindering a conformational change at this segment. In F1-ATPase, the flexible loop may, by its position, control both the accessibility and the ATP/ADP equilibrium constant on the enzyme. Images PMID:2869483

  19. Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.

    PubMed

    Donahue, Renee N; McLaughlin, Patricia J; Zagon, Ian S

    2011-09-01

    Naltrexone (NTX) is an opioid antagonist that inhibits or accelerates cell proliferation in vivo when utilized in a low (LDN) or high (HDN) dose, respectively. The mechanism of opioid antagonist action on growth is not well understood. We established a tissue culture model of LDN and HDN using short-term and continuous opioid receptor blockade, respectively, in human ovarian cancer cells, and found that the duration of opioid receptor blockade determines cell proliferative response. The alteration of growth by NTX also was detected in cells representative of pancreatic, colorectal and squamous cell carcinomas. The opioid growth factor (OGF; [Met(5)]-enkephalin) and its receptor (OGFr) were responsible for mediating the action of NTX on cell proliferation. NTX upregulated OGF and OGFr at the translational but not at the transcriptional level. The mechanism of inhibition by short-term NTX required p16 and/or p21 cyclin-dependent inhibitory kinases, but was not dependent on cell survival (necrosis, apoptosis). Sequential administration of short-term NTX and OGF had a greater inhibitory effect on cell proliferation than either agent alone. Given the parallels between short-term NTX in vitro and LDN in vivo, we now demonstrate at the molecular level that the OGF-OGFr axis is a common pathway that is essential for the regulation of cell proliferation by NTX.

  20. Mechanistic Implications of the Unique Structural Features and Dimerization of the Cytoplasmic Domain of the Pseudomonas Sigma Regulator, PupR.

    PubMed

    Jensen, Jaime L; Balbo, Andrea; Neau, David B; Chakravarthy, Srinivas; Zhao, Huaying; Sinha, Sangita C; Colbert, Christopher L

    2015-09-29

    Gram-negative bacteria tightly regulate intracellular levels of iron, an essential nutrient. To ensure this strict control, some outer membrane TonB-dependent transporters (TBDTs) that are responsible for iron import stimulate their own transcription in response to extracellular binding by an iron-laden siderophore. This process is mediated by an inner membrane sigma regulator protein (an anti-sigma factor) that transduces an unknown periplasmic signal from the TBDT to release an intracellular sigma factor from the inner membrane, which ultimately upregulates TBDT transcription. Here, we use the Pseudomonas putida ferric-pseudobactin BN7/BN8 sigma regulator, PupR, as a model system to understand the molecular mechanism of this conserved class of sigma regulators. We have determined the X-ray crystal structure of the cytoplasmic anti-sigma domain (ASD) of PupR to 2.0 Å. Size exclusion chromatography, small-angle X-ray scattering, and sedimentation velocity analytical ultracentrifugation all indicate that, in contrast to other ASDs, the PupR-ASD exists as a dimer in solution. Mutagenesis of residues at the dimer interface identified from the crystal structure disrupts dimerization and protein stability, as determined by sedimentation velocity analytical ultracentrifugation and thermal denaturation circular dichroism spectroscopy. These combined results suggest that this type of inner membrane sigma regulator may utilize an unusual mechanism to sequester their cognate sigma factors and prevent transcription activation.

  1. Mechanistic Implications of the Unique Structural Features and Dimerization of the Cytoplasmic Domain of the Pseudomonas Sigma Regulator, PupR

    DOE PAGES

    Jensen, Jaime L.; Balbo, Andrea; Neau, David B.; ...

    2015-09-29

    Gram-negative bacteria tightly regulate intracellular levels of iron, an essential nutrient. To ensure this tight regulation, some outer membrane TonB-dependent transporters (TBDTs) that are responsible for iron import stimulate their own transcription in response to extracellular binding by an iron-laden siderophore. This process is mediated by an inner membrane sigma regulator protein (an anti-sigma factor) that transduces an unknown periplasmic signal from the TBDT to release an intracellular sigma factor from the inner membrane, which ultimately upregulates TBDT transcription. Here we use the Pseudomonas putida ferric-pseudobactin BN7/BN8 sigma regulator, PupR, as a model system to understand the molecular mechanism ofmore » this conserved class of sigma regulators. We have determined the X-ray crystal structure of the cytoplasmic anti-sigma domain (ASD) of PupR to 2.0 Å. Size exclusion chromatography, small angle X-ray scattering, and sedimentation velocity analytical ultracentrifugation, all indicate that in contrast to other ASDs, the PupR-ASD exists as a dimer in solution. Mutagenesis of residues at the dimer interface identified from the crystal structure disrupts dimerization and protein stability, as determined by sedimentation velocity analytical ultracentrifugation and thermal denaturation circular dichroism spectroscopy. Lastly, these combined results suggest that this type of inner membrane sigma regulator may utilize an unusual mechanism to sequester their cognate sigma factors and prevent transcription activation.« less

  2. Mechanistic Implications of the Unique Structural Features and Dimerization of the Cytoplasmic Domain of the Pseudomonas Sigma Regulator, PupR

    SciTech Connect

    Jensen, Jaime L.; Balbo, Andrea; Neau, David B.; Chakravarthy, Srinivas; Zhao, Huaying; Sinha, Sangita C.; Colbert, Christopher L.

    2015-09-29

    Gram-negative bacteria tightly regulate intracellular levels of iron, an essential nutrient. To ensure this tight regulation, some outer membrane TonB-dependent transporters (TBDTs) that are responsible for iron import stimulate their own transcription in response to extracellular binding by an iron-laden siderophore. This process is mediated by an inner membrane sigma regulator protein (an anti-sigma factor) that transduces an unknown periplasmic signal from the TBDT to release an intracellular sigma factor from the inner membrane, which ultimately upregulates TBDT transcription. Here we use the Pseudomonas putida ferric-pseudobactin BN7/BN8 sigma regulator, PupR, as a model system to understand the molecular mechanism of this conserved class of sigma regulators. We have determined the X-ray crystal structure of the cytoplasmic anti-sigma domain (ASD) of PupR to 2.0 Å. Size exclusion chromatography, small angle X-ray scattering, and sedimentation velocity analytical ultracentrifugation, all indicate that in contrast to other ASDs, the PupR-ASD exists as a dimer in solution. Mutagenesis of residues at the dimer interface identified from the crystal structure disrupts dimerization and protein stability, as determined by sedimentation velocity analytical ultracentrifugation and thermal denaturation circular dichroism spectroscopy. Lastly, these combined results suggest that this type of inner membrane sigma regulator may utilize an unusual mechanism to sequester their cognate sigma factors and prevent transcription activation.

  3. The mare reproductive loss syndrome and the eastern tent caterpillar: a toxicokinetic/statistical analysis with clinical, epidemiologic, and mechanistic implications.

    PubMed

    Sebastian, Manu; Gantz, Marie G; Tobin, Thomas; Harkins, J Daniel; Bosken, Jeffrey M; Hughes, Charlie; Harrison, Lenn R; Bernard, William V; Richter, Dana L; Fitzgerald, Terrence D

    2003-01-01

    During 2001, central Kentucky experienced acute transient epidemics of early and late fetal losses, pericarditis, and unilateral endophthalmitis, collectively referred to as mare reproductive loss syndrome (MRLS). A toxicokinetic/statistical analysis of experimental and field MRLS data was conducted using accelerated failure time (AFT) analysis of abortions following administration of Eastern tent caterpillars (ETCs; 100 or 50 g/day or 100 g of irradiated caterpillars/day) to late-term pregnant mares. In addition, 2001 late-term fetal loss field data were used in the analysis. Experimental data were fitted by AFT analysis at a high (P <.0001) significance. Times to first abortion ("lag time") and abortion rates were dose dependent. Lag times decreased and abortion rates increased exponentially with dose. Calculated dose x response data curves allow interpretation of abortion data in terms of "intubated ETC equivalents." Analysis suggested that field exposure to ETCs in 2001 in central Kentucky commenced on approximately April 27, was initially equivalent to approximately 5 g of intubated ETCs/day, and increased to approximately 30 g/day at the outbreak peak. This analysis accounts for many aspects of the epidemiology, clinical presentations, and manifestations of MRLS. It allows quantitative interpretation of experimental and field MRLS data and has implications for the basic mechanisms underlying MRLS. The results support suggestions that MRLS is caused by exposure to or ingestion of ETCs. The results also show that high levels of ETC exposure produce intense, focused outbreaks of MRLS, closely linked in time and place to dispersing ETCs, as occurred in central Kentucky in 2001. With less intense exposure, lag time is longer and abortions tend to spread out over time and may occur out of phase with ETC exposure, obscuring both diagnosis of this syndrome and the role of the caterpillars.

  4. Development of the Reasonable Accommodation Factor Survey: Results and Implications

    ERIC Educational Resources Information Center

    Dong, Shengli; MacDonald-Wilson, Kim L.; Fabian, Ellen

    2010-01-01

    The purpose of this study was (a) to explore the latent factors in the "Reasonable Accommodation Factor Survey" (RAFS) instrument and (b) to compare scores on the latent factors of the RAFS by participant's role. Eight latent factors were identified through an exploratory factor analysis with orthogonal rotation. The reliability tests…

  5. Targeted Regulation of PI3K/Akt/mTOR/NF-κB Signaling by Indole Compounds and their Derivatives: Mechanistic Details and Biological Implications for Cancer Therapy

    PubMed Central

    Ahmad, Aamir; Biersack, Bernhard; Li, Yiwei; Kong, Dejuan; Bao, Bin; Schobert, Rainer; Padhye, Subhash B.; Sarkar, Fazlul H.

    2014-01-01

    Indole compounds, found in cruciferous vegetables, are potent anti-cancer agents. Studies with indole-3-carbinol (I3C) and its dimeric product, 3,3’-diindolylmethane (DIM) suggest that these compounds have the ability to deregulate multiple cellular signaling pathways, including PI3K/Akt/mTOR signaling pathway. These natural compounds are also effective modulators of downstream transcription factor NF-κB signaling which might help explain their ability to inhibit invasion and angiogenesis, and the reversal of epithelial-to-mesenchymal transition (EMT) phenotype and drug resistance. Signaling through PI3K/Akt/mTOR and NF-κB pathway is increasingly being realized to play important role in EMT through the regulation of novel miRNAs which further validates the importance of this signaling network and its regulations by indole compounds. Here we will review the available literature on the modulation of PI3K/Akt/mTOR/NF-κB signaling by both parental I3C and DIM, as well as their analogs/derivatives, in an attempt to catalog their anticancer activity. PMID:23272910

  6. Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma: relevance of p53 and its clinical implications.

    PubMed

    Valdez, Benigno C; Wang, Guiyun; Murray, David; Nieto, Yago; Li, Yang; Shah, Jatin; Turturro, Francesco; Wang, Michael; Weber, Donna M; Champlin, Richard E; Qazilbash, Muzaffar H; Andersson, Borje S

    2013-08-01

    Hematopoietic stem cell transplantation (HSCT) is an established treatment for multiple myeloma (MM), a plasma cell malignancy. To identify an improved pretransplant conditioning regimen, we investigated the cytotoxicity of gemcitabine (Gem) and clofarabine (Clo) combinations toward MM cell lines and patient cell samples. A strong synergism of the two nucleoside analogs, when combined at their approximate IC10 concentrations, was observed. This synergism could be partly due to the observed Gem-mediated phosphorylation and activation of deoxycytidine kinase, resulting in enhanced phosphorylation of Gem and Clo. Their cytotoxicity correlated with a robust activation of the DNA damage response pathway. [Gem+Clo] decreased the mitochondrial membrane potential with a concomitant release of proapoptotic factors into the cytoplasm and nucleus and the activation of apoptosis. Exposure of MM cells to [Gem+Clo] also decreased the level of ribosomal RNA (rRNA), which might have resulted in nucleolar stress, as reported previously, and caused a p53-dependent cell death. A reduction by approximately 50% in the cytotoxicity of Gem and Clo was observed in the presence of pifithrin α, a p53 inhibitor. Furthermore, MM cell lines with mutant p53 exhibited greater resistance to Gem and Clo, supporting a role for the p53 protein in these cytotoxic responses. Our results provide a rationale for clinical trials incorporating [Gem+Clo] combinations as part of conditioning therapy for high-risk patients with MM undergoing HSCT.

  7. Mechanistic Indicators of Childhood Asthma (MICA) Study

    EPA Science Inventory

    The Mechanistic Indicators of Childhood Asthma (MICA) Study has been designed to incorporate state-of-the-art technologies to examine the physiological and environmental factors that interact to increase the risk of asthmatic responses. MICA is primarily a clinically-bases obser...

  8. Biosynthesis, processing and secretion of von Willebrand factor: biological implications.

    PubMed

    de Wit, T R; van Mourik, J A

    2001-06-01

    von Willebrand factor is a multimeric plasma glycoprotein that is required for normal haemostasis. von Willebrand factor is synthesized by endothelial cells and megakaryocytes, and originates from its precursor pro-von Willebrand factor. The endoproteolytic processing of pro-von Willebrand factor results in mature von Willebrand factor and von Willebrand factor propeptide (also known as von Willebrand Ag II). In endothelial cells, the propeptide controls the polymerization and subsequent targeting of von Willebrand factor to the storage vesicles, the so-called Weibel-Palade bodies. Upon stimulation of the endothelial cells, the Weibel-Palade bodies are translocated to the plasma membrane of the cell, and mature von Willebrand factor and its propeptide are co-secreted. After release, these polypeptides have divergent fates and serve different biological functions. Mature von Willebrand factor both controls platelet adhesion and aggregation at sites of vascular injury and acts as a chaperone protein for coagulation factor VIII. The von Willebrand factor propeptide may serve a role in modulating inflammatory processes. This still growing body of information indicates that the biological function of the von Willebrand factor gene product is more diverse than was previously thought.

  9. Problems with Single Interest Scales: Implications of the General Factor

    ERIC Educational Resources Information Center

    Tracey, Terence J. G.

    2012-01-01

    The presence of the general factor in interest and self-efficacy assessment and its meaning are reviewed. The general factor is found in all interest and self-efficacy assessment and has been viewed as (a) a nuisance factor with little effect on assessment, (b) a variable having substantive meaning and thus worthy of including in interpretation,…

  10. Brain-derived neurotrophic factor and its clinical implications.

    PubMed

    Bathina, Siresha; Das, Undurti N

    2015-12-10

    Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus.

  11. [Compliance in schizophrenia: predictive factors, therapeutical considerations and research implications].

    PubMed

    Misdrahi, D; Llorca, P M; Lançon, C; Bayle, F J

    2002-01-01

    Compliance has been defined as the extent to which a person's behavior coincides with the medical advice given. Medication compliance is one of the foremost problems affecting neuroleptic efficacy in psychiatric patients. Since chlorpromazine introduction in 1952, antipsychotics are the principal element of schizophrenia treatment. Actually progress links to the use of new antipsychotics are conditioned by quality of compliance. The problem of nonadherence to medication could concern 50% of prescription. The reported incidence of non-compliance with antipsychotic medication ranges from 11 to 80%. In a two thirds of case rehospitalization is the result of complete or partial noncompliance. After one year of first hospitalisation, 40% of relapse results from non adherence to medication. Medication adherence problems increase hospitalisation, morbidity and mortality. Social consequences, professional problems and family troubles linked to hospitalisations lead to low quality of life for patients and high cost for society. There are three main methods of measuring compliance. These include patient and clinical self-report, pill counts, and biological measures. Self-report methods are generally the most cost-effective and time-efficient way of obtaining an indication of compliance. In psychiatric research, the most commonly used self-report measure of compliance is the Drug Attitude Inventory (DAI) originally devised by Hogan et al. On the basis of criticism concerning DAI reliability, a new questionnaire of medication compliance was proposed: the Medication Adherence Rating scale (MARS). The main goal of compliance evaluation is to quantify this phenomenon with accuracy and to find predictive factors of medication nonadherence. Three types of factors influencing compliance are identified: factors due to medications, factors linked to patients and factors depending on the therapeutic relation with the clinician. Tolerance is considered as the principal reason explaining

  12. Factors associated with self-reported health: implications for ...

    EPA Pesticide Factsheets

    BACKGROUND: Advocates for environmental justice, local, state, and national public health officials, exposure scientists, need broad-based heath indices to identify vulnerable communities. Longitudinal studies show that perception of current health status predicts subsequent mortality, suggesting that self-reported health (SRH) may be useful in screening-level community assessments. This paper evaluates whether SRH is an appropriate surrogate indicator of health status by evaluating relationships between SRH and sociodemographic, lifestyle, and health care factors as well as serological indicators of nutrition, health risk, and environmental exposures.METHODS: Data were combined from the 2003-2006 National Health and Nutrition Examination Surveys for 1372 nonsmoking 20-50 year olds. Ordinal and binary logistic regression was used to estimate odds ratios and 95 % confidence intervals of reporting poorer health based on measures of nutrition, health condition, environmental contaminants, and sociodemographic, health care, and lifestyle factors.RESULTS: Poorer SRH was associated with several serological measures of nutrition, health condition, and biomarkers of toluene, cadmium, lead, and mercury exposure. Race/ethnicity, income, education, access to health care, food security, exercise, poor mental and physical health, prescription drug use, and multiple health outcome measures (e.g., diabetes, thyroid problems, asthma) were also associated with poorer SRH.CONCLUS

  13. Otomycosis; clinical features, predisposing factors and treatment implications

    PubMed Central

    Anwar, Khurshid; Gohar, Muhammad Shahid

    2014-01-01

    Objectives : The aim of this study was to determine the frequency of otomycosis, the clinical presentation, predisposing factors and treatment outcomes. Methods: This observational study was conducted at ENT department of Combined Military Hospital Attock, from October, 2010 to September, 2012. Convenient sample comprising 180 patients of both sexes and all age groups were selected from ENT OPD. The frequency, predisposing factors and most common symptoms of otomycosis were recorded. The response to different antifungal agents was also observed. Results were recorded in percentages. Results: There were 180 patients with documented diagnosis of otomycosis. There were 107 (59%) males and 73 (41%) females. The age of patients ranged from 1½ years to 75 years with a mean age of 38.5 years. Mean follow up time was 2 years. Most common presenting symptom was hearing loss (77.7%) followed by pruritis (68.8%) and otalgia (40%). We prescribed 1% clotrimazole drops or lotion in 58% patients and 2% salicylic acid in 31% cases. Both of these agents are effective. Topical 1% clotrimazole drops yielded highest resolution rate with lowest recurrent rate. Overall 149 (83%) patients were improved with initial treatment and 31 (17%) did not respond to initial treatment. Eight (4.4%) patients had a history of otological procedures. Four (2.2%) patients had canal wall down procedures that resulted in mastoid cavity. To analyse the efficacy of 1% clotrimazole and 2% salicylic acid we applied Z-Test to calculate the difference between 2 proportions of patients before treatment with those patients who remained uncured after treatment. Conclusion: Otomycosisis commonly presented with decreased hearing, pruritis, otalgia & otorrhoea. It usually resolves with local toilet of ear and instillation of antifungal agents. Eradication of disease is difficult in presence of a mastoid cavity and metabolic diseases like diabetes mellitus. PMID:24948980

  14. Psychiatric factors in asthma: implications for diagnosis and therapy.

    PubMed

    Rietveld, Simon; Creer, Thomas L

    2003-01-01

    Emotional factors are an obstacle in the diagnosis and management of asthma. This review discusses three problem patterns: negative emotions in relatively normal patients with asthma; patients presenting possible functional symptoms and; patients presenting asthma in conjunction with psychiatric deviations. Negative emotions influence the symptoms and management of asthma, even in relatively normal patients. Psychogenic symptoms appear normal, but culminate in functional symptoms in a minority of patients. Diagnosing and treating asthma in patients with comorbid asthma and psychiatric symptoms is very difficult. On the one hand, treating asthma may often be just treating the emotions. On the other hand, negative emotions make the treatment of asthma guesswork. Physicians should estimate emotional influences in their patients' symptoms for an optimal evaluation of medication efficacy. Assessment and analysis of emotional factors surrounding exacerbations seems essential, e.g. emotional precipitants of asthma and asthma-evoked negative emotions. Moreover, patients should be informed about stress-induced breathlessness and the consequences of overuse of bronchodilators. When patients present with atypical symptoms, or do not properly respond to asthma medication, functional symptoms should be suspected. Psychiatric analysis may often lead to the conclusion that symptoms have a functional basis. In patients with comorbid asthma and anxiety disorders, asthma should be the focus for treatment since difficult-to-control asthma often causes anxiety problems in the first place. Moreover, panic-like symptoms in asthma are often related to sudden onset asthma exacerbations. However, in patients with comorbid asthma and depression, depression should become the focus of treatment. The reason is that optimal treatment of depressive asthmatics is probably impossible. Special issues include specific problems with children, compliance problems, and physicians' dilemmas regarding

  15. Head and neck sarcomas: prognostic factors and implications for treatment.

    PubMed Central

    Eeles, R. A.; Fisher, C.; A'Hern, R. P.; Robinson, M.; Rhys-Evans, P.; Henk, J. M.; Archer, D.; Harmer, C. L.

    1993-01-01

    One hundred and thirty patients with soft tissue sarcoma of the head and neck were treated at the Royal Marsden Hospital between 1944 and 1988. Pathological review was possible in 103 of these cases; only pathologically reviewed cases have been analysed. The median age at presentation was 36 years, and 53% were male. Four had neurofibromatosis type I, and one previous bilateral retinoblastoma. Six had undergone previous radiotherapy, 12 to 45 years prior to developing sarcoma. The tumours were < or = 5 cm in 78% of cases and high grade in 48%. Only one patient presented with lymph node metastases and only one with distant metastases (to lung). Malignant fibrous histiocytoma was the commonest histological type, occurring in 30 cases. The overall 5 year survival was 50% (95% CI 39-60). Local tumour was the cause of death in 63% of cases and 5 year local control was only 47% (95% CI 36-58) with local recurrence occurring as late as 15 years after treatment. The only favourable independent prognostic factor for survival was the ability to perform surgery (other than biopsy), with or without radiotherapy, as opposed to radiotherapy alone (hazard ratio 0.39; P = 0.003). Only one patient had a biopsy with no further treatment. Favourable independent prognostic factors for local control at 5 years were site (tumours of the head as opposed to the neck, hazard ratio 0.42; P = 0.02) and modality of treatment (combined surgery and radiotherapy compared to either alone, hazard ratio 0.31; P = 0.002). Patients in the combined modality and single treatment modality groups were well balanced for T stage, grade and tumour site. The patients in the combined treatment group had less extensive surgery, yet their local recurrence-free survival was longer. Unlike soft tissue sarcomas at other sites, those in the head and neck region more often cause death by local recurrence. The addition of radiotherapy to surgery may result in longer local recurrence-free survival. PMID:8318414

  16. Snail Family Transcription Factors Are Implicated in Thyroid Carcinogenesis

    PubMed Central

    Hardy, Robert G.; Vicente-Dueñas, Carolina; González-Herrero, Ines; Anderson, Catriona; Flores, Teresa; Hughes, Sharon; Tselepis, Chris; Ross, James A.; Sánchez-García, Isidro

    2007-01-01

    E-Cadherin (CDH1) expression is reduced in thyroid carcinomas by primarily unknown mechanisms. In several tissues, SNAIL (SNAI1) and SLUG (SNAI2) induce epithelial-mesenchymal transition by altering target gene transcription, including CDH1 repression, but these transcription factors have not been studied in thyroid carcinoma. Recently, our group has provided direct evidence that ectopic SNAI1 expression induces epithelial and mesenchymal mouse tumors. SNAI1, SNAI2, and CDH1 expression were analyzed in thyroid-derived cell lines and samples of human follicular and papillary thyroid carcinoma by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. The effect of SNAI1 expression on CDH1 transcription was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting in ori-3 cells. Thyroid carcinoma development was analyzed in CombitTA-Snail mice, in which SNAI1 levels are up-regulated. SNAI1 and SNAI2 were not expressed in cells derived from normal thyroid tissue, or in normal human thyroid samples, but were highly expressed in cell lines derived from thyroid carcinomas, in human thyroid carcinoma samples, and their metastases. SNAI1 expression in ori-3 cells repressed CDH1 transcription. Combi-TA mice developed papillary thyroid carcinomas, the incidence of which was increased by concomitant radiotherapy. In conclusion, SNAI1 and SNAI2 are ectopically expressed in thyroid carcinomas, and aberrant expression in mice is associated with papillary carcinoma development. PMID:17724139

  17. Generation Y Student-Teachers' Motivational Factors: Retention Implications for K-12 Educational Leaders

    ERIC Educational Resources Information Center

    Bontempo, Brian

    2010-01-01

    Generation Y represents a growing number of student-teachers who will impact the future of educational practice, yet little research has been conducted for this demographic group. The purpose of this mixed-method study was to identify motivational factors of neophyte teachers and the retention implications these findings had on Kindergarten…

  18. AIR POLLUTION, INFLAMMATION AND PRETERM BIRTH: A POTENTIAL MECHANISTIC LINK

    PubMed Central

    Vadillo-Ortega, Felipe; Osornio-Vargas, Alvaro; Buxton, Miatta A.; Sánchez, Brisa N.; Rojas-Bracho, Leonora; Viveros-Alcaráz, Martin; Castillo-Castrejón, Marisol; Beltrán-Montoya, Jorge; Brown, Daniel G.; O´Neill, Marie S.

    2014-01-01

    Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth. PMID:24382337

  19. Air pollution, inflammation and preterm birth: a potential mechanistic link.

    PubMed

    Vadillo-Ortega, Felipe; Osornio-Vargas, Alvaro; Buxton, Miatta A; Sánchez, Brisa N; Rojas-Bracho, Leonora; Viveros-Alcaráz, Martin; Castillo-Castrejón, Marisol; Beltrán-Montoya, Jorge; Brown, Daniel G; O'Neill, Marie S

    2014-02-01

    Preterm birth is a public health issue of global significance, which may result in mortality during the perinatal period or may lead to major health and financial consequences due to lifelong impacts. Even though several risk factors for preterm birth have been identified, prevention efforts have failed to halt the increasing rates of preterm birth. Epidemiological studies have identified air pollution as an emerging potential risk factor for preterm birth. However, many studies were limited by study design and inadequate exposure assessment. Due to the ubiquitous nature of ambient air pollution and the potential public health significance of any role in causing preterm birth, a novel focus investigating possible causal mechanisms influenced by air pollution is therefore a global health priority. We hypothesize that air pollution may act together with other biological factors to induce systemic inflammation and influence the duration of pregnancy. Evaluation and testing of this hypothesis is currently being conducted in a prospective cohort study in Mexico City and will provide an understanding of the pathways that mediate the effects of air pollution on preterm birth. The important public health implication is that crucial steps in this mechanistic pathway can potentially be acted on early in pregnancy to reduce the risk of preterm birth.

  20. From mechanistic to functional behaviorism.

    PubMed

    Moxley, R A

    1992-11-01

    A shift from mechanistic behaviorism to functional behaviorism is presented against the background of two historical traditions, one with an emphasis on form, the other with an emphasis on function. Skinner's work, which made more contributions to a functional behaviorism than to a mechanistic behaviorism, exemplifies this shift. The two traditions and an account of Skinner's development of functional relations are presented in order to show Skinner's contributions to aligning modern behavior analysis with the functional tradition.

  1. Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

    PubMed Central

    Woodhead, Jeffrey L.; Brock, William J.; Roth, Sharin E.; Shoaf, Susan E.; Brouwer, Kim L.R.; Church, Rachel; Grammatopoulos, Tom N.; Stiles, Linsey; Siler, Scott Q.; Howell, Brett A.; Mosedale, Merrie; Watkins, Paul B.; Shoda, Lisl K.M.

    2017-01-01

    Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30  mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies. PMID:27655350

  2. Molecular Motions as a Drug Target: Mechanistic Simulations of Anthrax Toxin Edema Factor Function Led to the Discovery of Novel Allosteric Inhibitors

    PubMed Central

    Laine, Élodie; Martínez, Leandro; Ladant, Daniel; Malliavin, Thérèse; Blondel, Arnaud

    2012-01-01

    Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavities at the surface of EF were determined for each path intermediate to identify potential sites where the binding of a ligand could block activation. A non-catalytic cavity (allosteric) was found to shrink rapidly at early stages of the path and was chosen to perform virtual screening. Amongst 18 compounds selected in silico and tested in an enzymatic assay, 6 thiophen ureidoacid derivatives formed a new family of EF allosteric inhibitors with IC50 as low as 2 micromolars. PMID:23012649

  3. A mechanistic pharmacokinetic/pharmacodynamic model of factor D inhibition in cynomolgus monkeys by lampalizumab for the treatment of geographic atrophy.

    PubMed

    Le, Kha N; Gibiansky, Leonid; Good, Jeremy; Davancaze, Teresa; van Lookeren Campagne, Menno; Loyet, Kelly M; Morimoto, Alyssa; Jin, Jin; Damico-Beyer, Lisa A; Hanley, William D

    2015-11-01

    Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a rate-limiting enzyme in the activation and amplification of the alternative complement pathway (ACP), which is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited but crucial for selecting doses that provide optimal efficacy and safety. Here, we sought to construct a semimechanistic and integrated ocular-systemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account target-mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow, with a τ1/2 of approximately 3 days, whereas systemic elimination is rapid, with a τ1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas target-mediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (<10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.

  4. Affinity proteomics reveals human host factors implicated in discrete stages of LINE-1 retrotransposition.

    PubMed

    Taylor, Martin S; LaCava, John; Mita, Paolo; Molloy, Kelly R; Huang, Cheng Ran Lisa; Li, Donghui; Adney, Emily M; Jiang, Hua; Burns, Kathleen H; Chait, Brian T; Rout, Michael P; Boeke, Jef D; Dai, Lixin

    2013-11-21

    LINE-1s are active human DNA parasites that are agents of genome dynamics in evolution and disease. These streamlined elements require host factors to complete their life cycles, whereas hosts have developed mechanisms to combat retrotransposition's mutagenic effects. As such, endogenous L1 expression levels are extremely low, creating a roadblock for detailed interactomic analyses. Here, we describe a system to express and purify highly active L1 RNP complexes from human suspension cell culture and characterize the copurified proteome, identifying 37 high-confidence candidate interactors. These data sets include known interactors PABPC1 and MOV10 and, with in-cell imaging studies, suggest existence of at least three types of compositionally and functionally distinct L1 RNPs. Among the findings, UPF1, a key nonsense-mediated decay factor, and PCNA, the polymerase-delta-associated sliding DNA clamp, were identified and validated. PCNA interacts with ORF2p via a PIP box motif; mechanistic studies suggest that this occurs during or immediately after target-primed reverse transcription.

  5. Implications of Our Developing Understanding of Risk and Protective Factors in the Treatment of Adult Male Sexual Offenders

    ERIC Educational Resources Information Center

    Thornton, David

    2013-01-01

    This paper summarizes our developing knowledge of factors that contribute added risk of sexual recidivism (risk factors) and factors that are associated with a reduced risk of sexual recidivism (protective factors). Specific implications for the design of future treatment programs are drawn. This information is contrasted with the common foci of…

  6. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    SciTech Connect

    Ngo, J.C.; Huang, M.; Roth, D.A.; Furie, B.C.; Furie, B.

    2008-06-03

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca{sup 2+} and two Cu{sup 2+} ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  7. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    SciTech Connect

    Chi Ki Ngo,J.; Huang, M.; Roth, D.; Furie, B.; Furie, B.

    2008-01-01

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca(2+) and two Cu(2+) ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  8. Human factors in space station architecture 1: Space station program implications for human factors research

    NASA Technical Reports Server (NTRS)

    Cohen, M. M.

    1985-01-01

    The space station program is based on a set of premises on mission requirements and the operational capabilities of the space shuttle. These premises will influence the human behavioral factors and conditions on board the space station. These include: launch in the STS Orbiter payload bay, orbital characteristics, power supply, microgravity environment, autonomy from the ground, crew make-up and organization, distributed command control, safety, and logistics resupply. The most immediate design impacts of these premises will be upon the architectural organization and internal environment of the space station.

  9. Physiological functions and underlying mechanisms of fibroblast growth factor (FGF) family members: recent findings and implications for their pharmacological application.

    PubMed

    Imamura, Toru

    2014-01-01

    Despite their name, fibroblast growth factors (FGFs) are multifunctional regulators affecting a wide variety of physiological events. This review summarizes our recent studies on FGFs from mechanistic, physiological and application-oriented viewpoints. These include studies on the importance of βKlotho and glycosaminoglycans for the signaling of hormonal FGFs (FGF21 and FGF19); the physiological role of a paracrine FGF (FGF18) in hair cycle regulation; and the development of a stable, chimeric FGF protein composed of FGF1 and FGF2 domains suitable for radioprotection.

  10. Sociocultural factors and breast cancer in sub-Saharan Africa: implications for diagnosis and management.

    PubMed

    Tetteh, Dinah A; Faulkner, Sandra L

    2016-01-01

    The incidence of breast cancer is on the rise in sub-Saharan Africa (SSA) and efforts at early diagnosis have not been very successful because the public has scant knowledge about the disease, a large percentage of breast cancer cases are diagnosed late and mainly rural SSA women's practice of breast self-examination is poor. In this paper, we argue that an examination of the social and cultural contexts of SSA that influence breast cancer diagnosis and management in the region is needed. We discuss the implications of sociocultural factors, such as gender roles and spirituality, on breast cancer diagnosis and management in SSA.

  11. Obesity, Diabetes and Cancer: A Mechanistic Perspective

    PubMed Central

    Cifarelli, V; Hursting, SD

    2016-01-01

    Nearly 35% of adults and 20% of children in the United States are obese, defined as having a body mass index (BMI) ≥ 30 kg/m2. Obesity is an established risk factor for many cancers, and obesity-associated metabolic perturbations often manifest in Type 2 diabetes mellitus and/or the metabolic syndrome. As part of the growth-promoting, proinflammatory microenvironment of the obese and/or diabetic state, crosstalk between macrophages, adipocytes, and epithelial cells occurs via metabolically-regulated hormones, cytokines, and other mediators to enhance cancer risk and/or progression. This review synthesizes the evidence on key biological mechanisms underlying the associations between obesity, diabetes and cancer, with particular emphasis on enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent mechanistic targets for disrupting the obesity-diabetes-cancer link, and several diabetes drugs, such as metformin and rosiglitazone, are being intensely studied for repurposing as cancer chemopreventive agents.

  12. The Transcription Factor XBP1 in Memory and Cognition: Implications in Alzheimer’s Disease

    PubMed Central

    Cissé, Moustapha; Duplan, Eric; Checler, Frédéric

    2016-01-01

    X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor that was isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein that regulates many physiological functions, including the immune system, inflammatory responses and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays an important role in pathological settings, since its activity as a transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration and diabetes. Here we provide an overview of recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases, with an emphasis on Alzheimer’s disease. PMID:28079229

  13. Spatialised fate factors for nitrate in catchments: modelling approach and implication for LCA results.

    PubMed

    Basset-Mens, Claudine; Anibar, Lamiaa; Durand, Patrick; van der Werf, Hayo M G

    2006-08-15

    The challenge for environmental assessment tools, such as Life Cycle Assessment (LCA) is to provide a holistic picture of the environmental impacts of a given system, while being relevant both at a global scale, i.e., for global impact categories such as climate change, and at a smaller scale, i.e., for regional impact categories such as aquatic eutrophication. To this end, the environmental mechanisms between emission and impact should be taken into account. For eutrophication in particular, which is one of the main impacts of farming systems, the fate factor of eutrophying pollutants in catchments, and particularly of nitrate, reflects one of these important and complex environmental mechanisms. We define this fate factor as: the ratio of the amount of nitrate at the outlet of the catchment over the nitrate emitted from the catchment's soils. In LCA, this fate factor is most often assumed equal to 1, while the observed fate factor is generally less than 1. A generic approach for estimating the range of variation of nitrate fate factors in a region of intensive agriculture was proposed. This approach was based on the analysis of different catchment scenarios combining different catchment types and different effective rainfalls. The evolution over time of the nitrate fate factor as well as the steady state fate factor for each catchment scenario was obtained using the INCA simulation model. In line with the general LCA model, the implications of the steady state fate factors for nitrate were investigated for the eutrophication impact result in the framework of an LCA of pig production. A sensitivity analysis to the fraction of nitrate lost as N(2)O was presented for the climate change impact category. This study highlighted the difference between the observed fate factor at a given time, which aggregates both storage and transformation processes and a "steady state fate factor", specific to the system considered. The range of steady state fate factors obtained for

  14. Modeling the epidermal growth factor -- epidermal growth factor receptor l2 domain interaction: implications for the ligand binding process.

    PubMed

    Jorissen, Robert N; Treutlein, Herbert R; Epa, V Chandana; Burgess, Antony W

    2002-06-01

    Signaling from the epidermal growth factor (EGF) receptor is triggered by the binding of ligands such as EGF or transforming growth factor alpha (TGF-alpha) and subsequent receptor dimerization. An understanding of these processes has been hindered by the lack of structural information about the ligand-bound, dimerized EGF receptor. Using an NMR-derived structure of EGF and a homology model of the major ligand binding domain of the EGF receptor and experimental data, we modeled the binding of EGF to this EGF receptor fragment. In this low resolution model of the complex, EGF sits across the second face of the EGF receptor L2 domain and EGF residues 10-16, 36-37, 40-47 bind to this face. The structural model is largely consistent with previously published NMR data describing the residues of TGF-alpha which interact strongly with the EGF receptor. Other EGF residues implicated in receptor binding are accounted by our proposal that the ligand binding is a two-step process with the EGF binding to at least one other site of the receptor. This three-dimensional model is expected to be useful in the design of ligand-based antagonists of the receptor.

  15. Mechanistically Consistent Reduced Models of Synthetic Gene Networks

    PubMed Central

    Mier-y-Terán-Romero, Luis; Silber, Mary; Hatzimanikatis, Vassily

    2013-01-01

    Designing genetic networks with desired functionalities requires an accurate mathematical framework that accounts for the essential mechanistic details of the system. Here, we formulate a time-delay model of protein translation and mRNA degradation by systematically reducing a detailed mechanistic model that explicitly accounts for the ribosomal dynamics and the cleaving of mRNA by endonucleases. We exploit various technical and conceptual advantages that our time-delay model offers over the mechanistic model to probe the behavior of a self-repressing gene over wide regions of parameter space. We show that a heuristic time-delay model of protein synthesis of a commonly used form yields a notably different prediction for the parameter region where sustained oscillations occur. This suggests that such heuristics can lead to erroneous results. The functional forms that arise from our systematic reduction can be used for every system that involves transcription and translation and they could replace the commonly used heuristic time-delay models for these processes. The results from our analysis have important implications for the design of synthetic gene networks and stress that such design must be guided by a combination of heuristic models and mechanistic models that include all relevant details of the process. PMID:23663853

  16. Metabolic Risk Factors of Sporadic Alzheimer’s Disease: Implications in the Pathology, Pathogenesis and Treatment

    PubMed Central

    Chakrabarti, Sasanka; Khemka, Vineet Kumar; Banerjee, Anindita; Chatterjee, Gargi; Ganguly, Anirban; Biswas, Atanu

    2015-01-01

    Alzheimer’s disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors. PMID:26236550

  17. Early Health Risk Factors for Violence: Conceptualization, Review of the Evidence, and Implications.

    PubMed

    Liu, Jianghong

    2011-01-01

    Violence and aggression are public health problems that can benefit from ongoing research into risk reduction and prevention. Current developmental theories of violence and aggression emphasize biological and psychosocial factors, particularly during adolescence. However, there has been less focus on understanding the interactive, multiplicative effects of these processes. Furthermore, little attention has been given to the pre-, peri-, and postnatal periods, where prevention and intervention may yield effective results. Early health risk factors that influence negative behavioral outcomes include prenatal and postnatal nutrition, tobacco use during pregnancy, maternal depression, birth complications, traumatic brain injury, lead exposure, and child abuse. There is an ample literature to suggest that these early health risk factors may increase the likelihood of childhood externalizing behaviors, aggression, juvenile delinquency, adult criminal behavior, and/or violence. This paper proposes an early health risk factors framework for violence prediction, built on existing developmental theories of criminal behavior and supported by empirical findings. This framework addresses gaps in the adolescent psychopathology literature and presents a novel conceptualization of behavioral disturbance that emphasizes the pre-, peri-, and post-natal periods, when a child's development is critical and the opportunity for behavioral and environmental modification is high. Implications for such a framework on violence prevention programs are discussed.

  18. Early Health Risk Factors for Violence: Conceptualization, Review of the Evidence, and Implications

    PubMed Central

    Liu, Jianghong

    2010-01-01

    Violence and aggression are public health problems that can benefit from ongoing research into risk reduction and prevention. Current developmental theories of violence and aggression emphasize biological and psychosocial factors, particularly during adolescence. However, there has been less focus on understanding the interactive, multiplicative effects of these processes. Furthermore, little attention has been given to the pre-, peri-, and postnatal periods, where prevention and intervention may yield effective results. Early health risk factors that influence negative behavioral outcomes include prenatal and postnatal nutrition, tobacco use during pregnancy, maternal depression, birth complications, traumatic brain injury, lead exposure, and child abuse. There is an ample literature to suggest that these early health risk factors may increase the likelihood of childhood externalizing behaviors, aggression, juvenile delinquency, adult criminal behavior, and/or violence. This paper proposes an early health risk factors framework for violence prediction, built on existing developmental theories of criminal behavior and supported by empirical findings. This framework addresses gaps in the adolescent psychopathology literature and presents a novel conceptualization of behavioral disturbance that emphasizes the pre-, peri-, and post-natal periods, when a child’s development is critical and the opportunity for behavioral and environmental modification is high. Implications for such a framework on violence prevention programs are discussed. PMID:21399727

  19. The ecological impacts of nighttime light pollution: a mechanistic appraisal.

    PubMed

    Gaston, Kevin J; Bennie, Jonathan; Davies, Thomas W; Hopkins, John

    2013-11-01

    The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights.

  20. Modeling Bird Migration under Climate Change: A Mechanistic Approach

    NASA Technical Reports Server (NTRS)

    Smith, James A.

    2009-01-01

    How will migrating birds respond to changes in the environment under climate change? What are the implications for migratory success under the various accelerated climate change scenarios as forecast by the Intergovernmental Panel on Climate Change? How will reductions or increased variability in the number or quality of wetland stop-over sites affect migratory bird species? The answers to these questions have important ramifications for conservation biology and wildlife management. Here, we describe the use of continental scale simulation modeling to explore how spatio-temporal changes along migratory flyways affect en-route migration success. We use an individually based, biophysical, mechanistic, bird migration model to simulate the movement of shorebirds in North America as a tool to study how such factors as drought and wetland loss may impact migratory success and modify migration patterns. Our model is driven by remote sensing and climate data and incorporates important landscape variables. The energy budget components of the model include resting, foraging, and flight, but presently predation is ignored. Results/Conclusions We illustrate our model by studying the spring migration of sandpipers through the Great Plains to their Arctic breeding grounds. Why many species of shorebirds have shown significant declines remains a puzzle. Shorebirds are sensitive to stop-over quality and spacing because of their need for frequent refueling stops and their opportunistic feeding patterns. We predict bird "hydrographs that is, stop-over frequency with latitude, that are in agreement with the literature. Mean stop-over durations predicted from our model for nominal cases also are consistent with the limited, but available data. For the shorebird species simulated, our model predicts that shorebirds exhibit significant plasticity and are able to shift their migration patterns in response to changing drought conditions. However, the question remains as to whether this

  1. Food for Thought ... Mechanistic Validation

    PubMed Central

    Hartung, Thomas; Hoffmann, Sebastian; Stephens, Martin

    2013-01-01

    Summary Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high-throughput testing in the ToxCast/ Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification. PMID:23665802

  2. Implications of diesel emissions control failures to emission factors and road transport NOx evolution

    NASA Astrophysics Data System (ADS)

    Ntziachristos, Leonidas; Papadimitriou, Giannis; Ligterink, Norbert; Hausberger, Stefan

    2016-09-01

    Diesel NOx emissions have been at the forefront of research and regulation scrutiny as a result of failures of late vehicle technologies to deliver on-road emissions reductions. The current study aims at identifying the actual emissions levels of late light duty vehicle technologies, including Euro 5 and Euro 6 ones. Mean NOx emission factor levels used in the most popular EU vehicle emission models (COPERT, HBEFA and VERSIT+) are compared with latest emission information collected in the laboratory over real-world driving cycles and on the road using portable emissions measurement systems (PEMS). The comparison shows that Euro 5 passenger car (PC) emission factors well reflect on road levels and that recently revealed emissions control failures do not call for any significant corrections. However Euro 5 light commercial vehicles (LCVs) and Euro 6 PCs in the 2014-2016 period exhibit on road emission levels twice as high as used in current models. Moreover, measured levels vary a lot for Euro 6 vehicles. Scenarios for future evolution of Euro 6 emission factors, reflecting different degree of effectiveness of emissions control regulations, show that total NOx emissions from diesel Euro 6 PC and LCV may correspond from 49% up to 83% of total road transport emissions in 2050. Unless upcoming and long term regulations make sure that light duty diesel NOx emissions are effectively addressed, this will have significant implications in meeting future air quality and national emissions ceilings targets.

  3. A critical examination of the U.S. nursing shortage: contributing factors, public policy implications.

    PubMed

    Fox, Rebekah L; Abrahamson, Kathleen

    2009-01-01

    BACKGROUND. Despite short-lived periods of adequacy in nurse availability, the nursing shortage has endured. In order to better understand the myriad factors that influence the current shortage of nurses, as well as possible solutions, this project addresses the influence of social factors and government policy on nurse staffing inadequacy. When the government intervenes in a philosophically free-market economy, the assumption is that a problem, such as the current nursing shortage, could not be solved without such intervention. PURPOSE. Nursing care arguably falls into the realm of protecting the common good, and therefore requires government oversight. We provide a critical analysis of policy intervention efforts into the nursing shortage debate by examining the passage of legislation, the provision of educational assistance, and the establishment of minimum staffing requirements and minimum quality standards for reimbursement, which all impact nursing supply and demand. RESULTS. Arguments supporting and opposing policy intervention in general, and its impact on the overall provision of nursing care in the United States, were examined. Without policy incentive to place financial value on the quality of care provided by nurses, a simple increase in the number of available nurses is unlikely to solve the current problem. IMPLICATIONS. Important considerations that should be factored into policy creation include measurement and compensation for quality care, the nature of recruitment efforts of new nurses, and the complex nature of a nursing work.

  4. A review of factors that affect contact angle and implications for flotation practice.

    PubMed

    Chau, T T; Bruckard, W J; Koh, P T L; Nguyen, A V

    2009-09-30

    Contact angle and the wetting behaviour of solid particles are influenced by many physical and chemical factors such as surface roughness and heterogeneity as well as particle shape and size. A significant amount of effort has been invested in order to probe the correlation between these factors and surface wettability. Some of the key investigations reported in the literature are reviewed here. It is clear from the papers reviewed that, depending on many experimental conditions such as the size of the surface heterogeneities and asperities, surface cleanliness, and the resolution of measuring equipment and data interpretation, obtaining meaningful contact angle values is extremely difficult and such values are reliant on careful experimental control. Surface wetting behaviour depends on not only surface texture (roughness and particle shape), and surface chemistry (heterogeneity) but also on hydrodynamic conditions in the preparation route. The inability to distinguish the effects of each factor may be due to the interplay and/or overlap of two or more factors in each system. From this review, it was concluded that: Surface geometry (and surface roughness of different scales) can be used to tune the contact angle; with increasing surface roughness the apparent contact angle decreases for hydrophilic materials and increases for hydrophobic materials. For non-ideal surfaces, such as mineral surfaces in the flotation process, kinetics plays a more important role than thermodynamics in dictating wettability. Particle size encountered in flotation (10-200 microm) showed no significant effect on contact angle but has a strong effect on flotation rate constant. There is a lack of a rigid quantitative correlation between factors affecting wetting, wetting behaviour and contact angle on minerals; and hence their implication for flotation process. Specifically, universal correlation of contact angle to flotation recovery is still difficult to predict from first principles

  5. Implication of fibroblast growth factors in epileptogenesis-associated circuit rearrangements

    PubMed Central

    Paradiso, Beatrice; Zucchini, Silvia; Simonato, Michele

    2013-01-01

    The transformation of a normal brain in epileptic (epileptogenesis) is associated with extensive morpho-functional alterations, including cell death, axonal and dendritic plasticity, neurogenesis, and others. Neurotrophic factors (NTFs) appear to be very strongly implicated in these phenomena. In this review, we focus on the involvement of fibroblast growth factor (FGF) family members. Available data demonstrate that the FGFs are highly involved in the generation of the morpho-functional alterations in brain circuitries associated with epileptogenesis. For example, data on FGF2, the most studied member, suggest that it may be implicated both in seizure susceptibility and in seizure-induced plasticity, exerting different, and apparently contrasting effects: favoring acute seizures but reducing seizure-induced cell death. Even if many FGF members are still unexplored and very limited information is available on the FGF receptors, a complex and fascinating picture is emerging: multiple FGFs producing synergic or antagonistic effects one with another (and/or with other NTFs) on biological parameters that, in turn, facilitate or oppose transformation of the normal tissue in epileptic. In principle, identifying key elements in these phenomena may lead to effective therapies, but reaching this goal will require confronting a huge complexity. One first step could be to generate a “neurotrophicome” listing the FGFs (and all other NTFs) that are active during epileptogenesis. This should include identification of the extent to which each NTF is active (concentrations at the site of action); how it is active (local representation of receptor subtypes); when in the natural history of disease this occurs; how the NTF at hand will possibly interact with other NTFs. This is extraordinarily challenging, but holds the promise of a better understanding of epileptogenesis and, at large, of brain function. PMID:24062643

  6. Genetic Variation of Goat Interferon Regulatory Factor 3 Gene and Its Implication in Goat Evolution

    PubMed Central

    Shu, Liping; Zhang, Yesheng; Wang, Yangzi; Sanni, Timothy M.; Imumorin, Ikhide G.; Peters, Sunday O.; Zhang, Jiajin; Dong, Yang; Wang, Wen

    2016-01-01

    The immune systems are fundamentally vital for evolution and survival of species; as such, selection patterns in innate immune loci are of special interest in molecular evolutionary research. The interferon regulatory factor (IRF) gene family control many different aspects of the innate and adaptive immune responses in vertebrates. Among these, IRF3 is known to take active part in very many biological processes. We assembled and evaluated 1356 base pairs of the IRF3 gene coding region in domesticated goats from Africa (Nigeria, Ethiopia and South Africa) and Asia (Iran and China) and the wild goat (Capra aegagrus). Five segregating sites with θ value of 0.0009 for this gene demonstrated a low diversity across the goats’ populations. Fu and Li tests were significantly positive but Tajima’s D test was significantly negative, suggesting its deviation from neutrality. Neighbor joining tree of IRF3 gene in domesticated goats, wild goat and sheep showed that all domesticated goats have a closer relationship than with the wild goat and sheep. Maximum likelihood tree of the gene showed that different domesticated goats share a common ancestor and suggest single origin. Four unique haplotypes were observed across all the sequences, of which, one was particularly common to African goats (MOCH-K14-0425, Poitou and WAD). In assessing the evolution mode of the gene, we found that the codon model dN/dS ratio for all goats was greater than one. Phylogenetic Analysis by Maximum Likelihood (PAML) gave a ω0 (dN/dS) value of 0.067 with LnL value of -6900.3 for the first Model (M1) while ω2 = 1.667 in model M2 with LnL value of -6900.3 with positive selection inferred in 3 codon sites. Mechanistic empirical combination (MEC) model for evaluating adaptive selection pressure on particular codons also confirmed adaptive selection pressure in three codons (207, 358 and 408) in IRF3 gene. Positive diversifying selection inferred with recent evolutionary changes in domesticated goat

  7. HTGR Mechanistic Source Terms White Paper

    SciTech Connect

    Wayne Moe

    2010-07-01

    The primary purposes of this white paper are: (1) to describe the proposed approach for developing event specific mechanistic source terms for HTGR design and licensing, (2) to describe the technology development programs required to validate the design methods used to predict these mechanistic source terms and (3) to obtain agreement from the NRC that, subject to appropriate validation through the technology development program, the approach for developing event specific mechanistic source terms is acceptable

  8. Factors implicated in the initiation of human parturition in term and preterm labor: a review.

    PubMed

    Ravanos, Konstantinos; Dagklis, Themistoklis; Petousis, Stamatios; Margioula-Siarkou, Chrysoula; Prapas, Yannis; Prapas, Nikolaos

    2015-01-01

    After accommodating the pregnancy for an average of 40 weeks, the uterus expels the fetus, the placenta and the membranes through the birth canal in a process named parturition. The absolute sequence of events that trigger and sustain human parturition are not yet fully clarified. Evidence suggests that spontaneous preterm and term labor seem to share a common inflammatory pathway. However, there are several other factors being involved in the initiation of human parturition. Placental corticotropin releasing hormone production seems to serve as a placental clock that might be set to ring earlier or later determining the duration of pregnancy and timing of labor. Estrogens do not cause contractions but their properties seem to capacitate uterus to coordinate and enhance contractions. Cytokines, prostaglandins, nitric oxide and steroids seem also to induce ripening by mediating remodeling of the extracellular matrix and collagen. Infection and microbe invasion resulting in chorioamnionitis also represents a common cause of early preterm labour. This review provides an overview of all these factors considered to be implicated in the initiation of human parturition.

  9. Insulin-like growth factor 1, glycation and bone fragility: implications for fracture resistance of bone.

    PubMed

    Sroga, Grażyna E; Wu, Ping-Cheng; Vashishth, Deepak

    2015-01-01

    Despite our extensive knowledge of insulin-like growth factor 1 (IGF1) action on the growing skeleton, its role in skeletal homeostasis during aging and age-related development of certain diseases is still unclear. Advanced glycation end products (AGEs) derived from glucose are implicated in osteoporosis and a number of diabetic complications. We hypothesized that because in humans and rodents IGF1 stimulates uptake of glucose (a glycation substrate) from the bloodstream in a dose-dependent manner, the decline of IGF1 could be associated with the accumulation of glycation products and the decreasing resistance of bone to fracture. To test the aforementioned hypotheses, we used human tibial posterior cortex bone samples to perform biochemical (measurement of IGF1, fluorescent AGEs and pentosidine (PEN) contents) and mechanical tests (crack initiation and propagation using compact tension specimens). Our results for the first time show a significant, age-independent association between the levels of IGF1 and AGEs. Furthermore, AGEs (fAGEs, PEN) predict propensity of bone to fracture (initiation and propagation) independently of age in human cortical bone. Based on these results we propose a model of IGF1-based regulation of bone fracture. Because IGF1 level increases postnatally up to the juvenile developmental phase and decreases thereafter with aging, we propose that IGF1 may play a protective role in young skeleton and its age-related decline leads to bone fragility and an increased fracture risk. Our results may also have important implications for current understanding of osteoporosis- and diabetes-related bone fragility as well as in the development of new diagnostic tools to screen for fragile bones.

  10. Risk factors for victimization in romantic relationships of young women: a review of empirical studies and implications for prevention.

    PubMed

    Vézina, Johanne; Hébert, Martine

    2007-01-01

    This article reviews the literature on risk factors for victimization in romantic relationships of adolescent girls and young adult women. The review includes 61 empirical studies published between 1986 and 2006 that have investigated risk factors for sustained psychological, sexual, and physical violence in romantic relationships of young women ages 12 to 24. An ecological approach is used as a conceptual model to review risk factors into four categories: sociodemographic factors, individual factors (personal and interpersonal), environmental factors (family, community, and peers), and contextual factors (linked to the romantic relationship). Methodological limitations of the studies in terms of measurement issues, samples studied, research designs, and underlying conceptual models are discussed. Finally, implications for prevention programming are considered. Recommendations are presented about which clientele should be targeted, which risk factors should be considered, and when programs should be implemented.

  11. Transcription initiation factor IID-interactive histone chaperone CIA-II implicated in mammalian spermatogenesis.

    PubMed

    Umehara, Takashi; Horikoshi, Masami

    2003-09-12

    Histones are thought to have specific roles in mammalian spermatogenesis, because several subtypes of histones emerge that are post-translationally modified during spermatogenesis. Though regular assembly of nucleosome is guaranteed by histone chaperones, their involvement in spermatogenesis is yet to be characterized. Here we identified a histone chaperone-related factor, which we designated as CCG1-interacting factor A-II (CIA-II), through interaction with bromodomains of TAFII250/CCG1, which is the largest subunit of human transcription initiation factor IID (TFIID). We found that human CIA-II (hCIA-II) localizes in HeLa nuclei and is highly expressed in testis and other proliferating cell-containing tissues. Expression of mouse CIA-II (mCIA-II) does not occur in the germ cell-lacking testes of adult WBB6F1-W/Wv mutant mice, indicating its expression in testis to be specific to germ cells. Fractionation of testicular germ cells revealed that mCIA-II transcripts accumulate in pachytene spermatocytes but not in spermatids. In addition, the mCIA-II transcripts in testis were present as early as 4 days after birth and decreased at 56 days after birth. These findings indicate that mCIA-II expression in testis is restricted to premeiotic to meiotic stages during spermatogenesis. Also, we found that hCIA-II interacts with histone H3 in vivo and with histones H3/H4 in vitro and that it facilitates supercoiling of circular DNA when it is incubated with core histones and topoisomerase I in vitro. These data suggest that CIA-II is a histone chaperone and is implicated in the regulation of mammalian spermatogenesis.

  12. FACTORS IMPLICATED IN AMPHIBIAN POPULATION DECLINES IN THE US, AND AN EVALUATION OF THE CASE FOR INVASIVE SPECIES

    EPA Science Inventory

    Factors known or suspected to be adversely affecting native amphibian populations in the US were identified using information from 267 species accounts written in a standardized format by multiple authors in a forthcoming book. Land use was the most frequently implicated adverse ...

  13. Kinetic Model Facilitates Analysis of Fibrin Generation and Its Modulation by Clotting Factors: Implications for Hemostasis-Enhancing Therapies

    DTIC Science & Technology

    2014-01-01

    investigating its potential as a hemostatic agent in trauma and surgery.6,7 These applications necessitate a detailed understanding of fibrin ...facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies† Alexander Y...ability of the suggested molecular mechanisms to account for fibrin generation and degradation kinetics in diverse, physiologically relevant in vitro

  14. A Meta-Analysis of Factors Influencing the Development of Trust in Automation: Implications for Human-Robot Interaction

    DTIC Science & Technology

    2014-07-01

    Consequences and Human Factors Issues. The International Journal of Medical Robotics and Computer Assisted Surgery 2009, 5 (3), 297–308. Marsh, S...Medical Robotics and Computer Assisted Surgery 2009, 5, 297–308. doi:10.1002/rcs.261 *Merritt, S. M.; Heimbaugh, H.; LaChapell, J.; Lee, D. I Trust...A Meta-Analysis of Factors Influencing the Development of Trust in Automation: Implications for Human- Robot Interaction by Kristin E

  15. Rational and Mechanistic Perspectives on Reinforcement Learning

    ERIC Educational Resources Information Center

    Chater, Nick

    2009-01-01

    This special issue describes important recent developments in applying reinforcement learning models to capture neural and cognitive function. But reinforcement learning, as a theoretical framework, can apply at two very different levels of description: "mechanistic" and "rational." Reinforcement learning is often viewed in mechanistic terms--as…

  16. Individual, employment and psychosocial factors influencing walking to work: Implications for intervention design

    PubMed Central

    Esliger, Dale W.; Taylor, Ian M.; Sherar, Lauren B.

    2017-01-01

    Background Promoting walking for the journey to and from work (commuter walking) is a potential strategy for increasing physical activity. Understanding the factors influencing commuter walking is important for identifying target groups and designing effective interventions. This study aimed to examine individual, employment-related and psychosocial factors associated with commuter walking and to discuss the implications for targeting and future design of interventions. Methods 1,544 employees completed a baseline survey as part of the ‘Walking Works’ intervention project (33.4% male; 36.3% aged <30 years). Multivariate logistic regression was used to examine the associations of individual (age, ethnic group, educational qualifications, number of children <16 and car ownership), employment-related (distance lived from work, free car parking at work, working hours, working pattern and occupation) and psychosocial factors (perceived behavioural control, intention, social norms and social support from work colleagues) with commuter walking. Results Almost half of respondents (n = 587, 49%) were classified as commuter walkers. Those who were aged <30 years, did not have a car, had no free car parking at work, were confident of including some walking or intended to walk to or from work on a regular basis, and had support from colleagues for walking were more likely to be commuter walkers. Those who perceived they lived too far away from work to walk, thought walking was less convenient than using a car for commuting, did not have time to walk, needed a car for work or had always travelled the same way were less likely to be commuter walkers. Conclusions A number of individual, employment-related and psychosocial factors were associated with commuter walking. Target groups for interventions to promote walking to and from work may include those in older age groups and those who own or have access to a car. Multi-level interventions targeting individual level behaviour

  17. Mechanistic Indicators of Childhood Asthma (MICA): piloting ...

    EPA Pesticide Factsheets

    Background: Modem methods in molecular biology and advanced computational tools show promise in elucidating complex interactions that occur between genes and environmental factors in diseases such as asthma; however appropriately designed studies are critical for these methods to reach their full potential. Objective: We used a case-control study to investigate whether genomic data (blood gene expression), viewed together with a spectrum of exposure effects and susceptibility markers (blood, urine and nail), can provide a mechanistic explanation for the increased susceptibility of asthmatics to ambient air pollutants. Methods: We studied 205 non-asthmatic and asthmatic children, (9-12 years of age) who participated in a clinical study in Detroit, Michigan. The study combines a traditional epidemiological design with an integrative approach to investigate the environmental exposure of children to indoor-outdoor air. The study includes measurements of internal dose (metals, allergen specific IgE, PAH and VOC metabolites) and clinical measures of health outcome (immunological, cardiovascular and respiratory). Results: Expected immunological indications of asthma have been obtained. In addition, initial results from our analyses point to the complex nature of childhood health and risk factors linked to metabolic syndrome (obesity, blood pressure and dyslipidemia). For example, 31% and 34% of the asthmatic MICA subjects were either overweight (BMI > 25) o

  18. Factors affecting post-stroke motor recovery: Implications on neurotherapy after brain injury.

    PubMed

    Alawieh, Ali; Zhao, Jing; Feng, Wuwei

    2016-08-13

    Neurological disorders are a major cause of chronic disability globally among which stroke is a leading cause of chronic disability. The advances in the medical management of stroke patients over the past decade have significantly reduced mortality, but at the same time increased numbers of disabled survivors. Unfortunately, this reduction in mortality was not paralleled by satisfactory therapeutics and rehabilitation strategies that can improve functional recovery of patients. Motor recovery after brain injury is a complex, dynamic, and multifactorial process in which an interplay among genetic, pathophysiologic, sociodemographic and therapeutic factors determines the overall recovery trajectory. Although stroke recovery is the most well-studied form of post-injury neuronal recovery, a thorough understanding of the pathophysiology and determinants affecting stroke recovery is still lacking. Understanding the different variables affecting brain recovery after stroke will not only provide an opportunity to develop therapeutic interventions but also allow for developing personalized platforms for patient stratification and prognosis. We aim to provide a narrative review of major determinants for post-stroke recovery and their implications in other forms of brain injury.

  19. Cadmium in edible mushrooms from NW Spain: Bioconcentration factors and consumer health implications.

    PubMed

    Melgar, M Julia; Alonso, Julián; García, M Angeles

    2016-02-01

    Mushrooms do not constitute a significant portion of the human diet, but the consumption of wild and cultivated mushrooms has become increasingly in recent years. Some species accumulate high levels of toxic metals, both in unpolluted and polluted areas. In this study, we examined the accumulation capacity of cadmium in edible mushrooms in relation to certain factors and their possible toxicological implications. Cadmium concentrations were determined by an ICP-MS spectrometer in 238 samples of the fruiting bodies of 28 wild and cultivated growing edible mushrooms species and the underlying soil. The hymenophore (H) and the rest of the fruiting body (RFB) were analysed separately. The highest mean cadmium concentration (mg/kg dry weight) was found in Agaricus macrosporus (52.9 in H and 28.3 in RFB). All mushroom species accumulated cadmium in relation to the underlying soils. There were statistically significant differences between the hymenophore and the rest of the fruiting body (p < 0.001). Cadmium concentrations were compared to data in the literature and to levels set by legislation. It was concluded that consumption of our studied mushrooms is not a toxicological risk as far as cadmium content is concerned, although the species A. macrosporus should not be consumed.

  20. The risk factors and prognostic implication of acute pulmonary edema in resuscitated cardiac arrest patients

    PubMed Central

    Kang, Dae-hyun; Kim, Joonghee; Rhee, Joong Eui; Kim, Taeyun; Kim, Kyuseok; Jo, You Hwan; Lee, Jin Hee; Lee, Jae Hyuk; Kim, Yu Jin; Hwang, Seung Sik

    2015-01-01

    Objective Pulmonary edema is frequently observed after a successful resuscitation in out-of-hospital cardiac arrest (OHCA) patients. Currently, its risk factors and prognostic implications are mostly unknown. Methods Adult OHCA patients with a presumed cardiac etiology who achieved sustained return of spontaneous circulation (ROSC) in emergency department were retrospectively analyzed. The patients were grouped according to the severity of consolidation on their initial chest X-ray (group I, no consolidation; group II, patchy consolidations; group III, consolidation involving an entire lobe; group IV, total white-out of any lung). The primary objective was to identify the risk factors of developing severe pulmonary edema (group III or IV). The secondary objective was to evaluate the association between long-term prognosis and the severity of pulmonary edema. Results One hundred and seven patients were included. Total duration of cardiopulmonary resuscitation (CPR) and initial pCO2 level were both independent predictors of developing severe pulmonary edema with their odds ratio (OR) being 1.02 (95% confidence interval [CI], 1.00 to 1.04; per 1 minute) and 1.04 (95% CI, 1.01 to 1.07; per 1 mmHg), respectively. The long term prognosis was significantly poor in patients with severe pulmonary edema with a OR for good outcome (6-month cerebral performance category 1 or 2) being 0.22 (95% CI, 0.06 to 0.79) in group III and 0.16 (95% CI, 0.04 to 0.63) in group IV compared to group I. Conclusion The duration of CPR and initial pCO2 level were both independent predictors for the development of severe pulmonary edema after resuscitation in emergency department. The severity of the pulmonary edema was significantly associated with long-term outcome. PMID:27752581

  1. Negative mechanistic reasoning in medical intervention assessment.

    PubMed

    Jerkert, Jesper

    2015-12-01

    Traditionally, mechanistic reasoning has been assigned a negligible role in standard EBM (evidence-based medicine) literature, although some recent authors have argued for an upgrade. Even so, the mechanistic reasoning that has received attention has almost exclusively been positive--both in an epistemic sense of claiming that there is a mechanistic chain and in a health-related sense of there being claimed benefits for the patient. Negative mechanistic reasoning has been neglected, both in the epistemic and in the health-related sense. I distinguish three main types of negative mechanistic reasoning and subsume them under a new definition of mechanistic reasoning in the context of assessing medical interventions. This definition is wider than a previous suggestion in the literature. Each negative type corresponds to a range of evidential strengths, and it is argued that there are differences with respect to typical evidential strengths. The variety of negative mechanistic reasoning should be acknowledged in EBM, and it presents a serious challenge to proponents of so-called medical hierarchies of evidence.

  2. Induction of proinflammatory cytokines by a soluble factor of Propionibacterium acnes: implications for chronic inflammatory acne.

    PubMed Central

    Vowels, B R; Yang, S; Leyden, J J

    1995-01-01

    Although many cytokines have been implicated in the development and persistence of inflammatory immune responses, it is unknown if any of these are important in inflammatory acne. This study investigated the production of the proinflammatory cytokines interleukin-8 (IL-8), IL-1 beta, and tumor necrosis factor alpha (TNF-alpha) by human monocytic cell lines, ThP-1 and U937, and by freshly isolated peripheral blood mononuclear cells from acne patients. Both Propionibacterium acnes and supernatants obtained from 72-h P. acnes cultures could induce significant concentrations of IL-1 beta, TNF-alpha, and IL-8 by both cell lines and by peripheral blood mononuclear cells as determined by enzyme-linked immunosorbent assay. There was no significant difference between acne and non-acne subjects. Endotoxin quantification and addition of polymyxin B to assays indicated no lipopolysaccharide (LPS) contamination. P. acnes supernatant was fractionated into components with molecular weights of < 3,000, < 10,000, and < 30,000 and assayed for the ability to induce IL-8 and TNF production in ThP-1 cells. Nearly 90% of the original activity was found in the < 30,000-molecular-weight fraction, 50% was in the < 10,000-molecular-weight fraction, and only 15% remained in the < 3,000-molecular-weight fraction. The effluent from the < 3,000-molecular-weight fraction contained about 70% activity, indicating that the inducing factor was not retained in the membrane. Incubation of P. acnes supernatant with various concentrations of mutanolysin or lysozyme resulted in a loss of 60% of the original activity. The addition of jimson lectin, which binds peptidoglycan, resulted in a loss of 70% of the activity in a dose-response manner, whereas peanut lectin had little or no effect on the activity. Heating of the P. acnes supernatant to 65 degrees C also had no effect on the activity. Blocking of CD14, a receptor for both LPS and peptidoglycan, reduced cytokine production by > 50%, suggesting that

  3. Factors affecting computer mouse use for young children: implications for AAC.

    PubMed

    Costigan, F Aileen; Light, Janice C; Newell, Karl M

    2012-06-01

    More than 12% of preschoolers receiving special education services have complex communication needs, including increasing numbers of children who do not have significant motor impairments (e.g., children with autism spectrum disorders, Down syndrome, etc.). In order to meet their diverse communication needs (e.g., face-to-face, written, Internet, telecommunication), these children may use mainstream technologies accessed via the mouse, yet little is known about factors that affect the mouse performance of young children. This study used a mixed factorial design to investigate the effects of age, target size, and angle of approach on accuracy and time required for accurate target selection with a mouse for 20 3-year-old and 20 4-year-old children. The 4-year-olds were generally more accurate and faster than the 3-year-olds. Target size and angle mediated differences in performance within age groups. The 3-year-olds were more accurate and faster in selecting the medium and large targets relative to the small target, were faster in selecting the large relative to the medium target, and were faster in selecting targets along the vertical relative to the diagonal angle. The 4-year-olds were faster in selecting the medium and large targets relative to the small target. Implications for improving access to AAC include the preliminary suggestion of age-related threshold target sizes that support sufficient accuracy, the possibility of efficiency benefits when target size is increased up to an age-related threshold, and identification of the potential utility of the vertical angle as a context for training navigational input device use.

  4. Biomechanical factors associated with shoe/pedal interfaces. Implications for injury.

    PubMed

    Gregor, R J; Wheeler, J B

    1994-02-01

    The principal demand on the body during cycling is on the lower extremities as they are responsible for producing a majority of the energy imparted to the bike. As a result the legs, due to high reactive forces between the foot and pedal, experience high loads on the joints. These loads may adversely affect joint tissues and contribute to overuse injuries, e.g. knee pain. The mechanical link between the leg and the bike is the shoe/pedal interface. This transmission site, by design, can either create smooth transfer of energy or abnormally high repetitive loads which are potentially injurious to the body. Incidence of lower extremity injury in cycling is high, and historically biomechanical analyses of this activity have focused their attention on either the rider or the bike, but not the link between the two. Recently, pedal designs have changed in response to complaints of sore knees with the development of pedals allowing varying degrees of float. This form of transmission is intended to enhance power transfer from rider to bike as well as minimise trauma to the legs by permitting the foot to rotate during the pedalling cycle in a toe-in/heel-out or heel-in/toe-out movement pattern. Recent evidence suggests this type of pedal design does reduce trauma and maintains power output. This article reviews common lower extremity overuse injuries and biomechanical factors during the pedalling cycle with the primary focus on the shoe/pedal interface. We will summarise information available on lower extremity kinematics and kinetics as well as recent data specifically related to shoe/pedal interface kinetics, evaluation of different pedal types-specifically comparison between clipless 'fixed' and clipless 'float' systems-and discuss their resultant effect on lower extremity dynamics and their implications for injury.

  5. Admixture in Mexico City: implications for admixture mapping of type 2 diabetes genetic risk factors.

    PubMed

    Martinez-Marignac, Veronica L; Valladares, Adan; Cameron, Emily; Chan, Andrea; Perera, Arjuna; Globus-Goldberg, Rachel; Wacher, Niels; Kumate, Jesús; McKeigue, Paul; O'Donnell, David; Shriver, Mark D; Cruz, Miguel; Parra, Esteban J

    2007-02-01

    Admixture mapping is a recently developed method for identifying genetic risk factors involved in complex traits or diseases showing prevalence differences between major continental groups. Type 2 diabetes (T2D) is at least twice as prevalent in Native American populations as in populations of European ancestry, so admixture mapping is well suited to study the genetic basis of this complex disease. We have characterized the admixture proportions in a sample of 286 unrelated T2D patients and 275 controls from Mexico City and we discuss the implications of the results for admixture mapping studies. Admixture proportions were estimated using 69 autosomal ancestry-informative markers (AIMs). Maternal and paternal contributions were estimated from geographically informative mtDNA and Y-specific polymorphisms. The average proportions of Native American, European and, West African admixture were estimated as 65, 30, and 5%, respectively. The contributions of Native American ancestors to maternal and paternal lineages were estimated as 90 and 40%, respectively. In a logistic model with higher educational status as dependent variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions was 9.4 (95%, credible interval 3.8-22.6). This association of socioeconomic status with individual admixture proportion shows that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The effective number of generations back to unadmixed ancestors was 6.7 (95% CI 5.7-8.0), from which we can estimate that genome-wide admixture mapping will require typing about 1,400 evenly distributed AIMs to localize genes underlying disease risk between populations of European and Native American ancestry. Sample sizes of about 2,000 cases will be required to detect any locus that contributes an ancestry risk ratio of at least 1.5.

  6. Factors promoting larch dominance in Eastern Siberia: fire versus growth performance and implications for carbon dynamics

    NASA Astrophysics Data System (ADS)

    Schulze, E.-D.; Wirth, C.; Mollicone, D.; von Lüpke, N.; Ziegler, W.; Achard, F.; Mund, M.; Prokushkin, A.; Scherbina, S.

    2012-01-01

    The relative roles of fire and climate in determining canopy species composition and aboveground carbon stocks were investigated. Measurements were made along a transect extending from the dark taiga zone of Central Siberia, where Picea and Abies dominate the canopy, into the Larix zone of Eastern Siberia. We test the hypotheses that the change in canopy species composition is based (1) on climate-driven performance only, (2) on fire only, or (3) on fire-performance interactions. We show that the evergreen conifers Picea obovata and Abies sibirica are the natural late-successional species both in Central and Eastern Siberia, provided there has been no fire for an extended period of time. There are no changes in the climate-driven performance of the observed species. Fire appears to be the main factor explaining the dominance of Larix. Of lesser influence were longitude, hydrology and active-layer thickness. Stand-replacing fires decreased from 300 to 50 yr between the Yenisei Ridge and the upper Tunguska. Repeated non-stand-replacing surface fires eliminated the regeneration of Abies and Picea. With every 100 yr since the last fire, the percentage of Larix decreased by 20 %. Biomass of stems of single trees did not show signs of age-related decline. Relative diameter increment was 0.41 ± 0.20 % at breast height and stem volume increased linearly over time with a rate of about 0.36 t C ha-1 yr-1 independent of age class and species. Stand volumes reached about 130 t C ha-1 (equivalent to about 520 m3 ha-1). Individual trees of Larix were older than 600 yr. The maximum age and biomass seemed to be limited by fungal rot of heart wood. 60 % of old Larix and Picea and 30 % of Pinus sibirica trees were affected by stem rot. Implications for the future role of fire and of plant diseases are discussed.

  7. Targeting N-cadherin through fibroblast growth factor receptor-4: distinct pathogenetic and therapeutic implications.

    PubMed

    Ezzat, Shereen; Zheng, Lei; Winer, Daniel; Asa, Sylvia L

    2006-11-01

    Several molecular aberrations have been implicated in the pathogenesis of pituitary tumors, but few have proven thus far to be of therapeutic value. Pituitary tumor-derived fibroblast growth factor receptor-4 (ptd-FGFR4) is an alternatively transcribed cytoplasmic isoform lacking most of the extracellular domain. This oncogene recapitulates the morphological features of human pituitary tumors in transgenic mice. To investigate the therapeutic potential of targeting ptd-FGFR4, we examined the impact of FGFR4 tyrosine kinase inhibition in xenografted mice. GH4 pituitary cells expressing ptd-FGFR4 develop into invasive tumors. Systemic treatment of mice bearing ptd-FGFR4 tumors with the FGFR-selective inhibitor PD173074 resulted in recovery of membranous N-cadherin staining and a significant reduction in tumor volume with less invasive growth behavior. Mutation of tyrosine Y754F in ptd-FGFR4 abrogated the effect of PD173074-mediated inhibition. The pivotal role of N-cadherin as a mediator of this pituitary cell growth was demonstrated by small interfering RNA mediated down-regulation, which promoted invasive growth in xenografted mice. To validate this model in primary human pituitary tumors, we examined the expression of ptd-FGFR4, N-cadherin, and clinical behavior. Loss of membranous N-cadherin correlated with cytoplasmic FGFR4 expression and with tumor invasiveness in surgically resected human pituitary tumors. Primary human pituitary tumor cells treated with PD173074 showed restoration of N-cadherin to the membrane with dephosphorylation of retinoblastoma protein. These data highlight the pathogenetic significance of N-cadherin misexpression and emphasize the importance of FGFR partnership in mediating its functions.

  8. Clinical implications of APEX1 and Jagged1 as chemoresistance factors in biliary tract cancer

    PubMed Central

    Kim, Hong-Beum; Cho, Won Jin; Choi, Nam Gyu; Kim, Sung-Soo; Park, Jun Hee; Lee, Hee-Jeong

    2017-01-01

    Purpose Biliary cancer is a highly malignant neoplasm with poor prognosis and most patients need to undergo palliative chemotherapy, however major clinical problem associated with the use of chemotherapy is chemoresistance. So far, we aimed at investigating clinical implications of apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) and Jagged1 as chemoresistance factors in biliary tract cancer. Methods We used 5 human biliary tract cancer cell lines (SNU-245, SNU-308, SNU-478, SNU-1079, and SNU-1196), and investigated the chemosensitivity of APEX1 and Jagged1 through 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and Western blot. Alternately, the 10 patients of advanced biliary cancer consist of 2 group according to the chemotherapy response examined by immunohistochemistry using APEX1 and Jagged1 antibody, and protein expression level was scored for staining intensity and percent positive cell. Results The result of MTT assay after APEX1 knockdown showed that strong coexpression of APEX1 and Jagged1 cell line (SNU-245, SNU-1079, and SNU-1196) showed a greater decrease in IC50 of chemotherapeutic agent (5-fluorouracil, gemcitabine and cisplatin). The Western blot analysis of APEX1 and Jagged1 expression in biliary cancer cell lines after APEX1 knockdown definitively demonstrated decreased Jagged1 expression. The APEX1 and Jagged1expression level of immunohistochemistry represented that chemorefractory patients had higher than chemoresponsive patients. Conclusion These results demonstrate that simultaneous high expression of APEX1 and Jagged1 is associated with chemoresistance in biliary cancer and suggest that is a potential therapeutic target for chemoresistance in advanced biliary cancer. PMID:28090501

  9. Assessment of risk factors for oro-facial pain and recent developments in classification: implications for management.

    PubMed

    Svensson, P; Kumar, A

    2016-12-01

    Oro-facial pain research has during the last decades provided important novel insights into the basic underlying mechanisms, the need for standardised diagnostic procedures and classification systems, and multiple treatment options for successful rehabilitation of the patient in pain. Notwithstanding the significant progress in our knowledge spanning from molecules to chair, there may also be limitations in our ability to integrate and interpret the tremendous amount of new data and information, in particular in terms of the clinical implications and overriding conceptual models for oro-facial pain. The aim of the present narrative review is to briefly summarise some of the current thoughts on oro-facial pain mechanisms and recent attempts to identify biomarkers and risk factors leading to the proposal of a new risk assessment diagram for oro-facial pain (RADOP) and a provocative new concept based on stochastic variation between multiple risk factors. Finally, the implications for novel management strategies will briefly be discussed.

  10. Implications of the new Food and Drug Administration draft guidance on human factors engineering for diabetes device manufacturers.

    PubMed

    Wilcox, Stephen B; Drucker, Daniel

    2012-03-01

    This article discusses the implications of the new Food and Drug Administration's draft guidance on human factors and usability engineering for the development of diabetes-related devices. Important considerations include the challenge of identifying users, when the user population is so dramatically broad, and the challenge of identifying use environments when the same can be said for use environments. Another important consideration is that diabetes-related devices, unlike many other medical devices, are used constantly as part of the user's lifestyle--adding complexity to the focus on human factors and ease of use emphasized by the draft guidance.

  11. Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes

    PubMed Central

    Huffman, Jacob; Hoffmann, Christina; Taylor, George T

    2017-01-01

    Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through

  12. [Food addiction: Definition, measurement and limits of the concept, associated factors, therapeutic and clinical implications].

    PubMed

    Cathelain, Sarah; Brunault, Paul; Ballon, Nicolas; Réveillère, Christian; Courtois, Robert

    2016-12-01

    Addictions, which are characterized by the inability to control a behavior despite existence of physical or psychological consequences, have biological, psychological and social determinants. Although the possibility of developing an addiction to some psychoactive substances (e.g. alcohol, tobacco, cannabis) and to gambling (i.e., gambling disorder) is now well demonstrated, the possibility to develop a non-drug addiction (i.e., behavioral addiction) to certain behaviors which provide pleasure (e.g. eating, having sex, buying things) is still in debate. The concept of food addiction, which refers to people who exhibit substance dependence criteria in relation to some high-fat and high-sugar foods, was recently proposed by applying substance dependence DSM criteria to eating behavior. To assess food addiction, the Yale Food Addiction Scale is now the only self-administered questionnaire (diagnosis and estimate of the number of symptoms of food addiction). Prevalence for food addiction is higher in overweight and obese patients, and in patients with certain psychopathological characteristics (i.e., depression, Attention Deficit Hyperactivity Disorder, high impulsivity), in patients who are single and in patients with neurobiological alterations in the reward system. However, it is still unclear whether food addiction is necessary associated with subsequent increase in body weight and/or obesity. An increasing number of studies demonstrated that drug addiction and food addiction shares some similar clinical, neurobiological and psychopathological and sociocultural risk factors. To test the pertinence to include food addiction as an addiction, it would be interesting to conduct future studies in patients who may experience harms related to their food addiction, including not only patients with obesity, but also patients with metabolic syndrome, type 2 diabetes, hypertension, dyslipidemia, atherosclerosis, stroke, or coronary heart disease. Food addiction is a clinical

  13. Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

    PubMed

    Ainsbury, Elizabeth A; Barnard, Stephen; Bright, Scott; Dalke, Claudia; Jarrin, Miguel; Kunze, Sarah; Tanner, Rick; Dynlacht, Joseph R; Quinlan, Roy A; Graw, Jochen; Kadhim, Munira; Hamada, Nobuyuki

    The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection.

  14. Perceptual discrimination in fear generalization: Mechanistic and clinical implications.

    PubMed

    Struyf, Dieter; Zaman, Jonas; Vervliet, Bram; Van Diest, Ilse

    2015-12-01

    For almost a century, Pavlovian conditioning is the imperative experimental paradigm to investigate the development and generalization of fear. However, despite the rich research tradition, the conceptualization of fear generalization has remained somewhat ambiguous. In this selective review, we focus explicitly on some challenges with the current operationalization of fear generalization and their impact on the ability to make inferences on its clinical potential and underlying processes. The main conclusion is that, despite the strong evidence that learning influences perception, current research has largely neglected the role of perceptual discriminability and its plasticity in fear generalization. We propose an alternative operationalization of generalization, where the essence is that Pavlovian conditioning itself influences the breadth of fear generalization via learning-related changes in perceptual discriminability. Hence a conceptualization of fear generalization is incomplete without an in-depth analysis of processes of perceptual discriminability. Furthermore, this highlights perceptual learning and discriminability as important future targets for pre-clinical and clinical research.

  15. PCDD/F TEQ INDICATORS AND THEIR MECHANISTIC IMPLICATIONS

    EPA Science Inventory

    Stack gas samples from two incinerator facilities with different operating conditions were investigated to find polychlorinated dibenzo-p-dioxin/furan (PCDD/F) toxic equivalent quantity (TEQ) indicators from amongst the 210 PCDD/F isomers. Similarities in isomer patterns were als...

  16. From the exposome to mechanistic understanding of chemical ...

    EPA Pesticide Factsheets

    BACKGROUND: Current definitions of the exposome expand beyond the initial idea to consider the totality of exposure and aim to relate to biological effects. While the exposome has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. OBJECTIVES: We explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept - a framework to structure and organize the sequence of toxicological events from an initial molecular interaction of a chemical to an adverse outcome.METHODS: This review was informed by a Workshop organized by the Integrated Project EXPOSOME at the UFZ Helmholtz Centre for Environmental Research in Leipzig, Germany. DISCUSSION: The exposome encompasses all chemicals, including exogenous chemicals and endogenous compounds that are produced in response to external factors. By complementing the exposome research with the AOP concept, we can achieve a better mechanistic understanding, weigh the importance of various components of the exposome, and determine primary risk drivers. The ability to interpret multiple exposures and mixture effects at the mechanistic level requires a more holistic approach facilitated by the exposome concept.CONCLUSION: Incorporating the AOP conc

  17. The Anthropological Implications of Sex Role Differences: Class and Ethnic Factors.

    ERIC Educational Resources Information Center

    Wright, Jerome W.

    The implications of physical and biological sex differences on sex role behavior cannot be understood without analyzing the complementary role of the sociocultural meaning of sex roles. The normative aspect of gender role behavior is fluid and can be affected by culture, class, and ethnicity. All societies recognize differences between the sexes.…

  18. Computer-assisted mechanistic structure-activity studies: application to diverse classes of chemical carcinogens.

    PubMed Central

    Loew, G H; Poulsen, M; Kirkjian, E; Ferrell, J; Sudhindra, B S; Rebagliati, M

    1985-01-01

    In the first part of this paper we have indicated how the techniques and capabilities of theoretical chemistry, together with experimental results, can be used in a mechanistic approach to structure-activity studies of toxicity. In the second part, we have illustrated how this computer-assisted approach has been used to identify and calculate causally related molecular indicators of relative carcinogenic activity in five classes of chemical carcinogens: polycyclic aromatic hydrocarbons and their methyl derivatives, aromatic amines, chloroethanes, chloroalkenes and dialkyl nitrosamines. In each class of chemicals studied, candidate molecular indicators have been identified that could be useful in predictive screening of unknown compounds. In addition, further insights into some mechanistic aspects of chemical carcinogenesis have been obtained. Finally, experiments have been suggested to both verify the usefulness of the indicators and test their mechanistic implications. PMID:3905382

  19. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications

    PubMed Central

    Ciarmela, Pasquapina; Islam, Md. Soriful; Reis, Fernando M.; Gray, Peter C.; Bloise, Enrrico; Petraglia, Felice; Vale, Wylie; Castellucci, Mario

    2011-01-01

    BACKGROUND Growth factors are proteins secreted by a number of cell types that are capable of modulating cellular growth, proliferation and cellular differentiation. It is well accepted that uterine cellular events such as proliferation and differentiation are regulated by sex steroids and their actions in target tissues are mediated by local production of growth factors acting through paracrine and/or autocrine mechanisms. Myometrial mass is ultimately modified in pregnancy as well as in tumour conditions such as leiomyoma and leiomyosarcoma. Leiomyomas, also known as fibroids, are benign tumours of the uterus, considered to be one of the most frequent causes of infertility in reproductive years in women. METHODS For this review, we searched the database MEDLINE and Google Scholar for articles with content related to growth factors acting on myometrium; the findings are hereby reviewed and discussed. RESULTS Different growth factors such as epidermal growth factor (EGF), transforming growth factor-α (TGF-α), heparin-binding EGF (HB-EGF), acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF) and TGF-β perform actions in myometrium and in leiomyomas. In addition to these growth factors, activin and myostatin have been recently identified in myometrium and leiomyoma. CONCLUSIONS Growth factors play an important role in the mechanisms involved in myometrial patho-physiology. PMID:21788281

  20. Mechanistic models in computational social science

    NASA Astrophysics Data System (ADS)

    Holme, Petter; Liljeros, Fredrik

    2015-09-01

    Quantitative social science is not only about regression analysis or, in general, data inference. Computer simulations of social mechanisms have an over 60 years long history. They have been used for many different purposes—to test scenarios, to test the consistency of descriptive theories (proof-of-concept models), to explore emergent phenomena, for forecasting, etc. In this essay, we sketch these historical developments, the role of mechanistic models in the social sciences and the influences from the natural and formal sciences. We argue that mechanistic computational models form a natural common ground for social and natural sciences, and look forward to possible future information flow across the social-natural divide.

  1. Brief Symptom Inventory Factor Structure in Antisocial Adolescents: Implications for Juvenile Justice

    ERIC Educational Resources Information Center

    Whitt, Ahmed; Howard, Matthew O.

    2012-01-01

    Objectives: The Brief Symptom Inventory (BSI) is widely used in juvenile justice settings; however, little is known regarding its factor structure in antisocial youth. The authors evaluated the BSI factor structure in a state residential treatment population. Methods: 707 adolescents completed the BSI. Exploratory and confirmatory factor analyses…

  2. Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression.

    PubMed

    Flanders, Kathleen C; Wakefield, Lalage M

    2009-06-01

    During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.

  3. Applying mechanistic models in bioprocess development.

    PubMed

    Lencastre Fernandes, Rita; Bodla, Vijaya Krishna; Carlquist, Magnus; Heins, Anna-Lena; Eliasson Lantz, Anna; Sin, Gürkan; Gernaey, Krist V

    2013-01-01

    The available knowledge on the mechanisms of a bioprocess system is central to process analytical technology. In this respect, mechanistic modeling has gained renewed attention, since a mechanistic model can provide an excellent summary of available process knowledge. Such a model therefore incorporates process-relevant input (critical process variables)-output (product concentration and product quality attributes) relations. The model therefore has great value in planning experiments, or in determining which critical process variables need to be monitored and controlled tightly. Mechanistic models should be combined with proper model analysis tools, such as uncertainty and sensitivity analysis. When assuming distributed inputs, the resulting uncertainty in the model outputs can be decomposed using sensitivity analysis to determine which input parameters are responsible for the major part of the output uncertainty. Such information can be used as guidance for experimental work; i.e., only parameters with a significant influence on model outputs need to be determined experimentally. The use of mechanistic models and model analysis tools is demonstrated in this chapter. As a practical case study, experimental data from Saccharomyces cerevisiae fermentations are used. The data are described with the well-known model of Sonnleitner and Käppeli (Biotechnol Bioeng 28:927-937, 1986) and the model is analyzed further. The methods used are generic, and can be transferred easily to other, more complex case studies as well.

  4. Reductive photocarboxylation of phenanthrene: A mechanistic investigation

    SciTech Connect

    Nikolaitchik, A.V.; Rodgers, M.A.J.; Neckers, D.C.

    1996-02-09

    Mechanistic aspects of photochemicl reactions between phenathrene and carbon dioxide while in the presence of N,N-dimethylaniline was studied. Five products were produced as characterized by NMR and GC-MS. The authors related changes in product yields to changes in reaction conditions. 31 refs., 6 figs., 3 tabs.

  5. Testing mechanistic models of growth in insects.

    PubMed

    Maino, James L; Kearney, Michael R

    2015-11-22

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes.

  6. Exploring Organic Mechanistic Puzzles with Molecular Modeling

    ERIC Educational Resources Information Center

    Horowitz, Gail; Schwartz, Gary

    2004-01-01

    The molecular modeling was used to reinforce more general skills such as deducing and drawing reaction mechanisms, analyzing reaction kinetics and thermodynamics and drawing reaction coordinate energy diagrams. This modeling was done through the design of mechanistic puzzles, involving reactions not familiar to the students.

  7. Testing mechanistic models of growth in insects

    PubMed Central

    Maino, James L.; Kearney, Michael R.

    2015-01-01

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg−1) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. PMID:26609084

  8. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing.

    PubMed

    Eppley, Barry L; Woodell, Jennifer E; Higgins, Joel

    2004-11-01

    Growth factors released from activated platelets initiate and modulate wound healing in both soft and hard tissues. A recent strategy to promote the wound-healing cascade is to prepare an autologous platelet concentrate suspended in plasma, also known as platelet-rich plasma, that contains growth factors and administer it to wound sites. The purpose of this study was to quantitate platelet number and growth factors released from a prepared platelet concentrate. Whole blood was drawn from 10 healthy patients undergoing cosmetic surgery and concentrated into platelet-rich plasma. Platelet counts on whole blood and platelet-rich plasma were determined using a Cell-Dyn 3200. Platelet-derived growth factor-BB, transforming growth factor-beta1, vascular endothelial growth factor, endothelial growth factor, and insulin-like growth factor-1 were measured in the platelet-rich plasma using the enzyme-linked immunosorbent assay method. In addition, platelet activation during the concentration procedure was analyzed by measuring P selectin values in blood serum. An 8-fold increase in platelet concentration was found in the platelet-rich plasma compared with that of whole blood (baseline whole blood, 197 +/- 42 x 10 platelets/microl; platelet concentrate, 1600 +/- 330 x 10 platelets/microl). The concentration of growth factors also increased with increasing platelet number. However, growth factor concentration varied from patient to patient. On average for the whole blood as compared with platelet-rich plasma, the platelet-derived growth factor-BB concentration increased from 3.3 +/- 0.9 ng/ml to 17 +/- 8 ng/ml, transforming growth factor-beta1 concentration increased from 35 +/- 8 ng/ml to 120 +/- 42 ng/ml, vascular endothelial growth factor concentration increased from 155 +/- 110 pg/ml to 955 +/- 1030 pg/ml, and endothelial growth factor concentration increased from 129 +/- 61 pg/ml to 470 +/- 320 pg/ml. No increase was found for insulin-like growth factor-1. In addition, no

  9. Mechanistic species distribution modelling as a link between physiology and conservation

    PubMed Central

    Evans, Tyler G.; Diamond, Sarah E.; Kelly, Morgan W.

    2015-01-01

    Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and

  10. Mechanistic determinants of MBNL activity

    PubMed Central

    Sznajder, Łukasz J.; Michalak, Michał; Taylor, Katarzyna; Cywoniuk, Piotr; Kabza, Michał; Wojtkowiak-Szlachcic, Agnieszka; Matłoka, Magdalena; Konieczny, Patryk; Sobczak, Krzysztof

    2016-01-01

    Muscleblind-like (MBNL) proteins are critical RNA processing factors in development. MBNL activity is disrupted in the neuromuscular disease myotonic dystrophy type 1 (DM1), due to the instability of a non-coding microsatellite in the DMPK gene and the expression of CUG expansion (CUGexp) RNAs. Pathogenic interactions between MBNL and CUGexp RNA lead to the formation of nuclear complexes termed foci and prevent MBNL function in pre-mRNA processing. The existence of multiple MBNL genes, as well as multiple protein isoforms, raises the question of whether different MBNL proteins possess unique or redundant functions. To address this question, we coexpressed three MBNL paralogs in cells at equivalent levels and characterized both specific and redundant roles of these proteins in alternative splicing and RNA foci dynamics. When coexpressed in the same cells, MBNL1, MBNL2 and MBNL3 bind the same RNA motifs with different affinities. While MBNL1 demonstrated the highest splicing activity, MBNL3 showed the lowest. When forming RNA foci, MBNL1 is the most mobile paralog, while MBNL3 is rather static and the most densely packed on CUGexp RNA. Therefore, our results demonstrate that MBNL paralogs and gene-specific isoforms possess inherent functional differences, an outcome that could be enlisted to improve therapeutic strategies for DM1. PMID:27733504

  11. The T-box transcription factor Tbx2: its role in development and possible implication in cancer.

    PubMed

    Abrahams, Amaal; Parker, M Iqbal; Prince, Sharon

    2010-02-01

    Tbx2 is a member of the T-box family of transcription factors that are crucial in embryonic development. Recent studies suggest that T-box factors may also play a role in controlling cell cycle progression and in the genesis of cancer. Tbx2 has been implicated in several developmental processes such as coordinating cell fate, patterning and morphogenesis of a wide range of tissues and organs including limbs, kidneys, lungs, mammary glands, heart, and craniofacial structures. Importantly, Tbx2 is overexpressed in several cancers including melanoma, small cell lung carcinoma, breast, pancreatic, liver, and bladder cancers and can suppress senescence, a cellular process, which serves as a barrier to cancer development. This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer.

  12. Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration

    PubMed Central

    Marei, Hadir; Carpy, Alejandro; Woroniuk, Anna; Vennin, Claire; White, Gavin; Timpson, Paul; Macek, Boris; Malliri, Angeliki

    2016-01-01

    The small GTPase Rac1 has been implicated in the formation and dissemination of tumours. Upon activation by guanine nucleotide exchange factors (GEFs), Rac1 associates with a variety of proteins in the cell thereby regulating various functions, including cell migration. However, activation of Rac1 can lead to opposing migratory phenotypes raising the possibility of exacerbating tumour progression when targeting Rac1 in a clinical setting. This calls for the identification of factors that influence Rac1-driven cell motility. Here we show that Tiam1 and P-Rex1, two Rac GEFs, promote Rac1 anti- and pro-migratory signalling cascades, respectively, through regulating the Rac1 interactome. In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner. PMID:26887924

  13. Contextual approach to technology assessment: Implications for one-factor fix solutions to complex social problems

    NASA Technical Reports Server (NTRS)

    Mayo, L. H.

    1975-01-01

    The contextual approach is discussed which undertakes to demonstrate that technology assessment assists in the identification of the full range of implications of taking a particular action and facilitates the consideration of alternative means by which the total affected social problem context might be changed by available project options. It is found that the social impacts of an application on participants, institutions, processes, and social interests, and the accompanying interactions may not only induce modifications in the problem contest delineated for examination with respect to the design, operations, regulation, and use of the posited application, but also affect related social problem contexts.

  14. Higher-order factor structures for the WISC-IV: implications for neuropsychological test interpretation.

    PubMed

    Decker, Scott L; Englund, Julia A; Roberts, Alycia M

    2014-01-01

    Factor-analytic studies support a hierarchical four-factor model for the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) with a prominent general, third-order factor. However, there is substantial disagreement on which type of higher-order model best fits the data and how different models should guide test interpretation in clinical practice, with many studies concluding interpretation should primarily be focused on general indicators of intelligence. We performed a series of confirmatory factor analyses with the WISC-IV standardization sample (N = 2,200, ages 6-16 years) to examine model fit and reexamined models used to support test interpretation at the general level. Consistent with previous research, bifactor models were difficult to identify; however, compared with bifactor and hierarchical models, the correlated factors model with no general higher-order factor provided the best fit to the data. Results from this study support the basic four-factor model specified in the WISC-IV technical manual, with test interpretation primarily focused at the factor level, rather than the general level suggested in previous studies.

  15. Wellness Factors as Predictors of Alcohol Use among Undergraduates: Implications for Prevention and Intervention

    ERIC Educational Resources Information Center

    Lewis, Todd F.; Myers, Jane E.

    2010-01-01

    A pilot study examining holistic wellness factors and drinking behaviors among undergraduate students revealed several significant relationships. Two second-order wellness factors of the Indivisible Self model of wellness--Coping Self and Essential Self--were negatively associated with both alcohol use intensity and drinking consequences.…

  16. Analysis of Factors and Implications Influencing Leadership Ascension of Female Athletic Directors in Intercollegiate Athletics

    ERIC Educational Resources Information Center

    Burney, Rolanda C.

    2010-01-01

    This narrative analysis/life story study was designed to understand the factors influencing the career trajectory of female athletic directors in National Collegiate Athletic Association affiliated institutions and to discover how those factors functioned as a road map for future female administrators. Both social role and role congruity theories…

  17. Atrial Fibrillation and Hypertension: Mechanistic, Epidemiologic, and Treatment Parallels.

    PubMed

    Ogunsua, Adedotun A; Shaikh, Amir Y; Ahmed, Mohamed; McManus, David D

    2015-01-01

    Atrial fibrillation (AF) is an increasingly prevalent condition and the most common sustained arrhythmia encountered in ambulatory and hospital practice. Several clinical risk factors for AF include age, sex, valvular heart disease, obesity, sleep apnea, heart failure, and hypertension (HTN). Of all the risk factors, HTN is the most commonly encountered condition in patients with incident AF. Hypertension is associated with a 1.8-fold increase in the risk of developing new-onset AF and a 1.5-fold increase in the risk of progression to permanent AF. Hypertension predisposes to cardiac structural changes that influence the development of AF such as atrial remodeling. The renin angiotensin aldosterone system has been demonstrated to be a common mechanistic link in the pathogenesis of HTN and AF. Importantly, HTN is one of the few modifiable AF risk factors, and guideline-directed management of HTN may reduce the incidence of AF.

  18. Dipole-field sums and Lorentz factors for orthorhombic lattices, and implications for polarizable molecules

    NASA Technical Reports Server (NTRS)

    Purvis, C. K.; Taylor, P. L.

    1982-01-01

    A method for computing the Lorentz tensor components in single crystals via rapidly convergent sums of Bessels functions is developed using the relationship between dipole-field sums and the tensor components. The Lorentz factors for simple, body-centered, and base-centered orthorhombic lattices are computed using this method, and the derivative Lorentz factors for simple orthorhombic lattices are also determined. Both the Lorentz factors and their derivatives are shown to be very sensitive to a lattice structure. The equivalent of the Clausius-Mossotti relation for general orthorhombic lattices is derived using the Lorentz-factor formalism, and the permanent molecular dipole moment is related to crystal polarization for the case of a ferroelectric of polarizable point dipoles. It is concluded that the polarization enhancement due to self-polarization familiar from classical theory may actually be a reduction in consequences of negative Lorentz factors in one or two lattice directions for noncubic crystals.

  19. BioAge: Toward A Multi-Determined, Mechanistic Account of Cognitive Aging

    PubMed Central

    DeCarlo, Correne A.; Tuokko, Holly A.; Williams, Dorothy; Dixon, Roger A.; MacDonald, Stuart W.S.

    2014-01-01

    The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline. PMID:25278166

  20. Human factors/ergonomics implications of big data analytics: Chartered Institute of Ergonomics and Human Factors annual lecture.

    PubMed

    Drury, Colin G

    2015-01-01

    In recent years, advances in sensor technology, connectedness and computational power have come together to produce huge data-sets. The treatment and analysis of these data-sets is known as big data analytics (BDA), and the somewhat related term data mining. Fields allied to human factors/ergonomics (HFE), e.g. statistics, have developed computational methods to derive meaningful, actionable conclusions from these data bases. This paper examines BDA, often characterised by volume, velocity and variety, giving examples of successful BDA use. This examination provides context by considering examples of using BDA on human data, using BDA in HFE studies, and studies of how people perform BDA. Significant issues for HFE are the reliance of BDA on correlation rather than hypotheses and theory, the ethics of BDA and the use of HFE in data visualisation.

  1. Functional Genomic Screen Identifies Klebsiella pneumoniae Factors Implicated in Blocking Nuclear Factor κB (NF-κB) Signaling.

    PubMed

    Tomás, Anna; Lery, Leticia; Regueiro, Verónica; Pérez-Gutiérrez, Camino; Martínez, Verónica; Moranta, David; Llobet, Enrique; González-Nicolau, Mar; Insua, Jose L; Tomas, Juan M; Sansonetti, Philippe J; Tournebize, Régis; Bengoechea, José A

    2015-07-03

    Klebsiella pneumoniae is an etiologic agent of community-acquired and nosocomial pneumonia. It has been shown that K. pneumoniae infections are characterized by reduced early inflammatory response. Recently our group has shown that K. pneumoniae dampens the activation of inflammatory responses by antagonizing the activation of the NF-κB canonical pathway. Our results revealed that K. pneumoniae capsule polysaccharide (CPS) was necessary but not sufficient to attenuate inflammation. To identify additional Klebsiella factors required to dampen inflammation, we standardized and applied a high-throughput gain-of-function screen to examine a Klebsiella transposon mutant library. We identified 114 mutants that triggered the activation of NF-κB. Two gene ontology categories accounted for half of the loci identified in the screening: metabolism and transport genes (32% of the mutants) and envelope-related genes (17%). Characterization of the mutants revealed that the lack of the enterobactin siderophore was linked to a reduced CPS expression, which in turn underlined the NF-κB activation induced by the mutant. The lipopolysaccharide (LPS) O-polysaccharide and the pullulanase (PulA) type 2 secretion system (T2SS) are required for full effectiveness of the immune evasion. Importantly, these factors do not play a redundant role. The fact that LPS O-polysaccharide and T2SS mutant-induced responses were dependent on TLR2-TLR4-MyD88 activation suggested that LPS O-polysaccharide and PulA perturbed Toll-like receptor (TLR)-dependent recognition of K. pneumoniae. Finally, we demonstrate that LPS O-polysaccharide and pulA mutants are attenuated in the pneumonia mouse model. We propose that LPS O-polysaccharide and PulA T2SS could be new targets for the design of new antimicrobials. Increasing TLR-governed defense responses might provide also selective alternatives for the management of K. pneumoniae pneumonia.

  2. Analytic model for academic research productivity having factors, interactions and implications

    PubMed Central

    2011-01-01

    Financial support is dear in academia and will tighten further. How can the research mission be accomplished within new restraints? A model is presented for evaluating source components of academic research productivity. It comprises six factors: funding; investigator quality; efficiency of the research institution; the research mix of novelty, incremental advancement, and confirmatory studies; analytic accuracy; and passion. Their interactions produce output and patterned influences between factors. Strategies for optimizing output are enabled. PMID:22130145

  3. Factors predicting recall of mathematics terms by deaf students: implications for teaching.

    PubMed

    Lang, Harry; Pagliaro, Claudia

    2007-01-01

    In this study of deaf high school students, imagery and familiarity were found to be the best predictors of geometry word recall, whereas neither concreteness nor signability of the terms was a significant predictor variable. Recall of high imagery terms was significantly better than for low imagery terms, and the same result was found for high- over low-familiarity and signability. Concrete terms were recalled significantly better than abstract terms. Geometry terms that could be represented with single signs were recalled significantly better than those that are usually fingerspelled or those represented by compound signs. Teachers with degrees and/or certification in mathematics had significantly higher self-ratings for the strongest predictor variables, imagery (visualization), and familiarity, as compared with those without such formal training. Based on these findings, implications for mathematics instruction, teacher education, and research are provided.

  4. Mechanistic fracture criteria for the failure of human cortical bone

    SciTech Connect

    Nalla, Ravi K.; Kinney, John H.; Ritchie, Robert O.

    2002-12-13

    A mechanistic understanding of fracture in human bone is critical to predicting fracture risk associated with age and disease. Despite extensive work, a mechanistic framework for describing how the underlying microstructure affects the failure mode in bone is lacking.

  5. Plasmonic Purcell factor and coupling efficiency to surface plasmons. Implications for addressing and controlling optical nanosources

    NASA Astrophysics Data System (ADS)

    Colas des Francs, G.; Barthes, J.; Bouhelier, A.; Weeber, J. C.; Dereux, A.; Cuche, A.; Girard, C.

    2016-09-01

    The Purcell factor F p is a key quantity in cavity quantum electrodynamics (cQED) that quantifies the coupling rate between a dipolar emitter and a cavity mode. Its simple form {F}{{p}}\\propto Q/V unravels the possible strategies to enhance and control light-matter interaction. Practically, efficient light-matter interaction is achieved thanks to either (i) high quality factor Q at the basis of cQED or (ii) low modal volume V at the basis of nanophotonics and plasmonics. In the last decade, strong efforts have been done to derive a plasmonic Purcell factor in order to transpose cQED concepts to the nanocale, in a scale-law approach. In this work, we discuss the plasmonic Purcell factor for both delocalized (SPP) and localized (LSP) surface-plasmon-polaritons and briefly summarize the expected applications for nanophotonics. On the basis of the SPP resonance shape (Lorentzian or Fano profile), we derive closed form expression for the coupling rate to delocalized plasmons. The quality factor factor and modal confinement of both SPP and LSP are quantified, demonstrating their strongly subwavelength behavior.

  6. Hepatic leukemia factor promotes resistance to cell death: Implications for therapeutics and chronotherapy

    SciTech Connect

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation. - Highlights: ► Circadian-dependent physiological variation impacts therapeutic efficacy. ► Hepatic leukemia factor inhibits cell death and is a candidate circadian factor. ► Hepatic leukemia factor anti-death program is conserved in murine and human cells. ► Transcriptomics indicates the anti-death program results from a systems response.

  7. Development and Predictive Effects of Eating Disorder Risk Factors during Adolescence: Implications for Prevention Efforts

    PubMed Central

    Rohde, Paul; Stice, Eric; Marti, C. Nathan

    2014-01-01

    Objective Although several prospective studies have identified factors that increase risk for eating disorders, little is known about when these risk factors emerge and escalate, or when they begin to predict future eating disorder onset. The objective of this report was to address these key research gaps. Method Data were examined from a prospective study of 496 community female adolescents (M = 13.5, SD = 0.7 at baseline) who completed eight annual assessments of potential risk factors and eating disorders from preadolescence to young adulthood. Results Three variables exhibited positive linear increases: Perceived pressure to be thin, thin-ideal internalization and body dissatisfaction; three were best characterized as quadratic effects: dieting (essentially little change); negative affectivity (overall decrease), and BMI (overall increase). Elevated body dissatisfaction at ages 13, 14, 15, and 16 predicted DSM-5 eating disorders onset in the 4 year period after each assessment, but the predictive effects of other risk factors were largely confined to age 14; BMI did not predict eating disorders at any age. Discussion The results imply that these risk factors are present by early adolescence, though eating disorders tend to emerge in late adolescence and early adulthood. These findings emphasize the need for efficacious eating disorder prevention programs for early adolescent girls, perhaps targeting 14 year olds, when risk factors appear to be most predictive. In early adolescence, it might be fruitful to target girls with body dissatisfaction, as this was the most consistent predictor of early eating disorder onset in this study. PMID:24599841

  8. Memory factors in Rey AVLT: Implications for early staging of cognitive decline.

    PubMed

    Fernaeus, Sven-Erik; Ostberg, Per; Wahlund, Lars-Olof; Hellström, Ake

    2014-12-01

    Supraspan verbal list learning is widely used to assess dementia and related cognitive disorders where declarative memory deficits are a major clinical sign. While the overall learning rate is important for diagnosis, serial position patterns may give insight into more specific memory processes in patients with cognitive impairment. This study explored these patterns in a memory clinic clientele. One hundred eighty three participants took the Rey Auditory-Verbal Learning Test (RAVLT). The major groups were patients with Alzheimer's disease (AD), Vascular Dementia (VD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Impairment (SCI) as well as healthy controls (HC). Raw scores for the five trials and five serial partitions were factor analysed. Three memory factors were found and interpreted as Primacy, Recency, and Resistance to Interference. AD and MCI patients had impaired scores in all factors. SCI patients were significantly impaired in the Resistance to Interference factor, and in the Recency factor at the first trial. The main conclusion is that serial position data from word list testing reflect specific memory capacities which vary with levels of cognitive impairment.

  9. Triggering neurotrophic factor actions through adenosine A2A receptor activation: implications for neuroprotection

    PubMed Central

    Sebastião, Ana M; Ribeiro, Joaquim A

    2009-01-01

    G protein coupled receptors and tropomyosin-related kinase (Trk) receptors have distinct structure and transducing mechanisms; therefore, cross-talk among them was unexpected. Evidence has, however, accumulated showing that tonic adenosine A2A receptor activity is a required step to allow synaptic actions of neurotrophic factors, namely upon synaptic transmission at both pre- and post-synaptic level as well as upon synaptic plasticity. An enhancement of A2A receptor tonus upon ageing may partially compensate the loss of TrkB receptors, rescuing to certain degree the facilitatory action of brain derived neurotrophic factor in aged animals, which might prove particularly relevant in the prevention of neurodegeneration upon ageing. A2A receptors also trigger synaptic actions of other neurotrophic factors, such as glial derived neurotrophic factor at dopaminergic striatal nerve endings. The growing evidence that tonic adenosine A2A receptor activity is a crucial step to allow actions of neurotrophic factors in neurones will be reviewed and discussed in the light of therapeutic strategies for neurodegenerative diseases. PMID:19508402

  10. Toward mechanistic classification of enzyme functions.

    PubMed

    Almonacid, Daniel E; Babbitt, Patricia C

    2011-06-01

    Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-grained functional descriptions than provided by the Enzyme Commission (EC) system currently in use. Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic similarities. Together, these provide a foundation for new classifications of enzyme function.

  11. Epigenetics and the environment: emerging patterns and implications.

    PubMed

    Feil, Robert; Fraga, Mario F

    2012-01-04

    Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.

  12. Interactions of host APOBEC3 restriction factors with HIV-1 in vivo: implications for therapeutics.

    PubMed

    Albin, John S; Harris, Reuben S

    2010-01-22

    Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarise, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins, and survey strategies and progress towards developing therapeutics aimed at the APOBEC3-Vif axis.

  13. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease.

    PubMed

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.

  14. Hepatic Leukemia Factor Promotes Resistance To Cell Death: Implications For Therapeutics and Chronotherapy

    SciTech Connect

    Waters, Katrina M.; Sontag, Ryan L.; Weber, Thomas J.

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation.

  15. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease

    PubMed Central

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V.

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease. PMID:27015693

  16. Hepatic leukemia factor promotes resistance to cell death: implications for therapeutics and chronotherapy.

    PubMed

    Waters, Katrina M; Sontag, Ryan L; Weber, Thomas J

    2013-04-15

    Physiological variation related to circadian rhythms and aberrant gene expression patterns are believed to modulate therapeutic efficacy, but the precise molecular determinants remain unclear. Here we examine the regulation of cell death by hepatic leukemia factor (HLF), which is an output regulator of circadian rhythms and is aberrantly expressed in human cancers, using an ectopic expression strategy in JB6 mouse epidermal cells and human keratinocytes. Ectopic HLF expression inhibited cell death in both JB6 cells and human keratinocytes, as induced by serum-starvation, tumor necrosis factor alpha and ionizing radiation. Microarray analysis indicates that HLF regulates a complex multi-gene transcriptional program encompassing upregulation of anti-apoptotic genes, downregulation of pro-apoptotic genes, and many additional changes that are consistent with an anti-death program. Collectively, our results demonstrate that ectopic expression of HLF, an established transcription factor that cycles with circadian rhythms, can recapitulate many features associated with circadian-dependent physiological variation.

  17. New mechanistic interpretations for nitrone reactivity.

    PubMed

    Merino, Pedro; Tejero, Tomás; Delso, Ignacio; Matute, Rosa

    2017-03-22

    The reactivity of nitrones in cycloadditions and related reactions is revisited by introducing a topological perspective. In particular, the study of electron localization function (ELF) along a reaction pathway allows evaluating bond reorganization showing that in several cases the bonds are formed in a sequential way, the second one being formed once the first one is already formed. Both classical 1,3-dipolar cycloadditions and Mannich-type reactions revealed unexpected features often underestimated in classical mechanistic studies.

  18. Factors that influence physical activity for pregnant and postpartum women and implications for primary care.

    PubMed

    Doran, Frances; Davis, Kierrynn

    2011-01-01

    Many pregnant women and women of child-bearing age do not engage in the recommended levels of physical activity despite the well known benefits. Pregnancy and the postpartum period can be a time when inactivity actually increases. Women who experience gestational diabetes mellitus (GDM) during their pregnancy are often advised to become more active in order to ameliorate their increased risk of developing type 2 diabetes. Health professionals have an influential role in promoting physical activity, which would be enhanced with an understanding of the factors that positively and negatively influence women's participation in physical activity during pregnancy and in the postpartum period. This research sought to explore these factors with pregnant and postpartum women including those who had experienced GDM and the attention given to physical activity during pregnancy. A survey was developed after a critical review of factors identified from previous studies. Women were recruited from the antenatal clinic, community health centres and the local media. Results from 72 women are reported from a predominately well educated, Caucasian population. Overall, the results were confirmatory of factors previously identified. Lack of child care, time constraints, no time and feeling unwell during pregnancy hindered activity and factors that facilitated activity included family support, enjoyment of activity and to prevent later health problems. It was also found that non-GDM women are given minimal advice about exercise during pregnancy. A checklist has been developed for health professionals, in partnership with women, to direct attention to the factors that enable and hinder participation in physical activity during and after pregnancy.

  19. Individual and Contextual Factors for Bullying and Peer Victimization: Implications for Prevention

    ERIC Educational Resources Information Center

    Vivolo, Alana M.; Holt, Melissa K.; Massetti, Greta M.

    2011-01-01

    The Division of Violence Prevention (DVP) at the Centers for Disease Control and Prevention (CDC) is committed to preventing youth violence. For the past decade, DVP has supported research on risk and protective factors associated with youth interpersonal violence and the development and evaluation of prevention programs. This commentary addresses…

  20. The Common Factors Model: Implications for Transtheoretical Clinical Social Work Practice

    ERIC Educational Resources Information Center

    Cameron, Mark; Keenan, Elizabeth King

    2010-01-01

    Direct practice social workers today are challenged to address the requirements of the complex array of professional, organizational, institutional, and regulatory demands placed on them in the broader socioeconomic context of fewer resources and diminished public support for social welfare services in the United States. The common factors model…

  1. Rhodopseudomonas palustris CGA010 Proteome Implicates Extracytoplasmic Function Sigma Factor in Stress Response

    DOE PAGES

    Allen, Michael S.; Hurst, Gregory B.; Lu, Tse-Yuan S.; ...

    2015-04-08

    Rhodopseudomonas palustris encodes 16 extracytoplasmic function (ECF) σ factors. In this paper, to begin to investigate the regulatory network of one of these ECF σ factors, the whole proteome of R. palustris CGA010 was quantitatively analyzed by tandem mass spectrometry from cultures episomally expressing the ECF σRPA4225 (ecfT) versus a WT control. Among the proteins with the greatest increase in abundance were catalase KatE, trehalose synthase, a DPS-like protein, and several regulatory proteins. Alignment of the cognate promoter regions driving expression of several upregulated proteins suggested a conserved binding motif in the -35 and -10 regions with the consensus sequencemore » GGAAC-18N-TT. Additionally, the putative anti-σ factor RPA4224, whose gene is contained in the same predicted operon as RPA4225, was identified as interacting directly with the predicted response regulator RPA4223 by mass spectrometry of affinity-isolated protein complexes. Furthermore, another gene (RPA4226) coding for a protein that contains a cytoplasmic histidine kinase domain is located immediately upstream of RPA4225. The genomic organization of orthologs for these four genes is conserved in several other strains of R. palustris as well as in closely related α-Proteobacteria. Finally, taken together, these data suggest that ECF σRPA4225 and the three additional genes make up a sigma factor mimicry system in R. palustris.« less

  2. Rhodopseudomonas palustris CGA010 Proteome Implicates Extracytoplasmic Function Sigma Factor in Stress Response

    SciTech Connect

    Allen, Michael S.; Hurst, Gregory B.; Lu, Tse-Yuan S.; Perry, Leslie M.; Pan, Chongle; Lankford, Patricia K.; Pelletier, Dale A.

    2015-04-08

    Rhodopseudomonas palustris encodes 16 extracytoplasmic function (ECF) σ factors. In this paper, to begin to investigate the regulatory network of one of these ECF σ factors, the whole proteome of R. palustris CGA010 was quantitatively analyzed by tandem mass spectrometry from cultures episomally expressing the ECF σRPA4225 (ecfT) versus a WT control. Among the proteins with the greatest increase in abundance were catalase KatE, trehalose synthase, a DPS-like protein, and several regulatory proteins. Alignment of the cognate promoter regions driving expression of several upregulated proteins suggested a conserved binding motif in the -35 and -10 regions with the consensus sequence GGAAC-18N-TT. Additionally, the putative anti-σ factor RPA4224, whose gene is contained in the same predicted operon as RPA4225, was identified as interacting directly with the predicted response regulator RPA4223 by mass spectrometry of affinity-isolated protein complexes. Furthermore, another gene (RPA4226) coding for a protein that contains a cytoplasmic histidine kinase domain is located immediately upstream of RPA4225. The genomic organization of orthologs for these four genes is conserved in several other strains of R. palustris as well as in closely related α-Proteobacteria. Finally, taken together, these data suggest that ECF σRPA4225 and the three additional genes make up a sigma factor mimicry system in R. palustris.

  3. Adolescent Girls' Perceptions of Smoking Risk and Protective Factors: Implications for Message Design

    ERIC Educational Resources Information Center

    Curbow, Barbara; Bowie, Janice; Binko, JoAnn; Smith, Stephanie; Dreyling, Erin; McDonnell, Karen A.

    2007-01-01

    Using a snowball technique, in-depth interviews were conducted with 108 girls emanating from seven demographically dissimilar social networks. Girls were asked to classify 58 items as either a risk or protective factor for smoking initiation and then to assign an importance weighting to each. All items except one (worries about her weight) were…

  4. Factors of Peak Performance in the Death Crisis: Implications for Death Counseling and Education.

    ERIC Educational Resources Information Center

    Privette, Gayle

    Peak performance in the death crisis as a critical incident of creative response to the awareness of one's own or another person's death is the concern of this report. The topology of peak performance in the death crisis was examined in an investigation of retrospective self-reports of 20 adult respondents and a factor structure of peak…

  5. Factor Structure of the Restricted Academic Situation Scale: Implications for ADHD

    ERIC Educational Resources Information Center

    Karama, Sherif; Amor, Leila Ben; Grizenko, Natalie; Ciampi, Antonio; Mbekou, Valentin; Ter-Stepanian, Marina; Lageix, Philippe; Baron, Chantal; Schwartz, George; Joober, Ridha

    2009-01-01

    Background: To study the factor structure of the Restricted Academic Situation Scale (RASS), a psychometric tool used to assess behavior in children with ADHD, 117 boys and 21 girls meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed.; "DSM-IV") criteria for ADHD and aged between 6 and 12 years were recruited. Assessments were…

  6. Factors Affecting Faculty Use of Learning Technologies: Implications for Models of Technology Adoption

    ERIC Educational Resources Information Center

    Buchanan, Tom; Sainter, Phillip; Saunders, Gunter

    2013-01-01

    This study examines factors associated with the use of learning technologies by higher education faculty. In an online survey in a UK university, 114 faculty respondents completed a measure of Internet self-efficacy, and reported on their use of learning technologies along with barriers to their adoption. Principal components analysis suggested…

  7. A Synthesis of Studies Searching for School Factors: Implications for Theory and Research

    ERIC Educational Resources Information Center

    Kyriakides, Leonidas; Creemers, Bert; Antoniou, Panayiotis; Demetriou, Demetris

    2010-01-01

    This paper reports the results of a meta-analysis in which the dynamic model of educational effectiveness is used as a framework to search for school factors associated with student achievement. The methods and results of a synthesis of 67 studies are presented. Findings reveal that effective schools are able to develop policies and take actions…

  8. Nuclearly encoded splicing factors implicated in RNA splicing in higher plant organelles.

    PubMed

    de Longevialle, Andéol Falcon; Small, Ian D; Lurin, Claire

    2010-07-01

    Plant organelles arose from two independent endosymbiosis events. Throughout evolutionary history, tight control of chloroplasts and mitochondria has been gained by the nucleus, which regulates most steps of organelle genome expression and metabolism. In particular, RNA maturation, including RNA splicing, is highly dependent on nuclearly encoded splicing factors. Most introns in organelles are group II introns, whose catalytic mechanism closely resembles that of the nuclear spliceosome. Plant group II introns have lost the ability to self-splice in vivo and require nuclearly encoded proteins as cofactors. Since the first splicing factor was identified in chloroplasts more than 10 years ago, many other proteins have been shown to be involved in splicing of one or more introns in chloroplasts or mitochondria. These new proteins belong to a variety of different families of RNA binding proteins and provide new insights into ribonucleo-protein complexes and RNA splicing machineries in organelles. In this review, we describe how splicing factors, encoded by the nucleus and targeted to the organelles, take part in post-transcriptional steps in higher plant organelle gene expression. We go on to discuss the potential for these factors to regulate organelle gene expression.

  9. Contextual Factors Affecting Learning in Laos and the Implications for Information Literacy Education

    ERIC Educational Resources Information Center

    Dorner, Daniel G.; Gorman, G. E.

    2011-01-01

    Introduction: Laos is used as a case study of how factors such as culture and indigenous knowledge must be considered to plan for information literacy education that is culturally and contextually appropriate. Method: Data were obtained from observations during visits to four Lao schools and from interviews with fourteen teachers at these schools.…

  10. Autonomic nervous system factors underlying disinhibited, antisocial, and violent behavior. Biosocial perspectives and treatment implications.

    PubMed

    Raine, A

    1996-09-20

    This paper reviews the autonomic psychophysiological correlates of antisocial and aggressive behavior in children and adolescents, outlines a biosocial perspective, and draws implications for treatment and prevention. Findings of studies on resting skin conductance and heart rate indicate that antisocial individuals are characterized by underarousal; these findings suggest that aggressive children may be stimulation seekers who are relatively fearless. Autonomic underarousal also typifies infants and young children with a disinhibited temperament that is thought to be a predisposition to juvenile delinquency and adult aggressive behavior. Deficits in the orienting response, a measure of attention allocation, also predisposes to later antisocial and criminal behavior. Initial studies have shown that particularly high levels of orienting, arousal, and conditionability may protect against crime development in those predisposed to such an outcome. From a biosocial standpoint, it is hypothesized that the psychophysiological correlates of antisocial and violent behavior may be greatest in those from more benign home backgrounds where the psychosocial push forward is relatively weaker. Alternatively, early environmental stress may underlie autonomic underarousal and hyporeactivity in antisocial individuals. Finally, it is possible that biofeedback, in combination with a multimodal treatment program, may be one benign intervention technique that may increase arousal and reduce aggression in underaroused antisocial children.

  11. Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions?

    PubMed Central

    Aloui, Chaker; Sut, Caroline; Prigent, Antoine; Fagan, Jocelyne; Cognasse, Fabrice; Granados-Herbepin, Viviana; Touraine, Renaud; Pozzetto, Bruno; Aouni, Mahjoub; Fendri, Chedlia; Hassine, Mohsen; Chakroun, Tahar; Jemni-Yacoub, Saloua; Garraud, Olivier; Laradi, Sandrine

    2014-01-01

    The CD40 ligand (CD40L/CD154), a member of TNF superfamily, is notably expressed on activated CD4+ T-cells and stimulated platelets. CD40L is linked to a variety of pathologies and to acute transfusion reactions (ATR). Mutations in this gene (CD40LG) lead to X-linked hyper-IgM syndrome. Some CD40LG polymorphisms are associated with variable protein expression. The rationale behind this study is that CD40L protein has been observed to be involved in ATR. We wondered whether genetic polymorphisms are implicated. We investigated genetic diversity in the CD40LG using DHPLC and capillary electrophoresis for screening and genotyping (n = 485 French and Tunisian blood donors). We identified significant difference in the CD40LG linkage pattern between the two populations. Variant minor alleles were significantly over-represented in Tunisian donors (P<0.0001 to 0.0270). We found higher heterogeneity in the Tunisian, including three novel low frequency variants. As there was not a particular pattern of CD40LG in single apheresis donors whose platelet components induced an ATR, we discuss how this information may be useful for future disease association studies on CD40LG. PMID:25430087

  12. Exercise and brain health--implications for multiple sclerosis: Part 1--neuronal growth factors.

    PubMed

    White, Lesley J; Castellano, Vanessa

    2008-01-01

    The benefits of regular exercise to promote general health and reduce the risk of hypokinetic diseases associated with sedentary lifestyles are well recognized. Recent studies suggest that exercise may enhance neurobiological processes that promote brain health in aging and disease. A current frontier in the neurodegenerative disorder multiple sclerosis (MS) concerns the role of physical activity for promoting brain health through protective, regenerative and adaptive neural processes. Research on neuromodulation, raises the possibility that regular physical activity may mediate favourable changes in disease factors and symptoms associated with MS, in part through changes in neuroactive proteins. Insulin-like growth factor-I appears to act as a neuroprotective agent and studies indicate that exercise could promote this factor in MS. Neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor likely play roles in neuronal survival and activity-dependent plasticity. Physical activity has also been shown to up-regulate hippocampal BDNF, which may play a role in mood states, learning and memory to lessen the decline in cognitive function associated with MS. In addition, exercise may promote anti-oxidant defences and neurotrophic support that could attenuate CNS vulnerability to neuronal degeneration. Exercise exposure (preconditioning) may serve as a mechanism to enhance stress resistance and thereby may support neuronal survival under heightened stress conditions. Considering that axonal loss and cerebral atrophy occur early in the disease, exercise prescription in the acute stage could promote neuroprotection, neuroregeneration and neuroplasticity and reduce long-term disability. This review concludes with a proposed conceptual model to connect these promising links between exercise and brain health.

  13. Implications of the Fukushima Nuclear Disaster: Man-Made Hazards, Vulnerability Factors, and Risk to Environmental Health.

    PubMed

    Eddy, Christopher; Sase, Eriko

    2015-01-01

    The objective of this article was to examine the environmental health implications of the 2011 Fukushima nuclear disaster from an all-hazards perspective. The authors performed a literature review that included Japanese and international nuclear guidance and policy, scientific papers, and reports on the Chernobyl and Three Mile Island disasters while also considering all-hazards preparedness rubrics in the U.S. The examination of the literature resulted in the following: a) the authors' "All-Hazards Planning Reference Model" that distinguishes three planning categories-Disaster Trigger Event, Man-Made Hazards, and Vulnerability Factors; b) the generalization of their model to other countries; and c) advocacy for environmental health end fate to be considered in planning phases to minimize risk to environmental health. This article discusses inconsistencies in disaster planning and nomenclature existing in the studied materials and international guidance and proposes new opportunity for developing predisaster risk assessment, risk communication, and prevention capacity building.

  14. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brain-related diseases

    PubMed Central

    Adachi, Naoki; Numakawa, Tadahiro; Richards, Misty; Nakajima, Shingo; Kunugi, Hiroshi

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia. PMID:25426265

  15. Transforming Growth Factor-Beta and Urokinase-Type Plasminogen Activator: Dangerous Partners in Tumorigenesis—Implications in Skin Cancer

    PubMed Central

    Santibanez, Juan F.

    2013-01-01

    Transforming growth factor-beta (TGF-β) is a pleiotropic factor, with several different roles in health and disease. TGF-β has been postulated as a dual factor in tumor progression, since it represses epithelial tumor development in early stages, whereas it stimulates tumor progression in advanced stages. During tumorigenesis, cancer cells acquire the capacity to migrate and invade surrounding tissues and to metastasize different organs. The urokinase-type plasminogen activator (uPA) system, comprising uPA, the uPA cell surface receptor, and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and regulates key cellular events by activating intracellular signal pathways, which together allow cancer cells to survive, thus, enhancing cell malignance during tumor progression. Due to their importance, uPA and its receptor are tightly transcriptionally regulated in normal development, but are deregulated in cancer, when their activity and expression are related to further development of cancer. TGF-β regulates uPA expression in cancer cells, while uPA, by plasminogen activation, may activate the secreted latent TGF-β, thus, producing a pernicious cycle which contributes to the enhancement of tumor progression. Here we review the specific roles and the interplay between TGF-β and uPA system in cancer cells and their implication in skin cancer. PMID:23984088

  16. Targeting hypoxia-inducible factor-1 (HIF-1) signaling in therapeutics: implications for the treatment of inflammatory bowel disease.

    PubMed

    Hirota, Simon A; Beck, Paul L; MacDonald, Justin A

    2009-01-01

    In response to hypoxia, adaptive hypoxia-inducible factor-1 (HIF-1) signaling events are activated to increase oxygen transport, anaerobic energy production and protective pathways to minimize ischemic tissue damage. Although the activation and subsequent induction of gene transcription by HIF-1 is normally associated with hypoxia, it is now established that HIF-1 signaling can be triggered under inflammatory conditions. HIF-1 has been implicated in a number of inflammatory diseases including rheumatoid arthritis, allergic asthma, psoriasis and inflammatory bowel disease (IBD). In the gastrointestinal tract, HIF-1-regulated gene products, such as vascular endothelial growth factor, intestinal trefoil factor and CD73, have been shown to provide protection in animal models of intestinal inflammation. Given the importance of HIF-1 signaling in the aforementioned diseases, there exists considerable interest in the development of methods to modulate HIF-1 expression as well as down-stream signaling events. This review examines HIF-1 signaling with a special focus on the gastrointestinal tract. The patents pertaining to the modulation of HIF-1 signaling are summarized, and their relevance to the treatment of inflammatory bowel disease is discussed.

  17. Jacquelines of all trades or masters of some? Negative implications of focusing on common factors.

    PubMed

    Smith, Douglas C

    2012-07-01

    The emphasis on common factors initially grew out of increasingly frustrating findings from randomized clinical trials that head-to-head comparison of different treatments rarely found one to be superior (Luborsky et al., 2002; Luborsky, Singer, & Luborsky, 1975). In this regard, Cameron and Keenan (2010) have done well calling attention to a fundamental problem we deal with in researching, practicing, and teaching. As an instructor, it is difficult to teach practice- minded MSW students about empirically supported treatments when, with few exceptions, most theoretically distinct treatments that have been contrasted are not so different in terms of outcomes. This beckons us to teach students to think critically and understand the limits of current research on empirically supported treatments. However, I have argued here that there are benefits to teaching students about specific ESTs. It is plausible that providing extensive training in specific ESTs could be a platform for teaching about common factors, rather than focusing on developing generalist skills and later learning specific techniques that are needed in certain practice areas. Doing so gives students some useful techniques, which are associated with clinical improvement and can be adapted to other practice settings. It is unclear if the same can be said for teaching a common factors approach, which is already the dominant training model in social work. Of course, empirical research is needed to determine whether varying degrees of training emphasis on common factors or specific ESTs affect clinical skill development or adoption of ESTs. With regard to the issue of common factors in clinical research, health services researchers are already being encouraged to propose novel techniques for how we might affect common factors. Although it is clear that such mechanisms are not always unique to particular treatments, such research is typically being done incrementally by studying in-session processes operating

  18. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression.

    PubMed

    Masi, Gabriele; Brovedani, Paola

    2011-11-01

    Depression is a prevalent, highly debilitating mental disorder affecting up to 15% of the population at least once in their lifetime, with huge costs for society. Neurobiological mechanisms of depression are still not well known, although there is consensus about interplay between genetic and environmental factors. Antidepressant medications are frequently used in depression, but at least 50% of patients are poor responders, even to more recently discovered medications. Furthermore, clinical response only occurs following weeks to months of treatment and only chronic treatment is effective, suggesting that actions beyond the rapidly occurring effect of enhancing monoaminergic systems, such as adaptation of these systems, are responsible for the effects of antidepressants. Recent studies indicate that an impairment of synaptic plasticity (neurogenesis, axon branching, dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors, namely brain-derived neurotrophic factor (BDNF), which play a central role in plasticity. As BDNF is repressed by stress, epigenetic regulation of the BDNF gene may play an important role in depression. The hippocampus is smaller in depressed patients, although it is unclear whether smaller size is a consequence of depression or a pre-existing, vulnerability marker for depression. Environmental stressors triggering activation of the hypothalamic-pituitary-adrenal axis cause the brain to be exposed to corticosteroids, affecting neurobehavioural functions with a strong downregulation of hippocampal neurogenesis, and are a major risk factor for depression. Antidepressant treatment increases BDNF levels, stimulates neurogenesis and reverses the inhibitory effects of stress, but this effect is evident only after 3-4 weeks of administration, the time course

  19. Host immunity to Bacillus anthracis lethal factor and other immunogens: implications for vaccine design.

    PubMed

    Altmann, Daniel M

    2015-03-01

    Infections of humans with Bacillus anthracis are an issue with respect to the biothreat both to civilians and military personnel, infections of individuals by infected livestock in endemic regions and, recently, infections of intravenous drug users injecting anthrax-contaminated heroin. Existing vaccination regimens are reliant on protective antigen neutralization induced by repeated boosts with the AVA or AVP vaccines. However, there is ongoing interest in updated approaches in light of the intensive booster regime and extent of reactogenicity inherent in the current protocols. Several other immunogens from the B. anthracis proteome have been characterized in recent years, including lethal factor. Lethal factor induces strong CD4 T-cell immunity and encompasses immunodominant epitopes of relevance across diverse HLA polymorphisms. Taken together, recent studies emphasize the potential benefits of vaccines able to confer synergistic immunity to protective antigen and to other immunogens, targeting both B-cell and T-cell repertoires.

  20. Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment.

    PubMed

    Castrén, Eero; Rantamäki, Tomi

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a critical mediator of activity-dependent neuronal plasticity in the cerebral cortex. Deficits in neurotrophic factors have been proposed to underlie mood disorders. However, recent evidence suggests that mood disorders may be produced by abnormalities in the adaptation of neural networks to environmental conditions. Antidepressants may act by enhancing neuronal plasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. Recent observations in the visual cortex directly support this idea. According to the network hypothesis of depression, changes in the levels of neurotrophins including BDNF may not directly produce depression or an antidepressant effect, but neurotrophins may act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment. This hypothesis suggests that antidepressant drugs should not be used alone but should always be combined with rehabilitation to guide the plastic networks within the brain.

  1. The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications

    PubMed Central

    Zimmermann, Michel; Zouhair, Abderrahim; Azria, David; Ozsahin, Mahmut

    2006-01-01

    Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptors. Its stimulation by endogenous ligands, EGF or transforming growth factor-alpha (TGF-α) results in activation of intracellular tyrosine kinase, therefore, cell cycle progression. High levels of EGFR expression are correlated with poor prognosis and resistance to radiation therapy in a variety of cancers, mostly in squamous-cell carcinoma of the head and neck (SCCHN). Blocking the EGFR by a monoclonal antibody results in inhibition of the stimulation of the receptor, therefore, in inhibition of cell proliferation, enhanced apoptosis, and reduced angiogenesis, invasiveness and metastases. The EGFR is a prime target for new anticancer therapy in SCCHN, and other agents in development include small molecular tyrosine kinase inhibitors and antisense therapies. PMID:16722544

  2. Sleep disturbances in caregivers of persons with dementia: Contributing factors and treatment implications

    PubMed Central

    McCurry, Susan M.; Logsdon, Rebecca G.; Teri, Linda; Vitiello, Michael V.

    2007-01-01

    Estimates suggest that there are more than 10 million adult caregivers of persons with dementia, two-thirds of who experience some form of sleep disturbance during the course of their caregiving career. Health care professionals are in the best position to detect and address this significant public health problem. Three major contributors to caregiver sleep disturbance are discussed in this paper: 1) the presence of caregiver disrupted sleep routines; 2) caregiver burden and depression; and, 3) the caregiver’s physical health status. Successful treatment of a caregiver’s sleep disturbance requires careful consideration of each of these contributors. We review and analyze the scientific literature concerning the multiple complex factors associated with the development and maintenance of sleep disturbances in caregivers. We provide a clinical vignette that illustrates the interplay of these contributing factors, and close by providing recommendations for clinicians and researchers treating and investigating the development and maintenance of sleep problems in family caregivers. PMID:17287134

  3. Human factor implications of the Eurocopter AS332L-1 Super Puma cockpit

    NASA Technical Reports Server (NTRS)

    Padfield, R. Randall

    1993-01-01

    The purpose of this paper is to identify and describe some of the human factor problems which can occur in the cockpit of a modern civilian helicopter. After examining specific hardware and software problems in the cockpit design of the Eurocopter (Aerospatiale) AS332L-1 Super Puma, the author proposes several principles that can be used to avoid similar human factors problems in the design of future cockpits. These principles relate to the use and function of warning lights, the design of autopilots in two-pilot aircraft, and the labeling of switches and warning lights, specifically with respect to abbreviations and translations from languages other than English. In the final section of the paper, the author describes current trends in society which he suggests should be taken into consideration when designing future aircraft cockpits.

  4. Risk Factors for HIV Acquisition in Urban Latinos and Implications for Prevention.

    PubMed

    Angelo, Kristina Marie; Burton, Nicole; Ruiz, Marco Andres

    2015-01-01

    The risk of HIV in the Latino population in the United States is increasing. This population has a disproportionate number of new HIV cases, with the largest burden in the seventeen southern states. The purpose of this study is to assess risk factors for HIV among HIV-positive Latinos in care in New Orleans, Louisiana, through a retrospective chart review. The Chi square test of proportions, Student's t-test, and Wilcox rank sum test were used to test differences by sex and immigration status. Men were more likely to be incarcerated, use drugs, and drink alcohol. Undocumented Latinos were younger and had increased language barriers. Legally documented participants were more likely to use drugs, have a psychiatric diagnosis, and syphilis. Understanding the complex risk factors that surround HIV in the Latino population is useful for the development of effective and comprehensive prevention programs.

  5. Dioxin induces a novel nuclear factor, DIF-3, that is implicated in spermatogenesis.

    PubMed

    Ohbayashi, T; Oikawa, K; Iwata, R; Kameta, A; Evine, K; Isobe, T; Matsuda, Y; Mimura, J; Fujii-Kuriyama, Y; Kuroda, M; Mukai, K

    2001-11-23

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD; dioxin), a member of a class of environmental pollutants represented by polychlorinated dibenzo-p-dioxins and dibenzofurans, is one of the most toxic artificial compounds ever developed. In this study, we identified a novel TCDD target gene, DIF-3 (dioxin inducible factor-3), by cDNA representational difference analysis. DIF-3 protein is a nuclear factor and possesses a zinc-finger motif at its N-terminus. High DIF-3 mRNA expression in the testes was demonstrated by Northern blot analysis and abundant DIF-3 protein was detected during spermatogenesis. Thus, these results suggest that DIF-3 may be a target gene mediating the reproductive toxicity induced by TCDD.

  6. Direct calibration in megavoltage photon beams using Monte Carlo conversion factor: validation and clinical implications.

    PubMed

    Wright, Tracy; Lye, Jessica E; Ramanathan, Ganesan; Harty, Peter D; Oliver, Chris; Webb, David V; Butler, Duncan J

    2015-01-21

    The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has established a method for ionisation chamber calibrations using megavoltage photon reference beams. The new method will reduce the calibration uncertainty compared to a (60)Co calibration combined with the TRS-398 energy correction factor. The calibration method employs a graphite calorimeter and a Monte Carlo (MC) conversion factor to convert the absolute dose to graphite to absorbed dose to water. EGSnrc is used to model the linac head and doses in the calorimeter and water phantom. The linac model is validated by comparing measured and modelled PDDs and profiles. The relative standard uncertainties in the calibration factors at the ARPANSA beam qualities were found to be 0.47% at 6 MV, 0.51% at 10 MV and 0.46% for the 18 MV beam. A comparison with the Bureau International des Poids et Mesures (BIPM) as part of the key comparison BIPM.RI(I)-K6 gave results of 0.9965(55), 0.9924(60) and 0.9932(59) for the 6, 10 and 18 MV beams, respectively, with all beams within 1σ of the participant average. The measured kQ values for an NE2571 Farmer chamber were found to be lower than those in TRS-398 but are consistent with published measured and modelled values. Users can expect a shift in the calibration factor at user energies of an NE2571 chamber between 0.4-1.1% across the range of calibration energies compared to the current calibration method.

  7. The role of intrinsic factors in control of arm movement direction: implications from directional preferences.

    PubMed

    Dounskaia, Natalia; Goble, Jacob A; Wang, Wanyue

    2011-03-01

    The role of extrinsic and intrinsic factors in control of arm movement direction remains under debate. We addressed this question by investigating preferences in selection of movement direction and whether factors causing these preferences have extrinsic or intrinsic nature. An unconstrained free-stroke drawing task was used during which participants produced straight strokes on a horizontal table, choosing the direction and the beginning and end of each stroke arbitrarily. The variation of the initial arm postures across strokes provided a possibility to distinguish between the extrinsic and intrinsic origins of directional biases. Although participants were encouraged to produce strokes equally in all directions, each participant demonstrated preferences for some directions over the others. However, the preferred directions were not consistent across participants, suggesting no directional preferences in extrinsic space. Consistent biases toward certain directions were revealed in intrinsic space representing initial arm postures. Factors contributing to the revealed preferences were analyzed within the optimal control framework. The major bias was explained by a tendency predicted by the leading joint hypothesis (LJH) to minimize active interference with interaction torque generated by shoulder motion at the elbow. Some minor biases may represent movements of minimal inertial resistance or maximal kinematic manipulability. These results support a crucial role of intrinsic factors in control of the movement direction of the arm. Based on the LJH interpretation of the major bias, we hypothesize that the dominant tendency was to minimize neural effort for control of arm intersegmental dynamics. Possible organization of neural processes underlying optimal selection of movement direction is discussed.

  8. New web-based applications for mechanistic case diagramming.

    PubMed

    Dee, Fred R; Haugen, Thomas H; Kreiter, Clarence D

    2014-01-01

    The goal of mechanistic case diagraming (MCD) is to provide students with more in-depth understanding of cause and effect relationships and basic mechanistic pathways in medicine. This will enable them to better explain how observed clinical findings develop from preceding pathogenic and pathophysiological events. The pedagogic function of MCD is in relating risk factors, disease entities and morphology, signs and symptoms, and test and procedure findings in a specific case scenario with etiologic pathogenic and pathophysiological sequences within a flow diagram. In this paper, we describe the addition of automation and predetermined lists to further develop the original concept of MCD as described by Engelberg in 1992 and Guerrero in 2001. We demonstrate that with these modifications, MCD is effective and efficient in small group case-based teaching for second-year medical students (ratings of ~3.4 on a 4.0 scale). There was also a significant correlation with other measures of competency, with a 'true' score correlation of 0.54. A traditional calculation of reliability showed promising results (α =0.47) within a low stakes, ungraded environment. Further, we have demonstrated MCD's potential for use in independent learning and TBL. Future studies are needed to evaluate MCD's potential for use in medium stakes assessment or self-paced independent learning and assessment. MCD may be especially relevant in returning students to the application of basic medical science mechanisms in the clinical years.

  9. Addressing occupational factors in the management of low back pain: implications for physical therapist practice.

    PubMed

    Shaw, William S; Main, Chris J; Johnston, Venerina

    2011-05-01

    There is mounting evidence that occupational factors influence the extent of sickness absence following an episode of low back pain, but there have been limited efforts to integrate the identification and management of occupational factors into the routine practice of physical therapists. Systematic reviews suggest that a client's report of heavy physical demands, inability to modify job tasks, work stress, lack of organizational support, job dissatisfaction, poor expectations for resuming usual work, and fear of reinjury are indications of significant barriers to returning to work. Recommended strategies for evaluating and addressing occupational factors are explored with respect to the physical therapist's role in client assessment, development of activity and lifestyle recommendations, therapeutic exercise, communication with other providers, and summary reports. Primary recommendations include: (1) administration of self-report questionnaires to assess a client's perspective of physical job demands, (2) client-centered interviewing to highlight individual return-to-work concerns, (3) early discussions with clients about possible job modifications, and (4) incorporation of clients' workplace concerns in progress reports and summaries. These strategies may improve low back pain outcomes by encouraging effective communication with key stakeholders and by developing clients' ability to resolve obstacles to returning to work.

  10. Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1

    PubMed Central

    Hou, Caixia; Weidenbach, Stevi; Cano, Kristin E.; Wang, Zhonghua; Mitra, Prithiba; Ivanov, Dmitri N.; Rohr, Jürgen; Tsodikov, Oleg V.

    2016-01-01

    Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS–FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS–FLI1. We report a crystal structure of an MTM analogue MTM SA–Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA–Phe in complex with DNA. MTM SA–Phe is bound to sites AGGG and GGGT on one DNA, and to AGGG and GGGA(T) (a FLI1 binding site) on the other, revealing how MTM recognizes different DNA sequences. Unexpectedly, at sub-micromolar concentrations MTMs stabilize FLI1–DNA complex on GGAA repeats, which are critical for the oncogenic function of EWS–FLI1. We also directly demonstrate by nuclear magnetic resonance formation of a ternary FLI1–DNA–MTM complex on a single GGAA FLI1/MTM binding site. These biochemical and structural data and a new FLI1–DNA structure suggest that MTM binds the minor groove and perturbs FLI1 bound nearby in the major groove. This ternary complex model may lead to development of novel MTM analogues that selectively target EWS–FLI1 or other oncogenic transcription factors, as anti-cancer therapeutics. PMID:27587584

  11. The role of genetic factors in autoimmune disease: implications for environmental research.

    PubMed Central

    Cooper, G S; Miller, F W; Pandey, J P

    1999-01-01

    Studies in both humans and in animal models of specific disorders suggest that polymorphisms of multiple genes are involved in conferring either a predisposition to or protection from autoimmune diseases. Genes encoding polymorphic proteins that regulate immune responses or the rates and extent of metabolism of certain chemical structures have been the focus of much of the research regarding genetic susceptibility. We examine the type and strength of evidence concerning genetic factors and disease etiology, drawing examples from a number of autoimmune diseases. Twin studies of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type I diabetes, and multiple sclerosis (MS) indicate that disease concordance in monozygotic twins is 4 or more times higher than in dizygotic twins. Strong familial associations (odds ratio ranging from 5-10) are seen in studies of MS, type I diabetes, Graves disease, discoid lupus, and SLE. Familial association studies have also reported an increased risk of several systemic autoimmune diseases among relatives of patients with a systemic autoimmune disease. This association may reflect a common etiologic pathway with shared genetic or environmental influences among these diseases. Recent genomewide searches in RA, SLE, and MS provide evidence for multiple susceptibility genes involving major histocompatibility complex (MHC) and non-MHC loci; there is also evidence that many autoimmune diseases share a common set of susceptibility genes. The multifactorial nature of the genetic risk factors and the low penetrance of disease underscore the potential influence of environmental factors and gene-environment interactions on the etiology of autoimmune diseases. PMID:10502533

  12. Nodular histogenetic type -- the most significant factor for thick melanoma: implications for prevention.

    PubMed

    Bergenmar, M; Ringborg, U; Månsson Brahme, E; Brandberg, Y

    1998-10-01

    Tumour thickness is the most important prognostic factor in malignant melanoma. To reduce the melanoma-related mortality, factors related to the presentation of thick melanoma have to be identified. Three samples of melanoma patients (n=694) were studied for this purpose. Histogenetic type was the only factor which differentiated between 'thin' (< or = 0.8 mm) and 'thick' (> 2.0 mm) lesions. During a 10-year period only 3% of the nodular lesions were 'thin' at diagnosis. Differences in knowledge about melanoma or the location of the lesion (either 'easy' or 'difficult' for the patient to observe) did not explain differences in tumour thickness. The most common tumour site irrespective of histogenetic type and gender was 'back of the trunk'. 'Increase in diameter' and 'bleeding' were the symptoms most frequently reported by patients with 'thick' melanoma. 'Thick' lesions were diagnosed in older age groups and in men to a greater extent. Considering these results, melanoma prevention should also be targeted to older age groups and attention should be paid to symptoms such as 'increase in diameter' even in the absence of other characteristic symptoms of melanoma. An increased proportion of nodular melanoma diagnosed as 'thin' lesions can be interpreted as a step forward in secondary prevention.

  13. Factors associated with uterine endometrial hyperplasia and pyometra in wild canids: implications for fertility.

    PubMed

    Asa, Cheryl S; Bauman, Karen L; Devery, Sarah; Zordan, Martín; Camilo, Gerardo R; Boutelle, Sally; Moresco, Anneke

    2014-01-01

    The ability to safely and effectively manage reproduction is central to the success of AZA captive-breeding programs. Although the AZA Wildlife Contraception Center routinely monitors contraceptive safety, there have been no studies that compare the effects of contraceptive use to separation of males from females, the other option for preventing reproduction. We used retrospective medical records and pathology reports submitted by AZA and related facilities for the seven AZA-managed canid species to assess rates of uterine pathology relative to female reproductive life histories. Our results showed that the prevalence of both pyometra and endometrial hyperplasia (EH) was associated not only with treatment with the two most common contraceptives (Suprelorin® and MGA implants) but also with the number of years barren (i.e., not producing a litter and not contracepted). Rates of pyometra and EH were especially high in African painted dogs and red wolves, but lowest in swift and fennec foxes. The number of years producing a litter had a low association, suggesting it could be protective against uterine pathology. A more recently developed Suprelorin® protocol using Ovaban® to prevent the initial stimulation phase, followed by implant removal when reversal is desired, may be a safer contraceptive option. These results concerning the relationship between reproductive management and uterine health have important implications for AZA-managed programs, since the unsustainability of many captive populations may be due at least in part to infertility. Managing a female's reproductive lifespan to optimize or maintain fertility will require a reconsideration of how breeding recommendations are formulated.

  14. Exploring the role of nerve growth factor in multiple sclerosis: implications in myelin repair.

    PubMed

    Acosta, C M R; Cortes, C; MacPhee, H; Namaka, M P

    2013-12-01

    Multiple sclerosis (MS) is a chronic disease resulting from targeted destruction of central nervous system (CNS) myelin. MS is suggested to be an autoimmune disease involving the pathogenic activation of CD4(+) T cells by a foreign antigen in the peripheral blood. The activated CD4(+) T cells liberate inflammatory cytokines that facilitate the breakdown of the blood-brain barrier (BBB) promoting their passage into the CNS. Inside the CNS, CD4(+) T cells become re-activated by myelin proteins sharing a similar structure to the foreign antigen that initially triggered the immune response. The CD4(+) T cells continue to liberate inflammatory cytokines, such as tumor necrosis factor α (TNFα), which activates macrophages and antibodies responsible for the phagocytosis of myelin. Acute CNS lesions can be re-myelinated, however, the repair of chronic demyelinating lesions is limited, leading to permanent neurological deficits. Although current MS treatments reduce severity and slow disease progression, they do not directly repair damaged myelin. Henceforth, recent treatment strategies have focused on neurotrophins, such as nerve growth factor (NGF) for myelin repair. NGF promotes axonal regeneration, survival, protection and differentiation of oligodendrocytes (OGs) and facilitates migration and proliferation of oligodendrocyte precursors (OPs) to the sites of myelin damage. NGF also directly regulates key structural proteins that comprise myelin. Interestingly, NGF also induces the production of brain-derived neurotrophic factor (BDNF), another integral neurotrophin involved in myelination. The intricate signaling between neurotrophins and cytokines that governs myelin repair supports the role of NGF as a leading therapeutic candidate in white matter disorders, such as MS.

  15. Variability in Isotope Discrimination Factors in Coral Reef Fishes: Implications for Diet and Food Web Reconstruction

    PubMed Central

    Wyatt, Alex S. J.; Waite, Anya M.; Humphries, Stuart

    2010-01-01

    Interpretation of stable isotope ratios of carbon and nitrogen (δ13C and δ15N) is generally based on the assumption that with each trophic level there is a constant enrichment in the heavier isotope, leading to diet-tissue discrimination factors of 3.4‰ for 15N (ΔN) and ∼0.5‰ for 13C (ΔC). Diet-tissue discrimination factors determined from paired tissue and gut samples taken from 152 individuals from 26 fish species at Ningaloo Reef, Western Australia demonstrate a large amount of variability around constant values. While caution is necessary in using gut contents to represent diet due to the potential for high temporal variability, there were significant effects of trophic position and season that may also lead to variability in ΔN under natural conditions. Nitrogen enrichment increased significantly at higher trophic levels (higher tissue δ15N), with significantly higher ΔN in carnivorous species. Changes in diet led to significant changes in ΔN, but not tissue δ15N, between seasons for several species: Acanthurus triostegus, Chromis viridis, Parupeneus signatus and Pomacentrus moluccensis. These results confirm that the use of meta-analysis averages for ΔN is likely to be inappropriate for accurately determining diets and trophic relationships using tissue stable isotope ratios. Where feasible, discrimination factors should be directly quantified for each species and trophic link in question, acknowledging the potential for significant variation away from meta-analysis averages and, perhaps, controlled laboratory diets and conditions. PMID:21060681

  16. Sexually transmitted diseases in Ethiopia. Social factors contributing to their spread and implications for developing countries.

    PubMed

    Plorde, D S

    1981-12-01

    Sexually transmitted diseases in developing countries are causing concern to those responsible for their control and eradication. To gain a better understanding of the problems involved in a country struggling with development, the economic and psychosocial factors influencing the spread of STD in Ethiopia have been studied. Increased migration and urbanisation and the changing role of women have led to a rise in prostitution. Thus changes in the social structure--particularly in relation to the education and employment of women--and improved medical services are essential for the long-term control of STD.

  17. Factors associated with changing cognitive function in older adults: implications for nursing rehabilitation.

    PubMed

    Myers, Jamie S

    2008-01-01

    This article reviews the significant effects of aging on cognitive function. As people age, brain tissue volume decreases, white matter hyperintensities increase, and associated deficits are seen in working memory, attention, and executive function. Comorbidities include hypertension, diabetes, and cardiovascular risk factors. Another factor that affects cognitive function is the presence of apolipoprotein E-4, which is negatively correlated with cognitive function. In addition, decreased serum levels of endogenous sex hormones are related to changes in cognitive function, but hormone replacement therapy may be detrimental. Improved cognition has been associated with moderate alcohol intake, regular exercise, and exposure to novel stimuli. This article also examines research evaluating brain-plasticity-based training and rehabilitation to reverse losses in sensory, cognitive, and motor processing. Rehabilitation nursing strategies for dealing with the decline of cognitive function include educating patients and developing a program about lifestyle changes that will enhance cognitive stimulation; minimizing risks for and effects of hypertension, diabetes, and cardiovascular disease; recognizing and accommodating sensory deficits; and maintaining awareness of current research outcomes to guide evidence-based practice.

  18. MRN1 Implicates Chromatin Remodeling Complexes and Architectural Factors in mRNA Maturation

    PubMed Central

    Düring, Louis; Thorsen, Michael; Petersen, Darima Sophia Njama; Køster, Brian; Jensen, Torben Heick; Holmberg, Steen

    2012-01-01

    A functional relationship between chromatin structure and mRNA processing events has been suggested, however, so far only a few involved factors have been characterized. Here we show that rsc nhp6ΔΔ mutants, deficient for the function of the chromatin remodeling factor RSC and the chromatin architectural proteins Nhp6A/Nhp6B, accumulate intron-containing pre-mRNA at the restrictive temperature. In addition, we demonstrate that rsc8-ts16 nhp6ΔΔ cells contain low levels of U6 snRNA and U4/U6 di-snRNA that is further exacerbated after two hours growth at the restrictive temperature. This change in U6 snRNA and U4/U6 di-snRNA levels in rsc8-ts16 nhp6ΔΔ cells is indicative of splicing deficient conditions. We identify MRN1 (multi-copy suppressor of rsc nhp6ΔΔ) as a growth suppressor of rsc nhp6ΔΔ synthetic sickness. Mrn1 is an RNA binding protein that localizes both to the nucleus and cytoplasm. Genetic interactions are observed between 2 µm-MRN1 and the splicing deficient mutants snt309Δ, prp3, prp4, and prp22, and additional genetic analyses link MRN1, SNT309, NHP6A/B, SWI/SNF, and RSC supporting the notion of a role of chromatin structure in mRNA processing. PMID:23028530

  19. Factors Influencing Self-Assessment of Cognition and Functioning in Schizophrenia: Implications For Treatment Studies

    PubMed Central

    Durand, Dante; Strassnig, Martin; Sabbag, Samir; Gould, Felicia; Twamley, Elizabeth W.; Patterson, Thomas L.; Harvey, Philip D.

    2014-01-01

    Awareness of illness is a major factor in schizophrenia and extends into unawareness of cognitive and functional deficits. This unawareness of functional limitations has been shown to be influenced by several different predictive factors, including greater impairment and less severe depression. As treatment efforts are aimed at reducing cognitive deficits, discovery of the most efficient assessment strategies for detection of cognitive and functional changes is critical. In this study, we collected systematic assessments from high contact clinicians focusing on their impressions of the cognitive deficits and everyday functioning in a sample of 169 community dwelling patients with schizophrenia. The patients provided self-report on those same rating scales, as well as self-reporting their depression and performing an assessment of cognitive performance and functional skills. There was essentially no correlation between patients' self reports of their cognitive performance and functional skills and either clinician ratings of these skills or the results of the performance-based assessments. In contrast, clinician reports of cognitive impairments and everyday functioning were correlated with objective performance data. Depression on the part of patients was associated with ratings of functioning that were both more impaired and more congruent with clinician impressions, while overall patients reported less impairment than clinicians. These results underscore the limitations of self reported cognitive functioning even with structured rating scales. Concurrently, clinicians provided ratings of cognitive performance that were related to scores on objective tests, even though they were unaware of the results of those assessments. PMID:25104226

  20. Segmental distribution of some common molecular markers for colorectal cancer (CRC): influencing factors and potential implications.

    PubMed

    Papagiorgis, Petros Christakis

    2016-05-01

    Proximal and distal colorectal cancers (CRCs) are regarded as distinct disease entities, evolving through different genetic pathways and showing multiple clinicopathological and molecular differences. Segmental distribution of some common markers (e.g., KRAS, EGFR, Ki-67, Bcl-2, COX-2) is clinically important, potentially affecting their prognostic or predictive value. However, this distribution is influenced by a variety of factors such as the anatomical overlap of tumorigenic molecular events, associations of some markers with other clinicopathological features (stage and/or grade), and wide methodological variability in markers' assessment. All these factors represent principal influences followed by intratumoral heterogeneity and geographic variation in the frequency of detection of particular markers, whereas the role of other potential influences (e.g., pre-adjuvant treatment, interaction between markers) remains rather unclear. Better understanding and elucidation of the various influences may provide a more accurate picture of the segmental distribution of molecular markers in CRC, potentially allowing the application of a novel patient stratification for treatment, based on particular molecular profiles in combination with tumor location.

  1. Young children who commit crime: epidemiology, developmental origins, risk factors, early interventions, and policy implications.

    PubMed

    Loeber, R; Farrington, D P

    2000-01-01

    An early onset of delinquency prior to age 13 years increases the risk of later serious, violent, and chronic offending by a factor of 2-3. Also child delinquents, compared to juveniles who start offending at a later age, tend to have longer delinquent careers. This article summarizes the report of the Office of Juvenile Justice and Delinquency Prevention's Study Group on Very Young Offenders, chaired by Rolf Loeber and David P. Farrington. The Study Group, consisting of 16 scholars and 23 coauthors, worked for 2 years on preparing a report, undertaking extensive secondary data analyses, and writing chapters in different speciality areas. The report consists of a state of the art review of the developmental background of child delinquents. The report also summarizes risk and protective factors in the individual, family, peer group, school, and neighborhood that affect that development. Lastly, the report renews relevant preventive and remedial interventions in the juvenile justice system, families, peer groups, schools. and neighborhoods, and makes a case for improvement in the integration of services for child delinquents. Policy recommendations are presented to improve methods of dealing with child delinquents by juvenile justice, child welfare, and mental health agencies.

  2. Growth factors induce monocyte binding to vascular smooth muscle cells: implications for monocyte retention in atherosclerosis.

    PubMed

    Cai, Qiangjun; Lanting, Linda; Natarajan, Rama

    2004-09-01

    Adhesive interactions between monocytes and vascular smooth muscle cells (VSMC) may contribute to subendothelial monocyte-macrophage retention in atherosclerosis. We investigated the effects of angiotensin II (ANG II) and platelet-derived growth factor (PDGF)-BB on VSMC-monocyte interactions. Treatment of human aortic VSMC (HVSMC) with ANG II or PDGF-BB significantly increased binding to human monocytic THP-1 cells and to peripheral blood monocytes. This was inhibited by antibodies to monocyte beta(1)- and beta(2)-integrins. The binding was also attenuated by blocking VSMC arachidonic acid (AA) metabolism by inhibitors of 12/15-lipoxygenase (12/15-LO) or cyclooxygenase-2 (COX-2). Conversely, binding was enhanced by overexpression of 12/15-LO or COX-2. Direct treatment of HVSMC with AA or its metabolites also increased binding. Furthermore, VSMC derived from 12/15-LO knockout mice displayed reduced binding to mouse monocytic cells relative to genetic control mice. Using specific signal transduction inhibitors, we demonstrated the involvement of Src, phosphoinositide 3-kinase, and MAPKs in ANG II- or PDGF-BB-induced binding. Interestingly, after coculture with HVSMC, THP-1 cell surface expression of the scavenger receptor CD36 was increased. These results show for the first time that growth factors may play additional roles in atherosclerosis by increasing monocyte binding to VSMC via AA metabolism and key signaling pathways. This can lead to monocyte subendothelial retention, CD36 expression, and foam cell formation.

  3. Factors associated with children being driven to school: implications for walk to school programs.

    PubMed

    Wen, Li Ming; Fry, Denise; Rissel, Chris; Dirkis, Helen; Balafas, Angela; Merom, Dafna

    2008-04-01

    In this study, we examined factors associated with children being driven to school. Participants were 1603 students (aged 9-11 years) and their parents from 24 public primary schools in inner western Sydney, Australia. Students recorded their modes of travel to and from school for 5 days in a student survey. Parents recorded their demographic data, their attitudes to travel, and their modes of travel to work, using a self-administered survey. An analysis of the two linked data sets found that 41% of students travelled by car to or from school for more than 5 trips per week. Almost a third (32%) of students walked all the way. Only 1% of students rode a bike and 22% used more than one mode of travel. Of those who were driven, 29% lived less than 1 km and a further 18% lived between 1 and 1.5 km from school. Factors associated with car travel (after adjusting for other potential confounders) were mode of parents' travel to work, parent attitudes, number of cars in the household, and distance from home to school. To be effective, walk to school programs need to address the link between parent journey to work and student journey to school.

  4. Implications of Dna-Nanostructures by Hoogsteen-Dinucleotides on Transcription Factor Binding

    NASA Astrophysics Data System (ADS)

    Wanke, Dierk; Brand, Luise H.; Fischer, Nina M.; Peschke, Florian; Kilian, Joachim; Berendzen, Kenneth W.

    2013-01-01

    Recent findings showed that non-harmonic DNA-nanostructures are formed by Hoogsteen (HG) dinucleotides in vivo. In contrast to Waston-Crick (WC) base pairing, the purine base component is flipped from anti- to syn-conformation. This change consequently alters the width of the DNA-helix, the sizes of minor and major groove and biophysical properties, such as the melting temperature. Three dinucleotides (CA, TG and TA) have been identified that form stable HG conformations. Functional data and structural models imply that transcription factors specifically bind DNA-motifs that consist of both HG and WC base pairs - especially at the topological transition between HG and WC dinucleotides. We could show that most know cis -regulatory elements contain at least one HG dinucleotide. In addition, we focused our work on human promoter sequences that encode gene regulatory information within double stranded DNA. We compared occurrences of HG dinucleotides to all 16 dinucleotides. These ratios differed most in sequences closer to gene transcripts, where the promoters are located. These findings imply that transcription factors might explicitly recognize their DNA-motifs in regulatory promoter sequences that exhibit HG nanostructure islands.

  5. TRANSCRIPTION FACTOR GLI-SIMILAR 3 (GLIS3): IMPLICATIONS FOR THE DEVELOPMENT OF CONGENITAL HYPOTHYROIDISM

    PubMed Central

    Lichti-Kaiser, Kristin; ZeRuth, Gary; Jetten, Anton M.

    2014-01-01

    Congenital hypothyroidism (CH) is the most frequent endocrine disorder in neonates. While several genetic mutations have been identified that result in developmental defects of the thyroid gland or thyroid hormone synthesis, genetic factors have yet to be identified in many CH patients along with the mechanisms underlying their pathophysiology. Mutations in the gene encoding the Krüppel-like transcription factor, GLI-similar 3 (GLIS3) have been associated with the development of a syndrome characterized by congenital hypothyroidism and neonatal diabetes and similar phenotypes were observed in mouse knockout models of Glis3. Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated thyroid stimulating hormone (TSH) and thyroglobulin (TG). However, the inconsistent presentation of clinical features associated with this CH has made it difficult to ascertain a causative mechanism. Future elucidation of the biological functions of GLIS3 in the thyroid will be crucial to the discovery of new therapeutic opportunities for the treatment of CH. PMID:25133201

  6. Stem CO2 efflux in six co-occurring tree species: underlying factors and ecological implications.

    PubMed

    Rodríguez-Calcerrada, Jesús; López, Rosana; Salomón, Roberto; Gordaliza, Guillermo G; Valbuena-Carabaña, María; Oleksyn, Jacek; Gil, Luis

    2015-06-01

    Stem respiration plays a role in species coexistence and forest dynamics. Here we examined the intra- and inter-specific variability of stem CO2 efflux (E) in dominant and suppressed trees of six deciduous species in a mixed forest stand: Fagus sylvatica L., Quercus petraea [Matt.] Liebl, Quercus pyrenaica Willd., Prunus avium L., Sorbus aucuparia L. and Crataegus monogyna Jacq. We conducted measurements in late autumn. Within species, dominants had higher E per unit stem surface area (Es ) mainly because sapwood depth was higher than in suppressed trees. Across species, however, differences in Es corresponded with differences in the proportion of living parenchyma in sapwood and concentration of non-structural carbohydrates (NSC). Across species, Es was strongly and NSC marginally positively related with an index of drought tolerance, suggesting that slow growth of drought-tolerant trees is related to higher NSC concentration and Es . We conclude that, during the leafless period, E is indicative of maintenance respiration and is related with some ecological characteristics of the species, such as drought resistance; that sapwood depth is the main factor explaining variability in Es within species; and that the proportion of NSC in the sapwood is the main factor behind variability in Es among species.

  7. Apple FLOWERING LOCUS T proteins interact with transcription factors implicated in cell growth and organ development.

    PubMed

    Mimida, Naozumi; Kidou, Shin-Ichiro; Iwanami, Hiroshi; Moriya, Shigeki; Abe, Kazuyuki; Voogd, Charlotte; Varkonyi-Gasic, Erika; Kotoda, Nobuhiro

    2011-05-01

    Understanding the flowering process in apple (Malus × domestica Borkh.) is essential for developing methods to shorten the breeding period and regulate fruit yield. It is known that FLOWERING LOCUS T (FT) acts as a transmissible floral inducer in the Arabidopsis flowering network system. To clarify the molecular network of two apple FT orthologues, MdFT1 and MdFT2, we performed a yeast two-hybrid screen to identify proteins that interact with MdFT1. We identified several transcription factors, including two members of the TCP (TEOSINTE BRANCHED1, CYCLOIDEA and PROLIFERATING CELL FACTORs) family, designated MdTCP2 and MdTCP4, and an Arabidopsis thaliana VOZ1 (Vascular plant One Zinc finger protein1)-like protein, designated MdVOZ1. MdTCP2 and MdVOZ1 also interacted with MdFT2 in yeast. The expression domain of MdTCP2 and MdVOZ1 partially overlapped with that of MdFT1 and MdFT2, most strikingly in apple fruit tissue, further suggesting a potential interaction in vivo. Constitutive expression of MdTCP2, MdTCP4 and MdVOZ1 in Arabidopsis affected plant size, leaf morphology and the formation of leaf primordia on the adaxial side of cotyledons. On the other hand, chimeric MdTCP2, MdTCP4 and MdVOZ1 repressors that included the ethylene-responsive transcription factors (ERF)-associated amphiphilic repression (EAR) domain motif influenced reproduction and inflorescence architecture in transgenic Arabidopsis. These results suggest that MdFT1 and/or MdFT2 might be involved in the regulation of cellular proliferation and the formation of new tissues and that they might affect leaf and fruit development by interacting with TCP- and VOZ-family proteins. DDBJ accession nos. AB531019 (MdTCP2a mRNA), AB531020 (MdTCP2b mRNA), AB531021 (MdTCP4a mRNA), AB531022 (MdTCP4b mRNA) and AB531023 (MdVOZ1a mRNA).

  8. Mechanistic Modeling of Emergency Events: Assessing the Impact of Hypothetical Releases of Anthrax

    PubMed Central

    Isukapalli, S. S.; Lioy, P. J.; Georgopoulos, P. G.

    2011-01-01

    A modular system for source-to-dose-to-effect modeling analysis has been developed based on the modeling environment for total risk studies (MENTOR),(1) and applied to study the impacts of hypothetical atmospheric releases of anthrax spores. The system, MENTOR-2E (MENTOR for Emergency Events), provides mechanistically consistent analysis of inhalation exposures for various release scenarios, while allowing consideration of specific susceptible subpopulations (such as the elderly) at the resolution of individual census tracts. The MENTOR-2E application presented here includes atmospheric dispersion modeling, statistically representative samples of individuals along with corresponding activity patterns, and population-based dosimetry modeling that accounts for activity and physiological variability. Two hypothetical release scenarios were simulated: a 100 g release of weaponized B. anthracis over a period of (a) one hour and (b) 10 hours, and the impact of these releases on population in the State of New Jersey was studied. Results were compared with those from simplified modeling of population dynamics (location, activities, etc.), and atmospheric dispersion of anthrax spores. The comparisons showed that in the two release scenarios simulated, each major approximation resulted in an overestimation of the number of probable infections by a factor of 5 to 10; these overestimations can have significant public health implications when preparing for and responding effectively to an actual release. This is in addition to uncertainties in dose-response modeling, which result in an additional factor of 5 to 10 variation in estimated casualties. The MENTOR-2E system has been developed in a modular fashion so that improvements in individual modules can be readily made without impacting the other modules, and provides a first step toward the development of models that can be used in supporting real-time decision making. PMID:18643828

  9. T cell expansion is the limiting factor of virus control in mice with attenuated TCR signaling: implications for human immunodeficiency.

    PubMed

    Hillen, Kristina M; Gather, Ruth; Enders, Anselm; Pircher, Hanspeter; Aichele, Peter; Fisch, Paul; Blumenthal, Britta; Schamel, Wolfgang W; Straub, Tobias; Goodnow, Christopher C; Ehl, Stephan

    2015-03-15

    Defining the minimal thresholds for effective antiviral T cell immunity is important for clinical decisions in immunodeficient patients. TCR signaling is critical for T cell development, activation, and effector functions. In this article, we analyzed which of these TCR-mediated processes is limiting for antiviral immunity in a mouse strain with reduced expression of SLP-76 (twp mice). Despite severe T cell activation defects in vitro, twp mice generated a normal proportion of antiviral effector T cells postinfection with lymphocytic choriomeningitis virus (LCMV). Twp CD8(+) T cells showed impaired polyfunctional cytokine production, whereas cytotoxicity as the crucial antiviral effector function for LCMV control was normal. The main limiting factor in the antiviral response of twp mice was impaired T cell proliferation and survival, leading to a 5- to 10-fold reduction of antiviral T cells at the peak of the immune response. This was still sufficient to control infection with the LCMV Armstrong strain, but the more rapidly replicating LCMV-WE induced T cell exhaustion and viral persistence. Thus, under conditions of impaired TCR signaling, reduced T cell expansion was the limiting factor in antiviral immunity. These findings have implications for understanding antiviral immunity in patients with T cell deficiencies.

  10. An evaluation of factors influencing pore pressure in accretionary complexes: Implications for taper angle and wedge mechanics

    USGS Publications Warehouse

    Saffer, D.M.; Bekins, B.A.

    2006-01-01

    At many subduction zones, accretionary complexes form as sediment is off-scraped from the subducting plate. Mechanical models that treat accretionary complexes as critically tapered wedges of sediment demonstrate that pore pressure controls their taper angle by modifying basal and internal shear strength. Here, we combine a numerical model of groundwater flow with critical taper theory to quantify the effects of sediment and de??collement permeability, sediment thickness, sediment partitioning between accretion and underthrusting, and plate convergence rate on steady state pore pressure. Our results show that pore pressure in accretionary wedges can be viewed as a dynamically maintained response to factors which drive pore pressure (source terms) and those that limit flow (permeability and drainage path length). We find that sediment permeability and incoming sediment thickness are the most important factors, whereas fault permeability and the partitioning of sediment have a small effect. For our base case model scenario, as sediment permeability is increased, pore pressure decreases from near-lithostatic to hydrostatic values and allows stable taper angles to increase from ??? 2.5?? to 8??-12.5??. With increased sediment thickness in our models (from 100 to 8000 m), increased pore pressure drives a decrease in stable taper angle from 8.4??-12.5?? to 15?? to <4??) with increased sediment thickness (from <1 to 7 km). One key implication is that hydrologic properties may strongly influence the strength of the crust in a wide range of geologic settings. Copyright 2006 by the American Geophysical Union.

  11. Growth Hormone Induces Transforming Growth Factor-Beta-Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria.

    PubMed

    Chitra, P Swathi; Swathi, T; Sahay, Rakesh; Reddy, G Bhanuprakash; Menon, Ram K; Kumar, P Anil

    2015-09-01

    The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR-array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN.

  12. Estimates of utility weights in hemophilia: implications for cost-utility analysis of clotting factor prophylaxis

    PubMed Central

    Grosse, Scott D; Chaugule, Shraddha S; Hay, Joel W

    2015-01-01

    Estimates of preference-weighted health outcomes or health state utilities are needed to assess improvements in health in terms of quality-adjusted life-years. Gains in quality-adjusted life-years are used to assess the cost–effectiveness of prophylactic use of clotting factor compared with on-demand treatment among people with hemophilia, a congenital bleeding disorder. Published estimates of health utilities for people with hemophilia vary, contributing to uncertainty in the estimates of cost–effectiveness of prophylaxis. Challenges in estimating utility weights for the purpose of evaluating hemophilia treatment include selection bias in observational data, difficulty in adjusting for predictors of health-related quality of life and lack of preference-based data comparing adults with lifetime or primary prophylaxis versus no prophylaxis living within the same country and healthcare system. PMID:25585817

  13. Fine scale spatial variability of microbial pesticide degradation in soil: scales, controlling factors, and implications

    PubMed Central

    Dechesne, Arnaud; Badawi, Nora; Aamand, Jens; Smets, Barth F.

    2014-01-01

    Pesticide biodegradation is a soil microbial function of critical importance for modern agriculture and its environmental impact. While it was once assumed that this activity was homogeneously distributed at the field scale, mounting evidence indicates that this is rarely the case. Here, we critically examine the literature on spatial variability of pesticide biodegradation in agricultural soil. We discuss the motivations, methods, and main findings of the primary literature. We found significant diversity in the approaches used to describe and quantify spatial heterogeneity, which complicates inter-studies comparisons. However, it is clear that the presence and activity of pesticide degraders is often highly spatially variable with coefficients of variation often exceeding 50% and frequently displays non-random spatial patterns. A few controlling factors have tentatively been identified across pesticide classes: they include some soil characteristics (pH) and some agricultural management practices (pesticide application, tillage), while other potential controlling factors have more conflicting effects depending on the site or the pesticide. Evidence demonstrating the importance of spatial heterogeneity on the fate of pesticides in soil has been difficult to obtain but modeling and experimental systems that do not include soil's full complexity reveal that this heterogeneity must be considered to improve prediction of pesticide biodegradation rates or of leaching risks. Overall, studying the spatial heterogeneity of pesticide biodegradation is a relatively new field at the interface of agronomy, microbial ecology, and geosciences and a wealth of novel data is being collected from these different disciplinary perspectives. We make suggestions on possible avenues to take full advantage of these investigations for a better understanding and prediction of the fate of pesticides in soil. PMID:25538691

  14. Factors Affecting Diet Variation in the Pyrenean Rock Ptarmigan (Lagopus muta pyrenaica): Conservation Implications

    PubMed Central

    García-González, Ricardo; Aldezabal, Arantza; Laskurain, Nere Amaia; Margalida, Antoni; Novoa, Claude

    2016-01-01

    The Pyrenean rock ptarmigan (Lagopus muta pyrenaica) lives at one of the southernmost limits of the ptarmigan range. Their small population sizes and the impacts of global changes are limiting factors in the conservation of this threatened subspecies. An effective conservation policy requires precise basic knowledge of a species' food and habitat requirements, information that is practically non-existent for this Pyrenean population. Here, we describe the diet of a ptarmigan population in the Eastern Pyrenees, the environmental factors influencing its variability and the relationship between diet floristic composition and quality. Diet composition was determined by microhistological analysis of faeces and diet quality was estimated from free-urate faecal N content. Our results show that grouse diet is based mainly on arctic-alpine shrubs of the Ericaceae family, as well as dwarf willows (Salix spp.) and Dryas octopetala. The most frequently consumed plant species was Rhododendron ferrugineum, but its abundance in the diet was negatively related to the diet nitrogen content. Conversely, the abundance of Salix spp., grass leaves and arthropods increased the nitrogen content of the diet. Seasonality associated with snow-melting contributed the most to variability in the Pyrenean ptarmigan diet, differentiating winter from spring/summer diets. The latter was characterised by a high consumption of dwarf willows, flowers, arthropods and tender forb leaves. Geographic area and sex-age class influenced diet variability to a lesser extent. Current temperature increases in the Pyrenees due to global warming may reduce the persistence and surface area of snow-packs where preferred plants for rock ptarmigan usually grow, thus reducing food availability. The high consumption of Rh. ferrugineum characterised the diet of the Pyrenean population. Given the toxicity of this plant for most herbivores, its potential negative effect on Pyrenean ptarmigan populations should be

  15. Prevalence and risk factors for viral hepatitis in the Kosovarian population: implications for health policy.

    PubMed

    Quaglio, Gianluca; Ramadani, Naser; Pattaro, Cristian; Cami, Arben; Dentico, Pietro; Volpe, Anna; Pellizzer, Giampiero; Berisha, Ali; Smacchia, Camillo; Figliomeni, Mario; Schinaia, Nicola; Rezza, Giovanni; Putoto, Giovanni

    2008-05-01

    The prevalence of hepatitis infection among the Kosovarian population is largely unknown. The aim of the study was to evaluate the prevalence and risk factors of hepatitis A, B, C, and D (HAV, HBV, HCV, HDV) infection among the general population and in a group of health care workers in the Kosovo region. Overall, 1,287 participants were recruited, 460 males (36%) and 827 females (64%). Health care workers accounted for 253 individuals (20%), 301 were blood donor candidates (23%), 334 were pregnant women (26%), and 399 (31%) were subjects who had been examined in two clinics for routine laboratory testing. The prevalence of total anti-HAV was 88.6% (95% CI: 86.69-90.25). Prevalence of anti-HAV among children up to 10 years was 40.5% (95% CI: 29.6-53.15), reaching 70% (95% CI: 62.25-77.10) in the 11-20 age group. Age, living in rural areas and unemployment were factors associated with higher risk of HAV infection. HBsAg was detected in 2.4% (95% CI: 1.57-3.38%) of the study sample, with a significant age trend (P-value:0.0110). Positivity for total anti-HBc was detected in 18.4% (95% CI = 16.27-20.59) of the subjects. Ninety-three subjects (7.2%) were positive for anti-HBs alone. An association between age, HSV-2 positivity, working nurses and HBV infection has been observed. One patient was HDV positive. The prevalence for HCV was 0.5% (95% CI: 0.22-1.12%). HAV infection seems to be high-intermediate, while HBV shows an intermediate endemicity. It is necessary to highlight the importance of an immunization strategy against HAV and HBV in reducing the incidence of the infection. The prevalence for HCV was very low.

  16. Factors associated with early growth in Egyptian infants: implications for addressing the dual burden of malnutrition

    PubMed Central

    Flax, Valerie L.; Abdelmegeid, Ali; Salah, Farouk; Hafez, Seham; Ramzy, Magda; Hamed, Doaa; Saleh, Gulsen; Galloway, Rae

    2016-01-01

    Abstract Optimal nutrition is critical to the attainment of healthy growth, human capital and sustainable development. In Egypt, infants and young children face overlapping forms of malnutrition, including micronutrient deficiencies, stunting and overweight. Yet, in this setting, little is known about the factors associated with growth during the first year of life. A rise in stunting in Lower Egypt from 2005 to 2008 prompted this implementation research study, which followed a longitudinal cohort of infants from birth to 1 year of age within the context of a USAID‐funded maternal and child health integrated programme. We sought to determine if growth patterns and factors related to early growth differed in Lower and Upper Egypt, and examined the relationship between weight loss and subsequent stunting at 12 months of age. Growth patterns revealed that length‐for‐age z‐score (LAZ) decreased and weight‐for‐length z‐score (WLZ) increased from 6 to 12 months of age in both regions. One‐quarter of infants were stunted and nearly one‐third were overweight by 12 months of age in lower Egypt. Minimum dietary diversity was significantly associated with WLZ in Lower Egypt (β = 0.22, P < 0.05), but not in Upper Egypt. Diarrhoea, fever and programme exposure were not associated with any growth outcome. Weight loss during any period was associated with a twofold likelihood of stunting at 12 months in Lower Egypt, but not Upper Egypt. In countries, like Egypt, facing the nutrition transition, infant and young child nutrition programmes need to address both stunting and overweight through improving dietary quality and reducing reliance on energy‐dense foods. PMID:26373408

  17. Lead in New York City Community Garden Chicken Eggs: Influential Factors and Health Implications

    PubMed Central

    Spliethoff, Henry M.; Mitchell, Rebecca G.; Ribaudo, Lisa N.; Taylor, Owen; Shayler, Hannah A.; Greene, Virginia; Oglesby, Debra

    2014-01-01

    Raising chickens for eggs in urban areas is becoming increasingly common. Urban chickens may be exposed to lead, a common urban soil contaminant. We measured lead concentrations in chicken eggs from New York City (NYC) community gardens and collected information on factors that might affect those concentrations. Lead was detected between 10 and 167 μg/kg in 48% of NYC eggs. Measures of lead in eggs from a henhouse were significantly associated (p<0.005) with lead concentrations in soil. The association between soil and egg lead has been evaluated only once before, by a study of a rural region in Belgium. In our study, the apparent lead soil-to-egg transfer efficiency was considerably lower than that found in Belgium, suggesting that there may be important geographic differences in this transfer. We developed models that suggested that, for sites like ours, lead concentrations in >50% of eggs from a henhouse would exceed store-bought egg concentrations (<7–13 μg/kg; 3% above detection limit) at soil lead concentrations >120 mg/kg, and that the concentration in one of six eggs from a henhouse would exceed a 100 μg/kg guidance value at soil lead concentrations >410 mg/kg. Our models also suggested that the availability of dietary calcium supplements was another influential factor that reduced egg lead concentrations. Estimates of health risk from consuming eggs with the lead concentrations we measured generally were not significant. However, soil lead concentrations in this study were <600 mg/kg, and considerably higher concentrations are not uncommon. Efforts to reduce lead transfer to chicken eggs and associated exposure are recommended for urban chicken keepers. PMID:24287691

  18. HPV Literacy and Associated Factors Among Hmong American Immigrants: Implications for Reducing Cervical Cancer Disparity.

    PubMed

    Beltran, Raiza; Simms, Tina; Lee, Hee Yun; Kwon, Melissa

    2016-06-01

    Previous studies show that certain minority and ethnic communities experience low human papillomavirus (HPV) vaccination rates despite a higher cervical cancer burden. HPV is known to be responsible for almost all cervical cancer cases. Hmong Americans, a growing Asian American population, appear to be at increased risk. The cervical cancer incidence rate among Hmong American women is three times higher than other Asian/Pacific Islanders and more than four times higher than Non-Hispanic Whites. Despite such alarming statistics, there is limited research focusing on HPV literacy and its associated factors in the Hmong American community. This study's objectives are to investigate: (1) the level of HPV knowledge among Hmong Americans; (2) HPV vaccination initiation and completion rates of Hmong Americans; and (3) factors associated with HPV literacy in the Hmong American community. Andersen's Behavioral Model of Health Services Use was used as the study's theoretical framework. A self-administered paper and online health survey was completed by192 Hmong Americans living in a major metropolitan area in Minnesota. Results revealed a mean score of 4.76 (SD 1.67) for the 7-item questionnaire measuring HPV knowledge. The HPV vaccination initiation rate was 46.3 % (n = 56), with 32.7 % completing the recommended three doses. Multiple regression analysis found that participants' level of education, number of doctor visits, and cervical cancer screening literacy were significantly associated with HPV knowledge. This study's results indicate the important role of health providers in educating Hmong Americans patients about HPV and cervical cancer prevention to decrease the cervical cancer burden in this high-risk population.

  19. Factors Affecting Diet Variation in the Pyrenean Rock Ptarmigan (Lagopus muta pyrenaica): Conservation Implications.

    PubMed

    García-González, Ricardo; Aldezabal, Arantza; Laskurain, Nere Amaia; Margalida, Antoni; Novoa, Claude

    2016-01-01

    The Pyrenean rock ptarmigan (Lagopus muta pyrenaica) lives at one of the southernmost limits of the ptarmigan range. Their small population sizes and the impacts of global changes are limiting factors in the conservation of this threatened subspecies. An effective conservation policy requires precise basic knowledge of a species' food and habitat requirements, information that is practically non-existent for this Pyrenean population. Here, we describe the diet of a ptarmigan population in the Eastern Pyrenees, the environmental factors influencing its variability and the relationship between diet floristic composition and quality. Diet composition was determined by microhistological analysis of faeces and diet quality was estimated from free-urate faecal N content. Our results show that grouse diet is based mainly on arctic-alpine shrubs of the Ericaceae family, as well as dwarf willows (Salix spp.) and Dryas octopetala. The most frequently consumed plant species was Rhododendron ferrugineum, but its abundance in the diet was negatively related to the diet nitrogen content. Conversely, the abundance of Salix spp., grass leaves and arthropods increased the nitrogen content of the diet. Seasonality associated with snow-melting contributed the most to variability in the Pyrenean ptarmigan diet, differentiating winter from spring/summer diets. The latter was characterised by a high consumption of dwarf willows, flowers, arthropods and tender forb leaves. Geographic area and sex-age class influenced diet variability to a lesser extent. Current temperature increases in the Pyrenees due to global warming may reduce the persistence and surface area of snow-packs where preferred plants for rock ptarmigan usually grow, thus reducing food availability. The high consumption of Rh. ferrugineum characterised the diet of the Pyrenean population. Given the toxicity of this plant for most herbivores, its potential negative effect on Pyrenean ptarmigan populations should be

  20. A cross-regional assessment of the factors affecting ecoliteracy: implications for policy and practice.

    PubMed

    Pilgrim, Sarah; Smith, David; Pretty, Jules

    2007-09-01

    The value of accumulated ecological knowledge, termed ecoliteracy, is vital to both human and ecosystem health. Maintenance of this knowledge is essential for continued support of local conservation efforts and the capacity of communities to self- or co-manage their local resources sustainably. Most previous studies have been qualitative and small scale, documenting ecoliteracy in geographically isolated locations. In this study, we take a different approach, focusing on (1) the primary factors affecting individual levels of ecoliteracy, (2) whether these factors shift with economic development, and (3) if different knowledge protection strategies are required for the future. We compared non-resource-dependent communities in the United Kingdom with resource-dependent communities in India and Indonesia (n=1250 interviews). We found that UK residents with the highest levels of ecoliteracy visited the countryside frequently, lived and grew up in rural areas, and acquired their knowledge from informal word-of-mouth sources, such as parents and friends, rather than television and schooling. The ecoliteracy of resource-dependent community members, however, varied with wealth status and gender. The least wealthy families depended most on local resources for their livelihoods and had the highest levels of ecoliteracy. Gender roles affected both the level and content of an individual's ecoliteracy. The importance of reciprocal oral transfer of this knowledge in addition to direct experience to the maintenance of ecoliteracy was apparent at all sites. Lessons learned may contribute to new local resource management strategies for combined ecoliteracy conservation. Without novel policies, local community management capacity is likely to be depleted in the future.

  1. Factors associated with early growth in Egyptian infants: implications for addressing the dual burden of malnutrition.

    PubMed

    Kavle, Justine A; Flax, Valerie L; Abdelmegeid, Ali; Salah, Farouk; Hafez, Seham; Ramzy, Magda; Hamed, Doaa; Saleh, Gulsen; Galloway, Rae

    2016-01-01

    Optimal nutrition is critical to the attainment of healthy growth, human capital and sustainable development. In Egypt, infants and young children face overlapping forms of malnutrition, including micronutrient deficiencies, stunting and overweight. Yet, in this setting, little is known about the factors associated with growth during the first year of life. A rise in stunting in Lower Egypt from 2005 to 2008 prompted this implementation research study, which followed a longitudinal cohort of infants from birth to 1 year of age within the context of a USAID-funded maternal and child health integrated programme. We sought to determine if growth patterns and factors related to early growth differed in Lower and Upper Egypt, and examined the relationship between weight loss and subsequent stunting at 12 months of age. Growth patterns revealed that length-for-age z-score (LAZ) decreased and weight-for-length z-score (WLZ) increased from 6 to 12 months of age in both regions. One-quarter of infants were stunted and nearly one-third were overweight by 12 months of age in lower Egypt. Minimum dietary diversity was significantly associated with WLZ in Lower Egypt (β = 0.22, P < 0.05), but not in Upper Egypt. Diarrhoea, fever and programme exposure were not associated with any growth outcome. Weight loss during any period was associated with a twofold likelihood of stunting at 12 months in Lower Egypt, but not Upper Egypt. In countries, like Egypt, facing the nutrition transition, infant and young child nutrition programmes need to address both stunting and overweight through improving dietary quality and reducing reliance on energy-dense foods.

  2. Factors supporting self-management in Parkinson's disease: implications for nursing practice.

    PubMed

    Chenoweth, Lynn; Gallagher, Robyn; Sheriff, June N; Donoghue, Judith; Stein-Parbury, Jane

    2008-09-01

    Aim.  To identify the factors associated with better self-management in people with moderate to high levels of Parkinson's disease following an acute illness event. Design and methods.  A prospective, descriptive study conducted with 75 persons with Parkinson's disease over the age of 55, collected twice: within a week of an acute event and 1 month later, after resuming usual life at home. Participants completed a questionnaire on self-rated health status, self-efficacy, sense of coherence, symptom monitoring and medication and general self-management. Background.  Parkinson's disease is a chronic neurological condition that affects many dimensions of life, including threats to self-identity and confidence in self-management. Self-management has the potential to reduce costs through decreased hospital admissions, disease progression and avoidance of complications. While evidence for the relationships between self-management and self-efficacy and sense of coherence has been demonstrated in some chronic illness groups, this has not previously been demonstrated in Parkinson's disease. Results.  The independent predictors of better self-management were not being hospitalized in the last 6 months, more frequent symptom checking and better self-efficacy for self-management. The influence of other factors on self-management, such as sense of coherence, was mediated through self-efficacy. Support of family and others was associated with better self-efficacy both directly and through an improved sense of coherence. Conclusions and relevance to nursing practice.  The presence of informal support plays an important role in sustaining self-efficacy and sense of coherence and hence self-management in persons with Parkinson's disease. Since these attributes are amenable to change, nurses are in a good position to encourage participation in Parkinson's support groups, teach self-management skills through regular symptom monitoring and to assess and promote self

  3. Density profiles of CDM microhalos and their implications for annihilation boost factors

    NASA Astrophysics Data System (ADS)

    Anderhalden, Donnino; Diemand, Juerg

    2013-04-01

    In a standard cold dark matter (CDM) cosmology, microhalos at the CDM cutoff scale are the first and smallest objects expected to form in the universe. Here we present results of high resolution simulations of three representative roughly Earth-mass microhalos in order to determine their inner density profile. We find that CDM microhalos in simulations without a cutoff in the power spectrum roughly follow the NFW density profile, just like the much larger CDM halos on galaxy and galaxy cluster scales. But having a cutoff in the initial power spectrum at a typical neutralino free streaming scale of 10-7Msolar makes their inner density profiles considerably steeper, i.e. ρproptor-(1.3-1.4), in good agreement with the results from Ishiyama et al. (2010). An extrapolation of the halo and subhalo mass functions down to the cutoff scale indicates that microhalos are extremely abundant throughout the present day dark matter distribution and might contribute significantly to indirect dark matter detection signals. Assuming a transition from a NFW to a steeper inner profile (ρproptor-1.4) two orders of magnitude above the cutoff scale, the total boost factor for a Milky Way sized dark matter halo increases from about 3.5 to 4. We further find that CDM microhalo concentrations are consistent with the Bullock et al. (2001) model and clearly rule out simplistic power law models for the mass dependence of concentrations and subhalo annihilation, which would erroneously lead to very large boost factors (a few hundred for galaxy halos and over 1000 for clusters).

  4. Lead in New York City community garden chicken eggs: influential factors and health implications.

    PubMed

    Spliethoff, Henry M; Mitchell, Rebecca G; Ribaudo, Lisa N; Taylor, Owen; Shayler, Hannah A; Greene, Virginia; Oglesby, Debra

    2014-08-01

    Raising chickens for eggs in urban areas is becoming increasingly common. Urban chickens may be exposed to lead, a common urban soil contaminant. We measured lead concentrations in chicken eggs from New York City (NYC) community gardens and collected information on factors that might affect those concentrations. Lead was detected between 10 and 167 μg/kg in 48 % of NYC eggs. Measures of lead in eggs from a henhouse were significantly associated (p < 0.005) with lead concentrations in soil. The association between soil and egg lead has been evaluated only once before, by a study of a rural region in Belgium. In our study, the apparent lead soil-to-egg transfer efficiency was considerably lower than that found in Belgium, suggesting that there may be important geographic differences in this transfer. We developed models that suggested that, for sites like ours, lead concentrations in >50 % of eggs from a henhouse would exceed store-bought egg concentrations (<7-13 μg/kg; 3 % above detection limit) at soil lead concentrations >120 mg/kg and that the concentration in one of six eggs from a henhouse would exceed a 100 μg/kg guidance value at soil lead concentrations >410 mg/kg. Our models also suggested that the availability of dietary calcium supplements was another influential factor that reduced egg lead concentrations. Estimates of health risk from consuming eggs with the lead concentrations we measured generally were not significant. However, soil lead concentrations in this study were <600 mg/kg, and considerably higher concentrations are not uncommon. Efforts to reduce lead transfer to chicken eggs and associated exposure are recommended for urban chicken keepers.

  5. Mechanistic studies of carbon monoxide reduction

    SciTech Connect

    Geoffroy, G.L.

    1990-06-12

    The progress made during the current grant period (1 January 1988--1 April 1990) in three different areas of research is summarized. The research areas are: (1) oxidatively-induced double carbonylation reactions to form {alpha}-ketoacyl complexes and studies of the reactivity of the resulting compounds, (2) mechanistic studies of the carbonylation of nitroaromatics to form isocyanates, carbamates, and ureas, and (3) studies of the formation and reactivity of unusual metallacycles and alkylidene ligands supported on binuclear iron carbonyl fragments. 18 refs., 5 figs., 1 tab.

  6. Mechanistic facility safety and source term analysis

    SciTech Connect

    PLYS, M.G.

    1999-06-09

    A PC-based computer program was created for facility safety and source term analysis at Hanford The program has been successfully applied to mechanistic prediction of source terms from chemical reactions in underground storage tanks, hydrogen combustion in double contained receiver tanks, and proccss evaluation including the potential for runaway reactions in spent nuclear fuel processing. Model features include user-defined facility room, flow path geometry, and heat conductors, user-defined non-ideal vapor and aerosol species, pressure- and density-driven gas flows, aerosol transport and deposition, and structure to accommodate facility-specific source terms. Example applications are presented here.

  7. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations have been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are presented graphically and discussed with respect to their practical significance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distribution with discontinuous changes from mode to mode.

  8. Composite Nanomechanics: A Mechanistic Properties Prediction

    NASA Technical Reports Server (NTRS)

    Chamis, Christos C.; Handler, Louis M.; Manderscheid, Jane M.

    2007-01-01

    A unique mechanistic theory is described to predict the properties of nanocomposites. The theory is based on composite micromechanics with progressive substructuring down to a nanoscale slice of a nanofiber where all the governing equations are formulated. These equations hav e been programmed in a computer code. That computer code is used to predict 25 properties of a mononanofiber laminate. The results are pr esented graphically and discussed with respect to their practical sig nificance. Most of the results show smooth distributions. Results for matrix-dependent properties show bimodal through-the-thickness distr ibution with discontinuous changes from mode to mode.

  9. Factors associated to duration of hepatitis a outbreaks: implications for control.

    PubMed

    Torner, Nuria; Broner, Sonia; Martinez, Ana; Tortajada, Cecilia; Garcia de Olalla, Patricia; Barrabeig, Irene; Sala, MariaRosa; Camps, Neus; Minguell, Sofia; Alvarez, Josep; Ferrús, Gloria; Torra, Roser; Godoy, Pere; Dominguez, Angela

    2012-01-01

    Even though hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. The aim of this study was to investigate the association between duration and characteristics of hepatitis A outbreaks. Hepatitis A (HA) outbreaks reported between 1991 and 2007 were studied. An outbreak was defined as ≥2 epidemiologically-linked cases with ≥1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM) antibodies. Relationships between explanatory variables and outbreak duration were assessed by logistic regression. During the study period, 268 outbreaks (rate 2.45 per million persons-year) and 1396 cases (rate 1.28 per 10(5) persons-year) were reported. Factors associated with shorter duration were time to intervention (OR = 0.96; 95% CI: 0.94-0.98) and school setting (OR = 0.39; 95% CI: 0.16-0.92). In person-to-person transmission outbreaks only time to intervention was associated with shorter outbreak duration (OR = 0.96; 95% CI: 0.95-0.98). The only variables associated with shorter outbreak duration were early administration of IG or vaccine and a school setting. Timely reporting HA outbreaks was associated with outbreak duration. Making confirmed HA infections statutory reportable for clinical laboratories could diminish outbreak duration.

  10. Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications

    PubMed Central

    Lambert, Michele P.; Rauova, Lubica; Bailey, Matthew; Sola-Visner, Martha C.; Kowalska, M. Anna

    2007-01-01

    Platelet factor 4 (PF4) is a negative regulator of megakaryopoiesis in vitro. We have now examined whether PF4 regulates megakaryopoiesis in vivo by studying PF4 knockout mice and transgenic mice that overexpress human (h) PF4. Steady-state platelet count and thrombocrit in these animals was inversely related to platelet PF4 content. Growth of megakaryocyte colonies was also inversely related to platelet PF4 content. Function-blocking anti-PF4 antibody reversed this inhibition of megakaryocyte colony growth, indicating the importance of local PF4 released from developing megakaryocytes. The effect of megakaryocyte damage and release of PF4 on 5-fluorouracil–induced marrow failure was then examined. Severity of thrombocytopenia and time to recovery of platelet counts were inversely related to initial PF4 content. Recovery was faster and more extensive, especially in PF4-overexpressing mice, after treatment with anti-PF4 blocking antibodies, suggesting a means to limit the duration of such a chemotherapy-induced thrombocytopenia, especially in individuals with high endogenous levels of PF4. We found that approximately 8% of 250 healthy adults have elevated (> 2 times average) platelet PF4 content. These individuals with high levels of platelet PF4 may be especially sensitive to developing thrombocytopenia after bone marrow injury and may benefit from approaches that block the effects of released PF4. PMID:17495129

  11. [Expression of SOX11 transcription factor. Its implication in mantle cell lymphoma].

    PubMed

    Roisman, Alejandro; Slavutsky, Irma

    2014-01-01

    SOX11, belonging to the family of genes SOXC, is a transcript factor involved in the embryonic neurogenesis and tissue remodeling, also participating in the control of cell proliferation. Its role in lymphomagenesis still remains unknown. Recent studies have shown aberrant SOX11 nuclear protein expression as well as mRNA levels in patients with mantle cell lymphoma (MCL). Although the majority of these lymphomas have an aggressive clinical course, there is a subgroup of patients with an indolent clinical evolution, suggesting a greater heterogeneity of this disease. Currently, there are contradictions regarding the association of SOX11 gene expression and outcome in MCL, while some authors have related the lack of SOX11 expression with good prognosis, others find it associated with an adverse clinical course. This difference in the gene expression could be associated to epigenetic mechanisms such as modifications at the histone level and DNA methylation that would allow the aberrant expression of this gene in some lymphoid neoplasias, including LCM. More knowledge of gene SOX11 in LCM will lead to a greater understanding of those mechanisms involved in the pathogenesis and progression of this lymphoma, also the involvement of SOX11 in these processes.

  12. Factors influencing sorption of ciprofloxacin onto activated sludge: experimental assessment and modelling implications.

    PubMed

    Polesel, Fabio; Lehnberg, Kai; Dott, Wolfgang; Trapp, Stefan; Thomas, Kevin V; Plósz, Benedek Gy

    2015-01-01

    Many of the pharmaceuticals and personal care products occurring in municipal sewage are ionizing substances, and their partitioning behaviour is affected by ionic interactions with solid matrices. In activated sludge systems, such interactions have currently not been adequately understood and described, particularly for zwitterionic chemicals. Here we present an assessment of the effects of pH and iron salt dosing on the sorption of ciprofloxacin onto activated sludge using laboratory experiments and full-scale fate modelling. Experimental results were described with Freundlich isotherms and showed that non-linear sorption occurred under all the conditions tested. The greatest sorption potential was measured at pH=7.4, at which ciprofloxacin is speciated mostly as zwitterion. Iron salt dosing increased sorption under aerobic and, to a lesser extent, anoxic conditions, whereas no effect was registered under anaerobic conditions. The activated sludge model for xenobiotics (ASM-X) was extended with Freundlich-based sorption kinetics and used to predict the fate of ciprofloxacin in a wastewater treatment plant (WWTP). Scenario simulations, using experimental Freundlich parameters, were used to identify whether the assessed factors caused a significant increase of aqueous ciprofloxacin concentration in full-scale bioreactors. Simulation results suggest that a pH increase, rather than a reduction in iron salt dosing, could be responsible for a systematic deterioration of sorption of ciprofloxacin in the WWTP.

  13. Factors determining milk quality and implications for production structure under somatic cell count standard modification.

    PubMed

    Dong, F; Hennessy, D A; Jensen, H H

    2012-11-01

    Consumer and processor demand for high-quality milk has placed increasing pressure on US milk producers to achieve higher product standards. International standards for somatic cell count (SCC) are becoming more stringent, but in May 2011, the United States National Conference on Interstate Milk Shipments chose to retain the 750,000 cells/mL standard. Using ordinary least squares and quantile regressions on US Department of Agriculture Agricultural Resource Management Survey Dairy Costs and Returns Report data for 2005, we model producer and farm-level characteristics associated with SCC. Quantile regression analysis allows for a more parsed inquiry into statistical associations. Dairy Costs and Returns Report data provide cross-sectional information on the physical structure, input expenses, demographics, and outputs for farms in selected states. Location outside the Southeast, lower herd age, full-time farming status, use of biosecurity guidelines, good milking facilities and operations management, and application of related quality tests are all associated with lower SCC levels. Size of operation had little effect on SCC levels after controlling for other factors. Many of the operations that did not attain a more demanding SCC standard of 400,000 cells/mL had older operators, operators who expressed intention to exit within 10 yr, smaller size, and location in the Southeast when compared with those meeting the tighter standard. The results suggest that the stricter scheme favors larger farms that are more committed to production and are less likely to be sole or family proprietorships.

  14. Psychological factors influencing adoption of postural training devices: implications for practice.

    PubMed

    Fleiter, Judy; Walsh, Shari; Biggs, Herbert

    2009-01-01

    This paper details an exploratory investigation of psychological factors that may influence the adoption/rejection of postural training devices from the perspectives of two potential user groups (clients and practitioners). The aim was to elicit perceived advantages and disadvantages from potential users and to apply psychological principles to examine, and potentially counter perceived barriers to use. A small sample (50) of general public members, physiotherapists and occupational therapists were surveyed using open-ended questions designed to elicit information about current practices and attitudinal beliefs about postural training. Results suggested that members of the public fall into two categories according to whether they would use the device for prevention or treatment. This group identified issues such as lack of need, time consuming, and motivations to comply. Practitioners highlighted that lack of research, lack of ability to trial a product, and issues of cost and non-compliance by consumers and were seen as prohibitory to use. A number of theoretical principles of behaviour change were then related to the findings including: the stages of change model, behavioural learning, message framing, persuasion, attitude-behaviour relationships, motivations and impression management. Client cost objections to treatments and the need to integrate research findings into practice are also discussed.

  15. Fear of Pain as a Prognostic Factor in Chronic Pain: Conceptual Models, Assessment, and Treatment Implications

    PubMed Central

    Wilson, Hilary D.

    2010-01-01

    Chronic pain is a pervasive health care issue affecting over 50 million Americans and costing more than $100 billion dollars annually in lost productivity and health care costs. As a financially and emotionally taxing condition, the families and friends of people with chronic pain, as well as society at large, are affected. Current theory supports the role of biological, psychological, and environmental factors in the etiology, exacerbation, and maintenance of chronic pain. Recently, the specific role of pain-related fear in pain experience has received increasing attention. This article summarizes current understanding of the role of pain-related fear in the onset of acute pain incidents, the transition of acute pain to chronic, and the pain severity and disability of patients with ongoing chronic pain conditions. Treatments demonstrated to reduce pain-related fear are presented, evidence demonstrating their efficacy at reducing disability and pain severity are summarized, and recent criticisms of the fear-avoidance model and future directions are considered. PMID:20425197

  16. Factors influencing the oxidation of cysteamine and other thiols: implications for hyperthermic sensitization and radiation protection

    SciTech Connect

    Biaglow, J.E.; Issels, R.W.; Gerweck, L.E.; Varnes, M.E.; Jacobson, B.; Mittchell, J.B.; Russo, A.

    1984-11-01

    Some of the factors influencing the oxygen uptake and peroxide formation for cysteamine (MEA) and other thiols in serum-supplemented modified McCoy's 5A, a well-known medium used to cultivate a variety of cells in vitro, have been studied. The oxidation of MEA and cysteine in modified McCoy's 5A has been compared with that in Ham's F-12, MEM, and phosphate-buffered saline. The ability to produce peroxide is dependent upon the temperature, the concentration of thiol, the presence of copper ions, and pH of the medium. Catalase also reduces the oxygen uptake for all thiols. Superoxide dismutase (SOD) was found to stimulate the oxygen uptake in the case of MEA and cysteine, but had little or no effect with DTT and glutathione. The combined presence of SOD and catalase resulted in less inhibition of oxygen uptake than that obtained by catalase alone. Alkaline pH was found to enhance the oxidation of cysteine and MEA. The results indicate that many problems may arise when thiols are added to various media. A major consideration is concerned with the production of peroxide, superoxide, and reduced trace metal intermediates. The presence of these intermediates may result in the production of hydroxyl radical intermediates as well as the eventual oxygen depletion from the medium.

  17. Cooking-related pediatric burns: risk factors and the role of differential cooling rates among commonly implicated substances.

    PubMed

    Dissanaike, Sharmila; Boshart, Kimberly; Coleman, Alan; Wishnew, Jenna; Hester, Cynthia

    2009-01-01

    Cooking-related injuries are a common problem worldwide, resulting in more pediatric burns than any other cause. We identified risk factors-associated mechanisms and determined cooling curves for common substances. A retrospective review of children admitted to a Level I burn center between 2001 and 2006 was performed. Variables including injury mechanism, age, sex, race, burn area, length of stay, and outcome were recorded. Commonly implicated substances were identified, and cooling curves for each were measured at room temperature. Logistic regression analysis was performed to identify risk factors for cooking injury. A total of 541 pediatric burn patients were admitted, of whom 123 had cooking-related injuries. Common substances involved included soup (27%), grease (26%), coffee (18%), beans (9%), and menudo (2.3%), a traditional Mexican soup based on tripe, hominy, and chile. Children with cooking injuries were significantly younger than other groups, with a mean age of 2.7 years. The most common mechanism was the child pulling the substance down from a height, accounting for nearly half of all injuries. This resulted in a characteristic scald pattern involving a wide area across chest and shoulders narrowing to a point near the pelvis. The average burn area was 7%, associated with a hospital stay of 4 days and mortality below 1%. Analysis of cooling curves revealed surprising variation in heat retention, with semisolid or high-density liquids posing a markedly increased burn risk. Cooking injuries predominantly affect toddlers, with clearly recognized mechanisms and risk factors. Injury prevention measures should be targeted accordingly.

  18. Calorie restriction and cancer prevention: a mechanistic perspective

    PubMed Central

    2013-01-01

    Calorie restriction (CR) is one of the most potent broadly acting dietary interventions for inducing weight loss and for inhibiting cancer in experimental models. Translation of the mechanistic lessons learned from research on CR to cancer prevention strategies in human beings is important given the high prevalence of excess energy intake, obesity, and metabolic syndrome in many parts of the world and the established links between obesity-associated metabolic perturbations and increased risk or progression of many types of cancer. This review synthesizes findings on the biological mechanisms underlying many of the anticancer effects of CR, with emphasis on the impact of CR on growth factor signaling pathways, inflammation, cellular and systemic energy homeostasis pathways, vascular perturbations, and the tumor microenvironment. These CR-responsive pathways and processes represent targets for translating CR research into effective cancer prevention strategies in human beings. PMID:24280167

  19. Relationship between Audio-Visual Materials and Environmental Factors on Students Academic Performance in Senior Secondary Schools in Borno State: Implications for Counselling

    ERIC Educational Resources Information Center

    Bello, S.; Goni, Umar

    2016-01-01

    This is a survey study, designed to determine the relationship between audio-visual materials and environmental factors on students' academic performance in Senior Secondary Schools in Borno State: Implications for Counselling. The study set two research objectives, and tested two research hypotheses. The population of this study is 1,987 students…

  20. A Peacetime/Wartime Framework. Soviet and Chinese Views of Military and Non-Military Factors in the Balance of Power and Their Implications for the United States

    DTIC Science & Technology

    1984-01-31

    8217Military Factors the Balance of Power and their Implications for the United States Banning N. Garrett 0 Bennie S. Glaser LJI C ~~ Palomar Corporation 1715...fuel for diesel engines, the Soviets have stored hundreds of coal-burning locomotives . pp. 125-126. The Soviets also have huge stacks of assembled

  1. Gender perspective on the factors predicting recycling behavior: Implications from the theory of planned behavior.

    PubMed

    Oztekin, Ceren; Teksöz, Gaye; Pamuk, Savas; Sahin, Elvan; Kilic, Dilek Sultan

    2017-02-17

    This study aimed to assess the role of some socio-psychological attributes in explaining recycling behavior of Turkish university community from a gender perspective within the context of the theory of planned behavior with an additional variable (past experience). The recycling behavior of whole sample, females and males, has been examined in 3 sessions -depending on the arguments that explain gendered pattern of private and public environmental behavior and sticking to the fact why females' stronger environmental values, beliefs, and attitudes do not translate consistently into greater engagement in public behavior. As a result of model runs, different variables shaping intention for behavior have been found, namely perceived behavior control for females and past behavior for males. Due to the low percent of the variance in explaining recycling behavior of females, they have been identified as the ones who do not carry out intentions (non-recyclers). Since intentions alone are capable of identifying recyclers accurately but not non-recyclers, there may be other factors to be considered to understand the reason for females not carrying out the intentions. The results of descriptive statistics supported the identification by attitudes toward recycling. Female attitudes were innate (recycling is good, necessary, useful and sensitive), whereas those of males were learnt (recycling is healthy, valuable and correct). Thus, it has been concluded that males' intention for recycling is shaped by their past behavior and the conclusion is supported by males having learnt attitude toward recycling whereas females' lack of intention for recycling is shaped by their perceived behavior control and is supported by their innate attitude for recycling. All in all, the results of the present study provide further support for the utility of the TPB as a model of behavioral prediction and concur with other studies examining the utility of the TPB in the context of recycling.

  2. Factors influencing the study of peroxidase-generated iodine species and implications for thyroglobulin synthesis.

    PubMed

    Kessler, Jack; Obinger, Christian; Eales, Geoff

    2008-07-01

    A key issue in the mechanism of thyroglobulin (Tg) iodination by thyroperoxidase (TPO) is whether a TPO-bound iodine intermediate directly iodinates Tg-incorporated tyrosines (specific iodination) or whether reactive iodine species released from TPO effectuate Tg iodination (nonspecific iodination). We addressed these alternatives by (a) determining the aqueous equilibria of the iodine species potentially involved in the kinetic studies of TPO-mediated iodination, and (b) reviewing the structure of the substrate channel in mammalian peroxidases. Redox-potentiometric analysis of aqueous iodine combined with integrated mathematical modelling demonstrates that I2 reacts with water to form several iodine species including hypoiodious acid (HOI). The HOI/I2 ratio depends on time, iodide concentration, buffering agents, and pH varying dramatically from pH 4 to 7.4. These factors may confound the use of Michaelis-Menten kinetics to determine the mechanism of TPO-catalyzed iodination since both I2 and HOI iodinate tyrosine but with different specificities and reaction rates. Consequently there is as yet no conclusive kinetic evidence that iodination occurs via formation of a TPO-bound iodinated intermediate. Furthermore, knowledge of TPO structure, gained from X-ray crystallographic studies indicates that access of Tg-bound tyrosyl groups to the active site of TPO is not possible. Thus the emerging conclusion is that the mechanism of Tg iodination is nonspecific. This is consistent with the occurrence of thyroid hormone formation in prevertebrate ascidians which exhibit TPO-like activity but lack the Tg gene.

  3. Appropriateness of mechanistic and non-mechanistic models for the application of ultrafiltration to mixed waste

    SciTech Connect

    Foust, Henry; Ghosehajra, Malay

    2007-07-01

    This study asks two questions: (1) How appropriate is the use of a basic filtration equation to the application of ultrafiltration of mixed waste, and (2) How appropriate are non-parametric models for permeate rates (volumes)? To answer these questions, mechanistic and non-mechanistic approaches are developed for permeate rates and volumes associated with an ultrafiltration/mixed waste system in dia-filtration mode. The mechanistic approach is based on a filtration equation which states that t/V vs. V is a linear relationship. The coefficients associated with this linear regression are composed of physical/chemical parameters of the system and based the mass balance equation associated with the membrane and associated developing cake layer. For several sets of data, a high correlation is shown that supports the assertion that t/V vs. V is a linear relationship. It is also shown that non-mechanistic approaches, i.e., the use of regression models to are not appropriate. One models considered is Q(p) = a*ln(Cb)+b. Regression models are inappropriate because the scale-up from a bench scale (pilot scale) study to full-scale for permeate rates (volumes) is not simply the ratio of the two membrane surface areas. (authors)

  4. Tear gas: an epidemiological and mechanistic reassessment

    PubMed Central

    Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R.

    2016-01-01

    Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved—with aerial drone systems tested and requested by law enforcement—epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain‐sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed. PMID:27391380

  5. Tear gas: an epidemiological and mechanistic reassessment.

    PubMed

    Rothenberg, Craig; Achanta, Satyanarayana; Svendsen, Erik R; Jordt, Sven-Eric

    2016-08-01

    Deployments of tear gas and pepper spray have rapidly increased worldwide. Large amounts of tear gas have been used in densely populated cities, including Cairo, Istanbul, Rio de Janeiro, Manama (Bahrain), and Hong Kong. In the United States, tear gas was used extensively during recent riots in Ferguson, Missouri. Whereas tear gas deployment systems have rapidly improved-with aerial drone systems tested and requested by law enforcement-epidemiological and mechanistic research have lagged behind and have received little attention. Case studies and recent epidemiological studies revealed that tear gas agents can cause lung, cutaneous, and ocular injuries, with individuals affected by chronic morbidities at high risk for complications. Mechanistic studies identified the ion channels TRPV1 and TRPA1 as targets of capsaicin in pepper spray, and of the tear gas agents chloroacetophenone, CS, and CR. TRPV1 and TRPA1 localize to pain-sensing peripheral sensory neurons and have been linked to acute and chronic pain, cough, asthma, lung injury, dermatitis, itch, and neurodegeneration. In animal models, transient receptor potential inhibitors show promising effects as potential countermeasures against tear gas injuries. On the basis of the available data, a reassessment of the health risks of tear gas exposures in the civilian population is advised, and development of new countermeasures is proposed.

  6. The Hormonal Fingerprints and BMI: Implications for Risk Factors in Dental Caries and Malocclusion

    PubMed Central

    Priyanka, Goguladinne Naga Deepthi; Radhakrishna, Ambati Naga; Ramakrishna, Juvva; Jyothi, Velagapudi

    2016-01-01

    Introduction The hormonal fingerprint is the ratio between 2nd and 4th digit lengths. It was evidenced in the medical scenario that it can be used as an indirect marker in many diseases like Coronary Heart Disease (CHD) and metabolic syndromes. As far as dentistry is concerned very few studies in the literature have been done to evaluate the influence of hormonal fingerprint on oral health, thus provoking us to formulate new method for predicting dental caries and malocclusion and its association with Body Mass Index (BMI). Aim The purpose of this retrospective study was to highlight the role of new biological marker–Hormonal fingerprints in the early detection of malocclusion, caries, the influence of BMI on malocclusion and caries. We also attempted to study the correlation of BMI with hormonal fingerprints. Materials and Methods A total of 300 children were randomly selected from both sexes of age group 10-15 years. The hormonal fingerprint was made by measuring the length ratio of the index and ring finger with the help of digital Vernier caliper. Anthropometric measures (weight in kilograms and height in metres) for the calculation of BMI were recorded. Caries assessment was done using standard mouth mirrors and Community Periodontal Index probes. DMFT index was followed for assessment of caries according to the WHO assessment form, 1997. Occlusal characteristics of the children evaluated were molar relation, anterior and posterior cross bite, open bite, deep bite, lower anterior crowding. All the factors were recorded by two investigators. Results The results of the study showed that majority of the children among study population were having 2D:4D <1. The rate of occurrence of malocclusion was increasing with increase in the value of 2D:4D ratio with a statistically significant p-value of <0.001. Higher BMI values were associated with normal occlusal conditions (p= 0.041) and lower 2D:4D ratio (p= 0.037). High caries experience was noticed in children with

  7. Mechanistic modeling of aberrant energy metabolism in human disease

    PubMed Central

    Sangar, Vineet; Eddy, James A.; Simeonidis, Evangelos; Price, Nathan D.

    2012-01-01

    Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. PMID:23112774

  8. A brief review of exercise, bipolar disorder, and mechanistic pathways

    PubMed Central

    Thomson, Daniel; Turner, Alyna; Lauder, Sue; Gigler, Margaret E.; Berk, Lesley; Singh, Ajeet B.; Pasco, Julie A.; Berk, Michael; Sylvia, Louisa

    2015-01-01

    Despite evidence that exercise has been found to be effective in the treatment of depression, it is unclear whether these data can be extrapolated to bipolar disorder. Available evidence for bipolar disorder is scant, with no existing randomized controlled trials having tested the impact of exercise on depressive, manic or hypomanic symptomatology. Although exercise is often recommended in bipolar disorder, this is based on extrapolation from the unipolar literature, theory and clinical expertise and not empirical evidence. In addition, there are currently no available empirical data on program variables, with practical implications on frequency, intensity and type of exercise derived from unipolar depression studies. The aim of the current paper is to explore the relationship between exercise and bipolar disorder and potential mechanistic pathways. Given the high rate of medical co-morbidities experienced by people with bipolar disorder, it is possible that exercise is a potentially useful and important intervention with regard to general health benefits; however, further research is required to elucidate the impact of exercise on mood symptomology. PMID:25788889

  9. Physical activity and its mechanistic effects on prostate cancer.

    PubMed

    Wekesa, A; Harrison, M; Watson, R W

    2015-09-01

    Beneficial effects of physical activity have been illustrated in numerous aspects of health. With the increasing incidence of prostate cancer and changes in physical activity of men, understanding the link between the two has important implications for changing this cancer burden. Both positive and negative associations between physical activity and prostate cancer have been previously demonstrated in observational epidemiological studies. Elucidating the biological mechanisms would lead to a better understanding of how physical activity influences the progression of prostate cancer. This review was undertaken to: (1) identify evidence in literature that demonstrates the effects of physical activity on skeletal muscle secretomes, (2) indicate the plausible signaling pathways these proteins might activate, and (3) identify evidence in literature that demonstrates the roles of the signaling pathways in prostate cancer progression and regression. We also discuss proposed biological mechanisms and signaling pathways by which physical activity may prevent the development and progression of prostate cancer. We discuss proteins involved in the normal and aberrant growth and development of the prostate gland that may be affected by physical activity. We further identify future directions for research, including a better understanding of the biological mechanisms, the need to standardize physical activity and identify mechanistic end points of physical activity that can then be correlated with outcomes.

  10. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment.

    PubMed

    Chatzizisis, Yiannis S; Koskinas, Konstantinos C; Misirli, Gesthimani; Vaklavas, Christos; Hatzitolios, Apostolos; Giannoglou, George D

    2010-03-01

    HMG-CoA reductase inhibitors ('statins') represent the most effective and widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, a critical therapeutic target for primary and secondary prevention of cardiovascular atherosclerotic disease. In the face of the established lipid lowering and the emerging pleiotropic properties of statins, the patient population suitable for long-term statin treatment is expected to further expand. An overall positive safety and tolerability profile of statins has been established, although adverse events have been reported. Skeletal muscle-related events are the most common adverse events of statin treatment. Statin-induced myopathy can (rarely) manifest with severe and potentially fatal cases of rhabdomyolysis, thus rendering the identification of the underlying predisposing factors critical. The purpose of this review is to summarize the factors that increase the risk of statin-related myopathy. Data from published clinical trials, meta-analyses, postmarketing studies, spontaneous report systems and case reports for rare effects were reviewed. Briefly, the epidemiology, clinical spectrum and molecular mechanisms of statin-associated myopathy are discussed. We further analyse in detail the risk factors that precipitate or increase the likelihood of statin-related myopathy. Individual demographic features, genetic factors and co-morbidities that may account for the significant interindividual variability in the myopathic risk are presented. Physicochemical properties of statins have been implicated in the differential risk of currently marketed statins. Pharmacokinetic interactions with concomitant medications that interfere with statin metabolism and alter their systemic bioavailability are reviewed. Of particular clinical interest in cases of resistant dyslipidaemia is the interaction of statins with other classes of lipid-lowering agents; current data on the relative safety of available

  11. Stable isotope composition in Daphnia is modulated by growth, temperature, and toxic exposure: implications for trophic magnification factor assessment.

    PubMed

    Ek, Caroline; Karlson, Agnes M L; Hansson, Sture; Garbaras, Andrius; Gorokhova, Elena

    2015-06-02

    The potential for using stable isotope analysis in risk assessment of environmental contaminants is crucially dependent on the predictability of the trophic transfer of isotopes in food webs. The relationship between contaminant levels and trophic position of consumers is widely used to assess biomagnification properties of various pollutants by establishing trophic magnification factors (TMF). However, contaminant-induced variability of the isotopic composition in biota is poorly understood. Here, we investigated effects of toxic exposure on δ(15)N and δ(13)C values in a consumer, with a main hypothesis that these effects would be largely mediated via growth rate and metabolic turnover of the test animals. The cladoceran Daphnia magna was used in two experiments that were conducted to manipulate growth and body condition (assayed as C:N ratio) by food availability and temperature (Experiment 1) and by toxic exposure to the pesticide lindane (Experiment 2). We found a significant negative effect of growth rate and a positive effect of temperature on the consumer-diet discrimination factor for δ(15)N and δ(13)C, with no effects on the C:N ratio (Experiment 1). In lindane-exposed daphnids, a significant growth inhibition was observed, with concomitant increase in metabolic costs and significantly elevated size-specific δ(15)N and δ(13)C values. Moreover, a significantly higher incorporation of carbon relative to nitrogen, yet a concomitant decrease in C:N ratio was observed in the exposed animals. Together, these results have methodological implications for determining trophic positions and TMF in polluted environments, where elevated δ(15)N values would translate into overestimated trophic positions and underestimated TMF. Furthermore, altered δ(13)C values may lead to erroneous food-chain assignment of the consumer in question.

  12. DNA methylation analysis of Homeobox genes implicates HOXB7 hypomethylation as risk factor for neural tube defects.

    PubMed

    Rochtus, Anne; Izzi, Benedetta; Vangeel, Elise; Louwette, Sophie; Wittevrongel, Christine; Lambrechts, Diether; Moreau, Yves; Winand, Raf; Verpoorten, Carla; Jansen, Katrien; Van Geet, Chris; Freson, Kathleen

    2015-01-01

    Neural tube defects (NTDs) are common birth defects of complex etiology. Though family- and population-based studies have confirmed a genetic component, the responsible genes for NTDs are still largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, epigenetic factors, such as DNA methylation, are predicted to be involved in NTDs. Homeobox (HOX) genes play a role in spinal cord development and are tightly regulated in a spatiotemporal and collinear manner, partly by epigenetic modifications. We have quantified DNA methylation for the different HOX genes by subtracting values from a genome-wide methylation analysis using leukocyte DNA from 10 myelomeningocele (MMC) patients and 6 healthy controls. From the 1575 CpGs profiled for the 4 HOX clusters, 26 CpGs were differentially methylated (P-value < 0.05; β-difference > 0.05) between MMC patients and controls. Seventy-seven percent of these CpGs were located in the HOXA and HOXB clusters, with the most profound difference for 3 CpGs within the HOXB7 gene body. A validation case-control study including 83 MMC patients and 30 unrelated healthy controls confirmed a significant association between MMC and HOXB7 hypomethylation (-14.4%; 95% CI: 11.9-16.9%; P-value < 0.0001) independent of the MTHFR 667C>T genotype. Significant HOXB7 hypomethylation was also present in 12 unaffected siblings, each related to a MMC patient, suggestive of an epigenetic change induced by the mother. The inclusion of a neural tube formation model using zebrafish showed that Hoxb7a overexpression but not depletion resulted in deformed body axes with dysmorphic neural tube formation. Our results implicate HOXB7 hypomethylation as risk factor for NTDs and highlight the importance for future genome-wide DNA methylation analyses without preselecting candidate pathways.

  13. Reaction Coordinates and Mechanistic Hypothesis Tests

    NASA Astrophysics Data System (ADS)

    Peters, Baron

    2016-05-01

    Reaction coordinates are integral to several classic rate theories that can (a) predict kinetic trends across conditions and homologous reactions, (b) extract activation parameters with a clear physical interpretation from experimental rates, and (c) enable efficient calculations of free energy barriers and rates. New trajectory-based rare events methods can provide rates directly from dynamical trajectories without a reaction coordinate. Trajectory-based frameworks can also generate ideal (but abstract) reaction coordinates such as committors and eigenfunctions of the master equation. However, rates and mechanistic insights obtained from trajectory-based methods and abstract coordinates are not readily generalized across simulation conditions or reaction families. We discuss methods for identifying physically meaningful reaction coordinates, including committor analysis, variational transition state theory, Kramers-Langer-Berezhkovskii-Szabo theory, and statistical inference methods that can use path sampling data to screen, mix, and optimize thousands of trial coordinates. Special focus is given to likelihood maximization and inertial likelihood maximization approaches.

  14. Mechanistic investigations of the ethylene tetramerisation reaction.

    PubMed

    Overett, Matthew J; Blann, Kevin; Bollmann, Annette; Dixon, John T; Haasbroek, Daleen; Killian, Esna; Maumela, Hulisani; McGuinness, David S; Morgan, David H

    2005-08-03

    The unprecedented selective tetramerisation of ethylene to 1-octene was recently reported. In the present study various mechanistic aspects of this novel transformation were investigated. The unusually high 1-octene selectivity in chromium-catalyzed ethylene tetramerisation reactions is caused by the unique extended metallacyclic mechanism in operation. Both 1-octene and higher 1-alkenes are formed by further ethylene insertion into a metallacycloheptane intermediate, whereas 1-hexene is formed by elimination from this species as in other reported trimerisation reactions. This is supported by deuterium labeling studies, analysis of the molar distribution of 1-alkene products, and identification of secondary co-oligomerization reaction products. In addition, the formation of two C6 cyclic products, methylenecyclopentane and methylcyclopentane, is discussed, and a bimetallic disproportionation mechanism to account for the available data is proposed.

  15. Mechanistic issues in asparagine synthetase catalysis.

    PubMed

    Richards, N G; Schuster, S M

    1998-01-01

    The enzymatic synthesis of asparagine is an ATP-dependent process that utilizes the nitrogen atom derived from either glutamine or ammonia. Despite a long history of kinetic and mechanistic investigation, there is no universally accepted catalytic mechanism for this seemingly straightforward carboxyl group activating enzyme, especially as regards those steps immediately preceding amide bond formation. This chapter considers four issues dealing with the mechanism: (a) the structural organization of the active site(s) partaking in glutamine utilization and aspartate activation; (b) the relationship of asparagine synthetase to other amidotransferases; (c) the way in which ATP is used to activate the beta-carboxyl group; and (d) the detailed mechanism by which nitrogen is transferred.

  16. Mechanistic interplay between ceramide and insulin resistance

    PubMed Central

    Reali, Federico; Morine, Melissa J.; Kahramanoğulları, Ozan; Raichur, Suryaprakash; Schneider, Hans-Christoph; Crowther, Daniel; Priami, Corrado

    2017-01-01

    Recent research adds to a growing body of literature on the essential role of ceramides in glucose homeostasis and insulin signaling, while the mechanistic interplay between various components of ceramide metabolism remains to be quantified. We present an extended model of C16:0 ceramide production through both the de novo synthesis and the salvage pathways. We verify our model with a combination of published models and independent experimental data. In silico experiments of the behavior of ceramide and related bioactive lipids in accordance with the observed transcriptomic changes in obese/diabetic murine macrophages at 5 and 16 weeks support the observation of insulin resistance only at the later phase. Our analysis suggests the pivotal role of ceramide synthase, serine palmitoyltransferase and dihydroceramide desaturase involved in the de novo synthesis and the salvage pathways in influencing insulin resistance versus its regulation. PMID:28112248

  17. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

    PubMed Central

    Perl, Andras

    2017-01-01

    Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4−CD8− (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4+CD25+FoxP3+ T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of Tfollicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases. PMID:26698023

  18. Evaluating National Environmental Sustainability: Performance Measures and Influential Factors for OECD-Member Countries featuring Canadian Performance and Policy Implications

    NASA Astrophysics Data System (ADS)

    Calbick, Kenneth S.

    This research reviews five studies that evaluate national environmental sustainability with composite indices; performs uncertainty and sensitivity analyses of techniques for building a composite index; completes principal components factor analysis to help build subindices measuring waste and pollution, sustainable energy, sustainable food, nature conservation, and sustainable cities (Due to its current importance, the greenhouse gases (GHG) indicator is included individually as another policy measure.); analyses factors that seem to influence performance: climate, population growth, population density, economic output, technological development, industrial structure, energy prices, environmental governance, pollution abatement and control expenditures, and environmental pricing; and explores Canadian policy implications of the results. The techniques to build composite indices include performance indicator selection, missing data treatment, normalisation technique, scale-effect adjustments, weights, and aggregation method. Scale-effect adjustments and normalisation method are significant sources of uncertainty inducing 68% of the observed variation in a country's final rank at the 95% level of confidence. Choice of indicators also introduces substantial variation as well. To compensate for this variation, the current study recommends that a composite index should always be analysed with other policy subindices and individual indicators. Moreover, the connection between population and consumption indicates that per capita scale-effect adjustments should be used for certain indicators. Rather than ranking normalisation, studies should use a method that retains information from the raw indicator values. Multiple regression and cluster analyses indicate economic output, environmental governance, and energy prices are major influential factors, with energy prices the most important. It is statistically significant for five out of seven performance measures at the 95

  19. Mechanistic Differences Leading to Infectious and Sterile Inflammation.

    PubMed

    Behnia, Faranak; Sheller, Samantha; Menon, Ramkumar

    2016-05-01

    Inflammation is a physiologic component of pregnancy and parturition. Overwhelming intrauterine inflammatory load promotes quiescent feto-maternal tissues into a contractile phenotype. Like inflammation, oxidative stress is an inevitable component of both pregnancy and parturition. Pathologic activation of host innate immune response to adverse pregnancy conditions can lead to premature activation of inflammatory and oxidative stress. Inflammation and oxidative stress markers seen with both sterile and infectious inflammation are often similar; therefore, it is difficult to understand causality of conditions like spontaneous preterm birth. This review demonstrates potential mechanistic pathways of activation of sterile and infectious inflammation. We demonstrate the activation of two unique pathways of inflammation by factors that are well-documented proxies for oxidative stress (cigarette smoke extract) and infection (lipopolysaccharide). Sterile inflammation seen after exposure to an oxidative stress inducer is due to cellular elemental damage resulting in p38 mitogen-activated protein kinase (MAPK) induced cellular senescence. Infectious inflammation is through activation of transcription factor NF-κB and independent of oxidative stress-associated damages and p38 MAPK-induced senescence. Understanding the differences in the inflammatory pathway activation by various risk factors is important to design better screening, diagnostic and intervention strategies to reduce the risks of adverse pregnancy outcomes.

  20. Framingham Risk Score underestimates cardiovascular disease risk in severe psoriatic patients: implications in cardiovascular risk factors management and primary prevention of cardiovascular disease.

    PubMed

    Torres, Tiago; Sales, Rita; Vasconcelos, Carlos; Martins da Silva, Berta; Selores, Manuela

    2013-11-01

    Severe psoriasis has been associated with increase cardiovascular mortality, due to a higher prevalence of traditional cardiovascular risk factors and premature atherosclerosis, as a consequence of its systemic inflammation. Recently, it has been estimated that severe psoriasis may confer an increased 6.2% on long-term risk of cardiovascular disease based on Framingham Risk Score, which can have practical implications in the treatment of cardiovascular risk factors and primary prevention of cardiovascular disease, as treatment guidelines account for the risk of cardiovascular disease in treatment goals. The aim of this study was to analyze the influence of the attributable risk of severe psoriasis on long-term risk of cardiovascular disease and its implication on the correct treatment of cardiovascular risk factors and primary prevention of cardiovascular disease on a real-world cohort of patients. One hundred severe psoriasis patients without psoriatic arthritis or previous cardiovascular disease were evaluated and it was found that more than half of the patients were reclassified to a higher cardiovascular risk category with important clinical implications on the correct management of their cardiovascular risk factors and primary prevention of cardiovascular disease, as a considerable proportion of patients with hypertension, hypercholesterolemia and coronary heart disease equivalent risk were not being correctly managed.

  1. Diversity Takes Shape: Understanding the Mechanistic and Adaptive Basis of Bacterial Morphology

    PubMed Central

    2016-01-01

    The modern age of metagenomics has delivered unprecedented volumes of data describing the genetic and metabolic diversity of bacterial communities, but it has failed to provide information about coincident cellular morphologies. Much like metabolic and biosynthetic capabilities, morphology comprises a critical component of bacterial fitness, molded by natural selection into the many elaborate shapes observed across the bacterial domain. In this essay, we discuss the diversity of bacterial morphology and its implications for understanding both the mechanistic and the adaptive basis of morphogenesis. We consider how best to leverage genomic data and recent experimental developments in order to advance our understanding of bacterial shape and its functional importance. PMID:27695035

  2. Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection: mechanistic considerations and clinical relevance

    PubMed Central

    Bencherif, Merouane

    2009-01-01

    A number of studies have confirmed the potential for neuronal nicotinic acetylcholine receptor (NNR)-mediated neuroprotection and, more recently, its anti-inflammatory effects. The mechanistic overlap between these pathways and the ubiquitous effects observed following diverse insults suggest that NNRs modulate fundamental pathways involved in cell survival. These results have wide-reaching implications for the design of experimental therapeutics that regulate inflammatory and anti-apoptotic responses through NNRs and represent an initial step toward understanding the benefits of novel therapeutic strategies for the management of central nervous system disorders that target neuronal survival and associated inflammatory processes. PMID:19498416

  3. Intriguing mechanistic labyrinths in gold(i) catalysis

    PubMed Central

    Obradors, Carla

    2014-01-01

    Many mechanistically intriguing reactions have been developed in the last decade using gold(i) as catalyst. Here we review the main mechanistic proposals in gold-catalysed activation of alkynes and allenes, in which this metal plays a central role by stabilising a variety of complex cationic intermediates. PMID:24176910

  4. Crystal Structure of Human Plasma Platelet-activating Factor Acetylhydrolase: Structural Implication to Liporprotein Binding and Catalysis

    SciTech Connect

    Samanta, Uttamkumar; Bahnson, Brian J.

    2009-02-23

    Human plasma platelet-activating factor (PAF) acetylhydrolase functions by reducing PAF levels as a general anti-inflammatory scavenger and is linked to anaphylactic shock, asthma, and allergic reactions. The enzyme has also been implicated in hydrolytic activities of other pro-inflammatory agents, such as sn-2 oxidatively fragmented phospholipids. This plasma enzyme is tightly bound to low and high density lipoprotein particles and is also referred to as lipoprotein-associated phospholipase A2. The crystal structure of this enzyme has been solved from x-ray diffraction data collected to a resolution of 1.5 angstroms. It has a classic lipase alpha/beta-hydrolase fold, and it contains a catalytic triad of Ser273, His351, and Asp296. Two clusters of hydrophobic residues define the probable interface-binding region, and a prediction is given of how the enzyme is bound to lipoproteins. Additionally, an acidic patch of 10 carboxylate residues and a neighboring basic patch of three residues are suggested to play a role in high density lipoprotein/low density lipoprotein partitioning. A crystal structure is also presented of PAF acetylhydrolase reacted with the organophosphate compound paraoxon via its active site Ser273. The resulting diethyl phosphoryl complex was used to model the tetrahedral intermediate of the substrate PAF to the active site. The model of interface binding begins to explain the known specificity of lipoprotein-bound substrates and how the active site can be both close to the hydrophobic-hydrophilic interface and at the same time be accessible to the aqueous phase.

  5. Predictive mechanistic bioenergetics to model habitat suitability of shellfish culture in coastal lakes

    NASA Astrophysics Data System (ADS)

    Rinaldi, A.; Montalto, V.; Manganaro, A.; Mazzola, A.; Mirto, S.; Sanfilippo, M.; Sarà, G.

    2014-05-01

    Quantitative tools based on mechanistic modelling of functional traits able to enhance the sustainability of aquaculture and most other human activities (i.e. reducing the likelihood of detrimental impacts optimising productions), are especially important factors in the decision to site aquaculture facilities in coastal lakes, ponds and lagoons and, in the case of detrimental impact, to adopt mitigation measures. We tested the ability of mechanistic functional trait based models to predict life history traits of cultivable shellfish in shallow coastal lakes. Dynamic Energy Budget (DEB) models were run to generate spatially explicit predictions of Mytilus galloprovincialis life history (LH) traits (e.g. body size and fecundity). Using fortnightly data of food supply and hourly data of body temperatures, and exploiting the power of mechanistic rules, we estimated the amount of faeces ejected by a fixed quantity of organisms cultivated in two shallow Southern Mediterranean (Sicily) lakes. These differed in terms of temperature and food density, implying large differences in life history traits of mussels in the two study areas. This information could help facilitate the selection of sites where environmental conditions are more suitable for aquaculture and contextually compatible with sustainability. The validation exercise obtained by comparing the predicted and observed data was nearly consistent. Therefore, a mechanistic functional traits-based model seems able to capture the link between habitat characteristics and functional traits of organisms, delineating the fundamental portion of an ecological niche, the possibility of predicting LH traits and potential ecological applications in the management of natural coastal resources.

  6. The mechanistic-holistic divide revisited: The case of the lac operon.

    PubMed

    Racine, Valérie

    2016-10-01

    In this paper, I revisit the development of the repression model of genetic regulation in the lac operon to challenge a common application of a conceptual framework in the history of biology. I take Allen's (1978) account of the changes in the life sciences during the early and mid-twentieth century as an example of a common application of a framework based on the dichotomy between a mechanistic, or reductionist, approach to science and a holistic one. From this conceptual framework, Allen infers two general claims about the process of science and its goals: (1) that "mechanistic materialism" has often presented a more practical way to begin the study of complex phenomena in the life sciences, and (2) that the approach described as "holistic materialism" provides a more complete or accurate description of the natural world. The development of the lac operon model does not fit Allen's generalizations about scientific developments, and it can be used to cast some doubt on the scope of application of that conceptual framework. I argue that a better framework to interpret particular episodes in the history of molecular biology is to consider the ways in which biologists prioritize and track different aspects of the phenomena under study, rather than to focus on whether certain scientific practices are best described as developing from mechanistic to more holistic approaches. I end with some implications for the historiography of science by considering the appropriateness of different conceptual frameworks for different grains of resolution in the history of biology.

  7. Integrating mechanistic and polymorphism data to characterize human genetic susceptibility for environmental chemical risk assessment in the 21st century

    SciTech Connect

    Mortensen, Holly M.; Euling, Susan Y.

    2013-09-15

    Response to environmental chemicals can vary widely among individuals and between population groups. In human health risk assessment, data on susceptibility can be utilized by deriving risk levels based on a study of a susceptible population and/or an uncertainty factor may be applied to account for the lack of information about susceptibility. Defining genetic susceptibility in response to environmental chemicals across human populations is an area of interest in the NAS' new paradigm of toxicity pathway-based risk assessment. Data from high-throughput/high content (HT/HC), including -omics (e.g., genomics, transcriptomics, proteomics, metabolomics) technologies, have been integral to the identification and characterization of drug target and disease loci, and have been successfully utilized to inform the mechanism of action for numerous environmental chemicals. Large-scale population genotyping studies may help to characterize levels of variability across human populations at identified target loci implicated in response to environmental chemicals. By combining mechanistic data for a given environmental chemical with next generation sequencing data that provides human population variation information, one can begin to characterize differential susceptibility due to genetic variability to environmental chemicals within and across genetically heterogeneous human populations. The integration of such data sources will be informative to human health risk assessment.

  8. Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling

    PubMed Central

    Ye, Hao; Beamish, Richard J.; Glaser, Sarah M.; Grant, Sue C. H.; Hsieh, Chih-hao; Richards, Laura J.; Schnute, Jon T.; Sugihara, George

    2015-01-01

    It is well known that current equilibrium-based models fall short as predictive descriptions of natural ecosystems, and particularly of fisheries systems that exhibit nonlinear dynamics. For example, model parameters assumed to be fixed constants may actually vary in time, models may fit well to existing data but lack out-of-sample predictive skill, and key driving variables may be misidentified due to transient (mirage) correlations that are common in nonlinear systems. With these frailties, it is somewhat surprising that static equilibrium models continue to be widely used. Here, we examine empirical dynamic modeling (EDM) as an alternative to imposed model equations and that accommodates both nonequilibrium dynamics and nonlinearity. Using time series from nine stocks of sockeye salmon (Oncorhynchus nerka) from the Fraser River system in British Columbia, Canada, we perform, for the the first time to our knowledge, real-data comparison of contemporary fisheries models with equivalent EDM formulations that explicitly use spawning stock and environmental variables to forecast recruitment. We find that EDM models produce more accurate and precise forecasts, and unlike extensions of the classic Ricker spawner–recruit equation, they show significant improvements when environmental factors are included. Our analysis demonstrates the strategic utility of EDM for incorporating environmental influences into fisheries forecasts and, more generally, for providing insight into how environmental factors can operate in forecast models, thus paving the way for equation-free mechanistic forecasting to be applied in management contexts. PMID:25733874

  9. Mechanistically based mapping of human cardiac fibrillation

    PubMed Central

    Zaman, Junaid A. B.

    2016-01-01

    Abstract The mechanisms underpinning human cardiac fibrillation remain elusive. In his 1913 paper ‘On dynamic equilibrium in the heart’, Mines proposed that an activation wave front could propagate repeatedly in a circle, initiated by a stimulus in the vulnerable period. While the dynamics of activation and recovery are central to cardiac fibrillation, these physiological data are rarely used in clinical mapping. Fibrillation is a rapid irregular rhythm with spatiotemporal disorder resulting from two fundamental mechanisms – sources in preferred cardiac regions or spatially diffuse self‐sustaining activity, i.e. with no preferred source. On close inspection, however, this debate may also reflect mapping technique. Fibrillation is initiated from triggers by regional dispersion in repolarization, slow conduction and wavebreak, then sustained by non‐uniform interactions of these mechanisms. Notably, optical mapping of action potentials in atrial fibrillation (AF) show spiral wave sources (rotors) in nearly all studies including humans, while most traditional electrogram analyses of AF do not. Techniques may diverge in fibrillation because electrograms summate non‐coherent waves within an undefined field whereas optical maps define waves with a visually defined field. Also fibrillation operates at the limits of activation and recovery, which are well represented by action potentials while fibrillatory electrograms poorly represent repolarization. We conclude by suggesting areas for study that may be used, until such time as optical mapping is clinically feasible, to improve mechanistic understanding and therapy of human cardiac fibrillation. PMID:26607671

  10. Mechanistic simulation of line-edge roughness

    NASA Astrophysics Data System (ADS)

    Biafore, John J.; Smith, Mark D.; Robertson, Stewart A.; Graves, Trey

    2007-03-01

    Physically-based photoresist models, such as those in PROLITH, have been very successful in describing photolithography from a continuum standpoint. These models allow engineers to accurately predict the final resist CD on the wafer and to analyze process robustness. However, as the critical dimension continues to shrink, yield-limiting phenomena are observed that are related to the molecular nature and reaction kinetics of photoresist materials. An example of these phenomena is line-edge roughness (LER). In this paper, the origin of LER is hypothesized to be caused by fluctuations occurring in the initial position of the reactants, fluctuations during the exposure process (shot noise) and fluctuations occurring during thermally-induced reaction-diffusion (post-exposure bake). We have developed a lattice-based mechanistic simulator to better understand the stochastic nature of reactant initial position, the exposure step, the importance of the discrete nature of the reactants, the coupling to the deprotection kinetics and the deep complexity evident in the diffusion-limited acid-quencher reaction.

  11. Mechanistic Reactive Burn Modeling of Solid Explosives

    SciTech Connect

    Y.Horie; Y.Hamate; D.Greening

    2003-04-01

    This report describes a computational framework for reactive burn modeling of solid explosives and the development of a test case where physical mechanisms represent RDX or RDX-based materials. The report is a sequel to LA-13794-MS, ''A Unifying Framework for Hot Spots and the Ignition of Energetic Materials,'' where we proposed a new approach to the building of a general purpose model that captures the essential features of the three primary origins of hot-spot formation: void collapse, shear banding, friction. The purpose of the present report is to describe the continuing task of coupling the unifying hot-spot model to hydrodynamic calculations to develop a mechanistic reactive burn model. The key components of the coupling include energy localization, the growth of hot spots, overall hot-spot behavior, and a phase-averaged mixture equation of state (EOS) in a Mie-Grueneisen form. The nucleation and growth of locally heated regions is modeled by a phenomenological treatment as well as a statistical model based on an exponential size distribution. The Mie-Grueneisen form of the EOS is one of many possible choices and is not a critical selection for implementing the model. In this report, model calculations are limited to proof-of-concept illustrations for shock loading. Results include (1) shock ignition and growth-to-detonation, (2) double shock ignition, and (3) quenching and reignition. A comparative study of Pop-plots is discussed based on the statistical model.

  12. Mechanistic studies of ubiquitin C-terminal hydrolase L1.

    PubMed

    Case, April; Stein, Ross L

    2006-02-21

    Ubiquitin C-terminal hydrolases (UCHs) cleave Ub-X bonds (Ub is ubiquitin and X an alcohol, an amine, or a protein) through a thioester intermediate that is produced by nucleophilic attack of the Cys residue of a Cys-SH/His-Im catalytic diad. We are studying the mechanism of UCH-L1, a UCH that is implicated in Parkinson's disease, and now wish to report our initial findings. (i) Pre-steady-state kinetic studies for UCH-L1-catalyzed hydrolysis of Ub-AMC (AMC, 7-amido-4-methylcoumarin) indicate that k(cat) is rate-limited by acyl-enzyme formation. Thus, K(m) = K(s), the dissociation constant for the Michaelis complex, and k(cat) = k(2), the rate constant for acyl-enzyme formation. (ii) For K(assoc) (=K(s)(-)(1)), DeltaC(p) = -0.8 kcal mol(-)(1) deg(-)(1) and is consistent with coupling between substrate association and a conformational change of the enzyme. For k(2), DeltaS(++) = 0 and suggests that in the E-S, substrate and active site residues are precisely aligned for reaction. (iii) Solvent isotope effects are (D)K(assoc) = 0.5 and (D)k(2) = 0.9, suggesting that the substrate binds to a form of free enzyme in which the active site Cys exists as the thiol. In the resultant Michaelis complex, the diad has tautomerized to ion pair Cys-S(-)/His-ImH(+). Subsequent attack of thiolate produces the acyl-enzyme species. In contrast, isotope effects for association of UCH-L1 with transition-state analogue ubiquitin aldehyde suggest that an alternative mechanistic pathway can sometimes be available to UCH-L1 involving general base-catalyzed attack of Cys-SH by His-Im.

  13. Ligand interactions with galactose oxidase: mechanistic insights.

    PubMed Central

    Whittaker, M M; Whittaker, J W

    1993-01-01

    Interactions between galactose oxidase and small molecules have been explored using a combination of optical absorption, circular dichroism, and electron paramagnetic resonance (EPR) spectroscopies to detect complex formation and characterize the products. Anions bind directly to the cupric center in both active and inactive galactose oxidase, converting to complexes with optical and EPR spectra that are distinctly different from those of the starting aquo enzyme. Azide binding is coupled to stoichiometric proton uptake by the enzyme, reflecting the generation of a strong base (pKa > 9) in the active site anion adduct. At low temperature, the aquo enzyme converts to a form that exhibits the characteristic optical and EPR spectra of an anion complex, apparently reflecting deprotonation of the coordinated water. Anion binding results in a loss of the optical transition arising from coordinated tyrosine, implying displacement of the axial tyrosine ligand on forming the adduct. Nitric oxide binds to galactose oxidase, forming a specific complex exhibiting an unusual EPR spectrum with all g values below 2. The absence of Cu splitting in this spectrum and the observation that the cupric EPR signal from the active site metal ion is not significantly decreased in the complex suggest a nonmetal interaction site for NO in galactose oxidase. These results have been interpreted in terms of a mechanistic scheme where substrate binding displaces a tyrosinate ligand from the active site cupric ion, generating a base that may serve to deprotonate the coordinated hydroxyl group of the substrate, activating it for oxidation. The protein-NO interactions may probe a nonmetal O2 binding site in this enzyme. PMID:8386015

  14. Clinical and Mechanistic Drivers of Acute Traumatic Coagulopathy

    PubMed Central

    Cohen, Mitchell Jay; Kutcher, Matt; Redick, Britt; Nelson, Mary; Call, Mariah; Knudson, M Margaret; Schreiber, Martin A; Bulger, Eileen M; Muskat, Peter; Alarcon, Louis H; Myers, John G; Rahbar, Mohammad H; Brasel, Karen J; Phelan, Herb A; del Junco, Deborah J; Fox, Erin E; Wade, Charles E; Holcomb, John B; Cotton, Bryan A; Matijevic, Nena

    2013-01-01

    Background Acute Traumatic Coagulopathy (ATC) occurs after severe injury and shock and is associated with increased bleeding, morbidity and mortality. The effects of ATC and hemostatic resuscitation on outcome are not well-explored. The PRospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study provided a unique opportunity to characterize coagulation and the effects of resuscitation on ATC after severe trauma. Methods Blood samples were collected upon arrival on a subset of PROMMTT patients. Plasma clotting factor levels were prospectively assayed for coagulation factors. These data were analyzed with comprehensive PROMMTT clinical data. Results There were 1198 patients with laboratory results of whom 41.6% were coagulopathic. Using International Normalized Ratio (INR)≥1.3, 41.6% (448) of patients were coagulopathic while 20.5% (214) were coagulopathic using partial thromboplastin time (PTT)≥35. Coagulopathy was primarily associated with a combination of an ISS>15 and a BD<−6 (P<.05). Regression modeling for INR-based coagulopathy shows that pre-hospital crystalloid (odds ratio (OR)=1.05), Injury Severity Score (ISS, OR=1.03), Glasgow Coma Scale (OR=0.93), heart rate (OR=1.08), systolic blood pressure (OR=0.96), base deficit (BD, OR=0.92) and temperature (OR=0.84) were significant predictors of coagulopathy (all P<.03). A subset of 165 patients had blood samples collected and coagulation factor analysis performed. Elevated ISS and BD were associated with elevation of aPC and depletion of factors (all P<.05). Reductions in factors I, II, V, VIII and an increase in aPC drive ATC (all p<.04). Similar results were found for PTT-defined coagulopathy. Conclusions ATC is associated with depletion of factors I, II, V, VII, VIII, IX and X and is driven by the activation of the protein C system. These data provide additional mechanistic understanding of the drivers of coagulation abnormalities after injury. Further understanding of the drivers of

  15. Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation

    PubMed Central

    Yap, Wei Hsum; Lim, Yang Mooi

    2015-01-01

    Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs) are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX) enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS). The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-κB)/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli. PMID:26491566

  16. Mechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone.

    PubMed

    Kundu, Juthika; Chun, Kyung-Soo; Aruoma, Okezie I; Kundu, Joydeb Kumar

    2014-10-01

    The bioactive natural products (plant secondary metabolites) are widely known to possess therapeutic value for the prevention and treatment of various chronic diseases including cancer. Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ), a monoterpene present in black cumin seeds, exhibits pleiotropic pharmacological activities including antioxidant, anti-inflammatory, antidiabetic and antitumor effects. TQ inhibits experimental carcinogenesis in a wide range of animal models and has been shown to arrest the growth of various cancer cells in culture as well as xenograft tumors in vivo. The mechanistic basis of anticancer effects of TQ includes the inhibition of carcinogen metabolizing enzyme activity and oxidative damage of cellular macromolecules, attenuation of inflammation, induction of cell cycle arrest and apoptosis in tumor cells, blockade of tumor angiogenesis, and suppression of migration, invasion and metastasis of cancer cells. TQ shows synergistic and/or potentiating anticancer effects when combined with clinically used chemotherapeutic agents. At the molecular level, TQ targets various components of intracellular signaling pathways, particularly a variety of upstream kinases and transcription factors, which are aberrantly activated during the course of tumorigenesis.

  17. Mechanistic evaluation of virus clearance by depth filtration.

    PubMed

    Venkiteshwaran, Adith; Fogle, Jace; Patnaik, Purbasa; Kowle, Ron; Chen, Dayue

    2015-01-01

    Virus clearance by depth filtration has not been well-understood mechanistically due to lack of quantitative data on filter charge characteristics and absence of systematic studies. It is generally believed that both electrostatic interactions and sized based mechanical entrapment contribute to virus clearance by depth filtration. In order to establish whether the effectiveness of virus clearance correlates with the charge characteristics of a given depth filter, a counter-ion displacement technique was employed to determine the ionic capacity for several depth filters. Two depth filters (Millipore B1HC and X0HC) with significant differences in ionic capacities were selected and evaluated for their ability to eliminate viruses. The high ionic capacity X0HC filter showed complete porcine parvovirus (PPV) clearance (eliminating the spiked viruses to below the limit of detection) under low conductivity conditions (≤2.5 mS/cm), achieving a log10 reduction factor (LRF) of > 4.8. On the other hand, the low ionic capacity B1HC filter achieved only ∼2.1-3.0 LRF of PPV clearance under the same conditions. These results indicate that parvovirus clearance by these two depth filters are mainly achieved via electrostatic interactions between the filters and PPV. When much larger xenotropic murine leukemia virus (XMuLV) was used as the model virus, complete retrovirus clearance was obtained under all conditions evaluated for both depth filters, suggesting the involvement of mechanisms other than just electrostatic interactions in XMuLV clearance.

  18. Bioavailability and Pharmacokinetics of Genistein: Mechanistic Studies on its ADME

    PubMed Central

    Yang, Zhen; Kulkarni, Kaustubh; Zhu, Wei; Hu, Ming

    2014-01-01

    Genistein, one of the most active natural flavonoids, exerts various biological effects including chemoprevention, antioxidation, antiproliferation and anticancer. More than 30 clinical trials of genistein with various disease indications have been conducted to evaluate its clinical efficacy. Based on many animals and human pharmacokinetic studies, it is well known that the most challenge issue for developing genistein as a chemoprevention agent is the low oral bioavailability, which may be the major reason relating to its ambiguous therapeutic effects and large interindividual variations in clinical trials. In order to better correlate pharmacokinetic to pharmacodynamics results in animals and clinical studies, an in-depth understanding of pharmacokinetic behavior of genistein and its ADME properties are needed. Numerous in vitro/in vivo ADME studies had been conducted to reveal the main factors contributing to the low oral bioavailability of genistein. Therefore, this review focuses on summarizing the most recent progress on mechanistic studies of genistein ADME and provides a systemic view of these processes to explain genistein pharmacokinetic behaviors in vivo. The better understanding of genistein ADME property may lead to development of proper strategy to improve genistein oral bioavailability via mechanism-based approaches. PMID:22583407

  19. Mechanistic Enzymology of the Radical SAM Enzyme DesII.

    PubMed

    Ruszczycky, Mark W; Liu, Hung-Wen

    2015-04-01

    DesII is a member of the radical SAM family of enzymes that catalyzes radical-mediated transformations of TDP-4-amino-4,6-didexoy-D-glucose as well as other sugar nucleotide diphosphates. Like nearly all radical SAM enzymes, the reactions begin with the reductive homolysis of SAM to produce a 5'-deoxyadenosyl radical which is followed by regiospecific hydrogen atom abstraction from the substrate. What happens next, however, depends on the nature of the substrate radical so produced. In the case of the biosynthetically relevant substrate, a radical-mediated deamination ensues; however, when this amino group is replaced with a hydroxyl, one instead observes dehydrogenation. The factors that govern the fate of the initially generated substrate radical as well as the mechanistic details underlying these transformations have been a key focus of research into the chemistry of DesII. This review will discuss recent discoveries pertaining to the enzymology of DesII, how it may relate to understanding other radical-mediated lyases and dehydrogenases and the working hypotheses currently being investigated regarding the mechanism of DesII catalysis.

  20. Mechanistic rationales for targeting interleukin-17A in spondyloarthritis.

    PubMed

    Raychaudhuri, Siba P; Raychaudhuri, Smriti K

    2017-03-08

    The term spondyloarthritis (SpA) is used to describe a group of inflammatory autoimmune diseases, including ankylosing spondylitis and psoriatic arthritis, with common genetic risk factors and clinical features. SpA is clinically distinct from rheumatoid arthritis and typically affects the spine, sacroiliac joints, entheses, and, less commonly, peripheral joints. Although the pathogenesis of SpA is not fully understood, recent findings have identified the interleukin (IL)-17 pathway as a key mediator of disease pathogenesis. Clinical evidence for the efficacy of IL-17A inhibition by biologic agents was initially shown in patients with chronic plaque psoriasis, another autoimmune disease mediated by the IL-17 pathway. Subsequently, similar positive efficacy for inhibition of IL-17A was seen in patients with ankylosing spondylitis and psoriatic arthritis. Inhibition of IL-17A may also improve cardiovascular and metabolic comorbidities often found in patients with SpA because studies have linked these disorders to the IL-17 pathway. In this review, we will examine key preclinical studies that demonstrated the mechanistic role of IL-17A in the development SpA and discuss how these observations were translated into clinical practice.

  1. Application of Mechanistic Toxicology Data to Ecological Risk Assessments

    EPA Science Inventory

    The ongoing evolution of knowledge and tools in the areas of molecular biology, bioinformatics, and systems biology holds significant promise for reducing uncertainties associated with ecological risk assessment. As our understanding of the mechanistic basis of responses of organ...

  2. Non-directed aromatic C–H amination: catalytic and mechanistic studies enabled by Pd catalyst and reagent design†

    PubMed Central

    Bandara, H. M. D.; Jin, D.; Mantell, M. A.; Field, K. D.; Wang, A.; Narayanan, R. P.; Deskins, N. A.; Emmert, M. H.

    2016-01-01

    This manuscript describes the systematic development of pyridine-type ligands, which promote the Pd catalyzed, non-directed amination of benzene in combination with novel, hydroxylamine-based electrophilic amination reagents. DFT calculations and mechanistic experiments provide insights into the factors influencing the arene C–H amination protocol. PMID:28066540

  3. Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI

    DTIC Science & Technology

    2015-10-01

    efficacy of veliparib and NAD as agents for suppressing inflammation and improving outcomes after traumatic brain injury. The animal models include...1 AWARD NUMBER: W81XWH-13-2-0091 TITLE: Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI PRINCIPAL INVESTIGATOR...COVERED 25 Sep 2014 - 24 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI 5b. GRANT

  4. A factor analytic investigation of the BASC-2 Behavioral and Emotional Screening System Parent Form: psychometric properties, practical implications, and future directions.

    PubMed

    Dowdy, Erin; Chin, Jenna K; Twyford, Jennifer M; Dever, Bridget V

    2011-06-01

    The Behavior Assessment System for Children, Second Edition (BASC-2) Behavioral and Emotional Screening System Parent Form (BESS Parent; Kamphaus & Reynolds, 2007) is a recently developed instrument designed to identify behavioral and emotional risk in students. To describe the underlying factor structure for this instrument, exploratory (EFA) and confirmatory factor analyses (CFA) were conducted utilizing two subsets of a large, nationally-representative sample. The results of the EFA suggested that the BESS Parent contained a four-factor latent structure (i.e., Externalizing, Internalizing, Adaptive Skills, and Inattention), which was supported by CFA. Results support further investigation into utilizing four subscales in addition to an overall risk score; distributional and reliability information for the BESS Parent subscales is provided. Practical implications for school psychologists interested in early identification and directions for future research are discussed.

  5. Attention-deficit hyperactivity disorder may be associated with decreased central brain-derived neurotrophic factor activity: clinical and therapeutic implications.

    PubMed

    Tsai, Shih-Jen

    2007-01-01

    Attention-deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder. Despite intensive research efforts, the aetiology of ADHD remains unknown. Current evidence suggests that the aetiology of ADHD is heterogeneous, comprising of multiple factors. Recently, it has been proposed that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be implicated in the pathogenesis of ADHD. This hypothesis is supported by recent genetic studies in ADHD. Drawing on findings from studies into the drugs for ADHD relating to central BDNF expression, hyperactivity in BDNF knockout mice, BDNF effects in midbrain dopaminergic function and the close association between BDNF and the dopamine transporter (an important molecule for ADHD pathogenesis), it is proposed here that decreased central BDNF, particularly in the midbrain region, may play an important role in the pathogenesis ADHD. This hypothesis may have some implications for clinical findings in ADHD (for example, the co-morbidity between ADHD and major depression), and provide a new direction for the development of medication for ADHD treatment.

  6. World-View Entrapment: Moral-Ethical Implications for Gifted Education.

    ERIC Educational Resources Information Center

    Ambrose, Don

    2000-01-01

    This article explores the moral-ethical implications of the mechanistic world view and related issues such as technological determinism, social Darwinism, and androcentrism. It finds that educational approaches reinforced by the mechanistic world view include positivistic approaches to curriculum, instruction, and research. Recommendations for…

  7. Structural and Mechanistic Roles of Novel Chemical Ligands on the SdiA Quorum-Sensing Transcription Regulator

    SciTech Connect

    Nguyen, Y.; Nguyen, Nam X.; Rogers, Jamie L.; Liao, Jun; MacMillan, John B.; Jiang, Youxing; Sperandio, Vanessa

    2015-05-19

    Bacteria engage in chemical signaling, termed quorum sensing (QS), to mediate intercellular communication, mimicking multicellular organisms. The LuxR family of QS transcription factors regulates gene expression, coordinating population behavior by sensing endogenous acyl homoserine lactones (AHLs). However, some bacteria (such as Escherichia coli) do not produce AHLs. These LuxR orphans sense exogenous AHLs but also regulate transcription in the absence of AHLs. Importantly, this AHL-independent regulatory mechanism is still largely unknown. Here we present several structures of one such orphan LuxR-type protein, SdiA, from enterohemorrhagic E. coli (EHEC), in the presence and absence of AHL. SdiA is actually not in an apo state without AHL but is regulated by a previously unknown endogenous ligand, 1-octanoyl-rac-glycerol (OCL), which is ubiquitously found throughout the tree of life and serves as an energy source, signaling molecule, and substrate for membrane biogenesis. While exogenous AHL renders to SdiA higher stability and DNA binding affinity, OCL may function as a chemical chaperone placeholder that stabilizes SdiA, allowing for basal activity. Structural comparison between SdiA-AHL and SdiA-OCL complexes provides crucial mechanistic insights into the ligand regulation of AHL-dependent and -independent function of LuxR-type proteins. Importantly, in addition to its contribution to basic science, this work has implications for public health, inasmuch as the SdiA signaling system aids the deadly human pathogen EHEC to adapt to a commensal lifestyle in the gastrointestinal (GI) tract of cattle, its main reservoir. These studies open exciting and novel avenues to control shedding of this human pathogen in the environment. IMPORTANCE Quorum sensing refers to bacterial chemical signaling. The QS acyl homoserine lactone (AHL) signals are recognized by LuxR-type receptors that regulate gene transcription. However, some bacteria have orphan LuxR-type receptors and

  8. Structural and Mechanistic Roles of Novel Chemical Ligands on the SdiA Quorum-Sensing Transcription Regulator

    DOE PAGES

    Nguyen, Y.; Nguyen, Nam X.; Rogers, Jamie L.; ...

    2015-05-19

    Bacteria engage in chemical signaling, termed quorum sensing (QS), to mediate intercellular communication, mimicking multicellular organisms. The LuxR family of QS transcription factors regulates gene expression, coordinating population behavior by sensing endogenous acyl homoserine lactones (AHLs). However, some bacteria (such as Escherichia coli) do not produce AHLs. These LuxR orphans sense exogenous AHLs but also regulate transcription in the absence of AHLs. Importantly, this AHL-independent regulatory mechanism is still largely unknown. Here we present several structures of one such orphan LuxR-type protein, SdiA, from enterohemorrhagic E. coli (EHEC), in the presence and absence of AHL. SdiA is actually not inmore » an apo state without AHL but is regulated by a previously unknown endogenous ligand, 1-octanoyl-rac-glycerol (OCL), which is ubiquitously found throughout the tree of life and serves as an energy source, signaling molecule, and substrate for membrane biogenesis. While exogenous AHL renders to SdiA higher stability and DNA binding affinity, OCL may function as a chemical chaperone placeholder that stabilizes SdiA, allowing for basal activity. Structural comparison between SdiA-AHL and SdiA-OCL complexes provides crucial mechanistic insights into the ligand regulation of AHL-dependent and -independent function of LuxR-type proteins. Importantly, in addition to its contribution to basic science, this work has implications for public health, inasmuch as the SdiA signaling system aids the deadly human pathogen EHEC to adapt to a commensal lifestyle in the gastrointestinal (GI) tract of cattle, its main reservoir. These studies open exciting and novel avenues to control shedding of this human pathogen in the environment. IMPORTANCE Quorum sensing refers to bacterial chemical signaling. The QS acyl homoserine lactone (AHL) signals are recognized by LuxR-type receptors that regulate gene transcription. However, some bacteria have orphan Lux

  9. The Continuum of Disclosure: Exploring Factors Predicting Tentative Disclosure of Child Sexual Abuse Allegations During Forensic Interviews and the Implications for Practice, Policy, and Future Research.

    PubMed

    Anderson, Gwendolyn D

    2016-01-01

    When a child sexual abuse investigation ensues, many children do not disclose readily to professionals. Defining disclosure beyond the disclosure versus nondisclosure dichotomy is essential, yet little research exists on factors associated with a continuum of disclosure, including active and tentative disclosure. Through the coding of 196 forensic interviews using content analysis and subsequent regression analysis, findings suggest that children of color, children abused by adults, unintentional initial disclosure, and those lacking family support were more likely to tentatively disclose in this study. Implications include a need to understand tentative disclosure as part of a normal continuum of disclosure within court proceedings and investigations of abuse allegations.

  10. Structural and mechanistic diversity of multidrug transporters.

    PubMed

    Mousa, Jarrod J; Bruner, Steven D

    2016-10-26

    Covering: 2009 to mid 2016Multidrug transporters are common and prevalent in all orders of life, having diverse functions from the removal of toxins, resistance to cytotoxins, and the transport of specific eluents. In addition, multidrug transporters pose a significant threat to modern medicine. Able to transport structurally diverse small molecule drugs, these transporters are implicated in antibiotic resistant strains of bacteria, as well as chemotherapeutic-resistance cancer cells. Although important in such resistance, a relatively small number of multidrug transporters have been structurally characterized, primarily due to the difficulty in purifying and crystallizing active membrane proteins and protein complexes. This review will cover recent structural breakthroughs in the past six years that have led to increased knowledge of the mechanisms of multidrug transporter chemistry, and the role of these transporters in exporting secondary metabolites.

  11. Role of the Transforming-Growth-Factor-β1 Gene in Late-Onset Alzheimer’s Disease: Implications for the Treatment

    PubMed Central

    Bosco, Paolo; Ferri, Raffaele; Salluzzo, Maria Grazia; Castellano, Sabrina; Signorelli, Maria; Nicoletti, Ferdinando; Nuovo, Santo Di; Drago, Filippo; Caraci, Filippo

    2013-01-01

    Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. LOAD has a complex and largely unknown etiology with strong genetic determinants. Genetics of LOAD is known to involve several genetic risk factors among which the Apolipoprotein E (APOE) gene seems to be the major recognized genetic determinant. Recent efforts have been made to identify other genetic factors involved in the pathophysiology of LOAD such as genes associated with a deficit of neurotrophic factors in the AD brain. Genetic variations of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), and transforming-growth-factor-β1 (TGF-β1) are known to increase the risk to develop LOAD and have also been related to depression susceptibility in LOAD. Transforming-Growth-Factor-β1 (TGF-β1) is a neurotrophic factor that exerts neuroprotective effects against ß-amyloid-induced neurodegeneration. Recent evidence suggests that a specific impairment in the signaling of TGF-β is an early event in the pathogenesis of AD. TGF-β1 protein levels are predominantly under genetic control, and the TGF-β1 gene, located on chromosome 19q13.1–3, con-tains several single nucleotide polymorphisms (SNPs) upstream and in the transcript region, such as the SNP at codon +10 (T/C) and +25 (G/C), which is known to influence the level of expression of TGF-β1. In the present review, we summarize the current literature on genetic risk factors for LOAD, focusing on the role of the TGF-β1 gene, finally discussing the possible implications of these genetic studies for the selection of patients eligible for neuroprotective strategies in AD. PMID:24082824

  12. Thermal degradation events as health hazards: Particle vs gas phase effects, mechanistic studies with particles

    NASA Astrophysics Data System (ADS)

    Oberdörster, G.; Ferin, J.; Finkelstein, J.; Soderholm, S.

    Exposure to thermal degradation products arising from fire or smoke could be a major concern for manned space missions. Severe acute lung damage has been reported in people after accidental exposure to fumes from plastic materials, and animal studies revealed the extremely high toxicity of freshly generated fumes whereas a decrease in toxicity of aged fumes has been found. This and the fact that toxicity of the freshly generated fumes can be prevented with filters raises the question whether the toxicity may be due to the particulate rather than the gas phase components of the thermodegradation products. Indeed, results from recent studies implicate ultrafine particles (particle diameter in the nm range) as potential severe pulmonary toxicants. We have conducted a number of in vivo (inhalation and instillation studies in rats) and in vitro studies to test the hypothesis that ultrafine particles possess an increased potential to injure the lung compared to larger-sized particles. We used as surrogate particles ultrafine TiO 2 particles (12 and 20 nm diameter). Results in exposed rats showed that the ultrafine TiO 2 particles not only induce a greater acute inflammatory reaction in the lung than larger-sized TiO 2 particles, but can also lead to persistent chronic effects, as indicated by an adverse effect on alveolar macrophage mediated clearance function of particles. Release of mediators from alveolar macrophages during phagocytosis of the ultrafine particles and an increased access of the ultrafine particles to the pulmonary interstitium are likely factors contributing to their pulmonary toxicity. In vitro studies with lung cells (alveolar macrophages) showed, in addition, that ultrafine TiO 2 particles have a greater potential to induce cytokines than larger-sized particles. We conclude from our present studies that ultrafine particles have a significant potential to injure the lung and that their occurrence in thermal degradation events can play a major role in

  13. Mechanistic analytical models for long-distance seed dispersal by wind.

    PubMed

    Katul, G G; Porporato, A; Nathan, R; Siqueira, M; Soons, M B; Poggi, D; Horn, H S; Levin, S A

    2005-09-01

    We introduce an analytical model, the Wald analytical long-distance dispersal (WALD) model, for estimating dispersal kernels of wind-dispersed seeds and their escape probability from the canopy. The model is based on simplifications to well-established three-dimensional Lagrangian stochastic approaches for turbulent scalar transport resulting in a two-parameter Wald (or inverse Gaussian) distribution. Unlike commonly used phenomenological models, WALD's parameters can be estimated from the key factors affecting wind dispersal--wind statistics, seed release height, and seed terminal velocity--determined independently of dispersal data. WALD's asymptotic power-law tail has an exponent of -3/2, a limiting value verified by a meta-analysis for a wide variety of measured dispersal kernels and larger than the exponent of the bivariate Student t-test (2Dt). We tested WALD using three dispersal data sets on forest trees, heathland shrubs, and grassland forbs and compared WALD's performance with that of other analytical mechanistic models (revised versions of the tilted Gaussian Plume model and the advection-diffusion equation), revealing fairest agreement between WALD predictions and measurements. Analytical mechanistic models, such as WALD, combine the advantages of simplicity and mechanistic understanding and are valuable tools for modeling large-scale, long-term plant population dynamics.

  14. Mechanistic Modelling of DNA Repair and Cellular Survival Following Radiation-Induced DNA Damage

    NASA Astrophysics Data System (ADS)

    McMahon, Stephen J.; Schuemann, Jan; Paganetti, Harald; Prise, Kevin M.

    2016-09-01

    Characterising and predicting the effects of ionising radiation on cells remains challenging, with the lack of robust models of the underlying mechanism of radiation responses providing a significant limitation to the development of personalised radiotherapy. In this paper we present a mechanistic model of cellular response to radiation that incorporates the kinetics of different DNA repair processes, the spatial distribution of double strand breaks and the resulting probability and severity of misrepair. This model enables predictions to be made of a range of key biological endpoints (DNA repair kinetics, chromosome aberration and mutation formation, survival) across a range of cell types based on a set of 11 mechanistic fitting parameters that are common across all cells. Applying this model to cellular survival showed its capacity to stratify the radiosensitivity of cells based on aspects of their phenotype and experimental conditions such as cell cycle phase and plating delay (correlation between modelled and observed Mean Inactivation Doses R2 > 0.9). By explicitly incorporating underlying mechanistic factors, this model can integrate knowledge from a wide range of biological studies to provide robust predictions and may act as a foundation for future calculations of individualised radiosensitivity.

  15. Explanation and inference: mechanistic and functional explanations guide property generalization.

    PubMed

    Lombrozo, Tania; Gwynne, Nicholas Z

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations.

  16. From formamide to purine: an energetically viable mechanistic reaction pathway.

    PubMed

    Wang, Jing; Gu, Jiande; Nguyen, Minh Tho; Springsteen, Greg; Leszczynski, Jerzy

    2013-02-28

    A step-by-step mechanistic pathway following the transformation of formamide to purine through a five-membered ring intermediate has been explored by density functional theory computations. The highlight of the mechanistic route detailed here is that the proposed pathway represents the simplest reaction pathway. All necessary reactants are generated from a single starting compound, formamide, through energetically viable reactions. Several important reaction steps are involved in this mechanistic route: formylation-dehydration, Leuckart reduction, five- and six-membered ring-closure, and deamination. On the basis of the study of noncatalytic pathways, catalytic water has been found to provide energetically viable step-by-step mechanistic pathways. Among these reaction steps, five-member ring-closure is the rate-determining step. The energy barrier (ca. 42 kcal/mol) of this rate-control step is somewhat lower than the rate-determining step (ca. 44 kcal/mol) for a pyrimidine-based pathway reported previously. The mechanistic pathway reported herein is less energetically demanding than for previously proposed routes to adenine.

  17. Explanation and inference: mechanistic and functional explanations guide property generalization

    PubMed Central

    Lombrozo, Tania; Gwynne, Nicholas Z.

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations. PMID:25309384

  18. Predicting interactions from mechanistic information: Can omic data validate theories?

    SciTech Connect

    Borgert, Christopher J.

    2007-09-01

    To address the most pressing and relevant issues for improving mixture risk assessment, researchers must first recognize that risk assessment is driven by both regulatory requirements and scientific research, and that regulatory concerns may expand beyond the purely scientific interests of researchers. Concepts of 'mode of action' and 'mechanism of action' are used in particular ways within the regulatory arena, depending on the specific assessment goals. The data requirements for delineating a mode of action and predicting interactive toxicity in mixtures are not well defined from a scientific standpoint due largely to inherent difficulties in testing certain underlying assumptions. Understanding the regulatory perspective on mechanistic concepts will be important for designing experiments that can be interpreted clearly and applied in risk assessments without undue reliance on extrapolation and assumption. In like fashion, regulators and risk assessors can be better equipped to apply mechanistic data if the concepts underlying mechanistic research and the limitations that must be placed on interpretation of mechanistic data are understood. This will be critically important for applying new technologies to risk assessment, such as functional genomics, proteomics, and metabolomics. It will be essential not only for risk assessors to become conversant with the language and concepts of mechanistic research, including new omic technologies, but also, for researchers to become more intimately familiar with the challenges and needs of risk assessment.

  19. Stress and food allergy: mechanistic considerations

    PubMed Central

    Schreier, Hannah M.C.; Wright, Rosalind J.

    2014-01-01

    Recent years have seen a marked increase in food allergy prevalence among children, particularly in Western countries, that cannot be explained by genetic factors alone. This has resulted in an increased effort to identify environmental risk factors underlying food allergies and to understand how these factors may be modified through interventions. Food allergy is an immune-mediated adverse reaction to food. Consequently, considerations of candidate risk factors have begun to focus on environmental influences that perturb the healthy development of the emerging immune system during critical periods of development (eg, prenatally and during early childhood), particularly in the gut. Given that psychosocial stress is known to play an important role in other allergic and inflammatory diseases, such as asthma, its potential role in food allergy is a growing area of research. However, research to date has largely focused on animal studies. This review synthesizes relevant animal research and epidemiological data, providing proof of concept for moderating influences of psychological stress on food allergy outcomes in humans. Pathways that may underlie associations between psychosocial stress and the expression of food allergy are discussed. PMID:24428964

  20. Inferring Mechanistic Parameters from Amyloid Formation Kinetics by Approximate Bayesian Computation.

    PubMed

    Nakatani-Webster, Eri; Nath, Abhinav

    2017-03-14

    Amyloid formation is implicated in a number of human diseases, and is thought to proceed via a nucleation-dependent polymerization mechanism. Experimenters often wish to relate changes in amyloid formation kinetics, for example, in response to small molecules to specific mechanistic steps along this pathway. However, fitting kinetic fibril formation data to a complex model including explicit rate constants results in an ill-posed problem with a vast number of potential solutions. The levels of uncertainty remaining in parameters calculated from these models, arising both from experimental noise and high levels of degeneracy or codependency in parameters, is often unclear. Here, we demonstrate that a combination of explicit mathematical models with an approximate Bayesian computation approach can be used to assign the mechanistic effects of modulators on amyloid fibril formation. We show that even when exact rate constants cannot be extracted, parameters derived from these rate constants can be recovered and used to assign mechanistic effects and their relative magnitudes with a great deal of confidence. Furthermore, approximate Bayesian computation provides a robust method for visualizing uncertainty remaining in the model parameters, regardless of its origin. We apply these methods to the problem of heparin-mediated tau polymerization, which displays complex kinetic behavior not amenable to analysis by more traditional methods. Our analysis indicates that the role of heparin cannot be explained by enhancement of nucleation alone, as has been previously proposed. The methods described here are applicable to a wide range of systems, as models can be easily adapted to account for new reactions and reversibility.

  1. Mechanistic kinetic models of enzymatic cellulose hydrolysis-a review.

    PubMed

    Jeoh, Tina; Cardona, Maria J; Karuna, Nardrapee; Mudinoor, Akshata R; Nill, Jennifer

    2017-02-28

    Bioconversion of lignocellulose forms the basis for renewable, advanced biofuels, and bioproducts. Mechanisms of hydrolysis of cellulose by cellulases have been actively studied for nearly 70 years with significant gains in understanding of the cellulolytic enzymes. Yet, a full mechanistic understanding of the hydrolysis reaction has been elusive. We present a review to highlight new insights gained since the most recent comprehensive review of cellulose hydrolysis kinetic models by Bansal et al. () Biotechnol Adv 27:833-848. Recent models have taken a two-pronged approach to tackle the challenge of modeling the complex heterogeneous reaction-an enzyme-centric modeling approach centered on the molecularity of the cellulase-cellulose interactions to examine rate limiting elementary steps and a substrate-centric modeling approach aimed at capturing the limiting property of the insoluble cellulose substrate. Collectively, modeling results suggest that at the molecular-scale, how rapidly cellulases can bind productively (complexation) and release from cellulose (decomplexation) is limiting, while the overall hydrolysis rate is largely insensitive to the catalytic rate constant. The surface area of the insoluble substrate and the degrees of polymerization of the cellulose molecules in the reaction both limit initial hydrolysis rates only. Neither enzyme-centric models nor substrate-centric models can consistently capture hydrolysis time course at extended reaction times. Thus, questions of the true reaction limiting factors at extended reaction times and the role of complexation and decomplexation in rate limitation remain unresolved. Biotechnol. Bioeng. 2017;9999: 1-16. © 2017 Wiley Periodicals, Inc.

  2. Gender Differences in Factor Scores of Anxiety and Depression among Australian University Students: Implications for Counselling Interventions

    ERIC Educational Resources Information Center

    Bitsika, Vicki; Sharpley, Chris F.; Melham, Therese C.

    2010-01-01

    Anxiety and depression inventory scores from 200 male and female university students attending a private university in Australia were examined for their factor structure. Once established, the two sets of factors were tested for gender-based differences, revealing that females were more likely than males to report symptomatology associated with…

  3. Suicidal ideation and suicide attempts among human immunodeficiency virus-infected adults: differences in risk factors and their implications.

    PubMed

    Kang, Cho Ryok; Bang, Ji Hwan; Cho, Sung-Il; Kim, Kui Nam; Lee, Hee-Jin; Ryu, Bo Yeong; Cho, Soo Kyung; Lee, Young Hwa; Oh, Myoung-Don; Lee, Jong-Koo

    2016-01-01

    Many studies have investigated risk factors for suicidal ideation and suicide attempt; however, most have failed to show differences in risk factors between suicidal ideation and suicide attempt among the human immunodeficiency virus (HIV)-infected population. This study was designed to identify differences in risk factors between suicidal ideation and suicide attempts among HIV-infected adults in Seoul. A face-to-face survey of 457 HIV-infected adults was conducted by the Seoul Metropolitan Government in 2013. Multivariate logistic regression analysis was used to identify factors associated with suicidal ideation and suicide attempt. Among 422 participants, 44% had suicidal ideation, and 11% had suicide attempts. The independent risk factors for suicidal ideation were young and middle age, living with someone, history of AIDS-defining opportunistic disease, history of treatment for depression, lower social support, and psychological status. Beneficiaries of National Medical Aid, economic barriers to treatment, history of treatment for depression, and lower psychological status were independently associated with suicide attempts. Patients with HIV in Korea were treated without cost in some centers. Thus, experiencing an economic barrier to treatment might be due in part to ignorance of HIV care policies. Our findings indicate that suicide attempts are associated with socioeconomic factors and information inequality regarding medical care. In conclusion, suicidal ideation closely associated with the psychosocial factors, whereas suicide attempt demonstrates a stronger association with socioeconomic factors. Suicide prevention measures should be implemented to provide information to help HIV-infected patients.

  4. Identification of two nuclear factor-binding domains on the chicken cardiac actin promoter: implications for regulation of the gene.

    PubMed Central

    Quitschke, W W; DePonti-Zilli, L; Lin, Z Y; Paterson, B M

    1989-01-01

    The cis-acting regions that appear to be involved in negative regulation of the chicken alpha-cardiac actin promoter both in vivo and in vitro have been identified. A nuclear factor(s) binding to the proximal region mapped over the TATA element between nucleotides -50 and -25. In the distal region, binding spanned nucleotides -136 to -112, a region that included a second CArG box (CArG2) 5' to the more familiar CCAAT-box (CArG1) consensus sequence. Nuclear factors binding to these different domains were found in both muscle and nonmuscle preparations but were detectable at considerably lower levels in tissues expressing the alpha-cardiac actin gene. In contrast, concentrations of the beta-actin CCAAT-box binding activity were similar in all extracts tested. The role of these factor-binding domains on the activity of the cardiac actin promoter in vivo and in vitro and the prevalence of the binding factors in nonmuscle extracts are consistent with the idea that these binding domains and their associated factors are involved in the tissue-restricted expression of cardiac actin through both positive and negative regulatory mechanisms. In the absence of negative regulatory factors, these same binding domains act synergistically, via other factors, to activate the cardiac actin promoter during myogenesis. Images PMID:2552286

  5. Religion as a Support Factor for Women of Color Pursuing Science Degrees: Implications for Science Teacher Educators

    ERIC Educational Resources Information Center

    Ceglie, Robert

    2013-01-01

    This study explores the influence of religion as a support factor for a group of Latina and African-American women majoring in science. The current project is a part of a larger study that investigated persistence factors of underrepresented woman who were enrolled as science majors at United States colleges and universities. This paper focuses on…

  6. A NEW FACTOR ANALYSIS OF THE SVIB--SUGGESTED MODIFICATION OF EXISTING GROUPS AND IMPLICATIONS FOR COUNSELING.

    ERIC Educational Resources Information Center

    SMITH, STUART E.; AND OTHERS

    FACTOR ANALYSIS WAS CARRIED OUT TO ASCERTAIN THE BEST OCCUPATIONAL GROUP LOCATION FOR EACH OF FOUR STRONG VOCATIONAL INTEREST BLANK (SVIB) SCALES--VETERMINARIAN, SENIOR CPA, PHARMACIST, AND MORTICIAN. THE SVIB WAS ADMINISTERED TO 125 MALE LIBERAL ARTS FRESHMEN. MEANS, STANDARD DEVIATIONS, AND INTERCORRELATIONS WERE COMPUTED. THIS FACTOR ANALYSIS…

  7. Why did Jacques Monod make the choice of mechanistic determinism?

    PubMed

    Loison, Laurent

    2015-06-01

    The development of molecular biology placed in the foreground a mechanistic and deterministic conception of the functioning of macromolecules. In this article, I show that this conception was neither obvious, nor necessary. Taking Jacques Monod as a case study, I detail the way he gradually came loose from a statistical understanding of determinism to finally support a mechanistic understanding. The reasons of the choice made by Monod at the beginning of the 1950s can be understood only in the light of the general theoretical schema supported by the concept of mechanistic determinism. This schema articulates three fundamental notions for Monod, namely that of the rigidity of the sequence of the genetic program, that of the intrinsic stability of macromolecules (DNA and proteins), and that of the specificity of molecular interactions.

  8. Mechanistic Effects of Calcitriol in Cancer Biology

    PubMed Central

    Díaz, Lorenza; Díaz-Muñoz, Mauricio; García-Gaytán, Ana Cristina; Méndez, Isabel

    2015-01-01

    Besides its classical biological effects on calcium and phosphorus homeostasis, calcitriol, the active vitamin D metabolite, has a broad variety of actions including anticancer effects that are mediated either transcriptionally and/or via non-genomic pathways. In the context of cancer, calcitriol regulates the cell cycle, induces apoptosis, promotes cell differentiation and acts as anti-inflammatory factor within the tumor microenvironment. In this review, we address the different mechanisms of action involved in the antineoplastic effects of calcitriol. PMID:26102214

  9. Radical behaviorism and scientific frameworks. From mechanistic to relational accounts.

    PubMed

    Chiesa, M

    1992-11-01

    A substantial portion of B. F. Skinner's scholarship was devoted to developing methods and terms for a scientific study of behavior. Three concepts central to scientific accounts--cause, explanation, and theory--are examined to illustrate the distinction between mechanistic and relational frameworks and radical behaviorism's relationship to those frameworks. Informed by a scientific tradition that explicitly rejects mechanistic interpretations, radical behaviorism provides a distinctive stance in contemporary psychology. The present analysis suggests that radical behaviorism makes closer contact with the "new world view" advocated by physicists and philosophers of science than does much of contemporary psychology.

  10. Assessment of economic factors affecting the satellite power system. Volume 2: The systems implications of rectenna siting issues

    NASA Technical Reports Server (NTRS)

    Chapman, P. K.; Bugos, B. J.; Csigi, K. I.; Glaser, P. E.; Schimke, G. R.; Thomas, R. G.

    1979-01-01

    The feasibility was evaluated of finding potential sites for Solar Power Satellite (SPS) receiving antennas (rectennas) in the continental United States, in sufficient numbers to permit the SPS to make a major contribution to U.S. generating facilities, and to give statistical validity to an assessment of the characteristics of such sites and their implications for the design of the SPS system. It is found that the cost-optimum power output of the SPS does not depend on the particular value assigned to the cost per unit area of a rectenna and its site, as long as it is independent of rectenna area. Many characteristics of the sites chosen affect the optimum design of the rectenna itself.

  11. The Krüppel-like Factor 15 as a Molecular Link between Myogenic Factors and a Chromosome 4q Transcriptional Enhancer Implicated in Facioscapulohumeral Dystrophy*

    PubMed Central

    Dmitriev, Petr; Petrov, Andrei; Ansseau, Eugenie; Stankevicins, Luiza; Charron, Sébastien; Kim, Elena; Bos, Tomas Jan; Robert, Thomas; Turki, Ahmed; Coppée, Frédérique; Belayew, Alexandra; Lazar, Vladimir; Carnac, Gilles; Laoudj, Dalila; Lipinski, Marc; Vassetzky, Yegor S.

    2011-01-01

    Facioscapulohumeral muscular dystrophy (FSHD), a dominant hereditary disease with a prevalence of 7 per 100,000 individuals, is associated with a partial deletion in the subtelomeric D4Z4 repeat array on chromosome 4q. The D4Z4 repeat contains a strong transcriptional enhancer that activates promoters of several FSHD-related genes. We report here that the enhancer within the D4Z4 repeat binds the Krüppel-like factor KLF15. KLF15 was found to be up-regulated during myogenic differentiation induced by serum starvation or by overexpression of the myogenic differentiation factor MYOD. When overexpressed, KLF15 activated the D4Z4 enhancer and led to overexpression of DUX4c (Double homeobox 4, centromeric) and FRG2 (FSHD region gene 2) genes, whereas its silencing caused inactivation of the D4Z4 enhancer. In immortalized human myoblasts, the D4Z4 enhancer was activated by the myogenic factor MYOD, an effect that was abolished upon KLF15 silencing or when the KLF15-binding sites within the D4Z4 enhancer were mutated, indicating that the myogenesis-related activation of the D4Z4 enhancer was mediated by KLF15. KLF15 and several myogenesis-related factors were found to be expressed at higher levels in myoblasts, myotubes, and muscle biopsies from FSHD patients than in healthy controls. We propose that KLF15 serves as a molecular link between myogenic factors and the activity of the D4Z4 enhancer, and it thus contributes to the overexpression of the DUX4c and FRG2 genes during normal myogenic differentiation and in FSHD. PMID:21937448

  12. Human adult chondrocytes express hepatocyte growth factor (HGF) isoforms but not HgF: potential implication of osteoblasts on the presence of HGF in cartilage.

    PubMed

    Guévremont, Melanie; Martel-Pelletier, Johanne; Massicotte, Frédéric; Tardif, Ginette; Pelletier, Jean-Pierre; Ranger, Pierre; Lajeunesse, Daniel; Reboul, Pascal

    2003-06-01

    HGF is increased in human OA cartilage, possibly from Ob's. RT-PCR shows HGF isoforms are differently regulated between chondrocytes and Ob. A paracrine cross-talk between subchondral bone and cartilage may occur during OA. Recently, hepatocyte growth factor (HGF) has been identified by immunohistochemistry in cartilage and more particularly in the deep zone of human osteoarthritic (OA) cartilage. By investigating HGF expression in cartilage, we found that chondrocytes did not express HGF; however, they expressed the two truncated isoforms, namely HGF/NK1 and HGF/NK2. Because the only other cells localized near the deep zone are osteoblasts from the subchondral bone plate, we hypothesized that they were expressing HGF. Indeed, we found that HGF was synthesized by osteoblasts from the subchondral bone plate. Moreover, OA osteoblasts produced five times more HGF than normal osteoblasts and almost no HGF/NK1, unlike normal osteoblasts. Because prostaglandin E2 (PGE2) and pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6 are involved in OA progression, we investigated whether these factors impact HGF produced by normal osteoblasts. PGE2 was the only factor tested that was able to stimulate HGF synthesis. However, the addition of NS398, a selective inhibitor of cyclo-oxygenase-2 (COX-2) had no effect on HGF produced by OA osteoblasts. HGF/NK2 had a moderate stimulating effect on HGF production by normal osteoblasts, whereas osteocalcin was not modulated by either HGF or HGF/NK2. When investigating signaling routes that might be implicated in OA osteoblast-produced HGF, we found that protein kinase A was at least partially involved. In summary, this study raises the hypothesis that the HGF found in articular cartilage is produced by osteoblasts, diffuses into the cartilage, and may be implicated in the OA process.

  13. MECHANISTIC STUDIES OF IMPROVED FOAM EOR PROCESSES

    SciTech Connect

    William R. Rossen

    2004-06-14

    The objective of this research is to widen the application of foam to enhanced oil recovery (EOR) by investigating fundamental mechanisms of foams in porous media. This research will lay the groundwork for more applied research on foams for improved sweep efficiency in miscible gas, steam and surfactant-based EOR. Task 1 investigates the pore-scale interactions between foam bubbles and polymer molecules. Task 2 examines the mechanisms of gas trapping, and interaction between gas trapping and foam effectiveness. Task 3 investigates mechanisms of foam generation in porous media. Significant progress was made during this period on all three Tasks. Regarding Task 1, we continued comparisons of foam behavior in sandpacks with and without polymer and oil. As in our previous results, decane was moderately destabilizing to foam. Xanthan polymer did not stabilize foam in the presence of decane in this case. Rather, it appears to have destabilized foam, so that pressure gradient decreased in spite of the increase in aqueous-phase viscosity. Research on Task 2 included the first shake-down experiments with our new apparatus for gas-phase tracer tests for direct measurement of trapped-gas saturation with foam. In addition, we began to analyze CT images of gas-phase tracer in foam displacements, which offers an independent measure of trapped-gas fraction and insights into the roles of convection of tracer in flowing gas and diffusion into trapped gas. Research on Task 3 included foam generation experiments in heterogeneous sandpacks and beadpacks and modeling of discontinuous changes in state such as foam generation. The experiments found the same three regimes (coarse foam, strong foam, and intermediate regime) in heterogeneous sandpacks previously identified in homogeneous porous media. One implication is that there may be a minimum flow rate required for foam generation in even heterogeneous porous media. The dynamics in SAG foam processes in heterogeneous media are complex

  14. Factor Structure of Cognition and Functional Capacity in Two Studies of Schizophrenia and Bipolar Disorder: Implications for Genomic Studies

    PubMed Central

    Harvey, Philip D.; Aslan, Mihaela; Du, Mengtian; Zhao, Hongyu; Siever, Larry J.; Pulver, Ann; Gaziano, J. Michael; Concato, John

    2015-01-01

    Objective Impairments in cognition and everyday functioning are common in schizophrenia and bipolar disorder. Based on two studies of schizophrenia (SCZ) and bipolar I disorder (BPI) with similar methods, this paper presents factor analyses of cognitive and functional capacity (FC) measures. The overall goal of these analyses was to determine whether performance-based assessments should be examined individually, or aggregated on the basis of the correlational structure of the tests and as well as to evaluate the similarity of factor structures in SCZ and BPI. Method Veterans Affairs (VA) Cooperative Studies Program study #572, evaluated cognitive and FC measures among 5,414 BPI and 3,942 SZ patients. A second study evaluated similar neuropsychological (NP) and FC measures among 368 BPI and 436 SZ patients. Principal components analysis, as well as exploratory and confirmatory factor analyses, were used to examine the data. Results Analyses in both datasets suggested that NP and FC measures were explained by of a single underlying factor in BPI and SCZ patients, both when analyzed separately or as in a combined sample. The factor structure in both studies was similar, with or without inclusion of FC measures; homogeneous loadings were observed for that single factor across cognitive and FC domains across the samples. Conclusions The empirically derived factor model suggests that NP performance and FC are best explained as a single latent trait applicable to people with schizophrenia and bipolar illness. This single measure may enhance the robustness of the analyses relating genomic data to performance-based phenotypes. PMID:26710094

  15. Protein Kinases and Transcription Factors Activation in Response to UV-Radiation of Skin: Implications for Carcinogenesis

    PubMed Central

    López-Camarillo, César; Ocampo, Elena Aréchaga; Casamichana, Mavil López; Pérez-Plasencia, Carlos; Álvarez-Sánchez, Elizbeth; Marchat, Laurence A.

    2012-01-01

    Solar ultraviolet (UV) radiation is an important environmental factor that leads to immune suppression, inflammation, photoaging, and skin carcinogenesis. Here, we reviewed the specific signal transduction pathways and transcription factors involved in the cellular response to UV-irradiation. Increasing experimental data supporting a role for p38, MAPK, JNK, ERK1/2, and ATM kinases in the response network to UV exposure is discussed. We also reviewed the participation of NF-κB, AP-1, and NRF2 transcription factors in the control of gene expression after UV-irradiation. In addition, we discussed the promising chemotherapeutic intervention of transcription factors signaling by natural compounds. Finally, we focused on the review of data emerging from the use of DNA microarray technology to determine changes in global gene expression in keratinocytes and melanocytes in response to UV treatment. Efforts to obtain a comprehensive portrait of the transcriptional events regulating photodamage of intact human epidermis after UV exposure reveals the existence of novel factors participating in UV-induced cell death. Progress in understanding the multitude of mechanisms induced by UV-irradiation could lead to the potential use of protein kinases and novel proteins as specific targets for the prevention and control of skin cancer. PMID:22312244

  16. Protein kinases and transcription factors activation in response to UV-radiation of skin: implications for carcinogenesis.

    PubMed

    López-Camarillo, César; Ocampo, Elena Aréchaga; Casamichana, Mavil López; Pérez-Plasencia, Carlos; Alvarez-Sánchez, Elizbeth; Marchat, Laurence A

    2012-01-01

    Solar ultraviolet (UV) radiation is an important environmental factor that leads to immune suppression, inflammation, photoaging, and skin carcinogenesis. Here, we reviewed the specific signal transduction pathways and transcription factors involved in the cellular response to UV-irradiation. Increasing experimental data supporting a role for p38, MAPK, JNK, ERK1/2, and ATM kinases in the response network to UV exposure is discussed. We also reviewed the participation of NF-κB, AP-1, and NRF2 transcription factors in the control of gene expression after UV-irradiation. In addition, we discussed the promising chemotherapeutic intervention of transcription factors signaling by natural compounds. Finally, we focused on the review of data emerging from the use of DNA microarray technology to determine changes in global gene expression in keratinocytes and melanocytes in response to UV treatment. Efforts to obtain a comprehensive portrait of the transcriptional events regulating photodamage of intact human epidermis after UV exposure reveals the existence of novel factors participating in UV-induced cell death. Progress in understanding the multitude of mechanisms induced by UV-irradiation could lead to the potential use of protein kinases and novel proteins as specific targets for the prevention and control of skin cancer.

  17. Cognitive changes and dementia risk after traumatic brain injury: implications for aging military personnel.

    PubMed

    Vincent, Andrea S; Roebuck-Spencer, Tresa M; Cernich, Alison

    2014-06-01

    Traumatic brain injury (TBI) is recognized as an important risk factor for the long-term cognitive health of military personnel, particularly in light of growing evidence that TBI increases risk for Alzheimer's disease and other dementias. In this article, we review the neurocognitive and neuropathologic changes after TBI with particular focus on the potential risk for cognitive decline across the life span in military service members. Implications for monitoring and surveillance of cognition in the aging military population are discussed. Additional studies are needed to clarify the factors that increase risk for later life cognitive decline, define the mechanistic link between these factors and dementia, and provide empirically supported interventions to mitigate the impact of TBI on cognition across the life span.

  18. Tumor burden as the most important prognostic factor in early stage Hodgkin's disease. Relations to other prognostic factors and implications for choice of treatment

    SciTech Connect

    Specht, L.; Nordentoft, A.M.; Cold, S.; Clausen, N.T.; Nissen, N.I.

    1988-04-15

    Two hundred ninety patients with Hodgkin's disease pathologic stage (PS) I or II were treated in the prospective randomized trial of the Danish National Hodgkin Study with radiotherapy +/- adjuvant combination chemotherapy. The initial tumor burden of each patient was assessed, combining tumor size of each involved region and number of regions involved. Multivariate analyses of prognostic factors including treatment, tumor burden, histologic subtype, pathologic stage, number of involved regions, mediastinal size, systemic symptoms, erythrocyte sedimentation rate (ESR), sex, and age were carried out. With regard to disease-free survival tumor burden was by far the most important prognostic factor for patients treated with adjuvant chemotherapy as well as for patients treated with radiotherapy alone. With regard to survival from Hodgkin's disease only tumor burden and age were independently significant. A combination of tumor burden, histologic subtype, and sex singled out patients with a high relapse rate both after radiotherapy only, and after radiotherapy plus chemotherapy. This combination also singled out patients destined to die from Hodgkin's disease more accurately than other prognostic factors.

  19. Anti-inflammatory drugs and tumor necrosis factor-alpha production from monocytes: role of transcription factor NF-kappa B and implication for rheumatoid arthritis therapy.

    PubMed

    Lavagno, Luisa; Gunella, Gabriele; Bardelli, Claudio; Spina, Simona; Fresu, Luigia Grazia; Viano, Ilario; Brunelleschi, Sandra

    2004-10-06

    Inhibition of tumor necrosis factor-alpha (TNF-alpha) represents a relevant target in rheumatoid arthritis therapy. Besides inhibiting cyclooxygenase, anti-inflammatory drugs can affect the activation of transcription factors. We investigated the ability of dexamethasone, indomethacin, and rofecoxib to modulate nuclear factor-kappaB (NF-kappaB) activation and TNF-alpha release from human monocytes challenged with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA). Both stimuli induced NF-kappaB nuclear translocation and TNF-alpha secretion. Dexamethasone potently inhibited TNF-alpha release, indomethacin inhibited only PMA-evoked release, while rofecoxib had no effect. In the electrophoretic mobility shift assay, dexamethasone and rofecoxib dose-dependently inhibited the DNA binding activity of NF-kappaB in stimulated monocytes, whereas indomethacin failed to inhibit the LPS-evoked one. These results were further confirmed by evaluating the drugs' ability to reduce nuclear NF-kappaB subunits, as well as the amount of phosphorylated IkappaBalpha in cytosolic fractions. In conclusion, these results indicate that anti-inflammatory drugs differ largely in their ability to inhibit NF-kappaB activity and/or TNF-alpha release from human monocytes. These effects can be relevant to rheumatoid arthritis therapy.

  20. Mechanistic interpretation of nondestructive pavement testing deflections

    NASA Astrophysics Data System (ADS)

    Hoffman, M. S.

    1980-06-01

    A method is proposed for the backcalculation of material properties in flexible pavements based on the interpretation of surface deflection measurements. ILLI-PAVE, a stress dependent finite element pavement model, was used to generate data for developing algorithms and nomographs for deflection basin interpretation. Over 11,000 deflection measurements for 24 different flexible pavement sections were collected and analyzed. Deflections were measured using the Benkelman Beam, the IDOT Road Rater, the Falling Weight Deflectometer, and an accelerometer to measure deflections under moving trucks. Loading mode effects on pavement response were investigated using dynamic and viscous pavement models. The factors controlling the pavement response to different loading modes were explained and identified. Correlations between different devices were developed. The proposed evaluation procedure is illustrated for three different flexible pavements using deflection data collected on several testing dates.

  1. Application of mechanistic models for bioventing

    SciTech Connect

    Wit, J.C.M. de; Urlings, L.G.C.M.; Alphenaar, P.A.

    1995-12-31

    During many full-scale, in situ bioremediations the remediation process stagnates. Slow, diffusion-controlled release of the contaminants is the most important factor that causes this stagnation. Most likely, this slow release is caused by stagnant phases in the soil where convective flow is absent. For sound design and operation of in situ soil bioremediations, these nonequilibrium phenomena have to be considered explicitly. To do this, tools and models are needed that are applicable in the practical field, a field where time, budget, and data are always limited. In this paper, the authors have tried to use such a model for the prediction of the bioremediation of a toluene-contaminated site. The site has a sandy soil with, locally, a high clay and organic matter content. The calculations show that, to optimize biodegradation, soil vapor extraction with a low average extraction rate obtained, for example, by an intermittent extraction, should be favored over extraction with a high flowrate.

  2. Genetic Factors Involved in Fumonisin Accumulation in Maize Kernels and Their Implications in Maize Agronomic Management and Breeding

    PubMed Central

    Santiago, Rogelio; Cao, Ana; Butrón, Ana

    2015-01-01

    Contamination of maize with fumonisins depends on the environmental conditions; the maize resistance to contamination and the interaction between both factors. Although the effect of environmental factors is a determinant for establishing the risk of kernel contamination in a region, there is sufficient genetic variability among maize to develop resistance to fumonisin contamination and to breed varieties with contamination at safe levels. In addition, ascertaining which environmental factors are the most important in a region will allow the implementation of risk monitoring programs and suitable cultural practices to reduce the impact of such environmental variables. The current paper reviews all works done to address the influence of environmental variables on fumonisin accumulation, the genetics of maize resistance to fumonisin accumulation, and the search for the biochemical and/or structural mechanisms of the maize plant that could be involved in resistance to fumonisin contamination. We also explore the outcomes of breeding programs and risk monitoring of undertaken projects. PMID:26308050

  3. Genetic Factors Involved in Fumonisin Accumulation in Maize Kernels and Their Implications in Maize Agronomic Management and Breeding.

    PubMed

    Santiago, Rogelio; Cao, Ana; Butrón, Ana

    2015-08-20

    Contamination of maize with fumonisins depends on the environmental conditions; the maize resistance to contamination and the interaction between both factors. Although the effect of environmental factors is a determinant for establishing the risk of kernel contamination in a region, there is sufficient genetic variability among maize to develop resistance to fumonisin contamination and to breed varieties with contamination at safe levels. In addition, ascertaining which environmental factors are the most important in a region will allow the implementation of risk monitoring programs and suitable cultural practices to reduce the impact of such environmental variables. The current paper reviews all works done to address the influence of environmental variables on fumonisin accumulation, the genetics of maize resistance to fumonisin accumulation, and the search for the biochemical and/or structural mechanisms of the maize plant that could be involved in resistance to fumonisin contamination. We also explore the outcomes of breeding programs and risk monitoring of undertaken projects.

  4. Clinical Implications of Adipocytokines and Newly Emerging Metabolic Factors with Relation to Insulin Resistance and Cardiovascular Health

    PubMed Central

    Choi, Sung Hee; Hong, Eun Shil; Lim, Soo

    2013-01-01

    Adipose tissue is known to secrete hormones actively and produces many biologically active proteins called adipocytokines. Typically, obesity is followed by low-grade inflammation, which is characterized by increased circulating levels of pro-inflammatory cytokines. Macrophages play a role in the inflammatory process by secreting many cytokines such as tumor necrosis factor alpha, interleukin-6, resistin, and retinol binding protein-4. These cytokines and chemokines participate in low-grade pro-inflammatory processes leading to insulin resistance, metabolic impairment, and cardiovascular diseases. More metabolic regulators, such as fibroblast growth factor (FGF)21, FGF19, FGF1, vaspin, and visfatin have now been discovered but their exact roles in human diseases are still unclear. This review focuses on recent research regarding the role of adipokines and new metabolic factors in metabolic derangement or cardiovascular disease. PMID:23970879

  5. Mechanistic features of recombination in HIV.

    PubMed

    Galetto, Román; Negroni, Matteo

    2005-01-01

    The importance of recombination in retroviral evolution has been acknowledged for several decades. Consequently, after the identification of HIV as the etiological agent of AIDS, it was suspected that recombination could also play a central role in the evolution of this virus. However, only recently, extensive epidemiologic studies of HIV infections worldwide have provided an estimate for the occurrence of recombination in vivo, unveiling recombination frequencies that dwarf those initially expected. Nowadays, recombination is regarded as an integral part of the infectious cycle of this retrovirus, which impacts on diagnosis and treatment of infections, especially when genetically distant viruses have been at the origin of the recombinant forms. Retroviral recombination is observed when two genetically divergent genomic RNA molecules are present in the same viral particle, and arises during the reverse transcription step. This review focuses on the mechanisms that have been proposed to account for the occurrence of recombination in retroviruses, from the strand displacement model, according to which recombination occurs during second DNA strand synthesis; to the description of the factors responsible for copy-choice recombination during first DNA strand synthesis, such as the presence of breaks, pause sites, or secondary structures in the genomic RNA. Most of these models have been supported by experimental data obtained from in vitro reconstituted systems or from cell infection studies using academic model sequences. The situation in vivo is expected to be more complex, since several factors come into play when recombination involves relatively distant isolates, as in the case of inter-subtype recombination. At present, it is clear that further studies are needed in order to evaluate whether a prevailing mechanism exists for in vivo recombination, and these studies will also be essential for understanding how the underlying mechanisms of recombination contribute

  6. Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

    PubMed

    Jana, Arundhati; Modi, Khushbu K; Roy, Avik; Anderson, John A; van Breemen, Richard B; Pahan, Kalipada

    2013-06-01

    This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

  7. [Prevalence and implicated risk factors associated with the exteriorization of cardiac pacemakers: 5 year follow-up].

    PubMed

    Argüello-Hurtado, Marco; Guevara-Valdivia, Milton Ernesto; Aranda-Ayala, Zulema Lisbeth; Hernández-Lara, Javier

    2015-01-01

    Introducción: el objetivo de este estudio es establecer la prevalencia y determinar la frecuencia de factores de riesgo de exteriorización de marcapasos definitivos (MPD), en el departamento de Electrofisiología Cardiaca de la UMAE Hospital de Especialidades "Dr. Antonio Fraga Mouret" del Centro Médico Nacional La Raza del Instituto Mexicano del Seguro Social.Métodos: se llevó a cabo un estudio transversal, descriptivo del periodo: septiembre del 2005 a septiembre del 2010, para el análisis de los factores se manejó como casos y controles; se eligieron emparejándose por edad, sexo y presencia, o no, de factores de riesgo. Se realizó el cálculo de medidas de tendencia central (media, mediana y moda), así como pruebas de chi cuadrada, test de Fisher y razón de momios.Resultados: se implantaron 3192 MPD, identificando 83 casos de exteriorizaciones, seleccionando 43 casos para casos y controles, la edad promedio fue de 71 años. Ninguno de los factores de riesgo ni el tipo de técnica quirúrgica presentó significancia estadística.Conclusiones: nuestra prevalencia de exteriorizaciones es del 2.6 %, valores muy similares a los reportes publicados. Ninguno de los factores de riesgo descritos se encuentra presente como causa de exteriorización en nuestra población. El análisis de la técnica quirúrgica utilizada puede ser un factor importante, por lo que se necesitan estudios posteriores.

  8. Factors influencing movement of two migratory fishes within the tailrace of a large neotropical dam and their implications for hydropower impacts

    USGS Publications Warehouse

    Suzuki, F. M.; Dunham, Jason; Silva, L. G. M.; Alves, C. B. M.; Pompeu, P.S.

    2016-01-01

    Fish attempting to move upstream through hydroelectric dams can be trapped and killed in turbines. Understanding fish movement patterns can provide useful insights for how to manage dam operations to minimize fish kill in turbines. We evaluated the movements of two migratory fish (Curimba—Prochilodus argenteus and Mandi—Pimelodus maculatus) using acoustic telemetry in the tailrace of Três Marias Dam (São Francisco River, Brazil) from 31 October 2011 to 16 February 2012. The majority of tagged fish left the tailrace in less than one week; however, some individuals returned, performing several visits to the tailrace. Mandi remained longer in the tailrace than Curimba. The number of visits was influenced by diel period, turbine and spillway discharge. Although the diel period was the only important contributor to the visits performed by Curimba, the movements of Mandi were significantly influenced by three factors. We found that whereas Curimba was predominantly diurnal, Mandi showed nocturnal habits. Additionally, visits of Mandi were significantly greater during higher turbine and spillway discharge. We discuss the implications of these results for understanding fish movements in the Três Marias Dam tailrace and their potential implications for adapting hydroelectric operations to minimize fish kills.

  9. Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation.

    PubMed

    Scotcher, Daniel; Jones, Christopher; Posada, Maria; Galetin, Aleksandra; Rostami-Hodjegan, Amin

    2016-09-01

    It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drug-drug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.

  10. A simple mechanistic model to interpret the effects of narcotics.

    PubMed

    Baas, J; Spurgeon, D; Broerse, M

    2015-01-01

    In this research we will show the advantages of using a time-independent dose metric in a mechanistic model to evaluate toxic effects for different narcotic compounds on different species. We will show how different already existing QSARs can be combined within a mechanistic framework to 1) make predictions of lethal thresholds; 2) show some limitations in the use of existing QSARs; 3) show how a mechanistic framework solves some conceptual problems in current approaches and 4) show how such a framework can be used to be of aid in an experimental setup in predicting the outcome of a survival experiment. The approach we chose is based on the simplest mechanistic model available, a scaled one-compartment model to describe uptake and elimination and hazard model to link the exposure to effects on survival. Within this theoretical framework a prediction for an internal threshold for effects on survival of 3 mmol/kg bw can be made, which should be similar for different species and independent of the partitioning characteristics of the toxicant. To demonstrate this, a threshold for 51 different species was derived, which indeed appeared to lie in a relatively small range, typically between 1 and 10 mmol/kg bw.

  11. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems

    PubMed Central

    Transtrum, Mark K.; Qiu, Peng

    2016-01-01

    The inherent complexity of biological systems gives rise to complicated mechanistic models with a large number of parameters. On the other hand, the collective behavior of these systems can often be characterized by a relatively small number of phenomenological parameters. We use the Manifold Boundary Approximation Method (MBAM) as a tool for deriving simple phenomenological models from complicated mechanistic models. The resulting models are not black boxes, but remain expressed in terms of the microscopic parameters. In this way, we explicitly connect the macroscopic and microscopic descriptions, characterize the equivalence class of distinct systems exhibiting the same range of collective behavior, and identify the combinations of components that function as tunable control knobs for the behavior. We demonstrate the procedure for adaptation behavior exhibited by the EGFR pathway. From a 48 parameter mechanistic model, the system can be effectively described by a single adaptation parameter τ characterizing the ratio of time scales for the initial response and recovery time of the system which can in turn be expressed as a combination of microscopic reaction rates, Michaelis-Menten constants, and biochemical concentrations. The situation is not unlike modeling in physics in which microscopically complex processes can often be renormalized into simple phenomenological models with only a few effective parameters. The proposed method additionally provides a mechanistic explanation for non-universal features of the behavior. PMID:27187545

  12. DEVELOPMENT AND VALIDATION OF A MECHANISTIC GROUND SPRAYER MODEL

    EPA Science Inventory

    In the last ten years the Spray Drift Task Force (SDTF), U.S. Environmental Protection Agency (EPA), USDA Agricultural Research Service, and USDA Forest Service cooperated in the refinement and evaluation of a mechanistically-based aerial spray model (contained within AGDISP and ...

  13. MECHANISTIC AND SOURCE UNDERSTANDING OF PCDD/F FORMATION

    EPA Science Inventory

    The paper discusses mechanistic and source understanding of polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/F) formation. (NOTE: Considerable research effort has been expended over the last 15-plus years to understand how combustion sources result in formation of PCDDs/F...

  14. Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

    ERIC Educational Resources Information Center

    Grove, Nathaniel P.; Cooper, Melanie M.; Cox, Elizabeth L.

    2012-01-01

    The use of the curved-arrow notation to depict electron flow during mechanistic processes is one of the most important representational conventions in the organic chemistry curriculum. Our previous research documented a disturbing trend: when asked to predict the products of a series of reactions, many students do not spontaneously engage in…

  15. Rearrangements of Allylic Sulfinates to Sulfones: A Mechanistic Study

    ERIC Educational Resources Information Center

    Ball, David B.; Mollard, Paul; Voigtritter, Karl R.; Ball, Jenelle L.

    2010-01-01

    Most current organic chemistry textbooks are organized by functional groups and those of us who teach organic chemistry use functional-group organization in our courses but ask students to learn organic chemistry from a mechanistic approach. To enrich and extend the chemical understanding and knowledge of pericyclic-type reactions for chemistry…

  16. Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVII...

  17. An Assessment of the Predictive Validity of Impact Factor Scores: Implications for Academic Employment Decisions in Social Work

    ERIC Educational Resources Information Center

    Holden, Gary; Rosenberg, Gary; Barker, Kathleen; Onghena, Patrick

    2006-01-01

    Objective: Bibliometrics is a method of examining scholarly communications. Concerns regarding the use of bibliometrics in general, and the impact factor score (IFS) in particular, have been discussed across disciplines including social work. Although there are frequent mentions in the literature of the IFS as an indicator of the impact or quality…

  18. A Comparison of Institutional Factors and Student Satisfaction: Retention Implications in a Hispanic-Serving Community College.

    ERIC Educational Resources Information Center

    Elrod, Michael R.

    The purpose of this study was to investigate and examine the relationship of institutional factors students perceived to be important while enrolled in a community college. A student satisfaction inventory was administered on campus to collect data on first-time students perceptions of their college experiences. Results of the study indicated…

  19. Protection of Nonself Surfaces from Complement Attack by Factor H-Binding Peptides: Implications for Therapeutic Medicine

    PubMed Central

    Wu, You-Qiang; Qu, Hongchang; Sfyroera, Georgia; Tzekou, Apostolia; Kay, Brian K.; Nilsson, Bo; Ekdahl, Kristina Nilsson; Ricklin, Daniel; Lambris, John D.

    2011-01-01

    Exposure of nonself surfaces such as those of biomaterials or transplanted cells and organs to host blood frequently triggers innate immune responses, thereby affecting both their functionality and tolerability. Activation of the alternative pathway of complement plays a decisive role in this unfavorable reaction. Whereas previous studies demonstrated that immobilization of physiological regulators of complement activation (RCA) can attenuate this foreign body-induced activation, simple and efficient approaches for coating artificial surfaces with intact RCA are still missing. The conjugation of small molecular entities that capture RCA with high affinity is an intriguing alternative, as this creates a surface with autoregulatory activity upon exposure to blood. We therefore screened two variable cysteine-constrained phage-displayed peptide libraries for factor H-binding peptides. We discovered three peptide classes that differed with respect to their main target binding areas. Peptides binding to the broad middle region of factor H (domains 5–18) were of particular interest, as they do not interfere with either regulatory or binding activities. One peptide in this group (5C6) was further characterized and showed high factor H-capturing activity while retaining its functional integrity. Most importantly, when 5C6 was coated to a model polystyrene surface and exposed to human lepirudin-anticoagulated plasma, the bound peptide captured factor H and substantially inhibited complement activation by the alternative pathway. Our study therefore provides a promising and novel approach to produce therapeutic materials with enhanced biocompatibility. PMID:21339361

  20. Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy

    PubMed Central

    Crane, Courtney A.; Ahn, Brian J.; Han, Seunggu J.; Parsa, Andrew T.

    2012-01-01

    In patients with glioma, the tumor microenvironment can significantly impact pro-inflammatory immune cell functions. However, the mechanisms by which this occurs are poorly defined. Because immunosuppressive regulatory T cells (Treg) are over represented in the tumor microenvironment compared with peripheral blood, we hypothesized that the tumor may have an effect on Treg survival, migration, expansion, and/or induction of a regulatory phenotype from non-Treg conventional CD4+ T cells. We defined the impact of soluble factors produced by tumor cells on Treg from healthy patients in vitro to determine mechanisms by which gliomas influence T cell populations. We found that tumor-derived soluble factors allowed for preferential proliferation and increased chemotaxis of Treg, compared with conventional T cells, indicating that these mechanisms may contribute to the increased Treg in the tumor microenvironment. Conventional T cells also exhibited a significantly increased expression of pro-apoptotic transcripts in the presence of tumor-derived factors, indicating that survival of Treg in the tumor site is driven by exposure to soluble factors produced by the tumor. Together, these data suggest that tumor burden may induce increased Treg infiltration, proliferation, and survival, negating productive anti-tumor immune responses in patients treated with immunotherapies. Collectively, our data indicate that several mechanisms of Treg recruitment and retention in the tumor microenvironment exist and may need to be addressed to improve the specificity of immunotherapies seeking to eliminate Treg in patients with glioma. PMID:22406925

  1. Factors Associated with Participation in Work-Site Wellness Programs: Implications for Increasing Willingness among Rural Service Employees

    ERIC Educational Resources Information Center

    Middlestadt, Susan E.; Sheats, Jylana L.; Geshnizjani, Alireza; Sullivan, Margaret R.; Arvin, Christopher S.

    2011-01-01

    The purpose of this study was to identify factors underlying decisions to participate in work-site wellness programs. A sample of 279 full-time workers from a service division of a rural Midwestern university completed a survey assessing demographic and job characteristics, health status and health behaviors, and Reasoned Action Approach (RAA)…

  2. Anger, Anxiety, and Depression as Risk Factors for Cardiovascular Disease: The Problems and Implications of Overlapping Affective Dispositions

    ERIC Educational Resources Information Center

    Sul, Jerry; Bunde, James

    2005-01-01

    Several recent reviews (e.g., L. C. Gallo & K. Matthews, 2003; A. Rozanski, J. A. Blumenthal, & J. Kaplan, 1999; R. Rugulies, 2002) have identified 3 affective dispositions--depression, anxiety, and anger-hostility--as putative risk factors for coronary heart disease. There are, however, mixed and negative results. Following a critical summary of…

  3. The Role of Community, Family, Peer, and School Factors in Group Bullying: Implications for School-Based Intervention

    ERIC Educational Resources Information Center

    Mann, Michael J.; Kristjansson, Alfgeir L.; Sigfusdottir, Inga Dora; Smith, Megan L.

    2015-01-01

    Background: Although an ecological perspective suggests the importance of multiple levels of intervention, most bullying research has emphasized individual- and school-focused strategies. This study investigated community and family factors that influence school efforts to reduce odds of group bullying behavior and victimization. Methods: We used…

  4. Factors Impacting Job Performance and Role Attractiveness in Academic Directors and Their Implications for Policy and Practice in Higher Education

    ERIC Educational Resources Information Center

    Vilkinas, Tricia; Ladyshewsky, Richard K.

    2014-01-01

    The purpose of this study was to identify factors that impacted on the performance and attractiveness of the Academic Director's role. Academic Directors are responsible for leading and managing an academic qualification. Academic Directors (n = 101) participating in a leadership development programme were invited to respond to an online 360…

  5. An Exploration of Closure as a Factor Influencing Group Member Satisfaction: Implications for Applications of Group Support Technology in Education.

    ERIC Educational Resources Information Center

    Small, Ruth V.; Venkatesh, Murali

    Research that identifies factors that facilitate information processing and enhance performance without reducing group confidence and decision satisfaction may influence future development of groupwork systems. This paper contains a review of the literature on cognitive and motivational issues in both group decision-making and learning contexts…

  6. Processes influencing chemical biomagnification and trophic magnification factors in aquatic ecosystems: Implications for chemical hazard and risk assessment.

    PubMed

    Mackay, Donald; Celsie, Alena K D; Arnot, Jon A; Powell, David E

    2016-07-01

    Bioconcentration factors (BCFs) and bioaccumulation factors (BAFs) are widely used in scientific and regulatory programs to assess chemical hazards. There is increasing interest in also using biomagnification factors (BMFs) and trophic magnification factors (TMFs) for this purpose, especially for highly hydrophobic substances that may reach high concentrations in predatory species that occupy high trophic level positions in ecosystems. Measurements of TMFs in specific ecosystems can provide invaluable confirmation that biomagnification or biodilution has occurred across food webs, but their use in a regulatory context can be controversial because of uncertainties related to the reliability of measurements and their regulatory interpretation. The objective of this study is to explore some of the recognized uncertainties and dependencies in field BMFs and TMFs. This is accomplished by compiling a set of three simple food web models (pelagic, demersal and combined pelagic-demersal) consisting of up to seven species to simulate field BMFs and TMFs and to explore their dependences on hydrophobicity (expressed as log KOW), rates of biotransformation and growth, sediment-water fugacity ratios, and extent of food web omnivory and issues that arise when chemical concentration gradients exist in aquatic ecosystems. It is shown that empirical TMFs can be highly sensitive to these factors, thus the use of TMFs in a regulatory context must recognize these sensitivities. It is suggested that simple but realistic evaluative food web models could be used to extend BCF and BAF assessments to include BMFs and TMFs, thus providing a tool to address bioaccumulation hazard and the potential risk of exposures to elevated chemical concentrations in organisms at high trophic levels.

  7. Mechanistic Studies of Planetary Haze Formation

    NASA Astrophysics Data System (ADS)

    Hicks, Raea Kay

    2015-10-01

    controlling the total mass produced depends on pressure. We also report an overall increase with pressure in the N/C ratio, which supports the importance of a pressure- dependent mechanism for nitrogen incorporation. In order to understand carbon incorporation into early Earth aerosols, we devised an analysis technique that allows retrieval of the elemental analysis from unit-mass resolution (UMR) mass spectra of isotopically-labeled data. A quadrupole aerosol mass spectrometer (Q-AMS) was used to obtain UMR data of 13C-labeled and unlabeled aerosol generated by FUV photochemistry of gas mixtures containing 0.1% of either CH4 or 13CH 4 in N2. In this method, the differences in the positions of ion groups in the resulting spectra are used to estimate the mass fraction of carbon in the aerosol, and estimation of the remaining elements follows. Analysis of the UMR data yields an elemental composition of 63+/-7% C, 8+/-1% H, and 29+/-7% N by mass. Unlabeled aerosols formed under the same conditions are found by the HR-ToF-AMS to have an elemental composition of 63+/-3% C, 8+/-1% H, 20+/-4% N, and 9+/-3% O by mass, in good agreement with the UMR method. This favorable comparison verifies the method, which expands the UMR mass spectrometry toolkit. Chemical mechanisms posited to explain the aerosol-forming chemistry treat CH4 as carbon source in these hazes and treat CO2 as a source of oxygen only. We have generated early Earth aerosol analogs in the laboratory by FUV irradiation of gas mixtures containing isotopically-labeled permutations of 1,000 ppmv unlabeled and 13C-labeled CH 4 and CO2 in N2. Products in the particle phase were analyzed by the Q-AMS and the HR-ToF-AMS. Results indicate that CH 4 can account for 100% of the total carbon contained in the hazes. These results have implications for the geochemical interpretations of inclusions found in Archaean rocks on Earth, and for the astrobiological potential of other planetary atmospheres.

  8. Correlation of mechanistic data and histopathology in the evaluation of selected toxic endpoints of the endocrine system.

    PubMed

    Capen, C C

    1998-12-28

    The objective of this review is to correlate endocrinologic data from mechanistic studies with quantitative histopathology in selected examples of toxic endpoints of the endocrine system in laboratory animals. Mechanistic data can aid in the interpretation of animal toxicology findings and help clarify their significance in risk assessment. Endocrine organs of rodents frequently undergo proliferative changes with advancing age and following chronic exposure to large doses of xenobiotic chemicals, and the sensitivity of rodent endocrine tissues appears to be increasing. Many xenobiotic chemicals in large doses disrupt thyroid function in rodents either by a direct effect on the thyroid influencing synthesis of thyroid hormones or by adversely influencing their peripheral metabolism. A number of chemicals disrupt thyroid function by inhibiting the important enzyme, thyroperoxidase (TPO). A contemporary example of a chemical acting as TPO-inhibitor is sulfamethazine. In short-term mechanistic studies in rats there was a log-dose response relationship in circulating levels of thyroid and pituitary hormones plus a similar non-linear dose-response in morphologic changes in thyroid follicular cells. Endocrinologic data from mechanistic studies and histopathologic/ultrastructural findings will also be presented for the effects of the food color, FDC Red No. 3 (Erythrosine), on the thyroid gland in rats and parathyroid hormone-related protein (a major causative factor in cancer-associated hypercalcemia) on parathyroid chief cells in mice.

  9. New Measurement of Parity Violation in Elastic Electron-Proton Scattering and Implications for Strange Form Factors

    SciTech Connect

    Konrad Aniol; David Armstrong; Todd Averett; Maud Baylac; Etienne Burtin; John Calarco; Gordon Cates; Christian Cavata; Zhengwei Chai; C. Chang; Jian-Ping Chen; Eugene Chudakov; Evaristo Cisbani; Marius Coman; Daniel Dale; Alexandre Deur; Pibero Djawotho; Martin Epstein; Stephanie Escoffier; Lars Ewell; Nicolas Falletto; John Finn; A. Fleck; Bernard Frois; Salvatore Frullani; Juncai Gao; Franco Garibaldi; Ashot Gasparian; G. M. Gerstner; Ronald Gilman; Oleksandr Glamazdin; Javier Gomez; Viktor Gorbenko; Jens-ole Hansen; F. Hersman; Douglas Higinbotham; Richard Holmes; Maurik Holtrop; Thomas Humensky; Sebastien Incerti; Mauro Iodice; Cornelis De Jager; Johann Jardillier; Xiaodong Jiang; Mark Jones; J. Jorda; Christophe Jutier; W. Kahl; James Kelly; Donghee Kim; M. -J. Kim; Minsuk Kim; Ioannis Kominis; Edgar Kooijman; Kevin Kramer; Krishna Kumar; Michael Kuss; John LeRose; Raffaele De Leo; M. Leuschner; David Lhuillier; Meihua Liang; Nilanga Liyanage; R. Lourie; Richard Madey; Sergey Malov; Demetrius Margaziotis; Frederic Marie; Pete Markowitz; Jacques Martino; Peter Mastromarino; Kathy McCormick; Justin McIntyre; Zein-Eddine Meziani; Robert Michaels; Brian Milbrath; Gerald Miller; Joseph Mitchell; Ludyvine Morand; Damien Neyret; Gerassimos Petratos; Roman Pomatsalyuk; John Price; David Prout; Thierry Pussieux; Gilles Quemener; Ronald Ransome; David Relyea; Yves Roblin; Julie Roche; Gary Rutledge; Paul Rutt; Marat Rvachev; Franck Sabatie; Arunava Saha; Paul Souder; Marcus Spradlin; Steffen Strauch; Riad Suleiman; Jeffrey Templon; T. Teresawa; James Thompson; Raphael Tieulent; Luminita Todor; Baris Tonguc; Paul Ulmer; Guido Urciuoli; Branislav Vlahovic; Krishni Wijesooriya; R. Wilson; Bogdan Wojtsekhowski; Rhett Woo; Wang Xu; Imran Younus; C. Zhang

    2001-06-01

    We have measured the parity-violating electroweak asymmetry in the elastic scattering of polarized electrons from the proton. The result is A = -15.05 +- 0.98(stat) {+-} 0.56(syst) ppm at the kinematic point theta{sub lab} = 12.3 degrees and Q{sup 2} = 0.477 (GeV/c){sup 2}. The measurement implies that the value for the strange form factor (G{sub E}{sup s} + 0.392 G{sub M}{sup s})/(G{sub M}{sup p} {mu}{sub p}) = 0.069 +- 0.056 +- 0.039, where the first error is experimental and the second arises from the uncertainties in electromagnetic form factors. This measurement is the first fixed-target parity violation experiment that used either a ''strained'' GaAs photocathode to produce highly polarized electrons or a Compton polarimeter to continuously monitor the electron beam polarization.

  10. A review of the factors causing paralysis in wild birds: Implications for the paralytic syndrome observed in the Baltic Sea.

    PubMed

    Sonne, Christian; Alstrup, Aage Kristian Olsen; Therkildsen, Ole Roland

    2012-02-01

    We reviewed paralysis in wild birds with a special focus on the Baltic Sea paralytic syndrome recently described by Balk et al. (2009) by assessing multiple causative factors. The review showed that paralysis may occur in various species and that the aetiology can be divided into biotoxins, nutritional deficiencies, environmental contaminants and infectious diseases. The review also showed that the symptoms are influenced by age, sex and species of the affected individual. It seemed that paralysis may be treated or relieved by e.g. thiamine injections or additives. Due to a lack of extensive diagnostic studies, the potentially negative effects of paralysis at the population level of wild birds remain unsolved. We recommend that when investigating paralysis in wild birds, a holistic study approach including multiple factors are undertaken in order to pinpoint cause-and-effect relationships as well as the potential impacts on wild bird populations including those in the Baltic Sea.

  11. Consequences of nocturnal water loss: a synthesis of regulating factors and implications for capacitance, embolism and use in models.

    PubMed

    Zeppel, M J B; Lewis, J D; Phillips, N G; Tissue, D T

    2014-10-01

    Total daily water use is a key factor influencing the growth of many terrestrial plants, and reflects both day-time and nocturnal water fluxes. However, while nocturnal sap flow (En) and stomatal conductance (gs,n) have been reported across a range of species, ecosystems and microclimatic conditions, the regulation of these fluxes remains poorly understood. Here, we present a framework describing the role of abiotic and biotic factors in regulating En and gs,n highlighting recent developments in this field. Across ecosystems, En and gs,n generally increased with increasing soil water content and vapor pressure deficit, but the interactive effects of these factors and the potential roles of wind speed and other abiotic factors remain unclear. On average, gs,n and En are higher in broad-leaved compared with needle-leaved plants, in C3 compared with C4 plants, and in tropical compared with temperate species. We discuss the impacts of leaf age, elevated [CO2] and refilling of capacitance on night-time water loss, and how nocturnal gs,n may be included in vegetation models. Younger leaves may have higher gs,n than older leaves. Embolism refilling and recharge of capacitance may affect sap flow such that total plant water loss at night may be less than estimated solely from En measurements. Our estimates of gs,n for typical plant functional types, based on the published literature, suggest that nocturnal water loss may be a significant fraction (10-25%) of total daily water loss. Counter-intuitively, elevated [CO2] may increase nocturnal water loss. Assumptions in process-based ecophysiological models and dynamic global vegetation models that gs is zero when solar radiation is zero are likely to be incorrect. Consequently, failure to adequately consider nocturnal water loss may lead to substantial under-estimation of total plant water use and inaccurate estimation of ecosystem level water balance.

  12. Growth-supporting activity for Legionella pneumophila in tap water cultures and implication of hartmannellid amoebae as growth factors.

    PubMed Central

    Wadowsky, R M; Butler, L J; Cook, M K; Verma, S M; Paul, M A; Fields, B S; Keleti, G; Sykora, J L; Yee, R B

    1988-01-01

    Photosynthetic cyanobacteria, heterotrophic bacteria, free-living amoebae, and ciliated protozoa may support growth of Legionella pneumophila. Studies were done with two tap water cultures (WS1 and WS2) containing L. pneumophila and associated microbiota to characterize growth-supporting activity and assess the relative importance of the microbiota in supporting multiplication of L. pneumophila. The water cultures were incubated in the dark at 35 degrees C. The growth-supporting factor(s) was separated from each culture by filtration through 1-micron-pore-size membrane filters. The retentate was then suspended in sterile tap water. Multiplication of L. pneumophila occurred when both the retentate suspension and the filtrate from either culture were inoculated into sterile tap water. L. pneumophila did not multiply in tap water inoculated with only the filtrate, even though filtration did not reduce the concentration of L. pneumophila or heterotrophic bacteria in either culture. Growth-supporting activity of the retentate suspension from WS1 was inactivated at 60 degrees C but unaffected at 0, 25, and 45 degrees C after 30-min incubations. Filtration experiments indicated that the growth-supporting factor(s) in WS1 was 2 to 5 micron in diameter. Ciliated protozoa were not detected in either culture. Hartmannellid amoebae were conclusively demonstrated in WS2 but not in WS1. L. pneumophila multiplied in tap water inoculated with the amoebae (10(3)/ml) and the 1-micron filtrate of WS2. No multiplication occurred in tap water inoculated with the filtrate only. Growth-supporting activity for L. pneumophila may be present in plumbing systems; hartmannellid amoebae appear to be important determinants of multiplication of L. pneumophila in some tap water cultures. PMID:3214153

  13. Religion as a Support Factor for Women of Color Pursuing Science Degrees: Implications for Science Teacher Educators

    NASA Astrophysics Data System (ADS)

    Ceglie, Robert

    2013-02-01

    This study explores the influence of religion as a support factor for a group of Latina and African-American women majoring in science. The current project is a part of a larger study that investigated persistence factors of underrepresented woman who were enrolled as science majors at United States colleges and universities. This paper focuses on one theme that emerged among six participants who disclosed how religion was a significant influence on their persistence in science fields. The strength and support offered by religious values is certainly not specific to science content; however, the support received from their beliefs highlights a potential area for further exploration. Given the importance of increasing participation by students from diverse backgrounds into science fields, it is critical to recognize how some of these differences may be the key factors influencing the way these students look at the world. This study offers evidence that science educators need to consider what role religious beliefs have for students who may be considering science or science education as a future career, particularly for those students from underrepresented groups.

  14. [Frequency of chronic bronchitis in an intensely polluted urban zone. Preliminary results in children. Analysis of the implicated factors].

    PubMed

    Bungeţianu, G; Radu, G; Opriş, C; Păltineanu, V; Ruşdea, N; Cresco, F; Silaghi, I

    1980-01-01

    The starting point is that environment factors induce chronic bronchitis in adults and children and that the disease in adult is a consequence of respiratory tree susceptibility which might be better evidenced during childhood. The authors have studied a group of children aged 0--14 years in a highly air-poluted workers' quarter in the city of Baia-Mare. The frequence of chronic bronchitis was 10.3% with higher values in children below 5 years and over 10 years, the age group 5--9 years being a group with higher resistance to this disease. The figures are three times higher in boys than in girls, on possible endogenous factors. The girls could be, however, more subjected to "passive smoking" because of smokers presence in family and in bed room. The number of children in a family did not correlate with chronic bronchitis frequence. This frequence was significantly influenced by allergic and ear-nose-throat phenomena in the history, more evidently in 0--4 years and 10-14 years groups of age. These elements could be thus considered as risk factors. They also indicate the place to be acted upon in order to prevent chronic bronchitis in children.

  15. The adolescent body image satisfaction scale for males: exploratory factor analysis and implications for strength and conditioning professionals.

    PubMed

    Leone, James E; Mullin, Elizabeth M; Maurer-Starks, Suanne S; Rovito, Michael J

    2014-09-01

    The purpose of this study was to determine whether there is evidence of reliability and validity for the Adolescent Body Image Satisfaction Scale (ABISS), an instrument previously developed to measure adolescent body image. A sample (N = 330) of adolescent males, aged 14-19 years, completed the ABISS to determine current body image satisfaction. Data were analyzed for measures of instrument composite reliability and initial content and construct validity. Exploratory factor analysis supported a 3-factor solution (16 total items), which explained 42.7% of variance in the model. Composite reliability for the subscales, body competence, body inadequacy, and internal conflict ranged from 0.64 to 0.82. Exploratory factor analysis of the ABISS provides initial psychometric support for a valid and reliable measure for assessing adolescent male body image, which also can be used as a needs assessment tool. Strength and conditioning professionals should be aware of their athlete and client psychological attributes, many of whom are adolescents. Understanding how adolescents view their bodies and their body image will assist professionals in designing appropriate, health-promotive strength programs, while at the same time monitoring for signs of body image dissatisfaction. Assessing body image can help heighten awareness and possibly encourage preventative programming to help avert negative health practices (e.g., performance-enhancing drug use, exercise addictions, disordered eating). The ABISS seems to have preliminary psychometric support to be a valid and reliable instrument that helps gauge at-risk populations.

  16. Implication of a multisubunit Ets-related transcription factor in synaptic expression of the nicotinic acetylcholine receptor.

    PubMed Central

    Schaeffer, L; Duclert, N; Huchet-Dymanus, M; Changeux, J P

    1998-01-01

    In adult muscle, transcription of the nicotinic acetylcholine receptor (AChR) is restricted to the nuclei located at the neuromuscular junction. The N-box, a new promoter element, was identified recently and shown to contribute to this compartmentalized synaptic expression of the AChR delta- and epsilon-subunits. We demonstrate that the N-box mediates transcriptional activation in cultured myotubes and identify the transcription factor that binds to the N-box as a heterooligomer in myotubes and adult muscle. The GABP (GA-binding protein) alpha-subunit belongs to the Ets family of transcription factors, whereas the beta-subunit shares homology with IkappaB and Drosophila Notch protein. GABP binding specificity to mutated N-box in vitro strictly parallels the sequence requirement for beta-galactosidase targeting to the endplate in vivo. In situ hybridization studies reveal that the mRNAs of both GABP subunits are abundant in mouse diaphragm, with preferential expression of the alpha-subunit at motor endplates. In addition, heregulin increases GABPalpha protein levels and regulates phosphorylation of both subunits in cultured chick myotubes. Finally, dominant-negative mutants of either GABPalpha or GABPbeta block heregulin-elicited transcriptional activation of the AChR delta and epsilon genes. These findings establish the expected connection with a presynaptic trophic factor whose release contributes to the accumulation of AChR subunit mRNAs at the motor endplate. PMID:9606190

  17. Implications of the recent high statistics determination of the pion electromagnetic form factor in the timelike region

    NASA Astrophysics Data System (ADS)

    Ananthanarayan, B.; Caprini, Irinel; Imsong, I. Sentitemsu

    2011-05-01

    The recently evaluated two-pion contribution to the muon g-2 and the phase of the pion electromagnetic form factor in the elastic region, known from ππ scattering by Fermi-Watson theorem, are exploited by analytic techniques for finding correlations between the coefficients of the Taylor expansion at t=0 and the values of the form factor at several points in the spacelike region. We do not use specific parametrizations, and the results are fully independent of the unknown phase in the inelastic region. Using for instance, from recent determinations, ⟨rπ2⟩=(0.435±0.005)fm2 and F(-1.6GeV2)=0.243-0.014+0.022, we obtain the allowed ranges 3.75GeV-4≲c≲3.98GeV-4 and 9.91GeV-6≲d≲10.46GeV-6 for the curvature and the next Taylor coefficient, with a strong correlation between them. We also predict a large region in the complex plane where the form factor cannot have zeros.

  18. Redox-based epigenetic status in drug addiction: a potential contributor to gene priming and a mechanistic rationale for metabolic intervention.

    PubMed

    Trivedi, Malav S; Deth, Richard

    2014-01-01

    Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a "gene priming" phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.

  19. Teachers' beliefs about science teaching and context factors: Implications for teaching and learning science at the middle school level

    NASA Astrophysics Data System (ADS)

    Pea, Celeste H.

    Current research shows that teachers' beliefs have been virtually ignored in science education reform efforts spearheaded by the development of national, state, and local standards. Since the aim of science education reform is to improve scientific literacy for all students, increasingly, researchers are questioning the lack of attention to teachers' beliefs and are calling for more research to examine teachers' beliefs and the influence of school environmental factors on their classroom practices. The purpose of this study was to explore, investigate, and analyze data that might reveal middle school science teachers' beliefs about science teaching and how school environmental factors influence their classroom behavior. The mixed methods study was conducted in a large urban/suburban county in an eastern state in the United States. Data were collected through a Likert-style survey and interview and observation sessions. Ninety-one middle school science teachers completed the survey. Three teachers from the survey sample also participated in the interview and observation sessions. The findings from the quantitative and qualitative data indicated that most of the middle school science teachers in this study believed that science teaching should be student-centered, and science instruction should be based on an inquiry-based approach to teaching and learning. They also believed that the state and county standards were the most important factors in helping teachers to use inquiry-based instructional strategies to teach science. In addition to the science standards, the middle school science teachers believed that peer and principal support were critical to their success as teachers, and that instructional materials and supplies were readily available to help them teach science. The findings from the study indicated that few school environmental factors affected the middle school teachers' classroom practices. However, time (to participate in more professional activities

  20. Selenium in thioredoxin reductase: a mechanistic perspective.

    PubMed

    Lacey, Brian M; Eckenroth, Brian E; Flemer, Stevenson; Hondal, Robert J

    2008-12-02

    Most high M(r) thioredoxin reductases (TRs) have the unusual feature of utilizing a vicinal disulfide bond (Cys(1)-Cys(2)) which forms an eight-membered ring during the catalytic cycle. Many eukaryotic TRs have replaced the Cys(2) position of the dyad with the rare amino acid selenocysteine (Sec). Here we demonstrate that Cys- and Sec-containing TRs are distinguished by the importance each class of enzymes places on the eight-membered ring structure in the catalytic cycle. This hypothesis was explored by studying the truncated enzyme missing the C-terminal ring structure in conjunction with oxidized peptide substrates to investigate the reduction and opening of this dyad. The peptide substrates were identical in sequence to the missing part of the enzyme, containing either a disulfide or selenylsulfide linkage, but were differentiated by the presence (cyclic) and absence (acyclic) of the ring structure. The ratio of these turnover rates informs that the ring is only of modest importance for the truncated mouse mitochondrial Sec-TR (ring/no ring = 32), while the ring structure is highly important for the truncated Cys-TRs from Drosophila melanogaster and Caenorhabditis elegans (ring/no ring > 1000). All three enzymes exhibit a similar dependence upon leaving group pK(a) as shown by the use of the acyclic peptides as substrates. These two factors can be reconciled for Cys-TRs if the ring functions to simultaneously allow for attack by a nearby thiolate while correctly positioning the leaving group sulfur atom to accept a proton from the enzymic general acid. For Sec-TRs the ring is unimportant because the lower pK(a) of the selenol relative to a thiol obviates its need to be protonated upon S-Se bond scission and permits physical separation of the selenol and the general acid. Further study of the biochemical properties of the truncated Cys and Sec TR enzymes demonstrates that the chemical advantage conferred on the eukaryotic enzyme by a selenol is the ability to

  1. Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

    PubMed Central

    Tran, Nicholas M.; Zhang, Alan; Zhang, Xiaodong; Huecker, Julie B.; Hennig, Anne K.; Chen, Shiming

    2014-01-01

    Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of

  2. Toward a mechanistic modeling of nitrogen limitation for photosynthesis

    NASA Astrophysics Data System (ADS)

    Xu, C.; Fisher, R. A.; Travis, B. J.; Wilson, C. J.; McDowell, N. G.

    2011-12-01

    The nitrogen limitation is an important regulator for vegetation growth and global carbon cycle. Most current ecosystem process models simulate nitrogen effects on photosynthesis based on a prescribed relationship between leaf nitrogen and photosynthesis; however, there is a large amount of variability in this relationship with different light, temperature, nitrogen availability and CO2 conditions, which can affect the reliability of photosynthesis prediction under future climate conditions. To account for the variability in nitrogen-photosynthesis relationship under different environmental conditions, in this study, we developed a mechanistic model of nitrogen limitation for photosynthesis based on nitrogen trade-offs among light absorption, electron transport, carboxylization and carbon sink. Our model shows that strategies of nitrogen storage allocation as determined by tradeoff among growth and persistence is a key factor contributing to the variability in relationship between leaf nitrogen and photosynthesis. Nitrogen fertilization substantially increases the proportion of nitrogen in storage for coniferous trees but much less for deciduous trees, suggesting that coniferous trees allocate more nitrogen toward persistence compared to deciduous trees. The CO2 fertilization will cause lower nitrogen allocation for carboxylization but higher nitrogen allocation for storage, which leads to a weaker relationship between leaf nitrogen and maximum photosynthesis rate. Lower radiation will cause higher nitrogen allocation for light absorption and electron transport but less nitrogen allocation for carboxylyzation and storage, which also leads to weaker relationship between leaf nitrogen and maximum photosynthesis rate. At the same time, lower growing temperature will cause higher nitrogen allocation for carboxylyzation but lower allocation for light absorption, electron transport and storage, which leads to a stronger relationship between leaf nitrogen and maximum

  3. Factors Predicting Bereaved Caregiver Perception of Quality of Care in the Final Week of Life: Implications for Health Care Providers

    PubMed Central

    Higgins, Philip C.; Garrido, Melissa M.

    2015-01-01

    Abstract Background: Cancer caregivers are key stakeholders in the final weeks of life and in bereavement. Research has highlighted end-of-life (EOL) factors important to caregivers, as well as factors contributing to caregiver mental health and bereavement outcomes. There has been limited data on factors predicting caregiver perceptions of quality of EOL care. Objective: This study's purpose was to identify modifiable predictors of caregivers' Caregiver Evaluation of Quality of End of Life Care (CEQUEL) scores, with the broader aim of informing clinical interventions to improve caregiver impressions of care and subsequent bereavement adjustment. Methods: Study data came from Coping with Cancer I (CwC1). CwC1 investigators interviewed advanced cancer patients and caregivers prior to the patient's death (Wave 1) and reinterviewed caregivers following the death (Wave 2) (N=275 dyads). The authors identified potential Wave 1 predictors of CEQUEL scores and performed a series of linear regression analyses to identify a parsimonious predictive model using corrected Akaike's Information Criterion (AICc) values. Results: In adjusted analyses, caregivers rated quality of care as poorer when patients died in a hospital (B=−1.40, SE=0.40, p=0.001) (B, unstandardized regression coefficient; SE, standard error) or had less than one week of inpatient hospice care (B=−1.98, SE=−0.70, p=0.006). Whole-person physician care and caregiver religiosity were associated with perceived higher quality of care in unadjusted, but not adjusted, analyses. Conclusions: Findings suggest that place of death and hospice length of stay best predict bereaved caregiver evaluations of quality of EOL care. These findings equip health care providers with modifiable targets to improve caregivers' experience of EOL care and subsequent bereavement. PMID:26186021

  4. Mechanistic Insight and Management of Diabetic Nephropathy: Recent Progress and Future Perspective

    PubMed Central

    Xue, Rui; Gui, Dingkun; Zheng, Liyang; Zhai, Ruonan

    2017-01-01

    Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes and the largest single cause of end-stage renal disease (ESRD) in many developed countries. DN is also associated with an increased cardiovascular mortality. It occurs as a result of interaction between both genetic and environmental factors. Hyperglycemia, hypertension, and genetic predisposition are the major risk factors. However, the exact mechanisms of DN are unclear. Despite the benefits derived from strict control of glucose and blood pressure, as well as inhibition of renin-angiotensin-aldosterone system, many patients continue to enter into ESRD. Thus, there is urgent need for improving mechanistic understanding of DN and then developing new and effective therapeutic approaches to delay the progression of DN. This review focuses on recent progress and future perspective about mechanistic insight and management of DN. Some preclinical relevant studies are highlighted and new perspectives of traditional Chinese medicine (TCM) for delaying DN progression are discussed in detail. These findings strengthen the therapeutic rationale for TCM in the treatment of DN and also provide new insights into the development of novel drugs for the prevention of DN. However, feasibility and safety of these therapeutic approaches and the clinical applicability of TCM in human DN need to be further investigated. PMID:28386567

  5. Climatic, tectonic, and biological factors affecting the oxidation state of the atmosphere and oceans: Implications for Phanerozoic O2 evolution

    NASA Astrophysics Data System (ADS)

    Ozaki, K.; Tajika, E.

    2015-12-01

    The Earth's atmosphere and oceans have seen fundamental changes in its oxidation state in response to the climatic, tectonic and geochemical variations. Over the past decade, several geochemical proxies have led to significant progress in understanding the paleredox states of ancient oceans. However, a quantitative interpretation of these data for atmospheric O2 levels remain unclear because the relationship between atmospheric O2 levels (pO2) and oceanic redox state depends on several environmental factors, such as terrestrial weathering rate, sea-level stands, and sinking rate of particulate organic matter (POM) in the water column and so on. It is widely thought that the redox-dependent P cycling also plays a crucial role in regulating pO2 because it acts as a negative feedback on a geological timescale. It is important that strength of this feedback for a given pO2 is also modulated by environmental factors, affecting not only O2 levels at steady state but also its susceptibility to environmental changes. In this study, a quantitative role of environmental factors in the oxidation state of Earth's surface environment is evaluated with an oceanic biogeochemical cycle model (CANOPS) coupled with global C cycle model, which enables us to understand the ancient CO2 and O2 evolution. Our results demonstrate that atmospheric O2 level at steady state is affected by CO2 input flux from Earth's interior via changes in biogeochemical cycles, but its response is modulated by several internal factors such as shelf area and POM sinking rate. We also found that early Paleozoic atmospheric O2 levels before the advent of land plant would be determined so that oceans may locate at the "edge of anoxia (EoA)" where the redox-dependency of marine P cycle plays a crucial role in regulating O2 cycle, and that POM sinking rate has a great impact on the EoA. Our findings provide insights into the O2 cycle over the Phanerozoic in response to the climatic and tectonic variations and

  6. Personality factors and attitudes toward euthanasia in Iran: implications for end-of-life research and practice.

    PubMed

    Aghababaei, Naser; Wasserman, Jason Adam; Hatami, Javad

    2014-01-01

    This article reports on the relationship of personality and euthanasia attitudes. Results from a survey of 165 Iranian students showed that religiosity, honesty-humility, agreeableness, and extraversion were related to negative attitudes toward euthanasia, whereas openness was related to acceptance of euthanasia, with the unconventionality facet driving this relationship. Moreover, openness explained additional variance when added to a multivariate model containing religiosity and HEXACO factors. This study illustrates the possibility of accounting for variation beyond the traditional group level predictors of attitudes toward euthanasia and promoting future cross-cultural studies into personality and end-of-life issues and informing end-of-life conversations at the bedside.

  7. The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival

    NASA Technical Reports Server (NTRS)

    Wallis, Deeann; Hamblen, Melanie; Zhou, Yi; Venken, Koen J T.; Schumacher, Armin; Grimes, H. Leighton; Zoghbi, Huda Y.; Orkin, Stuart H.; Bellen, Hugo J.

    2003-01-01

    Gfi1 was first identified as causing interleukin 2-independent growth in T cells and lymphomagenesis in mice. Much work has shown that Gfi1 and Gfi1b, a second mouse homolog, play pivotal roles in blood cell lineage differentiation. However, neither Gfi1 nor Gfi1b has been implicated in nervous system development, even though their invertebrate homologues, senseless in Drosophila and pag-3 in C. elegans are expressed and required in the nervous system. We show that Gfi1 mRNA is expressed in many areas that give rise to neuronal cells during embryonic development in mouse, and that Gfi1 protein has a more restricted expression pattern. By E12.5 Gfi1 mRNA is expressed in both the CNS and PNS as well as in many sensory epithelia including the developing inner ear epithelia. At later developmental stages, Gfi1 expression in the ear is refined to the hair cells and neurons throughout the inner ear. Gfi1 protein is expressed in a more restricted pattern in specialized sensory cells of the PNS, including the eye, presumptive Merkel cells, the lung and hair cells of the inner ear. Gfi1 mutant mice display behavioral defects that are consistent with inner ear anomalies, as they are ataxic, circle, display head tilting behavior and do not respond to noise. They have a unique inner ear phenotype in that the vestibular and cochlear hair cells are differentially affected. Although Gfi1-deficient mice initially specify inner ear hair cells, these hair cells are disorganized in both the vestibule and cochlea. The outer hair cells of the cochlea are improperly innervated and express neuronal markers that are not normally expressed in these cells. Furthermore, Gfi1 mutant mice lose all cochlear hair cells just prior to and soon after birth through apoptosis. Finally, by five months of age there is also a dramatic reduction in the number of cochlear neurons. Hence, Gfi1 is expressed in the developing nervous system, is required for inner ear hair cell differentiation, and its loss

  8. A framework for recognizing mechanistic reasoning in student scientific inquiry

    NASA Astrophysics Data System (ADS)

    Russ, Rosemary S.

    A central ambition of science education reform is to help students develop abilities for scientific inquiry. Education research is thus rightly focused on defining what constitutes "inquiry" and developing tools for assessing it. There has been progress with respect to particular aspects of inquiry, namely student abilities for controlled experimentation and scientific argumentation. However, we suggest that in addition to these frameworks for assessing the structure of inquiry we need frameworks for analyzing the substance of that inquiry. In this work we draw attention to and evaluate the substance of student mechanistic reasoning. Both within the history and philosophy of science and within science education research, scientific inquiry is characterized in part as understanding the causal mechanisms that underlie natural phenomena. The challenge for science education, however, is that there has not been the same progress with respect to making explicit what constitutes mechanistic reasoning as there has been in making explicit other aspects of inquiry. This dissertation attempts to address this challenge. We adapt an account of mechanism in professional research science to develop a framework for reliably recognizing mechanistic reasoning in student discourse. The coding scheme articulates seven specific aspects of mechanistic reasoning and can be used to systematically analyze narrative data for patterns in student thinking. It provides a tool for detecting quality reasoning that may be overlooked by more traditional assessments. We apply the mechanism coding scheme to video and written data from a range of student inquiries, from large group discussions among first grade students to the individual problem solving of graduate students. While the primary result of this work is the coding scheme itself and the finding that it provides a reliable means of analyzing transcript data for evidence of mechanistic thinking, the rich descriptions we develop in each case

  9. A review of factors affecting productivity of bald eagles in the Great Lakes region: implications for recovery.

    PubMed Central

    Bowerman, W W; Giesy, J P; Best, D A; Kramer, V J

    1995-01-01

    The bald eagle (Haliaeetus leucocephalus) population in North America declined greatly after World War II due primarily to the eggshell thinning effects of p,p'-DDE, a biodegradation product of DDT. After the banning of DDT in the United States and Canada during the early 1970s, the bald eagle population started to increase. However, this population recovery has not been uniform. Eagles nesting along the shorelines of the North American Great Lakes and rivers open to spawning runs of anadromous fishes from the Great Lakes still exhibit impaired reproduction. We have explored both ecological and toxicological factors that would limit reproduction of bald eagles in the Great Lakes region. Based on our studies, the most critical factors influencing eagle populations are concentrations of environmental toxicants. While there might be some continuing effects of DDE, total PCBs and most importantly 2,3,7,8-tetrachlordibenzo-p-dioxin equivalents (TCDD-EQ) in fishes from the Great Lakes and rivers open to spawning runs of anadromous fishes from the Great Lakes currently represent a significant hazard to bald eagles living along these shorelines or near these rivers and are most likely related to the impaired reproduction in bald eagles living there. PMID:7556024

  10. A Systematic Review of Built Environment Factors Related to Physical Activity and Obesity Risk: Implications for Smart Growth Urban Planning

    PubMed Central

    Durand, Casey P.; Andalib, Mohammad; Dunton, Genevieve F.; Wolch, Jennifer; Pentz, Mary Ann

    2010-01-01

    Introduction Smart growth is an approach to urban planning that provides a framework for making community development decisions. Despite its growing use, it is not known whether smart growth can impact physical activity. This review utilizes existing built environment research on factors that have been used in smart growth planning to determine whether they are associated with physical activity or body mass. Methods Searching the MEDLINE, Psycinfo and Web-of-Knowledge databases, 204 articles were identified for descriptive review, and 44 for a more in-depth review of studies that evaluated four or more smart growth planning principles. Results Five smart growth factors (diverse housing types, mixed land use, housing density, compact development patterns, and levels of open space) were associated with increased levels of physical activity and walking. Results varied by gender and method of environmental assessment. Body mass was largely unaffected. Discussion This review suggests that several features of the built environment that are typically associated with smart growth planning may promote physical activity. Future smart growth community planning could be modified to include a dedicated focus on health, and future research should explore whether combinations or a critical mass of smart growth features is associated with better population health outcomes. PMID:21348918

  11. Capsid-binding retrovirus restriction factors: discovery, restriction specificity and implications for the development of novel therapeutics.

    PubMed

    Sanz-Ramos, Marta; Stoye, Jonathan P

    2013-12-01

    The development of drugs against human immunodeficiency virus type 1 infection has been highly successful, and numerous combinational treatments are currently available. However, the risk of the emergence of resistance and the toxic effects associated with prolonged use of antiretroviral therapies have emphasized the need to consider alternative approaches. One possible area of investigation is provided by the properties of restriction factors, cellular proteins that protect organisms against retroviral infection. Many show potent viral inhibition. Here, we describe the discovery, properties and possible therapeutic uses of the group of restriction factors known to interact with the capsid core of incoming retroviruses. This group comprises Fv1, TRIM5α and TRIMCypA: proteins that all act shortly after virus entry into the target cell and block virus replication at different stages prior to integration of viral DNA into the host chromosome. They have different origins and specificities, but share general structural features required for restriction, with an N-terminal multimerization domain and a C-terminal capsid-binding domain. Their overall efficacy makes it reasonable to ask whether they might provide a framework for developing novel antiretroviral strategies.

  12. Factors influencing the selection of delivery with no one present in Northern Nigeria: implications for policy and programs

    PubMed Central

    Fapohunda, Bolaji; Orobaton, Nosakhare

    2014-01-01

    This paper examines the effects of demographic, socioeconomic, and women’s autonomy factors on the utilization of delivery assistance in Sokoto State, Nigeria. Data were obtained from the Nigeria 2008 Demographic and Health Survey (DHS). Bivariate analysis and logistic regression procedures were conducted. The study revealed that delivery with no one present and with unskilled attendance accounted for roughly 95% of all births in Sokoto State. Mothers with existing high risk factors, including higher parity, were more likely to select unsafe/unskilled delivery practices than younger, lower-parity mothers. Evidenced by the high prevalence of delivery with traditional birth attendants, this study demonstrates that expectant mothers are willing to obtain care from a provider, and their odds of using accessible, affordable, skilled delivery is high, should such an option be presented. This conclusion is supported by the high correlation between a mother’s socioeconomic status and the likelihood of using skilled attendance. To improve the access to, and increase the affordability of, skilled health attendants, we recommended two solutions: 1) the use of cash subsidies to augment women’s incomes in order to reduce finance-related barriers in the use of formal health services, thus increasing demand; and 2) a structural improvement that will increase women’s economic security by improving their access to higher education, income, and urban ideation. PMID:24516341

  13. A systematic review of built environment factors related to physical activity and obesity risk: implications for smart growth urban planning.

    PubMed

    Durand, C P; Andalib, M; Dunton, G F; Wolch, J; Pentz, M A

    2011-05-01

    Smart growth is an approach to urban planning that provides a framework for making community development decisions. Despite its growing use, it is not known whether smart growth can impact physical activity. This review utilizes existing built environment research on factors that have been used in smart growth planning to determine whether they are associated with physical activity or body mass. Searching the MEDLINE, Psycinfo and Web-of-Knowledge databases, 204 articles were identified for descriptive review, and 44 for a more in-depth review of studies that evaluated four or more smart growth planning principles. Five smart growth factors (diverse housing types, mixed land use, housing density, compact development patterns and levels of open space) were associated with increased levels of physical activity, primarily walking. Associations with other forms of physical activity were less common. Results varied by gender and method of environmental assessment. Body mass was largely unaffected. This review suggests that several features of the built environment associated with smart growth planning may promote important forms of physical activity. Future smart growth community planning could focus more directly on health, and future research should explore whether combinations or a critical mass of smart growth features is associated with better population health outcomes.

  14. Rapamycin and the transcription factor C/EBPbeta as a switch in osteoclast differentiation: implications for lytic bone diseases.

    PubMed

    Smink, Jeske J; Leutz, Achim

    2010-03-01

    Lytic bone diseases and in particular osteoporosis are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, osteoporosis poses a major global health-care problem due to the growth of the elderly population. Recently, it was found that the gene regulatory transcription factor CCAAT/enhancer binding protein beta (C/EBPbeta) is involved in bone metabolism. C/EBPbeta occurs as different protein isoforms of variable amino terminal length, and regulation of the C/EBPbeta isoform ratio balance was found to represent an important factor in osteoclast differentiation and bone homeostasis. Interestingly, adjustment of the C/EBPbeta isoform ratio by the process of translational control is downstream of the mammalian target of rapamycin kinase (mTOR), a sensor of the nutritional status and a target of immunosuppressive and anticancer drugs. The findings imply that modulating the process of translational control of C/EBPbeta isoform expression could represent a novel therapeutic approach in osteolytic bone diseases, including cancer and infection-induced bone loss.

  15. Expression of Eukaryotic Initiation Factor 5A and Hypusine Forming Enzymes in Glioblastoma Patient Samples: Implications for New Targeted Therapies

    PubMed Central

    Preukschas, Michael; Hagel, Christian; Schulte, Alexander; Weber, Kristoffer; Lamszus, Katrin; Sievert, Henning; Pällmann, Nora; Bokemeyer, Carsten; Hauber, Joachim; Braig, Melanie; Balabanov, Stefan

    2012-01-01

    Glioblastomas are highly aggressive brain tumors of adults with poor clinical outcome. Despite a broad range of new and more specific treatment strategies, therapy of glioblastomas remains challenging and tumors relapse in all cases. Recent work demonstrated that the posttranslational hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is a crucial regulator of cell proliferation, differentiation and an important factor in tumor formation, progression and maintenance. Here we report that eIF-5A as well as the hypusine-forming enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH) are highly overexpressed in glioblastoma patient samples. Importantly, targeting eIF-5A and its hypusine modification with GC7, a specific DHS-inhibitor, showed a strong antiproliferative effect in glioblastoma cell lines in vitro, while normal human astrocytes were not affected. Furthermore, we identified p53 dependent premature senescence, a permanent cell cycle arrest, as the primary outcome in U87-MG cells after treatment with GC7. Strikingly, combined treatment with clinically relevant alkylating agents and GC7 had an additive antiproliferative effect in glioblastoma cell lines. In addition, stable knockdown of eIF-5A and DHS by short hairpin RNA (shRNA) could mimic the antiproliferative effects of GC7. These findings suggest that pharmacological inhibition of eIF-5A may represent a novel concept to treat glioblastomas and may help to substantially improve the clinical course of this tumor entity. PMID:22927971

  16. Characteristic Features and Contributory Factors in Fatal Ciguatera Fish Poisoning—Implications for Prevention and Public Education

    PubMed Central

    Chan, Thomas Y. K.

    2016-01-01

    In this review, the main objective was to describe the characteristic features of fatal ciguatera fish poisoning and identify contributory factors, with a view to promote prevention and public education. Ciguatera-related deaths, although rare, have been reported from the Pacific, Caribbean, and Indian Ocean regions. The clinical features were generally dominated by convulsions and coma, with various focal neurological signs. Several contributory factors could be identified, including consumption of ciguatoxin (CTX)-rich fish parts (viscera and head) in larger amounts, the most ciguatoxic fish species (e.g., Gymnothorax flavimarginatus) and reef fish collected after storms and individuals' susceptibility. Mass ciguatera fish poisoning with mortalities also occurred when G. flavimarginatus and other ciguatoxic fish species were shared in gatherings and parties. The characteristic features of fatal ciguatera fish poisoning must be recognized early. The public should be repeatedly reminded to avoid eating the most ciguatoxic fish species and the CTX-rich parts of reef fish. To prevent mass poisoning in gatherings and parties, the most ciguatoxic fish species and potentially toxic fish species must be avoided. Particularly after hits by disastrous storms, it is important to monitor the toxicity of reef fish and the incidence rates of ciguatera. PMID:26787145

  17. Characteristic Features and Contributory Factors in Fatal Ciguatera Fish Poisoning--Implications for Prevention and Public Education.

    PubMed

    Chan, Thomas Y K

    2016-04-01

    In this review, the main objective was to describe the characteristic features of fatal ciguatera fish poisoning and identify contributory factors, with a view to promote prevention and public education. Ciguatera-related deaths, although rare, have been reported from the Pacific, Caribbean, and Indian Ocean regions. The clinical features were generally dominated by convulsions and coma, with various focal neurological signs. Several contributory factors could be identified, including consumption of ciguatoxin (CTX)-rich fish parts (viscera and head) in larger amounts, the most ciguatoxic fish species (e.g.,Gymnothorax flavimarginatus) and reef fish collected after storms and individuals' susceptibility. Mass ciguatera fish poisoning with mortalities also occurred when G. flavimarginatus and other ciguatoxic fish species were shared in gatherings and parties. The characteristic features of fatal ciguatera fish poisoning must be recognized early. The public should be repeatedly reminded to avoid eating the most ciguatoxic fish species and the CTX-rich parts of reef fish. To prevent mass poisoning in gatherings and parties, the most ciguatoxic fish species and potentially toxic fish species must be avoided. Particularly after hits by disastrous storms, it is important to monitor the toxicity of reef fish and the incidence rates of ciguatera.

  18. Implications for the functions of the four known midgut differentiation factors: An immunohistologic study of Heliothis virescens midgut.

    PubMed

    Loeb, Marcia J; Coronel, Nicholas; Natsukawa, Dai; Takeda, Makio

    2004-05-01

    Antibodies to the peptides that induce differentiation of midgut larval stem cells, the midgut differentiating factors MDF-2, MDF-3, and MDF-4, bind to columnar cells in midgut cultures and in intact midgut of Heliothis virescens, in manners similar to the binding of anti- MDF-1 to those tissues. Antibodies to MDF-2 and MDF-3 also stained droplets in the midgut lumen, suggesting that columnar cells may also release MDF-2- and MDF-3-like cytokines to the lumen. Antibody to MDF-4 exhibited similar staining patterns but also recognized stem and differentiating cells, the presumed targets of peptides that regulate stem cell differentiation. Antibody to MDF-4 also bound to one type of endocrine cell in midgut cultures and in sections of midgut, as well as to the endocrine secretion released both to the midgut lumen and the hemolymph. Antibodies to the MDFs 1, 2, and 3, incubated with cultures of midgut cells, did not appear to prevent differentiation of the stem cells in the cultures but affected viability of mature cells, reflected in increased apoptosis and doubling of the number of differentiating cells compared to controls. Only antibody to MDF-4 induced temporary necrosis and inhibition of population recovery, indicating that MDF4 may be the true differentiation factor. The other MDFs may have additional functions beyond regulation of midgut stem cell differentiation in vivo.

  19. A review of factors affecting productivity of bald eagles in the Great Lakes region: implications for recovery.

    PubMed

    Bowerman, W W; Giesy, J P; Best, D A; Kramer, V J

    1995-05-01

    The bald eagle (Haliaeetus leucocephalus) population in North America declined greatly after World War II due primarily to the eggshell thinning effects of p,p'-DDE, a biodegradation product of DDT. After the banning of DDT in the United States and Canada during the early 1970s, the bald eagle population started to increase. However, this population recovery has not been uniform. Eagles nesting along the shorelines of the North American Great Lakes and rivers open to spawning runs of anadromous fishes from the Great Lakes still exhibit impaired reproduction. We have explored both ecological and toxicological factors that would limit reproduction of bald eagles in the Great Lakes region. Based on our studies, the most critical factors influencing eagle populations are concentrations of environmental toxicants. While there might be some continuing effects of DDE, total PCBs and most importantly 2,3,7,8-tetrachlordibenzo-p-dioxin equivalents (TCDD-EQ) in fishes from the Great Lakes and rivers open to spawning runs of anadromous fishes from the Great Lakes currently represent a significant hazard to bald eagles living along these shorelines or near these rivers and are most likely related to the impaired reproduction in bald eagles living there.

  20. Comparative Genomics of NAC Transcriptional Factors in Angiosperms: Implications for the Adaptation and Diversification of Flowering Plants.

    PubMed

    Pereira-Santana, Alejandro; Alcaraz, Luis David; Castaño, Enrique; Sanchez-Calderon, Lenin; Sanchez-Teyer, Felipe; Rodriguez-Zapata, Luis

    2015-01-01

    NAC proteins constitute one of the largest groups of plant-specific transcription factors and are known to play essential roles in various developmental processes. They are also important in plant responses to stresses such as drought, soil salinity, cold, and heat, which adversely affect growth. The current knowledge regarding the distribution of NAC proteins in plant lineages comes from relatively small samplings from the available data. In the present study, we broadened the number of plant species containing the NAC family origin and evolution to shed new light on the evolutionary history of this family in angiosperms. A comparative genome analysis was performed on 24 land plant species, and NAC ortholog groups were identified by means of bidirectional BLAST hits. Large NAC gene families are found in those species that have experienced more whole-genome duplication events, pointing to an expansion of the NAC family with divergent functions in flowering plants. A total of 3,187 NAC transcription factors that clustered into six major groups were used in the phylogenetic analysis. Many orthologous groups were found in the monocot and eudicot lineages, but only five orthologous groups were found between P. patens and each representative taxa of flowering plants. These groups were called basal orthologous groups and likely expanded into more recent taxa to cope with their environmental needs. This analysis on the angiosperm NAC family represents an effort to grasp the evolutionary and functional diversity within this gene family while providing a basis for further functional research on vascular plant gene families.

  1. Tissue factor activity in human monocytes is regulated by plasma: implications for the high and low responder phenomenon.

    PubMed

    Nijziel, M; van Oerle, R; van 't Veer, C; van Pampus, E; Lindhout, T; Hamulyák, K

    2001-01-01

    The 'high and low responder phenomenon' of monocyte tissue factor (MTF) activity has been attributed to effects on monocytes by granulocytes, platelets and lipopolysaccharide (LPS). To study the possible contribution of plasma to the high and low responder phenomenon, we measured the MTF activity in isolated cryopreserved human monocytes from two donors (monocytes A and monocytes B) after incubation in a plasma environment depleted of granulocytes, platelets and LPS. In buffer only, MTF activity was 643 and 679 fM (fM = final concentration of tissue factor), in normal pooled plasma, it was 1478 and 1615 fM (P = 0.001), respectively, in monocytes A and in monocytes B. Incubation with individual plasma samples from healthy controls (n = 43) gave a median MTF of 1355 fM (range 1044-1976 fM) and 1329 fM (range 858-1951 fM) respectively. A plasma consistently induced a higher or lower level of MTF activity in both monocytes: r = 0.82 (P < 0.00001). Coumarin use did not influence the high and low responder phenomenon. In the absence of granulocytes, platelets and LPS, plasma determines the high and low responder phenomenon. This phenomenon is not influenced by coumarin treatment.

  2. Reproductive Performance of a Declining Forest Passerine in Relation to Environmental and Social Factors: Implications for Species Conservation

    PubMed Central

    Grendelmeier, Alex; Arlettaz, Raphaël; Gerber, Michael; Pasinelli, Gilberto

    2015-01-01

    Identifying factors influencing a species' ecological niche and demography is a prerequisite for species conservation. However, our understanding of the interplay between demographic rates and biotic/abiotic factors is still poor for most species of conservation concern. We evaluated relevance of eight hypotheses relating to timing of breeding, temporal nest exposure, nest concealment, topography, tree structure, predation risk and disturbance, density dependence and weather for explaining variation in reproductive performance of the declining wood warbler Phylloscopus sibilatrix in northern Switzerland. Reproductive performance was monitored with cameras at 136 nests from 2010 to 2012 and was associated to temporal exposure, timing of breeding and concealment of nests. Daily nest survival was positively related to the number of grass and sedge tussocks, nest concealment and nest age. Clutch size and number of fledglings decreased, the later in the season a nest was initiated. Nest survival over an average nesting period of 31 days was 46.9 ± 0.07% (mean ± SE), daily nest survival rate was 0.976 ± 0.002. As for many ground-breeding birds, nest predation was the principal cause of nest failure, accounting for 79% of all nest losses. Conservation measures should aim at increasing the area of relatively homogenous forest stands featuring suitable habitats characterized by abundant and accessible grass and sedge tussocks. In managed forests, such conditions can be found in stands of middle age (i.e. pole wood) with little to no shrub layer. PMID:26172954

  3. Methanosarcina acetivorans 16S rRNA and transcription factor nucleotide fluctuation with implications in exobiology and pathology

    NASA Astrophysics Data System (ADS)

    Holden, Todd; Tremberger, G., Jr.; Cheung, E.; Subramaniam, R.; Sullivan, R.; Schneider, P.; Flamholz, A.; Marchese, P.; Hiciano, O.; Yao, H.; Lieberman, D.; Cheung, T.

    2008-08-01

    Cultures of the methane-producing archaea Methanosarcina, have recently been isolated from Alaskan sediments. It has been proposed that methanogens are strong candidates for exobiological life in extreme conditions. The spatial environmental gradients, such as those associated with the polygons on Mars' surface, could have been produced by past methanogenesis activity. The 16S rRNA gene has been used routinely to classify phenotypes. Using the fractal dimension of nucleotide fluctuation, a comparative study of the 16S rRNA nucleotide fluctuation in Methanosarcina acetivorans C2A, Deinococcus radiodurans, and E. coli was conducted. The results suggest that Methanosarcina acetivorans has the lowest fractal dimension, consistent with its ancestral position in evolution. Variation in fluctuation complexity was also detected in the transcription factors. The transcription factor B (TFB) was found to have a higher fractal dimension as compared to transcription factor E (TFE), consistent with the fact that a single TFB in Methanosarcina acetivorans can code three different TATA box proteins. The average nucleotide pair-wise free energy of the DNA repair genes was found to be highest for Methanosarcina acetivorans, suggesting a relatively weak bonding, which is consistent with its low prevalence in pathology. Multitasking capacity comparison of type-I and type-II topoisomerases has been shown to correlate with fractal dimension using the methicillin-resistant strain MRSA 252. The analysis suggests that gene adaptation in a changing chemical environment can be measured in terms of bioinformatics. Given that the radiation resistant Deinococcus radiodurans is a strong candidate for an extraterrestrial origin and that the cold temperature Psychrobacter cryohalolentis K5 can function in Siberian permafrost, the fractal dimension comparison in this study suggests that a chemical resistant methanogen could exist in extremely cold conditions (such as that which existed on early

  4. Field enhancement factor dependence on electric field and implications on microscale gas breakdown: Theory and experimental interpretation

    NASA Astrophysics Data System (ADS)

    Alejandro Buendia, Jose; Venkattraman, Ayyaswamy

    2015-12-01

    In this letter, we obtain a better understanding of effective field enhancement factors (β eff) in the context of microscale gas breakdown with specific emphasis on its dependence on applied electric field. The theoretical dependence of β eff on electric field for various hemi-ellipsoidal asperities indicates that the value of β eff decreases with increasing electric field. The interpretation of experimental data using a typical one-dimensional modified Paschen law indicates a qualitatively similar electric field dependence even though the data could not be completely explained using a single effective asperity size. The values of β eff extracted from seven independent experimental datasets for microscale breakdown of argon and air are shown to be consistent and an empirical dependence on electric field is determined.

  5. Chios mastic fractions in experimental colitis: implication of the nuclear factor κB pathway in cultured HT29 cells.

    PubMed

    Papalois, Apostolos; Gioxari, Aristea; Kaliora, Andriana C; Lymperopoulou, Aikaterini; Agrogiannis, George; Papada, Efstathia; Andrikopoulos, Nikolaos K

    2012-11-01

    The Pistacia lentiscus tree gives a resinous exudate called Chios mastic (CM) rich in triterpenoids. CM can be fractionated into acidic and neutral fractions (AF and NF, respectively). Oleanolic acid (OA) is a major triterpenic acid in CM with several antioxidant and anti-inflammatory properties. We have recently shown that CM is beneficial in experimental colitis in the form of powder mixture with inulin, as supplied commercially. However, the bioactive fraction or compound of CM is unidentified. Thus, based on the hypothesis that terpenoids exhibit functional activities via distinguishable pathways, we fractionated CM and applied different fractions or individual OA in experimental colitis. Furthermore, we investigated the mechanism underlying this effect in human colon epithelial cells. CM powder mixture (100 mg/kg of body weight) or the respective CM powder mixture components (i.e., inulin, AF, NF, or OA) were individually administered in trinitrobenzene sulfonic acid-treated rats. Colonic damage was assessed microscopically, and levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and intercellular adhesion molecule-1were measured. A model of inflammation in co-cultured human colon epithelial HT29 cells and monocytes/macrophages was established. Lactate dehydrogenase release and levels of TNF-α, IL-8, and nuclear factor-κB (NF-κB) p65 were measured. In vivo, histological amelioration of colitis and significant regulation in inflammation occurred with CM powder mixture, even at the mRNA level. Although no histological improvement was observed, AF and NF reduced levels of inflammatory markers. Inulin was ineffective. In vitro, CM treatment down-regulated IL-8 and NF-κB p65. Neither fractions nor OA was the bioactive component solely. Most probably, the entire CM rather than its individual fractions reduces inflammation via NF-κB regulation.

  6. Migration/mobility and risk factors for HIV among female sex workers in Andhra Pradesh, India: implications for HIV prevention.

    PubMed

    Reed, E; Gupta, J; Biradavolu, M; Blankenship, K M

    2012-04-01

    We examined the relation between high mobility/migration (sex work in three or more villages/towns within the past year) and HIV risk factors among a sample of female sex workers (FSWs) in Andhra Pradesh, India. We recruited FSWs aged ≥18 years (n = 673) through respondent-driven sampling for a survey on HIV risk. Adjusted logistic and linear regression models assessed high mobility in relation to sexual and physical victimization, sexually transmitted infection (STI) symptoms and treatment, condom use and negotiation, number and/or types of sex trades, number of clients and number of days worked. Twelve percent (n = 82) of FSWs were highly mobile; those with high mobility were more likely to report recent HIV risk factors: sexual violence (adjusted odds ratio [AOR] = 5.2; 95% confidence interval [CI]: 3.0-8.9), physical violence (AOR = 1.7; 95% CI: 1.1-2.7), unprotected sex for more money (AOR = 1.7; 95% CI: 1.1-3.0), at least one STI symptom (AOR = 1.9; 95% CI: 1.1-3.1), a greater number of vaginal sex trades (β = 3.9, P = 0.003), a greater number of clients (β = 2.5, P = 0.02) and anal sex with clients (AOR = 2.4; 95% CI: 1.4-4.1). Findings from this study underscore the violence and HIV-related vulnerability faced by mobile/migrant FSWs and highlight the need to inform and tailor related prevention strategies.

  7. Seroprevalence and risk factors of brucellosis in goats in selected states in Nigeria and the public health implications.

    PubMed

    Ogugua, A J; Akinseye, V O; Ayoola, M C; Oyesola, O O; Shima, F K; Tijjani, A O; Musa, Aderemi N A; Adesokan, H K; Perrett, Lorraine; Taylor, Andrew; Stack, Judy A; Moriyon, I; Cadmus, S I B

    2014-09-01

    Available reports on brucellosis in Nigeria are largely confined to cattle while it is believed that other ruminants like sheep and goats are equally exposed to the disease. To have an insight into the role of goats in the epidemiology of brucellosis in Nigeria, we conducted a cross-sectional study between June 2011 and May 2013 to determine the seroprevalence of brucellosis in goats in some selected states in Nigeria. Serum samples were collected from goats at different locations and tested for antibodies to Brucella spp using the Rose Bengal Test (RBT), samples positive by RBT were further subjected to Competitive Enzyme Linked Immunosorbent Assay (cELISA). Data collected to determine risk factors were also analysed using chi-square and logistics regression statistics. Out of a total of 2827 samples tested from the different states (Benue = 331; Borno =195; Oyo = 2155; Sokoto = 146), we recorded an overall seroprevalence of 2.83% (Benue = 17.30%; Borno = 2.05%; Oyo = 0.60% and Sokoto = 0.00%) by RBT. The cELISA further supported 9.45% (7/74) of the total RBT positive samples. Logistic regression analysis showed that the location (p = 0.004) and source (p < 0.0001); are probable risk factors to be considered in the epidemiology of brucellosis with sex (p = 0.179); age (p = 0.791) and breed (p = 0.369) not playing any major role. Our findings reveal a relatively low seroprevalence of brucellosis among goats screened except for Benue State. Since most of the goats sampled in the present study were from the abattoirs, further farm level investigations are required to determine the role of goats in the epidemiology of brucellosis in Nigeria since they share common environment with sheep and cattle that are natural hosts of Brucella species which are of major public health threat.

  8. Analysis of the VMD2 promoter and implication of E-box binding factors in its regulation.

    PubMed

    Esumi, Noriko; Oshima, Yuji; Li, Yuanyuan; Campochiaro, Peter A; Zack, Donald J

    2004-04-30

    The retinal pigment epithelium (RPE) is crucial for the normal development and function of retinal photo-receptors, and mutations in several genes that are preferentially expressed in the RPE have been shown to cause retinal degeneration. We analyzed the 5'-up-stream region of human VMD2, a gene that is preferentially expressed in the RPE and, when mutated, causes Best macular dystrophy. Transgenic mouse studies with VMD2 promoter/lacZ constructs demonstrated that a-253 to +38 bp fragment is sufficient to direct RPE-specific expression in the eye. Transient transfection assays using the D407 human RPE cell line with VMD2 promoter/luciferase reporter constructs identified two positive regulatory regions, -585 to -541 bp for high level expression and -56 to -42 bp for low level expression. Mutation of a canonical E-box located in the -56 to -42 bp region greatly diminished luciferase expression in D407 cells and abolished the bands shifted with bovine RPE nuclear extract in electrophoretic mobility shift assays. Independently a candidate approach was used to select microphthalmia-associated transcription factor (MITF) for testing because it is expressed in the RPE and associated with RPE abnormalities when mutated. MITF-M significantly increased luciferase expression in D407 cells in an E-box-dependent manner. These studies define the VMD2 promoter region sufficient to drive RPE-specific expression in the eye, identify positive regulatory regions in vitro, and suggest that MITF as well as other E-box binding factors may act as positive regulators of VMD2 expression.

  9. Postpartum von Willebrand factor levels in women with and without von Willebrand disease and implications for prophylaxis.

    PubMed

    James, A H; Konkle, B A; Kouides, P; Ragni, M V; Thames, B; Gupta, S; Sood, S; Fletcher, S K; Philipp, C S

    2015-01-01

    The aim of this study was to elucidate the fall in von Willebrand factor (VWF) and factor VIII activity (FVIII) after childbirth in women with and without von Willebrand disease (VWD). VWF:RCo, VWF:Ag, and FVIII were obtained in the third trimester of pregnancy, on admission for childbirth, and 10 times postpartum. Specimens were processed within 4 h and analysed centrally. Means were calculated at each time point. Forty women (40 pregnancies) without VWD and 32 women (35 pregnancies) with VWD were enrolled. 15/32 with VWD were treated (30% of those with type 1 and all of those with type 2) in 17 pregnancies. Treatments prior to delivery consisted of desmopressin (2/17), VWF concentrate (15/17) and after delivery VWF concentrate (16/17). Duration of treatment was 0-21 days (median 6). VWF levels peaked at 250% of baseline--4 h postpartum in women with VWD and 12 h postpartum in women without VWD. Thereafter, VWF levels fell rapidly, approached baseline at 1 week and reached baseline at 3 weeks. Except immediately postpartum, when the levels among treated cases were higher, levels among women with VWD appeared to parallel, but were lower than those among women without VWD. Levels were lowest among those who received treatment. VWF levels fall rapidly after childbirth. Except immediately postpartum, current treatment strategies do not raise VWF levels to the levels of women without VWD or even to the levels of women with milder, untreated VWD. Consequently, women with VWD may be at risk of postpartum haemorrhage despite treatment.

  10. Seroprevalence and risk factors of brucellosis in goats in selected states in Nigeria and the public health implications

    PubMed Central

    Ogugua, A.J.; Akinseye, V.O.; Ayoola, M.C.; Oyesola, O.O.; Shima, F.K.; Tijjani, A.O.; Musa, Aderemi N. A.; Adesokan, H.K.; Perrett, Lorraine; Taylor, Andrew; Stack, Judy A.; Moriyon, I; Cadmus, S.I.B.

    2015-01-01

    Available reports on brucellosis in Nigeria are largely confined to cattle while it is believed that other ruminants like sheep and goats are equally exposed to the disease. To have an insight into the role of goats in the epidemiology of brucellosis in Nigeria, we conducted a cross-sectional study between June 2011 and May 2013 to determine the seroprevalence of brucellosis in goats in some selected states in Nigeria. Serum samples were collected from goats at different locations and tested for antibodies to Brucella spp using the Rose Bengal Test (RBT), samples positive by RBT were further subjected to Competitive Enzyme Linked Immunosorbent Assay (cELISA). Data collected to determine risk factors were also analysed using chi-square and logistics regression statistics. Out of a total of 2827 samples tested from the different states (Benue = 331; Borno =195; Oyo = 2155; Sokoto = 146), we recorded an overall seroprevalence of 2.83% (Benue = 17.30%; Borno = 2.05%; Oyo = 0.60% and Sokoto = 0.00%) by RBT. The cELISA further supported 9.45% (7/74) of the total RBT positive samples. Logistic regression analysis showed that the location (p = 0.004) and source (p < 0.0001); are probable risk factors to be considered in the epidemiology of brucellosis with sex (p = 0.179); age (p = 0.791) and breed (p = 0.369) not playing any major role. Our findings reveal a relatively low seroprevalence of brucellosis among goats screened except for Benue State. Since most of the goats sampled in the present study were from the abattoirs, further farm level investigations are required to determine the role of goats in the epidemiology of brucellosis in Nigeria since they share common environment with sheep and cattle that are natural hosts of Brucella species which are of major public health threat. PMID:26689681

  11. Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions

    SciTech Connect

    Derwahl, M.; Studer, H.; Huber, G.; Gerber, H.; Peter, H.J. )

    1990-11-01

    Five methods are commonly used to quantify FRTL-5 cells' and other thyrocytes' growth in vitro and the impact of growth inhibiting or stimulating maneuvers: Total cell count, mitotic index, DNA measurement, total (3H)thymidine incorporation, and the fraction of (3H)thymidine labeled cells. All of them assess cell growth as though all cells were homogeneous with an identical response to growth factors. We demonstrate here that this assumption is not valid. Rather, some intrinsically growth-prone cells appear to pass a growth signal to neighboring cells so that variably sized colonies of synchronized cells within each cluster growing from monodispersed cells are formed. This is true for FRTL-5 cells growing in vitro in monolayers and in three-dimensional, collagen embedded spheroids. The pattern is the same when cell suspensions or collagen-embedded spheroids are implanted onto nude mice. Patches with alternating high and low growth become particularly prominent in the large tumor-like organoids grown from monodispersed cells in nude mice. The pattern much reminds of similar observations in growing intact thyroids. Since there is no significant correlation between the fraction of (3H)thymidine labeled cells and the size of two- or three-dimensional clusters in any experiment, growth of signal-spreading cells is assumed to occur in leaps and bounds. Growth velocity in each subclone of a cell population depends on the mean interval between bursts of replications and on the number of cells synchronized by cell-to-cell diffusion of the growth signal emanating from one dividing cell. Thus, growth-promoting and growth-inhibiting factors may not only act on the mean interval between successive growth bursts, but they may also change cell-to-cell spreading of growth signals.

  12. Comparative Genomics of NAC Transcriptional Factors in Angiosperms: Implications for the Adaptation and Diversification of Flowering Plants

    PubMed Central

    Pereira-Santana, Alejandro; Alcaraz, Luis David; Castaño, Enrique; Sanchez-Calderon, Lenin; Sanchez-Teyer, Felipe; Rodriguez-Zapata, Luis

    2015-01-01

    NAC proteins constitute one of the largest groups of plant-specific transcription factors and are known to play essential roles in various developmental processes. They are also important in plant responses to stresses such as drought, soil salinity, cold, and heat, which adversely affect growth. The current knowledge regarding the distribution of NAC proteins in plant lineages comes from relatively small samplings from the available data. In the present study, we broadened the number of plant species containing the NAC family origin and evolution to shed new light on the evolutionary history of this family in angiosperms. A comparative genome analysis was performed on 24 land plant species, and NAC ortholog groups were identified by means of bidirectional BLAST hits. Large NAC gene families are found in those species that have experienced more whole-genome duplication events, pointing to an expansion of the NAC family with divergent functions in flowering plants. A total of 3,187 NAC transcription factors that clustered into six major groups were used in the phylogenetic analysis. Many orthologous groups were found in the monocot and eudicot lineages, but only five orthologous groups were found between P. patens and each representative taxa of flowering plants. These groups were called basal orthologous groups and likely expanded into more recent taxa to cope with their environmental needs. This analysis on the angiosperm NAC family represents an effort to grasp the evolutionary and functional diversity within this gene family while providing a basis for further functional research on vascular plant gene families. PMID:26569117

  13. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.

    PubMed Central

    Kilbourn, R G; Gross, S S; Jubran, A; Adams, J; Griffith, O W; Levi, R; Lodato, R F

    1990-01-01

    Clinical assessment of the activity of tumor necrosis factor (TNF) against human cancer has been limited by a dose-dependent cardiovascular toxicity, most frequently hypotension. TNF is also thought to mediate the vascular collapse resulting from bacterial endotoxin. The present studies address the mechanism by which TNF causes hypotension and provide evidence for elevated production of nitric oxide, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Nitric oxide is synthesized by several cell types, including endothelial cells and macrophages, from the guanidino nitrogen of L-arginine; the enzymatic pathway is competitively inhibited by NG-methyl-L-arginine. We found that hypotension induced in pentobarbital-anesthetized dogs by TNF (10 micrograms/kg, i.v., resulting in a fall in mean systemic arterial pressure from 124.7 +/- 7 to 62.0 +/- 22.9 mmHg; 1 mmHg = 133 Pa) was completely reversed within 2 min following administration of NG-methyl-L-arginine (4.4 mg/kg, i.v.). In contrast, NG-methyl-L-arginine failed to reverse the hypotensive response to an equivalent depressor dose of nitroglycerin, a compound that acts by forming nitric oxide by a nonenzymatic, arginine-independent mechanism. The effect of NG-methyl-L-arginine on TNF-induced hypotension was antagonized, and the hypotension restored, by administration of excess L-arginine (100 mg/kg, i.v.). Our findings suggest that excessive nitric oxide production mediates the hypotensive effect of TNF. PMID:2333306

  14. A dynamic and mechanistic model of PCB bioaccumulation in the European hake ( Merluccius merluccius)

    NASA Astrophysics Data System (ADS)

    Bodiguel, Xavier; Maury, Olivier; Mellon-Duval, Capucine; Roupsard, François; Le Guellec, Anne-Marie; Loizeau, Véronique

    2009-08-01

    Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions, and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake ( Merluccius merluccius, L. 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms.

  15. Mechanistic pathway modeling for industrial biotechnology: challenging but worthwhile.

    PubMed

    Wiechert, Wolfgang; Noack, Stephan

    2011-10-01

    Mechanistic (also called kinetic) models quantitatively describe dynamic and steady states of biochemical pathways. They are based on network structure (stoichiometry), regulatory information (enzyme inhibitors and activators) and the corresponding reaction kinetics. Although this approach to understand and predict the behavior of biochemical networks has now been in use for almost half a century, its experimental foundation has dramatically changed in the data-rich age of systems biology. Large mechanistic models, ranging up to the genome scale, are now being built and lots of data are available to validate and test them. From the broad scope of possible modeling applications, this survey focuses on the recent developments and central problems of metabolic network modeling in the field of bioprocess development for industrial biotechnology.

  16. Mechanistic model for catalytic recombination during aerobraking maneuvers

    NASA Technical Reports Server (NTRS)

    Willey, Ronald J.

    1989-01-01

    Several mechanistic models are developed to predict recombination coefficients for use in heat shield design for reusable surface insulation (RSI) on aerobraking vehicles such as space shuttles. The models are applied over a temperature range of 300 to 1800 K and a stagnation pressure range of 0 to 3,000 Pa. A four parameter model in temperature was found to work best; however, several models (including those with atom concentrations at the surface) were also investigated. Mechanistic models developed with atom concentration terms may be applicable when sufficient data becomes available. The requirement is shown for recombination experiments in the 300 to 1000 K and 1500 to 1850 K temperature range, with deliberate concentration variations.

  17. Hazard assessment of metals in invasive fish species of the Yamuna River, India in relation to bioaccumulation factor and exposure concentration for human health implications.

    PubMed

    Singh, Atul K; Srivastava, Sharad C; Verma, Pankaj; Ansari, Abubakar; Verma, Ambrish

    2014-06-01

    Monitoring of heavy metals was conducted in the Yamuna River considering bioaccumulation factor, exposure concentration, and human health implications which showed contamination levels of copper (Cu), lead (Pb), nickel (Ni), and chromium (Cr) and their dispersion patterns along the river. Largest concentration of Pb in river water was 392 μg L(-1); Cu was 392 μg L(-1) at the extreme downstream, Allahabad and Ni was 146 μg L(-1) at midstream, Agra. Largest concentration of Cu was 617 μg kg(-1), Ni 1,621 μg kg(-1) at midstream while Pb was 1,214 μg kg(-1) at Allahabad in surface sediment. The bioconcentration of Cu, Pb, Ni, and Cr was observed where the largest accumulation of Pb was 2.29 μg kg(-1) in Oreochromis niloticus and 1.55 μg kg(-1) in Cyprinus carpio invaded at Allahabad while largest concentration of Ni was 174 μg kg(-1) in O. niloticus and 124 μg kg(-1) in C. carpio in the midstream of the river. The calculated values of hazard index (HI) for Pb was found more than one which indicated human health concern. Carcinogenic risk value for Ni was again high i.e., 17.02 × 10(-4) which was larger than all other metals studied. The results of this study indicated bioconcentration in fish due to their exposures to heavy metals from different routes which had human health risk implications. Thus, regular environmental monitoring of heavy metal contamination in fish is advocated for assessing food safety since health risk may be associated with the consumption of fish contaminated through exposure to a degraded environment.

  18. Millifluidics for Chemical Synthesis and Time-resolved Mechanistic Studies

    PubMed Central

    Krishna, Katla Sai; Biswas, Sanchita; Navin, Chelliah V.; Yamane, Dawit G.; Miller, Jeffrey T.; Kumar, Challa S.S.R.

    2013-01-01

    Procedures utilizing millifluidic devices for chemical synthesis and time-resolved mechanistic studies are described by taking three examples. In the first, synthesis of ultra-small copper nanoclusters is described. The second example provides their utility for investigating time resolved kinetics of chemical reactions by analyzing gold nanoparticle formation using in situ X-ray absorption spectroscopy. The final example demonstrates continuous flow catalysis of reactions inside millifluidic channel coated with nanostructured catalyst. PMID:24327099

  19. Low-wind and other microclimatic factors in near-road black carbon variability: A case study and assessment implications

    PubMed Central

    Liang, Marissa S.; Keener, Timothy C.; Birch, M. Eileen; Baldauf, Richard; Neal, Jill; Yang, Y. Jeffrey

    2015-01-01

    Airborne black carbon from urban traffic is a climate forcing agent and has been associated with health risks to near-road populations. In this paper, we describe a case study of black carbon concentration and compositional variability at and near a traffic-laden multi-lane highway in Cincinnati, Ohio, using an onsite aethalometer and filter-based NIOSH Method 5040 measurements; the former measured 1-min average black carbon concentrations and the latter determined the levels of organic and elemental carbon (OC and EC) averaged over an approximately 2-h time interval. The results show significant wind and temperature effects on black carbon concentration and composition in a way more complex than predicted by Gaussian dispersion models. Under oblique low winds, namely ux[= u × sin(g=q)]~ (0,−0.5 m s−1), which mostly occurred during morning hours, black carbon concentrations per unit traffic flow were highest and had large variation. The variability did not always follow Gaussian dispersion but was characteristic of a uniform distribution at a near-road distance. Under all other wind conditions, the near-road black carbon variation met Gaussian dispersion characteristics. Significant differences in roadside dispersion are observed between OC and EC fractions, between PM2.5 and PM10–2.5, and between the morning period and rest of the day. In a general case, the overall black carbon variability at the multi-lane highway can be stated as bimodal consisting of Gaussian dispersion and non-Gaussian uniform distribution. Transition between the two types depends on wind velocity and wind angle to the traffic flow. In the order of decreasing importance, the microclimatic controlling factors over the black carbon variability are: 1) wind velocity and the angle with traffic; 2) diurnal temperature variations due to thermal buoyancy; and 3) downwind Gaussian dispersion. Combinations of these factors may have created various traffic–microclimate interactions that have

  20. Cataract surgery: factors influencing decision to treat and implications for training (south-east Scotland 2008–2014)

    PubMed Central

    Sniatecki, Jan J; Styles, Caroline; Boyle, Natalie; Sanders, Roshini

    2015-01-01

    Purpose To describe the population referred for cataract surgery, identify factors that influenced decision to treat, and patients suitable for ophthalmic training. Patients and methods A total of 2,693 consecutive referrals over 6 years were interrogated using Business Objects software on cataract electronic patient records. Results A total of 2,693 patients were referred for cataract surgery (group A). Of these patients 2,132 (79%) had surgery (group B) and 561 (21%) did not (group C). Age for group B vs group C: 672 (32%) vs 115 (20%) ≤69 years, P<0.001; 803 (38%) vs 225 (40%) 70–79 years, P=0.48; 586 (27%) vs 203 (36%) 80–89 years, P<0.05; 71 (3%) vs 18 (3%) ≥90 years, P=1.0. Visual acuity, group B vs group C: 556 (26%) vs 664 (59%) 6/12 or better; 1,275 (60%) vs 367 (33%) 6/18–6/60; 266 (12%) vs 64 (6%) counting fingers or worse, P<0.05. Medical history for group B vs C: cognitive impairment: 55 (2.6%) vs 29 (5.2%), P<0.05; cardiovascular accident: 158 (7.4%) vs 60 (10.7%), P<0.05; diabetes: 372 (17.4%) vs 96 (17.1%), P=0.87; COPD/asthma: 382 (17.9%) vs 93 (16.6%), P=0.53; heart disease: 535 (25.1%) vs 155 (27.6%), P=0.35; hypertension: 971 (45.5%) vs 263 (46.9%), P=0.73. Ocular history for group B vs C was significant (P<0.05) for age-related macular degeneration 255 (12.0%) vs 93 (16.6%), other macular pathology 38 (1.8%) vs 25 (4.5%), corneal pathology 92 (4.3%) vs 36 (6.4%), amblyopia 37 (1.7%) vs 22 (3.9%). Detailed data on presenting complaint, ophthalmic history, and social status is discussed. Conclusion We observed that surgery at a younger age with good levels of visual acuity was a factor in deferring cataract surgery. Cognitive impairment, cardiovascular accident, amblyopia, corneal and macular pathology significantly affected decision not to operate. We estimate that 80% of patients would be suitable for ophthalmic training. PMID:26491242

  1. Measurements of black and organic carbon emission factors for household coal combustion in China: implication for emission reduction.

    PubMed

    Chen, Yingjun; Zhi, Guorui; Feng, Yanli; Liu, Dongyan; Zhang, Gan; Li, Jun; Sheng, Guoying; Fu, Jiamo

    2009-12-15

    Household coal combustion is considered as the greatest emission source for black carbon (BC) and an important source for organic carbon (OC) in China. However, measurements on BC and OC emission factors (EF(BC) and EF(OC)) are still scarce, which result in large uncertainties in emission estimates. In this study, a detailed data set of EF(BC) and EF(OC) for household coal burning was presented on the basis of 38 coal/stove combination experiments. These experiments included 13 coals with a wide coverage of geological maturity which were tested in honeycomb-coal-briquette and raw-coal-chunk forms in three typical coal stoves. Averaged values of EF(BC) are 0.004 and 0.007 g/kg for anthracite in briquette and chunk forms and 0.09 and 3.05 g/kg for bituminous coal, respectively; EF(OC) are 0.06 and 0.10 g/kg for anthracite and 3.74 and 5.50 g/kg for bituminous coal in both forms, respectively. Coal maturity was found to be the most important influencing factor relative to coal's burning forms and the stove's burning efficiency, and when medium-volatile bituminous coals (MVB) are excluded from use, averaged EF(BC) and EF(OC) for bituminous coal decrease by 50% and 30%, respectively. According to these EFs, China's BC and OC emissions from the household sector in 2000 were 94 and 244 gigagrams (Gg), respectively. Compared with previous BC emission estimates for this sector (e.g., 465 Gg by Ohara et al., Atmos. Chem. Phys. 2007, 7, 4419-4444), a dramatic decrease was observed and was mainly attributed to the update of EFs. As suggested by this study, if MVB is prohibited as household fuel together with further promotion of briquettes, BC and OC emissions in this sector will be reduced by 80% and 34%, respectively, and then carbonaceous emissions can be controlled to a large extent in China.

  2. Syringe confiscation as an HIV risk factor: the public health implications of arbitrary policing in Tijuana and Ciudad Juarez, Mexico.

    PubMed

    Beletsky, Leo; Lozada, Remedios; Gaines, Tommi; Abramovitz, Daniela; Staines, Hugo; Vera, Alicia; Rangel, Gudelia; Arredondo, Jaime; Strathdee, Steffanie A

    2013-04-01

    Female sex workers who inject drugs (FSW-IDUs) face elevated risk for HIV/STIs and constitute a key population for public health prevention. Through direct and indirect pathways including human rights violations, policing practices like syringe confiscation can compound FSW-IDU health risk and facilitate the spread of disease. We studied correlates of experiencing syringe confiscation among FSW-IDUs in northern Mexico, where formal policy allows for syringes to be available over the counter without a prescription, but police practices are often at odds with the law. FSW-IDUs reporting recent syringe sharing and unprotected sex with clients in Tijuana and Ciudad Juarez were administered surveys and HIV/STI testing. Logistic regression was used to identify correlates of syringe confiscation. Among 624 respondent FSW-IDUs, prevalence of syringe confiscation in the last 6 months was 48%. The following factors were positively associated with syringe confiscation: testing positive for HIV (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.11-5.80), reporting sexual abuse by police (aOR = 12.76, 95% CI = 6.58-24.72), engaging in groin injection (aOR = 1.84, 95% CI = 1.15-2.93), injecting in public (aOR = 1.64; 95% CI = 1.14-2.36), and obtaining syringes from pharmacies (aOR = 1.54; 95% CI = 1.06-2.23). Higher education level was negatively associated with syringe confiscation (aOR = 0.92, 95% CI = 0.87-0.98) as was frequent injection with clients within the last month (aOR = 0.64, 95% CI = 0.44-0.94). This analysis adds to the body of evidence linking unauthorized law enforcement actions targeting high-risk groups with HIV and other adverse health outcomes. Using a public health lens to conceptualize abuse as a structural risk factor, we advocate for multi-prong prevention, systematic monitoring, and evidence-based intervention response to deleterious police practices.

  3. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.

    PubMed

    Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin

    2016-05-25

    The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: (1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) (2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) (3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and (4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1.

  4. Regulated proteolysis of the alternative sigma factor SigX in Streptococcus mutans: implication in the escape from competence

    PubMed Central

    2014-01-01

    Background SigX (σX), the alternative sigma factor of Streptococcus mutans, is the key regulator for transcriptional activation of late competence genes essential for taking up exogenous DNA. Recent studies reveal that adaptor protein MecA and the protease ClpC act as negative regulators of competence by a mechanism that involves MecA-mediated proteolysis of SigX by the ClpC in S. mutans. However, the molecular detail how MecA and ClpC negatively regulate competence in this species remains to be determined. Here, we provide evidence that adaptor protein MecA targets SigX for degradation by the protease complex ClpC/ClpP when S. mutans is grown in a complex medium. Results By analyzing the cellular levels of SigX, we demonstrate that the synthesis of SigX is transiently induced by competence-stimulating peptide (CSP), but the SigX is rapidly degraded during the escape from competence. A deletion of MecA, ClpC or ClpP results in the cellular accumulation of SigX and a prolonged competence state, while an overexpression of MecA enhances proteolysis of SigX and accelerates the escape from competence. In vitro protein-protein interaction assays confirm that MecA interacts with SigX via its N-terminal domain (NTD1–82) and with ClpC via its C-terminal domain (CTD123–240). Such an interaction mediates the formation of a ternary SigX-MecA-ClpC complex, triggering the ATP-dependent degradation of SigX in the presence of ClpP. A deletion of the N-terminal or C-terminal domain of MecA abolishes its binding to SigX or ClpC. We have also found that MecA-regulated proteolysis of SigX appears to be ineffective when S. mutans is grown in a chemically defined medium (CDM), suggesting the possibility that an unknown mechanism may be involved in negative regulation of MecA-mediated proteolysis of SigX under this condition. Conclusion Adaptor protein MecA in S. mutans plays a crucial role in recognizing and targeting SigX for degradation by the protease ClpC/ClpP. Thus, Mec

  5. Mechanistic framework for establishment, maintenance, and alteration of cell polarity in plants.

    PubMed

    Dhonukshe, Pankaj

    2012-01-01

    Cell polarity establishment, maintenance, and alteration are central to the developmental and response programs of nearly all organisms and are often implicated in abnormalities ranging from patterning defects to cancer. By residing at the distinct plasma membrane domains polar cargoes mark the identities of those domains, and execute localized functions. Polar cargoes are recruited to the specialized membrane domains by directional secretion and/or directional endocytic recycling. In plants, auxin efflux carrier PIN proteins display polar localizations in various cell types and play major roles in directional cell-to-cell transport of signaling molecule auxin that is vital for plant patterning and response programs. Recent advanced microscopy studies applied to single cells in intact plants reveal subcellular PIN dynamics. They uncover the PIN polarity generation mechanism and identified important roles of AGC kinases for polar PIN localization. AGC kinase family members PINOID, WAG1, and WAG2, belonging to the AGC-3 subclass predominantly influence the polar localization of PINs. The emerging mechanism for AGC-3 kinases action suggests that kinases phosphorylate PINs mainly at the plasma membrane after initial symmetric PIN secretion for eventual PIN internalization and PIN sorting into distinct ARF-GEF-regulated polar recycling pathways. Thus phosphorylation status directs PIN translocation to different cell sides. Based on these findings a mechanistic framework evolves that suggests existence of cell side-specific recycling pathways in plants and implicates AGC3 kinases for differential PIN recruitment among them for eventual PIN polarity establishment, maintenance, and alteration.

  6. Implications of Web of Science journal impact factor for scientific output evaluation in 16 institutions and investigators' opinion.

    PubMed

    Wáng, Yì-Xiáng J; Arora, Richa; Choi, Yongdoo; Chung, Hsiao-Wen; Egorov, Vyacheslav I; Frahm, Jens; Kudo, Hiroyuki; Kuyumcu, Suleyman; Laurent, Sophie; Loffroy, Romaric; Maurea, Simone; Morcos, Sameh K; Ni, Yicheng; Oei, Edwin H G; Sabarudin, Akmal; Yu, Xin

    2014-12-01

    Journal based metrics is known not to be ideal for the measurement of the quality of individual researcher's scientific output. In the current report 16 contributors from Hong Kong SAR, India, Korea, Taiwan, Russia, Germany, Japan, Turkey, Belgium, France, Italy, UK, The Netherlands, Malaysia, and USA are invited. The following six questions were asked: (I) is Web of Sciences journal impact factor (IF) and Institute for Scientific Information (ISI) citation the main academic output performance evaluation tool in your institution? and your country? (II) How does Google citation count in your institution? and your country? (III) If paper is published in a non-SCI journal but it is included in PubMed and searchable by Google scholar, how it is valued when compared with a paper published in a journal with an IF? (IV) Do you value to publish a piece of your work in a non-SCI journal as much as a paper published in a journal with an IF? (V) What is your personal view on the metric measurement of scientific output? (VI) Overall, do you think Web of Sciences journal IF is beneficial, or actually it is doing more harm? The results show that IF and ISI citation is heavily affecting the academic life in most of the institutions. Google citation and evaluation, while is being used and convenient and speedy, has not gain wide 'official' recognition as a tool for scientific output evaluation.

  7. Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

    PubMed Central

    Silverman, G J; Goldfien, R D; Chen, P; Mageed, R A; Jefferis, R; Goñi, F; Frangione, B; Fong, S; Carson, D A

    1988-01-01

    Rheumatoid factors (RFs) in humans have been studied intensively because of their association with autoimmune and lymphoproliferative diseases. Many human IgM-RFs express cross-reactive idiotypes (CRIs) and have homologous light chains, some of which are encoded by a single V kappa gene, termed V kappa 325. However, although antibody activity generally requires the interaction between heavy and light chain variable regions, much less is known about structural relationships among RF heavy chains. To delineate further the structural and genetic basis of RF autoantibody synthesis, we generated "sequence-dependent" reagents specific for the human heavy and kappa light chain subgroups, and used them to analyze a panel of 27 monoclonal RFs. In addition, these proteins were tested for the expression of a heavy chain-associated CRI (G6), and a light chain-associated CRI (17.109). The results showed that most 17.109-reactive RFs contain heavy chains of the VHI subgroup, which bear the G6 idiotypic marker. However, among the 14 17.109-reactive RFs, two have heavy chains of the VHII subgroup, and another two contain heavy chains of the VHIII subgroup. Previously, we have shown that 17.109 is a phenotypic marker of the human V kappa 325 gene. Accordingly, these results demonstrate that the same human V kappa gene can combine with several VH genes from different VH gene subgroups to generate RF activity. Images PMID:3136191

  8. Comparison of tropical and temperate freshwater animal species' acute sensitivities to chemicals: implications for deriving safe extrapolation factors.

    PubMed

    Kwok, Kevin W H; Leung, Kenneth M Y; Lui, Gilbert S G; Chu, S Vincent K H; Lam, Paul K S; Morritt, David; Maltby, Lorraine; Brock, Theo C M; Van den Brink, Paul J; Warne, Michael St J; Crane, Mark

    2007-01-01

    Toxicity data for tropical species are often lacking for ecological risk assessment. Consequently, tropical and subtropical countries use water quality criteria (WQC) derived from temperate species (e.g., United States, Canada, or Europe) to assess ecological risks in their aquatic systems, leaving an unknown margin of uncertainty. To address this issue, we use species sensitivity distributions of freshwater animal species to determine whether temperate datasets are adequately protective of tropical species assemblages for 18 chemical substances. The results indicate that the relative sensitivities of tropical and temperate species are noticeably different for some of these chemicals. For most metals, temperate species tend to be more sensitive than their tropical counterparts. However, for un-ionized ammonia, phenol, and some pesticides (e.g., chlorpyrifos), tropical species are probably more sensitive. On the basis of the results from objective comparisons of the ratio between temperate and tropical hazardous concentration values for 10% of species, or the 90% protection level, we recommend that an extrapolation factor of 10 should be applied when such surrogate temperate WQCs are used for tropical or subtropical regions and a priori knowledge on the sensitivity of tropical species is very limited or not available.

  9. Nanomechanical Contribution of Collagen and von Willebrand Factor A in Marine Underwater Adhesion and Its Implication for Collagen Manipulation.

    PubMed

    Yoo, Hee Young; Huang, Jun; Li, Lin; Foo, Mathias; Zeng, Hongbo; Hwang, Dong Soo

    2016-03-14

    Recent works on mussel adhesion have identified a load bearing matrix protein (PTMP1) containing von Willebrand factor (vWF) with collagen binding capability that contributes to the mussel holdfast by manipulating mussel collagens. Using a surface forces apparatus, we investigate for the first time, the nanomechanical properties of vWF-collagen interaction using homologous proteins of mussel byssus, PTMP1 and preCollagens (preCols), as collagen. Mimicking conditions similar to mussel byssus secretion (pH < 5.0) and seawater condition (pH 8.0), PTMP1 and preCol interact weakly in the "positioning" phase based on vWF-collagen binding and strengthen in "locked" phase due to the combined effects of electrostatic attraction, metal binding, and mechanical shearing. The progressive enhancement of binding between PTMP1 with porcine collagen under the aforementioned conditions is also observed. The binding mechanisms of PTMP1-preCols provide insights into the molecular interaction of the mammalian collagen system and the development of an artificial extracellular matrix based on collagens.

  10. Role of India's wildlife in the emergence and re-emergence of zoonotic pathogens, risk factors and public health implications.

    PubMed

    Singh, B B; Gajadhar, A A

    2014-10-01

    Evolving land use practices have led to an increase in interactions at the human/wildlife interface. The presence and poor knowledge of zoonotic pathogens in India's wildlife and the occurrence of enormous human populations interfacing with, and critically linked to, forest ecosystems warrant attention. Factors such as diverse migratory bird populations, climate change, expanding human population and shrinking wildlife habitats play a significant role in the emergence and re-emergence of zoonotic pathogens from India's wildlife. The introduction of a novel Kyasanur forest disease virus (family flaviviridae) into human populations in 1957 and subsequent occurrence of seasonal outbreaks illustrate the key role that India's wild animals play in the emergence and reemergence of zoonotic pathogens. Other high priority zoonotic diseases of wildlife origin which could affect both livestock and humans include influenza, Nipah, Japanese encephalitis, rabies, plague, leptospirosis, anthrax and leishmaniasis. Continuous monitoring of India's extensively diverse and dispersed wildlife is challenging, but their use as indicators should facilitate efficient and rapid disease-outbreak response across the region and occasionally the globe. Defining and prioritizing research on zoonotic pathogens in wildlife are essential, particularly in a multidisciplinary one-world one-health approach which includes human and veterinary medical studies at the wildlife-livestock-human interfaces. This review indicates that wild animals play an important role in the emergence and re-emergence of zoonotic pathogens and provides brief summaries of the zoonotic diseases that have occurred in wild animals in India.

  11. Substance abuse as a risk factor for violence in mental illness: some implications for forensic psychiatric practice and clinical ethics

    PubMed Central

    Pickard, Hanna; Fazel, Seena

    2014-01-01

    Purpose of review To review recent research on the relationship between substance abuse, crime, violence and mental illness, and suggest how this research could aid forensic psychiatrists, psychologists and other mental health professionals in assessing and managing risk, and balancing patient care and public protection. Recent findings Substance abuse in mentally ill forensic psychiatric patients should be considered an important risk factor for violence and re-offending. Summary Improved treatment for substance abuse in forensic psychiatric patients and other mentally disordered offenders together with the offer of monitored abstinence as a condition of leave or discharge could be usefully considered as a means of reducing and managing risk. This may improve patient care by addressing mental health needs and increasing opportunity and likelihood of successful re-integration into the community and better life prospects; protect the public by reducing risk of re-offending and offering real time monitoring and potential intervention when risk is heightened; and help forensic psychiatrists strike a balance between patient care and public protection, potentially alleviating some of the difficulty and anxiety that decisions to grant leave or discharge can create. PMID:23722099

  12. Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications.

    PubMed

    Torres, Fátima; Barbosa, Mafalda; Maciel, Patrícia

    2016-02-01

    Neurodevelopmental disorders (NDs) encompass a spectrum of neuropsychiatric manifestations. Chromosomal regions 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p13.1 and 22q11 harbour rare but recurrent CNVs that have been uncovered as being important risk factors for several of these disorders. These rearrangements may underlie a broad phenotypical spectrum, ranging from normal development, to learning problems, intellectual disability (ID), epilepsy and psychiatric diseases, such as autism spectrum disorders (ASDs) and schizophrenia (SZ). The highly increased risk of developing neurodevelopmental phenotypes associated with some of these CNVs makes them an unavoidable element in the clinical context in paediatrics, neurology and psychiatry. However, and although finding these risk loci has been the goal of neuropsychiatric genetics for many years, the translation of this recent knowledge into clinical practice has not been trivial. In this article, we will: (1) review the state of the art on recurrent CNVs associated with NDs, namely ASD, ID, epilepsy and SZ; (2) discuss the models used to dissect the underlying neurobiology of disease, (3) discuss how this knowledge can be used in clinical practice.

  13. Methyl tert-butyl ether (MTBE) in public and private wells in New Hampshire: occurrence, factors, and possible implications.

    PubMed

    Ayotte, Joseph D; Argue, Denise M; McGarry, Frederick J; Degnan, James R; Hayes, Laura; Flanagan, Sarah M; Helsel, Dennis R

    2008-02-01

    Methyl tert-butyl ether (MTBE) concentrations > or = 0.2 /microg/L were found in samples of untreated water in 18% of public-supply wells (n = 284) and 9.1% of private domestic wells (n = 264) sampled in 2005 and 2006 in New Hampshire. In counties that used reformulated gasoline (RFG), MTBE occurred at or above 0.2 microg/L in 30% of public- and 17% of private-supply wells. Additionally, 52% of public-supply wells collocated with fuel storage and 71% of mobile home park wells had MTBE. MTBE occurrence in public-supply wells was predicted by factors such as proximity to sources of fuel, land use, and population density, as well as low pH and distance from mapped lineaments. RFG use, land-use variables, and pH were important predictors of private-well MTBE occurrence. Variables representing sources of MTBE, such as the distance to known fuel sources, were not significant predictors of MTBE occurrence in private-supply wells. It is hypothesized that private wells may become contaminated from the collective effects of sources in high population areas and from undocumented incidental releases from onsite or proximal gasoline use. From 2003 to 2005, MTBE occurrence decreased in 63 public-supply wells and increased in 60 private-supply wells, but neither trend was statistically significant.

  14. Anti-tumor effects of pigment epithelium-derived factor (PEDF): implication for cancer therapy. A mini-review.

    PubMed

    Belkacemi, Louiza; Zhang, Shaun Xiaoliu

    2016-01-08

    Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein and a non-inhibitory member of the serine protease inhibitor (serpin) family. It is widely expressed in human fetal and adult tissues but its expression decreases with age and in malignant tissues. The main anti-cancer activities of PEDF derive from its dual effects, either indirectly on the tumor microenvironment (indirect antitumor action) or directly on the tumor itself (direct antitumor influence). The indirect antitumor activities of PEDF were uncovered from the early findings that it stimulates retinoblastoma cell differentiation and that additionally it possesses anti-angiogenic, anti-tumorigenic and anti-metastatic properties. The mechanisms of its direct antitumor effect, however, have not been fully elucidated. This review highlights recent progress in our understanding of the multifunctional activities of PEDF and, in particular, its anti-cancer signaling mechanisms. Additionally, we discuss the possibility of using novel phosphaplatin compounds that can upregulate PEDF expression as a chemotherapy for cancer treatment.

  15. Methyl tert-butyl ether (MTBE) in public and private wells in New Hampshire: Occurrence, factors, and possible implications

    USGS Publications Warehouse

    Ayotte, J.D.; Argue, D.M.; McGarry, F.J.; Degnan, J.R.; Hayes, L.; Flanagan, S.M.; Helsel, D.R.

    2008-01-01

    Methyl tert-butyl ether (MTBE) concentrations ???0.2 ??g/L were found in samples of untreated water in 18% of public-supply wells (n = 284) and 9.1% of private domestic wells (n = 264) sampled in 2005 and 2006 in New Hampshire. In counties that used reformulated gasoline (RFG), MTBE occurred at or above 0.2 ??g/L in 30% of public- and 17% of private-supply wells. Additionally, 52% of public-supply wells collocated with fuel storage and 71% of mobile home park wells had MTBE. MTBE occurrence in public-supply wells was predicted by factors such as proximity to sources of fuel, land use, and population density, as well as low pH and distance from mapped lineaments. RFG use, land-use variables, and pH were important predictors of private-well MTBE occurrence. Variables representing sources of MTBE, such as the distance to known fuel sources, were not significant predictors of MTBE occurrence in private-supply wells. It is hypothesized that private wells may become contaminated from the collective effects of sources in high population areas and from undocumented incidental releases from onsite or proximal gasoline use. From 2003 to 2005, MTBE occurrence decreased in 63 public-supply wells and increased in 60 private-supply wells, but neither trend was statistically significant. ?? 2008 American Chemical Society.

  16. Factors Influencing Quality of Life in Caregivers of People with Parkinson's Disease and Implications for Clinical Guidelines

    PubMed Central

    Morley, D.; Dummett, S.; Peters, M.; Kelly, L.; Hewitson, P.; Dawson, J.; Fitzpatrick, R.; Jenkinson, C.

    2012-01-01

    The quality of life (QoL) of informal caregivers can be adversely affected by a number of factors. This issue, however, has not been well explored for carers of people with Parkinson's (PwP), with research largely restricted to the assessment of caregiver burden and caregiver strain. This study aims to determine the main influences on carer QoL in this population and consider results in the context of current clinical guidelines for the management of Parkinson's disease (PD). Carers completed the newly validated PDQ-Carer, and PwP completed the PDQ-39. The sample comprised 238 carers (mean age 68.20 years) and 238 PwP (mean age 71.64). Results suggest multiple influences on caregiver QoL. These include carer age, gender, health status, and duration of the caregiving role. PwP levels of mobility and cognitive impairment are also significant influences on carer QoL. Not only should practitioners and service providers be particularly aware of the heightened impact of PD on carers over time and as PwP symptoms deteriorate, but this should also be reflected in clinical guidelines for the management of PD. PMID:23316414

  17. Factors influencing quality of life in caregivers of people with Parkinson's disease and implications for clinical guidelines.

    PubMed

    Morley, D; Dummett, S; Peters, M; Kelly, L; Hewitson, P; Dawson, J; Fitzpatrick, R; Jenkinson, C

    2012-01-01

    The quality of life (QoL) of informal caregivers can be adversely affected by a number of factors. This issue, however, has not been well explored for carers of people with Parkinson's (PwP), with research largely restricted to the assessment of caregiver burden and caregiver strain. This study aims to determine the main influences on carer QoL in this population and consider results in the context of current clinical guidelines for the management of Parkinson's disease (PD). Carers completed the newly validated PDQ-Carer, and PwP completed the PDQ-39. The sample comprised 238 carers (mean age 68.20 years) and 238 PwP (mean age 71.64). Results suggest multiple influences on caregiver QoL. These include carer age, gender, health status, and duration of the caregiving role. PwP levels of mobility and cognitive impairment are also significant influences on carer QoL. Not only should practitioners and service providers be particularly aware of the heightened impact of PD on carers over time and as PwP symptoms deteriorate, but this should also be reflected in clinical guidelines for the management of PD.

  18. Providers’ perspectives on inbound medical tourism in Central America and the Caribbean: factors driving and inhibiting sector development and their health equity implications

    PubMed Central

    Johnston, Rory; Crooks, Valorie A.; Cerón, Alejandro; Labonté, Ronald; Snyder, Jeremy; Núñez, Emanuel O.; Flores, Walter G.

    2016-01-01

    Background Many governments and health care providers worldwide are enthusiastic to develop medical tourism as a service export. Despite the popularity of this policy uptake, there is relatively little known about the specific local factors prospectively motivating and informing development of this sector. Objective To identify common social, economic, and health system factors shaping the development of medical tourism in three Central American and Caribbean countries and their health equity implications. Design In-depth, semi-structured interviews were conducted in Mexico, Guatemala, and Barbados with 150 health system stakeholders. Participants were recruited from private and public sectors working in various fields: trade and economic development, health services delivery, training and administration, and civil society. Transcribed interviews were coded using qualitative data management software, and thematic analysis was used to identify cross-cutting issues regarding the drivers and inhibitors of medical tourism development. Results Four common drivers of medical tourism development were identified: 1) unused capacity in existing private hospitals, 2) international portability of health insurance, vis-a-vis international hospital accreditation, 3) internationally trained physicians as both marketable assets and industry entrepreneurs, and 4) promotion of medical tourism by public export development corporations. Three common inhibitors for the development of the sector were also identified: 1) the high expense of market entry, 2) poor sector-wide planning, and 3) structural socio-economic issues such as insecurity or relatively high business costs and financial risks. Conclusion There are shared factors shaping the development of medical tourism in Central America and the Caribbean that help explain why it is being pursued by many hospitals and governments in the region. Development of the sector is primarily being driven by public investment promotion

  19. Providers' perspectives on inbound medical tourism in Central America and the Caribbean: factors driving and inhibiting sector development and their health equity implications.

    PubMed

    Johnston, Rory; Crooks, Valorie A; Cerón, Alejandro; Labonté, Ronald; Snyder, Jeremy; Núñez, Emanuel O; Flores, Walter G

    2016-01-01

    Background Many governments and health care providers worldwide are enthusiastic to develop medical tourism as a service export. Despite the popularity of this policy uptake, there is relatively little known about the specific local factors prospectively motivating and informing development of this sector. Objective To identify common social, economic, and health system factors shaping the development of medical tourism in three Central American and Caribbean countries and their health equity implications. Design In-depth, semi-structured interviews were conducted in Mexico, Guatemala, and Barbados with 150 health system stakeholders. Participants were recruited from private and public sectors working in various fields: trade and economic development, health services delivery, training and administration, and civil society. Transcribed interviews were coded using qualitative data management software, and thematic analysis was used to identify cross-cutting issues regarding the drivers and inhibitors of medical tourism development. Results Four common drivers of medical tourism development were identified: 1) unused capacity in existing private hospitals, 2) international portability of health insurance, vis-a-vis international hospital accreditation, 3) internationally trained physicians as both marketable assets and industry entrepreneurs, and 4) promotion of medical tourism by public export development corporations. Three common inhibitors for the development of the sector were also identified: 1) the high expense of market entry, 2) poor sector-wide planning, and 3) structural socio-economic issues such as insecurity or relatively high business costs and financial risks. Conclusion There are shared factors shaping the development of medical tourism in Central America and the Caribbean that help explain why it is being pursued by many hospitals and governments in the region. Development of the sector is primarily being driven by public investment promotion

  20. Degradation of circulating von Willebrand factor and its regulator ADAMTS13 implicates secreted Bacillus anthracis metalloproteases in anthrax consumptive coagulopathy.

    PubMed

    Chung, Myung-Chul; Popova, Taissia G; Jorgensen, Shelley C; Dong, Li; Chandhoke, Vikas; Bailey, Charles L; Popov, Serguei G

    2008-04-11

    Pathology data from the anthrax animal models show evidence of significant increases in vascular permeability coincident with hemostatic imbalances manifested by thrombocytopenia, transient leucopenia, and aggressive disseminated intravascular coagulation. In this study we hypothesized that anthrax infection modulates the activity of von Willebrand factor (VWF) and its endogenous regulator ADAMTS13, which play important roles in hemostasis and thrombosis, including interaction of endothelial cells with platelets. We previously demonstrated that purified anthrax neutral metalloproteases Npr599 and InhA are capable of cleaving a variety of host structural and regulatory proteins. Incubation of human plasma with these proteases at 37 degrees C in the presence of urea as a mild denaturant results in proteolysis of VWF. Also in these conditions, InhA directly cleaves plasma ADAMTS13 protein. Npr599 and InhA digest synthetic VWF substrate FRETS-VWF73. Amino acid sequencing of VWF fragments produced by InhA suggests that one of the cleavage sites of VWF is located at domain A2, the target domain of ADAMTS13. Proteolysis of VWF by InhA impairs its collagen binding activity (VWF:CBA) and ristocetin-induced platelet aggregation activity. In plasma from anthrax spore-challenged DBA/2 mice, VWF antigen levels increase up to 2-fold at day 3 post-infection with toxigenic Sterne 34F(2) strain, whereas VWF:CBA levels drop in a time-dependent manner, suggesting dysfunction of VWF instead of its quantitative deficiency. This conclusion is further supported by significant reduction in the amount of VWF circulating in blood in the ultra-large forms. In addition, Western blot analysis shows proteolytic depletion of ADAMTS13 from plasma of spore-challenged mice despite its increased expression in the liver. Our results suggest a new mechanism of anthrax coagulopathy affecting the levels and functional activities of both VWF and its natural regulator ADAMTS13. This mechanism may

  1. Brown carbon aerosols from burning of boreal peatlands: microphysical properties, emission factors, and implications for direct radiative forcing

    NASA Astrophysics Data System (ADS)

    Chakrabarty, Rajan K.; Gyawali, Madhu; Yatavelli, Reddy L. N.; Pandey, Apoorva; Watts, Adam C.; Knue, Joseph; Chen, Lung-Wen A.; Pattison, Robert R.; Tsibart, Anna; Samburova, Vera; Moosmüller, Hans

    2016-03-01

    The surface air warming over the Arctic has been almost twice as much as the global average in recent decades. In this region, unprecedented amounts of smoldering peat fires have been identified as a major emission source of climate-warming agents. While much is known about greenhouse gas emissions from these fires, there is a knowledge gap on the nature of particulate emissions and their potential role in atmospheric warming. Here, we show that aerosols emitted from burning of Alaskan and Siberian peatlands are predominantly brown carbon (BrC) - a class of visible light-absorbing organic carbon (OC) - with a negligible amount of black carbon content. The mean fuel-based emission factors for OC aerosols ranged from 3.8 to 16.6 g kg-1. Their mass absorption efficiencies were in the range of 0.2-0.8 m2 g-1 at 405 nm (violet) and dropped sharply to 0.03-0.07 m2 g-1 at 532 nm (green), characterized by a mean Ångström exponent of ≈ 9. Electron microscopy images of the particles revealed their morphologies to be either single sphere or agglomerated "tar balls". The shortwave top-of-atmosphere aerosol radiative forcing per unit optical depth under clear-sky conditions was estimated as a function of surface albedo. Only over bright surfaces with albedo greater than 0.6, such as snow cover and low-level clouds, the emitted aerosols could result in a net warming (positive forcing) of the atmosphere.

  2. Nerve growth factor-induced neurite sprouting in PC12 cells involves sigma-1 receptors: implications for antidepressants.

    PubMed

    Takebayashi, Minoru; Hayashi, Teruo; Su, Tsung-Ping

    2002-12-01

    One theory concerning the action of antidepressants relates to the drugs' ability to induce an adaptive plasticity in neurons such as neurite sprouting. Certain antidepressants are known to bind to sigma-1 receptors (Sig-1R) with high affinity. Sig-1R are dynamic endoplasmic reticulum proteins that are highly concentrated at the tip of growth cones in cultured cells. We therefore tested the hypotheses that Sig-1R might participate in the neurite sprouting and that antidepressants with Sig-1R affinity may promote the neuronal sprouting via Sig-1R. The prototypic Sig-1R agonist (+)-pentazocine [(+)PTZ], as well as the Sig-1R-active antidepressants imipramine and fluvoxamine, although ineffective by themselves, were found to enhance the nerve growth factor (NGF)-induced neurite sprouting in PC12 cells in a dose-dependent manner. A Sig-1R antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE100) blocked the enhancements caused by these Sig-1R agonists. In separate experiments, we found that NGF dose and time dependently increased Sig-1R in PC12 cells. Chronic treatment of cells with (+)PTZ, imipramine, or fluvoxamine also increased Sig-1R. These latter results suggested that NGF induces the neurite sprouting by increasing Sig-1R. Indeed, the overexpression of Sig-1R per se in PC12 cells enhanced the NGF-induced neurite sprouting. Furthermore, antisense deoxyoligonucleotides directed against Sig-1R attenuated the NGF-induced neurite sprouting. Thus, when taken together, our results indicate that Sig-1R play an important role in the NGF-induced neurite sprouting and that certain antidepressants may facilitate neuronal sprouting in the brain via Sig-1R.

  3. Factors associated with an individual's decision to withdraw from genetic testing for breast and ovarian cancer susceptibility: implications for counseling.

    PubMed

    Godard, Béatrice; Pratte, Annabelle; Dumont, Martine; Simard-Lebrun, Adèle; Simard, Jacques

    2007-01-01

    Our study aimed to examine why individuals withdraw from genetic testing for breast and ovarian cancer susceptibility. We explored the characteristics of 334 individuals from high-risk breast and ovarian cancer families who declined genetic testing for BRCA1/2 mutations, when, and why they did so. Individuals who declined genetic testing were older, and a greater proportion had never developed breast or ovarian cancer. Fifty one per cent (51.1%) of individuals withdrew after the first genetic counseling session. Most of those who declined were afraid of the psychological effects of genetic testing (36.3%). The next most-cited explanations concerned logistic problems such as a limited ability to travel, lack of time, personal issues, advanced age, or health problems (21.7%). The third category included individuals who did not see any advantage in being tested (14.5%). Insurability was a concern (5.9%), mainly for men. Surprisingly, confidentiality was not a frequently reported issue (1.3%). Sixty eight per cent (68%) of individuals belonging to a family in which at least one individual has been tested withdrew after the presence of a deleterious BRCA1/2 mutation in a relative was disclosed, compared to 42% after the disclosure of a nonconclusive test result in at least one relative. Concern about the psychological effects of the result was still one of the major reasons. Several factors may influence an individual's decision to decline genetic testing; a greater understanding of these issues may help health professionals to better meet the needs and concerns of individuals from high-risk families, thus possibly improving their health outcomes.

  4. Prognostic factor of mortality and its clinical implications in patients with necrotizing fasciitis caused by Vibrio vulnificus.

    PubMed

    Lee, Yao-Chou; Hor, Lien-I; Chiu, Haw-Yen; Lee, Jing-Wei; Shieh, Shyh-Jou

    2014-06-01

    In Taiwan, the aquatic environment and endemic hepatitis contribute to the high susceptibility of Vibrio vulnificus infection. A multidisciplinary treatment protocol for necrotizing fasciitis caused by V. vulnificus was developed in our institute, namely, ceftriaxone or ceftazidime combined with doxycycline or minocycline followed by an emergency fasciotomy and intensive care unit admission. We retrospectively reviewed 100 cases to evaluate the effectiveness of our treatment protocol and identify independent predictors of mortality to improve clinical outcomes. Cases of culture-confirmed V. vulnificus infection between January 1996 and December 2011 were reviewed. Necrotizing fasciitis was surgically diagnosed if these criteria were met: necrotic fascia, "dishwater discharge", and loss of resistance while doing finger dissection along the fascia plane. One hundred cases met these criteria and were included for analysis. Eighteen patients died (18 % mortality). Unknown injury events, presence of multiple skin lesions, leukocytes < 10,000 cells/mm(3), platelets < 100,000/mm(3), serum creatinine ≥1.3 mg/dL, serum albumin < 2.5 mg/dL, and delayed treatment beyond 3 days post-injury or symptom onset were associated with significantly higher mortality. Multivariate analysis showed that treatment delayed beyond 3 days is an independent factor indicating a poor prognosis (OR 10.75, 95 % CI 1.02-113.39, p = 0.048). Early diagnosis and prompt treatment within 3 days post-injury or symptom onset should be the goal for treating patients with necrotizing fasciitis caused by V. vulnificus. Additional investigations to rescue patients with a prolonged disease course of necrotizing fasciitis (≥3 days) may be important.

  5. Posttranslational modification of mitochondrial transcription factor A in impaired mitochondria biogenesis: implications in diabetic retinopathy and metabolic memory phenomenon.

    PubMed

    Santos, Julia M; Mishra, Manish; Kowluru, Renu A

    2014-04-01

    Mitochondrial transcription factor A (TFAM) is one of the key regulators of the transcription of mtDNA. In diabetes, despite increase in gene transcripts of TFAM, its protein levels in the mitochondria are decreased and mitochondria copy numbers become subnormal. The aim of this study is to investigate the mechanism(s) responsible for decreased mitochondrial TFAM in diabetes. Using retinal endothelial cells, we have investigated the effect of overexpression of cytosolic chaperone, Hsp70, and TFAM on glucose-induced decrease in mitochondrial TFAM levels, and the transcription of mtDNA-encoded genes, NADH dehydrogenase subunit 6 (ND6) and cytochrome b (Cytb). To investigate the role of posttranslational modifications in subnormal mitochondrial TFAM, ubiquitination of TFAM was assessed, and the results were confirmed in the retina from streptozotocin-induced diabetic rats. While overexpression of Hsp70 failed to prevent glucose-induced decrease in mitochondrial TFAM and transcripts of ND6 and Cytb, overexpression of TFAM ameliorated decrease in its mitochondrial protein levels and transcriptional activity. TFAM was ubiquitinated by high glucose, and PYR-41, an inhibitor of ubiquitination, prevented TFAM ubiquitination and restored the transcriptional activity. Similarly, TFAM was ubiquitinated in the retina from diabetic rats, and it continued to be modified after reinstitution of normal glycemia. Our results clearly imply that the ubiquitination of TFAM impedes its transport to the mitochondria resulting in subnormal mtDNA transcription and mitochondria dysfunction, and inhibition of ubiquitination restores mitochondrial homeostasis. Reversal of hyperglycemia does not provide any benefit to TFAM ubiquitination. Thus, strategies targeting posttranslational modification could provide an avenue to preserve mitochondrial homeostasis, and inhibit the development/progression of diabetic retinopathy.

  6. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment

    PubMed Central

    Wang, Qizhao; Dong, Biao; Firrman, Jenni; Wu, Wenman; Roberts, Sean; Moore, Andrea Rossi; Liu, LinShu; Chin, Mario P.S.; Diao, Yong; Kost, Joseph; Xiao, Weidong

    2016-01-01

    The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVIII(hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human HC (hHC) and LC (hLC). The secretion of cHC was 5~30 fold higher than hHC, with or without LCs. cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by 2~3-fold compared with hLC. Moreover, the cLC but not cHC, contributes the high stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC. PMID:27064790

  7. Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.

    PubMed

    Wang, Q; Dong, B; Firrman, J; Wu, W; Roberts, S; Moore, A R; Liu, L S; Chin, M P S; Diao, Y; Kost, J; Xiao, W

    2016-07-01

    The canine is the most important large animal model for testing novel hemophilia A (HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC.

  8. An insulin-like growth factor found in hepatopancreas implicates carbohydrate metabolism of the blue crab Callinectes sapidus.

    PubMed

    Chung, J Sook

    2014-04-01

    Hyperglycemia that is caused by the release of crustacean hyperglycemic hormone (CHH) from the sinus gland to hemolymph is one of the hallmark physiological phenomena, occurring in decapod crustaceans experiencing stressful conditions. However, the mechanism(s) by which such elevated glucose levels return to resting levels is still unknown. Interestingly, noted is a difference in the clearance rate of hemolymph glucose between adult females and adult males of the blue crab, Callinectes sapidus: the former with more rapid clearance than the latter. The presence of an endogenous-insulin-like molecule is suggested in C. sapidus because an injection of bovine insulin, significantly reduces the levels of hemolymph glucose that were previously elevated by emersion stress or the glucose injection. Using 5' and 3' RACE, the full-length cDNA of an insulin-like molecule is isolated from the hepatopancreas of an adult female C. sapidus and shows the same putative sequence of an insulin-like androgenic gland factor (IAG) but differs in 5' and 3' UTR sequences. A knock-down study using five injections of double-stranded RNA of CasIAG-hep (dsRNA-CasIAG-hep, 10μg/injection) over a 10-day period reduces CasIAG-hep expression by ∼50%. The levels of hemolymph glucose are also kept higher in dsRNA-CasIAG-hep injected group than those treated with dsRNA-green fluorescent protein (dsRNA-IAG-hep) or saline. Most importantly, the hepatopancreas of dsRNA-CasIAG-hep injected animals contains amounts of carbohydrate (glucose, trehalose, and glycogen) significantly lower than those of control groups, indicating that the function of CasIAG-hep in carbohydrate metabolism in crustaceans is similar to carbohydrate metabolism in vertebrates.

  9. Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement

    PubMed Central

    Herbert, Andrew P.; Makou, Elisavet; Chen, Zhuo A.; Kerr, Heather; Richards, Anna; Rappsilber, Juri

    2015-01-01

    In an attempt to evade annihilation by the vertebrate complement system, many microbes capture factor H (FH), the key soluble complement-regulating protein in human plasma. However, FH is normally an active complement suppressor exclusively on self-surfaces and this selective action of FH is pivotal to self versus non-self discrimination by the complement system. We investigated whether the bacterially captured FH becomes functionally enhanced and, if so, how this is achieved at a structural level. We found, using site-directed and truncation mutagenesis, surface plasmon resonance, nuclear magnetic resonance spectroscopy, and cross-linking and mass spectrometry, that the N-terminal domain of Streptococcus pneumoniae protein PspC (PspCN) not only binds FH extraordinarily tightly but also holds it in a previously uncharacterized conformation. Functional enhancement arises from exposure of a C-terminal cryptic second binding site in FH for C3b, the activation-specific fragment of the pivotal complement component, C3. This conformational change of FH doubles its affinity for C3b and increases 5-fold its ability to accelerate decay of the binary enzyme (C3bBb) responsible for converting C3 to C3b in an amplification loop. Despite not sharing critical FH-binding residues, PspCNs from D39 and Tigr4 S. pneumoniae exhibit similar FH-anchoring and enhancing properties. We propose that these bacterial proteins mimic molecular markers of self-surfaces, providing a compelling hypothesis for how FH prevents complement-mediated injury to host tissue while lacking efficacy on virtually all other surfaces. In hemolysis assays with 2-aminoethylisothiouronium bromide–treated erythrocytes that recapitulate paroxysmal nocturnal hemoglobinuria, PspCN enhanced protection of cells by FH, suggesting a new paradigm for therapeutic complement suppression. PMID:26459349

  10. Connectivity of runoff and sediments in reclaimed Mediterranean-dry slopes: controlling factors and long-term ecological implications

    NASA Astrophysics Data System (ADS)

    Moreno de las Heras, Mariano; Saco, Patricia M.; Espigares, Tíscar; Nicolau, José M.; Merino Martín, Luis

    2013-04-01

    Hydrological connectivity has emerged in recent years as a critical factor for understanding the transference of runoff, sediments and nutrients across scales. Here we examine its relevance for the successful reclamation of water-limited environments in which vegetation stability largely depends on optimal redistribution of water and soil resources for plant production. We studied the connectivity of runoff and sediments across plot to slope scales in three Mediterranean-dry reclaimed slopes that were restored about 25 years ago and have developed different levels of vegetation cover (24-51%) and rill density (0.5-0.0 m m-2), along a gradient of overland flow (slope-scale runoff coefficient 11.2%-0.5%). Event-based connectivity of runoff and sediments was controlled by the spatial organization of vegetation and rills, and at the same time was modulated by storm intensity. In absence of rill networks, both runoff and sediment yield per unit area decreased from patch to slope scales due to internal redistribution of both water and sediment fluxes. However, the connectivity of the slopes increased with rainfall intensity. Additionally, the presence of rills largely increased the connectivity of runoff and sediments, leading to increases in sediment yield across scales due to active rilling under high intensity storm conditions. Further simulations using an eco-geomorphic modelling approach showed that the development of rill networks structurally enhances the hydrological connectivity in these systems, providing persistent pathways for the routing of water and soil resources out of the slopes that can compromise the development and long-term stability of reclaimed vegetation. Overall, our results confirm the relevance and efficiency of using a surface connectivity analysis for understanding the spatial and temporal dynamics of water-limited eco-geomorphic systems, and call for its application in order to achieve a successful restoration of Mediterranean slopes.

  11. Projecting Future Land Use Changes in West Africa Driven by Climate and Socioeconomic Factors: Uncertainties and Implications for Adaptation

    NASA Astrophysics Data System (ADS)

    Wang, G.; Ahmed, K. F.; You, L.

    2015-12-01

    Land use changes constitute an important regional climate change forcing in West Africa, a region of strong land-atmosphere coupling. At the same time, climate change can be an important driver for land use, although its importance relative to the impact of socio-economic factors may vary significant from region to region. This study compares the contributions of climate change and socioeconomic development to potential future changes of agricultural land use in West Africa and examines various sources of uncertainty using a land use projection model (LandPro) that accounts for the impact of socioeconomic drivers on the demand side and the impact of climate-induced crop yield changes on the supply side. Future crop yield changes were simulated by a process-based crop model driven with future climate projections from a regional climate model, and future changes of food demand is projected using a model for policy analysis of agricultural commodities and trade. The impact of human decision-making on land use was explicitly considered through multiple "what-if" scenarios to examine the range of uncertainties in projecting future land use. Without agricultural intensification, the climate-induced decrease of crop yield together with increase of food demand are found to cause a significant increase in agricultural land use at the expense of forest and grassland by the mid-century, and the resulting land use land cover changes are found to feed back to the regional climate in a way that exacerbates the negative impact of climate on crop yield. Analysis of results from multiple decision-making scenarios suggests that human adaptation characterized by science-informed decision making to minimize land use could be very effective in many parts of the region.

  12. Bird Migration Under Climate Change - A Mechanistic Approach Using Remote Sensing

    NASA Technical Reports Server (NTRS)

    Smith, James A.; Blattner, Tim; Messmer, Peter

    2010-01-01

    migratory shorebirds in the central fly ways of North America. We demonstrated the phenotypic plasticity of a migratory population of Pectoral sandpipers consisting of an ensemble of 10,000 individual birds in response to changes in stopover locations using an individual based migration model driven by remotely sensed land surface data, climate data and biological field data. With the advent of new computing capabilities enabled hy recent GPU-GP computing paradigms and commodity hardware, it now is possible to simulate both larger ensemble populations and to incorporate more realistic mechanistic factors into migration models. Here, we take our first steps use these tools to study the impact of long-term drought variability on shorebird survival.

  13. Revisiting sesquiterpene biosynthetic pathways leading to santalene and its analogues: a comprehensive mechanistic study.

    PubMed

    Jindal, Garima; Sunoj, Raghavan B

    2012-10-21

    Santalene and bergamotene are the major olefinic sesquiterpenes responsible for the fragrance of sandalwood oil. Herein we report the details of density functional theory investigations on the biosynthetic pathway of this important class of terpenes. The mechanistic study has been found to be effective toward gaining significant new insight into different possibilities for the formation of the key intermediates involved in santalene and bergamotene biosynthesis. The stereoelectronic features of the transition states and intermediates for (i) ring closure of the initial bisabolyl cation, and (ii) skeletal rearrangements in the ensuing bicyclic carbocationic intermediates leading to (-)-epi-β-santalene, (-)-β-santalene, (-)-α-santalene, (+)-epi-β-santalene, exo-β-bergamotene, endo-β-bergamotene, exo-α-bergamotene, and endo-α-bergamotene are presented. Interesting structural features pertaining to certain new carbocationic intermediates (such as b) resulting from the ring closure of bisabolyl cation are discussed. Extensive conformational sampling of all key intermediates along the biosynthetic pathway offered new insight into the role of the isoprenyl side chain conformation in the formation of santalene and its analogues. Although the major bicyclic products in Santalum album appear to arise from the right or left handed helical form of farnesyl pyrophosphate (FPP), different alternatives for their formation are found to be energetically feasible. The interconversion of the exo and endo isomers of bisabolyl cation and a likely epimerization, both with interesting mechanistic implications, are presented. The exo to endo conversion is identified to be energetically more favorable than another pathway emanating from the left handed helical FPP. The role of pyrophosphate (OPP(-)) in the penultimate deprotonation step leading to olefinic sesquiterpenes is also examined.

  14. Variable δ(15)N diet-tissue discrimination factors among sharks: implications for trophic position, diet and food web models.

    PubMed

    Olin, Jill A; Hussey, Nigel E; Grgicak-Mannion, Alice; Fritts, Mark W; Wintner, Sabine P; Fisk, Aaron T

    2013-01-01

    The application of stable isotopes to characterize the complexities of a species foraging behavior and trophic relationships is dependent on assumptions of δ(15)N diet-tissue discrimination factors (∆(15)N). As ∆(15)N values have been experimentally shown to vary amongst consumers, tissues and diet composition, resolving appropriate species-specific ∆(15)N values can be complex. Given the logistical and ethical challenges of controlled feeding experiments for determining ∆(15)N values for large and/or endangered species, our objective was to conduct an assessment of a range of reported ∆(15)N values that can hypothetically serve as surrogates for describing the predator-prey relationships of four shark species that feed on prey from different trophic levels (i.e., different mean δ(15)N dietary values). Overall, the most suitable species-specific ∆(15)N values decreased with increasing dietary-δ(15)N values based on stable isotope Bayesian ellipse overlap estimates of shark and the principal prey functional groups contributing to the diet determined from stomach content analyses. Thus, a single ∆(15)N value was not supported for this speciose group of marine predatory fishes. For example, the ∆(15)N value of 3.7‰ provided the highest percent overlap between prey and predator isotope ellipses for the bonnethead shark (mean diet δ(15)N = 9‰) whereas a ∆(15)N value < 2.3‰ provided the highest percent overlap between prey and predator isotope ellipses for the white shark (mean diet δ(15)N = 15‰). These data corroborate the previously reported inverse ∆(15)N-dietary δ(15)N relationship when both isotope ellipses of principal prey functional groups and the broader identified diet of each species were considered supporting the adoption of different ∆(15)N values that reflect the predators' δ(15)N-dietary value. These findings are critical for refining the application of stable isotope modeling approaches as inferences regarding a

  15. Evaluation of Cucurbita maxima extract against scopolamine-induced amnesia in rats: implication of tumour necrosis factor alpha.

    PubMed

    Jawaid, Talha; Shakya, Ashok K; Siddiqui, Hefazat Hussain; Kamal, Mehnaz

    2014-01-01

    Cucurbita maxima (CM) seed oil is commonly used in Indian folk medicine to treat various ailments. We have investigated the effect of CM seed oil on memory impairment induced by scopolamine in rats. Male adult Wistar rats were administered scopolamine 1 mg/kg body weight, i.p. or 1.25 mg/kg body weight, s.c. to induce memory impairment. The nootropic agent piracetam 100 mg/kg body weight, i.p. and CM seed oil 100 and 200 mg/kg body weight, p.o. were administered daily for five consecutive days. The memory function was evaluated in the Morris water maze (MWM) test, the social recognition test (SRT), the elevated plus maze (EPM) test, and the pole climbing test (PCT). Acetylcholinesterase (AChE) activity and oxidative stress parameters were estimated in the cortex, hippocampus, and cerebellum of the brains after completion of the behavioural studies. The effects of scopolamine on the levels of the tumour necrosis factor alpha (TNF-α) transcript were also investigated. Scopolamine caused memory impairment in all the behavioural paradigms along with a significant increase in the AChE activity and oxidative stress in the brain. Scopolamine also caused a significant increase in the expression of TNF-α in the hippocampus. CM seed oil exhibited antiamnesic activity as indicated by a significant reduction in the latency time in the MWM test and decreased social interaction during trial 2 in the SRT. Further, treatment with CM seed oil significantly decreased the AChE activity and malondialdehyde levels and increased the glutathione level in brain regions. CM seed oil also significantly decreased the expression of TNF-α in the hippocampus. The effect of CM seed oil on behavioural and biochemical parameters was comparable to that observed in rats treated with piracetam. These results indicate that CM seed oil may exert antiamnesic activity which may be attributed to the inhibition of AChE and inflammation as well as its antioxidant activity in the brain.

  16. Variable δ15N Diet-Tissue Discrimination Factors among Sharks: Implications for Trophic Position, Diet and Food Web Models

    PubMed Central

    Olin, Jill A.; Hussey, Nigel E.; Grgicak-Mannion, Alice; Fritts, Mark W.; Wintner, Sabine P.; Fisk, Aaron T.

    2013-01-01

    The application of stable isotopes to characterize the complexities of a species foraging behavior and trophic relationships is dependent on assumptions of δ15N diet-tissue discrimination factors (∆15N). As ∆15N values have been experimentally shown to vary amongst consumers, tissues and diet composition, resolving appropriate species-specific ∆15N values can be complex. Given the logistical and ethical challenges of controlled feeding experiments for determining ∆15N values for large and/or endangered species, our objective was to conduct an assessment of a range of reported ∆15N values that can hypothetically serve as surrogates for describing the predator-prey relationships of four shark species that feed on prey from different trophic levels (i.e., different mean δ15N dietary values). Overall, the most suitable species-specific ∆15N values decreased with increasing dietary-δ15N values based on stable isotope Bayesian ellipse overlap estimates of shark and the principal prey functional groups contributing to the diet determined from stomach content analyses. Thus, a single ∆15N value was not supported for this speciose group of marine predatory fishes. For example, the ∆15N value of 3.7‰ provided the highest percent overlap between prey and predator isotope ellipses for the bonnethead shark (mean diet δ15N = 9‰) whereas a ∆15N value < 2.3‰ provided the highest percent overlap between prey and predator isotope ellipses for the white shark (mean diet δ15N = 15‰). These data corroborate the previously reported inverse ∆15N-dietary δ15N relationship when both isotope ellipses of principal prey functional groups and the broader identified diet of each species were considered supporting the adoption of different ∆15N values that reflect the predators’ δ15N-dietary value. These findings are critical for refining the application of stable isotope modeling approaches as inferences regarding a species’ ecological role in their

  17. Spatial distribution and controlling factors of stable isotopes in meteoric waters on the Tibetan Plateau: Implications for paleoelevation reconstruction

    NASA Astrophysics Data System (ADS)

    Li, Lin; Garzione, Carmala N.

    2017-02-01

    Debates persist about the interpretations of stable isotope based proxies for the surface uplift of the central-northern Tibetan Plateau. These disputes arise from the uncertain relationship between elevation and the δ18 O values of meteoric waters, based on modern patterns of isotopes in precipitation and surface waters. We present a large river water data set (1,340 samples) covering most parts of the Tibetan Plateau to characterize the spatial variability and controlling factors of their isotopic compositions. Compared with the amount-weighted mean annual oxygen isotopic values of precipitation, we conclude that river water is a good substitute for isotopic studies of precipitation in the high flat (e.g., elevation >3,300 m) interior of the Tibetan Plateau in the mean annual timescale. We construct, for the first time based on field data, contour maps of isotopic variations of meteoric waters (δ18 O, δD and d-excess) on the Tibetan Plateau. In the marginal mountainous regions of the Plateau, especially the southern through eastern margins, the δ18 O and δD values of river waters decrease with increasing mean catchment elevation, which can be modeled as a Rayleigh distillation process. However, in the interior of the Plateau, northward increasing trends in δ18 O and δD values are pronounced and present robust linear relations; d-excess values are lower than the marginal regions and exhibit distinct contrasts between the eastern (8 ‰- 12 ‰) and western (<8‰) Plateau. We suggest that these isotopic features of river waters in the interior of the Tibetan Plateau result from the combined effects of: 1) mixing of different moisture sources transported by the South Asian monsoon and Westerly winds; 2) contribution of moisture from recycled surface water; and 3) sub-cloud evaporation. We further provide a sub-cloud evaporation modified Rayleigh distillation and mixing model to simulate the isotopic variations in the western Plateau. Results of this work

  18. MRI Predictive Factors for Tumor Response in Rectal Cancer Following Neoadjuvant Chemoradiation Therapy - Implications for Induction Chemotherapy?

    SciTech Connect

    Yu, Stanley K.T.; Tait, Diana

    2013-11-01

    predictive factors could be taken into account in the pursuit of individualized neoadjuvant treatments for patients with rectal cancer.

  19. The Risk Factors of Symptomatic Communicating Hydrocephalus After Stereotactic Radiosurgery for Unilateral Vestibular Schwannoma: The Implication of Brain Atrophy

    SciTech Connect

    Han, Jung Ho; Kim, Dong Gyu; Chung, Hyun-Tai; Paek, Sun Ha; Park, Chul-Kee; Kim, Chae-Yong; Hwang, Seung-Sik; Park, Jeong-Hoon; Kim, Young-Hoon; Kim, Jin Wook; Kim, Yong Hwy; Song, Sang Woo; Kim, In Kyung; Jung, Hee-Won

    2012-11-15

    Purpose: To identify the effect of brain atrophy on the development of symptomatic communicating hydrocephalus (SCHCP) after stereotactic radiosurgery (SRS) for sporadic unilateral vestibular schwannomas (VS). Methods and Materials: A total of 444 patients with VS were treated with SRS as a primary treatment. One hundred eighty-one patients (40.8%) were male, and the mean age of the patients was 53 {+-} 13 years (range, 11-81 years). The mean follow-up duration was 56.8 {+-} 35.8 months (range, 12-160 months). The mean tumor volume was 2.78 {+-} 3.33 cm{sup 3} (range, 0.03-23.30 cm{sup 3}). The cross-sectional area of the lateral ventricles (CALV), defined as the combined area of the lateral ventricles at the level of the mammillary body, was measured on coronal T1-weighted magnetic resonance images as an indicator of brain atrophy. Results: At distant follow-up, a total of 25 (5.6%) patients had SCHCP. The median time to symptom development was 7 months (range, 1-48 months). The mean CALV was 334.0 {+-} 194.0 mm{sup 2} (range, 44.70-1170 mm{sup 2}). The intraclass correlation coefficient was 0.988 (95% confidence interval [CI], 0.976-0.994; p < 0.001). In multivariate analysis, the CALV had a significant relationship with the development of SCHCP (p < 0.001; odds ration [OR] = 1.005; 95% CI, 1.002-1.007). Tumor volume and female sex also had a significant association (p < 0.001; OR = 1.246; 95% CI, 1.103-1.409; p < 0.009; OR = 7.256; 95% CI, 1.656-31.797, respectively). However, age failed to show any relationship with the development of SCHCP (p = 0.364). Conclusion: Brain atrophy may be related to de novo SCHCP after SRS, especially in female patients with a large VS. Follow-up surveillance should be individualized, considering the risk factors involved for each patient, for prompt diagnosis of SCHCP.

  20. Persistence factors among engineering students at the Polytechnic University of Puerto Rico: Student perceptions and curricular implications

    NASA Astrophysics Data System (ADS)

    Gonzalez Juarbe, Juan M.

    Various persistence studies demonstrate that there is a direct correlation between college or university academic program completion and the amount of students' involvement in the college or university on a social, academic, and institutional level. These studies suggest that, over the course of time, the greater the level of involvement the greater the probability of increased persistence towards program completion. Student persistence among Hispanic engineering students was researched at the Polytechnic University of Puerto Rico during the period of January 2002 to April 2003. Persistence factors lead students to either one of the following behaviors: (1) to re-enroll, (2) to switch to another educational program, or (3) to depart from the institution. Increased student persistence is the result of recurring decisions to re-enroll each trimester. Decreased student persistence is the outcome associated with a decision to either depart or switch to another educational vocation. Early departure at the institution is linked to perceptions formed day-to-day as the student experiences the educational environment. These perceptions inspire behavioral outcomes to either persist or depart the education process. Desirable behavioral outcomes are closely related with educational commitments leading to increased persistence. Likewise, undesirable behavioral outcomes are those resulting in decreased persistence. Satisfactory student experiences in successfully achieving social, academic, and institutional responsibilities set the course towards increased persistence. In the research undertaken, student and faculty educational experiences were analyzed and documented. This was accomplished by the use of a combined quantitative and qualitative research methodology. The volunteer participants in this study included: six full time professors, eight part time professors, eighty-one students at a job fair, and seven individual student participants. Personal data on the participants

  1. Induced polarization dependence on pore space geometry: Empirical observations and mechanistic predictions

    NASA Astrophysics Data System (ADS)

    Weller, A.; Slater, L. D.

    2015-12-01

    We use an extensive database to compare empirical observations and previously proposed empirical models against recently developed mechanistic formulations for the induced polarization (IP) response in porous media as a function of pore space geometry and interfacial chemistry. These comparisons support the argument that the pore-volume normalized internal surface (Spor) is the most important geometric parameter influencing the polarization. The specific polarizability derived from the empirical relationship between imaginary conductivity σ″ and Spor is independent of the porosity. By contrast, equivalent specific polarizability terms in recently proposed mechanistic models are found to be significantly correlated with porosity, and thus do not appear to represent an interfacial chemistry factor independent of the pore space geometry. Furthermore, the database shows no evidence for a significant decrease in the counterion mobility of clayey materials relative to clay-free materials, as postulated in recent studies. On the contrary, a single value of cp is consistent with no significant differences in ionic mobility given that all samples were saturated with a NaCl solution close to a common salinity of about 100 mS/m.

  2. Mechanistic approach to multi-element isotope modeling of organic contaminant degradation.

    PubMed

    Jin, Biao; Rolle, Massimo

    2014-01-01

    We propose a multi-element isotope modeling approach to simultaneously predict the evolution of different isotopes during the transformation of organic contaminants. The isotopic trends of different elements are explicitly simulated by tracking position-specific isotopologues that contain the isotopes located at fractionating positions. Our approach is self-consistent and provides a mechanistic description of different degradation pathways that accounts for the influence of both primary and secondary isotope effects during contaminant degradation. The method is particularly suited to quantitatively describe the isotopic evolution of relatively large organic contaminant molecules. For such compounds, an integrated approach, simultaneously considering all possible isotopologues, would be impractical due to the large number of isotopologues. We apply the proposed modeling approach to the degradation of toluene, methyl tert-butyl ether (MTBE) and nitrobenzene observed in previous experimental studies. Our model successfully predicts the multi-element isotope data (both 2D and 3D), and accurately captures the distinct trends observed for different reaction pathways. The proposed approach provides an improved and mechanistic methodology to interpret multi-element isotope data and to predict the extent of multi-element isotope fractionation that goes beyond commonly applied modeling descriptions and simplified methods based on the ratio between bulk enrichment factors or on linear regression in dual-isotope plots.

  3. Use of mechanistic data in assessing human risks from exposure to particles.

    PubMed Central

    McClellan, R O

    1997-01-01

    The ultimate goal of toxicologic investigations of both natural and man-made fibrous and nonfibrous particles is to provide essential input for the assessment of potential human risks from exposure to these materials. The development of risk assessment procedures for airborne particles has evolved over the years. The earliest assessments for naturally occurring materials used direct human observations and incorporated safety factors to arrive at allowable human exposures. More recently, there has been a need to assess the potential risk associated with production and use of certain man-made materials for which human data are not available or are inadequate. For these materials, it has been necessary to assess human risks using data obtained from studies conducted in laboratory animals and with cells or tissues. During the last several decades, it has been suggested that data on the mechanisms by which particles cause disease could be used to reduce the uncertainty in estimates of human risks of particle exposures. This article provides comments on the use of mechanistic data in the risk assessment process and suggestions for increasing the successful development and use of mechanistic data in risk assessments conducted in the future. PMID:9400751

  4. The iron isotope composition of enstatite meteorites: Implications for their origin and the metal/sulfide Fe isotopic fractionation factor

    NASA Astrophysics Data System (ADS)

    Wang, Kun; Savage, Paul S.; Moynier, Frédéric

    2014-10-01

    due to intensive impact-induced shearing stress, or the ultimate destruction of the Shallowater parent body. Analysis of separated enstatite meteorite mineral phases show that the magnetic phase (Fe metal) is systematically enriched in the heavier Fe isotopes when compared to non-magnetic phases (Fe hosted in troilite), which agrees with previous experimental observations and theoretical calculations. The difference between magnetic and non-magnetic phases from enstatite achondrites provides an equilibrium metal-sulfide Fe isotopic fractionation factor of Δ56Femetal-troilite = δ56Femetal - δ56Fetroilite of 0.129 ± 0.060‰ (2 SE) at 1060 ± 80 K, which confirms the predictions of previous theoretical calculations.

  5. Epidermal growth factor receptor transactivation is implicated in IL-6-induced proliferation and ERK1/2 activation in non-transformed prostate epithelial cells.

    PubMed

    Poncet, Nadège; Guillaume, Johann; Mouchiroud, Guy

    2011-03-01

    Epidermal growth factor receptor (EGF-R) is a receptor tyrosine kinase that can be activated by molecules other than its cognate ligands. This form of crosstalk called transactivation is frequently observed in both physiological and pathological cellular responses, yet it involves various mechanisms. Using the RWPE-1 cell line as a model of non-transformed prostate epithelial progenitor cells, we observed that interleukin-6 (IL-6) is able to promote cell proliferation and ERK1/2 activation provided that EGF-R kinase activity is not impaired. Treatment with GM6001, a general matrix metalloprotease inhibitor, indicated that IL-6 activates EGF-R through cleavage and release of membrane-anchored EGF-R ligands. Several inhibitors were used to test implication of "a disintegrin and metalloprotease" ADAM10 and ADAM17. GW280264X that targets both ADAM10 and ADAM17 blocked IL-6-induced proliferation and ERK1/2 phosphorylation with same potency as GM6001. However, ADAM10 inhibitor GI254023X and ADAM17 inhibitor TAPI-2 were less efficient in inhibiting response of RWPE-1 cells to IL-6, indicating possible cooperation of ADAM17 with ADAM10 or other metalloproteases. Accordingly, our findings suggest that IL-6 stimulates shedding of EGF-R ligands and transactivation of EGF-R in normal prostate epithelial cells, which may be an important mechanism to promote cell proliferation in inflammatory prostate.

  6. Binding of host-cell factors to DNA sequences in the long terminal repeat of human T-cell leukemia virus type I: implications for viral gene expression

    SciTech Connect

    Nyborg, J.K.; Dynan, W.S.; Chen, I.S.Y.; Wachsman, W.

    1988-03-01

    Efficient expression of human T-cell leukemia virus type I (HTLV-I) genes requires both host and viral proteins and is dependent on DNA sequences in the proviral long terminal repeats (LTRs). The authors have used DNase I-protection assays (footprinting) to construct a map of protein-DNA interactions over a 250-nucleotide region of the LTR upstream of the start site for viral RNA synthesis. They find that a host factor (host expression factor 1, or HEF-1) binds to the imperfect 21-nucleotide repeats that have previously been implicated in HTLV-I gene expression. HEF-1 binding activity is present in preparations from both lymphoid and nonlymphoid cells lines. However, the boundaries of the protected regions and the presence of a flanking DNase-hypersensitive site vary with cell type. Several regions of binding are detected in addition to the HEF-1 sites, including a complex group of sites 40-90 nucleotides upstream of the RNA start site. A comparison of HTLV-I transformed T lymphocytes that do and do not express the viral trans-activating protein p40/sup xI/ shows that none of the observed features of the DNase I footprint pattern correlate directly with the presence of this protein in the extract. These results suggest (i) that the primary recognition of promoter elements in the HTLV-I LTR involves specific interactions with host-cell proteins and (ii) that p40/sup xI/ influences the activity of one or more of these proteins, rather than interacting directly with the DNA.

  7. Mechanistic species distribution modeling reveals a niche shift during invasion.

    PubMed

    Chapman, Daniel S; Scalone, Romain; Štefanić, Edita; Bullock, James M

    2017-04-02

    Niche shifts of non-native plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by re-analyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially-invaded ranges of individual populations. Northern-origin populations that were established outside the generally-accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially-invaded range northwards and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual

  8. Mechanistic implications from structures of yeast alcohol dehydrogenase complexed with coenzyme and an alcohol.

    PubMed

    Plapp, Bryce V; Charlier, Henry A; Ramaswamy, S

    2016-02-01

    Yeast alcohol dehydrogenase I is a homotetramer of subunits with 347 amino acid residues, catalyzing the oxidation of alcohols using NAD(+) as coenzyme. A new X-ray structure was determined at 3.0 Å where both subunits of an asymmetric dimer bind coenzyme and trifluoroethanol. The tetramer is a pair of back-to-back dimers. Subunit A has a closed conformation and can represent a Michaelis complex with an appropriate geometry for hydride transfer between coenzyme and alcohol, with the oxygen of 2,2,2-trifluoroethanol ligated at 2.1 Å to the catalytic zinc in the classical tetrahedral coordination with Cys-43, Cys-153, and His-66. Subunit B has an open conformation, and the coenzyme interacts with amino acid residues from the coenzyme binding domain, but not with residues from the catalytic domain. Coenzyme appears to bind to and dissociate from the open conformation. The catalytic zinc in subunit B has an alternative, inverted coordination with Cys-43, Cys-153, His-66 and the carboxylate of Glu-67, while the oxygen of trifluoroethanol is 3.5 Å from the zinc. Subunit B may represent an intermediate in the mechanism after coenzyme and alcohol bind and before the conformation changes to the closed form and the alcohol oxygen binds to the zinc and displaces Glu-67.

  9. Nickel Alloy Primary Water Bulk Surface and SCC Corrosion Film Analytical Characterization and SCC Mechanistic Implications

    SciTech Connect

    Morton, D.; Lewis, N.; Hanson, M.; Rice, S.; Sanders, P.

    2007-04-18

    Alloy 600 corrosion coupon tests were performed: (1) to quantify the temperature dependency of general corrosion and (2) to characterize the composition and structure of bulk surface corrosion films for comparison with ongoing primary water SCC (PWSCC) crack tip corrosion film analyses. Results suggest that the thermal activation energy of Alloy 600 corrosion is consistent with the thermal activation energy of nickel alloy PWSCC. Analytical investigations of the structure and composition of Alloy 600 bulk surface corrosion oxides revealed a duplex (inner and outer) oxide layer structure. The outer layer is discontinuous and comprised of relatively large (1 to 3 {micro}m) nickel ferrite crystals and smaller ({approx}0.1 {micro}m) chromium containing nickel ferrite crystals. The inner layer consists of a relatively continuous chromite spinel (major phase) and chromia (Cr{sub 2}O{sub 3} minor phase) which formed through non-selective oxidation. Chromia and dealloyed Alloy 600 (highly Ni enriched metal) were only observed at 337 C (640 F) and only along the boundaries of deformation induced fine grains and subcells. Specimens having deformation free surfaces exhibited continuous uniform inner chromite spinel oxide layers. Specimens with machining induced surface deformation produced non-uniform inner layer oxides (chromite spinel, Cr{sub 2}O{sub 3} and unoxidized material). PWSCC crack tip oxides, in contrast, were fine grain (no duplex structure) and consisted of both chromium rich spinels and ''NiO'' structure oxides. Generally, nickel rich oxides were more abundant under more oxidized conditions (reduced coolant hydrogen) and spinel rich crack tip oxides were favored under more reducing conditions (increased coolant hydrogen). Bulk surface corrosion film thickness did not correlate with observed SCC growth rates. These results suggest that corrosion is not the rate controlling step of PWSCC but rather that PWSCC and corrosion have a common rate controlling sub process (e.g., cation diffusion, oxygen ingress).

  10. Rates of primary electron transfer in photosynthetic reaction centres and their mechanistic implications

    NASA Astrophysics Data System (ADS)

    Fleming, G. R.; Martin, J. L.; Breton, J.

    1988-05-01

    The conversion of light energy to chemical energy during photosyn-thesis involves the transfer of electrons between pigments embedded in a membrane protein. This process occurs with high quantum efficiency, the result of extremely fast electron transfer over a long distance preventing back transfer and energy loss. Recently the three-dimensional structures of the photosynthetic reaction centres of the bacteria Rhodopseudomonas viridis1 and Rhodobacter sphaeroides2 have been determined, allowing a molecular descrip-tion of the primary charge separation process. There are two symmetrically related branches of pigments in the structure (L and M), extending from the special pair of bacteriochlorophyll molecules (P) to the two bacteriopheophytins (HL and HM) via two bacteriochlorophylls (BLand BM). Many features of the electron transfer process are poorly understood, such as the nature of the excited states involved, the identity of the primary charge separation step and the roles of the protein and of B3-13. We have determined the rates of electron transfer in isolated reaction centre complexes of Rps. viridis and Rb. sphaeroides as a function of temperature. The rates increase as temperature is decreased, which may be due to either changes in electronic coupling of the pigments or changes in the population of coupled vibrational modes, or a combination of the two. We see no evidence of a B-L intermediate, which sets a lower limit on the rate of electron transfer from BL to HL. This is so high as to rule out transfer by two non-adiabatic steps.

  11. Mechanistic implications in the phosphatase activity of Mannich-based dinuclear zinc complexes with theoretical modeling.

    PubMed

    Sanyal, Ria; Zhang, Xuepeng; Kundu, Priyanka; Chattopadhyay, Tanmay; Zhao, Cunyuan; Mautner, Franz A; Das, Debasis

    2015-03-02

    An "end-off" compartmental ligand has been synthesized by an abnormal Mannich reaction, namely, 2-[bis(2-methoxyethyl)aminomethyl]-4-isopropylphenol yielding three centrosymmetric binuclear μ-phenoxozinc(II) complexes having the molecular formula [Zn2(L)2X2] (Zn-1, Zn-2, and Zn-3), where X = Cl(-), Br (-), and I (-), respectively. X-ray crystallographic analysis shows that the ZnO3NX chromophores in each molecule form a slightly distorted trigonal-bipyramidal geometry (τ = 0.55-0.68) with an intermetallic distance of 3.068, 3.101, and 3.083 Å (1-3, respectively). The spectrophotometrical investigation on their phosphatase activity established that all three of them possess significant hydrolytic efficiency. Michaelis-Menten-derived kinetic parameters indicate that the competitiveness of the rate of P-O bond fission employing the phosphomonoester (4-nitrophenyl)phosphate in 97.5% N,N-dimethylformamide is 3 > 1 > 2 and the kcat value lies in the range 9.47-11.62 s(-1) at 298 K. Theoretical calculations involving three major active catalyst forms, such as the dimer-cis form (D-Cis), the dimer-trans form (D-Trans), and the monoform (M-1 and M-2), systematically interpret the reaction mechanism wherein the dimer-cis form with the binuclear-bridged hydroxide ion acting as the nucleophile and one water molecule playing a role in stabilizing the leaving group competes as the most favored pathway.

  12. Current thinking on the mechanistic basis of Alzheimer's and implications for drug development.

    PubMed

    Ising, C; Stanley, M; Holtzman, D M

    2015-11-01

    Alzheimer disease (AD) is the most common cause of dementia and is characterized by the aggregation and accumulation of two proteins in the brain, amyloid-β (Aβ) and tau. Aβ and tau begin to buildup 15-20 years before the clinical onset of AD dementia. Increasing evidence suggests that preventing or decreasing the amount of aggregated forms of both Aβ and tau in the brain can serve as potential disease-modifying treatments for AD.

  13. Nano-biomimetic carriers are implicated in mechanistic evaluation of intracellular gene delivery

    PubMed Central

    Alipour, Mohsen; Hosseinkhani, Saman; Sheikhnejad, Reza; Cheraghi, Roya

    2017-01-01

    Several tissue specific non-viral carriers have been developed for gene delivery purposes. However, the inability to escape endosomes, undermines the efficacy of these carriers. Researchers inspired by HIV and influenza virus, have randomly used Gp41 and H5WYG fusogenic peptides in several gene delivery systems without any rational preference. Here for the first time, we have genetically engineered two Nano-biomimetic carriers composed of either HWYG (HNH) or Gp41 (GNH) that precisely provide identical conditions for the study and evaluation of these fusogenic peptides. The luciferase assay demonstrated a two-fold higher transfection efficiency of HNH compared to GNH. These nanocarriers also displayed equivalent properties in terms of DNA binding ability and DNA protection against serum nucleases and formed similar nanoparticles in terms of surface charge and size. Interestingly, hemolysis and cellular analysis demonstrated both of nanoparticles internalized into cells in similar rate and escaped from endosome with different efficiency. Furthermore, the structural analysis revealed the mechanisms responsible for the superior endosomal escaping capability of H5WYG. In conclusion, this study describes the rationale for using H5WYG peptide to deliver nucleic acids and suggests that using nano-biomimetic carriers to screen different endosomal release peptides, improves gene delivery significantly. PMID:28128339

  14. Mechanistic Investigation of Acid-Catalyzed Cleavage of Aryl-Ether Linkages: Implications for Lignin Depolymerization

    SciTech Connect

    Sturgeon, M. R.; Kim, S.; Chmely, S. C.; Foust, T. D.; Beckham, G. T.

    2013-01-01

    Carbon-oxygen bonds are the primary inter-monomer linkages lignin polymers in plant cell walls, and as such, catalyst development to cleave these linkages is of paramount importance to deconstruct biomass to its constituent monomers for the production of renewable fuels and chemicals. For many decades, acid catalysis has been used to depolymerize lignin. Lignin is a primary component of plant cell walls, which is connected primarily by aryl-ether linkages, and the mechanism of its deconstruction by acid is not well understood, likely due to its heterogeneous and complex nature compared to cellulose. For effective biomass conversion strategies, utilization of lignin is of significant relevance and as such understanding the mechanisms of catalytic lignin deconstruction to constituent monomers and oligomers is of keen interest. Here, we present a comprehensive experimental and theoretical study of the acid catalysis of a range of dimeric species exhibiting the b-O-4 linkage, the most common inter-monomer linkage in lignin. We demonstrate that the presence of a phenolic species dramatically increases the rate of cleavage in acid at 150 degrees C. Quantum mechanical calculations on dimers with the para-hydroxyl group demonstrate that this acid-catalyzed pathway differs from the nonphenolic dimmers. Importantly, this result implies that depolymerization of native lignin in the plant cell wall will proceed via an unzipping mechanism wherein b-O-4 linkages will be cleaved from the ends of the branched, polymer chains inwards toward the center of the polymer. To test this hypothesis further, we synthesized a homopolymer of b-O-4 with a phenolic hydroxyl group, and demonstrate that it is cleaved in acid from the end containing the phenolic hydroxyl group. This result suggests that genetic modifications to lignin biosynthesis pathways in plants that will enable lower severity processes to fractionate lignin for upgrading and for easier access to the carbohydrate fraction of the plant cell wall.

  15. Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data.

    PubMed

    Bates, Susan E; Eisch, Robin; Ling, Alexander; Rosing, Douglas; Turner, Maria; Pittaluga, Stefania; Prince, H Miles; Kirschbaum, Mark H; Allen, Steven L; Zain, Jasmine; Geskin, Larisa J; Joske, David; Popplewell, Leslie; Cowen, Edward W; Jaffe, Elaine S; Nichols, Jean; Kennedy, Sally; Steinberg, Seth M; Liewehr, David J; Showe, Louise C; Steakley, Caryn; Wright, John; Fojo, Tito; Litman, Thomas; Piekarz, Richard L

    2015-07-01

    Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

  16. ON THE INTERACTION OF ADENINE WITH IONIZING RADIATION: MECHANISTICAL STUDIES AND ASTROBIOLOGICAL IMPLICATIONS

    SciTech Connect

    Evans, Nicholas L.; Ullrich, Susanne; Bennett, Chris J.; Kaiser, Ralf I.

    2011-04-01

    The molecular inventory available on the prebiotic Earth was likely derived from both terrestrial and extraterrestrial sources. A complete description of which extraterrestrial molecules may have seeded early Earth is therefore necessary to fully understand the prebiotic evolution which led to life. Galactic cosmic rays (GCRs) are expected to cause both the formation and destruction of important biomolecules-including nucleic acid bases such as adenine-in the interstellar medium within the ices condensed on interstellar grains. The interstellar ultraviolet (UV) component is expected to photochemically degrade gas-phase adenine on a short timescale of only several years. However, the destruction rate is expected to be significantly reduced when adenine is shielded in dense molecular clouds or even within the ices of interstellar grains. Here, biomolecule destruction by the energetic charged particle component of the GCR becomes important as it is not fully attenuated. Presented here are results on the destruction rate of the nucleobase adenine in the solid state at 10 K by energetic electrons, as generated in the track of cosmic ray particles as they penetrate ices. When both UV and energetic charged particle destructive processes are taken into account, the half-life of adenine within dense interstellar clouds is found to be {approx}6 Myr, which is on the order of a star-forming molecular cloud. We also discuss chemical reaction pathways within the ices to explain the production of observed species, including the formation of nitriles (R-C{identical_to}N), epoxides (C-O-C), and carbonyl functions (R-C=O).

  17. Neddylation Pathway as a Novel Anti-cancer Target: Mechanistic Investigation and Therapeutic Implication.

    PubMed

    Jiang, Yanan; Jia, Lijun

    2015-01-01

    Protein neddylation, a newly characterized posttranslational modification that adds the ubiquitin-like molecule NEDD8 to substrates, modulates important biological processes, whereas dysfunction of neddylation may cause several serious diseases, such as cancer. Inhibition of neddylation pathway has emerged as a promising anticancer strategy, as evidenced by development of the NEDD8-activating enzyme (NAE) inhibitor MLN4924. Due to its potent anti-cancer efficacy and well-tolerated toxicity, MLN4924 has been evaluated in multiple Phase I clinical trials for solid tumors and hematologic malignancies. Recently, accumulating evidences indicate that neddylation pathway also plays a pivotal role in the regulation of multiple processes of tumor microenvironment (TME), such as tumor angiogenesis and the function of immune cells. In this review, we briefly summarize the latest progresses in this field and highlight neddylation pathway as an attractive therapeutic target against human cancer.

  18. Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications

    PubMed Central

    Uthayathas, Subramaniam; Masilamoni, Gunasingh J.; Shaffer, Christopher L.; Schmidt, Christopher J.; Menniti, Frank S.; Papa, Stella M.

    2013-01-01

    Phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium spiny neurons of both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10A inhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10A inhibitors as a new treatment for schizophrenia. However, PDE10A inhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classes may have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10A inhibitor MP-10 to those of the clinical standard D2 antagonist risperidone in rhesus monkeys using a standardized motor disability scale for parkinsonian primates and a newly designed “Drug Effects on Nervous System” scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidone broadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10A inhibitors for the treatment of psychotic symptoms. PMID:24490227

  19. Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

    NASA Astrophysics Data System (ADS)

    Rutkowska, Eva; Baker, Colin; Nahum, Alan

    2010-04-01

    A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

  20. Nano-biomimetic carriers are implicated in mechanistic evaluation of intracellular gene delivery

    NASA Astrophysics Data System (ADS)

    Alipour, Mohsen; Hosseinkhani, Saman; Sheikhnejad, Reza; Cheraghi, Roya

    2017-01-01

    Several tissue specific non-viral carriers have been developed for gene delivery purposes. However, the inability to escape endosomes, undermines the efficacy of these carriers. Researchers inspired by HIV and influenza virus, have randomly used Gp41 and H5WYG fusogenic peptides in several gene delivery systems without any rational preference. Here for the first time, we have genetically engineered two Nano-biomimetic carriers composed of either HWYG (HNH) or Gp41 (GNH) that precisely provide identical conditions for the study and evaluation of these fusogenic peptides. The luciferase assay demonstrated a two-fold higher transfection efficiency of HNH compared to GNH. These nanocarriers also displayed equivalent properties in terms of DNA binding ability and DNA protection against serum nucleases and formed similar nanoparticles in terms of surface charge and size. Interestingly, hemolysis and cellular analysis demonstrated both of nanoparticles internalized into cells in similar rate and escaped from endosome with different efficiency. Furthermore, the structural analysis revealed the mechanisms responsible for the superior endosomal escaping capability of H5WYG. In conclusion, this study describes the rationale for using H5WYG peptide to deliver nucleic acids and suggests that using nano-biomimetic carriers to screen different endosomal release peptides, improves gene delivery significantly.

  1. Homologous recombination in the archaeon Sulfolobus acidocaldarius: effects of DNA substrates and mechanistic implications.

    PubMed

    Rockwood, Jananie; Mao, Dominic; Grogan, Dennis W

    2013-09-01

    Although homologous recombination (HR) is known to influence the structure, stability, and evolution of microbial genomes, few of its functional properties have been measured in cells of hyperthermophilic archaea. The present study manipulated various properties of the parental DNAs in high-resolution assays of Sulfolobus acidocaldarius transformation, and measured the impact on the efficiency and pattern of marker transfer to the recipient chromosome. The relative orientation of homologous sequences, the type and position of chromosomal mutation being replaced, and the length of DNA flanking the marked region all affected the efficiency, linkage, tract continuity, and other parameters of marker transfer. Effects predicted specifically by the classical reciprocal-exchange model of HR were not observed. One analysis observed only 90 % linkage between markers defined by adjacent bases; in another series of experiments, sequence divergence up to 4 % had no detectable impact on overall efficiency of HR or on the co-transfer of a distal non-selected marker. The effects of introducing DNA via conjugation, rather than transformation, were more difficult to assess, but appeared to increase co-transfer (i.e. linkage) of relatively distant non-selected markers. The results indicate that HR events between gene-sized duplex DNAs and the S. acidocaldarius chromosome typically involve neither crossing over nor interference from a mismatch-activated anti-recombination system. Instead, the donor DNA may anneal to a transient chromosomal gap, as in the mechanism proposed for oligonucleotide-mediated transformation of Sulfolobus and other micro-organisms.

  2. Mass Spectrometry Based Mechanistic Insights into Formation of Tris Conjugates: Implications on Protein Biopharmaceutics

    NASA Astrophysics Data System (ADS)

    Kabadi, Pradeep G.; Sankaran, Praveen Kallamvalliillam; Palanivelu, Dinesh V.; Adhikary, Laxmi; Khedkar, Anand; Chatterjee, Amarnath

    2016-10-01

    We present here extensive mass spectrometric studies on the formation of a Tris conjugate with a therapeutic monoclonal antibody. The results not only demonstrate the reactive nature of the Tris molecule but also the sequence and reaction conditions that trigger this reactivity. The results corroborate the fact that proteins are, in general, prone to conjugation and/or adduct formation reactions and any modification due to this essentially leads to formation of impurities in a protein sample. Further, the results demonstrate that the conjugation reaction happens via a succinimide intermediate and has sequence specificity. Additionally, the data presented in this study also shows that the Tris formation is produced in-solution and is not an in-source phenomenon. We believe that the facts given here will open further avenues on exploration of Tris as a conjugating agent as well as ensure that the use of Tris or any ionic buffer in the process of producing a biopharmaceutical drug is monitored closely for the presence of such conjugate formation.

  3. Surface energetics and protein-protein interactions: analysis and mechanistic implications

    NASA Astrophysics Data System (ADS)

    Peri, Claudio; Morra, Giulia; Colombo, Giorgio

    2016-04-01

    Understanding protein-protein interactions (PPI) at the molecular level is a fundamental task in the design of new drugs, the prediction of protein function and the clarification of the mechanisms of (dis)regulation of biochemical pathways. In this study, we use a novel computational approach to investigate the energetics of aminoacid networks located on the surface of proteins, isolated and in complex with their respective partners. Interestingly, the analysis of individual proteins identifies patches of surface residues that, when mapped on the structure of their respective complexes, reveal regions of residue-pair couplings that extend across the binding interfaces, forming continuous motifs. An enhanced effect is visible across the proteins of the dataset forming larger quaternary assemblies. The method indicates the presence of energetic signatures in the isolated proteins that are retained in the bound form, which we hypothesize to determine binding orientation upon complex formation. We propose our method, BLUEPRINT, as a complement to different approaches ranging from the ab-initio characterization of PPIs, to protein-protein docking algorithms, for the physico-chemical and functional investigation of protein-protein interactions.

  4. Mechanistic modeling of CHF in forced-convection subcooled boiling

    SciTech Connect

    Podowski, M.Z.; Alajbegovic, A.; Kurul, N.; Drew, D.A.; Lahey, R.T. Jr.

    1997-05-01

    Because of the complexity of phenomena governing boiling heat transfer, the approach to solve practical problems has traditionally been based on experimental correlations rather than mechanistic models. The recent progress in computational fluid dynamics (CFD), combined with improved experimental techniques in two-phase flow and heat transfer, makes the use of rigorous physically-based models a realistic alternative to the current simplistic phenomenological approach. The objective of this paper is to present a new CFD model for critical heat flux (CHF) in low quality (in particular, in subcooled boiling) forced-convection flows in heated channels.

  5. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling

    PubMed Central

    Shang, Yi; Filizola, Marta

    2015-01-01

    Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery. PMID:25981301

  6. Opioid receptors: Structural and mechanistic insights into pharmacology and signaling.

    PubMed

    Shang, Yi; Filizola, Marta

    2015-09-15

    Opioid receptors are important drug targets for pain management, addiction, and mood disorders. Although substantial research on these important subtypes of G protein-coupled receptors has been conducted over the past two decades to discover ligands with higher specificity and diminished side effects, currently used opioid therapeutics remain suboptimal. Luckily, recent advances in structural biology of opioid receptors provide unprecedented insights into opioid receptor pharmacology and signaling. We review here a few recent studies that have used the crystal structures of opioid receptors as a basis for revealing mechanistic details of signal transduction mediated by these receptors, and for the purpose of drug discovery.

  7. Mechanistic equations for membrane transport of multicomponent solutions.

    PubMed

    Suchanek, G

    2006-03-01

    In the present article, mechanistic equations for membrane transport of N + 1-component solutions have been derived. The major specific investigation result is the introduction - for ternary solutions - of two diffusion coefficients omega(d1) and omega(d2) for solutes, as well as two cross coefficients omega(d12) and omega(d21) for these solutes. The latter parameters may be treated as coefficients of interdiffusion. The expansion of the description of substance transport to include the N + 1-component solutions does not formulate any additional physical phenomena other than those which are formulated by the transport equations for three-component solutions.

  8. [Mechanistic examination of organometallic electron transfer reactions: Annual report, 1989

    SciTech Connect

    Not Available

    1989-12-31

    Our mechanistic examination of electron transfer reactions between organometallic complexes has required data from our stopped-flow infrared spectrophotometer that was constructed in the first year. Our research on organometallic electron transfer reaction mechanisms was recognized by an invitation to the Symposium on Organometallic Reaction Mechanisms at the National ACS meeting in Miami. We have obtained a reasonable understanding of the electron transfer reactions between metal cations and anions and between metal carbonyl anions and metal carbonyl dimers. In addition we have begun to obtain data on the outer sphere electron transfer between metal carbonyl anions and coordination complexes and on reactions involving cluster anions.

  9. Unification and mechanistic detail as drivers of model construction: models of networks in economics and sociology.

    PubMed

    Kuorikoski, Jaakko; Marchionni, Caterina

    2014-12-01

    We examine the diversity of strategies of modelling networks in (micro) economics and (analytical) sociology. Field-specific conceptions of what explaining (with) networks amounts to or systematic preference for certain kinds of explanatory factors are not sufficient to account for differences in modelling methodologies. We argue that network models in both sociology and economics are abstract models of network mechanisms and that differences in their modelling strategies derive to a large extent from field-specific conceptions of the way in which a good model should be a general one. Whereas the economics models aim at unification, the sociological models aim at a set of mechanism schemas that are extrapolatable to the extent that the underlying psychological mechanisms are general. These conceptions of generality induce specific biases in mechanistic explanation and are related to different views of when knowledge from different fields should be seen as relevant.

  10. Combating Pathogenic Microorganisms Using Plant-Derived Antimicrobials: A Minireview of the Mechanistic Basis

    PubMed Central

    Upadhyaya, Indu; Kollanoor-Johny, Anup

    2014-01-01

    The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs) as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed. PMID:25298964

  11. Insulin-Like Growth Factor-I–Forkhead Box O Transcription Factor 3a Counteracts High Glucose/Tumor Necrosis Factor-α-Mediated Neuronal Damage: Implications for Human Immunodeficiency Virus Encephalitis

    PubMed Central

    Wilk, Anna; Urbanska, Katarzyna; Yang, Shuo; Wang, Jin Ying; Amini, Shohreh; Del Valle, Luis; Peruzzi, Francesca; Meggs, Leonard; Reiss, Krzysztof

    2012-01-01

    In HIV patients, antiretroviral medications trigger metabolic abnormalities, including insulin resistance. In addition, the inflammatory cytokine tumor necrosis factor-α (TNFα), which is elevated in human immunodeficiency virus encephalitis (HIVE), also induces insulin resistance and inflicts neuronal damage in vitro. In differentiated PC12 cells and rat cortical neurons, high glucose (HG; 25 mM) triggers reactive oxygen species (ROS) accumulation, contributing to the retraction of neuronal processes, with only a minimal involvement of neuronal apoptosis. In the presence of TNFα, HG-treated neurons undergo massive apoptosis. Because mammalian homolog of the Forkhead family of transcription factors, Forkhead box O transcription factor 3a (FOXO3a), controls ROS metabolism, we asked whether FOXO3a could affect the fate of differentiated neurons in the paradigm of HIVE. We observed FOXO3a nuclear translocation in HG-treated neuronal cultures, accompanied by partial loss of mitochondrial potential and gradual retraction of neuronal processes. Addition of TNFα to HG-treated neurons increased expression of the FOXO-dependent proapoptotic gene Bim, which resulted in extensive apoptotic death. Insulin-like growth factor-I (IGF-I) significantly lowered intracellular ROS, which was accompanied by IGF-I-mediated FOXO3a nuclear export and decrease in its transcriptional activity. The clinical relevance of these findings is supported by detection of nuclear FOXO3a in TUNEL-positive cortical neurons from HIVE, especially in brain areas characterized by elevated TNFα. PMID:21162126

  12. Mechanistic insight into the ribosome biogenesis functions of the ancient protein KsgA

    PubMed Central

    Connolly, Keith; Rife, Jason P.; Culver, Gloria

    2009-01-01

    Summary While the general blueprint of ribosome biogenesis is evolutionarily conserved, most details have diverged considerably. A striking exception to this divergence is the universally conserved KsgA/Dim1p enzyme family, which modifies two adjacent adenosines in the terminal helix of small subunit ribosomal RNA (rRNA). While localization of KsgA on 30S subunits (SSUs) and genetic interaction data have suggested that KsgA acts as a ribosome biogenesis factor, mechanistic details and a rationale for its extreme conservation are still lacking. To begin to address these questions we have characterized the function of E. coli KsgA in vivo using both a ksgA deletion strain and a methyltransferase deficient form of this protein. Our data reveals cold sensitivity and altered ribosomal profiles are associated with a ΔksgA genotype in E. coli. Our work also indicates that loss of KsgA alters 16S rRNA processing. These findings allow KsgAs role in SSU biogenesis to be integrated into the network of other identified factors. Moreover, a methyltransferase-inactive form of KsgA, which we show to be deleterious to cell growth, profoundly impairs ribosome biogenesis prompting discussion of KsgA as a possible anti-microbial drug target. These unexpected data suggest that methylation is a second layer of function for KsgA and that its critical role is as a supervisor of biogenesis of SSUs in vivo. These new findings and this proposed regulatory role offer a mechanistic explanation for the extreme conservation of the KsgA/Dim1p enzyme family. PMID:18990185

  13. Trichloroethylene: Mechanistic, Epidemiologic and Other Supporting Evidence of Carcinogenic Hazard

    PubMed Central

    Rusyn, Ivan; Chiu, Weihsueh A.; Lash, Lawrence H.; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z.

    2013-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including from hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. Strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin's lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. PMID:23973663

  14. Modeling of batch sorber system: kinetic, mechanistic, and thermodynamic modeling

    NASA Astrophysics Data System (ADS)

    Mishra, Vishal

    2016-09-01

    The present investigation has dealt with the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase. Various rate models were evaluated to elucidate the kinetics of copper and zinc biosorptions, and the results indicated that the pseudo-second-order model was more appropriate than the pseudo-first-order model. The curve of the initial sorption rate versus the initial concentration of copper and zinc ions also complemented the results of the pseudo-second-order model. Models used for the mechanistic modeling were the intra-particle model of pore diffusion and Bangham's model of film diffusion. The results of the mechanistic modeling together with the values of pore and film diffusivities indicated that the preferential mode of the biosorption of copper and zinc ions on the surface of egg-shell particles in the liquid phase was film diffusion. The results of the intra-particle model showed that the biosorption of the copper and zinc ions was not dominated by the pore diffusion, which was due to macro-pores with open-void spaces present on the surface of egg-shell particles. The thermodynamic modeling reproduced the fact that the sorption of copper and zinc was spontaneous, exothermic with the increased order of the randomness at the solid-liquid interface.

  15. Noncanonical IFN Signaling: Mechanistic Linkage of Genetic and Epigenetic Events

    PubMed Central

    Ahmed, Chulbul M.

    2016-01-01

    The canonical model of cytokine signaling via the JAK/STAT pathway dominates our view of signal transduction but provides no insight into the significance of the simultaneous presence of activated JAKs and STATs in the nucleus of cells treated with cytokines. Such a mechanistic shortcoming challenges the usefulness of the model in its present form. Focusing on the interferon (IFN) cytokines, we have developed a noncanonical model of IFN signaling that naturally connects activated JAKs and STATs at or near response elements of genes that are activated by the IFNs. Specifically, cells treated with IFNγ showed association of activated STAT1α and JAK2 at the GAS element of genes activated by IFNγ. For IFNα treated cells, the association involved activated STAT1α and TYK2 JAK kinase at the ISRE promoter. The power of the noncanonical model is that it provides mechanistic insight into specific gene activation at the level of the associated epigenetics, akin to that of steroid/steroid receptor signaling. PMID:28077919

  16. From Data Patterns to Mechanistic Models in Acute Critical Illness

    PubMed Central

    Aerts, Jean-Marie; Haddad, Wassim M.; An, Gary; Vodovotz, Yoram