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Sample records for hit cells role

  1. Cell Phones and PDA's Hit K-6

    ERIC Educational Resources Information Center

    Dodds, Richard; Mason, Christine Y.

    2005-01-01

    Although cell phones keep kids in touch with families and personal digital assistants (PDA's) help organize assignments and give Internet access, when they are added to the school climate, educators must reassess policies so technology does not interfere with instruction time. This article discusses the several effects of cell phones to K-6…

  2. Multiple cell hits by particle tracks in solid tissues.

    PubMed

    Todd, P

    1992-01-01

    Relative Biological Effectiveness (RBE) and Quality Factor (Q) at extreme values of Linear Energy Transfer (LET) have been determined on the basis of experiments with single-cell systems and specific tissue responses. In typical single cell systems, each heavy particle (Ar or Fe) passes through a single cell or no cell. In tissue end-point experiments each heavy particle passes through several cells, and the LET can exceed 200 keV/micrometer in every cell. In most laboratory animal tissue systems, however, only a small portion of the hit cells are capable of expressing the end-point of interest to the investigator, such as cell killing, mutation or carcinogenesis. The following question must therefore be addressed: Do RBE's and Q factors derived from single-cell experiments properly account for the increased probability of multiple-cell damage by HZE tracks? A model is offered in which measured radiation effects and known tissue properties are combined to estimate the value of a multiplier of damage effectiveness on the basis of number of cells at risk, p3n, per track containing a hit cell, where n is the number of cells per track, based on tissue and organ geometry, and P3 is the probability that a cell in the track is capable of expressing the experimental end-point. PMID:11537036

  3. Estimated Radiation on Mars, Hits per Cell Nucleus

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This global map of Mars shows estimates for amounts of high-energy-particle cosmic radiation reaching the surface, a serious health concern for any future human exploration of the planet.

    The estimates are based on cosmic-radiation measurements made on the way to Mars by the Mars radiation environment experiment, an instrument on NASA's 2001 Mars Odyssey spacecraft, plus information about Mars' surface elevations from the laser altimeter instrument on NASA's Mars Global Surveyor. The areas of Mars expected to have least radiation are where elevation is lowest, because those areas have more atmosphere above them to block out some of the radiation. Earth's thick atmosphere shields us from most cosmic radiation, but Mars has a much thinner atmosphere than Earth does.

    Colors in the map refer to the estimated average number of times per year each cell nucleus in a human there would be hit by a high-energy cosmic ray particle. The range is generally from two hits (color-coded green), a moderate risk level, to eight hits (coded red), a high risk level.

    NASA's Jet Propulsion Laboratory, Pasadena, Calif. manages the 2001 Mars Odyssey and Mars Global Surveyor missions for NASA's Office of Space Science, Washington D.C. The Mars radiation environment experiment was developed by NASA's Johnson Space Center. Lockheed Martin Astronautics, Denver, is the prime contractor for Odyssey, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  4. Performance of bifacial HIT solar cells on n-type silicon substrates

    NASA Astrophysics Data System (ADS)

    Liu, Qin; Ye, Xiao-Jun; Liu, Cheng; Chen, Ming-Bo

    2010-03-01

    The performance of amorphous silicon (a-Si:H) / crystalline silicon (c-Si) heterojunction is studied, and the effects of the emitter layer thickness, doping concentration, intrinsic layer thickness, back heavily-doped n layer, interface state and band offset on the optical and electrical performance of bifacial heterojunction with intrinsic thin-layer (HIT) solar cells on ntype silicon substrates are discussed. It is found that the HIT solar cells on n-type substrates can obtain a higher conversion efficiency than those on p-type substrates by calculating the band diagrams and parameters of HIT solar cells.

  5. HITS-CLIP: panoramic views of protein-RNA regulation in living cells

    PubMed Central

    Darnell, Robert B.

    2011-01-01

    The study of gene regulation in cells has recently begun to shift from a period dominated by the study of transcription factor-DNA interactions to a new focus on RNA regulation. This was sparked by the still-emerging recognition of the central role for RNA in cellular complexity emanating from the RNA World hypothesis, and has been facilitated by technologic advances, in particular high throughput RNA sequencing and crosslinking methods (RNA-Seq, CLIP, and HITS-CLIP). This article will place these advances in context, and, focusing on CLIP, will explain the method, what it can be used for, and how to approach using it. Examples of the successes, limitations and future of the technique will be discussed. Crosslinking immunoprecipitation (CLIP), coupled with high throughput sequencing (HITS-CLIP), has caught the attention of the RNA community as a means of achieving a new depth of understanding about how protein-RNA complexes interactions regulate gene expression in living cells1–4. This review will describe the context in which CLIP was developed, and provide an up-to-date review of its uses in developing genome-wide maps of RNA-protein interactions and, more recently, microRNA (miRNA) binding sites. The uses, limitations, and future of CLIP will be discussed. PMID:21935890

  6. Stem cell therapy for cardiac regeneration: hits and misses.

    PubMed

    Padda, Jagjit; Sequiera, Glen Lester; Sareen, Niketa; Dhingra, Sanjiv

    2015-10-01

    Cardiac injury and loss of cardiomyocytes is a causative as well as a resultant condition of cardiovascular disorders, which are the leading cause of death throughout the world. This loss of cardiomyocytes cannot be completely addressed through the currently available drugs being administered, which mainly function only in relieving the symptoms. There is a huge potential being investigated for regenerative and cell replacement therapies through recruiting stem cells of various origins namely embryonic, reprogramming/induction, and adult tissue. These sources are being actively studied for translation to clinical scenarios. In this review, we attempt to discuss some of these promising scenarios, including the clinical trials and the obstacles that need to be overcome, and hope to address the direction in which stem cell therapy is heading. PMID:26443930

  7. Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides

    NASA Technical Reports Server (NTRS)

    Polig, E.; Jee, W. S.; Kruglikov, I. L.

    1992-01-01

    Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

  8. Protective effects of Quercus salicina on alloxan-induced oxidative stress in HIT-T15 pancreatic β cells

    PubMed Central

    SONG, JIA-LE; ZHAO, XIN; WANG, QIANG

    2013-01-01

    The present study was designed to investigate the protective effect of hot water extracts from Quercus salicina leaves (QSWE) on alloxan-induced oxidative stress in HIT-T15 Syrian hamster pancreatic insulinoma cells. The HIT-T15 cells were treated with alloxan (1 mM) for 1 h and then co-incubated with the QSWE for 24 h. Alloxan significantly decreased the viability of the HIT-T15 cells (P<0.05). QSWE did not exhibit significantly cytotoxic effects and increased the viability of the HIT-T15 cells in a concentration-dependent manner. To further investigate the protective effects of QSWE on alloxan-induced oxidative stress in HIT-T15 cells, the cellular levels of reactive oxygen species (ROS), lipid peroxidation and endogenous antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were analyzed. QSWE decreased the intracellular levels of ROS and lipid peroxidation and increased the activity of antioxidant enzymes. These results suggest that QSWE exerted cytoprotective activity against alloxan-induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, reduction of ROS levels and stimulation of antioxidant enzyme activity. In addition, QSWE also increased the insulin secretion activity of the alloxan-treated HIT-T15 cells. PMID:23408741

  9. A "Hit and Run" Approach to Inducible Direct Reprogramming of Astrocytes to Neural Stem Cells.

    PubMed

    Poulou, Maria; Mandalos, Nikolaos P; Karnavas, Theodoros; Saridaki, Marannia; McKay, Ronald D G; Remboutsika, Eumorphia

    2016-01-01

    Temporal and spatial control of gene expression can be achieved using an inducible system as a fundamental tool for regulated transcription in basic, applied and eventually in clinical research. We describe a novel "hit and run" inducible direct reprogramming approach. In a single step, 2 days post-transfection, transiently transfected Sox2(FLAG) under the Leu3p-αIPM inducible control (iSox2) triggers the activation of endogenous Sox2, redirecting primary astrocytes into abundant distinct nestin-positive radial glia cells. This technique introduces a unique novel tool for safe, rapid and efficient reprogramming amendable to regenerative medicine. PMID:27148066

  10. Stimulus-response coupling in insulin-secreting HIT cells. Effects of secretagogues on cytosolic Ca2+, diacylglycerol, and protein kinase C activity.

    PubMed

    Regazzi, R; Li, G D; Deshusses, J; Wollheim, C B

    1990-09-01

    The hamster islet B cell line HIT retains the ability to secret insulin in response to glucose and several receptor agonists. We used HIT cells to study the initial signaling events in glucose or receptor agonist-stimulated insulin secretion. Glucose stimulated insulin release from HIT cells in a dose-dependent manner with a half-maximal effect seen already at 1 mM. Insulin release was also stimulated by carbachol in a glucose-dependent manner. Glucose depolarized the HIT cell membrane potential as assessed with the fluorescent probe bisoxonol and raised intracellular Ca2+ as revealed by fura-2 measurements. Using a Mn2+ fura-2 quenching technique, we could show that the rise in intracellular Ca2+ was due to Ca2+ influx following opening of voltage-gated Ca2+ channels. Glucose is thought to increase the diacylglycerol (DAG) content of insulin-secreting cells. However, although HIT cells respond to glucose in terms of insulin secretion, membrane depolarization, and Ca2+ rise, the hexose was unable to increase the proportion of protein kinase C activity associated with membranes. In contrast, the membrane-associated protein kinase C activity increased in HIT cells exposed to the two receptor agonists carbachol and bombesin. Bombesin was shown to generate DAG with the expected fatty acid composition of activators of phospholipase C. Glucose, in contrast, only caused minor increases in DAG containing myristic and palmitic acid without affecting total DAG mass. The failure to detect stimulation of protein kinase C by glucose could be due to both the limited amount and to the different fatty acid composition of the metabolically generated DAG. The latter was in part supported by experiments performed on protein kinase C partially purified from HIT cells. Indeed, 1,2-dipalmitoylglycerol, presumed to be the main DAG species generated by glucose, was only one-third as active as 1,2-dioleoylglycerol and 1-stearoyl-2-arachidonylglycerol in stimulating the isolated enzyme at

  11. The prognosis of MYC translocation positive diffuse large B‐cell lymphoma depends on the second hit

    PubMed Central

    Clipson, Alexandra; Barrans, Sharon; Zeng, Naiyan; Crouch, Simon; Grigoropoulos, Nicholas F; Liu, Hongxiang; Kocialkowski, Sylvia; Wang, Ming; Huang, Yuanxue; Worrillow, Lisa; Goodlad, John; Buxton, Jenny; Neat, Michael; Fields, Paul; Wilkins, Bridget; Grant, John W; Wright, Penny; EI‐Daly, Hesham; Follows, George A; Roman, Eve; Watkins, A James; Johnson, Peter W M; Jack, Andrew

    2015-01-01

    Abstract A proportion of MYC translocation positive diffuse large B‐cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double‐hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double‐hit DLBCL, and whether there is a difference in clinical outcome between the double‐hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R‐CHOP (n = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double‐hits had the worst overall survival, followed by those with MYC/BCL2 double‐hits. In MYC translocation negative DLBCL treated by R‐CHOP (n = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double‐hit DLBCLs from those with an isolated MYC translocation. PMID:27347428

  12. Radial junction solar cells based on heterojunction with intrinsic thin layer (HIT) structure

    NASA Astrophysics Data System (ADS)

    Shen, Haoting

    The radial junction wire array structure was previously proposed as a solar cell geometry to separate the direction of carrier collection from the direction of light absorption, thereby circumventing the need to use high quality but expensive single crystal silicon (c-Si) material that has long minority carrier diffusion lengths. The Si radial junction structure can be realized by forming radial p-n junctions on Si pillar/wire arrays that have a diameter comparable to the minority carrier diffusion length. With proper design, the Si pillar arrays are also able to enhance light trapping and thereby increase the light absorption. However, the larger junction area and surface area on the pillar arrays compared to traditional planar junction Si solar cells makes it challenging to fabricate high performance devices due an in increase in surface defects. Therefore, effective surface passivation strategies are essential for radial junction devices. Hydrogenated amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition (PECVD) using a heterojunction with intrinsic thin layer (HIT) structure has previously been demonstrated as a very effective surface passivation layer for planar c-Si solar cells. It is therefore of interest to use a-Si:H in a HIT layer structure for radial p-n junction c-Si pillar array solar cells. This poses several challenges, however, including the need to fabricate ultra-thin a-Si:H layers conformally on high aspect ratio Si pillars, control the crystallinity at the a-Si:H/c-Si interface to yield a low interface state density and optimize the layer thicknesses, doping and contacts to yield high performance devices. This research in this thesis was aimed at developing the processing technology required to apply the HIT structure to radial junction Si pillar array solar cell devices and to evaluate the device characteristics. Initial studies focused on understanding the effects of process conditions on the growth rate and

  13. Organizations disseminating health messages: the roles of organizational identification and HITs.

    PubMed

    Stephens, Keri K; Goins, Elizabeth S; Dailey, Stephanie L

    2014-01-01

    Research into the dissemination of health information now includes more focus on how various organizations (e.g., beauty shops, schools, workplaces, and churches) and health information technologies (HITs) reach and affect audiences. One relational feature of organizations is identification--the feeling of belongingness. Our study explores how it influences audiences, especially in combination with HITs such as e-mail, websites, and social media. We use social identity theory to predict how organizational identification and social media might function in health communication. Using a 3 × 2 experimental design, we find that people's identification with a message source mediates the effect of social media on outcomes. These findings improve our understanding of when organizations might be most helpful for disseminating health information. PMID:23829343

  14. Radial junction solar cells based on heterojunction with intrinsic thin layer (HIT) structure

    NASA Astrophysics Data System (ADS)

    Shen, Haoting

    The radial junction wire array structure was previously proposed as a solar cell geometry to separate the direction of carrier collection from the direction of light absorption, thereby circumventing the need to use high quality but expensive single crystal silicon (c-Si) material that has long minority carrier diffusion lengths. The Si radial junction structure can be realized by forming radial p-n junctions on Si pillar/wire arrays that have a diameter comparable to the minority carrier diffusion length. With proper design, the Si pillar arrays are also able to enhance light trapping and thereby increase the light absorption. However, the larger junction area and surface area on the pillar arrays compared to traditional planar junction Si solar cells makes it challenging to fabricate high performance devices due an in increase in surface defects. Therefore, effective surface passivation strategies are essential for radial junction devices. Hydrogenated amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition (PECVD) using a heterojunction with intrinsic thin layer (HIT) structure has previously been demonstrated as a very effective surface passivation layer for planar c-Si solar cells. It is therefore of interest to use a-Si:H in a HIT layer structure for radial p-n junction c-Si pillar array solar cells. This poses several challenges, however, including the need to fabricate ultra-thin a-Si:H layers conformally on high aspect ratio Si pillars, control the crystallinity at the a-Si:H/c-Si interface to yield a low interface state density and optimize the layer thicknesses, doping and contacts to yield high performance devices. This research in this thesis was aimed at developing the processing technology required to apply the HIT structure to radial junction Si pillar array solar cell devices and to evaluate the device characteristics. Initial studies focused on understanding the effects of process conditions on the growth rate and

  15. Effect of disruption of actin filaments by Clostridium botulinum C2 toxin on insulin secretion in HIT-T15 cells and pancreatic islets.

    PubMed Central

    Li, G; Rungger-Brändle, E; Just, I; Jonas, J C; Aktories, K; Wollheim, C B

    1994-01-01

    To examine their role in insulin secretion, actin filaments (AFs) were disrupted by Clostridium botulinum C2 toxin that ADP-ribosylates G-actin. Ribosylation also prevents polymerization of G-actin to F-actin and inhibits AF assembly by capping the fast-growing end of F-actin. Pretreatment of HIT-T15 cells with the toxin inhibited stimulated insulin secretion in a time- and dose-dependent manner. The toxin did not affect cellular insulin content or nonstimulated secretion. In static incubation, toxin treatment caused 45-50% inhibition of secretion induced by nutrients alone (10 mM glucose + 5 mM glutamine + 5 mM leucine) or combined with bombesin (phospholipase C-activator) and 20% reduction of that potentiated by forskolin (stimulator of adenylyl cyclase). In perifusion, the stimulated secretion during the first phase was marginally diminished, whereas the second phase was inhibited by approximately 80%. Pretreatment of HIT cells with wartmannin, a myosin light chain kinase inhibitor, caused a similar pattern of inhibition of the biphasic insulin release as C2 toxin. Nutrient metabolism and bombesin-evoked rise in cytosolic free Ca2+ were not affected by C2 toxin, indicating that nutrient recognition and the coupling between receptor activation and second messenger generation was not changed. In the toxin-treated cells, the AF web beneath the plasma membrane and the diffuse cytoplasmic F-actin fibers disappeared, as shown both by staining with an antibody against G- and F-actin and by staining F-actin with fluorescent phallacidin. C2 toxin dose-dependently reduced cellular F-actin content. Stimulation of insulin secretion was not associated with changes in F-actin content and organization. Treatment of cells with cytochalasin E and B, which shorten AFs, inhibited the stimulated insulin release by 30-50% although differing in their effects on F-actin content. In contrast to HIT-T15 cells, insulin secretion was potentiated in isolated rat islets after disruption of

  16. Mozambique Hit by a Flood Disaster, Again: What Role for the Scientific Community

    NASA Astrophysics Data System (ADS)

    Matonse, A. H.; Zucula, P.

    2007-05-01

    The Lower Zambezi basin in Mozambique covers an area of approximately 225,000 km2 from the Cahora Bassa Reservoir to the Zambezi Delta, and supports more than 3.8 million people (25% of the total population of Mozambique). The Zambezi Delta is a broad, flat alluvial plain along the coast of central Mozambique. Some 800 Mozambicans died in floods caused by two cyclones in 2000 and 2001 in the Zambezi River Valley in central Mozambique. Recently, seven years later, the same Zambezi River Valley was hit by heavy rain which was followed by Cyclone Favio. This event triggered flash floods along the Zambezi River and its tributaries, washing away homes, bridges, livestock and crops, and killing at least 45 people. The country's national relief agency INGC established an emergency operation centre to coordinate relief operations. By February 25, 2007, 53,000 people have been moved to accommodation centers and an estimated 36,000 people have lost virtually all their possessions. Due to the extent of the flooded area, rescue and supply operations are very difficult, and conditioned upon the availability of helicopters. Temporary accommodation centres have faced problems of food and fuel shortages, and delays in the distribution of food and fresh water are raising concerns with malnutrition and the outbreak of waterborne diseases. One of the major problems in the region is water management and regulation. The main structure to regulate water discharge in the Zambezi River is the Mozambique's largest Hydro-electric dam, Cahora Bassa. Water regulation from this structure during floods is particularly difficult due to transnational inflows passing through the neighbouring countries of Malawi, Zambia and Zimbabwe. Since the flood disaster of 2000/2001 occurred, the need to improve and strengthen disaster prevention has been a high priority of the Mozambique Government and its donors. Mozambique's Action Plan for the reduction of Absolute Poverty identified vulnerability to such

  17. Φ-score: A cell-to-cell phenotypic scoring method for sensitive and selective hit discovery in cell-based assays

    PubMed Central

    Guyon, Laurent; Lajaunie, Christian; fer, Frédéric; bhajun, Ricky; sulpice, Eric; pinna, Guillaume; campalans, Anna; radicella, J. Pablo; rouillier, Philippe; mary, Mélissa; combe, Stéphanie; obeid, Patricia; vert, Jean-Philippe; gidrol, Xavier

    2015-01-01

    Phenotypic screening monitors phenotypic changes induced by perturbations, including those generated by drugs or RNA interference. Currently-used methods for scoring screen hits have proven to be problematic, particularly when applied to physiologically relevant conditions such as low cell numbers or inefficient transfection. Here, we describe the Φ-score, which is a novel scoring method for the identification of phenotypic modifiers or hits in cell-based screens. Φ-score performance was assessed with simulations, a validation experiment and its application to gene identification in a large-scale RNAi screen. Using robust statistics and a variance model, we demonstrated that the Φ-score showed better sensitivity, selectivity and reproducibility compared to classical approaches. The improved performance of the Φ-score paves the way for cell-based screening of primary cells, which are often difficult to obtain from patients in sufficient numbers. We also describe a dedicated merging procedure to pool scores from small interfering RNAs targeting the same gene so as to provide improved visualization and hit selection. PMID:26382112

  18. Caribbean maitotoxin elevates [Ca2+]i and activates non-selective cation channels in HIT-T15 cells

    PubMed Central

    Lu, Xin-Zhong; Deckey, Robert; Jiao, Guo-Liang; Ren, Hui-Feng; Li, Ming

    2013-01-01

    AIM: To investigate the cytotoxic mechanism of caribbean maitotoxin (MTX-C) in mammalian cells. METHODS: We used whole-cell patch-clamp techniques and fluorescence calcium imaging to determine the cellular toxic mechanisms of MTX-C in insulin secreting HIT-T15 cells, which is a system where the effects of MTX have been observed. HIT-T15 cells stably express L-type calcium current, making it a suitable model for this study. Using the fluorescence calcium indicator Indo-1 AM, we found that there is a profound increase in HIT-T15 intracellular free calcium 3 min after application of 200 nmol/L MTX-C. RESULTS: About 3 min after perfusion of MTX-C, a gradual increase in free calcium concentration was observed. This elevation was sustained throughout the entire recording period. Application of MTX-C did not elicit the L-type calcium current, but large cationic currents appeared after applying MTX-C to the extracellular solution. The current-voltage relationship of the cation current is approximately linear within the voltage range from -60 to 50 mV, but flattened at voltages at -80 and -100 mV. These results indicate that MTX-C induces a non-voltage activated, inward current under normal physiological conditions, which by itself or through a secondary mechanism results in a large amount of cationic influx. The biophysical mechanism of MTX-C is different to its isoform, pacific maitotoxin (MTX-P), when the extracellular calcium is removed. CONCLUSION: We conclude that MTX-C causes the opening of non-selective, non-voltage-activated ion channels, which elevates level of intracellular calcium concentration and leads to cellular toxicities. PMID:23772275

  19. A “Hit and Run” Approach to Inducible Direct Reprogramming of Astrocytes to Neural Stem Cells

    PubMed Central

    Poulou, Maria; Mandalos, Nikolaos P.; Karnavas, Theodoros; Saridaki, Marannia; McKay, Ronald D. G.; Remboutsika, Eumorphia

    2016-01-01

    Temporal and spatial control of gene expression can be achieved using an inducible system as a fundamental tool for regulated transcription in basic, applied and eventually in clinical research. We describe a novel “hit and run” inducible direct reprogramming approach. In a single step, 2 days post-transfection, transiently transfected Sox2FLAG under the Leu3p-αIPM inducible control (iSox2) triggers the activation of endogenous Sox2, redirecting primary astrocytes into abundant distinct nestin-positive radial glia cells. This technique introduces a unique novel tool for safe, rapid and efficient reprogramming amendable to regenerative medicine. PMID:27148066

  20. A role for dual viral hits in causation of subacute sclerosing panencephalitis.

    PubMed

    Oldstone, Michael B A; Dales, Samuel; Tishon, Antoinette; Lewicki, Hanna; Martin, Lee

    2005-11-01

    Subacute sclerosing panencephalitis (SSPE) is a progressive fatal neurodegenerative disease associated with persistent infection of the central nervous system (CNS) by measles virus (MV), biased hypermutations of the viral genome affecting primarily the matrix (M) gene with the conversion of U to C and A to G bases, high titers of antibodies to MV, and infiltration of B cells and T cells into the CNS. Neither the precipitating event nor biology underlying the MV infection is understood, nor is their any satisfactory treatment. We report the creation of a transgenic mouse model that mimics the cardinal features of SSPE. This was achieved by initially infecting mice expressing the MV receptor with lymphocytic choriomeningitis virus Cl 13, a virus that transiently suppressed their immune system. Infection by MV 10 days later resulted in persistent MV infection of neurons. Analysis of brains from infected mice showed the biased U to C hypermutations in the MV M gene and T and B lymphocyte infiltration. These sera contained high titers of antibodies to MV. Thus, a small animal model is now available to both molecularly probe the pathogenesis of SSPE and to test a variety of therapies to treat the disease. PMID:16260490

  1. Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel.

    PubMed

    Pietrofesa, Ralph A; Velalopoulou, Anastasia; Lehman, Stacey L; Arguiri, Evguenia; Solomides, Pantelis; Koch, Cameron J; Mishra, Om P; Koumenis, Constantinos; Goodwin, Thomas J; Christofidou-Solomidou, Melpo

    2016-01-01

    Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to >95% O₂ for 8 h only (O₂), 0.25 Gy ionizing γ-radiation (IR) only, or a double-hit combination of both challenges (O₂ + IR) followed by 16 h of normoxia (ambient air containing 21% O₂ and 5% CO₂) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p < 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45α and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O₂ + IR exacerbated cell death and DNA damage compared to individual exposures O₂ or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia

  2. Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity.

    PubMed

    Harmon, J S; Tanaka, Y; Olson, L K; Robertson, R P

    1998-06-01

    We have reported that chronic culture of HIT-T15 cells in medium containing supraphysiologic glucose concentrations (11.1 mmol/l) causes a decrease in insulin mRNA levels, insulin content, and insulin release. Furthermore, decreases in insulin gene transcription and binding activity of two essential beta-cell transcription factors, somatostatin transcription factor-1 (STF-1; also known as GSTF, IDX-1, IPF-1, PDX-1, and GSF) and RIPE-3b1 activator, are associated with this glucotoxic effect. In this study, we observed that the loss of RIPE-3b1 occurs much earlier (79% decrease at passage [p]81) than the loss of STF-1 (65% decrease at p104), with abolishment of both factors by p122. Since the STF-1, but not the RIPE-3b1 activator, gene has been cloned, we examined its restorative effects on insulin gene promoter activity after reconstitution with STF-1 cDNA. Basal insulin promoter activities normalized to early (p71-74) passage cells (1.000 +/- 0.069) were 0.4066 +/- 0.093 and 0.142 +/- 0.034 for intermediate (p102-106) and late (p118-122) passage cells, respectively. Early, intermediate, and late passage cells, all chronically cultured in medium containing 11.1 mmol/l glucose, were transfected with STF-1 alone or cotransfected with E2-5, an E-box factor known to be synergistically associated with STF-1. Compared with basal levels, we observed a trend toward an increase in insulin promoter activity in intermediate passage cells with STF-1 transfection (1.43-fold) that became a significant increase when E2-5 was cotransfected (1.78-fold). In late passage cells, transfection of STF-1 alone significantly stimulated a 2.2-fold increase in the insulin promoter activity. Cotransfection of STF-1 and E2-5 in late passage cells stimulated insulin promoter activity 2.8-fold, which was 40% of the activity observed in early passage cells. Control studies in glucotoxic betaTC-6 cells deficient in RIPE-3b1 activator but not STF-1 did not demonstrate an increase in insulin promoter

  3. Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel

    PubMed Central

    Pietrofesa, Ralph A.; Velalopoulou, Anastasia; Lehman, Stacey L.; Arguiri, Evguenia; Solomides, Pantelis; Koch, Cameron J.; Mishra, Om P.; Koumenis, Constantinos; Goodwin, Thomas J.; Christofidou-Solomidou, Melpo

    2016-01-01

    Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to >95% O2 for 8 h only (O2), 0.25 Gy ionizing γ-radiation (IR) only, or a double-hit combination of both challenges (O2 + IR) followed by 16 h of normoxia (ambient air containing 21% O2 and 5% CO2) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p < 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45α and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O2 + IR exacerbated cell death and DNA damage compared to individual exposures O2 or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia exposure that

  4. Determinants of glucose toxicity and its reversibility in the pancreatic islet beta-cell line, HIT-T15.

    PubMed

    Gleason, C E; Gonzalez, M; Harmon, J S; Robertson, R P

    2000-11-01

    HIT-T15 cells, a clonal beta-cell line, were cultured and passaged weekly for 6 mo in RPMI 1640 media containing various concentrations of glucose. Insulin content decreased in the intermediate- and late-passage cells as a continuous rather than a threshold glucose concentration effect. In a second series of experiments, cells were grown in media containing either 0.8 or 16.0 mM glucose from passages 76 through 105. Subcultures of passages 86, 92, and 99 that had been grown in media containing 16.0 mM glucose were switched to media containing 0.8 mM glucose and also carried forward to passage 105. Dramatic increases in insulin content and secretion and insulin gene expression were observed when the switches were made at passages 86 and 92 but not when the switch was made at passage 99. These findings suggest that glucose toxicity of insulin-secreting cells is a continuous rather than a threshold function of glucose concentration and that the shorter the period of antecedent glucose toxicity, the more likely that full recovery of cell function will occur. PMID:11052953

  5. Targeting tumor cell metabolism via the mevalonate pathway: Two hits are better than one

    PubMed Central

    Pandyra, Aleksandra; Penn, Linda Z

    2014-01-01

    Statins are promising anticancer agents that target the mevalonate pathway. Tumor cells are sensitive to depletion of mevalonate-derived products but this activity triggers a homeostatic feedback loop that blunts statin efficacy. We showed that dipyridamole inhibits this feedback response and potentiates statin antitumor activity. This study identifies statins plus dypridamole as a preclinically effective combination of approved agents. PMID:27308369

  6. Cell death-independent functions of granzymes: hit viruses where it hurts.

    PubMed

    van Domselaar, Robert; Bovenschen, Niels

    2011-09-01

    Granule exocytosis by cytotoxic lymphocytes is the key mechanism of our immune response to eliminate virus-infected cells. These lytic granules contain the pore-forming protein perforin and a set of five serine proteases called granzymes (GrA, GrB, GrH, GrK, GrM) that display distinct substrate specificities. Granzymes have mostly been studied for their ability to induce cell death. However, viruses have evolved many inhibitors to effectively block apoptosis. Evidence is emerging that granzymes also use noncytotoxic strategies to inhibit viral replication and potential viral reactivation from latency. Granzymes directly cleave viral or host cell proteins that are required in the viral life cycle. Furthermore, granzymes induce a pro-inflammatory cytokine response to create an antiviral environment. In this review, we summarize and discuss these novel strategies by which the immune system counteracts viral infections, and we will address the potential therapeutic applications that could emerge from this intriguing mechanism. PMID:21714121

  7. Formulation of the Multi-Hit Model With a Non-Poisson Distribution of Hits

    SciTech Connect

    Vassiliev, Oleg N.

    2012-07-15

    Purpose: We proposed a formulation of the multi-hit single-target model in which the Poisson distribution of hits was replaced by a combination of two distributions: one for the number of particles entering the target and one for the number of hits a particle entering the target produces. Such an approach reflects the fact that radiation damage is a result of two different random processes: particle emission by a radiation source and interaction of particles with matter inside the target. Methods and Materials: Poisson distribution is well justified for the first of the two processes. The second distribution depends on how a hit is defined. To test our approach, we assumed that the second distribution was also a Poisson distribution. The two distributions combined resulted in a non-Poisson distribution. We tested the proposed model by comparing it with previously reported data for DNA single- and double-strand breaks induced by protons and electrons, for survival of a range of cell lines, and variation of the initial slopes of survival curves with radiation quality for heavy-ion beams. Results: Analysis of cell survival equations for this new model showed that they had realistic properties overall, such as the initial and high-dose slopes of survival curves, the shoulder, and relative biological effectiveness (RBE) In most cases tested, a better fit of survival curves was achieved with the new model than with the linear-quadratic model. The results also suggested that the proposed approach may extend the multi-hit model beyond its traditional role in analysis of survival curves to predicting effects of radiation quality and analysis of DNA strand breaks. Conclusions: Our model, although conceptually simple, performed well in all tests. The model was able to consistently fit data for both cell survival and DNA single- and double-strand breaks. It correctly predicted the dependence of radiation effects on parameters of radiation quality.

  8. B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas.

    PubMed

    Li, Shaoying; Seegmiller, Adam C; Lin, Pei; Wang, Xuan J; Miranda, Roberto N; Bhagavathi, Sharathkumar; Medeiros, L Jeffrey

    2015-02-01

    Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n=14) or more aggressive chemotherapy regimens (n=17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P=0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P=0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (P<0.01), less frequently expressed CD10 (P<0.01), and patients less often had an elevated serum lactate dehydrogenase level (P=0.01). In aggregate, these results support expanding the category of MYC/BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations. PMID:25103070

  9. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    SciTech Connect

    Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

    2010-07-30

    Research highlights: {yields} GLP-1 prevents AGEs-induced cell death. {yields} GLP-1 prevents AGEs-induced oxidative stress. {yields} GLP-1 ameliorated AGEs-induced cell dysfunction. {yields} GLP-1 attenuates AGEs-induced RAGE increment. {yields} GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  10. "You Have to Get Hit a Couple of Times": The Role of Conflict in Learning How to "Be" a Skateboarder

    ERIC Educational Resources Information Center

    Petrone, Robert

    2010-01-01

    By examining the role of conflict in learning how to "be" a skateboarder at a skate park in the United States, this article illustrates how conflicts constitute key aspects of learning and teaching within communities of practice. Specifically, this article demonstrates how the practices of "snaking" and "heckling" are used by a group of…

  11. The SVT Hit Buffer

    SciTech Connect

    Belforte, S.; Dell`Orso, M.; Donati, S.

    1996-06-01

    The Hit Buffer is part of the Silicon Vertex Tracker, a trigger processor dedicated to the reconstruction of particle trajectories in the Silicon Vertex Detector and the Central Tracking Chamber of the Collider Detector at Fermilab. The Hit Buffer is a high speed data-traffic node, where thousands of words are received in arbitrary order and simultaneously organized in an internal structured data base, to be later promptly retrieved and delivered in response to specific requests. The Hit Buffer is capable of processing data at a rate of 25 MHz, thanks to the use of special fast devices like Cache-Tag RAMs and high performance Erasable Programmable Logic Devices from the XILINX XC7300 family.

  12. LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes

    PubMed Central

    Carlson, Hanqian L.; Quinn, Jeffrey J.; Yang, Yul W.; Thornburg, Chelsea K.; Chang, Howard Y.; Stadler, H. Scott

    2015-01-01

    Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage. PMID:26633036

  13. But Can You Hit?

    ERIC Educational Resources Information Center

    Johnson, R. E.

    2009-01-01

    The author shares a story told to him by a colleague more than thirty years ago. The dean of a midsized American university was explaining the path to tenure to a roomful of newly appointed assistant professors. "We know you boys can all "field"," he declared. "Now we want to see if you can hit." A lot has changed over the intervening decades. If…

  14. Simulation and study of the influence of the buffer intrinsic layer, back-surface field, densities of interface defects, resistivity of p-type silicon substrate and transparent conductive oxide on heterojunction with intrinsic thin-layer (HIT) solar cell

    SciTech Connect

    Dao, Vinh Ai; Heo, Jongkyu; Choi, Hyungwook; Kim, Yongkuk; Park, Seungman; Jung, Sungwook; Lakshminarayan, Nariangadu; Yi, Junsin

    2010-05-15

    The influence of various parameters such as buffer intrinsic layers, back-surface fields, densities of interface defects (D{sub it}), the resistivity of p-type silicon substrates ({rho}) and then work function of transparent conductive oxide ({phi}{sub TCO}) on heterojunction with intrinsic thin-layer (HIT) solar cell performance was investigated using software simulation. Automat for the simulation of heterostructures (AFORS-HET) software was used for that purpose. Our results indicate that band bending, which is determined by the band offsets at the buffer intrinsic/c-Si and/or the c-Si/back-surface field heterointerface, could be critical to solar cell performance. The effect of band bending on solar cell performance and the dependence of cell performance on {rho} and {phi}{sub TCO} were investigated in detail. Eventually, suggestive design parameters for HIT solar cell fabrication are proposed. (author)

  15. Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death

    PubMed Central

    Ralph, Stephen John; Pritchard, Rhys; Rodríguez-Enríquez, Sara; Moreno-Sánchez, Rafael; Ralph, Raymond Keith

    2015-01-01

    Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs. PMID:25688484

  16. Cosmic ray hit frequencies in critical sites in the central nervous system

    NASA Astrophysics Data System (ADS)

    Curtis, S. B.; Vazquez, M. E.; Wilson, J. W.; Atwell, W.; Kim, M.; Capala, J.

    One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many ``hits'' might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the ``target site'' within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the ``critical sites'' of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 mum^2 or 471 mum^2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells and 55

  17. Cosmic ray hit frequencies in critical sites in the central nervous system.

    PubMed

    Curtis, S B; Vazquez, M E; Wilson, J W; Atwell, W; Kim, M; Capala, J

    1998-01-01

    One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells

  18. Optoelectronic hit/miss transform for screening cervical smear slides

    NASA Astrophysics Data System (ADS)

    Narayanswamy, R.; Turner, R. M.; McKnight, D. J.; Johnson, K. M.; Sharpe, J. P.

    1995-06-01

    An optoelectronic morphological processor for detecting regions of interest (abnormal cells) on a cervical smear slide using the hit/miss transform is presented. Computer simulation of the algorithm tested on 184 Pap-smear images provided 95% detection and 5% false alarm. An optoelectronic implementation of the hit/miss transform is presented, along with preliminary experimental results.

  19. Combined hit theory-microdosimetric explanation of cellular radiobiological action

    SciTech Connect

    Bond, V.P.; Varma, M.N.

    1983-01-01

    Hit theory is combined with microdosimetry in a stochastic approach that explains the observed responses of cell populations exposed in radiation fields of different qualities. The central thesis is that to expose a population of cells in a low-level radiation field is to subject the cells to the potential for interaction with charged particles in the vicinity of the cells, quantifiable in terms of the charged particle fluence theta. When such an interaction occurs there is a resulting stochastic transfer of energy to a critical volume (CV) of cross section sigma, within the cell(s). The severity of cell injury is dependent on the amount of energy thus imparted, or the hit size. If the severity is above some minimal level, there is a non-zero probability that the injury will result in a quantal effect (e.g., a mutational or carcinogenic initial event, cell transformation). A microdosimetric proportional counter, viewed here as a phantom cell CV that permits measurements not possible in the living cell, is used to determine the incidence of hit cells and the spectrum of hit sizes. Each hit is then weighted on the basis of an empirically-determined function that provides the fraction of cells responding quantally, as a function of hit size. The sum of the hits so weighted provides the incidence of quantally-responding cells, for any amount of exposure theta in a radiation field of any quality or mixture qualities. The hit size weighting function for pink mutations in Tradescantia is discussed, as are its implications in terms of a replacement for RBE and dose equivalent. 14 references, 9 figures.

  20. Hurricane Iris Hits Belize

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Hurricane Iris hit the small Central American country of Belize around midnight on October 8, 2001. At the time, Iris was the strongest Atlantic hurricane of the season, with sustained winds up to 225 kilometers per hour (140 mph). The hurricane caused severe damage-destroying homes, flooding streets, and leveling trees-in coastal towns south of Belize City. In addition, a boat of American recreational scuba divers docked along the coast was capsized by the storm, leaving 20 of the 28 passengers missing. Within hours the winds had subsided to only 56 kph (35 mph), a modest tropical depression, but Mexico, Guatemala, El Salvador, and Honduras were still expecting heavy rains. The above image is a combination of visible and thermal infrared data (for clouds) acquired by a NOAA Geostationary Operational Environmental Satellite (GOES-8) on October 8, 2001, at 2:45 p.m., and the Moderate-resolution Imaging Spectroradiometer (MODIS) (for the color of the ground). The three-dimensional view is from the south-southeast (north is towards the upper left). Belize is off the image to the left. Image courtesy Marit Jentoft-Nilsen, NASA GSFC Visualization Analysis Lab

  1. Heat Waves Hit Seniors Hardest

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_160425.html Heat Waves Hit Seniors Hardest Risk of high-temperature trouble ... much of the Northeast struggles with a heat wave that isn't expected to ease until the ...

  2. Hit the spleen, JAK!

    PubMed

    Lane, Steven W; Mullally, Ann

    2014-11-01

    In this issue of Blood, Wang et al report on the response of splenic-derived hematopoietic stem and progenitor cells from patients with myelofibrosis (MF) to the Janus kinase (JAK) inhibitor, AZD1480. PMID:25377558

  3. Postponed Is Not Canceled: Role of Craniospinal Radiation Therapy in the Management of Recurrent Infant Medulloblastoma—An Experience From the HIT-REZ 1997 and 2005 Studies

    SciTech Connect

    Müller, Klaus; Mynarek, Martin; Zwiener, Isabella; Siegler, Nele; Zimmermann, Martina; Christiansen, Hans; Budach, Wilfried; Henke, Guido; Warmuth-Metz, Monika; Pietsch, Torsten; Hoff, Katja von; Bueren, Andre von; Bode, Udo; and others

    2014-04-01

    Purpose: To evaluate the efficacy of craniospinal irradiation (CSI) in the management of recurrent infant medulloblastoma after surgery and chemotherapy alone. Methods and Materials: Seventeen pediatric medulloblastoma patients registered in the HIT-REZ 1997 and 2005 studies underwent CSI as salvage treatment at first recurrence. All patients had achieved complete remission after first-line treatment consisting of surgery and chemotherapy. Eleven patients showed metastatic disease at relapse. Five patients underwent surgery prior to radiation therapy, which resulted in complete resection in 1 case. In 1 patient, complete resection of the residual tumor was performed after CSI. Eleven patients received chemotherapy prior, 6 patients during and 8 patients after CSI. All patients received CSI with a median total dose of 35.2 Gy, and all but 1 received a boost to the posterior fossa (median total dose, 55.0 Gy). Metastases were boosted with an individual radiation dose, depending on their location and extent. Results: During a median follow-up time of 6.2 years since recurrence, 11 patients showed progressive disease and died. Median progression-free (overall) survival was 2.9 ± 1.1 (3.8 ± 0.8) years. Progression-free survival (PFS) rates at 1, 3, and 5 years were 88% ± 8%, 46% ± 12%, and 40% ± 12%, respectively. Overall survival (OS) rates at 1, 3, and 5 years were 94% ± 6%, 58% ± 12%, and 39% ± 12%, respectively. For 11 patients with classic medulloblastoma, 3-year (and 5-year) PFS and OS were 62% ± 15% and 72% ± 14% (52% ± 16% and 51% ± 16%), respectively. On univariate analysis, metastatic disease was not associated with poorer progression-free and overall survival. Conclusions: Our results suggest that salvage treatment of relapsed medulloblastomas consisting of CSI and chemotherapy offers a second chance for cure, even for patients with classic histological findings. Metastatic disease at relapse did not have an impact

  4. Beyond "Hitting the Books"

    ERIC Educational Resources Information Center

    Entress, Cole; Wagner, Aimee

    2014-01-01

    Scientists, science teachers, and serious students recognize that success in science classes requires consistent practice--including study at home. Whether balancing chemical equations, calculating angular momentum, or memorizing the steps of cell division, students must review material repeatedly to fully understand new ideas--and must practice…

  5. Essential role of AKT in tumor cells addicted to FGFR.

    PubMed

    Hu, Yi; Lu, Huiru; Zhang, Jinchao; Chen, Jun; Chai, Zhifang; Zhang, Jingxin

    2014-02-01

    Tumor cells with genetic amplifications or mutations in the fibroblast growth factor receptor (FGFR) family are often addicted to FGFR and heavily dependent on its signaling to survive. Although it is critical to understand which signaling pathway downstream of FGFR plays an essential role to guide the research and development of FGFR inhibitors, it has remained unclear partly because the tool compounds used in the literature also hit many other kinases, making the results difficult to interpret. With the development of a potent FGFR-specific inhibitor, BGJ398, we are now able to dissect various pathways with low drug concentrations to minimize multiple-target effects. Importantly, here, we show that inhibition of FGFR signaling by BGJ398 leads to only transient inhibition of ERK1/2 phosphorylation, whereas the inhibitory effect on AKT phosphorylation is sustainable, indicating that AKT, not ERK as commonly believed, serves as an appropriate pharmacodynamic biomarker for BGJ398. Although AKT inhibition by a pan-PI3K inhibitor alone has almost no effect on cell growth, heterologous expression of myr-AKT, an active form of AKT, rescues BGJ398-mediated suppression of tumor cell proliferation. These results indicate that AKT is an essential component downstream of FGFR. Finally, combination of the FGFR inhibitor BGJ398 with rapamycin significantly inhibits AKT phosphorylation and enhances their antiproliferative effects in FGFR-addicted cells, suggesting an effective combination strategy for clinical development of FGFR inhibitors. PMID:24100276

  6. Car Hits Boy on Bicycle

    ERIC Educational Resources Information Center

    Ruiz, Michael J.

    2005-01-01

    In this article we present the fascinating reconstruction of an accident where a car hit a boy riding his bicycle. The boy dramatically flew several metres through the air after the collision and was injured, but made a swift and complete recovery from the accident with no long-term after-effects. Students are challenged to determine the speed of…

  7. Distributed generation hits market

    SciTech Connect

    1997-10-01

    The pace at which vendors are developing and marketing gas turbines and reciprocating engines for small-scale applications may signal the widespread growth of distributed generation. Loosely defined to refer to applications in which power generation equipment is located close to end users who have near-term power capacity needs, distributed generation encompasses a broad range of technologies and load requirements. Disagreement is inevitable, but many industry observers associate distributed generation with applications anywhere from 25 kW to 25 MW. Ten years ago, distributed generation users only represented about 2% of the world market. Today, that figure has increased to about 4 or 5%, and probably could settle in the 20% range within a 3-to-5-year period, according to Michael Jones, San Diego, Calif.-based Solar Turbines Inc. power generation marketing manager. The US Energy Information Administration predicts about 175 GW of generation capacity will be added domestically by 2010. If 20% comes from smaller plants, distributed generation could account for about 35 GW. Even with more competition, it`s highly unlikely distributed generation will totally replace current market structures and central stations. Distributed generation may be best suited for making market inroads when and where central systems need upgrading, and should prove its worth when the system can`t handle peak demands. Typical applications include small reciprocating engine generators at remote customer sites or larger gas turbines to boost the grid. Additional market opportunities include standby capacity, peak shaving, power quality, cogeneration and capacity rental for immediate demand requirements. Integration of distributed generation systems--using gas-fueled engines, gas-fired combustion engines and fuel cells--can upgrade power quality for customers and reduce operating costs for electric utilities.

  8. Hitting Is Contagious in Baseball: Evidence from Long Hitting Streaks

    PubMed Central

    Bock, Joel R.; Maewal, Akhilesh; Gough, David A.

    2012-01-01

    Data analysis is used to test the hypothesis that “hitting is contagious”. A statistical model is described to study the effect of a hot hitter upon his teammates’ batting during a consecutive game hitting streak. Box score data for entire seasons comprising streaks of length games, including a total observations were compiled. Treatment and control sample groups () were constructed from core lineups of players on the streaking batter’s team. The percentile method bootstrap was used to calculate confidence intervals for statistics representing differences in the mean distributions of two batting statistics between groups. Batters in the treatment group (hot streak active) showed statistically significant improvements in hitting performance, as compared against the control. Mean for the treatment group was found to be to percentage points higher during hot streaks (mean difference increased points), while the batting heat index introduced here was observed to increase by points. For each performance statistic, the null hypothesis was rejected at the significance level. We conclude that the evidence suggests the potential existence of a “statistical contagion effect”. Psychological mechanisms essential to the empirical results are suggested, as several studies from the scientific literature lend credence to contagious phenomena in sports. Causal inference from these results is difficult, but we suggest and discuss several latent variables that may contribute to the observed results, and offer possible directions for future research. PMID:23251507

  9. A Two-Hit Model of Autism: Adolescence as the Second Hit

    PubMed Central

    Picci, Giorgia; Scherf, K. Suzanne

    2015-01-01

    Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a “first hit” that sets up a neural system that is “built to fail” in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the “second hit” that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence. PMID:26609500

  10. Roles of sucrose in guard cell regulation.

    PubMed

    Daloso, Danilo M; Dos Anjos, Leticia; Fernie, Alisdair R

    2016-08-01

    The control of stomatal aperture involves reversible changes in the concentration of osmolytes in guard cells. Sucrose has long been proposed to have an osmolytic role in guard cells. However, direct evidence for such a role is lacking. Furthermore, recent evidence suggests that sucrose may perform additional roles in guard cells. Here, we provide an update covering the multiple roles of sucrose in guard cell regulation, highlighting the knowledge accumulated regarding spatiotemporal differences in the synthesis, accumulation, and degradation of sucrose as well as reviewing the role of sucrose as a metabolic connector between mesophyll and guard cells. Analysis of transcriptomic data from previous studies reveals that several genes encoding sucrose and hexose transporters and genes involved in gluconeogenesis, sucrose and trehalose metabolism are highly expressed in guard cells compared with mesophyll cells. Interestingly, this analysis also showed that guard cells have considerably higher expression of C4 -marker genes than mesophyll cells. We discuss the possible roles of these genes in guard cell function and the role of sucrose in stomatal opening and closure. Finally, we provide a perspective for future experiments which are required to fill gaps in our understanding of both guard cell metabolism and stomatal regulation. PMID:27060199

  11. Improvements to the stand and hit algorithm

    SciTech Connect

    Boneh, A.; Boneh, S.; Caron, R.; Jibrin, S.

    1994-12-31

    The stand and hit algorithm is a probabilistic algorithm for detecting necessary constraints. The algorithm stands at a point in the feasible region and hits constraints by moving towards the boundary along randomly generated directions. In this talk we discuss methods for choosing the standing point. As well, we present the undetected first rule for determining the hit constraints.

  12. Hitting is contagious in baseball: evidence from long hitting streaks.

    PubMed

    Bock, Joel R; Maewal, Akhilesh; Gough, David A

    2012-01-01

    Data analysis is used to test the hypothesis that "hitting is contagious". A statistical model is described to study the effect of a hot hitter upon his teammates' batting during a consecutive game hitting streak. Box score data for entire seasons comprising [Formula: see text] streaks of length [Formula: see text] games, including a total [Formula: see text] observations were compiled. Treatment and control sample groups ([Formula: see text]) were constructed from core lineups of players on the streaking batter's team. The percentile method bootstrap was used to calculate [Formula: see text] confidence intervals for statistics representing differences in the mean distributions of two batting statistics between groups. Batters in the treatment group (hot streak active) showed statistically significant improvements in hitting performance, as compared against the control. Mean [Formula: see text] for the treatment group was found to be [Formula: see text] to [Formula: see text] percentage points higher during hot streaks (mean difference increased [Formula: see text] points), while the batting heat index [Formula: see text] introduced here was observed to increase by [Formula: see text] points. For each performance statistic, the null hypothesis was rejected at the [Formula: see text] significance level. We conclude that the evidence suggests the potential existence of a "statistical contagion effect". Psychological mechanisms essential to the empirical results are suggested, as several studies from the scientific literature lend credence to contagious phenomena in sports. Causal inference from these results is difficult, but we suggest and discuss several latent variables that may contribute to the observed results, and offer possible directions for future research. PMID:23251507

  13. Keratinocyte cytoskeletal roles in cell sheet engineering

    PubMed Central

    2013-01-01

    Background There is an increasing need to understand cell-cell interactions for cell and tissue engineering purposes, such as optimizing cell sheet constructs, as well as for examining adhesion defect diseases. For cell-sheet engineering, one major obstacle to sheet function is that cell sheets in suspension are fragile and, over time, will contract. While the role of the cytoskeleton in maintaining the structure and adhesion of cells cultured on a rigid substrate is well-characterized, a systematic examination of the role played by different components of the cytoskeleton in regulating cell sheet contraction and cohesion in the absence of a substrate has been lacking. Results In this study, keratinocytes were cultured until confluent and cell sheets were generated using dispase to remove the influence of the substrate. The effects of disrupting actin, microtubules or intermediate filaments on cell-cell interactions were assessed by measuring cell sheet cohesion and contraction. Keratin intermediate filament disruption caused comparable effects on cell sheet cohesion and contraction, when compared to actin or microtubule disruption. Interfering with actomyosin contraction demonstrated that interfering with cell contraction can also diminish cell cohesion. Conclusions All components of the cytoskeleton are involved in maintaining cell sheet cohesion and contraction, although not to the same extent. These findings demonstrate that substrate-free cell sheet biomechanical properties are dependent on the integrity of the cytoskeleton network. PMID:23442760

  14. Cutaneous presentation of Double Hit Lymphoma

    PubMed Central

    Khelfa, Yousef; Lebowicz, Yehuda

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), representing approximately 25% of diagnosed NHL. DLBCL is heterogeneous disease both clinically and genetically. The 3 most common chromosomal translocations in DLBCL involve the oncogenes BCL2, BCL6, and MYC. Double hit (DH) DLBCL is an aggressive form in which MYC rearrangement is associated with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass, often with B symptoms. Extranodal disease is often present. Though there is a paucity of prospective trials in this subtype, double hit lymphoma (DHL) has been linked to very poor outcomes when patients are treated with standard R-CHOP. There is, therefore, a lack of consensus regarding the standard treatment for DHL. Several retrospective analyses have been conducted to help guide treatment of this disease. These suggest that DA EPOCH-R may be the most promising regimen and that achievement of complete resolution predicts better long-term outcomes. PMID:27115017

  15. Mitochondrial role in cell aging

    NASA Technical Reports Server (NTRS)

    Miquel, J.; Fleming, J.; Economos, A. C.; Johnson, J. E., Jr.

    1980-01-01

    The experimental studies on the mitochondria of insect and mammalian cells are examined with a view to an analysis of intrinsic mitochondrial senescence, and its relation to the age-related changes in other cell organelles. The fine structural and biochemical data support the concept that the mitochondria of fixed postmitotic cells may be the site of intrinsic aging because of the attack by free radicals and lipid peroxides originating in the organelles as a by-product of oxygen reduction during respiration. Although the cells have numerous mechanisms for counteracting lipid peroxidation injury, there is a slippage in the antioxidant protection. Intrinsic mitochondrial aging could thus be considered as a specific manifestation of oxygen toxicity. It is proposed that free radical injury renders an increasing number of the mitochondria unable to divide, probably because of damage to the lipids of the inner membrane and to mitochondrial DNA.

  16. Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens

    PubMed Central

    Nwaka, Solomon; Besson, Dominique; Ramirez, Bernadette; Maes, Louis; Matheeussen, An; Bickle, Quentin; Mansour, Nuha R.; Yousif, Fouad; Townson, Simon; Gokool, Suzanne; Cho-Ngwa, Fidelis; Samje, Moses; Misra-Bhattacharya, Shailja; Murthy, P. K.; Fakorede, Foluke; Paris, Jean-Marc; Yeates, Clive; Ridley, Robert; Van Voorhis, Wesley C.; Geary, Timothy

    2011-01-01

    New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach. PMID:22247786

  17. HITS - The Navy's new DATPG system

    NASA Astrophysics Data System (ADS)

    Hosley, L.; Modi, M.

    A new digital automatic test program generation standard called HITS (Hierarchical Integrated Test Simulator), developed by the U.S. Navy as the answer to digital LSI/VLSI circuit technology is discussed. Three major areas of the HITS program which include system flow/unique capabilities, modeling language structures, and management of HITS are preseented. HITS contains the following major software modules: the primary model processor, the secondary model processor, the test language processor, the simulator, and the tester output generator. The functions performed by the individual system modules are described. A circuit description language, which provides user flexibility when describing complex circuit models, and its components are considered. The major areas of HITS management include: (1) HITS accessibility, distribution, and availability; (2) user support; (3) advanced development; and (4) Navy/DOD coordination and standardization.

  18. Developing Health Information Technology (HIT) Programs and HIT Curriculum: The Southern Polytechnic State University Experience

    ERIC Educational Resources Information Center

    Zhang, Chi; Reichgelt, Han; Rutherfoord, Rebecca H.; Wang, Andy Ju An

    2014-01-01

    Health Information Technology (HIT) professionals are in increasing demand as healthcare providers need help in the adoption and meaningful use of Electronic Health Record (EHR) systems while the HIT industry needs workforce skilled in HIT and EHR development. To respond to this increasing demand, the School of Computing and Software Engineering…

  19. Hitting Is Contagious: Experience and Action Induction

    ERIC Educational Resources Information Center

    Gray, Rob; Beilock, Sian L.

    2011-01-01

    In baseball, it is believed that "hitting is contagious," that is, probability of success increases if the previous few batters get a hit. Could this effect be partially explained by action induction--that is, the tendency to perform an action related to one that has just been observed? A simulation was used to investigate the effect of inducing…

  20. Recognition of Hits in a Target

    NASA Astrophysics Data System (ADS)

    Semerak, Vojtech; Drahansky, Martin

    This paper describes two possible ways of hit recognition in a target. First method is based on frame differencing with use of a stabilization algorithm to eliminate movements of a target. Second method uses flood fill with random seed point definition to find hits in the target scene.

  1. Antibacterial effects of quaternary bis-phosphonium and ammonium salts of pyridoxine on Staphylococcus aureus cells: A single base hitting two distinct targets?

    PubMed

    Nikitina, Elena V; Zeldi, Marina I; Pugachev, Mikhail V; Sapozhnikov, Sergey V; Shtyrlin, Nikita V; Kuznetsova, Svetlana V; Evtygin, Vladimir E; Bogachev, Mikhail I; Kayumov, Airat R; Shtyrlin, Yurii G

    2016-01-01

    We studied the effects of quaternary bis-phosphonium and bis-ammonium salts of pyridoxine with lipophilic substituents on the survival and morphology of Staphylococcus aureus cells. We found that, while originating from the same base, they exhibit considerably different antimicrobial mechanisms. In the presence of Ca(2+) ions the MIC and MBC values of ammonium salt increased 100-fold, suggesting that Ca(2+) ions can successfully impede the membrane Ca(2+) ions exchange required for ammonium salt incorporation. In contrast, in the presence of quaternary phosphonium salt, the artificial capsular-like material was formed around the cells and the filamentous and chain-like growth of the cells was observed suggesting the disruption of the cell division mechanisms. Altogether, both pyridoxine derivatives successfully inhibited the growth of gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis) and Escherichia coli considerably, while demonstrated nearly no effect against Klebsiella pneumoniae and Pseudomonas aeruginosa. We suggest that due to their effects on distinct and likely complementary targets the derivatives of pyridoxine represent potentially perspective antibacterials with complicated adaptation and thus with lower risk of drug resistance development. PMID:26712620

  2. The role of mast cells in cancers

    PubMed Central

    Maciel, Thiago T.; Moura, Ivan C.

    2015-01-01

    Mast cells are immune cells that accumulate in the tumors and their microenvironment during disease progression. Mast cells are armed with a wide array of receptors that sense environment modifications and, upon stimulation, they are able to secrete several biologically active factors involved in the modulation of tumor growth. For example, mast cells are able to secrete pro-angiogenic and growth factors but also pro- and anti-inflammatory mediators. Recent studies have allowed substantial progress in understanding the role of mast cells in tumorigenesis/disease progression but further studies are necessary to completely elucidate their impact in the pathophysiology of cancer. Here we review observations suggesting that mast cells could modulate tumor growth in humans. We also discuss the drawbacks related to observations from mast cell-deficient mouse models, which could have consequences in the determination of a potential causative relationship between mast cells and cancer. We believe that the understanding of the precise role of mast cells in tumor development and progression will be of critical importance for the development of new targeted therapies in human cancers. PMID:25705392

  3. Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.

    PubMed

    Heinemann, Scott D; Posimo, Jessica M; Mason, Daniel M; Hutchison, Daniel F; Leak, Rehana K

    2016-08-01

    The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies

  4. Rising Blood Sugar Hitting More Obese Adults

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_159853.html Rising Blood Sugar Hitting More Obese Adults To curb diabetes, researchers ... HealthDay News) -- Among obese American adults, control of blood sugar is worsening, leading to more diabetes and heart ...

  5. Role of liver stem cells in hepatocarcinogenesis

    PubMed Central

    Xu, Lei-Bo; Liu, Chao

    2014-01-01

    Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the “cancer stem cell hypothesis”, which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future. PMID:25426254

  6. Plasmacytoid dendritic cell role in cutaneous malignancies.

    PubMed

    Saadeh, Dana; Kurban, Mazen; Abbas, Ossama

    2016-07-01

    Plasmacytoid dendritic cells (pDCs) correspond to a specialized dendritic cell population that exhibit plasma cell morphology, express CD4, CD123, HLA-DR, blood-derived dendritic cell antigen-2 (BDCA-2), and Toll-like receptor (TLR)7 and TLR9 within endosomal compartments. Through their production of type I interferons (IFNs) and other pro-inflammatory cytokines, pDCs provide anti-viral resistance and link the innate and adaptive immunity by controlling the function of myeloid DCs, lymphocytes, and natural killer (NK) cells. While lacking from normal skin, pDCs are usually recruited to the skin in several cutaneous pathologies where they appear to be involved in the pathogenesis of several infectious, inflammatory/autoimmune, and neoplastic entities. Among the latter group, pDCs have the potential to induce anti-tumour immunity; however, the complex interaction of pDCs with tumor cells and their micro-environment appears to contribute to immunologic tolerance. In this review, we aim at highlighting the role played by pDCs in cutaneous malignancies with special emphasis on the underlying mechanisms. PMID:27236509

  7. HIT: time to end behavioral health discrimination.

    PubMed

    Rosenberg, Linda

    2012-10-01

    While the Health Information Technology for Economic and Clinical Health Act, enacted as part of the American Recovery and Reinvestment Act of 2009, provided $20.6 billion for incentive payments to support the adoption and meaningful use of health information technology (HIT), behavioral health organizations were not eligible to receive facility payments. The consequences of excluding behavioral health from HIT incentive payments are found in the results of the "HIT Adoption and Meaningful Use Readiness in Community Behavioral Health" survey. The survey found that only 2% of community behavioral health organizations are able to meet federal meaningful use (MU) requirements-compare this to the 27% of Federally Qualified Health Centers and 20% of hospitals that already meet some level of MU requirements. Behavioral health organizations, serving more than eight million adults, children, and families with mental illnesses and addiction disorders, are ready and eager to adopt HIT to meet the goals of better healthcare, better health, and lower costs. But reaching these goals may prove impossible unless behavioral health achieves "parity" within healthcare and receives resources for the adoption of HIT. PMID:22956203

  8. Hitting is contagious: experience and action induction.

    PubMed

    Gray, Rob; Beilock, Sian L

    2011-03-01

    In baseball, it is believed that "hitting is contagious," that is, probability of success increases if the previous few batters get a hit. Could this effect be partially explained by action induction--that is, the tendency to perform an action related to one that has just been observed? A simulation was used to investigate the effect of inducing stimuli on batting performance for more-experienced (ME) and less-experienced (LE) baseball players. Three types of inducing stimuli were compared with a no-induction condition: action (a simulated ball traveling from home plate into left, right, or center field), outcome (a ball resting in either left, right, or center field), and verbal (the word "left", "center", or "right"). For both ME and LE players, fewer pitchers were required for a successful hit in the action condition. For ME players, there was a significant relationship between the inducing stimulus direction and hit direction for both the action and outcome prompts. For LE players, the prompt only had a significant effect on batting performance in the action condition, and the magnitude of the effect was significantly smaller than for ME. The effect of the inducing stimulus decreased as the delay (i.e., no. of pitches between prompt and hit) increased, with the effect being eliminated after roughly 4 pitches for ME and 2 pitches for LE. It is proposed that the differences in the magnitude and time course of action induction as a function of experience occurred because ME have more well-developed perceptual-motor representations for directional hitting. PMID:21443380

  9. Role of polyphenols in cell death control.

    PubMed

    Giovannini, Claudio; Masella, Roberta

    2012-05-01

    Dietary consumption of fruit, vegetables, fish, and olive oil has been demonstrated to exert beneficial effects on human health. This finding may be due to the high content of antioxidant compounds including polyphenols. Current evidence strongly supports a contribution of polyphenols to the prevention of several chronic degenerative diseases such as cancer, atherosclerosis and cardiovascular diseases, central nervous system disorders, as well as aging. Apoptosis is a genetically controlled and evolutionarily conserved form of cell death of critical importance for the maintenance of tissue homeostasis in the adult organism. The malfunction of the death machinery may play a primary role in various pathologic processes, leading to proliferative or degenerative diseases. Polyphenols can interact with specific steps and/or proteins regulating the apoptotic process in different ways depending on their concentration, the cell system, the type or stage of the pathological process. Because of their ability to modulate cell death, polyphenols have been proposed as chemopreventive and therapeutic agents. This paper reviews and discusses the last 3-year findings related to the principal molecular mechanisms involved in the control of the balance between apoptosis and cell proliferation exerted by polyphenols. PMID:22584012

  10. Evidence for a one-hit theory in the immune bactericidal reaction and demonstration of a multi-hit response for hemolysis by streptolysin O and Clostridium perfringens theta-toxin.

    PubMed Central

    Inoue, K; Akiyama, Y; Kinoshita, T; Higashi, Y; Amano, T

    1976-01-01

    An analytical method was developed for estimating the number of hits necessary to lyse or kill cells in which various concentrations of the cells are treated with a constant amount of the lytic or killing agent in a constant reaction volume. The reaction may be due to a single-component agent or occur by a sequential chain of reactions due to a multi-component agent, even including side, abortive, or counter-reactions. It was clearly shown by this method that immune bactericidal reactions followed a one-hit theory. It was shown by this method that streptolysin O required four or five hits for hemolysis and Clostridium perfringens theta-toxin required two hits. These results were confirmed by both logarithmic dose-response and survival analyses. It was also shown that streptolysin O and theta-toxin can act complementarily on accumulation of the hits for hemolysis. PMID:177364

  11. Statistical properties and pre-hit dynamics of price limit hits in the Chinese stock markets.

    PubMed

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders' short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners. PMID:25874716

  12. Statistical Properties and Pre-Hit Dynamics of Price Limit Hits in the Chinese Stock Markets

    PubMed Central

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders’ short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners. PMID:25874716

  13. Improvements of HITS Algorithms for Spam Links

    NASA Astrophysics Data System (ADS)

    Asano, Yasuhito; Tezuka, Yu; Nishizeki, Takao

    The HITS algorithm proposed by Kleinberg is one of the representative methods of scoring Web pages by using hyperlinks. In the days when the algorithm was proposed, most of the pages given high score by the algorithm were really related to a given topic, and hence the algorithm could be used to find related pages. However, the algorithm and the variants including Bharat's improved HITS, abbreviated to BHITS, proposed by Bharat and Henzinger cannot be used to find related pages any more on today's Web, due to an increase of spam links. In this paper, we first propose three methods to find “linkfarms,” that is, sets of spam links forming a densely connected subgraph of a Web graph. We then present an algorithm, called a trust-score algorithm, to give high scores to pages which are not spam pages with a high probability. Combining the three methods and the trust-score algorithm with BHITS, we obtain several variants of the HITS algorithm. We ascertain by experiments that one of them, named TaN+BHITS using the trust-score algorithm and the method of finding linkfarms by employing name servers, is most suitable for finding related pages on today's Web. Our algorithms take time and memory no more than those required by the original HITS algorithm, and can be executed on a PC with a small amount of main memory.

  14. Precise timing when hitting falling balls

    PubMed Central

    Brenner, Eli; Driesen, Ben; Smeets, Jeroen B. J.

    2014-01-01

    People are extremely good at hitting falling balls with a baseball bat. Despite the ball's constant acceleration, they have been reported to time hits with a standard deviation of only about 7 ms. To examine how people achieve such precision, we compared performance when there were no added restrictions, with performance when looking with one eye, when vision was blurred, and when various parts of the ball's trajectory were hidden from view. We also examined how the size of the ball and varying the height from which it was dropped influenced temporal precision. Temporal precision did not become worse when vision was blurred, when the ball was smaller, or when balls falling from different heights were randomly interleaved. The disadvantage of closing one eye did not exceed expectations from removing one of two independent estimates. Precision was higher for slower balls, but only if the ball being slower meant that one saw it longer before the hit. It was particularly important to see the ball while swinging the bat. Together, these findings suggest that people time their hits so precisely by using the changing elevation throughout the swing to adjust the bat's movement to that of the ball. PMID:24904380

  15. Precise timing when hitting falling balls.

    PubMed

    Brenner, Eli; Driesen, Ben; Smeets, Jeroen B J

    2014-01-01

    People are extremely good at hitting falling balls with a baseball bat. Despite the ball's constant acceleration, they have been reported to time hits with a standard deviation of only about 7 ms. To examine how people achieve such precision, we compared performance when there were no added restrictions, with performance when looking with one eye, when vision was blurred, and when various parts of the ball's trajectory were hidden from view. We also examined how the size of the ball and varying the height from which it was dropped influenced temporal precision. Temporal precision did not become worse when vision was blurred, when the ball was smaller, or when balls falling from different heights were randomly interleaved. The disadvantage of closing one eye did not exceed expectations from removing one of two independent estimates. Precision was higher for slower balls, but only if the ball being slower meant that one saw it longer before the hit. It was particularly important to see the ball while swinging the bat. Together, these findings suggest that people time their hits so precisely by using the changing elevation throughout the swing to adjust the bat's movement to that of the ball. PMID:24904380

  16. Science hit by US government crisis

    NASA Astrophysics Data System (ADS)

    Gwynne, Peter

    2013-11-01

    A 16-day government shutdown last month hit the US physics community hard as research projects ranging from space missions to polar geophysics were closed down after Congress failed to vote on its budget for the financial year 2014, which started on 1 October.

  17. Spirit Hits a Home Run

    NASA Technical Reports Server (NTRS)

    2006-01-01

    This week, NASA's Mars Exploration Rover Spirit arrived at 'Home Plate,' a feature that, when seen from orbit, looks like the home plate of a baseball diamond. Home Plate is a roughly circular feature about 80 meters (260 feet) in diameter that might be an old impact crater or volcanic feature. The Spirit team has been eager to get to Home Plate and has been enjoying distant views of the feature and a curious 'bathtub ring' of light-colored materials along its edges. The team has pushed the rover hard to get here before the deep Martian winter sets in.

    After scientists had identified Home Plate from orbit, they had many theories about what it could be and what they might see. But when Spirit's panoramic camera (Pancam) took this and other images, the science team was stunned. This Pancam image is of an outcrop nicknamed 'Barnhill' and surrounding rocks on the north side of Home Plate, showing the most spectacular layering that Spirit has seen.

    Pancam and microscopic imager views of the layers in the rocks reveal a range of grain sizes and textures that change from the lower to the upper part of the outcrop. This may help scientists figure out how the material was emplaced. Spirit is also conducting work with its arm instruments to figure out the chemistry and mineralogy of the rocks. Scientists have several hypotheses about what Home Plate could be, including features made by volcanoes and impact craters, and ways that water could have played a role. They are busy trying to figure out what the data from Spirit is really telling us.

    As Spirit works at Home Plate during February, the science team is choosing informal names for rocks from the great players and managers of the Negro Leagues of baseball. This outcrop, 'Barnhill,' is informally named for David Barnhill, the ace of the New York Cubans' pitching staff during the early 1940s. He compiled an 18-3 record in 1941 and defeated Satchel Paige in the 1942 East-West all-star game. Other rocks in

  18. Physical role for the nucleus in cell migration

    NASA Astrophysics Data System (ADS)

    Fruleux, Antoine; Hawkins, Rhoda J.

    2016-09-01

    Cell migration is important for the function of many eukaryotic cells. Recently the nucleus has been shown to play an important role in cell motility. After giving an overview of cell motility mechanisms we review what is currently known about the mechanical properties of the nucleus and the connections between it and the cytoskeleton. We also discuss connections to the extracellular matrix and mechanotransduction. We identify key physical roles of the nucleus in cell migration.

  19. Physical role for the nucleus in cell migration.

    PubMed

    Fruleux, Antoine; Hawkins, Rhoda J

    2016-09-14

    Cell migration is important for the function of many eukaryotic cells. Recently the nucleus has been shown to play an important role in cell motility. After giving an overview of cell motility mechanisms we review what is currently known about the mechanical properties of the nucleus and the connections between it and the cytoskeleton. We also discuss connections to the extracellular matrix and mechanotransduction. We identify key physical roles of the nucleus in cell migration. PMID:27406341

  20. Hitting and trapping times on branched structures

    NASA Astrophysics Data System (ADS)

    Agliari, Elena; Sartori, Fabio; Cattivelli, Luca; Cassi, Davide

    2015-05-01

    In this work we consider a simple random walk embedded in a generic branched structure and we find a close-form formula to calculate the hitting time H (i ,f ) between two arbitrary nodes i and j . We then use this formula to obtain the set of hitting times {H (i,f)} for combs and their expectation values, namely, the mean first-passage time, where the average is performed over the initial node while the final node f is given, and the global mean first-passage time, where the average is performed over both the initial and the final node. Finally, we discuss applications in the context of reaction-diffusion problems.

  1. Probability of Brownian motion hitting an obstacle

    SciTech Connect

    Knessl, C.; Keller, J.B.

    2000-02-01

    The probability p(x) that Brownian motion with drift, starting at x, hits an obstacle is analyzed. The obstacle {Omega} is a compact subset of R{sup n}. It is shown that p(x) is expressible in terms of the field U(x) scattered by {Omega} when it is hit by plane wave. Therefore results for U(x), and methods for finding U(x) can be used to determine p(x). The authors illustrate this by obtaining exact and asymptotic results for p(x) when {Omega} is a slit in R{sup 2}, and asymptotic results when {Omega} is a disc in R{sup 3}.

  2. Hitting and trapping times on branched structures.

    PubMed

    Agliari, Elena; Sartori, Fabio; Cattivelli, Luca; Cassi, Davide

    2015-05-01

    In this work we consider a simple random walk embedded in a generic branched structure and we find a close-form formula to calculate the hitting time H(i,f) between two arbitrary nodes i and j. We then use this formula to obtain the set of hitting times {H(i,f)} for combs and their expectation values, namely, the mean first-passage time, where the average is performed over the initial node while the final node f is given, and the global mean first-passage time, where the average is performed over both the initial and the final node. Finally, we discuss applications in the context of reaction-diffusion problems. PMID:26066144

  3. Visual factors in hitting and catching.

    PubMed

    Regan, D

    1997-12-01

    To hit or catch an approaching ball, it is necessary to move a bat or hand to the right place at the right time. The performance of top sports players is remarkable: positional errors of less than 5 cm and temporal errors of less than 2 or 3 ms are reliably maintained. There are three schools of thought about how this is achieved. One holds that predictive visual information about where the ball will be at some future instance (when) is used to achieve the hit or catch. The second holds that the bat or hand is moved to the correct position by exploiting some relation between visual information and the required movement. The third focuses on the use of prior knowledge to supplement inadequate visual information. For a rigid spherical ball travelling at constant speed along or close to the line of sight, the retinal images contain both binocular and monocular correlates of the ball's instantaneous direction of motion in depth. Also, the retinal images contain both binocular and monocular information about time of arrival. Humans can unconfound and use this visual information, but they are unable to estimate the absolute distance of the ball or its approach speed other than crudely. In cricket, this visual inadequacy allows a slow bowler to cause the batsman to misjudge where the ball will hit the ground. Such a bowler uses a three-pronged strategy: first, to deliver the ball in such a way as to prevent the batsman from obtaining the necessary visual information until it is too late to react; secondly, to force the batsman to rely entirely on inadequate retinal image information; thirdly, to allow the batsman to learn a particular relationship between the early part of the ball's flight and the point where the ball hits the ground, and then to change the relationship with such skill that the batsman does not detect the change. PMID:9486432

  4. Boolean computation of optimum hitting sets

    SciTech Connect

    Hulme, B.L.; Baca, L.S.; Shiver, A.W.; Worrell, R.B.

    1984-04-01

    This report presents the results of computational experience in solving weighted hitting set problems by Boolean algebraic methods. The feasible solutions are obtained by Boolean formula manipulations, and the optimum solutions are obtained by comparing the weight sums of the feasible solutions. Both the algebra and the optimization can be accomplished using the SETS language. One application is to physical protection problems. 8 references, 2 tables.

  5. Role of Calmodulin in Cell Proliferation

    NASA Technical Reports Server (NTRS)

    Chafouleas, J.

    1983-01-01

    Calmodulin levels were found to increase as cells enter plateau. The data suggest that the cells are exiting the cell cycle late in the G sub 1 phase, or that the calmodulin levels in plateau cells are uncoupled to progression into S phase in plateau cells. Upon release, calmodulin levels rapidly decrease. Following this decrease, there is a increase prior to S phase.

  6. Hitting a baseball: a biomechanical description.

    PubMed

    Welch, C M; Banks, S A; Cook, F F; Draovitch, P

    1995-11-01

    A tremendous amount of time and energy has been dedicated to the development of conditioning programs, mechanics drills, and rehabilitation protocols for the throwing athlete. In comparison, a significantly smaller amount has been spent on the needs of the hitting athlete. Before these needs can be addressed, an understanding of mechanics and the demands placed on the body during the swing must be developed. This study uses three-dimensional kinematic and kinetic data to define and quantify biomechanics during the baseball swing. The results show that a hitter starts the swing with a weight shift toward the rear foot and the generation of trunk coil. As the hitter strides forward, force applied by the front foot equal to 123% of body weight promotes segment acceleration around the axis of the trunk. The hip segment rotates to a maximum speed of 714 degrees/sec followed by a maximum shoulder segment velocity of 937 degrees/sec. The product of this kinetic link is a maximum linear bat velocity of 31 m/sec. By quantifying the hitting motion, a more educated approach can be made in developing rehabilitation, strength, and conditioning programs for the hitting athlete. PMID:8580946

  7. Prohibitin( PHB) roles in granulosa cell physiology.

    PubMed

    Chowdhury, Indrajit; Thomas, Kelwyn; Thompson, Winston E

    2016-01-01

    Ovarian granulosa cells (GC) play an important role in the growth and development of the follicle in the process known as folliculogenesis. In the present review, we focus on recent developments in prohibitin (PHB) research in relation to GC physiological functions. PHB is a member of a highly conserved eukaryotic protein family containing the repressor of estrogen activity (REA)/stomatin/PHB/flotillin/HflK/C (SPFH) domain (also known as the PHB domain) found in diverse species from prokaryotes to eukaryotes. PHB is ubiquitously expressed in a circulating free form or is present in multiple cellular compartments including mitochondria, nucleus and plasma membrane. In mitochondria, PHB is anchored to the mitochondrial inner membrane and forms complexes with the ATPases associated with proteases having diverse cellular activities. PHB continuously shuttles between the mitochondria, cytosol and nucleus. In the nucleus, PHB interacts with various transcription factors and modulates transcriptional activity directly or through interactions with chromatin remodeling proteins. Many functions have been attributed to the mitochondrial and nuclear PHB complexes such as cellular differentiation, anti-proliferation, morphogenesis and maintenance of the functional integrity of the mitochondria. However, to date, the regulation of PHB expression patterns and GC physiological functions are not completely understood. PMID:26496733

  8. Interleukin 33: A Switch-Hitting Cytokine

    PubMed Central

    Villarreal, Daniel O.; Weiner, David B.

    2014-01-01

    For many years IL-33 has been widely studied in the context of T helper type 2 (TH2)-driven inflammatory disorders. Interestingly, IL-33 has now emerged as a cytokine with a plethora of pleiotropic properties. Depending on the immune cells targeted by IL-33, it is reported to not only promote TH2 immunity, but also to induce T helper type 1 (TH1) immunity. Furthermore, recent studies have revealed that IL-33 can activate CD8+ T cells. These new studies provide evidence for its beneficial role in antiviral and antitumor immunity. Here we review the evidence of IL-33 to drive protective T cell immunity plus its potential use as an adjuvant in vaccination and tumor therapy. PMID:24762410

  9. Being selective at the plate: processing dependence between perceptual variables relates to hitting goals and performance.

    PubMed

    Gray, Rob

    2013-08-01

    Performance of a skill that involves acting on a goal object (e.g., a ball to be hit) can influence one's judgment of the size and speed of that object. The present study examined how these action-specific effects are affected when the goal of the actor is varied and they are free to choose between alternative actions. In Experiment 1, expert baseball players were asked to perform three different directional hitting tasks in a batting simulation and make interleaved perceptual judgments about three ball parameters (speed, plate crossing location, and size). Perceived ball size was largest (and perceived speed was slowest) when the ball crossing location was optimal for the particular hitting task the batter was performing (e.g., an "outside" pitch for opposite-field hitting). The magnitude of processing dependency between variables (speed vs. location and size vs. location) was positively correlated with batting performance. In Experiment 2, the action-specific effects observed in Experiment 1 were mimicked by systematically changing the ball diameter in the simulation as a function of plate crossing location. The number of swing initiations was greater when ball size was larger, and batters were more successful in the hitting task for which the larger pitches were optimal (e.g., greater number of pull hits than opposite-field hits when "inside" pitches were larger). These findings suggest attentional accentuation of goal-relevant targets underlies action-related changes in perception and are consistent with an action selection role for these effects. PMID:23163787

  10. Health Information Technology Knowledge and Skills Needed by HIT Employers

    PubMed Central

    Fenton, S.H.; Gongora-Ferraez, M.J.; Joost, E.

    2012-01-01

    Objective To evaluate the health information technology (HIT) workforce knowledge and skills needed by HIT employers. Methods Statewide face-to-face and online focus groups of identified HIT employer groups in Austin, Brownsville, College Station, Dallas, El Paso, Houston, Lubbock, San Antonio, and webinars for rural health and nursing informatics. Results HIT employers reported needing an HIT workforce with diverse knowledge and skills ranging from basic to advanced, while covering information technology, privacy and security, clinical practice, needs assessment, contract negotiation, and many other areas. Consistent themes were that employees needed to be able to learn on the job and must possess the ability to think critically and problem solve. Many employers wanted persons with technical skills, yet also the knowledge and understanding of healthcare operations. Conclusion The HIT employer focus groups provided valuable insight into employee skills needed in this fast-growing field. Additionally, this information will be utilized to develop a statewide HIT workforce needs assessment survey. PMID:23646090

  11. Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides.

    PubMed

    Floyd, David M; Stein, Philip; Wang, Zheng; Liu, Jian; Castro, Steve; Clark, Julie A; Connelly, Michele; Zhu, Fangyi; Holbrook, Gloria; Matheny, Amy; Sigal, Martina S; Min, Jaeki; Dhinakaran, Rajkumar; Krishnan, Senthil; Bashyum, Sridevi; Knapp, Spencer; Guy, R Kiplin

    2016-09-01

    Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate. PMID:27505686

  12. Roles of membrane trafficking in plant cell wall dynamics

    PubMed Central

    Ebine, Kazuo; Ueda, Takashi

    2015-01-01

    The cell wall is one of the characteristic components of plant cells. The cell wall composition differs among cell types and is modified in response to various environmental conditions. To properly generate and modify the cell wall, many proteins are transported to the plasma membrane or extracellular space through membrane trafficking, which is one of the key protein transport mechanisms in eukaryotic cells. Given the diverse composition and functions of the cell wall in plants, the transport of the cell wall components and proteins that are involved in cell wall-related events could be specialized for each cell type, i.e., the machinery for cell wall biogenesis, modification, and maintenance could be transported via different trafficking pathways. In this review, we summarize the recent progress in the current understanding of the roles and mechanisms of membrane trafficking in plant cells and focus on the biogenesis and regulation of the cell wall. PMID:26539200

  13. Roles of imprinted genes in neural stem cells.

    PubMed

    Hoffmann, Anke; Daniel, Guillaume; Schmidt-Edelkraut, Udo; Spengler, Dietmar

    2014-01-01

    Imprinted genes and neural stem cells (NSC) play an important role in the developing and mature brain. A central theme of imprinted gene function in NSCs is cell survival and G1 arrest to control cell division, cell-cycle exit, migration and differentiation. Moreover, genomic imprinting can be epigenetically switched off at some genes to ensure stem cell quiescence and differentiation. At the genome scale, imprinted genes are organized in dynamic networks formed by interchromosomal interactions and transcriptional coregulation of imprinted and nonimprinted genes. Such multilayered networks may synchronize NSC activity with the demand from the niche resembling their roles in adjusting fetal size. PMID:25431944

  14. T follicular helper cell differentiation, function, and roles in disease

    PubMed Central

    Crotty, Shane

    2014-01-01

    Summary Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. Tfh cell differentiation is a multi-stage, multi-factorial process involving B cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh cell biology, including their differentiation, migration, transcriptional regulation, and B cell help functions. Tfh cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh cells to improve vaccination strategies. Tfh cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh cell biology in the interest of applying that knowledge to biomedical needs. PMID:25367570

  15. The role of the bi-compartmental stem cell niche in delaying cancer

    NASA Astrophysics Data System (ADS)

    Shahriyari, Leili; Komarova, Natalia L.

    2015-10-01

    In recent years, by using modern imaging techniques, scientists have found evidence of collaboration between different types of stem cells (SCs), and proposed a bi-compartmental organization of the SC niche. Here we create a class of stochastic models to simulate the dynamics of such a heterogeneous SC niche. We consider two SC groups: the border compartment, S1, is in direct contact with transit-amplifying (TA) cells, and the central compartment, S2, is hierarchically upstream from S1. The S1 SCs differentiate or divide asymmetrically when the tissue needs TA cells. Both groups proliferate when the tissue requires SCs (thus maintaining homeostasis). There is an influx of S2 cells into the border compartment, either by migration, or by proliferation. We examine this model in the context of double-hit mutant generation, which is a rate-limiting step in the development of many cancers. We discover that this type of a cooperative pattern in the stem niche with two compartments leads to a significantly smaller rate of double-hit mutant production compared with a homogeneous, one-compartmental SC niche. Furthermore, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs, consistent with the literature. Finally, the optimal architecture (which minimizes the rate of double-hit mutant production) requires a large proliferation rate of S1 cells along with a small, but non-zero, proliferation rate of S2 cells. This result is remarkably similar to the niche structure described recently by several authors, where one of the two SC compartments was found more actively engaged in tissue homeostasis and turnover, while the other was characterized by higher levels of quiescence (but contributed strongly to injury recovery). Both numerical and analytical results are presented.

  16. The role of fuel cells in NASA's space power systems

    NASA Technical Reports Server (NTRS)

    Been, J. F.

    1979-01-01

    A history of the fuel cell technology is presented and compared with NASA's increasing space power requirements. The role of fuel cells is discussed in perspective with other energy storage systems applicable for space using such criteria as type of mission, weight, reliability, costs, etc. Potential applications of space fuel cells with projected technology advances were examined.

  17. A protective role of mast cells in intestinal tumorigenesis.

    PubMed

    Sinnamon, Mark J; Carter, Kathy J; Sims, Lauren P; Lafleur, Bonnie; Fingleton, Barbara; Matrisian, Lynn M

    2008-04-01

    Mast cells have been observed in numerous types of tumors; however, their role in carcinogenesis remains poorly understood. The majority of epidemiological evidence suggests a negative association between the presence of mast cells and tumor progression in breast, lung and colonic neoplasms. Intestinal adenomas in the multiple intestinal neoplasia (Min, APC(Min/+)) mouse displayed increased numbers of mast cells and increased abundance of mast cell-associated proteinases as determined by transcriptional profiling with the Hu/Mu ProtIn microarray. To examine the role of mast cells in intestinal tumorigenesis, a mutant mouse line deficient in mast cells, Sash mice (c-kit(W-sh/W-sh)), was crossed with the Min mouse, a genetic model of intestinal neoplasia. The resulting mast cell-deficient Min-Sash mice developed 50% more adenomas than littermate controls and the tumors were 33% larger in Min-Sash mice. Mast cell deficiency did not affect tumor cell proliferation; however, apoptosis was significantly inhibited in mast cell-deficient mice. Mast cells have been shown to act as critical upstream regulators of numerous inflammatory cells. Neutrophil, macrophage and T cell populations were similar between Min and Min-Sash mice; however, eosinophils were significantly less abundant in tumors obtained from Min-Sash animals. These results indicate a protective, antitumor role of mast cells in a genetic model of early-stage intestinal tumorigenesis. PMID:18258601

  18. Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).

    PubMed

    Cai, Zheng; Zhu, Zhiqiang; Greene, Mark I; Cines, Douglas B

    2016-07-01

    Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease. PMID:26970483

  19. 77 FR 32639 - HIT Standards Committee and HIT Policy Committee; Call for Nominations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-01

    ... Committee was established under the American Recovery and Reinvestment ] Act 2009 (ARRA)(Pub. L. 111-5... participating in payment reform initiatives, accountable care organizations, pharmacists, behavioral health.... The HIT Policy Committee was established under the American Recovery and Reinvestment Act 2009...

  20. 77 FR 23250 - HIT Standards Committee; Schedule for the Assessment of HIT Policy Committee Recommendations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-18

    ... timeline, which may also account for NIST testing, where appropriate, and include dates when the HIT... timeline provided by the subcommittee, and, if necessary, revise it; and (2) Assign subcommittee(s) to... in a timely manner. (C) Advise the National Coordinator, consistent with the accepted timeline in...

  1. 76 FR 25355 - HIT Standards Committee; Schedule for the Assessment of HIT Policy Committee Recommendations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-04

    ... gaps; and (3) A timeline, which may also account for NIST testing, where appropriate, and include dates...) Upon receipt of a subcommittee report, the HIT Standards Committee will: (1) Accept the timeline... timely manner. (C) Advise the National Coordinator, consistent with the accepted timeline in (B)(1)...

  2. HitKeeper, a generic software package for hit list management

    PubMed Central

    Hau, Jörg; Muller, Michael; Pagni, Marco

    2007-01-01

    Background The automated annotation of biological sequences (protein, DNA) relies on the computation of hits (predicted features) on the sequences using various algorithms. Public databases of biological sequences provide a wealth of biological "knowledge", for example manually validated annotations (features) that are located on the sequences, but mining the sequence annotations and especially the predicted and curated features requires dedicated tools. Due to the heterogeneity and diversity of the biological information, it is difficult to handle redundancy, frequent updates, taxonomic information and "private" data together with computational algorithms in a common workflow. Results We present HitKeeper, a software package that controls the fully automatic handling of multiple biological databases and of hit list calculations on a large scale. The software implements an asynchronous update system that introduces updates and computes hits as soon as new data become available. A query interface enables the user to search sequences by specifying constraints, such as retrieving sequences that contain specific motifs, or a defined arrangement of motifs ("metamotifs"), or filtering based on the taxonomic classification of a sequence. Conclusion The software provides a generic and modular framework to handle the redundancy and incremental updates of biological databases, and an original query language. It is published under the terms and conditions of version 2 of the GNU Public License and available at . PMID:17391514

  3. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas.

    PubMed

    Sarkozy, Clémentine; Traverse-Glehen, Alexandra; Coiffier, Bertrand

    2015-11-01

    Double-hit lymphoma (DHL) is a subgroup of aggressive lymphomas with both MYC and BCL2 gene rearrangements, characterised by a rapidly progressing clinical course that is refractory to aggressive treatment and short survival. Over time, the definition was modified and now includes diffuse large B-cell lymphoma (DLBCL) with MYC translocation combined with an additional translocation involving BCL2 or BCL6. Some cases that have a similar clinical course with concomitant overexpression of MYC or BCL2 proteins were recently characterised as immunohistochemical double-hit lymphomas (ie, double-protein-expression lymphomas [DPLs]). The clinical course of these DPLs is worse than so-called standard DLBCL but suggested by some studies to be slightly better than DHL, although there is overlap between the two categories. Present treatment does not allow cure or long-term survival in patients with genetic or immunohistochemical double-hit lymphomas, but several new drugs are being developed. PMID:26545844

  4. Mast cells: potential positive and negative roles in tumor biology.

    PubMed

    Marichal, Thomas; Tsai, Mindy; Galli, Stephen J

    2013-11-01

    Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors. PMID:24777963

  5. Protective role of Th17 cells in pulmonary infection.

    PubMed

    Rathore, Jitendra Singh; Wang, Yan

    2016-03-18

    Th17 cells are characterized as preferential producer of interleukins including IL-17A, IL-17F, IL-21 and IL-22. Corresponding receptors of these cytokines are expressed on number of cell types found in the mucosa, including epithelial cells and fibroblasts which constitute the prime targets of the Th17-associated cytokines. Binding of IL-17 family members to their corresponding receptors lead to modulation of antimicrobial functions of target cells including alveolar epithelial cells. Stimulated alveolar epithelial cells produce antimicrobial peptides and are involved in granulepoesis, neutrophil recruitment and tissue repair. Mucosal immunity mediated by Th17 cells is protective against numerous pulmonary pathogens including extracellular bacterial and fungal pathogens. This review focuses on the protective role of Th17 cells during pulmonary infection, highlighting subset differentiation, effector cytokines production, followed by study of the binding of these cytokines to their corresponding receptors, the subsequent signaling pathway they engender and their effector role in host defense. PMID:26878294

  6. Imidazolopiperazines: hit to lead optimization of new antimalarial agents.

    PubMed

    Wu, Tao; Nagle, Advait; Kuhen, Kelli; Gagaring, Kerstin; Borboa, Rachel; Francek, Caroline; Chen, Zhong; Plouffe, David; Goh, Anne; Lakshminarayana, Suresh B; Wu, Jeanette; Ang, Hui Qing; Zeng, Peiting; Kang, Min Low; Tan, William; Tan, Maria; Ye, Nicole; Lin, Xuena; Caldwell, Christopher; Ek, Jared; Skolnik, Suzanne; Liu, Fenghua; Wang, Jianling; Chang, Jonathan; Li, Chun; Hollenbeck, Thomas; Tuntland, Tove; Isbell, John; Fischli, Christoph; Brun, Reto; Rottmann, Matthias; Dartois, Veronique; Keller, Thomas; Diagana, Thierry; Winzeler, Elizabeth; Glynne, Richard; Tully, David C; Chatterjee, Arnab K

    2011-07-28

    Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development. PMID:21644570

  7. Biofilms’ Role in Planktonic Cell Proliferation

    PubMed Central

    Bester, Elanna; Wolfaardt, Gideon M.; Aznaveh, Nahid B.; Greener, Jesse

    2013-01-01

    The detachment of single cells from biofilms is an intrinsic part of this surface-associated mode of bacterial existence. Pseudomonas sp. strain CT07gfp biofilms, cultivated in microfluidic channels under continuous flow conditions, were subjected to a range of liquid shear stresses (9.42 mPa to 320 mPa). The number of detached planktonic cells was quantified from the effluent at 24-h intervals, while average biofilm thickness and biofilm surface area were determined by confocal laser scanning microscopy and image analysis. Biofilm accumulation proceeded at the highest applied shear stress, while similar rates of planktonic cell detachment was maintained for biofilms of the same age subjected to the range of average shear rates. The conventional view of liquid-mediated shear leading to the passive erosion of single cells from the biofilm surface, disregards the active contribution of attached cell metabolism and growth to the observed detachment rates. As a complement to the conventional conceptual biofilm models, the existence of a biofilm surface-associated zone of planktonic cell proliferation is proposed to highlight the need to expand the traditional perception of biofilms as promoting microbial survival, to include the potential of biofilms to contribute to microbial proliferation. PMID:24201127

  8. Role of bentonite clays on cell growth.

    PubMed

    Cervini-Silva, Javiera; Ramírez-Apan, María Teresa; Kaufhold, Stephan; Ufer, Kristian; Palacios, Eduardo; Montoya, Ascención

    2016-04-01

    Bentonites, naturally occurring clays, are produced industrially because of their adsorbent capacity but little is known about their effects on human health. This manuscript reports on the effect of bentonites on cell growth behaviour. Bentonites collected from India (Bent-India), Hungary (Bent-Hungary), Argentina (Bent-Argentina), and Indonesia (Bent-Indonesia) were studied. All four bentonites were screened in-vitro against two human cancer cell lines [U251 (central nervous system, glioblastoma) and SKLU-1 (lung adenocarcinoma)] supplied by the National Cancer Institute (USA). Bentonites induced growth inhibition in the presence of U251 cells, and growth increment in the presence of SKLU-1 cells, showing that interactions between bentonite and cell surfaces were highly specific. The proliferation response for U251 cells was explained because clay surfaces controlled the levels of metabolic growth components, thereby inhibiting the development of high-grade gliomas, particularly primary glioblastomas. On the other hand, the proliferation response for SKLU-1 was explained by an exacerbated growth favoured by swelling, and concomitant accumulation of solutes, and their hydration and transformation via clay-surface mediated reactions. PMID:26849195

  9. Collective Behavior of Brain Tumor Cells: the Role of Hypoxia

    NASA Astrophysics Data System (ADS)

    Khain, Evgeniy; Katakowski, Mark; Hopkins, Scott; Szalad, Alexandra; Zheng, Xuguang; Jiang, Feng; Chopp, Michael

    2013-03-01

    We consider emergent collective behavior of a multicellular biological system. Specifically we investigate the role of hypoxia (lack of oxygen) in migration of brain tumor cells. We performed two series of cell migration experiments. The first set of experiments was performed in a typical wound healing geometry: cells were placed on a substrate, and a scratch was done. In the second set of experiments, cell migration away from a tumor spheroid was investigated. Experiments show a controversy: cells under normal and hypoxic conditions have migrated the same distance in the ``spheroid'' experiment, while in the ``scratch'' experiment cells under normal conditions migrated much faster than under hypoxic conditions. To explain this paradox, we formulate a discrete stochastic model for cell dynamics. The theoretical model explains our experimental observations and suggests that hypoxia decreases both the motility of cells and the strength of cell-cell adhesion. The theoretical predictions were further verified in independent experiments.

  10. Vanadium Nitrogenase: A Two-Hit Wonder?

    PubMed Central

    Hu, Yilin; Lee, Chi Chung; Ribbe, Markus W.

    2013-01-01

    Nitrogenase catalyzes the biological conversion of atmospheric dinitrogen to bioavailable ammonia. The molybdenum (Mo)- and vanadium (V)-dependent nitrogenases are two homologous members of this metalloenzyme family. However, despite their similarities in structure and function, the characterization of V-nitrogenase has taken a much longer and more winding path than that of its Mo-counterpart. From the initial discovery of this nitrogen-fixing system, to the recent finding of its CO-reducing capacity, V-nitrogenase has proven to be a two-hit wonder in the over-a-century-long research of nitrogen fixation. This perspective provides a brief account of the catalytic function and structural basis of V-nitrogenase, as well as a short discussion of the theoretical and practical potentials of this unique metalloenzyme. PMID:22101422

  11. Vanadium nitrogenase: a two-hit wonder?

    PubMed

    Hu, Yilin; Lee, Chi Chung; Ribbe, Markus W

    2012-01-28

    Nitrogenase catalyzes the biological conversion of atmospheric dinitrogen to bioavailable ammonia. The molybdenum (Mo)- and vanadium (V)-dependent nitrogenases are two homologous members of this metalloenzyme family. However, despite their similarities in structure and function, the characterization of V-nitrogenase has taken a much longer and more winding path than that of its Mo-counterpart. From the initial discovery of this nitrogen-fixing system, to the recent finding of its CO-reducing capacity, V-nitrogenase has proven to be a two-hit wonder in the over-a-century-long research of nitrogen fixation. This perspective provides a brief account of the catalytic function and structural basis of V-nitrogenase, as well as a short discussion of the theoretical and practical potentials of this unique metalloenzyme. PMID:22101422

  12. Role of Calcium and Calmodulin in Plant Cell Regulation

    NASA Technical Reports Server (NTRS)

    Cormier, M. J.

    1983-01-01

    The role of calcium and calmodulin in plant cell regulation is discussed. Experiments are done to discover the level of calcium in plants and animals. The effect of intracellular calcium on photosynthesis is discussed.

  13. Role of autophagy in the regulation of epithelial cell junctions.

    PubMed

    Nighot, Prashant; Ma, Thomas

    2016-01-01

    Autophagy is a cell survival mechanism by which bulk cytoplasmic material, including soluble macromolecules and organelles, is targeted for lysosomal degradation. The role of autophagy in diverse cellular processes such as metabolic stress, neurodegeneration, cancer, aging, immunity, and inflammatory diseases is being increasingly recognized. Epithelial cell junctions play an integral role in the cell homeostasis via physical binding, regulating paracellular pathways, integrating extracellular cues into intracellular signaling, and cell-cell communication. Recent data indicates that cell junction composition is very dynamic. The junctional protein complexes are actively regulated in response to various intra- and extra-cellular clues by intracellular trafficking and degradation pathways. This review discusses the recent and emerging information on how autophagy regulates various epithelial cell junctions. The knowledge of autophagy regulation of epithelial junctions will provide further rationale for targeting autophagy in a wide variety of human disease conditions. PMID:27583189

  14. The role of natural killer cells in viral infections.

    PubMed

    See, D M; Khemka, P; Sahl, L; Bui, T; Tilles, J G

    1997-09-01

    Natural killer (NK) cells are important effectors for the lysis of both neoplastic and virus-infected cells. Lectin-like receptors on human NK cells, such as NKR-PIA and CD94, bind to target cell carbohydrate ligands and initiate the lytic process. In addition, P58 and P70 bind to major histocompatibility class I antigens on targets and mediate negative signals. Models using NK cell-deficient mice have proven useful in elaborating the role of NK cells in the immune defence against multiple viral agents. In addition, studies in humans have suggested a vital role of NK cells in the host defence against human immunodeficiency virus, herpesviruses, hepatitis B and C and other viruses. Several genetic disorders, chronic illnesses and infections have been associated with decreased NK function. PMID:9315107

  15. Role of Innate Lymphoid Cells in Lung Disease.

    PubMed

    Marashian, Sayed Mehran; Mortaz, Esmaeil; Jamaati, Hamid Reza; Alavi-Moghaddam, Mostafa; Kiani, Arda; Abedini, Atefeh; Garssen, Johan; Adcock, Ian M; Velayati, Ali Akbar

    2015-08-01

    Innate lymphoid cells (ILCs) are identified as novel population of hematopoietic cells which protect the body by coordinating the innate immune response against a wide range of threats including infections, tissue damages and homeostatic disturbances. ILCs, particularly ILC2 cells, are found throughout the body including the brain. ILCs are morphologically similar to lymphocytes, express and release high levels of T-helper (Th)1, Th2 and Th17 cytokines but do not express classical cell-surface markers that are associated with other immune cell lineages. Three types of ILCs (ILC1, 2 & 3) have been reported depending upon the cytokines produced. ILC1 cells encompass natural killer (NK) cells and interferon (IFN)-g releasing cells; ILC2 cells release the Th2 cytokines, IL-5, IL-9 and IL-13 in response to IL-25 and IL-33; and ILC3 cells which release IL-17 and IL-22. ILC2 cells have been implicated inmucosal reactions occurring in animal models of allergic asthma and virus-induced lung disorders resulting in the regulation of airway remodeling and tissue homeostasis. There is evidence for increased ILC2 cell numbers in allergic responses in man but little is known about the role of ILCs in chronic obstructive pulmonary disease (COPD). Further understanding of the characteristics of ILCs such as their origin, location and phenotypes and function would help to clarify the role of these cells in the pathogenesis of various lung diseases. In this review we will focus on the role of ILC2 cells and consider their origin, function,location and possible role in the pathogenesis of the chronic inflammatory disorders such as asthma and COPD. PMID:26547702

  16. The Role of microRNAs in Animal Cell Reprogramming.

    PubMed

    Cruz-Santos, María Concepción; Aragón-Raygoza, Alejandro; Espinal-Centeno, Annie; Arteaga-Vázquez, Mario; Cruz-Hernández, Andrés; Bako, Laszlo; Cruz-Ramírez, Alfredo

    2016-07-15

    Our concept of cell reprogramming and cell plasticity has evolved since John Gurdon transferred the nucleus of a completely differentiated cell into an enucleated Xenopus laevis egg, thereby generating embryos that developed into tadpoles. More recently, induced expression of transcription factors, oct4, sox2, klf4, and c-myc has evidenced the plasticity of the genome to change the expression program and cell phenotype by driving differentiated cells to the pluripotent state. Beyond these milestone achievements, research in artificial cell reprogramming has been focused on other molecules that are different than transcription factors. Among the candidate molecules, microRNAs (miRNAs) stand out due to their potential to control the levels of proteins that are involved in cellular processes such as self-renewal, proliferation, and differentiation. Here, we review the role of miRNAs in the maintenance and differentiation of mesenchymal stem cells, epimorphic regeneration, and somatic cell reprogramming to induced pluripotent stem cells. PMID:27224014

  17. External validation of the HIT Expert Probability (HEP) score.

    PubMed

    Joseph, Lee; Gomes, Marcelo P V; Al Solaiman, Firas; St John, Julie; Ozaki, Asuka; Raju, Manjunath; Dhariwal, Manoj; Kim, Esther S H

    2015-03-01

    The diagnosis of heparin-induced thrombocytopenia (HIT) can be challenging. The HIT Expert Probability (HEP) Score has recently been proposed to aid in the diagnosis of HIT. We sought to externally and prospectively validate the HEP score. We prospectively assessed pre-test probability of HIT for 51 consecutive patients referred to our Consultative Service for evaluation of possible HIT between August 1, 2012 and February 1, 2013. Two Vascular Medicine fellows independently applied the 4T and HEP scores for each patient. Two independent HIT expert adjudicators rendered a diagnosis of HIT likely or unlikely. The median (interquartile range) of 4T and HEP scores were 4.5 (3.0, 6.0) and 5 (3.0, 8.5), respectively. There were no significant differences between area under receiver-operating characteristic curves of 4T and HEP scores against the gold standard, confirmed HIT [defined as positive serotonin release assay and positive anti-PF4/heparin ELISA] (0.74 vs 0.73, p = 0.97). HEP score ≥ 2 was 100 % sensitive and 16 % specific for determining the presence of confirmed HIT while a 4T score > 3 was 93 % sensitive and 35 % specific. In conclusion, the HEP and 4T scores are excellent screening pre-test probability models for HIT, however, in this prospective validation study, test characteristics for the diagnosis of HIT based on confirmatory laboratory testing and expert opinion are similar. Given the complexity of the HEP scoring model compared to that of the 4T score, further validation of the HEP score is warranted prior to widespread clinical acceptance. PMID:25588983

  18. Role of dendritic cells in the induction of regulatory T cells

    PubMed Central

    2011-01-01

    Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-β, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3+ regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction. PMID:21711933

  19. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1997-01-01

    Specific aims include: (1) Application of the bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC); (2) Based on clues from spaceflight: compare the frequency and function of DC in normal donors and immunocompromised cancer patients; and (3) Initiate studies on the efficiency of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in animal models of experimental fungal infections.

  20. Role for different cell proteinases in cancer invasion and cytolysis.

    PubMed Central

    Zucker, S.; Beck, G.; DiStefano, J. F.; Lysik, R. M.

    1985-01-01

    The crucial role of non-plasminogen dependent serine proteinases is tissue invasive and cytolytic functions of Walker 256 cancer cells has been documented using a rat urinary bladder invasion and a 125I-labelled fibroblast cytolysis assay. The invasive capacity of these cancer cells was abrogated by non toxic concentrations of the serine proteinase inhibitors, diisopropylfluorophosphate and phenylmethylsulfonylfluoride, but not by metallo or cysteine proteinase inhibitors. Although tumour cell collagenase activity and plasminogen activator were demonstrated, these proteolytic enzymes were not essential in these in vitro assays. These results suggest that different categories of proteinases play specific roles in the complicated process of cancer invasion. PMID:2992566

  1. The Role of MicroRNAs in Cardiac Stem Cells

    PubMed Central

    Purvis, Nima; Bahn, Andrew; Katare, Rajesh

    2015-01-01

    Stem cells are considered as the next generation drug treatment in patients with cardiovascular disease who are resistant to conventional treatment. Among several stem cells used in the clinical setting, cardiac stem cells (CSCs) which reside in the myocardium and epicardium of the heart have been shown to be an effective option for the source of stem cells. In normal circumstances, CSCs primarily function as a cell store to replace the physiologically depleted cardiovascular cells, while under the diseased condition they have been shown to experimentally regenerate the diseased myocardium. In spite of their major functional role, molecular mechanisms regulating the CSCs proliferation and differentiation are still unknown. MicroRNAs (miRs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level. Recent studies have demonstrated the important role of miRs in regulating stem cell proliferation and differentiation, as well as other physiological and pathological processes related to stem cell function. This review summarises the current understanding of the role of miRs in CSCs. A deeper understanding of the mechanisms by which miRs regulate CSCs may lead to advances in the mode of stem cell therapies for the treatment of cardiovascular diseases. PMID:25802528

  2. Combining Computational Methods for Hit to Lead Optimization in Mycobacterium tuberculosis Drug Discovery

    PubMed Central

    Ekins, Sean; Freundlich, Joel S.; Hobrath, Judith V.; White, E. Lucile; Reynolds, Robert C

    2013-01-01

    Purpose Tuberculosis treatments need to be shorter and overcome drug resistance. Our previous large scale phenotypic high-throughput screening against Mycobacterium tuberculosis (Mtb) has identified 737 active compounds and thousands that are inactive. We have used this data for building computational models as an approach to minimize the number of compounds tested. Methods A cheminformatics clustering approach followed by Bayesian machine learning models (based on publicly available Mtb screening data) was used to illustrate that application of these models for screening set selections can enrich the hit rate. Results In order to explore chemical diversity around active cluster scaffolds of the dose-response hits obtained from our previous Mtb screens a set of 1924 commercially available molecules have been selected and evaluated for antitubercular activity and cytotoxicity using Vero, THP-1 and HepG2 cell lines with 4.3%, 4.2% and 2.7% hit rates, respectively. We demonstrate that models incorporating antitubercular and cytotoxicity data in Vero cells can significantly enrich the selection of non-toxic actives compared to random selection. Across all cell lines, the Molecular Libraries Small Molecule Repository (MLSMR) and cytotoxicity model identified ~10% of the hits in the top 1% screened (>10 fold enrichment). We also showed that seven out of nine Mtb active compounds from different academic published studies and eight out of eleven Mtb active compounds from a pharmaceutical screen (GSK) would have been identified by these Bayesian models. Conclusion Combining clustering and Bayesian models represents a useful strategy for compound prioritization and hit-to lead optimization of antitubercular agents. PMID:24132686

  3. The role of dental stem cells in regeneration

    PubMed Central

    MAXIM, MONICA ANGELA; SORITAU, OLGA; BACIUT, MIHAELA; BRAN, SIMION; BACIUT, GRIGORE

    2015-01-01

    Mesenchymal stem cells (MSCs) are adult stem cells that have the capacity of rising multiple cell types. A rich source of mesenchymal stem cells is represented by the dental tissues: the periodontal ligament, the dental pulp, the apical papilla, the dental follicle and the deciduous teeth. The aim of this review is to characterize the main dental- derived mesenchymal stem cell population, and to show their important role in tissue regeneration based on their properties : the multi-potency, the high proliferation rate, the differentiation in multiple cell lineages, the high cell viability and the positive expression for mesenchymal cell markers. Tissue regeneration or de novo’ formation of craniofacial structures is the future of regenerative medicine, offering a solution for congenital malformations, traumas and other diseases. PMID:26733745

  4. Adhesion in the stem cell niche: biological roles and regulation

    PubMed Central

    Chen, Shuyi; Lewallen, Michelle; Xie, Ting

    2013-01-01

    Stem cell self-renewal is tightly controlled by the concerted action of stem cell-intrinsic factors and signals within the niche. Niche signals often function within a short range, allowing cells in the niche to self-renew while their daughters outside the niche differentiate. Thus, in order for stem cells to continuously self-renew, they are often anchored in the niche via adhesion molecules. In addition to niche anchoring, however, recent studies have revealed other important roles for adhesion molecules in the regulation of stem cell function, and it is clear that stem cell-niche adhesion is crucial for stem cell self-renewal and is dynamically regulated. Here, we highlight recent progress in understanding adhesion between stem cells and their niche and how this adhesion is regulated. PMID:23250203

  5. Improved Curveball Hitting through the Enhancement of Visual Cues.

    ERIC Educational Resources Information Center

    Osborne, Kurt; And Others

    1990-01-01

    The study investigated the effectiveness of using visual cues to highlight the seams of baseballs, to improve the hitting of curveballs by five undergraduate varsity baseball team candidates. Results indicated that subjects hit a greater percentage of marked than unmarked balls. (Author/DB)

  6. Infants' Reactions to Object Collision on Hit and Miss Trajectories

    ERIC Educational Resources Information Center

    Schmuckler, Mark A.; Collimore, Lisa M.; Dannemiller, James L.

    2007-01-01

    This experiment investigated the impact of the path of approach of an object, from head on versus from the side, and the type of imminent contact with that object, a hit versus a miss, on young infants' perceptions of object looming. Consistent with earlier studies, we found that 4- to 5-month-old infants do indeed discriminate hits versus misses.…

  7. Object Rotation Effects on the Timing of a Hitting Action

    ERIC Educational Resources Information Center

    Scott, Mark A.; van der Kamp, John; Savelsbergh, Geert J. P.; Oudejans, Raoul R. D.; Davids, Keith

    2004-01-01

    In this article, the authors investigated how perturbing optical information affects the guidance of an unfolding hitting action. Using monocular and binocular vision, six participants were required to hit a rectangular foam object, released from two different heights, under four different approach conditions, two with object rotation (to perturb…

  8. Role of Dendritic Cells in Immune Dysfunction

    NASA Technical Reports Server (NTRS)

    Savary, Cherylyn A.

    1998-01-01

    The specific aims of the project were: (1) Application of the NASA bioreactor to enhance cytokine-regulated proliferation and maturation of dendritic cells (DC). (2) Compare the frequency and function of DC in normal donors and immunocompromised cancer patients. (3) Analyze the effectiveness of cytokine therapy and DC-assisted immunotherapy (using bioreactor-expanded DC) in a murine model of experimental fungal disease. Our investigations have provided new insight into DC immunobiology and have led to the development of methodology to evaluate DC in blood of normal donors and patients. Information gained from these studies has broadened our understanding of possible mechanisms involved in the immune dysfunction of space travelers and earth-bound cancer patients, and could contribute to the design of novel therapies to restore/preserve immunity in these individuals. Several new avenues of investigation were also revealed. The results of studies completed during Round 2 are summarized.

  9. An enduring role for quiescent stem cells.

    PubMed

    Richmond, Camilla A; Shah, Manasvi S; Carlone, Diana L; Breault, David T

    2016-07-01

    The intestine's ability to recover from catastrophic injury requires quiescent intestinal stem cells (q-ISCs). While rapidly cycling (Lgr5+) crypt base columnar (CBC) ISCs normally maintain the intestine, they are highly sensitive to pathological injuries (irradiation, inflammation) and must be restored by q-ISCs to sustain intestinal homeostasis. Despite clear relevance to human health, virtually nothing is known regarding the factors that regulate q-ISCs. A comprehensive understanding of these mechanisms would likely lead to targeted new therapies with profound therapeutic implications for patients with gastrointestinal conditions. We briefly review the current state of the literature, highlighting homeostatic mechanisms important for q-ISC regulation, listing key questions in the field, and offer strategies to address them. Developmental Dynamics 245:718-726, 2016. © 2016 Wiley Periodicals, Inc. PMID:27153394

  10. The role of human dendritic cells in HIV-1 infection.

    PubMed

    Ahmed, Zahra; Kawamura, Tatsuyoshi; Shimada, Shinji; Piguet, Vincent

    2015-05-01

    Dendritic cells (DCs) and their subsets have multifaceted roles in the early stages of HIV-1 transmission and infection. DC studies have led to remarkable discoveries, including identification of restriction factors, cellular structures promoting viral transmission including the infectious synapse or the interplay of the C-type lectins, Langerin on Langerhans cells (LCs), and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin on other DC subsets, limiting or facilitating HIV transmission to CD4(+) T cells, respectively. LCs/DCs are also exposed to encountering HIV-1 and other sexually transmitted infections (herpes simplex virus-2, bacteria, fungi), which reprogram HIV-1 interaction with these cells. This review will summarize advances in the role of DCs during HIV-1 infection and discuss their potential involvement in the development of preventive strategies against HIV-1 and other sexually transmitted infections. PMID:25407434

  11. Antarctic ozone hole hits record depth

    SciTech Connect

    Not Available

    1991-10-18

    A bad year for the ozone over Antarctica looked like a good bet this year. For the past 2 years, stratospheric ozone destruction has equaled the record set in 1987. Now things look even worse, with a record-setting ozone hole. In 1987, 1989, and 1990, the minimum amount of ozone over Antarctica early each October was 120 to 125 Dobson units compared to the typical level of 220 that prevailed before manmade Chlorofluorocarbons (CFCs) began eating into the ozone layer. The depletion allowed as much as twice the usual amount of biologically damaging ultraviolet light to reach the earth's surface. But researchers took some comfort in the fact that the hole seemed to have hit a barrier to further losses. Now that barrier may have been breached. On 6 October, the satellite-borne Total Ozone Mapping Spectrometer detected an ozone minimum of 110 Dobson units. The region of the lower stratosphere where icy cloud particles and the chlorine of CFCs combine to destroy ozone - between 14 and 24 kilometers - looks much the same as it did in 1987.

  12. The significant role of mast cells in cancer.

    PubMed

    Khazaie, Khashayarsha; Blatner, Nichole R; Khan, Mohammad Wasim; Gounari, Fotini; Gounaris, Elias; Dennis, Kristen; Bonertz, Andreas; Tsai, Fu-Nien; Strouch, Matthew J; Cheon, Eric; Phillips, Joseph D; Beckhove, Philipp; Bentrem, David J

    2011-03-01

    Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient. PMID:21287360

  13. HITS-CLIP yields genome-wide insights into brain alternative RNA processing

    NASA Astrophysics Data System (ADS)

    Licatalosi, Donny D.; Mele, Aldo; Fak, John J.; Ule, Jernej; Kayikci, Melis; Chi, Sung Wook; Clark, Tyson A.; Schweitzer, Anthony C.; Blume, John E.; Wang, Xuning; Darnell, Jennifer C.; Darnell, Robert B.

    2008-11-01

    Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

  14. 42 CFR 495.340 - As-needed HIT PAPD update and as-needed HIT IAPD update requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... update or a HIT IAPD no later than 60 days after the occurrence of project changes including but not... document or the HIT implementation advance planning document. (d) A change in implementation concept or a change to the scope of the project. (e) A change to the approved cost allocation methodology....

  15. Subsets of regulatory T cells and their roles in allergy.

    PubMed

    Zhang, Huiyun; Kong, Hui; Zeng, Xiaoning; Guo, Lianyi; Sun, Xiaoyun; He, Shaoheng

    2014-01-01

    In recent years, it is recognized that acquired immunity is controlled by regulatory T cell (Treg). Since fundamental pathophysiological changes of allergy are mainly caused by hyperresponsiveness of immune system to allergens that acquires after birth, Tregs likely play key roles in the pathogenesis of allergy, particularly during the sensitization phase. However, accumulated information indicate that there are several distinctive subtypes of Tregs in man, and each of them seems to play different role in controlling immune system, which complicates the involvement of Tregs in allergy. The aim of the present study is to attempt to classify subtypes of Tregs and summarize their roles in allergy. Tregs should include natural Tregs (nTreg) including inducible costimulator (ICOS)(+) Tregs, inducible/adaptive Tregs (iTreg), interleukin (IL)-10-producing type 1 Tregs (Tr1 cells), CD8(+) Tregs and IL-17-producing Tregs. These cells share some common features including expression of Foxp3 (except for Tr1 cells), and secretion of inhibitory cytokine IL-10 and/or TGF-β. Furthermore, it is noticeable that Tregs likely contribute to allergic disorders such as dermatitis and airway inflammation, and play a crucial role in the treatment of allergy through their actions on suppression of effector T cells and inhibition of activation of mast cells and basophils. Modulation of functions of Tregs may provide a novel strategy to prevent and treat allergic diseases. PMID:24886492

  16. Subsets of regulatory T cells and their roles in allergy

    PubMed Central

    2014-01-01

    In recent years, it is recognized that acquired immunity is controlled by regulatory T cell (Treg). Since fundamental pathophysiological changes of allergy are mainly caused by hyperresponsiveness of immune system to allergens that acquires after birth, Tregs likely play key roles in the pathogenesis of allergy, particularly during the sensitization phase. However, accumulated information indicate that there are several distinctive subtypes of Tregs in man, and each of them seems to play different role in controlling immune system, which complicates the involvement of Tregs in allergy. The aim of the present study is to attempt to classify subtypes of Tregs and summarize their roles in allergy. Tregs should include natural Tregs (nTreg) including inducible costimulator (ICOS)(+) Tregs, inducible/adaptive Tregs (iTreg), interleukin (IL)-10-producing type 1 Tregs (Tr1 cells), CD8(+) Tregs and IL-17-producing Tregs. These cells share some common features including expression of Foxp3 (except for Tr1 cells), and secretion of inhibitory cytokine IL-10 and/or TGF-β. Furthermore, it is noticeable that Tregs likely contribute to allergic disorders such as dermatitis and airway inflammation, and play a crucial role in the treatment of allergy through their actions on suppression of effector T cells and inhibition of activation of mast cells and basophils. Modulation of functions of Tregs may provide a novel strategy to prevent and treat allergic diseases. PMID:24886492

  17. Emerging role of Natural killer cells in oncolytic virotherapy

    PubMed Central

    Bhat, Rauf; Rommelaere, Jean

    2015-01-01

    Natural killer (NK) cells constitute a subtype of lymphocytes that initiate innate immune responses against tumors and virus-infected cells. The ability of NK cells to kill target cells or to produce cytokines depends on the balance between signals from activating and inhibitory cell-surface receptors. Therapies with NK cells involve activation of endogenous NK cells and/or exogenous transfer by hematopoietic stem cell transplantation/adoptive cell therapy. To exploit the diverse functional abilities of NK cells for cancer immunotherapy, it is important to understand NK cell biology and the underlying regulatory mechanisms. The state of immune suppression prevalent in malignancies creates the need for innovative therapies. Oncolytic viruses are novel anticancer agents showing selective tropism for tumor cells and lacking pathogenicity in humans, but the use of oncolytic virotherapy (OVT) presents multiple challenges. An increasing body of evidence suggests that the host immune response may critically influence the outcome of OVT. Classically, the immune system is thought to limit the efficacy of therapy through virus clearance mediated by innate immune effectors or through adaptive antiviral immune responses eliminating infected cells. Effective strategies do need to be designed in OVT to circumvent the early antiviral activity of NK cells and to augment late NK-cell-mediated antitumor responses. The intrinsic immunostimulating capacity of oncolytic viruses and the possibility of engineering them to express heterologous immunostimulatory molecules (eg, cytokines) support the use of these agents to enhance antitumor immune responses besides inducing direct oncolytic effects. OVT has indeed shown promising therapeutic outcomes in various clinical trials. Here, we review the biology of NK cells, strategies involving NK cells for achieving cancer therapy, and, more particularly, the emerging role of NK cells in OVT.

  18. Calreticulin: Roles in Cell-Surface Protein Expression

    PubMed Central

    Jiang, Yue; Dey, Sandeepa; Matsunami, Hiroaki

    2014-01-01

    In order to perform their designated functions, proteins require precise subcellular localizations. For cell-surface proteins, such as receptors and channels, they are able to transduce signals only when properly targeted to the cell membrane. Calreticulin is a multi-functional chaperone protein involved in protein folding, maturation, and trafficking. However, evidence has been accumulating that calreticulin can also negatively regulate the surface expression of certain receptors and channels. In these instances, depletion of calreticulin enhances cell-surface expression and function. In this review, we discuss the role of calreticulin with a focus on its negative effects on the expression of cell-surface proteins. PMID:25230046

  19. Role of Exosome Shuttle RNA in Cell-to-Cell Communication.

    PubMed

    Zhang, Wei; Peng, Peng; Shen, Keng

    2016-08-01

    There are several ways that transpire in cell-to-cell communication,with or without cell contact. Exosomes play an important role in cell-to-cell communication,which do not need cell contact,as that can result in a relatively long-distance influence. Exosome contains RNA components including mRNA and micro-RNA,which are protected by exosomes rigid membranes. This allows those components be passed long distance through the circulatory system. The mRNA components are far different from their donor cells,and the micro-RNA components may reflect the cell they originated. In this article we review the role of exosomes in cell-to-cell communication,with particular focus on their potentials in both diagnostic and therapeutic applications. PMID:27594165

  20. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex

    PubMed Central

    Tyburczy, Magdalena E.; Wang, Ji-an; Li, Shaowei; Thangapazham, Rajesh; Chekaluk, Yvonne; Moss, Joel; Kwiatkowski, David J.; Darling, Thomas N.

    2014-01-01

    Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet ‘signature’ mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions. PMID:24271014

  1. The Role of TRP Proteins in Mast Cells

    PubMed Central

    Freichel, Marc; Almering, Julia; Tsvilovskyy, Volodymyr

    2012-01-01

    Transient receptor potential (TRP) proteins form cation channels that are regulated through strikingly diverse mechanisms including multiple cell surface receptors, changes in temperature, in pH and osmolarity, in cytosolic free Ca2+ concentration ([Ca2+]i), and by phosphoinositides which makes them polymodal sensors for fine tuning of many cellular and systemic processes in the body. The 28 TRP proteins identified in mammals are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. When activated, they contribute to cell depolarization and Ca2+ entry. In mast cells, the increase of [Ca2+]i is fundamental for their biological activity, and several entry pathways for Ca2+ and other cations were described including Ca2+ release activated Ca2+ (CRAC) channels. Like in other non-excitable cells, TRP channels could directly contribute to Ca2+ influx via the plasma membrane as constituents of Ca2+ conducting channel complexes or indirectly by shifting the membrane potential and regulation of the driving force for Ca2+ entry through independent Ca2+ entry channels. Here, we summarize the current knowledge about the expression of individual Trp genes with the majority of the 28 members being yet identified in different mast cell models, and we highlight mechanisms how they can regulate mast cell functions. Since specific agonists or blockers are still lacking for most members of the TRP family, studies to unravel their function and activation mode still rely on experiments using genetic approaches and transgenic animals. RNAi approaches suggest a functional role for TRPC1, TRPC5, and TRPM7 in mast cell derived cell lines or primary mast cells, and studies using Trp gene knock-out mice reveal a critical role for TRPM4 in mast cell activation and for mast cell mediated cutaneous anaphylaxis, whereas a direct role of cold- and menthol-activated TRPM8 channels seems to be unlikely for the development of cold urticaria at least in mice. PMID:22701456

  2. Regulatory T Cells and Their Role in Animal Disease.

    PubMed

    Veiga-Parga, T

    2016-07-01

    In humans and mouse models, Foxp3(+) regulatory T cells are known to control all aspects of immune responses. However, only limited information exists on these cells' role in diseases of other animals. In this review, we cover the most important features and different types of regulatory T cells, which include those that are thymus-derived and peripherally induced, the mechanisms by which they control immune responses by targeting effector T cells and antigen-presenting cells, and most important, their role in animal health and diseases including cancer, infections, and other conditions such as hypersensitivities and autoimmunity. Although the literature regarding regulatory T cells in domestic animal species is still limited, multiple articles have recently emerged and are discussed. Moreover, we also discuss the evidence suggesting that regulatory T cells might limit the magnitude of effector responses, which can have either a positive or negative result, depending on the context of animal and human disease. In addition, the issue of plasticity is discussed because plasticity in regulatory T cells can result in the loss of their protective function in some microenvironments during disease. Lastly, the manipulation of regulatory T cells is discussed in assessing the possibility of their use as a treatment in the future. PMID:26945003

  3. Role(s) of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide.

    PubMed

    Huang, Weishan; August, Avery

    2016-06-01

    Mast cells play critical roles during immune responses to the bacterial endotoxin lipopolysaccharide (LPS) that can lead to fatal septic hypothermia [1], [2], [3]. IL-2 inducible T cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are non-receptor tyrosine kinases that act downstream of numerous receptors, and have been shown to modulate mast cell responses downstream of FcεRIα [4], however, their roles in regulating mast cell responses to endotoxic stimuli were unclear. We found that the absence of ITK and BTK alters the mast cell response to LPS, and leads to enhanced pro-inflammatory cytokine production by mast cells and more severe LPS-induced hypothermia in mice [5]. Here, we detail our investigation using microarray analysis to study the transcriptomic profiles of mast cell responses to LPS, and the roles of ITK and/or BTK expression in this process. Mouse whole genome array data of WT, Itk (-/-) , Btk (-/-) , and Itk (-/-)  Btk (-/-) bone marrow-derived mast cells (BMMCs) stimulated by PBS (control) or LPS for 1 h were used in our latest research article [5] and is available in the Gene Expression Omnibus under accession number GSE64287. PMID:27081634

  4. Ozone loss hits us where we live

    SciTech Connect

    Appenzeller, T.

    1991-11-01

    The news about Earth's ozone layer just keeps getting worse. Three weeks ago, NASA researchers reported that the ozone hole over the Antarctic hit a record depth this year. Now comes the United Nations Environment Program, together with the World Meteorological Organization, with an even more distressing assessment of the state of the ozone layer. For the first time, the 80-member UN panel said, measurements show the ozone shield is eroding over temperate latitudes in summer, exposing crops and people to a larger dose of ultraviolet light just when they are most vulnerable. For a small group of atmospheric modelers, though, the bad news is bittersweet. Four months ago researchers predicted summertime ozone losses of just the magnitude the UN panel has now reported: about 3% over the past decade for northern temperate latitudes. Ozone modelers are encouraged by the agreement, particularly because other models are now yielding the same result. The modeling effort was spurred by earlier measurements showing a serious erosion of ozone at midlatitudes, mainly in winter. In 1988, an analysis of data collected from the ground showed that ozone levels at the latitude of the US were dropping by about 1% to 3% per decade; last April, an analysis of measurements from the satellite-borne Total Ozone Mapping Spectrometer boosted that figure to between 4% and 5%. Those findings raised the question: What mechanisms could be driving the midlatitude losses The fact that the losses seemed to be concentrated in winter suggested one possibility. The winter ozone losses at the poles are driven by chemical reactions taking place on the surface of ice crystals in polar stratospheric clouds. Such clouds don't form at temperate latitudes. But some researchers suggested that masses of air already depleted in ozone or enriched in reactive chlorine by the chemistry in the polar clouds might be escaping to temperate latitudes during the winter.

  5. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak. PMID:26432864

  6. Switching roles: the functional plasticity of adult tissue stem cells.

    PubMed

    Wabik, Agnieszka; Jones, Philip H

    2015-05-01

    Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro-environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles. PMID:25812989

  7. Switching roles: the functional plasticity of adult tissue stem cells

    PubMed Central

    Wabik, Agnieszka; Jones, Philip H

    2015-01-01

    Adult organisms have to adapt to survive, and the same is true for their tissues. Rates and types of cell production must be rapidly and reversibly adjusted to meet tissue demands in response to both local and systemic challenges. Recent work reveals how stem cell (SC) populations meet these requirements by switching between functional states tuned to homoeostasis or regeneration. This plasticity extends to differentiating cells, which are capable of reverting to SCs after injury. The concept of the niche, the micro-environment that sustains and regulates stem cells, is broadening, with a new appreciation of the role of physical factors and hormonal signals. Here, we review different functions of SCs, the cellular mechanisms that underlie them and the signals that bias the fate of SCs as they switch between roles. PMID:25812989

  8. Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway

    PubMed Central

    Perez-Plasencia, Carlos; Duenas-Gonzalez, Alfonso; Alatorre-Tavera, Brenda

    2008-01-01

    The Human papillomavirus plays an important role in the initiation and progression of cervical cancer. However, it is a necessary but not sufficient cause to develop invasive carcinoma; hence, other factors are required in the pathogenesis of this malignancy. In this review we explore the hypothesis of the deregulation of wnt/β-catenin signaling pathway as a "second hit" required to develop cervical cancer. PMID:18606007

  9. The role of purinergic receptors in stem cell differentiation

    PubMed Central

    Kaebisch, Constanze; Schipper, Dorothee; Babczyk, Patrick; Tobiasch, Edda

    2014-01-01

    A major challenge modern society has to face is the increasing need for tissue regeneration due to degenerative diseases or tumors, but also accidents or warlike conflicts. There is great hope that stem cell-based therapies might improve current treatments of cardiovascular diseases, osteochondral defects or nerve injury due to the unique properties of stem cells such as their self-renewal and differentiation potential. Since embryonic stem cells raise severe ethical concerns and are prone to teratoma formation, adult stem cells are still in the focus of research. Emphasis is placed on cellular signaling within these cells and in between them for a better understanding of the complex processes regulating stem cell fate. One of the oldest signaling systems is based on nucleotides as ligands for purinergic receptors playing an important role in a huge variety of cellular processes such as proliferation, migration and differentiation. Besides their natural ligands, several artificial agonists and antagonists have been identified for P1 and P2 receptors and are already used as drugs. This review outlines purinergic receptor expression and signaling in stem cells metabolism. We will briefly describe current findings in embryonic and induced pluripotent stem cells as well as in cancer-, hematopoietic-, and neural crest-derived stem cells. The major focus will be placed on recent findings of purinergic signaling in mesenchymal stem cells addressed in in vitro and in vivo studies, since stem cell fate might be manipulated by this system guiding differentiation towards the desired lineage in the future. PMID:26900431

  10. Collective behavior of brain tumor cells: The role of hypoxia

    NASA Astrophysics Data System (ADS)

    Khain, Evgeniy; Katakowski, Mark; Hopkins, Scott; Szalad, Alexandra; Zheng, Xuguang; Jiang, Feng; Chopp, Michael

    2011-03-01

    We consider emergent collective behavior of a multicellular biological system. Specifically, we investigate the role of hypoxia (lack of oxygen) in migration of brain tumor cells. We performed two series of cell migration experiments. In the first set of experiments, cell migration away from a tumor spheroid was investigated. The second set of experiments was performed in a typical wound-healing geometry: Cells were placed on a substrate, a scratch was made, and cell migration into the gap was investigated. Experiments show a surprising result: Cells under normal and hypoxic conditions have migrated the same distance in the “spheroid” experiment, while in the “scratch” experiment cells under normal conditions migrated much faster than under hypoxic conditions. To explain this paradox, we formulate a discrete stochastic model for cell dynamics. The theoretical model explains our experimental observations and suggests that hypoxia decreases both the motility of cells and the strength of cell-cell adhesion. The theoretical predictions were further verified in independent experiments.

  11. Oncogenic roles of carbonic anhydrase 8 in human osteosarcoma cells.

    PubMed

    Wang, Tze-Kai; Lin, Yu-Ming; Lo, Che-Min; Tang, Chih-Hsin; Teng, Chieh-Lin Jerry; Chao, Wei-Ting; Wu, Min Huan; Liu, Chin-San; Hsieh, Mingli

    2016-06-01

    Carbonic anhydrase 8 (CA8), a member of the carbonic anhydrase family, is one of the three isozymes that do not catalyze the reversible hydration of carbon dioxide due to the lack of one important histidine. In the present study, we observed increased expression of CA8 in more aggressive types of human osteosarcoma (OS) cells and found that CA8 expression is correlated with disease stages, such that more intense expression occurs in the disease late stage. We also demonstrated that overexpression of CA8 in human OS (HOS) cells significantly increased cell proliferation both in vitro and in vivo. Downregulated CA8 sensitized cells to apoptotic stress induced by staurosporine and cisplatin, suggesting a specific role of CA8 to protect cells from stresses. In addition, downregulation of CA8 in HOS cells reduced cell invasion and colony formation ability in soft agar and further decreased matrix metalloproteinase 9 and focal adhesion kinase expression, indicating that CA8 might facilitate cancer cell invasion via the activation of FAK-MMP9 signaling. Interestingly, HOS cells with CA8 knockdown showed a significant decrease in glycolytic activity and cell death under glucose withdrawal, further indicating that CA8 may be involved in regulating aerobic glycolysis and enhancing cell viability. Knockdown of CA8 significantly decreased phosphorylated Akt expression suggesting that the oncogenic role of CA8 may be mediated by the regulation of Akt activation through p-Akt induction. Importantly, the inhibition of glycolysis by 2-deoxyglucose sensitized CA8 HOS-CA8-myc cells to cisplatin treatment under low glucose condition, highlighting a new therapeutic option for OS cancer. PMID:26711783

  12. Regulatory roles of B cells in infectious diseases.

    PubMed

    Fillatreau, Simon

    2016-01-01

    B lymphocytes provide essential mechanisms of protection against infectious diseases. The secretion of specific antibodies by long-lived plasma cells is thought to account for the improved resistance afforded by most successful vaccines against pathogens. Accordingly, a goal in vaccine development is to induce potent B cell responses in order to drive the efficient formation of long-lived antibody-secreting cells. However, the roles of activated B cells are complex in infectious diseases. It was recently observed that activated B cells could also negatively regulate host defence mechanisms, both during primary infection and, after vaccination, upon secondary challenge, via mechanisms involving their production of the anti-inflammatory cytokines interleukin (IL)-10 and IL-35. Remarkably, the B cells expressing IL-10 and IL-35 in vivo were distinct subsets of IgMhiCD19+CD138hi antibody-secreting cells. A better understanding of the diverse roles of these distinct antibody-secreting cell subsets in immunity and immunological memory, as well as of the signals controlling their generation, might help the rational development of better prophylactic and therapeutic vaccines. PMID:27586794

  13. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells

    PubMed Central

    Jin, Rong; Yang, Guojun; Li, Guohong

    2010-01-01

    Inflammation plays an important role in the pathogenesis of ischemic stroke and other forms of ischemic brain injury. Experimentally and clinically, the brain responds to ischemic injury with an acute and prolonged inflammatory process, characterized by rapid activation of resident cells (mainly microglia), production of proinflammatory mediators, and infiltration of various types of inflammatory cells (including neutrophils, different subtypes of T cells, monocyte/macrophages, and other cells) into the ischemic brain tissue. These cellular events collaboratively contribute to ischemic brain injury. Despite intense investigation, there are still numerous controversies concerning the time course of the recruitment of inflammatory cells in the brain and their pathogenic roles in ischemic brain injury. In this review, we provide an overview of the time-dependent recruitment of different inflammatory cells following focal cerebral I/R. We discuss how these cells contribute to ischemic brain injury and highlight certain recent findings and currently unanswered questions about inflammatory cells in the pathophysiology of ischemic stroke. PMID:20130219

  14. Glucocorticoids Play a Key Role in Circadian Cell Cycle Rhythms

    PubMed Central

    Dickmeis, Thomas; Lahiri, Kajori; Nica, Gabriela; Vallone, Daniela; Santoriello, Cristina; Neumann, Carl J; Hammerschmidt, Matthias; Foulkes, Nicholas S

    2007-01-01

    Clock output pathways play a pivotal role by relaying timing information from the circadian clock to a diversity of physiological systems. Both cell-autonomous and systemic mechanisms have been implicated as clock outputs; however, the relative importance and interplay between these mechanisms are poorly understood. The cell cycle represents a highly conserved regulatory target of the circadian timing system. Previously, we have demonstrated that in zebrafish, the circadian clock has the capacity to generate daily rhythms of S phase by a cell-autonomous mechanism in vitro. Here, by studying a panel of zebrafish mutants, we reveal that the pituitary–adrenal axis also plays an essential role in establishing these rhythms in the whole animal. Mutants with a reduction or a complete absence of corticotrope pituitary cells show attenuated cell-proliferation rhythms, whereas expression of circadian clock genes is not affected. We show that the corticotrope deficiency is associated with reduced cortisol levels, implicating glucocorticoids as a component of a systemic signaling pathway required for circadian cell cycle rhythmicity. Strikingly, high-amplitude rhythms can be rescued by exposing mutant larvae to a tonic concentration of a glucocorticoid agonist. Our work suggests that cell-autonomous clock mechanisms are not sufficient to establish circadian cell cycle rhythms at the whole-animal level. Instead, they act in concert with a systemic signaling environment of which glucocorticoids are an essential part. PMID:17373855

  15. Role of regulatory b cells in neuroimmunologic disorders.

    PubMed

    Han, Jinming; Sun, Li; Fan, Xueli; Wang, Zhongkun; Cheng, Yun; Zhu, Jie; Jin, Tao

    2016-08-01

    B lymphocytes augment the immune response by producing antibodies and activating T cells by antigen presentation. Recent studies have highlighted a specific and functionally significant B-cell subset that could downregulate excessive immune and inflammatory responses through a vast array of inhibitory cytokines, such as interleukin (IL)-10 and transforming growth factor-β (TGF-β). This subset of B cells is generally referred to as regulatory B cells (Bregs). In addition, recent studies have shown that IL-35-producing Bregs also play a role in downregulation of immunity. Diverse phenotypes of Bregs have been proposed to underlie human disorders and their animal models. Most studies have focused on the role of different subsets of Bregs and Bregs-associated molecules such as IL-10, TGF-β, and IL-35 in the pathogenesis of neuroimmunologic disorders. Furthermore, Bregs exert regulatory function mainly through suppressing the differentiation of Th1/Th17 cells and promoting regulatory T-cell expansion. Reduced presence of Bregs is reportedly associated with progression of several neuroimmunologic disorders. This Review summarizes the current knowledge on the role of Bregs in neuroimmunologic disorders, including multiple sclerosis, neuromyelitis optica, and myasthenia gravis. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc. PMID:27112131

  16. Role of allogeneic stem cell transplantation in mantle cell lymphoma.

    PubMed

    Cohen, Jonathon B; Burns, Linda J; Bachanova, Veronika

    2015-04-01

    Despite a wide spectrum of treatment options, mantle cell lymphoma (MCL) remains a challenging hematologic malignancy to manage. Advances in front-line therapy, including the monoclonal antibody rituximab and increasing use of cytarabine, have improved remission rates. Autologous hematopoietic cell transplantation (HCT) can effectively consolidate remission of MCL, leading to encouraging survival beyond 5 yr. However, nearly all patients with MCL will relapse and require salvage therapy. Novel agents such as ibrutinib, bortezomib, and lenalidomide have dramatically expanded the options for treating relapsed MCL. In this review, we summarize the clinical evidence supporting the use of allogeneic donor HCT in MCL and make recommendations on indications for its use. Data suggest that allogeneic donor HCT is the only curative therapy for patients with poor prognosis or aggressive MCL. Patient selection, timing, and optimal use remain a matter of scientific debate and given the rapidly changing therapeutic landscape of MCL, the outcomes of allogeneic HCT should be interpreted in the context of novel therapeutics. PMID:25154430

  17. Role of Innate T Cells in Anti-Bacterial Immunity

    PubMed Central

    Gao, Yifang; Williams, Anthony P.

    2015-01-01

    Innate T cells are a heterogeneous group of αβ and γδ T cells that respond rapidly (<2 h) upon activation. These innate T cells also share a non MHC class I or II restriction requirement for antigen recognition. Three major populations within the innate T cell group are recognized, namely, invariant NKT cells, mucosal associated invariant T cells, and gamma delta T cells. These cells recognize foreign/self-lipid presented by non-classical MHC molecules, such as CD1d, MR1, and CD1a. They are activated during the early stages of bacterial infection and act as a bridge between the innate and adaptive immune systems. In this review, we focus on the functional properties of these three innate T cell populations and how they are purposed for antimicrobial defense. Furthermore, we address the mechanisms through which their effector functions are targeted for bacterial control and compare this in human and murine systems. Lastly, we speculate on future roles of these cell types in therapeutic settings such as vaccination. PMID:26124758

  18. Role of osteoclasts in regulating hematopoietic stem and progenitor cells

    PubMed Central

    Miyamoto, Takeshi

    2013-01-01

    Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed “niche” to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization. PMID:24147255

  19. Incomplete penetrance: The role of stochasticity in developmental cell colonization.

    PubMed

    Binder, Benjamin J; Landman, Kerry A; Newgreen, Donald F; Ross, Joshua V

    2015-09-01

    Cell colonization during embryonic development involves cells migrating and proliferating over growing tissues. Unsuccessful colonization, resulting from genetic causes, can result in various birth defects. However not all individuals with the same mutation show the disease. This is termed incomplete penetrance, and it even extends to discordancy in monozygotic (identical) twins. A one-dimensional agent-based model of cell migration and proliferation within a growing tissue is presented, where the position of every cell is recorded at any time. We develop a new model that approximates this agent-based process - rather than requiring the precise configuration of cells within the tissue, the new model records the total number of cells, the position of the most advanced cell, and then invokes an approximation for how the cells are distributed. The probability mass function (PMF) for the most advanced cell is obtained for both the agent-based model and its approximation. The two PMFs compare extremely well, but using the approximation is computationally faster. Success or failure of colonization is probabilistic. For example for sufficiently high proliferation rate the colonization is assured. However, if the proliferation rate is sufficiently low, there will be a lower, say 50%, chance of success. These results provide insights into the puzzle of incomplete penetrance of a disease phenotype, especially in monozygotic twins. Indeed, stochastic cell behavior (amplified by disease-causing mutations) within the colonization process may play a key role in incomplete penetrance, rather than differences in genes, their expression or environmental conditions. PMID:26047851

  20. Role of cell surface oligosaccharides of mouse mammary tumor cell lines in cancer metastasis.

    PubMed

    Zhao, Yunxue; Li, Jing; Wang, Jingjian; Xing, Yanli; Geng, Meiyu

    2007-06-01

    Malignant transformation is associated with changes in the glycosylation of cell surface proteins and lipids. In tumor cells, alterations in cellular glycosylation may play a key role in their metastatic behaviour. In the present study, we have assessed the relationship between cell surface oligosaccharides and the metastasis ability of mouse mammary tumor cell lines 67NR and 4TO7. The cell surface oligosaccharides have been analyzed using specific binding assays with some plant lectins and the metastasis ability has been studied using transwell migration and invasion assays. In addition, we investigated the role of terminal sialic acids in the metastatic potential (cell adhesion on fibronectin, cell migration and invasion) in the 4TO7 cells on treatment with neuraminidase. The cell lines used in study have different metastasis abilities in vivo - the 67NR form primary tumors, but no tumor cells are detectable in any distant tissues, while cells of the 4TO7 line are able to spread to lung. In vitro metastasis experiments have revealed higher ability of adhesion, cell migration and invasion in the 4TO7 cells than the 67NR cells. Specific lectins binding assays show that the 4TO7 cells expressed more high-mannose type, multi-antennary complex-type N-glycans, beta-1,6-GlcNAc-branching, alpha-2,6-linked sialic acids, N-acetylgalactosamine and galactosyl(beta-1,3)-N-acetylgalactosamine. Removal of sialic acids on treatment with neuraminidase decreases adhesion, but increases the migration and has shown no significant change in the invasion ability of the 4TO7 cells. The study suggests that the sialic acids are not crucial for the cell migration and invasion in the 4TO7 cells. The findings provide the new insights in understanding the role of cell surface oligosaccharides in cancer metastasis. PMID:17650582

  1. Role of mTOR signaling in intestinal cell migration

    PubMed Central

    Rhoads, J. Marc; Niu, Xiaomei; Odle, Jack; Graves, Lee M.

    2006-01-01

    An early signaling event activated by amino acids and growth factors in many cell types is the phosphorylation of the mammalian target of rapamycin (mTOR; FRAP), which is functionally linked to ribosomal protein s6 kinase (p70s6k), a kinase that plays a critical regulatory role in the translation of mRNAs and protein synthesis. We previously showed that intestinal cell migration, the initial event in epithelial restitution, is enhanced by l-arginine (ARG). In this study, we used amino acids as prototypic activators of mTOR and ARG, IGF-1, or serum as recognized stimulators of intestinal cell migration. We found that 1) protein synthesis is required for intestinal cell migration, 2) mTOR/p70s6k pathway inhibitors (rapamycin, wortmannin, and intracellular Ca2+ chelation) inhibit cell migration, 3) ARG activates migration and mTOR/p70s6k (but not ERK-2) in migrating enterocytes, and 4) immunocytochemistry reveals abundant p70s6k staining in cytoplasm, whereas phosphop70s6k is virtually all intranuclear in resting cells but redistributes to the periphery on activation by ARG. We conclude that mTOR/p70s6k signaling is essential to intestinal cell migration, is activated by ARG, involves both nuclear and cytoplasmic events, and may play a role in intestinal repair. PMID:16710051

  2. The role of dendritic cells in male reproductive tract.

    PubMed

    Wang, Peng; Duan, Yong-Gang

    2016-09-01

    Dendritic cells (DCs) are the most potent professional antigen-presenting cells. The central role of various DC subsets as bridges between innate and adaptive immunity has become more and more evident. However, the role of DC subsets in male reproductive tract remains largely unexplored, in particular distinct DC subsets (including myeloid and plasmacytoid DCs), their maturation stage, and tissue distribution, as well as state of health or disease. Furthermore, infection and inflammation of male genital tract are thought to be a primary etiological factor of male infertility. This review sheds some light on this complex and rapidly growing field. It summarized the recent findings and deals with the characterization and role of DCs in male reproductive tract, that is, testis, epididymis, prostate, seminal vesicle, semen, and foreskin, which might help to understand the immunopathological mechanisms of male infertility and design effective vaccines for male reproductive health. PMID:27353336

  3. Even Mild Football Head Hits Can Harm Vision

    MedlinePlus

    ... www.nlm.nih.gov/medlineplus/news/fullstory_158807.html Even Mild Football Head Hits Can Harm Vision Study of college players raises concerns about repetitive non-concussive impacts To use the sharing features on ...

  4. Concussion Study Shows Player-To-Player Hits Most Damaging

    MedlinePlus

    ... Study Shows Player-to-Player Hits Most Damaging Running longer before the contact happens also spells more ... the University of Georgia. "We also found that running a long distance before colliding with an opponent ...

  5. People with learning disabilities are hit hard by funding cutbacks.

    PubMed

    Hughes, Charlie

    Thank you for publishing Ken Mack's letter (March 5) drawing attention to the suffering and distress caused by welfare reforms and cutbacks, and how people with disabilities and their families are being hit particularly hard. PMID:24617400

  6. Even Mild Football Head Hits Can Harm Vision

    MedlinePlus

    ... html Even Mild Football Head Hits Can Harm Vision Study of college players raises concerns about repetitive ... Repeated blows to the head can cause near vision to blur slightly, even if the individual impacts ...

  7. The Chelyabinsk Meteorite Hits an Anomalous Zone in the Urals

    NASA Astrophysics Data System (ADS)

    Kochemasov, G. G.

    2013-09-01

    The Chelyabinsk meteorite is "strange" because it hits an area in the Urals where anomalous events are observed: shining skies, light balls, UFOs, electrphonic bolids. The area tectonically occurs at the intersection of two fold belts: Urals and Timan.

  8. The putative role of mast cells in lung transplantation.

    PubMed

    Jungraithmayr, W

    2015-03-01

    Mast cells (MCs) were primarily recognized as effector cells of allergy. These cells are acting predominantly at the interface between the host and the external environment, such as skin, gastrointestinal and the respiratory tract. Only recently, MCs have gained increased recognition as cells of functional plasticity with immune-regulatory properties that influence both the innate and the adaptive immune response in inflammatory disorders, cancer and transplantation. Through the secretion of both proinflammatory and antiinflammatory mediators, MCs can either ameliorate or deteriorate the course and outcome in lung transplantation. Recent research from other models recognized the immune-protective activity of MCs including its role as an important source of IL-10 and TGF-β for the modulation of alloreactive T cell responses or assistance in Treg activity. This paper summarizes the current understanding of MCs in lung transplantation and discusses MC-mediated immune-mechanisms by which the outcome of the engrafted organ is modulated. PMID:25693471

  9. Role of topology in complex functional networks of beta cells

    NASA Astrophysics Data System (ADS)

    Cherubini, Christian; Filippi, Simonetta; Gizzi, Alessio; Loppini, Alessandro

    2015-10-01

    The activity of pancreatic β cells can be described by biological networks of coupled nonlinear oscillators that, via electrochemical synchronization, release insulin in response to augmented glucose levels. In this work, we analyze the emergent behavior of regular and percolated β -cells clusters through a stochastic mathematical model where "functional" networks arise. We show that the emergence and robustness of the synchronized dynamics depend both on intrinsic and extrinsic parameters. In particular, cellular noise level, glucose concentration, network spatial architecture, and cell-to-cell coupling strength are the key factors for the generation of a rhythmic and robust activity. Their role in the functional network topology associated with β -cells clusters is analyzed and discussed.

  10. Mammary Development and Breast Cancer: The Role of Stem Cells

    PubMed Central

    Ercan, C.; van Diest, P.J.; Vooijs, M.

    2014-01-01

    The mammary gland is a highly regenerative organ that can undergo multiple cycles of proliferation, lactation and involution, a process controlled by stem cells. The last decade much progress has been made in the identification of signaling pathways that function in these stem cells to control self-renewal, lineage commitment and epithelial differentiation in the normal mammary gland. The same signaling pathways that control physiological mammary development and homeostasis are also often found deregulated in breast cancer. Here we provide an overview on the functional and molecular identification of mammary stem cells in the context of both normal breast development and breast cancer. We discuss the contribution of some key signaling pathways with an emphasis on Notch receptor signaling, a cell fate determination pathway often deregulated in breast cancer. A further understanding of the biological roles of the Notch pathway in mammary stem cell behavior and carcinogenesis might be relevant for the development of future therapies. PMID:21506923

  11. Roles and relevance of mast cells in infection and vaccination

    PubMed Central

    Fang, Yu; Xiang, Zou

    2016-01-01

    Abstract In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases. PMID:26565602

  12. Bimodal role of Kupffer cells during colorectal cancer liver metastasis.

    PubMed

    Wen, Shu Wen; Ager, Eleanor I; Christophi, Christopher

    2013-07-01

    Kupffer cells (KCs) are resident liver macrophages that play a crucial role in liver homeostasis and in the pathogenesis of liver disease. Evidence suggests KCs have both stimulatory and inhibitory functions during tumor development but the extent of these functions remains to be defined. Using KC depletion studies in an orthotopic murine model of colorectal cancer (CRC) liver metastases we demonstrated the bimodal role of KCs in determining tumor growth. KC depletion with gadolinium chloride before tumor induction was associated with an increased tumor burden during the exponential growth phase. In contrast, KC depletion at the late stage of tumor growth (day 18) decreased liver tumor load compared with non-depleted animals. This suggests KCs exhibit an early inhibitory and a later stimulatory effect. These two opposing functions were associated with changes in iNOS and VEGF expression as well as T-cell infiltration. KC depletion at day 18 increased numbers of CD3 (+) T cells and iNOS-expressing infiltrating cells in the tumor, but decreased the number of VEGF-expressing infiltrating cells. These alterations may be responsible for the observed reduction in tumor burden following depletion of pro-tumor KCs at the late stage of metastatic growth. Taken together, our results indicate that the bimodal role of KC activity in liver tumors may provide the key to timing immunomodulatory intervention for the treatment of CRC liver metastases. PMID:23792646

  13. Education Blogs Hit Our Elections next Month

    ERIC Educational Resources Information Center

    Perlmutter, David D.

    2006-01-01

    In this article, the author examines the role blogs will play in future campaigns and elections and how bloggers will affect the election of the next commander in chief. A necessary starting point in discussing the role of blogs in the presidential election of 2008 is to consider how similar blogs are, as a new medium or genre or venue, to…

  14. Do pigeons prefer alternatives that include near-hit outcomes?

    PubMed

    Stagner, Jessica P; Case, Jacob P; Sticklen, Mary F; Duncan, Amanda K; Zentall, Thomas R

    2015-07-01

    Pigeons show suboptimal choice on a gambling-like task similar to that shown by humans. Humans also show a preference for gambles in which there are near hits (losses that come close to winning). In the present research, we asked if pigeons would show a preference for alternatives with near-hit-like trials. In Experiment 1, we included an alternative that presented a near hit, in which a stimulus associated with reinforcement (a presumed conditioned reinforcer) changed to a stimulus associated with the absence of reinforcement (a presumed conditioned inhibitor). The pigeons tended to avoid this alternative. In Experiment 2, we varied the duration of the presumed conditioned reinforcer (2 vs. 8 s) that changed to a presumed conditioned inhibitor (8 vs. 2 s) and found that the longer the conditioned reinforcer was presented, the more the pigeons avoided it. In Experiment 3, the near-hit alternative involved an ambiguous stimulus for 8 s that changed to a presumed conditioned reinforcer (or a presumed conditioned inhibitor) for 2 s, but the pigeons still avoided it. In Experiment 4, we controlled for the duration of the conditioned reinforcer by presenting it first for 2 s followed by the ambiguous stimulus for 8 s. Once again, the pigeons avoided the alternative with the near-hit trials. In all 4 experiments, the pigeons tended to avoid alternatives that provided near-hit-like trials. We concluded that humans may be attracted to near-hit trials because near-hit trials give them the illusion of control, whereas this does not appear to be a factor for pigeons. PMID:26167775

  15. Superfast Cosmic Jet "Hits the Wall"

    NASA Astrophysics Data System (ADS)

    1999-01-01

    -288. The jet travelled quickly until its advance suddenly was stopped and the endpoint of the jet became brighter than the core. "This fast-moving material obviously hit something," Hjellming said. What did it it hit? "Probably a mixture of external material plus material from a previous jet ejection." Further studies of the collision could yield new information about the physics of cosmic jets. Such jets are believed to be powered by black holes into which material is being drawn. The exact mechanism by which the black hole's gravitational energy accelerates particles to nearly the speed of light is not well understood. There is even dispute about the types of particles ejected. Competing models call for either a mixture of electrons and protons or a mixture of electrons and positrons. Because protons are more than 1,800 times more massive than electrons or positrons (the positively-charged antiparticle of the electron), the electron-proton mixture would be much more massive than the electron-positron pair. Thus, an electron-proton jet is called a heavy jet and an electron-positron jet is called a light jet. A light jet would be much more easily slowed or stopped by tenuous interstellar material than a heavy jet, so the collision of XTE J1748-288's jet may indicate that it is a light jet. "There's still a lot more work to do before anyone can conclude that, but the collision offers the possibility of answering the light-heavy jet question," Hjellming said. A 1998 VLA study by John Wardle of Brandeis University and his colleagues indicated that the jet of a distant quasar is a light, electron-positron jet. Though the black holes in quasars are supermassive, usually millions of times more massive than the Sun, the physics of jet production in them is thought to be similar to the physics of jet production by smaller black holes, only a few times more massive than the sun, such as the one possibly in XTE J1748-288. The VLA is an instrument of the National Radio Astronomy

  16. Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death

    PubMed Central

    2016-01-01

    Little is known about the regulation of nonapoptotic cell death. Using massive insertional mutagenesis of haploid KBM7 cells we identified nine genes involved in small-molecule-induced nonapoptotic cell death, including mediators of fatty acid metabolism (ACSL4) and lipid remodeling (LPCAT3) in ferroptosis. One novel compound, CIL56, triggered cell death dependent upon the rate-limiting de novo lipid synthetic enzyme ACC1. These results provide insight into the genetic regulation of cell death and highlight the central role of lipid metabolism in nonapoptotic cell death. PMID:25965523

  17. Thomson Scattering Measurements on HIT-SI3

    NASA Astrophysics Data System (ADS)

    Everson, C. J.; Morgan, K. D.; Jarboe, T. R.

    2015-11-01

    A multi-point Thomson Scattering diagnostic has been implemented on HIT-SI3 (Helicity Injected Torus - Steady Inductive 3) to measure electron temperature. The HIT-SI3 experiment is a modification of the original HIT-SI apparatus that uses three injectors instead of two. This modification alters the configuration of magnetic fields and thus the plasma behavior in the device. The scientific aim of HIT-SI3 is to develop a deeper understanding of how injector behavior and interactions influence current drive and plasma performance in the spheromak. The Thomson Scattering system includes a 20 J (1 GW pulse) Ruby laser that provides the incident beam, and collection optics that are installed such that measurements can be taken at four spatial locations in HIT-SI3 plasmas. For each measurement point, a 3-channel polychromator is used to detect the relative level of scattering. These measurements allow for the presence of temperature gradients in the spheromak to be investigated. Preliminary HIT-SI3 temperature data are presented and can be compared to predictions from computational models. Work supported by the D.O.E.

  18. Caveolin is present in intestinal cells: role in cholesterol trafficking?

    PubMed

    Field, F J; Born, E; Murthy, S; Mathur, S N

    1998-10-01

    It was postulated that specialized microdomains of the plasma membrane, consistent with caveolae, might play a role in cholesterol trafficking in intestinal cells. The existence, therefore, of caveolin and the role of detergent-resistant microdomains of the plasma membrane in cholesterol trafficking were investigated in human small intestine and CaCo-2 cells. Caveolin mRNA was detected by RT-PCR in small intestinal brushings and biopsies and in CaCo-2 cells. Northern hybridization of caveolin mRNA detected 3 kb and 0.8 kb transcripts in CaCo-2 cells. From brushings of distal duodenum and in CaCo-2 cells, Western analysis for detection of caveolin protein demonstrated a 21 kDa-sized protein and a 600 kDa homooligomer. In CaCo-2 cells, caveolin was demonstrated by immunofluorescence in apical membranes as well as within cells. Using sucrose-density gradients, caveolin was localized to detergent-resistant microdomains of the plasma membrane. As determined by cholesterol oxidase-accessible cholesterol, 3-5% of plasma membrane cholesterol in CaCo-2 cells was estimated to be in these detergent-resistant microdomains. After the absorption of cholesterol from bile-salt micelles, more plasma membrane cholesterol moved to these specialized microdomains within the plasma membrane and was esterified. In CaCo-2 cells, filipin, N-ethyl maleimide, and cholesterol depletion, treatments that disrupt caveolar function, interfered with the transport of plasma membrane cholesterol to the endoplasmic reticulum, whereas okadaic acid, sphingomyelinase, and cholesterol oxidase did not. Changes in cholesterol flux at the apical membrane of the cell did not alter mRNA levels or mass of caveolin. The results suggest that caveolin is present in intestinal and CaCo-2 cells and is associated with detergent-resistant microdomains of cellular membranes. With the influx of micellar cholesterol from the lumen, plasma membrane cholesterol moves or "clusters" to these microdomains and is transported

  19. Role of the microtubule-targeting drug vinflunine on cell-cell adhesions in bladder epithelial tumour cells

    PubMed Central

    2014-01-01

    Background Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells. Methods Human bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132. Results We show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation. Conclusions Our findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis. PMID:25012153

  20. A role for homologous recombination proteins in cell cycle regulation

    PubMed Central

    Kostyrko, Kaja; Bosshard, Sandra; Urban, Zuzanna; Mermod, Nicolas

    2015-01-01

    Eukaryotic cells respond to DNA breaks, especially double-stranded breaks (DSBs), by activating the DNA damage response (DDR), which encompasses DNA repair and cell cycle checkpoint signaling. The DNA damage signal is transmitted to the checkpoint machinery by a network of specialized DNA damage-recognizing and signal-transducing molecules. However, recent evidence suggests that DNA repair proteins themselves may also directly contribute to the checkpoint control. Here, we investigated the role of homologous recombination (HR) proteins in normal cell cycle regulation in the absence of exogenous DNA damage. For this purpose, we used Chinese Hamster Ovary (CHO) cells expressing the Fluorescent ubiquitination-based cell cycle indicators (Fucci). Systematic siRNA-mediated knockdown of HR genes in these cells demonstrated that the lack of several of these factors alters cell cycle distribution, albeit differentially. The knock-down of MDC1, Rad51 and Brca1 caused the cells to arrest in the G2 phase, suggesting that they may be required for the G2/M transition. In contrast, inhibition of the other HR factors, including several Rad51 paralogs and Rad50, led to the arrest in the G1/G0 phase. Moreover, reduced expression of Rad51B, Rad51C, CtIP and Rad50 induced entry into a quiescent G0-like phase. In conclusion, the lack of many HR factors may lead to cell cycle checkpoint activation, even in the absence of exogenous DNA damage, indicating that these proteins may play an essential role both in DNA repair and checkpoint signaling. PMID:26125600

  1. Targeting cancer stem cells: emerging role of Nanog transcription factor

    PubMed Central

    Wang, Mong-Lien; Chiou, Shih-Hwa; Wu, Cheng-Wen

    2013-01-01

    The involvement of stemness factors in cancer initiation and progression has drawn much attention recently, especially after the finding that introducing four stemness factors in somatic cells is able to reprogram the cells back to an embryonic stem cell-like state. Following accumulating data revealing abnormal elevated expression levels of key stemness factors, like Nanog, Oct4, and Sox2, in several types of cancer stem cells; the importance and therapeutic potential of targeting these stemness regulators in cancers has turned to research focus. Nanog determines cell fate in both embryonic and cancer stem cells; activating Nanog at an inappropriate time would result in cancer stem cells rather than normal pluripotent stem cells or differentiated somatic cells. Upregulated Nanog is correlated with poor survival outcome of patients with various types of cancer. The discoveries of downstream regulatory pathways directly or indirectly mediated by Nanog indicate that Nanog regulates several aspects of cancer development such as tumor cell proliferation, self-renewal, motility, epithelial-mesenchymal transition, immune evasion, and drug-resistance, which are all defined features for cancer stem cells. The current review paper illustrates the central role of Nanog in the regulatory networks of cancer malignant development and stemness acquirement, as well as in the communication between cancer cells and the surrounding stroma. Though a more defined model is needed to test the therapeutic efficacy of targeting Nanog as a cancer treatment method, current animal experiments using siNanog or shNanog have shown the promising therapeutic potential of Nanog targeting in several types of cancer. PMID:24043946

  2. Mothers with Serious Mental Illness: Their Experience of “Hitting Bottom”

    PubMed Central

    Montgomery, Phyllis; Mossey, Sharolyn; Bailey, Patricia; Forchuk, Cheryl

    2011-01-01

    This study sought to understand the experience of “hitting bottom” from the perspective of 32 mothers with serious mental illness. Secondary narrative analysis of 173 stories about experiences related to hitting bottom were identified. Enactment of their perceived mothering roles and responsibilities was compromised when confronted by the worst of illness. Subsequent to women's descent to bottom was their need for a timely and safe exit from bottom. An intense experience in bottom further jeopardized their parenting and treatment self-determination and, for some, their potential for survival. The results suggest that prevention of bottom is feasible with early assessment of the diverse issues contributing to mothers' vulnerabilities. Interventions to lessen their pain may circumvent bottom experiences. Healing necessitates purposeful approaches to minimize the private and public trauma of bottom experiences, nurture growth towards a future, and establish resources to actualize such a life. PMID:22007325

  3. The role of physical rehabilitation in stem cell transplantation patients

    PubMed Central

    Steinberg, Amir; Asher, Arash; Bailey, Charlotte; Fu, Jack B.

    2015-01-01

    The purpose of this paper is to review the evidence for the role of physical rehabilitation in stem cell transplantation patients. We will also review the literature and discuss professional experiences on how rehabilitation can play a role in stem cell transplant care and survivorship. Hematopoietic stem cell transplantation (HCT) is a procedure that has evolved substantially over the years to help treat multiple conditions, particularly hematologic malignancies. HCT can be very stressful on the body and can leave patients weakened and sometimes quite debilitated. Supportive care measures have advanced to improve the quality of life and overall survival of HCT survivors. One key component of improved supportive care is gaining increased attention, and that is physical medicine and rehabilitation. Its role in HCT survivorship care is expanding, and new insight and research within the discipline have focused on fatigue, inflammation, exercise, and the development of structured rehabilitation programs to improve the musculoskeletal sequelae of transplantation. This literature review has demonstrated the utility of physical rehabilitation in HCT, its impact on cancer-related fatigue, and to outline the current state of the literature on these topics. The paper delves into a background of HCT. Cancer-related fatigue in HCT is then discussed and summarized, and the role that exercise plays in modifying such fatigue is outlined. We then outline the models and the impact that physical rehabilitation may play in HCT recipients. PMID:25971213

  4. The role of physical rehabilitation in stem cell transplantation patients.

    PubMed

    Steinberg, Amir; Asher, Arash; Bailey, Charlotte; Fu, Jack B

    2015-08-01

    The purpose of this paper is to review the evidence for the role of physical rehabilitation in stem cell transplantation patients. We will also review the literature and discuss professional experiences on how rehabilitation can play a role in stem cell transplant care and survivorship. Hematopoietic stem cell transplantation (HCT) is a procedure that has evolved substantially over the years to help treat multiple conditions, particularly hematologic malignancies. HCT can be very stressful on the body and can leave patients weakened and sometimes quite debilitated. Supportive care measures have advanced to improve the quality of life and overall survival of HCT survivors. One key component of improved supportive care is gaining increased attention, and that is physical medicine and rehabilitation. Its role in HCT survivorship care is expanding, and new insight and research within the discipline have focused on fatigue, inflammation, exercise, and the development of structured rehabilitation programs to improve the musculoskeletal sequelae of transplantation. This literature review has demonstrated the utility of physical rehabilitation in HCT, its impact on cancer-related fatigue, and to outline the current state of the literature on these topics. The paper delves into a background of HCT. Cancer-related fatigue in HCT is then discussed and summarized, and the role that exercise plays in modifying such fatigue is outlined. We then outline the models and the impact that physical rehabilitation may play in HCT recipients. PMID:25971213

  5. Double-hit and triple-hit lymphomas arising from follicular lymphoma following acquisition of MYC: report of two cases and literature review.

    PubMed

    Xu, Xiaoxiao; Zhang, Le; Wang, Yafei; Zhang, Qing; Zhang, Lianyu; Sun, Baocun; Zhang, Yizhuo

    2013-01-01

    Double-hit or triple-hit B-cell lymphomas (DHL and THL) are rare subtype lymphomas usually associated with poor prognosis. It is defined by two or three recurrent chromosome translocations; MYC/8q24 loci, usually in combination with the t (14; 18) (q32; q21) bcl-2 gene or/and BCL6/3q27 chromosomal translocation. DHL was often observed both in de-novo diffuse large B cell lymphomas (DLBCL). It is otherwise unclassifiable, showing features intermediate that of large B-cell lymphoma and Burkitt lymphoma. Here, we present two follicular lymphoma patients; one transformed to THL, another transformed to DHL. Both cases revealed aggressive clinical courses with poor prognosis and associated with acquisition of c-Myc gene (MYC) and central nervous system (CNS) involvement. We reviewed the related literature, correlated the immunophenotype and clinical manifestations such as response to therapy and prognosis. Although the incidence of DHT and THL is low, cytogenetic and FISH analyses should be included when B-cell lymphoma patients experience relapse or refractory course of disease. We concluded that c-Myc may contribute to aggressive transformation, and more mechanism-based therapy should be explored. PMID:23573328

  6. The Role of Dendritic Cells in Central Tolerance.

    PubMed

    Oh, Jaehak; Shin, Jeoung-Sook

    2015-06-01

    Dendritic cells (DCs) play a significant role in establishing self-tolerance through their ability to present self-antigens to developing T cells in the thymus. DCs are predominantly localized in the medullary region of thymus and present a broad range of self-antigens, which include tissue-restricted antigens expressed and transferred from medullary thymic epithelial cells, circulating antigens directly captured by thymic DCs through coticomedullary junction blood vessels, and peripheral tissue antigens captured and transported by peripheral tissue DCs homing to the thymus. When antigen-presenting DCs make a high affinity interaction with antigen-specific thymocytes, this interaction drives the interacting thymocytes to death, a process often referred to as negative selection, which fundamentally blocks the self-reactive thymocytes from differentiating into mature T cells. Alternatively, the interacting thymocytes differentiate into the regulatory T (Treg) cells, a distinct T cell subset with potent immune suppressive activities. The specific mechanisms by which thymic DCs differentiate Treg cells have been proposed by several laboratories. Here, we review the literatures that elucidate the contribution of thymic DCs to negative selection and Treg cell differentiation, and discusses its potential mechanisms and future directions. PMID:26140042

  7. Roles of microRNA on cancer cell metabolism

    PubMed Central

    2012-01-01

    Advanced studies of microRNAs (miRNAs) have revealed their manifold biological functions, including control of cell proliferation, cell cycle and cell death. However, it seems that their roles as key regulators of metabolism have drawn more and more attention in the recent years. Cancer cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. MiRNAs regulate cell metabolic processes through complicated mechanisms, including directly targeting key enzymes or transporters of metabolic processes and regulating transcription factors, oncogenes / tumor suppressors as well as multiple oncogenic signaling pathways. MiRNAs like miR-375, miR-143, miR-14 and miR-29b participate in controlling cancer cell metabolism by regulating the expression of genes whose protein products either directly regulate metabolic machinery or indirectly modulate the expression of metabolic enzymes, serving as master regulators, which will hopefully lead to a new therapeutic strategy for malignant cancer. This review focuses on miRNA regulations of cancer cell metabolism,including glucose uptake, glycolysis, tricarboxylic acid cycle and insulin production, lipid metabolism and amino acid biogenesis, as well as several oncogenic signaling pathways. Furthermore, the challenges of miRNA-based strategies for cancer diagnosis, prognosis and therapeutics have been discussed. PMID:23164426

  8. The Role of Stem Cells in Wound Angiogenesis

    PubMed Central

    King, Alice; Balaji, Swathi; Keswani, Sundeep G.; Crombleholme, Timothy M.

    2014-01-01

    Significance: Revascularization plays a critical role in wound healing and is regulated by a complex milieu of growth factors and cytokines. Deficiencies in revascularization contribute to the development of chronic nonhealing wounds. Recent Advances: Stem-cell-based therapy provides a novel strategy to enhance angiogenesis and improve wound healing. With bioethical concerns associated with embryonic stem cells, focus has shifted to different populations of vascular precursors, isolated from adult somatic tissue. Three main populations have been identified: endothelial progenitor cells, mesenchymal stem cells, and induced-pluripotent stem cells. These populations demonstrate great promise to positively influence neovascularization and wound repair. Critical Issues: Further studies to more definitively define each population are necessary to efficiently translate stem-cell-based therapeutic angiogenesis to the bedside. Better understanding of the physiologic pathways of how stem cells contribute to angiogenesis in normal tissue repair will help identify targets for successful therapeutic angiogenesis. Future Directions: Active studies in both animal models and clinical trials are being conducted to develop effective delivery routes, including dosing, route, and timing. Stem-cell-based therapy holds significant potential as a strategy for therapeutic angiogenesis in the care of patients with chronic nonhealing wounds. PMID:25300298

  9. Role of myeloid-derived suppressor cells in autoimmune disease

    PubMed Central

    Crook, Kristen R; Liu, Peng

    2015-01-01

    Myeloid-derived suppressor cells (MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-based cell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy. PMID:25621222

  10. Alcoholic hepatitis: The pivotal role of Kupffer cells.

    PubMed

    Suraweera, Duminda B; Weeratunga, Ashley N; Hu, Robert W; Pandol, Stephen J; Hu, Richard

    2015-11-15

    Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis. PMID:26600966

  11. Alcoholic hepatitis: The pivotal role of Kupffer cells

    PubMed Central

    Suraweera, Duminda B; Weeratunga, Ashley N; Hu, Robert W; Pandol, Stephen J; Hu, Richard

    2015-01-01

    Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis. PMID:26600966

  12. The role of miR-145 in stem cell characteristics of human laryngeal squamous cell carcinoma Hep-2 cells.

    PubMed

    Karatas, Omer Faruk; Suer, Ilknur; Yuceturk, Betul; Yilmaz, Mehmet; Hajiyev, Yusif; Creighton, Chad J; Ittmann, Michael; Ozen, Mustafa

    2016-03-01

    The cancer stem-like cells (CSLCs) are tumorigenic cells promoting initiation, progression, and spread of the tumor. Accumulating evidences suggested the presence of CSLCs in distinct tumors including laryngeal squamous cell carcinoma (LSCC). MicroRNAs have been proposed as significant regulators of carcinogenesis, and several of them have been demonstrated to have direct roles in survival of CSLCs. In this study, we aimed to explore the role of miR-145, which is downregulated in LSCC, on cancer stem cell potency of laryngeal cancer cells. We initially showed the downregulation of miR-145 expression in tumor tissue samples and in CD133-enriched CSLCs. Quantitative reverse-transcription PCR (qRT-PCR) analysis of miR-145-transfected Hep-2 cells demonstrated the inhibitory role of miR-145 on stem cell markers like SOX2, OCT4, KLF4, and ABCG2. We, then, investigated the stem cell features of miR-145-overexpressing Hep-2 cells by sphere formation assay, single-cell cloning assay, and aldehyde dehydrogenase (ALDH) assay, which all demonstrated the inhibition of stem cell potency upon miR-145 overexpression. Further qRT-PCR analysis demonstrated altered expression of epithelial to mesenchymal transition markers in miR-145-overexpressing Hep-2 cells. In conclusion, we demonstrated the regulatory role of miR-145 in stem cell characteristics of Hep-2 cells. Based on these results, we propose that miR-145 might carry crucial roles in LSCC tumorigenesis, prognosis, metastasis, chemoresistance, and recurrence through regulating stem cell properties of tumor cells. PMID:26490990

  13. Role of leptin receptors in granulosa cells during ovulation.

    PubMed

    Dupuis, Lisa; Schuermann, Yasmin; Cohen, Tamara; Siddappa, Dayananda; Kalaiselvanraja, Anitha; Pansera, Melissa; Bordignon, Vilceu; Duggavathi, Raj

    2014-02-01

    Leptin is an important hormone influencing reproductive function. However, the mechanisms underpinning the role of leptin in the regulation of reproduction remain to be completely deciphered. In this study, our objective is to understand the mechanisms regulating the expression of leptin receptor (Lepr) and its role in ovarian granulosa cells during ovulation. First, granulosa cells were collected from superovulated mice to profile mRNA expression of Lepr isoforms (LeprA and LeprB) throughout follicular development. Expression of LeprA and LeprB was dramatically induced in the granulosa cells of ovulating follicles at 4 h after human chorionic gonadotropin (hCG) treatment. Relative abundance of both mRNA and protein of CCAAT/enhancer-binding protein β (Cebpβ) increased in granulosa cells from 1 to 7 h post-hCG. Furthermore, chromatin immunoprecipitation assay confirmed the recruitment of Cebpβ to Lepr promoter. Thus, hCG-induced transcription of Lepr appears to be regulated by Cebpβ, which led us to hypothesise that Lepr may play a role during ovulation. To test this hypothesis, we used a recently developed pegylated superactive mouse leptin antagonist (PEG-SMLA) to inhibit Lepr signalling during ovulation. I.p. administration of PEG-SMLA (10 μg/g) to superovulated mice reduced ovulation rate by 65% compared with control treatment. Although the maturation stage of the ovulated oocytes remained unaltered, ovulation genes Ptgs2 and Has2 were downregulated in PEG-SMLA-treated mice compared with control mice. These results demonstrate that Lepr is dramatically induced in the granulosa cells of ovulating follicles and this induction of Lepr expression requires the transcription factor Cebpβ. Lepr plays a critical role in the process of ovulation by regulating, at least in part, the expression of the important genes involved in the preovulatory maturation of follicles. PMID:24256641

  14. EPRI roles in fuel cell commercialization: Final report

    SciTech Connect

    Boyd, D.W.; Buckley, O.E.; Clark, C.E. Jr.; Fancher, R.B.; Spelman, J.R.

    1987-04-01

    Objective of this study was to identify conditions under which first generation phosphoric acid fuel cells would begin to enter the electric utility market place, and to identify the most useful and affordable roles for EPRI to assist in the market entry process. In performing the study, the applications of fuel cells in four specific utilities were investigated in detail. The conditions necessary for fuel cells to be selected for use by these utilities, in competition primarily with advanced combined-cycle and combustion turbine power plants, were studied closely to give insights into the market entry process and its sensitivity to many technical, economic and business factors. The study concludes that EPRI can best utilize its limited resources by helping to disseminate information and by contributing directly to market entry activities such as the demonstration of several of the initial 11 MW power plants being offered to the utility industry by International Fuel Cells Incorporated.

  15. Role of morphogens in neural crest cell determination.

    PubMed

    Jones, Natalie C; Trainor, Paul A

    2005-09-15

    The neural crest is a transient, migratory cell population found in all vertebrate embryos that generate a diverse range of cell and tissue derivatives including, but not limited, to the neurons and glia of the peripheral nervous system, smooth muscle, connective tissue, melanocytes, craniofacial cartilage, and bone. Over the past few years, many studies have provided tremendous insights into understanding the mechanisms regulating the induction and migration of neural crest cell development. This review highlights the surprising and perhaps unexpected roles for morphogens in these distinct processes. A comparison of studies performed in several different vertebrates emphasizes the requirement for coordination between multiple signaling pathways in the induction and migration of neural crest cells in the developing embryo. PMID:16041760

  16. 42 CFR 495.344 - Approval of the State Medicaid HIT plan, the HIT PAPD and update, the HIT IAPD and update, and...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) STANDARDS AND CERTIFICATION STANDARDS FOR THE ELECTRONIC HEALTH RECORD TECHNOLOGY INCENTIVE PROGRAM... include all of the information required under this subpart. ... 42 Public Health 5 2010-10-01 2010-10-01 false Approval of the State Medicaid HIT plan, the...

  17. Antimicrobial combinations: Bliss independence and Loewe additivity derived from mechanistic multi-hit models.

    PubMed

    Baeder, Desiree Y; Yu, Guozhi; Hozé, Nathanaël; Rolff, Jens; Regoes, Roland R

    2016-05-26

    Antimicrobial peptides (AMPs) and antibiotics reduce the net growth rate of bacterial populations they target. It is relevant to understand if effects of multiple antimicrobials are synergistic or antagonistic, in particular for AMP responses, because naturally occurring responses involve multiple AMPs. There are several competing proposals describing how multiple types of antimicrobials add up when applied in combination, such as Loewe additivity or Bliss independence. These additivity terms are defined ad hoc from abstract principles explaining the supposed interaction between the antimicrobials. Here, we link these ad hoc combination terms to a mathematical model that represents the dynamics of antimicrobial molecules hitting targets on bacterial cells. In this multi-hit model, bacteria are killed when a certain number of targets are hit by antimicrobials. Using this bottom-up approach reveals that Bliss independence should be the model of choice if no interaction between antimicrobial molecules is expected. Loewe additivity, on the other hand, describes scenarios in which antimicrobials affect the same components of the cell, i.e. are not acting independently. While our approach idealizes the dynamics of antimicrobials, it provides a conceptual underpinning of the additivity terms. The choice of the additivity term is essential to determine synergy or antagonism of antimicrobials.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. PMID:27160596

  18. Current challenges and novel treatment strategies in double hit lymphomas

    PubMed Central

    Anderson, Mary Ann; Tsui, Alpha; Wall, Meaghan; Huang, David C. S.; Roberts, Andrew W.

    2016-01-01

    High-grade B-cell lymphomas with recurrent chromosomal break points have been termed ‘double hit lymphoma’ (DHL). The most commonly seen DHL is diffuse large B-cell lymphoma (DLBCL) with t(14;18) and t(8;14) or t(8;22) resulting in overexpression of BCL2 and MYC, respectively. The increased proliferation due to MYC overexpression, without the ability for an apoptotic brake as a result of BCL2 overexpression, results in ‘the perfect storm of oncogenesis’. Thus this disease presents a number of diagnostic and therapeutic challenges for the hematologist. The first and foremost challenge is to recognize the DHL. As different morphological entities can be affected it is incumbent on pathologists and clinicians to maintain a high index of suspicion especially in disease that appears unusually aggressive or refractory to therapy. Diagnosis by fluorescence in situ hybridization (FISH) is a sensitive and specific method for detection of the disease but is time-consuming and expensive. While detection by immunohistochemistry (IHC) is sensitive and correlates with survival, standardized methods for this are not widely agreed upon. The second and equally important challenge in DHL is optimizing clinical outcome in a group of patients for whom the prognosis is widely regarded as poor. While improvements have been achieved by dose escalating standard chemotherapeutic regimens, many patients continue to do badly. Furthermore as a disease of aging many patients are unsuitable for dose-intensive chemotherapy regimens. There are now multiple novel targeted agents in various stages of clinical development that offer hope for better outcomes without undue toxicity. Among the most exciting of these developments include specific inhibitors of both BCL2 and MYC. PMID:26834954

  19. Role of mast cells in gastrointestinal mucosal defense.

    PubMed

    Penissi, Alicia B; Rudolph, María I; Piezzi, Ramón S

    2003-08-01

    The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators. PMID:14510234

  20. Role of Endothelial Cells in Myocardial Ischemia-Reperfusion Injury

    PubMed Central

    Singhal, Arun K.; Symons, J. David; Boudina, Sihem; Jaishy, Bharat; Shiu, Yan-Ting

    2014-01-01

    Minimizing myocardial ischemia-reperfusion injury has broad clinical implications and is a critical mediator of cardiac surgical outcomes. “Ischemic injury” results from a restriction in blood supply leading to a mismatch between oxygen supply and demand of a sufficient intensity and/or duration that leads to cell necrosis, whereas ischemia-reperfusion injury occurs when blood supply is restored after a period of ischemia and is usually associated with apoptosis (i.e. programmed cell death). Compared to vascular endothelial cells, cardiac myocytes are more sensitive to ischemic injury and have received the most attention in preventing myocardial ischemia-reperfusion injury. Many comprehensive reviews exist on various aspects of myocardial ischemia-reperfusion injury. The purpose of this review is to examine the role of vascular endothelial cells in myocardial ischemia-reperfusion injury, and to stimulate further research in this exciting and clinically relevant area. Two specific areas that are addressed include: 1) data suggesting that coronary endothelial cells are critical mediators of myocardial dysfunction after ischemia-reperfusion injury; and 2) the involvement of the mitochondrial permeability transition pore in endothelial cell death as a result of an ischemia-reperfusion insult. Elucidating the cellular signaling pathway(s) that leads to endothelial cell injury and/or death in response to ischemia-reperfusion is a key component to developing clinically applicable strategies that might minimize myocardial ischemia-reperfusion injury. PMID:25558187

  1. Role of Inflammation and Substrate Stiffness in Cancer Cell Transmigration

    NASA Astrophysics Data System (ADS)

    Hamilla, Susan; Stroka, Kimberly; Aranda-Espinoza, Helim

    2013-03-01

    Cancer metastasis, the ability for cancer cells to break away from the primary tumor site and spread to other organs of the body, is one of the main contributing factors to the deadliness of the disease. One of the rate-limiting steps in cancer metastasis that is not well understood is the adhesion of tumor cells to the endothelium followed by transmigration. Other factors include substrate stiffness and inflammation. To test these parameters, we designed an in vitro model of transendothelial migration. Our results suggest that cancer cell transmigration is a two-step process in which they first incorporate into the endothelium before migrating through. It was observed that the cumulative fraction of cancer cells that incorporate into the endothelium increases over time. Unlike leukocytes, which can directly transmigrate through the endothelium, cancer cells appear to have a two-step process of transmigration. Our results indicate that inflammation does not act as a signal for cancer cells to localize at specific sites and transmigrate similarly to leukocytes. Cancer cell transmigration also does not vary with substrate stiffness indicating that tissue stiffness may not play a role in cancer's propensity to metastasize to certain tissues.

  2. Cholera Toxin and Cell Growth: Role of Membrane Gangliosides

    PubMed Central

    Hollenberg, Morley D.; Fishman, Peter H.; Bennett, Vann; Cuatrecasas, Pedro

    1974-01-01

    The binding of cholera toxin to three transformed mouse cell lines derived from the same parent strain, and the effects of the toxin on DNA synthesis and adenylate cyclase activity, vary in parallel with the ganglioside composition of the cells. TAL/N cells of early passage, which contain large quantities of gangliosides GM3, GM2, GM1, and GDla, as well as the glycosyltransferases necessary for the synthesis of these gangliosides, bind the most cholera toxin and are the most sensitive to its action. TAL/N cells of later passage, which lack chemically detectable GM1 and GDla and which have no UDP-Gal:GM2 galactosyltransferase activity, are intermediate in binding and response to the toxin. SVS AL/N cells, which lack GM2 in addition to GM1 and GDla and which have little detectable UDP-GalNAc:GM3N-acetylgalactosaminyltransferase activity, bind the least amount of toxin. The SVS AL/N cells are the least responsive to inhibition of DNA synthesis and stimulation of adenylate cyclase activity by cholera toxin. Gangliosides (especially GM1), which appear to be the natural membrane receptors for cholera toxin, may normally have important roles in the regulation of cell growth and cAMP-mediated responses. PMID:4530298

  3. Growing the Mandible: Role of the Periosteum and Its Cells

    PubMed Central

    OCHAREON, PANNEE; HERRING, SUSAN W.

    2009-01-01

    Mandibular periosteum moves in the direction of new apposition. This displacement, usually termed “migration,” is thought to involve the fibrous layer of periosteum, with the deeper osteogenic layer remaining at its original location except for its blood vessels. To assess whether periosteal displacement includes cells as well as matrix and whether the osteogenic layer has a role, a longitudinal study was undertaken. Young pigs (n = 10) were injected with a replication marker and killed 3 hr, 2 weeks, or 4 weeks later. Sections of the mandibular ramus were scored for labeled cell density. Some sections were double-labeled with lectin to identify blood vessels. Statistical differences were seen between but not within age groups. Three hours after labeling, the fibroblastic layer had sparse, evenly distributed replicating cells, whereas the osteogenic layer had numerous replicating cells, especially at the caudal border. At 2 and 4 weeks later, a decrease in labeled osteogenic layer cells was accompanied by an increase in labeled osteocytes. Zones of labeled osteocytes in these late-sacrifice groups were used to approximate the position of the ramal borders at the time of injection. Beyond these zones, in active growing sites, labeled cells were found not only in the fibrous layer but also in the osteogenic layer and in bone. Therefore, periosteal displacement does involve cells and is not restricted to the fibrous layer. PMID:17847053

  4. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update

    PubMed Central

    Sultana, Misbah; Qazi, Aamer; Qazi, Mahmood Husain; Parveen, Gulshan; Waquar, Sulayman; Ashraf, Abdul Basit; Rasool, Mahmood

    2016-01-01

    Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds. PMID:26998418

  5. Microdosimetry of astatine-211 single-cell irradiation: role of daughter polonium-211 diffusion.

    PubMed

    Palm, Stig; Humm, John L; Rundqvist, Robert; Jacobsson, Lars

    2004-02-01

    A microdosimetric analysis of previously published data on 211At-albumin, free 211At, and 211At-C215 irradiation of Colo-205 cells in a slowly rotating single-cell suspension is presented. A custom-built computer program based on the Monte Carlo method was used to simulate the irradiation and the energy deposition in individual cell nuclei. Separate simulations were made for the assumption that the 211Po atom stays in the position where it is created, and that it diffuses away. The mean event number at which 37% of all cells survived, n37, and the frequency mean specific energy per event, zF, were estimated. The Poisson distribution of events and simulated single and multievent distributions of specific energy were used to find the single-cell specific energy at which the probability of survival is reduced to 37%, z37. The calculated single-cell radiosensitivity values show that 211Po atoms, created on a cell surface by the decay of 211At atoms, will diffuse from the cell during its life-span. The increasing distance to the cell nucleus will drastically decrease the probability of the emitted alpha particle to hit the nucleus. This will result in fewer alpha-particle events in the cell nucleus. For dispersed cells, the diffusion of 211Po atoms will reduce the total dose from cell-bound 211At by a factor of 2. PMID:15000607

  6. Role of NK, NKT cells and macrophages in liver transplantation

    PubMed Central

    Fahrner, René; Dondorf, Felix; Ardelt, Michael; Settmacher, Utz; Rauchfuss, Falk

    2016-01-01

    Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia-reperfusion injury are discussed in this review. PMID:27468206

  7. Don't Hit that "Delete" Button!

    ERIC Educational Resources Information Center

    O'Hanlon, Charlene

    2009-01-01

    On Dec. 1, 2006, the once ambiguous role of e-mails in court cases became much more clear. On that day, the Federal Rules of Civil Procedure (FRCP), which govern federal civil litigation, were amended to establish standards for the discovery of electronically stored information, now known as e-discovery. Many corporations began moving quickly to…

  8. Hitting the Road: Safe Student Transportation

    ERIC Educational Resources Information Center

    Labriola, Patrick

    2013-01-01

    This article highlights the importance of school administrators' taking an active role in selecting motor coach carriers for their school trips. School administrators must be able to prove due diligence in selecting safe motor carriers. If not, they risk significant liability exposure for neglecting this critical responsibility. The article…

  9. Role of cell death in the propagation of PrP(Sc) in immune cells.

    PubMed

    Takahashi, Kenichi; Inoshima, Yasuo; Ishiguro, Naotaka

    2015-03-01

    A number of studies have suggested that macrophages, dendritic cells, and follicular dendritic cells play an important role in the propagation of PrP(Sc). Both accumulation and proteolysis of PrP(Sc) have been demonstrated in peripheral macrophages. Macrophages may act as reservoirs for PrP(Sc) particles if the cells die during transient PrP(Sc) propagation. However, whether cell death plays a role in PrP(Sc) propagation in macrophages remains unclear. In this study, we investigated the possibility of propagation and transmission of PrP(Sc) between dead immune cells and living neural cells. We found that under specific conditions, transient PrP(Sc) propagation occurs in dead cells, indicating that interaction between PrP(C) and PrP(Sc) on plasma membrane lipid rafts might be important for PrP(Sc) propagation. Co-culturing of killed donor PrP(Sc)-infected macrophages with recipient N2a-3 neuroblastoma cells accelerated PrP(Sc) transmission. Our results suggest that cell death may play an important role in PrP(Sc) propagation, whereas transient PrP(Sc) propagation in macrophages has little effect on PrP(Sc) transmission. PMID:25559669

  10. Role of Geminin in cell fate determination of hematopoietic stem cells (HSCs).

    PubMed

    Yasunaga, Shin'ichiro; Ohno, Yoshinori; Shirasu, Naoto; Zhang, Bo; Suzuki-Takedachi, Kyoko; Ohtsubo, Motoaki; Takihara, Yoshihiro

    2016-09-01

    Geminin exerts two distinct molecular roles. Geminin negatively regulates DNA replication licensing through the direct interaction with Cdt1 to prevent re-replication in proliferating cells. Geminin also regulates chromatin remodeling through the direct interaction with Brahma/Brg1 to maintain undifferentiated states of stem cells. We previously uncovered that Polycomb-group complex 1 and Hoxb4/Hoxa9, well-known intrinsic factors that are essential for maintaining the hematopoietic stem cell (HSC) activity, alternatively act as ubiquitin-proteasome systems for Geminin protein to reduce the protein expression level, and sustain the HSC activity. Thus, Geminin is presumed to play an important role in determining cell fate, i.e., turning on and off cellular quiescence and proliferation/differentiation, in HSCs. We recently generated recombinant cell-penetrating Geminin (CP-Geminin), enabling rapid incorporation and withdraw of Geminin protein in cells. CP-Geminin may be useful in regulating the cell cycle and chromatin configuration. In this article, we summarize current information on the molecular functions of Geminin and the regulatory system for Geminin protein expression, and argue for the molecular role of Geminin in cell fate determination of HSCs, and future perspective of a new technology for manipulating the activities of HSCs and cancer stem cells (CSCs). PMID:27422432

  11. The role of pancreatic stellate cells in pancreatic cancer.

    PubMed

    Erkan, Mert

    2013-01-01

    Since conventional and targeted therapies aiming at cancer cells have largely failed to prolong survival in pancreatic cancer, targeting the infrastructure of the tumor, hence its stroma is a novel strategy. It is believed that fibrotic and hypovascular stroma forms a barrier around cancer cells, hindering effective delivery of chemotherapy. Theoretically, antifibrotic therapy should reduce the compactness of the stroma and reduce the interstitial pressure, allowing better delivery of chemotherapy. This approach has worked successfully in a genetically engineered mouse model but failed in humans, paradoxically increasing mortality in the treatment arm. Normally, stromal cells deposit extracellular matrix as an innate defensive reaction to form a barrier between what is harmful and the rest of the body. Despite the significant amount of in vitro data suggesting the pro-tumorigenic roles of activated stellate cells, there is no reason to believe that stellate cells around genetically mutated cells are from the beginning there to support carcinogenesis. Such a stromal activation is also observed around PanIN lesions (which harbor genetically mutated cells) in chronic pancreatitis, where no cancer develops. In pancreatic cancer, the selection pressure created by the fibrotic and hypoxic stroma eventually leads to the evolution of more aggressive clones, indirectly contributing to the aggressiveness of the tumor. Here, the main problem is the late diagnosis of pancreatic cancer, which gives cancer cells enough time for malignant evolution. Therefore, applying antifibrotic therapy at a late stage can be counterproductive. It may increase delivery of chemotherapy, but also lead to the escape of cancer cells. PMID:23561966

  12. The role of Cajal cells in chronic prostatitis.

    PubMed

    Haki Yuksel, Ozgur; Urkmez, Ahmet; Verit, Ayhan

    2016-01-01

    Types of prostatitis can be defined as groups of syndromes in adult men associated with infectious and noninfectious causes characterized frequently by lower abdominal and perineal signs and diverse clinical symptoms and complications. Etiopathogenesis of chronic prostatitis is not well defined. Moreover, its treatment outcomes are not satisfactory. Presence of c-kit positive interstitial cells in human prostate is already known. It has been demonstrated that these cells can be pacemaker cells which trigger spontaneous slow-wave electrical activity in the prostate and can be responsible for the transport of glandular secretion from acinar cells into major and minor prostatic ducts and finally into urethra. In the light of all these data, when presence of a possible inflammatory pathology is thought to involve prostate that secretes and has a reservoir which drains its secretion (for prostate, prostatic urethra), two points are worth mentioning. Impairment of secretion mechanism and collection of secretion within the organ with reflux of the microbial material from its reservoir back into prostate gland. Both of these potential conditions can be explained by ductal neuromuscular mechanism, which induces secretion. We think that in this neuromuscular mechanism interstitial Cajal cells have an important role in chronic prostatitis. Our hypothesis is that curability of prostatitis is correlated with the number of Cajal cells not subjected to apoptosis. PMID:27377090

  13. The role of nitric oxide in ocular surface cells.

    PubMed

    Kim, Jae Chan; Park, Gun Sic; Kim, Jin Kook; Kim, Young Myeong

    2002-06-01

    The role of nitric oxide (NO) in the ocular surface remains unknown. We investigated the conditions leading to an increase of NO generation in tear and the main sources of NO in ocular surface tissue. We evaluated the dual action (cell survival or cell death) of NO depending on its amount. We measured the concentration of nitrite plus nitrate in the tears of ocular surface diseases and examined the main source of nitric oxide synthase (NOS). When cultured human corneal fibroblast were treated with NO producing donor with or without serum, the viabilities of cells was studied. We found that the main sources of NO in ocular surface tissue were corneal epithelium, fibroblast, endothelium, and inflammatory cells. Three forms of NOS (eNOS, bNOS, and iNOS) were expressed in experimentally induced inflammation. In the fibroblast culture system, the NO donor (SNAP, S-nitroso-N-acetyl-D, L-penicillamine) prevented the death of corneal fibroblast cells caused by serum deprivation in a dose dependent manner up to 500 micrometer SNAP, but a higher dose decreased cell viability. This study suggested that NO might act as a double-edged sword in ocular surface diseases depending on the degree of inflammation related with NO concentration. PMID:12068145

  14. The Role of Lipid Domains in Bacterial Cell Processes

    PubMed Central

    Barák, Imrich; Muchová, Katarína

    2013-01-01

    Membranes are vital structures for cellular life forms. As thin, hydrophobic films, they provide a physical barrier separating the aqueous cytoplasm from the outside world or from the interiors of other cellular compartments. They maintain a selective permeability for the import and export of water-soluble compounds, enabling the living cell to maintain a stable chemical environment for biological processes. Cell membranes are primarily composed of two crucial substances, lipids and proteins. Bacterial membranes can sense environmental changes or communication signals from other cells and they support different cell processes, including cell division, differentiation, protein secretion and supplementary protein functions. The original fluid mosaic model of membrane structure has been recently revised because it has become apparent that domains of different lipid composition are present in both eukaryotic and prokaryotic cell membranes. In this review, we summarize different aspects of phospholipid domain formation in bacterial membranes, mainly in Gram-negative Escherichia coli and Gram-positive Bacillus subtilis. We describe the role of these lipid domains in membrane dynamics and the localization of specific proteins and protein complexes in relation to the regulation of cellular function. PMID:23429192

  15. Role of Ionic Strength in Staphylococcal Cell Aggregation.

    PubMed

    Vanzieleghem, Thomas; Couniot, Numa; Herman-Bausier, Philippe; Flandre, Denis; Dufrêne, Yves F; Mahillon, Jacques

    2016-07-26

    Cell aggregation plays a key role in biofilm formation and pathogenesis of Staphylococcus species. Although the molecular basis of aggregation in Staphylococci has already been extensively investigated, the influence of environmental factors, such as ionic strength, remains poorly understood. In this paper, we report a new type of cellular aggregation of Staphylococci that depends solely on ionic strength. Seven strains out of 14, all belonging to staphylococcal species, formed large cell clusters within minutes in buffers of ionic strength ranging from 1.5 to 50 mM, whereas isolates belonging to other Gram-positive species did not display this phenotype. Atomic force microscopy (AFM) with chemically functionalized tips provided direct evidence that ionic strength modulates cell surface adhesive properties through changes in cell surface charge. The optimal ionic strength for aggregation was found to be strain dependent, but in all cases, bacterial aggregates formed at an ionic strength of 1.5-50 mM were rapidly dispersed in a solution of higher ionic strength, indicating a reversibility of the cell aggregation process. These findings suggest that some staphylococcal isolates can respond to ionic strength as an external stimulus to trigger rapid cell aggregation in a way that has not yet been reported. PMID:27364477

  16. Role of mitochondria on muscle cell death and meat tenderization.

    PubMed

    Sierra, Verónica; Oliván, Mamen

    2013-05-01

    The possibility that mitochondria are involved in cellular dysfunction is particularly high in situations associated with increases in free radical activity, like hypoxia or ischemia; therefore its potential role in the muscle post-mortem metabolism is reviewed. In the dying muscle, different routes of cell death catabolism (apoptosis, autophagy) may occur having great influence on the process of conversion of muscle into meat. Mitochondria are the first and also one of the main organelles affected by post-mortem changes; therefore they are decisive in the subsequent cellular responses influencing the pathway to cell demise and thus, the final meat quality. Depending on the cell death programme followed by muscle cells after exsanguination, diverse proteases would be activated to a different extent, which is also reviewed in order to understand how they affect meat tenderization. This review also summarizes recent patents relating cell death processes and meat tenderness. Further research is encouraged as there is still a need of knowledge on cell death post-mortem processes to increase our understanding of the conversion of muscle into meat. PMID:23432120

  17. The role of chromatin structure in cell migration

    PubMed Central

    Gerlitz, Gabi; Bustin, Michael

    2010-01-01

    Chromatin dynamics play a major role in regulating genetic processes. Now, accumulating data suggest that chromatin structure may also affect the mechanical properties of the nucleus and cell migration. Global chromatin organization seems to modulate the shape, the size and the stiffness of the nucleus. Directed-cell migration, which often requires nuclear reshaping to allow cellular passage through narrow openings, is dependent not only on changes in cytoskeletal elements, but also on the global chromatin condensation. Conceivably, during cell migration a physical link between the chromatin and the cytoskeleton facilitates coordinated structural changes in these two components. Thus, in addition to regulating genetic processes, we suggest that alterations in chromatin structure may facilitate cellular reorganizations necessary for efficient migration. PMID:20951589

  18. The Role of Adenosine Signaling in Sickle Cell Therapeutics

    PubMed Central

    Field, Joshua J.; Nathan, David G.; Linden, Joel

    2014-01-01

    Recent data suggest a role for adenosine signaling in the pathogenesis of sickle cell disease (SCD). Signaling through the adenosine A2A receptor (A2AR) has demonstrated beneficial effects in SCD. Activation of A2ARs decreases inflammation in mice and patients with SCD largely by blocking activation of invariant NKT cells. Decreased inflammation may reduce the severity of vaso-occlusive crises. In contrast, adenosine signaling through the A2B receptor (A2BR) may be detrimental for patients with SCD. Priapism and the formation of sickle erythrocytes may be a consequence of A2BR activation on corpus cavernosal cells and erythrocytes, respectively. Whether adenosine signaling predominantly occurs through A2ARs or A2BRs may depend on differing levels of adenosine and disease state (steady state versus crisis). There may be opportunities to develop novel therapeutic approaches targeting A2ARs and/or A2BRs for patients with SCD. PMID:24589267

  19. The role of B cells and autoantibodies in neuropsychiatric lupus.

    PubMed

    Wen, Jing; Stock, Ariel D; Chalmers, Samantha A; Putterman, Chaim

    2016-09-01

    The central nervous system manifestations of SLE (neuropsychiatric lupus, NPSLE) occur frequently, though are often difficult to diagnose and treat. Symptoms of NPSLE can be quite diverse, including chronic cognitive and emotional manifestations, as well as acute presentations, such as stroke and seizures. Although the pathogenesis of NPSLE has yet to be well characterized, B-cell mediated damage is believed to be an important contributor. B-cells and autoantibodies may traverse the blood brain barrier promoting an inflammatory environment consisting of glia activation, neurodegeneration, and consequent averse behavioral outcomes. This review will evaluate the various suggested roles of B-cells and autoantibodies in NPSLE, as well as therapeutic modalities targeting these pathogenic mediators. PMID:27389531

  20. mRNAs Hit a Sticky Wicket.

    PubMed

    Voronina, Ekaterina

    2016-04-01

    Drosophila germ cell specification depends on localization of mRNAs required for patterning to the posterior of the oocyte during oogenesis. In a recent issue of Nature, Vourekas et al. (2016) suggest that Aubergine in complex with piRNAs may provide a low-specificity anchoring mechanism for posterior mRNAs. PMID:27046827

  1. Role of alloreactive KIR2DS1(+) NK cells in haploidentical hematopoietic stem cell transplantation.

    PubMed

    Marcenaro, Emanuela; Carlomagno, Simona; Pesce, Silvia; Della Chiesa, Mariella; Moretta, Alessandro; Sivori, Simona

    2011-10-01

    In allo-HSCT, donor-derived, "alloreactive" NK cells have been shown to play a crucial role in the treatment of acute leukemia, contributing to eradication of leukemic blasts (GvL effect) and to clearance of residual recipient DCs and T lymphocytes (thus, preventing GvHD and graft rejection, respectively). Such alloreactive NK cells do not express CD94/NKG2A but express inhibitory KIRs, specific for HLA class I allotypes, present in the donor but lacking in the recipient. This review is focused on the role of the activating KIR2DS1 receptor (specific for the C2-epitope of HLA-C) in haplo-HSCT. Recent data indicate that KIR2DS1 expression in HSC donors may represent a remarkable advantage in alloreactive NK responses. This is a result of a substantial increase in the NK-mediated capability to kill, not only recipients' leukemic cells but also DCs and T cell blasts. The beneficial effects mediated by alloreactive KIR2DS1(+) NK cells may occur after de novo expression of CCR7 upon interaction with allogeneic, KIR ligand-mismatched CCR7(+) cells. As a consequence, they can be redirected to LNs, where they can prevent priming of donor T cells and induction of GvHD. Finally, KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of "not alloreactive" NK cells into potent alloreactive cells. PMID:21791599

  2. Role of "cancer stem cells" and cell survival in tumor development and maintenance.

    PubMed

    Adams, J M; Kelly, P N; Dakic, A; Carotta, S; Nutt, S L; Strasser, A

    2008-01-01

    One critical issue for cancer biology is the nature of the cells that drive the inexorable growth of malignant tumors. Reports that only rare cell populations within human leukemias seeded leukemia in mice stimulated the now widely embraced hypothesis that only such "cancer stem cells" maintain all tumor growth. However, the mouse microenvironment might instead fail to support the dominant human tumor cell populations. Indeed, on syngeneic transplantation of mouse lymphomas and leukemias, we and other investigators have found that a substantial proportion (>10%) of their cells drive tumor growth. Thus, dominant clones rather than rare cancer stem cells appear to sustain many tumors. Another issue is the role of cell survival in tumorigenesis. Because tumor development can be promoted by the overexpression of prosurvival genes such as bcl-2, we are exploring the role of endogenous Bcl-2-like proteins in lymphomagenesis. The absence of endogenous Bcl-2 in mice expressing an Emu-myc transgene reduced mature B-cell numbers and enhanced their apoptosis, but unexpectedly, lymphoma development was undiminished or even delayed. This suggests that these tumors originate in an earlier cell type, such as the pro-B or pre-B cell, and that the nascent neoplastic clones do not require Bcl-2 but may instead be protected by a Bcl-2 relative. PMID:19022754

  3. Engrailed-2 might play an anti-oncogenic role in clear-cell renal cell carcinoma.

    PubMed

    Lai, Cai-Yong; Xu, Yin; Yu, Gan-Shen; Wu, Xun; Li, Yun-Fei; Pan, Bin; Heng, Bao-Li; Xue, Yi-Jun; Su, Ze-Xuan

    2016-06-01

    Our preliminary study indicated that Engrailed-2 (EN2) is downregulated but also ectopically expressed in clear-cell renal cell carcinoma (CCRCC), and the absence of EN2 expression was associated with poor histological grade. However, the specific roles of EN2 in CCRCC have yet to be elucidated. In the present study, we examined the effects of inhibiting EN2 expression by human renal tubular epithelial cells (HK-2) and overexpressing EN2 by human clear-cell renal cells (786-O). Results showed that EN2 inhibition accelerated HK-2 cell proliferation, shortened the cell cycle, reduced apoptosis, and acted more invasively. By contrast, EN2 overexpression in 786-O cells decelerated the proliferative ability of 786-O, increased the percentage of cell apoptosis, and weakened the invasive ability. Overall, the results demonstrated that EN2 might play an anti-oncogenic role in oncogenesis and development of CCRCC, thereby maintaining the normal growth of human renal tubular epithelial cells. PMID:26948025

  4. Improved curveball hitting through the enhancement of visual cues.

    PubMed

    Osborne, K; Rudrud, E; Zezoney, F

    1990-01-01

    This study investigated the effectiveness of using visual cues to highlight the seams of baseballs to improve the hitting of curveballs. Five undergraduate varsity baseball team candidates served as subjects. Behavior change was assessed through an alternating treatments design involving unmarked balls and two treatment conditions that included baseballs with 1/4-in. and 1/8-in. orange stripes marking the seams of the baseballs. Results indicated that subjects hit a greater percentage of marked than unmarked balls. These results suggest that the addition of visual cues may be a significant and beneficial technique to enhance hitting performance. Further research is suggested regarding the training procedures, effect of feedback, rate of fading cues, generalization to live pitching, and generalization to other types of pitches. PMID:2249972

  5. Influence of Running on Pistol Shot Hit Patterns.

    PubMed

    Kerkhoff, Wim; Bolck, Annabel; Mattijssen, Erwin J A T

    2016-01-01

    In shooting scene reconstructions, risk assessment of the situation can be important for the legal system. Shooting accuracy and precision, and thus risk assessment, might be correlated with the shooter's physical movement and experience. The hit patterns of inexperienced and experienced shooters, while shooting stationary (10 shots) and in running motion (10 shots) with a semi-automatic pistol, were compared visually (with confidence ellipses) and statistically. The results show a significant difference in precision (circumference of the hit patterns) between stationary shots and shots fired in motion for both inexperienced and experienced shooters. The decrease in precision for all shooters was significantly larger in the y-direction than in the x-direction. The precision of the experienced shooters is overall better than that of the inexperienced shooters. No significant change in accuracy (shift in the hit pattern center) between stationary shots and shots fired in motion can be seen for all shooters. PMID:26331462

  6. The role and importance of club cells (Clara cells) in the pathogenesis of some respiratory diseases.

    PubMed

    Rokicki, Wojciech; Rokicki, Marek; Wojtacha, Jacek; Dżeljijli, Agata

    2016-03-01

    The report presents the cellular structure of the respiratory system as well as the history of club cells (Clara cells), their ultrastructure, and location in the airways and human organs. The authors discuss the biochemical structure of proteins secreted by these cells and their importance for the integrity and regeneration of the airway epithelium. Their role as progenitor cells for the airway epithelium and their involvement in the biotransformation of toxic xenobiotics introduced into the lungs during breathing is emphasized. This is followed by a discussion of the clinical aspects associated with club cells, demonstrating that tracking the serum concentration of club cell-secreted proteins is helpful in the diagnosis of a number of lung tissue diseases. Finally, suggestions are provided regarding the possible use of proteins secreted by club cells in the treatment of serious respiratory conditions. PMID:27212975

  7. The role and importance of club cells (Clara cells) in the pathogenesis of some respiratory diseases

    PubMed Central

    Rokicki, Marek; Wojtacha, Jacek; Dżeljijli, Agata

    2016-01-01

    The report presents the cellular structure of the respiratory system as well as the history of club cells (Clara cells), their ultrastructure, and location in the airways and human organs. The authors discuss the biochemical structure of proteins secreted by these cells and their importance for the integrity and regeneration of the airway epithelium. Their role as progenitor cells for the airway epithelium and their involvement in the biotransformation of toxic xenobiotics introduced into the lungs during breathing is emphasized. This is followed by a discussion of the clinical aspects associated with club cells, demonstrating that tracking the serum concentration of club cell-secreted proteins is helpful in the diagnosis of a number of lung tissue diseases. Finally, suggestions are provided regarding the possible use of proteins secreted by club cells in the treatment of serious respiratory conditions. PMID:27212975

  8. Cosmic Ray Hits in the Central Nervous System at Solar Maximum

    NASA Technical Reports Server (NTRS)

    Curtis, S. B.; Vazquez, M. E.; Wilson, J. W.; Kim, M.-H. Y.

    1997-01-01

    It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of some interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus (100 mm2 area) are that the probability of any given cell nucleus being hit decreases from 10 percent at solar minimum to 6 percent at solar maximum for particles with z greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. We conclude that this modest decrease in hit frequency (less than a factor of two) is not a compelling reason to avoid solar minimum for a manned mission to Mars.

  9. PowerMV: a software environment for molecular viewing, descriptor generation, data analysis and hit evaluation.

    PubMed

    Liu, Kejun; Feng, Jun; Young, S Stanley

    2005-01-01

    Ideally, a team of biologists, medicinal chemists and information specialists will evaluate the hits from high throughput screening. In practice, it often falls to nonmedicinal chemists to make the initial evaluation of HTS hits. Chemical genetics and high content screening both rely on screening in cells or animals where the biological target may not be known. There is a need to place active compounds into a context to suggest potential biological mechanisms. Our idea is to build an operating environment to help the biologist make the initial evaluation of HTS data. To this end the operating environment provides viewing of compound structure files, computation of basic biologically relevant chemical properties and searching against biologically annotated chemical structure databases. The benefit is to help the nonmedicinal chemist, biologist and statistician put compounds into a potentially informative biological context. Although there are several similar public and private programs used in the pharmaceutical industry to help evaluate hits, these programs are often built for computational chemists. Our program is designed for use by biologists and statisticians. PMID:15807517

  10. Multiple NSAID-Induced Hits Injure the Small Intestine: Underlying Mechanisms and Novel Strategies

    PubMed Central

    Boelsterli, Urs A.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The “first hit” is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The “second hit” is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits. PMID:23091168

  11. Interval Throwing and Hitting Programs in Baseball: Biomechanics and Rehabilitation.

    PubMed

    Chang, Edward S; Bishop, Meghan E; Baker, Dylan; West, Robin V

    2016-01-01

    Baseball injuries from throwing and hitting generally occur as a consequence of the repetitive and high-energy motions inherent to the sport. Biomechanical studies have contributed to understanding the pathomechanics leading to injury and to the development of rehabilitation programs. Interval-based throwing and hitting programs are designed to return an athlete to competition through a gradual progression of sport-specific exercises. Proper warm-up and strict adherence to the program allows the athlete to return as quickly and safely as possible. PMID:26991569

  12. Direct determination of the hit locations from experimental HPGe pulses

    NASA Astrophysics Data System (ADS)

    Désesquelles, P.; Boston, A. J.; Boston, H. C.; Cresswell, J. R.; Dimmock, M. R.; Lazarus, I. H.; Ljungvall, J.; Nelson, L.; Nga, D.-T.; Nolan, P. J.; Rigby, S. V.; Simpson, J.; Van-Oanh, N.-T.

    2013-11-01

    The gamma-tracking technique optimises the determination of the energy and emission angle of gamma-rays detected by modern segmented HPGe detectors. This entails the determination, using the delivered pulse shapes, of the interaction points of the gamma-ray within the crystal. The direct method presented here allows the localisation of the hits using only a large sample of pulses detected in the actual operating conditions. No external crystal scanning system or pulse shape simulation code is needed. In order to validate this method, it is applied to sets of pulses obtained using the University of Liverpool scanning system. The hit locations are determined by the method with good precision.

  13. Multi-hit time-to-amplitude CAMAC module (MTAC)

    SciTech Connect

    Kang, H.

    1980-10-01

    A Multi-Hit Time-to-Amplitude Module (MTAC) for the SLAC Mark III drift chamber system has been designed to measure drift time by converting time-proportional chamber signals into analog levels, and converting the analog data by slow readout via a semi-autonomous controller in a CAMAC crate. The single width CAMAC module has 16 wire channels, each with a 4-hit capacity. An externally generated common start initiates an internal precision ramp voltage which is then sampled using a novel shift register gating scheme and CMOS sampling switches. The detailed design and performance specifications are described.

  14. Design of Thomson Scattering Diagnostic for HIT-SI

    NASA Astrophysics Data System (ADS)

    Morgan, Kyle; Fryett, Taylor; Golingo, Raymond; Jarboe, Tom; Victor, Brian

    2012-10-01

    Steady Inductive Helicity Injection (SIHI) is used to create a spheromak inside the HIT-SI machine. A multi-point Thomson scattering diagnostic has been designed and is under construction for the HIT-SI experiment. The system uses a 20J Ruby Laser with 20ns pulse length. The collection system allows for eight spatial measurement locations, with four being active at any time. Four polychromators are being used to spectrally resolve the scattered light. Present Langmuir probe measurements show an electron temperature of about 12eV, within the range the polychromators can resolve. Properties of system and expected measurement are given.

  15. The Paradox Role of Regulatory T Cells in Ischemic Stroke

    PubMed Central

    Li, Min; Jiang, Yongjun

    2013-01-01

    The underlying mechanism of ischemic stroke is not completely known. Regulatory T cells (Tregs), a subset of T cells, play a pivotal role in the pathophysiological process of ischemic stroke. However, there is also controversy over the role of Tregs in stroke. Hence, the function of Tregs in ischemic stroke has triggered a heated discussion recently. In this paper, we reviewed the current lines of evidence to describe the full view of Tregs in stroke. We would like to introduce the basic concepts of Tregs and then discuss their paradox function in ischemic stroke. On one side, Tregs could protect brain against ischemic injury via modulating the inflammation process. On the other side, they exaggerated the insult by causing microvascular dysfunction. They also interfered with the neurological function recovery. In addition, the reasons for this paradox role would be discussed in the review and the prospective of the clinical application of Tregs was also included. In conclusion, Tregs contributed to the outcome of ischemic stroke, while more lines of evidence are needed to understand how Tregs regulate the immune system and influence the outcome of stroke. PMID:24288462

  16. The role of the cell wall in plant immunity

    PubMed Central

    Malinovsky, Frederikke G.; Fangel, Jonatan U.; Willats, William G. T.

    2014-01-01

    The battle between plants and microbes is evolutionarily ancient, highly complex, and often co-dependent. A primary challenge for microbes is to breach the physical barrier of host cell walls whilst avoiding detection by the plant’s immune receptors. While some receptors sense conserved microbial features, others monitor physical changes caused by an infection attempt. Detection of microbes leads to activation of appropriate defense responses that then challenge the attack. Plant cell walls are formidable and dynamic barriers. They are constructed primarily of complex carbohydrates joined by numerous distinct connection types, and are subject to extensive post-synthetic modification to suit prevailing local requirements. Multiple changes can be triggered in cell walls in response to microbial attack. Some of these are well described, but many remain obscure. The study of the myriad of subtle processes underlying cell wall modification poses special challenges for plant glycobiology. In this review we describe the major molecular and cellular mechanisms that underlie the roles of cell walls in plant defense against pathogen attack. In so doing, we also highlight some of the challenges inherent in studying these interactions, and briefly describe the analytical potential of molecular probes used in conjunction with carbohydrate microarray technology. PMID:24834069

  17. Role of gamma delta T cells in inflammatory bowel disease.

    PubMed

    Kühl, Anja A; Loddenkemper, Christoph; Westermann, Jürgen; Hoffmann, Jörg C

    gammadelta T cells have previously been shown to play a protective role in various animal models of chronic inflammation (e.g., experimental autoimmune encephalomyelitis, collagen-induced arthritis, and non-obese diabetes). This immunoregulatory potential is exerted by synthesizing various anti-inflammatory cytokines and growth factors (e.g., transforming growth factor-beta). As the normal balance between inflammatory and regulatory cytokines is perturbed in inflammatory bowel disease (IBD) a protective effect of gammadelta T cells seems likely. This notion is supported by our finding of increased mortality of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis following gammadelta T cell depletion. In contrast, no effect was observed after depletion of gammadelta T cells in a Crohn's disease animal model with terminal ileitis (TNF(DeltaARE) mice). Therefore, future studies must further define where in the intestinal immune system gammadelta T cells exert their protective function and how this can be used in the treatment of IBD. PMID:12571419

  18. Role of mitochondrial function in cell death and body metabolism.

    PubMed

    Lee, Myung-Shik

    2016-01-01

    Mitochondria are the key players in apoptosis and necrosis. Mitochondrial DNA (mtDNA)-depleted r0 cells were resistant to diverse apoptosis inducers such as TNF-alpha, TNFSF10, staurosporine and p53. Apoptosis resistance was accompanied by the absence of mitochondrial potential loss or cytochrome c translocation. r0 cells were also resistant to necrosis induced by reactive oxygen species (ROS) donors due to upregulation of antioxidant enzymes such as manganese superoxide dismutase. Mitochondria also has a close relationship with autophagy that plays a critical role in the turnover of senescent organelles or dysfunctional proteins and may be included in 'cell death' category. It was demonstrated that autophagy deficiency in insulin target tissues such as skeletal muscle induces mitochondrial stress response, which leads to the induction of FGF21 as a 'mitokine' and affects the whole body metabolism. These results show that mitochondria are not simply the power plants of cells generating ATP, but are closely related to several types of cell death and autophagy. Mitochondria affect various pathophysiological events related to diverse disorders such as cancer, metabolic disorders and aging. PMID:27100503

  19. The Role of Latently Infected B Cells in CNS Autoimmunity

    PubMed Central

    Márquez, Ana Citlali; Horwitz, Marc Steven

    2015-01-01

    The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein–Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt’s lymphoma. EBV establishes a life-long latency in B cells with occasional reactivation of the virus throughout the individual’s life. The role played by B cells in MS pathology has been largely studied, yet is not clearly understood. In MS patients, Rituximab, a novel treatment that targets CD20+ B cells, has proven to have successful results in diminishing the number of relapses in remitting relapsing MS; however, the mechanism of how this drug acts has not been clearly established. In this review, we analyze the evidence of how B cells latently infected with EBV might be altering the immune system response and helping in the development of MS. We will also discuss how animal models, such as experimental autoimmune encephalomyelitis (EAE) and murine gammaherpesvirus-68 (γHV-68), can be used as powerful tools in the study of the relationship between EBV, MS, and B cells. PMID:26579121

  20. The role of dendritic cells and regulatory T cells in the pathogenesis of morphea

    PubMed Central

    Teresiak-Mikołajczak, Ewa; Dańczak-Pazdrowska, Aleksandra; Kowalczyk, Michał; Żaba, Ryszard; Adamski, Zygmunt

    2015-01-01

    Morphea is one of diseases characterised by fibrosis of the skin and subcutaneous tissue. It is a chronic disease that does not shorten the life of the patient, yet significantly affects its quality. The group of factors responsible for its pathogenesis is thought to include disturbed functioning of endothelial cells as well as immune disturbances leading to chronic inflammatory conditions, accompanied by increased production of collagen and of other extracellular matrix components. Dendritic cells (DC) are a type of professional antigen-presenting cells and can be found in almost all body tissues. Individual investigations have demonstrated high numbers of plasmacytoid DC (pDC) in morphoeic skin lesions, within deeper dermal layers, around blood vessels, and around collagen fibres in subcutaneous tissue. It appears that DC has a more pronounced role in the development of inflammation and T cell activation in morphea, as compared to systemic sclerosis (SSc). Regulatory T (Treg) cells represent a subpopulation of T cells with immunosuppressive properties. Recent studies have drawn attention to the important role played by Treg in the process of autoimmunisation. Just a few studies have demonstrated a decrease in the number and activity of Treg in patients with SSc, and only such studies involve morphea. This article reviews recent studies on the role of DC and regulatory T cells in the pathogenesis of morphea. Moreover, mechanisms of phototherapy and potential therapeutic targets in the treatment of morphea are discussed in this context. PMID:26155191

  1. Functional role of regulatory T cells in B cell lymphoma and related mechanisms.

    PubMed

    Wu, Wei; Wan, Jun; Xia, Ruixiang; Huang, Zhenqi; Ni, Jing; Yang, Mingzhen

    2015-01-01

    B cell lymphoma (BCL) has a higher degree of malignancy and complicated pathogenic mechanism. Regulatory T cells (Treg cells) are known to exert certain immune suppression functions, in addition to immune mediating effects. Recent studies have revealed the role of Treg cells in pathogenesis and progression of multiple malignant tumors. This study therefore investigated the functional role and related mechanism of Treg cells in BCL. A cohort of thirty patients who were diagnosed with BCL in our hospital between January 2013 and December 2014. Another thirty healthy individuals were recruited. Peripheral blood mononuclear cells (PBMCs) were separated and analyzed for the ratio of CD4+/CD25+ Treg cells. The mRNA expression levels of Foxp3, transforming growth factor (TGF)-β1 and interleukin (IL)-10 genes were quantified by real-time PCR, while their serum levels were determined by enzyme-linked immunosorbent assay (ELISA). Meanwhile all laboratory indexes for patients were monitored during the complete remission (CR) stage. BCL patients significantly elevated ratio of CD4+/CD25+ Treg cells, which were decreased at CR stage. mRNA levels of Foxp3, TGF-β1 and IL-10, in addition to protein levels of TGF-β1 and IL-10 were potentiated in lymphoma patients but decreased in CR patients (P<0.05 in all cases). CD4+/CD25+ Treg cells exert immune suppressing functions in BCL via regulating cytokines, thereby facilitating the pathogenesis and progression of lymphoma. PMID:26464657

  2. The regulatory role of cell mechanics for migration of differentiating myeloid cells.

    PubMed

    Lautenschläger, Franziska; Paschke, Stephan; Schinkinger, Stefan; Bruel, Arlette; Beil, Michael; Guck, Jochen

    2009-09-15

    Migration of cells is important for tissue maintenance, immune response, and often altered in disease. While biochemical aspects, including cell adhesion, have been studied in detail, much less is known about the role of the mechanical properties of cells. Previous measurement methods rely on contact with artificial surfaces, which can convolute the results. Here, we used a non-contact, microfluidic optical stretcher to study cell mechanics, isolated from other parameters, in the context of tissue infiltration by acute promyelocytic leukemia (APL) cells, which occurs during differentiation therapy with retinoic acid. Compliance measurements of APL cells reveal a significant softening during differentiation, with the mechanical properties of differentiated cells resembling those of normal neutrophils. To interfere with the migratory ability acquired with the softening, differentiated APL cells were exposed to paclitaxel, which stabilizes microtubules. This treatment does not alter compliance but reduces cell relaxation after cessation of mechanical stress six-fold, congruent with a significant reduction of motility. Our observations imply that the dynamical remodeling of cell shape required for tissue infiltration can be frustrated by stiffening the microtubular system. This link between the cytoskeleton, cell mechanics, and motility suggests treatment options for pathologies relying on migration of cells, notably cancer metastasis. PMID:19717452

  3. Role of stem cells during diabetic liver injury.

    PubMed

    Wan, Ying; Garner, Jessica; Wu, Nan; Phillip, Levine; Han, Yuyan; McDaniel, Kelly; Annable, Tami; Zhou, Tianhao; Francis, Heather; Glaser, Shannon; Huang, Qiaobing; Alpini, Gianfranco; Meng, Fanyin

    2016-02-01

    Diabetes mellitus is one of the most severe endocrine metabolic disorders in the world that has serious medical consequences with substantial impacts on the quality of life. Type 2 diabetes is one of the main causes of diabetic liver diseases with the most common being non-alcoholic fatty liver disease. Several factors that may explain the mechanisms related to pathological and functional changes of diabetic liver injury include: insulin resistance, oxidative stress and endoplasmic reticulum stress. The realization that these factors are important in hepatocyte damage and lack of donor livers has led to studies concentrating on the role of stem cells (SCs) in the prevention and treatment of liver injury. Possible avenues that the application of SCs may improve liver injury include but are not limited to: the ability to differentiate into pancreatic β-cells (insulin producing cells), the contribution for hepatocyte regeneration, regulation of lipogenesis, glucogenesis and anti-inflammatory actions. Once further studies are performed to explore the underlying protective mechanisms of SCs and the advantages and disadvantages of its application, there will be a greater understand of the mechanism and therapeutic potential. In this review, we summarize the findings regarding the role of SCs in diabetic liver diseases. PMID:26645107

  4. Roles of Nrf2 in cell proliferation and differentiation.

    PubMed

    Murakami, Shohei; Motohashi, Hozumi

    2015-11-01

    The Keap1-Nrf2 system plays pivotal roles in defense mechanisms by regulating cellular redox homeostasis. Nrf2 is an inducible transcription factor that activates a battery of genes encoding antioxidant proteins and phase II enzymes in response to oxidative stress and electrophilic xenobiotics. The activity of Nrf2 is regulated by Keap1, which promotes the ubiquitination and subsequent degradation of Nrf2 under normal conditions and releases the inhibited Nrf2 activity upon exposure to the stresses. Though an impressive contribution of the Keap1-Nrf2 system to the protection from exogenous and endogenous electrophilic insults has been well established, a line of evidence has suggested that the Keap1-Nrf2 system has various novel functions, particularly in cell proliferation and differentiation. Because the proliferation and differentiation of diverse cell types are often influenced and modulated by the cellular redox balance, Nrf2 has been considered to control these cellular processes by regulating the cellular levels of reactive oxygen species (ROS). In addition, analyses of the genome-wide distribution of Nrf2 have identified new sets of Nrf2 target genes whose products are involved in cell proliferation and differentiation but not necessarily in the regulation of oxidative stress. Considering the most characteristic features of Nrf2 as an inducible transcription factor, a newly emerged concept proposes that the Keap1-Nrf2 system translates environmental stresses into regulatory network signals in cell fate determination. In this review, we introduce the contribution of Nrf2 to lineage-specific differentiation, maintenance and differentiation of stem cells, and proliferation of normal and cancer cells, and we discuss how the response to fluctuating environments modulates cell behavior through the Keap1-Nrf2 system. PMID:26119783

  5. Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome

    PubMed Central

    Hagawane, T.N.; Gaikwad, R.V.; Kshirsagar, N.A.

    2016-01-01

    Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. PMID

  6. A Computational Investigation of the Multi-Hit Ballistic-Protection Performance of Laminated Transparent-armor Systems

    NASA Astrophysics Data System (ADS)

    Grujicic, Mica; Pandurangan, B.; Coutris, N.

    2012-06-01

    Multi-hit ballistic-protection performance of a prototypical laminated glass/polycarbonate transparent armor is investigated using a series of transient nonlinear dynamics analyses of armor impact with a sequence of four M2AP full metal jacket (FMJ) armor-piercing bullets. All calculations were carried out using ABAQUS/Explicit commercial finite element program (ABAQUS Version 6.7, User Documentation, Dessault Systems, 2007), and the computational results obtained were compared to their experimental counterparts obtained by Dolan (Ballistic Transparent-armor Testing Using a Multi-hit Rifle Pattern, Bachelors, Thesis, Kettering University, December 2007). The comparison revealed that (a) The proposed computational procedure can reasonably well account for the observed multi-hit ballistic-protection performance of the laminated transparent armor; (b) The role of prior bullet hits in reducing armor's ballistic-protection performance is clearly revealed; (c) The role of polycarbonate lamina in preventing glass fragments from entering the vehicle interior is clearly demonstrated; and (d) Experimentally observed inability of the transparent armor to defeat 0.50-caliber Fragment Simulating Projectiles (FSPs) is confirmed.

  7. Structure to function prediction of hypothetical protein KPN_00953 (Ycbk) from Klebsiella pneumoniae MGH 78578 highlights possible role in cell wall metabolism

    PubMed Central

    2014-01-01

    Background Klebsiella pneumoniae plays a major role in causing nosocomial infection in immunocompromised patients. Medical inflictions by the pathogen can range from respiratory and urinary tract infections, septicemia and primarily, pneumonia. As more K. pneumoniae strains are becoming highly resistant to various antibiotics, treatment of this bacterium has been rendered more difficult. This situation, as a consequence, poses a threat to public health. Hence, identification of possible novel drug targets against this opportunistic pathogen need to be undertaken. In the complete genome sequence of K. pneumoniae MGH 78578, approximately one-fourth of the genome encodes for hypothetical proteins (HPs). Due to their low homology and relatedness to other known proteins, HPs may serve as potential, new drug targets. Results Sequence analysis on the HPs of K. pneumoniae MGH 78578 revealed that a particular HP termed KPN_00953 (YcbK) contains a M15_3 peptidases superfamily conserved domain. Some members of this superfamily are metalloproteases which are involved in cell wall metabolism. BLASTP similarity search on KPN_00953 (YcbK) revealed that majority of the hits were hypothetical proteins although two of the hits suggested that it may be a lipoprotein or related to twin-arginine translocation (Tat) pathway important for transport of proteins to the cell membrane and periplasmic space. As lipoproteins and other components of the cell wall are important pathogenic factors, homology modeling of KPN_00953 was attempted to predict the structure and function of this protein. Three-dimensional model of the protein showed that its secondary structure topology and active site are similar with those found among metalloproteases where two His residues, namely His169 and His209 and an Asp residue, Asp176 in KPN_00953 were found to be Zn-chelating residues. Interestingly, induced expression of the cloned KPN_00953 gene in lipoprotein-deficient E. coli JE5505 resulted in smoother

  8. Role of Cytosolic Calcium Diffusion in Murine Cardiac Purkinje Cells

    PubMed Central

    Limbu, Bijay; Shah, Kushal; Weinberg, Seth H.; Deo, Makarand

    2016-01-01

    Cardiac Purkinje cells (PCs) are morphologically and electrophysiologically different from ventricular myocytes and, importantly, exhibit distinct calcium (Ca2+) homeostasis. Recent studies suggest that PCs are more susceptible to action potential (AP) abnormalities than ventricular myocytes; however, the exact mechanisms are poorly understood. In this study, we utilized a detailed biophysical mathematical model of a murine PC to systematically examine the role of cytosolic Ca2+ diffusion in shaping the AP in PCs. A biphasic spatiotemporal Ca2+ diffusion process, as recorded experimentally, was implemented in the model. In this study, we investigated the role of cytosolic Ca2+ dynamics on AP and ionic current properties by varying the effective Ca2+ diffusion rate. It was observed that AP morphology, specifically the plateau, was affected due to changes in the intracellular Ca2+ dynamics. Elevated Ca2+ concentration in the sarcolemmal region activated inward sodium–Ca2+ exchanger (NCX) current, resulting in a prolongation of the AP plateau at faster diffusion rates. Artificially clamping the NCX current to control values completely reversed the alterations in the AP plateau, thus confirming the role of NCX in modifying the AP morphology. Our results demonstrate that cytosolic Ca2+ diffusion waves play a significant role in shaping APs of PCs and could provide mechanistic insights in the increased arrhythmogeneity of PCs. PMID:27478391

  9. The role of regulatory T cells in cancer immunology

    PubMed Central

    Whiteside, Theresa L

    2015-01-01

    Regulatory T cells (Treg) are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well understood. This review attempts to provide insights into the importance of Treg subsets in cancer development and its progression. It also considers the role of Treg as potential biomarkers of clinical outcome in cancer. The strategies for monitoring Treg in cancer patients are discussed as is the need for caution in the use of therapies which indiscriminately ablate Treg. A greater understanding of molecular pathways operating in various tumor microenvironments is necessary for defining the Treg impact on cancer and for selecting immunotherapies targeting Treg.

  10. Role of stem cells in cancer therapy and cancer stem cells: a review

    PubMed Central

    Sagar, Jayesh; Chaib, Boussad; Sales, Kevin; Winslet, Marc; Seifalian, Alexander

    2007-01-01

    For over 30 years, stem cells have been used in the replenishment of blood and immune systems damaged by the cancer cells or during treatment of cancer by chemotherapy or radiotherapy. Apart from their use in the immuno-reconstitution, the stem cells have been reported to contribute in the tissue regeneration and as delivery vehicles in the cancer treatments. The recent concept of 'cancer stem cells' has directed scientific communities towards a different wide new area of research field and possible potential future treatment modalities for the cancer. Aim of this review is primarily focus on the recent developments in the use of the stem cells in the cancer treatments, then to discuss the cancer stem cells, now considered as backbone in the development of the cancer; and their role in carcinogenesis and their implications in the development of possible new cancer treatment options in future. PMID:17547749