Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2rγnull Mice by Lentiviral Expression of NUP98-HOXA10HD

PubMed Central

Zhao, Huifen; Humphries, Keith; Persons, Derek A.

2016-01-01

Techniques to expand human hematopoietic stem cells ex-vivo could be beneficial to the fields of clinical hematopoietic stem cell transplantation and gene therapy targeted at hematopoietic stem cells. NUP98-HOXA10HD is a relatively newly discovered fusion gene that in mouse transplant experiments has been shown to increase numbers of hematopoietic stem cells. We evaluated whether this fusion gene could be used to expand engrafting human primitive CD34+ cells in an immunodeficient mouse model. Gene transfer was achieved using a lentiviral based vector. The engraftment of mobilized peripheral blood human CD34+ cells grown in culture for one week after gene transfer was evaluated 3–4 months after transplant and found to be 2–3 fold higher in the NUP98-HOXA10HD groups as compared to controls. These data suggest an expansive effect at least at the short term human repopulating cell level. Further evaluation in long term repopulating models and investment in a NUP98-HOXA10HD protein seems worthy of consideration. Additionally, the results here provide strong impetus to utilize NUP98-HOXA10HD as a tool to search for underlying genes and pathways involved in hematopoietic stem cell expansion that can be enhanced and have an even more potent expansive effect. PMID:26761813

Foamy virus–mediated gene transfer to canine repopulating cells

PubMed Central

Kiem, Hans-Peter; Allen, James; Trobridge, Grant; Olson, Erik; Keyser, Kirsten; Peterson, Laura; Russell, David W.

2007-01-01

Foamy virus (FV) vectors are particularly attractive gene-transfer vectors for stem-cell gene therapy because they form a stable transduction intermediate in quiescent cells and can efficiently transduce hematopoietic stem cells. Here, we studied the use of FV vectors to transduce long-term hematopoietic repopulating cells in the dog, a clinically relevant large animal model. Mobilized canine peripheral blood (PB) CD34+ cells were transduced with an enhanced green fluorescent protein (EGFP)–expressing FV vector in an 18-hour transduction protocol. All 3 dogs studied had rapid neutrophil engraftment to greater than 500/μL with a median of 10 days. Transgene expression was detected in all cell lineages (B cells, T cells, granulocytes, red blood cells, and platelets), indicating multilineage engraftment of transduced cells. Up to 19% of blood cells were EGFP+, and this was confirmed at the DNA level by real-time polymerase chain reaction (PCR) and Southern blot analysis. These transduction rates were higher than the best results we obtained previously with lentiviral vectors in a similar transduction protocol. Integration site analysis also demonstrated polyclonal repopulation and the transduction of multipotential hematopoietic repopulating cells. These data suggest that FV vectors should be useful for stem-cell gene therapy, particularly for applications in which short transduction protocols are critical. PMID:16968897

SHIP deficiency enhances HSC proliferation and survival but compromises homing and repopulation

PubMed Central

Desponts, Caroline; Hazen, Amy L.; Paraiso, Kim H. T.; Kerr, William G.

2006-01-01

The SH2 domain–containing inositol 5′-phosphatase-1 (SHIP) has the potential to modulate multiple signaling pathways downstream of receptors that impact hematopoietic stem cell (HSC) biology. Therefore, we postulated that SHIP might play an important role in HSC homeostasis and function. Consistent with this hypothesis, HSC proliferation and numbers are increased in SHIP–/– mice. Despite expansion of the compartment, SHIP–/– HSCs exhibit reduced capacity for long-term repopulation. Interestingly, we observe that SHIP–/– stem/progenitor cells home inefficiently to bone marrow (BM), and consistent with this finding, have reduced surface levels of both CXCR4 and vascular cell adhesion marker-1 (VCAM-1). These studies demonstrate that SHIP is critical for normal HSC function, homeostasis, and homing. PMID:16467196

A New View of Radiation-Induced Cancer: Integrating Short-and Long-Term Processes. Part I: Approach

NASA Technical Reports Server (NTRS)

Shuryak, Igor; Hahnfeldt, Philip; Hlatky, Lynn; Sachs, Rainer K.; Brenner, David J.

2009-01-01

Mathematical models of radiation carcinogenesis are important for understanding mechanisms and for interpreting or extrapolating risk. There are two classes of such models: (1) long-term formalisms that track premalignant cell numbers throughout an entire lifetime but treat initial radiation dose-response simplistically and (2) short-term formalisms that provide a detailed initial dose-response even for complicated radiation protocols, but address its modulation during the subsequent cancer latency period only indirectly. We argue that integrating short- and long-term models is needed. As an example of this novel approach, we integrate a stochastic short-term initiation/ inactivation/repopulation model with a deterministic two-stage long-term model. Within this new formalism, the following assumptions are implemented: radiation initiates, promotes, or kills pre-malignant cells; a pre-malignant cell generates a clone, which, if it survives, quickly reaches a size limitation; the clone subsequently grows more slowly and can eventually generate a malignant cell; the carcinogenic potential of pre-malignant cells decreases with age.

High-efficiency Transduction of Rhesus Hematopoietic Repopulating Cells by a Modified HIV1-based Lentiviral Vector

PubMed Central

Uchida, Naoya; Hargrove, Phillip W.; Lap, Coen J.; Evans, Molly E.; Phang, Oswald; Bonifacino, Aylin C.; Krouse, Allen E.; Metzger, Mark E.; Nguyen, Anh-Dao; Hsieh, Matthew M.; Wolfsberg, Tyra G.; Donahue, Robert E.; Persons, Derek A.; Tisdale, John F.

2012-01-01

Human immunodeficiency virus type 1 (HIV1) vectors poorly transduce rhesus hematopoietic cells due to species-specific restriction factors, including the tripartite motif-containing 5 isoformα (TRIM5α) which targets the HIV1 capsid. We previously developed a chimeric HIV1 (χHIV) vector system wherein the vector genome is packaged with the simian immunodeficiency virus (SIV) capsid for efficient transduction of both rhesus and human CD34+ cells. To evaluate whether χHIV vectors could efficiently transduce rhesus hematopoietic repopulating cells, we performed a competitive repopulation assay in rhesus macaques, in which half of the CD34+ cells were transduced with standard SIV vectors and the other half with χHIV vectors. As compared with SIV vectors, χHIV vectors achieved higher vector integration, and the transgene expression rates were two- to threefold higher in granulocytes and red blood cells and equivalent in lymphocytes and platelets for 2 years. A recipient of χHIV vector-only transduced cells reached up to 40% of transgene expression rates in granulocytes and lymphocytes and 20% in red blood cells. Similar to HIV1 and SIV vectors, χHIV vector frequently integrated into gene regions, especially into introns. In summary, our χHIV vector demonstrated efficient transduction for rhesus long-term repopulating cells, comparable with SIV vectors. This χHIV vector should allow preclinical testing of HIV1-based therapeutic vectors in large animal models. PMID:22871664

Repopulating hematopoietic stem cells from steady-state blood before and after ex vivo culture are enriched in CD34+CD133+CXCR4low fraction.

PubMed

Lapostolle, Véronique; Chevaleyre, Jean; Duchez, Pascale; Rodriguez, Laura; Vlaski-Lafarge, Marija; Sandvig, Ioanna; Brunet de la Grange, Philippe; Ivanovic, Zoran

2018-06-01

Feasibility of ex vivo expansion allows us to consider the steady-state peripheral blood as an alternative source of hematopoietic stem progenitor cells for transplantation when growth factor-induced cell mobilization is contraindicated or inapplicable. Ex vivo expansion dramatically enhances the in vivo reconstituting cell population from steady-state blood. In order to investigate phenotype and the expression of homing molecules, CD34, CD133, CD90, CD45RA, CD26 and CD9 expression was determined on sorted CD34+ cells according to CXCR4 (neg, low, bright) and CD133 expression before and after ex vivo expansion. Hematopoietic stem cell activity was determined in vivo on the basis of hematopoietic repopulation of primary and secondary recipients - NSG immuno-deficient mice. In vivo reconstituting cells in steady-state blood CD34+ cell fraction before expansion belong to the CD133+ population and are CXCR4low or, to a lesser extent, CXCR4neg, while after ex vivo expansion they are contained in only the CD133+CXCR4low cells. The failure of CXCR4bright population to engraft is probably due to the exclusive expression of CD26 by these cells. The limiting-dilution analysis showed that both repopulating cell number and individual proliferative capacity were enhanced by ex vivo expansion. Thus, steady-state peripheral blood cells exhibit a different phenotype compared to mobilized and cord blood ones, as well as to those issued from the bone marrow. This data represent the first phenotypic characterization of steady-state blood cells exhibiting short and long term hematopoietic reconstituting potential, which can be expanded ex vivo, a sine qua non for their subsequent use for transplantation. Copyright © 2018, Ferrata Storti Foundation.

Second Cancers After Fractionated Radiotherapy: Stochastic Population Dynamics Effects

NASA Technical Reports Server (NTRS)

Sachs, Rainer K.; Shuryak, Igor; Brenner, David; Fakir, Hatim; Hahnfeldt, Philip

2007-01-01

When ionizing radiation is used in cancer therapy it can induce second cancers in nearby organs. Mainly due to longer patient survival times, these second cancers have become of increasing concern. Estimating the risk of solid second cancers involves modeling: because of long latency times, available data is usually for older, obsolescent treatment regimens. Moreover, modeling second cancers gives unique insights into human carcinogenesis, since the therapy involves administering well characterized doses of a well studied carcinogen, followed by long-term monitoring. In addition to putative radiation initiation that produces pre-malignant cells, inactivation (i.e. cell killing), and subsequent cell repopulation by proliferation can be important at the doses relevant to second cancer situations. A recent initiation/inactivation/proliferation (IIP) model characterized quantitatively the observed occurrence of second breast and lung cancers, using a deterministic cell population dynamics approach. To analyze ifradiation-initiated pre-malignant clones become extinct before full repopulation can occur, we here give a stochastic version of this I I model. Combining Monte Carlo simulations with standard solutions for time-inhomogeneous birth-death equations, we show that repeated cycles of inactivation and repopulation, as occur during fractionated radiation therapy, can lead to distributions of pre-malignant cells per patient with variance >> mean, even when pre-malignant clones are Poisson-distributed. Thus fewer patients would be affected, but with a higher probability, than a deterministic model, tracking average pre-malignant cell numbers, would predict. Our results are applied to data on breast cancers after radiotherapy for Hodgkin disease. The stochastic IIP analysis, unlike the deterministic one, indicates: a) initiated, pre-malignant cells can have a growth advantage during repopulation, not just during the longer tumor latency period that follows; b) weekend treatment gaps during radiotherapy, apart from decreasing the probability of eradicating the primary cancer, substantially increase the risk of later second cancers.

Bacterial repopulation of drinking water pipe walls after chlorination.

PubMed

Mathieu, Laurence; Francius, Grégory; El Zein, Racha; Angel, Edith; Block, Jean-Claude

2016-09-01

The short-term kinetics of bacterial repopulation were evaluated after chlorination of high-density polyethylene (HDPE) colonized with drinking water biofilms and compared with bare HDPE surfaces. The effect of chlorination was partial as a residual biofilm persisted and was time-limited as repopulation occurred immediately after water resupply. The total number of bacteria reached the same levels on both the bare and chlorinated biofilm-fouled HDPE after a seven-day exposure to drinking water. Due to the presence of a residual biofilm, the hydrophobicity of chlorinated biofilm-fouled surface exhibited much lower adhesion forces (2.1 nN) compared to bare surfaces (8.9 nN). This could explain the rapid repopulation after chlorination, with a twofold faster bacterial accumulation rate on the bare HDPE surface. γ-Proteobacteria dominated the early stages of repopulation of both surfaces and a shift in the dominance occurred over the colonization time. Such observations define a timescale for cleaning frequency in industrial environments and guidelines for a rinsing procedure using drinking water.

Clinical-scale validation of a new efficient procedure for cryopreservation of ex vivo expanded cord blood hematopoietic stem and progenitor cells.

PubMed

Duchez, Pascale; Rodriguez, Laura; Chevaleyre, Jean; De La Grange, Philippe Brunet; Ivanovic, Zoran

2016-12-01

Survival of ex vivo expanded hematopoietic stem cells (HSC) and progenitor cells is low with the standard cryopreservation procedure. We recently showed that the efficiency of cryopreservation of these cells may be greatly enhanced by adding a serum-free xeno-free culture medium (HP01 Macopharma), which improves the antioxidant and biochemical properties of the cryopreservation solution. Here we present the clinical-scale validation of this cryopreservation procedure. The hematopoietic cells expanded in clinical-scale cultures were cryopreserved applying the new HP01-based procedure. The viability, apoptosis rate and number of functional committed progenitors (methyl-cellulose colony forming cell test), short-term repopulating HSCs (primary recipient NSG mice) and long-term HSCs (secondary recipient NSG mice) were tested before and after thawing. The efficiency of clinical-scale procedure reproduced the efficiency of cryopreservation obtained earlier in miniature sample experiments. Furthermore, the full preservation of short- and long-term HSCs was obtained in clinical scale conditions. Because the results obtained in clinical-scale volume are comparable to our earlier results in miniature-scale cultures, the clinical-scale procedure should be considered validated. It allows cryopreservation of the whole ex vivo expanded culture content, conserving full short- and long-term HSC activity. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Sources of Hematopoietic Stem and Progenitor Cells and Methods to Optimize Yields for Clinical Cell Therapy.

PubMed

Panch, Sandhya R; Szymanski, James; Savani, Bipin N; Stroncek, David F

2017-08-01

Bone marrow (BM) aspirates, mobilized peripheral blood, and umbilical cord blood (UCB) have developed as graft sources for hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation and other cellular therapeutics. Individualized techniques are necessary to enhance graft HSPC yields and cell quality from each graft source. BM aspirates yield adequate CD34 + cells but can result in relative delays in engraftment. Granulocyte colony-stimulating factor (G-CSF)-primed BM HSPCs may facilitate faster engraftment while minimizing graft-versus-host disease in certain patient subsets. The levels of circulating HSPCs are enhanced using mobilizing agents, such as G-CSF and/or plerixafor, which act via the stromal cell-derived factor 1/C-X-C chemokine receptor type 4 axis. Alternate niche pathway mediators, including very late antigen-4/vascular cell adhesion molecule-1, heparan sulfate proteoglycans, parathyroid hormone, and coagulation cascade intermediates, may offer promising alternatives for graft enhancement. UCB grafts have been expanded ex vivo with cytokines, notch-ligand, or mesenchymal stromal cells, and most studies demonstrated greater quantities of CD34 + cells ex vivo and improved short-term engraftment. No significant changes were observed in long-term repopulating potential or in patient survival. Early phase clinical trials using nicotinamide and StemReginin1 may offer improved short- and long-term repopulating ability. Breakthroughs in genome editing and stem cell reprogramming technologies may hasten the generation of pooled, third-party HSPC grafts. This review elucidates past, present, and potential future approaches to HSPC graft optimization. Published by Elsevier Inc.

Large Animal Models for Foamy Virus Vector Gene Therapy

PubMed Central

Trobridge, Grant D.; Horn, Peter A.; Beard, Brian C.; Kiem, Hans-Peter

2012-01-01

Foamy virus (FV) vectors have shown great promise for hematopoietic stem cell (HSC) gene therapy. Their ability to efficiently deliver transgenes to multi-lineage long-term repopulating cells in large animal models suggests they will be effective for several human hematopoietic diseases. Here, we review FV vector studies in large animal models, including the use of FV vectors with the mutant O6-methylguanine-DNA methyltransferase, MGMTP140K to increase the number of genetically modified cells after transplantation. In these studies, FV vectors have mediated efficient gene transfer to polyclonal repopulating cells using short ex vivo transduction protocols designed to minimize the negative effects of ex vivo culture on stem cell engraftment. In this regard, FV vectors appear superior to gammaretroviral vectors, which require longer ex vivo culture to effect efficient transduction. FV vectors have also compared favorably with lentiviral vectors when directly compared in the dog model. FV vectors have corrected leukocyte adhesion deficiency and pyruvate kinase deficiency in the dog large animal model. FV vectors also appear safer than gammaretroviral vectors based on a reduced frequency of integrants near promoters and also near proto-oncogenes in canine repopulating cells. Together, these studies suggest that FV vectors should be highly effective for several human hematopoietic diseases, including those that will require relatively high percentages of gene-modified cells to achieve clinical benefit. PMID:23223198

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chertkov, J.L.; Drize, N.J.; Gurevitch, O.A.

Intravenously injected bone marrow cells do not participate in the regeneration of hemopoietic stromal progenitors in irradiated mice, nor in the curetted parts of the recipient's marrow. The hemopoietic stromal progenitors in allogeneic chimeras are of recipient origin. The adherent cell layer (ACL) of long-term cultures of allogeneic chimera bone marrow contains only recipient hemopoietic stromal progenitors. However, in ectopic hemopoietic foci produced by marrow implantation under the renal capsule and repopulated by the recipient hemopoietic cells after irradiation and reconstitution by syngeneic hemopoietic cells, the stromal progenitors were of implant donor origin, as were stromal progenitors of the ACLmore » in long-term cultures of hemopoietic cells from ectopic foci. Our results confirm that the stromal and hemopoietic progenitors differ in origin and that hemopoietic stromal progenitors are not transplantable by the intravenous route in mice.« less

Spontaneous circulation of myeloid-lymphoid-initiating cells and SCID-repopulating cells in sickle cell crisis.

PubMed

Lamming, Christopher E D; Augustin, Lance; Blackstad, Mark; Lund, Troy C; Hebbel, Robert P; Verfaillie, Catherine M

2003-03-01

The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid-initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture-initiating cells, consistent with the notion that SRCs are more primitive than long-term culture-initiating cells. As ML-ICs and SRCs were both detected in blood of AC-SCD patients only, these assays may both measure primitive progenitors. The frequency of ML-ICs also correlated with increases in stem cell factor, GCSF, and IL-8 levels in AC-SCD compared with steady-state SCD and normal-donor sera. Because significant numbers of ML-ICs and SRCs are mobilized in the blood without exogenous cytokine treatment during acute crisis of SCD, collection of peripheral blood progenitors during crisis may yield a source of autologous HSCs suitable for ex-vivo correction by gene therapy approaches and subsequent transplantation.

Unaltered repopulation properties of mouse hematopoietic stem cells transduced with lentiviral vectors

PubMed Central

Gonzalez-Murillo, Africa; Lozano, M. Luz; Montini, Eugenio; Bueren, Juan A.

2008-01-01

Recent studies of retroviral-mediated gene transfer have shown that retroviral integrations themselves may trigger nonmalignant clonal expansion of hematopoietic stem cells (HSCs) in transplant recipients. These observations suggested that previous conclusions of HSC dynamics based on gamma-retroviral gene marking should be confirmed with improved vectors having a more limited capacity to transactivate endogenous genes. Because of the low trans-activation activity of self-inactivating lentiviral vectors (LVs), we have investigated whether the LV marking of mouse HSCs induces a competitive repopulation advantage in recipients of serially transplants. As deduced from analyses conducted in primary and secondary recipients, we concluded that lentivirally transduced HSCs have no competitive repopulation advantages over untransduced HSCs. By linear amplification-mediated polymerase chain reaction (LAM-PCR) analysis, we characterized LV-targeted genes in HSC clones that engrafted up to quaternary recipients. Although 9 clones harbored integrations close to defined retroviral insertion sites, none was characterized as a common integration site, and none was present in HSC clones repopulating quaternary recipients. Taken together, our results show unaltered repopulation properties of HSCs transduced with LVs, and confirm early studies suggesting the natural capacity of a few HSC clones to generate a monoclonal or oligoclonal hematopoiesis in transplant recipients. PMID:18684860

Elements of planetary protection against asteroid and comet hazard

NASA Astrophysics Data System (ADS)

Steklov, A. F.; Vidmachenko, A. P.; Dashkiev, G. N.; Zhilyaev, B. E.

2018-05-01

The principles of protection against asteroid-comet hazard should constitute the main priority of the modern Proto-cosmic civilization on the planet Earth. Any impact of a fairly large asteroid or cometary nucleus with a size of 1 to 20 or more kilometers will lead to a global catastrophe and, perhaps, to the death of Mankind. Forces in order to withstand such a blow of the cosmic body during large space invasions, we do not have and, most likely, will not be for a long time . We need as soon as possible to create technical facilities and systems for long-term comfortable living of large colonies of people on the Moon, Mars, Venus and Mercury, having arranged there some elements of the biosphere. In these colonies people should live in extraterrestrial space settlements, and should periodically and constantly "outplay" scenarios of reliable and guaranteed re-population of the planet Earth by people. Such periodic "exercises" on the actual modeling of the return to the "post-catastrophic" Earth should ensure the survival of humanity even in the worst versions of the consequences of possible dangerous space invasions. That is, we should always be ready for the repopulation on the Earth by people and for the reconstruction of the basic elements of the man's biosphere.

Exonuclease 1 is a critical mediator of survival during DNA double strand break repair in nonquiescent hematopoietic stem and progenitor cells.

PubMed

Desai, Amar; Qing, Yulan; Gerson, Stanton L

2014-02-01

Hematopoietic stem cell (HSC) populations require DNA repair pathways to maintain their long-term survival and reconstitution capabilities, but mediators of these processes are still being elucidated. Exonuclease 1 (Exo1) participates in homologous recombination (HR) and Exo1 loss results in impaired 5' HR end resection. We use cultured Exo1(mut) fibroblasts and bone marrow to demonstrate that loss of Exo1 function results in defective HR in cycling cells. Conversely, in Exo1(mut) mice HR is not required for maintenance of quiescent HSCs at steady state, confirming the steady state HSC reliance on nonhomologous end joining (NHEJ). Exo1(mut) mice sustained serial repopulation, displayed no defect in competitive repopulation or niche occupancy, and exhibited no increased sensitivity to whole body ionizing radiation. However, when Exo1(mut) HSCs were pushed into cell cycle in vivo with 5-fluorouracil or poly IC, the hematopoietic population became hypersensitive to IR, resulting in HSC defects and animal death. We propose Exo1-mediated HR is dispensable for stem cell function in quiescent HSC, whereas it is essential to HSC response to DNA damage processing after cell cycle entry, and its loss is not compensated by intact NHEJ. In HSCs, the maintenance of stem cell function after DNA damage is dependent on the DNA repair capacity, segregated by active versus quiescent points in cell cycle. © AlphaMed Press.

Distinct bone marrow blood vessels differentially regulate haematopoiesis.

PubMed

Itkin, Tomer; Gur-Cohen, Shiri; Spencer, Joel A; Schajnovitz, Amir; Ramasamy, Saravana K; Kusumbe, Anjali P; Ledergor, Guy; Jung, Yookyung; Milo, Idan; Poulos, Michael G; Kalinkovich, Alexander; Ludin, Aya; Kollet, Orit; Shakhar, Guy; Butler, Jason M; Rafii, Shahin; Adams, Ralf H; Scadden, David T; Lin, Charles P; Lapidot, Tsvee

2016-04-21

Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.

Spontaneous circulation of myeloid-lymphoid–initiating cells and SCID-repopulating cells in sickle cell crisis

PubMed Central

Lamming, Christopher E.D.; Augustin, Lance; Blackstad, Mark; Lund, Troy C.; Hebbel, Robert P.; Verfaillie, Catherine M.

2003-01-01

The only curative therapy for sickle cell disease (SCD) is allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy approaches for autologous HSC transplantation are being developed. Although earlier engraftment is seen when cells from GCSF-mobilized blood are transplanted than when bone marrow is transplanted, administration of GCSF to patients with SCD can cause significant morbidity. We tested whether primitive hematopoietic progenitors are spontaneously mobilized in the blood of patients with SCD during acute crisis (AC-SCD patients). The frequency of myeloid-lymphoid–initiating cells (ML-ICs) and SCID-repopulating cells (SRCs) was significantly higher in blood from AC-SCD patients than in blood from patients with steady-state SCD or from normal donors. The presence of SRCs in peripheral blood was not associated with detection of long-term culture–initiating cells, consistent with the notion that SRCs are more primitive than long-term culture–initiating cells. As ML-ICs and SRCs were both detected in blood of AC-SCD patients only, these assays may both measure primitive progenitors. The frequency of ML-ICs also correlated with increases in stem cell factor, GCSF, and IL-8 levels in AC-SCD compared with steady-state SCD and normal-donor sera. Because significant numbers of ML-ICs and SRCs are mobilized in the blood without exogenous cytokine treatment during acute crisis of SCD, collection of peripheral blood progenitors during crisis may yield a source of autologous HSCs suitable for ex-vivo correction by gene therapy approaches and subsequent transplantation. PMID:12639987

The actin polymerization regulator WAVE2 is required for early bone marrow repopulation by hematopoietic stem cells.

PubMed

Ogaeri, Takunori; Eto, Koji; Otsu, Makoto; Ema, Hideo; Nakauchi, Hiromitsu

2009-05-01

The Rho GTPase family members play essential roles in hematopoiesis. Of these, Rac1 is thought to be required for the appropriate spatial localization of hematopoietic stem and/or progenitor cells (HSPCs) within the bone marrow (BM), whereas Rac2 likely plays a role in BM retention of HSPCs. To elucidate the molecular mechanisms underlying Rac-mediated functions in hematopoietic stem cells (HSCs), we studied Wiskott-Aldrich syndrome protein family verprolin-homologous proteins (WAVEs), the specific effectors downstream of the Rac GTPases in actin polymerization. We here showed that CD34(-/low)c-Kit(+)Sca-1(+)lineage(-) HSCs (CD34(-)KSL HSCs) express WAVE2 but neither WAVE1 nor WAVE3. Because WAVE2 knockout mice are embryonic-lethal, we utilized HSCs in which the expression of WAVE2 was reduced by small interfering RNA. We found that knockdown (KD) of WAVE2 in HSCs affected neither in vitro colony formation nor cell proliferation but did impair in vivo long-term reconstitution. Interestingly, WAVE2 KD HSCs exhibited unaltered homing but showed poor BM repopulation detected as early as day 5 after transplantation. The mechanistic studies on WAVE2 KD HSCs revealed modest but significant impairment in both cobblestone-like area-forming on stromal layers and actin polymerization upon integrin ligation by fibronectin. These results suggested that WAVE2-mediated actin polymerization, potentially downstream of Rac1, plays an important role in intramarrow mobilization and proliferation of HSCs, which are believed to be crucial steps for long-term marrow reconstitution after transplantation.

Mammary stem cells and the differentiation hierarchy: current status and perspectives

PubMed Central

Visvader, Jane E.; Stingl, John

2014-01-01

The mammary epithelium is highly responsive to local and systemic signals, which orchestrate morphogenesis of the ductal tree during puberty and pregnancy. Based on transplantation and lineage tracing studies, a hierarchy of stem and progenitor cells has been shown to exist among the mammary epithelium. Lineage tracing has highlighted the existence of bipotent mammary stem cells (MaSCs) in situ as well as long-lived unipotent cells that drive morphogenesis and homeostasis of the ductal tree. Moreover, there is accumulating evidence for a heterogeneous MaSC compartment comprising fetal MaSCs, slow-cycling cells, and both long-term and short-term repopulating cells. In parallel, diverse luminal progenitor subtypes have been identified in mouse and human mammary tissue. Elucidation of the normal cellular hierarchy is an important step toward understanding the “cells of origin” and molecular perturbations that drive breast cancer. PMID:24888586

HOXB4 overexpression mediates very rapid stem cell regeneration and competitive hematopoietic repopulation.

PubMed

Antonchuk, J; Sauvageau, G; Humphries, R K

2001-09-01

Hox transcription factors have emerged as important regulators of hematopoiesis. In particular, we have shown that overexpression of HOXB4 in mouse bone marrow can greatly enhance the level of hematopoietic stem cell (HSC) regeneration achieved at late times (> 4 months) posttransplantation. The objective of this study was to resolve if HOXB4 increases the rate and/or duration of HSC regeneration, and also to see if this enhancement was associated with impaired production of end cells or would lead to competitive reconstitution of all compartments. Retroviral vectors were generated with the GFP reporter gene +/- HOXB4 to enable the isolation and direct tracking of transduced cells in culture or following transplantation. Stem cell recovery was measured by limit dilution assay for long-term competitive repopulating cells (CRU). HOXB4-overexpressing cells have enhanced growth in vitro, as demonstrated by their rapid dominance in mixed cultures and their shortened population doubling time. Furthermore, HOXB4-transduced cells have a marked competitive repopulating advantage in vivo in both primitive and mature compartments. CRU recovery in HOXB4 recipients was extremely rapid, reaching 25% of normal by 14 days posttransplant or some 80-fold greater than control transplant recipients, and attaining normal numbers by 12 weeks. Mice transplanted with even higher numbers of HOXB4-transduced CRU regenerated up to but not beyond the normal CRU levels. HOXB4 is a potent enhancer of primitive hematopoietic cell growth, likely by increasing self-renewal probability but without impairing homeostatic control of HSC population size or the rate of production and maintenance of mature end cells.

Thrombopoietin treatment of one graft in a double cord blood transplant provides early platelet recovery while contributing to long-term engraftment in NSG mice.

PubMed

van der Garde, Mark; van Hensbergen, Yvette; Brand, Anneke; Slot, Manon C; de Graaf-Dijkstra, Alice; Mulder, Arend; Watt, Suzanne M; Zwaginga, Jaap Jan

2015-01-01

Human cord blood (CB) hematopoietic stem cell (HSC) transplants demonstrate delayed early neutrophil and platelet recovery and delayed longer term immune reconstitution compared to bone marrow and mobilized peripheral blood transplants. Despite advances in enhancing early neutrophil engraftment, platelet recovery after CB transplantation is not significantly altered when compared to contemporaneous controls. Recent studies have identified a platelet-biased murine HSC subset, maintained by thrombopoietin (TPO), which has enhanced capacity for short- and long-term platelet reconstitution, can self-renew, and can give rise to myeloid- and lymphoid-biased HSCs. In previous studies, we have shown that transplantation of human CB CD34(+) cells precultured in TPO as a single graft accelerates early platelet recovery as well as yielding long-term repopulation in immune-deficient mice. In this study, using a double CB murine transplant model, we investigated whether TPO cultured human CB CD34(+) cells have a competitive advantage or disadvantage over untreated human CB CD34(+) cells in terms of (1) short-term and longer term platelet recovery and (2) longer term hematological recovery. Our studies demonstrate that the TPO treated graft shows accelerated early platelet recovery without impairing the platelet engraftment of untreated CD34(+) cells. Notably, this was followed by a dominant contribution to platelet production through the untreated CD34(+) cell graft over the intermediate to longer term. Furthermore, although the contribution of the TPO treated graft to long-term hematological engraftment was reduced, the TPO treated and untreated grafts both contributed significantly to long-term chimerism in vivo.

In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene

PubMed Central

Larochelle, Andre; Choi, Uimook; Shou, Yan; Naumann, Nora; Loktionova, Natalia A.; Clevenger, Joshua R.; Krouse, Allen; Metzger, Mark; Donahue, Robert E.; Kang, Elizabeth; Stewart, Clinton; Persons, Derek; Malech, Harry L.; Dunbar, Cynthia E.; Sorrentino, Brian P.

2009-01-01

Major limitations to gene therapy using HSCs are low gene transfer efficiency and the inability of most therapeutic genes to confer a selective advantage on the gene-corrected cells. One approach to enrich for gene-modified cells in vivo is to include in the retroviral vector a drug resistance gene, such as the P140K mutant of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT*). We transplanted 5 rhesus macaques with CD34+ cells transduced with lentiviral vectors encoding MGMT* and a fluorescent marker, with or without homeobox B4 (HOXB4), a potent stem cell self-renewal gene. Transgene expression and common integration sites in lymphoid and myeloid lineages several months after transplantation confirmed transduction of long-term repopulating HSCs. However, all animals showed only a transient increase in gene-marked lymphoid and myeloid cells after O6-benzylguanine (BG) and temozolomide (TMZ) administration. In 1 animal, cells transduced with MGMT* lentiviral vectors were protected and expanded after multiple courses of BG/TMZ, providing a substantial increase in the maximum tolerated dose of TMZ. Additional cycles of chemotherapy using 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in similar increases in gene marking levels, but caused high levels of nonhematopoietic toxicity. Inclusion of HOXB4 in the MGMT* vectors resulted in no substantial increase in gene marking or HSC amplification after chemotherapy treatment. Our data therefore suggest that lentivirally mediated gene transfer in transplanted HSCs can provide in vivo chemoprotection of progenitor cells, although selection of long-term repopulating HSCs was not seen. PMID:19509470

Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts

PubMed Central

Kode, Aruna; Manavalan, John S.; Mosialou, Ioanna; Bhagat, Govind; Rathinam, Chozha V.; Luo, Na; Khiabanian, Hossein; Lee, Albert; Vundavalli, Murty; Friedman, Richard; Brum, Andrea; Park, David; Galili, Naomi; Mukherjee, Siddhartha; Teruya-Feldstein, Julie; Raza, Azra; Rabadan, Raul; Berman, Ellin; Kousteni, Stavroula

2014-01-01

Summary Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML. PMID:24429522

Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Suna; Piao, Jiyuan; Son, Youngsook

Stem cells have tremendous promise to treat intractable diseases. Notably, adipose-derived stem cells (ADSCs) are actively being investigated because of ease of sampling and high repopulation capacity in vitro. ADSCs can exert a therapeutic effect through differentiation and paracrine potential, and these actions have been proven in many diseases, including cutaneous and inflammatory diseases. Transplantation of ADSCs necessitates therapeutic quantities and thus, long term ex vivo culture of ADSCs. However, this procedure can impair the activity of ADSCs and provoke cellular senescence, leading to low efficacy in vivo. Accordingly, strategies to restore cellular activity and inhibit senescence of stem cells during ex vivo culturemore » are needed for stem cell-based therapies. This study evaluated a potential supplementary role of Substance P (SP) in ADSC ex vivo culture. After confirming that the ADSC cell cycle was damaged by passage 6 (p6), ADSCs at p6 were cultured with SP, and their proliferation rates, cumulative cell numbers, cytokine profiles, and impact on T/endothelial cells were assessed. Long-term culture weakened proliferation ability and secretion of the cytokines, transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), and stromal cell derived factor-1 alpha (SDF-1alpha) in ADSCs. However, SP treatment reduced the population doubling time (PDT), enabling gain of a sufficient number of ADSCs at early passages. In addition, SP restored cytokine secretion, enhancing the ADSC-mediated paracrine effect on T cell and human umbilical vein endothelial cells (HUVECs). Taken together, these results suggest that SP can retain the therapeutic effect of ADSCs by elevating their proliferative and paracrine potential in ex vivo culture. - Highlights: • Long-term culture of ADSCs leads to cell senescence. • Paracrine potential of ADSC decreases as passage number increases. • SP enhances the weakened proliferation capacity of ADSCs. • SP stimulates cytokine secretion from ADSC with impaired paracrine potential.« less

Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells

PubMed Central

Kobayashi, Hideki; Butler, Jason M.; O'Donnell, Rebekah; Kobayashi, Mariko; Ding, Bi-Sen; Bonner, Bryant; Chiu, Vi K.; Nolan, Daniel J.; Shido, Koji; Benjamin, Laura; Rafii, Shahin

2010-01-01

Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34−Flt3− KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34−Flt3− KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the upregulation of angiocrine factors, with Akt–mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs. PMID:20972423

Population Dynamics of Excited Atoms in Dissipative Cavities

NASA Astrophysics Data System (ADS)

Zou, Hong-Mei; Liu, Yu; Fang, Mao-Fa

2016-10-01

Population dynamics of excited atoms in dissipative cavities is investigated in this work. We present a method of controlling populations of excited atoms in dissipative cavities. For the initial state | e e> A B |00> a b , the repopulation of excited atoms can be obtained by using atom-cavity couplings and non-Markovian effects after the atomic excited energy decays to zero. For the initial state | g g> A B |11> a b , the two atoms can also be populated to the excited states from the initial ground states by using atom-cavity couplings and non-Markovian effects. And the stronger the atom-cavity coupling or the non-Markovian effect is, the larger the number of repopulation of excited atoms is. Particularly, when the atom-cavity coupling or the non-Markovian effect is very strong, the number of repopulation of excited atoms can be close to one in a short time and will tend to a steady value in a long time.

A Longitudinal Study on Feeding Behaviour and Activity Patterns of Released Chimpanzees in Conkouati-Douli National Park, Republic of Congo

PubMed Central

Renaud, Amandine; Jamart, Aliette; Goossens, Benoit; Ross, Caroline

2013-01-01

Simple Summary Wild chimpanzee populations are dramatically declining due to anthropogenic pressure. One way of increasing wild population numbers and/or repopulating areas where local extinction has occurred is to release captive animals. HELP Congo was the first project to successfully release wild-born orphan chimpanzees in their natural environment. We studied the behaviour of eight released chimpanzees over eight years. Over time, they modified their behaviour, suggesting long-term behavioural and ecological adaptations. This suggests that successful release programmes may reinforce existing populations of endangered species. Abstract Wild chimpanzee populations are still declining due to logging, disease transmission and hunting. The bushmeat trade frequently leads to an increase in the number of orphaned primates. HELP Congo was the first project to successfully release wild-born orphan chimpanzees into an existing chimpanzee habitat. A collection of post monitoring data over 16 years now offers the unique opportunity to investigate possible behavioural adaptations in these chimpanzees. We investigated the feeding and activity patterns in eight individuals via focal observation techniques from 1997–1999 and 2001–2005. Our results revealed a decline in the number of fruit and insect species in the diet of released chimpanzees over the years, whereas within the same period of time, the number of consumed seed species increased. Furthermore, we found a decline in time spent travelling, but an increase in time spent on social activities, such as grooming, as individuals matured. In conclusion, the observed changes in feeding and activity patterns seem to reflect important long-term behavioural and ecological adaptations in wild-born orphan released chimpanzees, demonstrating that the release of chimpanzees can be successful, even if it takes time for full adaptation. PMID:26487416

Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice.

PubMed

Xue, Xingkui; Pech, Nancy K; Shelley, W Christopher; Srour, Edward F; Yoder, Mervin C; Dinauer, Mary C

2010-12-09

Inherited hematologic defects that lack an in vivo selective advantage following gene correction may benefit from effective yet minimally toxic cytoreduction of endogenous hematopoietic stem cells (HSCs) prior to transplantation of gene-modified HSCs. We studied the efficacy of administering a novel sequential treatment of parenteral ACK2, an antibody that blocks KIT, followed by low-dose irradiation (LD-IR) for conditioning of wild-type and X-linked chronic granulomatous disease (X-CGD) mice. In wild-type mice, combining ACK2 and LD-IR profoundly decreased endogenous competitive long-term HSC repopulating activity, and permitted efficient and durable donor-derived HSC engraftment after congenic transplantation. ACK2 alone was ineffective. The combination of ACK2 and LD-IR was also effective conditioning in X-CGD mice for engraftment of X-CGD donor HSCs transduced ex vivo with a lentiviral vector. We conclude that combining ACK2 with LD-IR is a promising approach to effectively deplete endogenous HSCs and facilitate engraftment of transplanted donor HSCs.

PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells

PubMed Central

Gur-Cohen, Shiri; Itkin, Tomer; Chakrabarty, Sagarika; Graf, Claudine; Kollet, Orit; Ludin, Aya; Golan, Karin; Kalinkovich, Alexander; Ledergor, Guy; Wong, Eitan; Niemeyer, Elisabeth; Porat, Ziv; Erez, Ayelet; Sagi, Irit; Esmon, Charles T; Ruf, Wolfram; Lapidot, Tsvee

2016-01-01

Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation-related also control retention of EPCR+ LT-HSCs in the bone marrow and their recruitment to the blood via two different protease activated receptor 1 (PAR1)-mediated pathways. Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to TACE-mediated EPCR shedding, enhanced CXCL12-CXCR4-induced motility, and rapid stem and progenitor cell mobilization. Conversely, bone marrow blood vessels provide a microenvironment enriched with protein C that retain EPCR+ LT-HSCs by limiting NO generation, reducing Cdc42 activity and enhancing VLA4 affinity and adhesion. Inhibition of NO production by activated protein C (aPC)-EPCR-PAR1 signaling reduces progenitor cell egress, increases NOlow bone marrow EPCR+ LT-HSCs retention and protects mice from chemotherapy-induced hematological failure and death. Our study reveals new roles for PAR1 and EPCR that control NO production to balance maintenance and recruitment of bone marrow EPCR+ LT-HSCs with clinical relevance. PMID:26457757

[Liver engineering as a new source of donor organs : A systematic review].

PubMed

Mußbach, F; Dahmen, U; Dirsch, O; Settmacher, U

2016-06-01

Organ engineering is a new strategy to cope with the shortage of donor organs. A functional scaffold from explanted organs is prepared by removing all cellular components (decellularization) and the reseeding (repopulation) of the organ scaffold to generate a functional organ in vitro for transplantation. This technique was also applied to the liver (liver engineering). Outline of the current state of the art and resulting approaches for future research strategies. Systematic review according to the PRISMA guidelines: a PubMed-based literature search (search terms liver, decellularization), selection of relevant articles based on predetermined criteria for relevance (e.g. decellularization, repopulation and transplantation), extraction and critical appraisal of data and results concerning the conditions for decellularization, repopulation and transplantation. Decellularization was successfully performed in small and large animal models. Hepatocytes as well as stem cells and hepatic cell lines were applied for repopulation and 7 publications could show the successful transplantation of acellular and repopulated organ scaffolds. The current scientific need for further studies concerning the source of donor organs, optimization of the decellularization process, the cell type for the reseeding process and the establishment of the optimal conditions for the repopulation of the scaffold is still tremendous. For successful recellularization of the liver three goals need to be achieved: (1) reseeding of the organ scaffold with a sufficient amount of parenchymal cells, (2) endothelialization of the vascular tree to ensure the supply of oxygen and nutrients to parenchymal cells and (3) an appropriate epithelialization of the biliary tree. In order to progress to clinical trials a suitable transplantation model to verify the function of the organ constructs must be established. Liver engineering using biological cell-free organ scaffolds represents a scientific and ethical challenge. The existing results emphasize the potential of this new and promising strategy to create organs for transplantation in the future.

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

PubMed

Horwitz, Mitchell E; Chao, Nelson J; Rizzieri, David A; Long, Gwynn D; Sullivan, Keith M; Gasparetto, Cristina; Chute, John P; Morris, Ashley; McDonald, Carolyn; Waters-Pick, Barbara; Stiff, Patrick; Wease, Steven; Peled, Amnon; Snyder, David; Cohen, Einat Galamidi; Shoham, Hadas; Landau, Efrat; Friend, Etty; Peleg, Iddo; Aschengrau, Dorit; Yackoubov, Dima; Kurtzberg, Joanne; Peled, Tony

2014-07-01

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation. Clinicaltrials.gov NCT01221857. Gamida Cell Ltd.

Functional dissection of hematopoietic stem cell populations with a stemness-monitoring system based on NS-GFP transgene expression.

PubMed

Ali, Mohamed A E; Fuse, Kyoko; Tadokoro, Yuko; Hoshii, Takayuki; Ueno, Masaya; Kobayashi, Masahiko; Nomura, Naho; Vu, Ha Thi; Peng, Hui; Hegazy, Ahmed M; Masuko, Masayoshi; Sone, Hirohito; Arai, Fumio; Tajima, Atsushi; Hirao, Atsushi

2017-09-12

Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFP high cells exhibited significantly higher repopulating capacity than NS-GFP low cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFP high cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34 + cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.

Dietary restriction improves repopulation but impairs lymphoid differentiation capacity of hematopoietic stem cells in early aging

PubMed Central

Tang, Duozhuang; Tao, Si; Chen, Zhiyang; Koliesnik, Ievgen Oleksandrovich; Calmes, Philip Gerald; Hoerr, Verena; Han, Bing; Gebert, Nadja; Zörnig, Martin; Löffler, Bettina

2016-01-01

Dietary restriction (DR) improves health, delays tissue aging, and elongates survival in flies and worms. However, studies on laboratory mice and nonhuman primates revealed ambiguous effects of DR on lifespan despite improvements in health parameters. In this study, we analyzed consequences of adult-onset DR (24 h to 1 yr) on hematopoietic stem cell (HSC) function. DR ameliorated HSC aging phenotypes, such as the increase in number of HSCs and the skewing toward myeloid-biased HSCs during aging. Furthermore, DR increased HSC quiescence and improved the maintenance of the repopulation capacity of HSCs during aging. In contrast to these beneficial effects, DR strongly impaired HSC differentiation into lymphoid lineages and particularly inhibited the proliferation of lymphoid progenitors, resulting in decreased production of peripheral B lymphocytes and impaired immune function. The study shows that DR-dependent suppression of growth factors and interleukins mediates these divergent effects caused by DR. Supplementation of insulin-like growth factor 1 partially reverted the DR-induced quiescence of HSCs, whereas IL-6/IL-7 substitutions rescued the impairment of B lymphopoiesis exposed to DR. Together, these findings delineate positive and negative effects of long-term DR on HSC functionality involving distinct stress and growth signaling pathways. PMID:26951333

Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro.

PubMed

Kim, Suna; Piao, Jiyuan; Son, Youngsook; Hong, Hyun Sook

2017-03-25

Stem cells have tremendous promise to treat intractable diseases. Notably, adipose-derived stem cells (ADSCs) are actively being investigated because of ease of sampling and high repopulation capacity in vitro. ADSCs can exert a therapeutic effect through differentiation and paracrine potential, and these actions have been proven in many diseases, including cutaneous and inflammatory diseases. Transplantation of ADSCs necessitates therapeutic quantities and thus, long term ex vivo culture of ADSCs. However, this procedure can impair the activity of ADSCs and provoke cellular senescence, leading to low efficacy in vivo. Accordingly, strategies to restore cellular activity and inhibit senescence of stem cells during ex vivo culture are needed for stem cell-based therapies. This study evaluated a potential supplementary role of Substance P (SP) in ADSC ex vivo culture. After confirming that the ADSC cell cycle was damaged by passage 6 (p6), ADSCs at p6 were cultured with SP, and their proliferation rates, cumulative cell numbers, cytokine profiles, and impact on T/endothelial cells were assessed. Long-term culture weakened proliferation ability and secretion of the cytokines, transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), and stromal cell derived factor-1 alpha (SDF-1alpha) in ADSCs. However, SP treatment reduced the population doubling time (PDT), enabling gain of a sufficient number of ADSCs at early passages. In addition, SP restored cytokine secretion, enhancing the ADSC-mediated paracrine effect on T cell and human umbilical vein endothelial cells (HUVECs). Taken together, these results suggest that SP can retain the therapeutic effect of ADSCs by elevating their proliferative and paracrine potential in ex vivo culture. Copyright © 2017 Elsevier Inc. All rights reserved.

Absence of CD34 on some human SCID-repopulating cells.

PubMed

Dick, J E

1999-04-30

The availability of in vivo repopulation assays has greatly aided the study of human hematopoietic stem cells. Here, I shall review recent data that has identified a novel class of human repopulating cells that do not express classical stem cell markers including CD34 but still retain the ability to repopulate nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.

Application of biological effective dose (BED) to estimate the duration of symptomatic relief and repopulation dose equivalent in palliative radiotherapy and chemotherapy.

PubMed

Jones, Bleddyn; Cominos, Matilda; Dale, Roger G

2003-03-01

To investigate the potential for mathematic modeling in the assessment of symptom relief in palliative radiotherapy and cytotoxic chemotherapy. The linear quadratic model of radiation effect with the overall treatment time and the daily dose equivalent of repopulation is modified to include the regrowth time after completion of therapy. The predicted times to restore the original tumor volumes after treatment are dependent on the biological effective dose (BED) delivered and the repopulation parameter (K); it is also possible to estimate K values from analysis of palliative treatment response durations. Hypofractionated radiotherapy given at a low total dose may produce long symptom relief in slow-growing tumors because of their low alpha/beta ratios (which confer high fraction sensitivity) and their slow regrowth rates. Cancers that have high alpha/beta ratios (which confer low fraction sensitivity), and that are expected to repopulate rapidly during therapy, are predicted to have short durations of symptom control. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same duration of symptom relief as palliative chemotherapy. Relatively simple radiobiologic modeling can be used to guide decision-making regarding the choice of the most appropriate palliative schedules and has important implications in the design of radiotherapy or chemotherapy clinical trials. The methods described provide a rationalization for treatment selection in a wide variety of tumors.

Neodymium: yttrium-aluminum-garnet long impulse laser for the elimination of superfluous hair: experiences and considerations from 3 years of activity.

PubMed

Ferraro, G A; Perrotta, A; Rossano, F; D'Andrea, F

2004-01-01

This study examined the results obtained with a modern apparatus for laser hair removal (neodymium: yttrium-aluminum-garnet [Nd:YAG] laser at long impulses with a wave-length of 1,064 nm; Q-switched laser) over a follow-up period of 3 years. A large heterogeneous group of 480 patients was taken into consideration. These patients were treated according to a standard protocol with monthly checkups and a personalized protocol at deferred appointments. The results, discovered by means of the most objective procedure possible, were retrieved and put into a graph showing two different curves for the repopulation of hair. In their clinical travels, the authors observed an average variable regrowth of 40% to 65%, allowing them to affirm that laser hair removal using Nd:YAG at long impulses is decisively efficient in obtaining long-term results. The use of a protocol (denominated "prolonged monthly checkup") with laser sessions at ever-decreasing periods permits, among other things, more outstanding and advantageous results for the patient. Thanks to more efficiently synchronized phases of the biologic hair cycle, this shortens and moves the telegenic phases closer and also renders the anagenic phases (those in which the selective photoermolysis on the pilipheric follicle proves to be efficient) more efficient. Personalization of the treatment relative to the monthly health checkup sessions is of fundamental importance to the scope of obtaining the best results in terms of cost-benefit rate, provided submassimal fluxes are (i.e., those well-tolerated by the patient) used. All this allows hair removal that is not definitive, but which becomes progressively permanent (i.e., characterized by ever-growing periods of lack of hair sustained by sporadic maintenance laser sessions based on the individual's necessity).

Hematopoietic Stem Cell Regeneration Enhanced by Ectopic Expression of ROS-detoxifying Enzymes in Transplant Mice

PubMed Central

Miao, Weimin; XuFeng, Richard; Park, Moo-Rim; Gu, Haihui; Hu, Linping; Kang, Jin Wook; Ma, Shihui; Liang, Paulina H; Li, Yanxin; Cheng, Haizi; Yu, Hui; Epperly, Michael; Greenberger, Joel; Cheng, Tao

2013-01-01

High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo. PMID:23295952

Bat-mouse bone marrow chimera: a novel animal model for dissecting the uniqueness of the bat immune system.

PubMed

Yong, Kylie Su Mei; Ng, Justin Han Jia; Her, Zhisheng; Hey, Ying Ying; Tan, Sue Yee; Tan, Wilson Wei Sheng; Irac, Sergio Erdal; Liu, Min; Chan, Xue Ying; Gunawan, Merry; Foo, Randy Jee Hiang; Low, Dolyce Hong Wen; Mendenhall, Ian Hewitt; Chionh, Yok Teng; Dutertre, Charles-Antoine; Chen, Qingfeng; Wang, Lin-Fa

2018-03-16

Bats are an important animal model with long lifespans, low incidences of tumorigenesis and an ability to asymptomatically harbour pathogens. Currently, in vivo studies of bats are hampered due to their low reproduction rates. To overcome this, we transplanted bat cells from bone marrow (BM) and spleen into an immunodeficient mouse strain NOD-scid IL-2R -/- (NSG), and have successfully established stable, long-term reconstitution of bat immune cells in mice (bat-mice). Immune functionality of our bat-mouse model was demonstrated through generation of antigen-specific antibody response by bat cells following immunization. Post-engraftment of total bat BM cells and splenocytes, bat immune cells survived, expanded and repopulated the mouse without any observable clinical abnormalities. Utilizing bat's remarkable immunological functions, this novel model has a potential to be transformed into a powerful platform for basic and translational research.

Repopulation Kinetics and the Linear-Quadratic Model

NASA Astrophysics Data System (ADS)

O'Rourke, S. F. C.; McAneney, H.; Starrett, C.; O'Sullivan, J. M.

2009-08-01

The standard Linear-Quadratic (LQ) survival model for radiotherapy is used to investigate different schedules of radiation treatment planning for advanced head and neck cancer. We explore how these treament protocols may be affected by different tumour repopulation kinetics between treatments. The laws for tumour cell repopulation include the logistic and Gompertz models and this extends the work of Wheldon et al. [1], which was concerned with the case of exponential repopulation between treatments. Treatment schedules investigated include standarized and accelerated fractionation. Calculations based on the present work show, that even with growth laws scaled to ensure that the repopulation kinetics for advanced head and neck cancer are comparable, considerable variation in the survival fraction to orders of magnitude emerged. Calculations show that application of the Gompertz model results in a significantly poorer prognosis for tumour eradication. Gaps in treatment also highlight the differences in the LQ model with the effect of repopulation kinetics included.

Is There Any Reason to Prefer Cord Blood Instead of Adult Donors for Hematopoietic Stem Cell Transplants?

PubMed

Beksac, Meral

2015-01-01

As cord blood (CB) enables rapid access and tolerance to HLA mismatches, a number of unrelated CB transplants have reached 30,000. Such transplant activity has been the result of international accreditation programs maintaining highly qualified cord blood units (CBUs) reaching more than 600,000 CBUs stored worldwide. Efforts to increase stem cell content or engraftment rate of the graft by ex vivo expansion, modulation by molecules such as fucose, prostaglandin E2 derivative, complement CD26 inhibitors, or CXCR4/CXCL12 axis have been able to accelerate engraftment speed and rate. Furthermore, introduction of reduced intensity conditioning protocols, better HLA matching, and recognition of the importance of HLA-C have improved CB transplants success by decreasing transplant-related mortality. CB progenitor/stem cell content has been compared with adult stem cells revealing higher long-term repopulating capacity compared to bone marrow-mesenchymal stromal cells and lesser oncogenic potential than progenitor-induced stem cells. This chapter summarizes the advantages and disadvantages of CB compared to adult stem cells within the context of stem cell biology and transplantation.

Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

PubMed

Yan, Xiao; Himburg, Heather A; Pohl, Katherine; Quarmyne, Mamle; Tran, Evelyn; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J; Zhao, Liman; Doan, Phuong L; Chute, John P

2016-11-01

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10 m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10 +/+ mice. After total body irradiation (TBI), Grb10 m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10 +/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chromatin insulator bodies are nuclear structures that form in response to osmotic stress and cell death

PubMed Central

Schoborg, Todd; Rickels, Ryan; Barrios, Josh

2013-01-01

Chromatin insulators assist in the formation of higher-order chromatin structures by mediating long-range contacts between distant genomic sites. It has been suggested that insulators accomplish this task by forming dense nuclear foci termed insulator bodies that result from the coalescence of multiple protein-bound insulators. However, these structures remain poorly understood, particularly the mechanisms triggering body formation and their role in nuclear function. In this paper, we show that insulator proteins undergo a dramatic and dynamic spatial reorganization into insulator bodies during osmostress and cell death in a high osmolarity glycerol–p38 mitogen-activated protein kinase–independent manner, leading to a large reduction in DNA-bound insulator proteins that rapidly repopulate chromatin as the bodies disassemble upon return to isotonicity. These bodies occupy distinct nuclear territories and contain a defined structural arrangement of insulator proteins. Our findings suggest insulator bodies are novel nuclear stress foci that can be used as a proxy to monitor the chromatin-bound state of insulator proteins and provide new insights into the effects of osmostress on nuclear and genome organization. PMID:23878275

Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

PubMed Central

Nosadini, Margherita; Alper, Gulay; Riney, Catherine J.; Benson, Leslie A.; Mohammad, Shekeeb S.; Ramanathan, Sudarshini; Nolan, Melinda; Appleton, Richard; Leventer, Richard J.; Deiva, Kumaran; Brilot, Fabienne; Gorman, Mark P.; Waldman, Amy T.; Banwell, Brenda

2016-01-01

Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation and relapses. PMID:26819962

Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

PubMed

Zhao, Yawei; Cui, Lianzhi; Pan, Yue; Shao, Dan; Zheng, Xiao; Zhang, Fan; Zhang, Hansi; He, Kan; Chen, Li

2017-12-01

Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation. The transwell system was used to mimic the co-culture of surviving ovarian cancer cells in the microenvironment of cytotoxic chemotherapy-treated dying cells. Tumour cell proliferation was observed by crystal violet staining. AA and PGE 2 levels were measured by ELISA, and changes of protein expression were analysed by Western blot. Chemotherapy drug VP16 treatment triggered AA pathway, leading to the elevated PGE 2 level, and ultimately enhanced the repopulation of ovarian cancer cells. Berberine can block the caspase 3-iPLA 2 -AA-COX-2-PGE 2 pathway by inhibiting the expression of iPLA 2 and COX-2. Berberine can also reverse the increased phosphorylation of FAK caused by abnormal PGE 2 level and thus reverse the repopulation of ovarian cancer cells after VP16 treatment. Our observation suggested that Berberine could inhibit the chemotherapy-induced repopulation of ovarian cancer cells by suppressing the AA pathway and phosphorylation of FAK. And these findings implicated a novel combined use of Berberine and chemotherapeutics, which might prevent ovarian cancer recurrence by abrogating early tumour repopulation. © 2017 John Wiley & Sons Ltd.

Identifying States along the Hematopoietic Stem Cell Differentiation Hierarchy with Single Cell Specificity via Raman Spectroscopy.

PubMed

Ilin, Yelena; Choi, Ji Sun; Harley, Brendan A C; Kraft, Mary L

2015-11-17

A major challenge for expanding specific types of hematopoietic cells ex vivo for the treatment of blood cell pathologies is identifying the combinations of cellular and matrix cues that direct hematopoietic stem cells (HSC) to self-renew or differentiate into cell populations ex vivo. Microscale screening platforms enable minimizing the number of rare HSCs required to screen the effects of numerous cues on HSC fate decisions. These platforms create a strong demand for label-free methods that accurately identify the fate decisions of individual hematopoietic cells at specific locations on the platform. We demonstrate the capacity to identify discrete cells along the HSC differentiation hierarchy via multivariate analysis of Raman spectra. Notably, cell state identification is accurate for individual cells and independent of the biophysical properties of the functionalized polyacrylamide gels upon which these cells are cultured. We report partial least-squares discriminant analysis (PLS-DA) models of single cell Raman spectra enable identifying four dissimilar hematopoietic cell populations across the HSC lineage specification. Successful discrimination was obtained for a population enriched for long-term repopulating HSCs (LT-HSCs) versus their more differentiated progeny, including closely related short-term repopulating HSCs (ST-HSCs) and fully differentiated lymphoid (B cells) and myeloid (granulocytes) cells. The lineage-specific differentiation states of cells from these four subpopulations were accurately identified independent of the stiffness of the underlying biomaterial substrate, indicating subtle spectral variations that discriminated these populations were not masked by features from the culture substrate. This approach enables identifying the lineage-specific differentiation stages of hematopoietic cells on biomaterial substrates of differing composition and may facilitate correlating hematopoietic cell fate decisions with the extrinsic cues that elicited them.

Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells

PubMed Central

Wang, Xiaoli; Zhang, Wei; Tripodi, Joseph; Lu, Min; Xu, Mingjiang; Najfeld, Vesna; Li, Yan

2010-01-01

Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34+ cells. Treatment of PMF CD34+ cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34+ chemokine (C-X-C motif) receptor (CXCR)4+ cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F+. Furthermore, sequential treatment of PMF CD34+ cells but not normal CD34+ cells with decitabine (5-aza-2′-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F+ PMF CD34+ cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγnull mice, the percentage of JAK2V617F/JAK2total in human CD45+ marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F+ and that JAK2V617F+ HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC. PMID:20858855

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertoncello, I.; Hodgson, G.S.; Bradley, T.R.

A multiparameter cell separative procedure is described that enables normal transplantable hemopoietic stem cells that preferentially home to the marrow of lethally irradiated mice to be enriched and separated from the majority of spleen colony-forming cells that are assayed 13 days after transplantation (CFU-S13). First, bone marrow cells are centrifuged in a discontinuous bovine serum albumin gradient. Low-density cells are harvested and labeled with the supravital cationic fluorochrome rhodamine 123 (Rh123). Labeled cells are analyzed using a fluorescence-activated cell sorter, and cells are sorted on the basis of relative Rh123 fluorescence within a predetermined forward versus 90 degrees red lightmore » scatter window that has been optimized for the recovery and enrichment of cells with marrow repopulating ability (MRA). Cells with MRA were characterized by relatively low Rh123 fluorescence and could be separated from a fraction that fluoresced more intensely and contained the majority of CFU-S13 but low MRA. Cells with platelet repopulating ability cofractionate with MRA whereas cells with erythroid repopulating ability remain associated with CFU-S13.« less

The Diverse Geographies of Rural Gentrification in Scotland

ERIC Educational Resources Information Center

Stockdale, Aileen

2010-01-01

Gentrification has for too long been investigated as an urban phenomenon. Only relatively recently has it been viewed as an avenue for fruitful rural research. This paper focuses on the repopulation of rural Scotland. Using survey and interview data it examines evidence of gentrification among in-migration flows and seeks to explore both the…

Deep drilling into the Chesapeake Bay impact structure

USGS Publications Warehouse

Gohn, G.S.; Koeberl, C.; Miller, K.G.; Reimold, W.U.; Browning, J.V.; Cockell, C.S.; Horton, J. Wright; Kenkmann, T.; Kulpecz, A.A.; Powars, D.S.; Sanford, W.E.; Voytek, M.A.

2008-01-01

Samples from a 1.76-kilometer-deep corehole drilled near the center of the late Eocene Chesapeake Bay impact structure (Virginia, USA) reveal its geologic, hydrologic, and biologic history. We conducted stratigraphic and petrologic analyses of the cores to elucidate the timing and results of impact-melt creation and distribution, transient-cavity collapse, and ocean-water resurge. Comparison of post-impact sedimentary sequences inside and outside the structure indicates that compaction of the crater fill influenced long-term sedimentation patterns in the mid-Atlantic region. Salty connate water of the target remains in the crater fill today, where it poses a potential threat to the regional groundwater resource. Observed depth variations in microbial abundance indicate a complex history of impact-related thermal sterilization and habitat modification, and subsequent post-impact repopulation.

Deep drilling into the Chesapeake Bay impact structure.

PubMed

Gohn, G S; Koeberl, C; Miller, K G; Reimold, W U; Browning, J V; Cockell, C S; Horton, J W; Kenkmann, T; Kulpecz, A A; Powars, D S; Sanford, W E; Voytek, M A

2008-06-27

Samples from a 1.76-kilometer-deep corehole drilled near the center of the late Eocene Chesapeake Bay impact structure (Virginia, USA) reveal its geologic, hydrologic, and biologic history. We conducted stratigraphic and petrologic analyses of the cores to elucidate the timing and results of impact-melt creation and distribution, transient-cavity collapse, and ocean-water resurge. Comparison of post-impact sedimentary sequences inside and outside the structure indicates that compaction of the crater fill influenced long-term sedimentation patterns in the mid-Atlantic region. Salty connate water of the target remains in the crater fill today, where it poses a potential threat to the regional groundwater resource. Observed depth variations in microbial abundance indicate a complex history of impact-related thermal sterilization and habitat modification, and subsequent post-impact repopulation.

Mammary stem cells have myoepithelial cell properties

PubMed Central

Prater, Michael D.; Petit, Valérie; Russell, I. Alasdair; Giraddi, Rajshekhar; Shehata, Mona; Menon, Suraj; Schulte, Reiner; Kalajzic, Ivo; Rath, Nicola; Olson, Michael F.; Metzger, Daniel; Faraldo, Marisa M.; Deugnier, Marie-Ange; Glukhova, Marina A.; Stingl, John

2014-01-01

Contractile myoepithelial cells dominate the basal layer of the mammary epithelium and are considered to be differentiated cells. However, we observe that up to 54% of single basal cells can form colonies when seeded into adherent culture in the presence of agents that disrupt acin-myosin interactions, and on average, 65% of the single-cell-derived basal colonies can repopulate a mammary gland when transplanted in vivo. This indicates that a high proportion of basal myoepithelial cells can give rise to a mammary repopulating unit (MRU). We demonstrate that myoepithelial cells, flow-sorted using 2 independent myoepithelial-specific reporter strategies, have MRU capacity. Using an inducible lineage tracing approach we follow the progeny of α-smooth muscle actin-expressing myoepithelial cells and show that they function as long-lived lineage-restricted stem cells in the virgin state and during pregnancy. PMID:25173976

Angiocrine functions of organ-specific endothelial cells

PubMed Central

Rafii, Shahin; Butler, Jason M; Ding, Bi-Sen

2016-01-01

Preface Endothelial cells lining blood vessel capillaries are not just passive conduits for delivering blood. Tissue-specific endothelium establish specialized vascular niches that deploy specific sets of growth factors, known as angiocrine factors, which actively participate in inducing, specifying, patterning, and guiding organ regeneration and maintaining homeostasis and metabolism. Angiocrine factors upregulated in response to injury orchestrates self-renewal and differentiation of tissue-specific repopulating resident stem and progenitor cells into functional organs. Uncovering the precise mechanisms whereby physiological-levels of angiocrine factors are spatially and temporally produced, and distributed by organotypic endothelium to repopulating cells, will lay the foundation for driving organ repair without scarring. PMID:26791722

Nuclease-free Adeno-Associated Virus-Mediated Il2rg Gene Editing in X-SCID Mice.

PubMed

Hiramoto, Takafumi; Li, Li B; Funk, Sarah E; Hirata, Roli K; Russell, David W

2018-05-02

X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4 + and CD8 + T cells. Circulating, edited lymphocytes increased over time and appeared in secondary transplant recipients, demonstrating successful editing in long-term repopulating cells. Random vector integration events were nearly undetectable, and malignant transformation of the transplanted cells was not observed. Similar editing frequencies were observed in human hematopoietic cells. Our results demonstrate that therapeutically relevant HSC gene editing can be achieved by AAV vectors in the absence of site-specific nucleases and suggest that this may be a safe and effective therapy for hematopoietic diseases where in vivo selection can increase edited cell numbers. Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Revised radiobiological modelling of the contribution of synchronous chemotherapy to the rate of grades 3-4 mucositis in head and neck cancer.

PubMed

Meade, Sara; McConkey, Chris; Sanghera, Paul; Mehanna, Hisham; Hartley, Andrew

2013-12-01

Biological effective dose (BED) calculations modelled on reduced accelerated repopulation when synchronous chemotherapy is delivered significantly correlate with observed differences in local control in randomised trials of platinum-based chemoradiation. The purpose of this study was to examine whether a similar relationship existed in the context of grades 3-4 mucositis. Biological effective dose from radiotherapy and synchronous chemotherapy was calculated using three different models: AB using the additional BED attributable to chemotherapy and standard repopulation parameters; zero repopulation (ZRP) using zero correction for repopulation; and variable t(p) (Vt(p)) using a variable doubling time for mucosal stem cell repopulation. The correlation between the percentage change in biological effective dose between trial arms, and the observed percentage change in the rate of grades 3-4 mucositis was examined by using the Pearson product-moment correlation. With the AB model, there were no significant correlations with observed differences in rates of grades 3-4 mucositis. With either the ZRP or Vt(p) models, significant correlations were observed. A value of 5 days for the doubling time during repopulation (T(p)) was associated with the most significant correlation (P = 0.002). Models where the dose lost due to accelerated repopulation is reduced imply a therapeutic loss from the use of synchronous chemotherapy when only local control and the rate of acute grades 3-4 mucositis are considered. © 2013 The Royal Australian and New Zealand College of Radiologists.

Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering.

PubMed

Vukovic, Jana; Borlikova, Gilyana G; Ruitenberg, Marc J; Robinson, Gregory J; Sullivan, Robert K P; Walker, Tara L; Bartlett, Perry F

2013-04-10

It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.

A majority of mice show long-term expression of a human. beta. -globin gene after retrovirus transfer into hematopoietic stem cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bender, M.A.; Gelinas, R.E.; Miller

1989-04-01

Murine bone marrow was infected with a high-titer retrovirus vector containing the human {beta}-globin and neomycin phosphotransferase genes. Anemic W/W/sup v/ mice were transplanted with infected marrow which in some cases had been exposed to the selective agent G418. Human {beta}-globin expression was monitored in transplanted animals by using a monoclonal antibody specific for human {beta}-globin polypeptide, and hematopoietic reconstitution was monitored by using donor and recipient mice which differed in hemoglobin type. In some experiments all transplanted mice expressed the human {beta}-globin polypeptide for over 4 months, and up to 50% of peripheral erythrocytes contained detectable levels of polypeptide.more » DNA analysis of transplanted animals revealed that virtually every myeloid cell contained a provirus. Integration site analysis and reconstitution of secondary marrow recipients suggested that every mouse was reconstituted with at least one infected stem cell which had extensive repopulation capability. The ability to consistently transfer an active {beta}-globin gene into mouse hematopoietic cells improves the feasibility of using these techniques for somatic cell gene therapy in humans.« less

A role for GPx3 in activity of normal and leukemia stem cells

PubMed Central

Herault, Olivier; Hope, Kristin J.; Deneault, Eric; Mayotte, Nadine; Chagraoui, Jalila; Wilhelm, Brian T.; Cellot, Sonia; Sauvageau, Martin; Andrade-Navarro, Miguel A.; Hébert, Josée

2012-01-01

The determinants of normal and leukemic stem cell self-renewal remain poorly characterized. We report that expression of the reactive oxygen species (ROS) scavenger glutathione peroxidase 3 (GPx3) positively correlates with the frequency of leukemia stem cells (LSCs) in Hoxa9+Meis1-induced leukemias. Compared with a leukemia with a low frequency of LSCs, a leukemia with a high frequency of LSCs showed hypomethylation of the Gpx3 promoter region, and expressed high levels of Gpx3 and low levels of ROS. LSCs and normal hematopoietic stem cells (HSCs) engineered to express Gpx3 short hairpin RNA (shRNA) were much less competitive in vivo than control cells. However, progenitor cell proliferation and differentiation was not affected by Gpx3 shRNA. Consistent with this, HSCs overexpressing Gpx3 were significantly more competitive than control cells in long-term repopulation experiments, and overexpression of the self-renewal genes Prdm16 or Hoxb4 boosted Gpx3 expression. In human primary acute myeloid leukemia samples, GPX3 expression level directly correlated with adverse prognostic outcome, revealing a potential novel target for the eradication of LSCs. PMID:22508837

Endothelial cell repopulation after stenting determines in-stent neointima formation: effects of bare-metal vs. drug-eluting stents and genetic endothelial cell modification.

PubMed

Douglas, Gillian; Van Kampen, Erik; Hale, Ashley B; McNeill, Eileen; Patel, Jyoti; Crabtree, Mark J; Ali, Ziad; Hoerr, Robert A; Alp, Nicholas J; Channon, Keith M

2013-11-01

Understanding endothelial cell repopulation post-stenting and how this modulates in-stent restenosis is critical to improving arterial healing post-stenting. We used a novel murine stent model to investigate endothelial cell repopulation post-stenting, comparing the response of drug-eluting stents with a primary genetic modification to improve endothelial cell function. Endothelial cell repopulation was assessed en face in stented arteries in ApoE(-/-) mice with endothelial-specific LacZ expression. Stent deployment resulted in near-complete denudation of endothelium, but was followed by endothelial cell repopulation, by cells originating from both bone marrow-derived endothelial progenitor cells and from the adjacent vasculature. Paclitaxel-eluting stents reduced neointima formation (0.423 ± 0.065 vs. 0.240 ± 0.040 mm(2), P = 0.038), but decreased endothelial cell repopulation (238 ± 17 vs. 154 ± 22 nuclei/mm(2), P = 0.018), despite complete strut coverage. To test the effects of selectively improving endothelial cell function, we used transgenic mice with endothelial-specific overexpression of GTP-cyclohydrolase 1 (GCH-Tg) as a model of enhanced endothelial cell function and increased NO production. GCH-Tg ApoE(-/-) mice had less neointima formation compared with ApoE(-/-) littermates (0.52 ± 0.08 vs. 0.26 ± 0.09 mm(2), P = 0.039). In contrast to paclitaxel-eluting stents, reduced neointima formation in GCH-Tg mice was accompanied by increased endothelial cell coverage (156 ± 17 vs. 209 ± 23 nuclei/mm(2), P = 0.043). Drug-eluting stents reduce not only neointima formation but also endothelial cell repopulation, independent of strut coverage. In contrast, selective targeting of endothelial cell function is sufficient to improve endothelial cell repopulation and reduce neointima formation. Targeting endothelial cell function is a rational therapeutic strategy to improve vascular healing and decrease neointima formation after stenting.

Effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro.

PubMed

Lee, J S; Kim, J M; Hong, E K; Kim, S-O; Yoo, Y-J; Cha, J-H

2009-02-01

A growing amount of attention has been placed on periodontal regeneration and wound healing for periodontal therapy. This study was conducted in an effort to determine the effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro. Human periodontal ligament cells were acquired from explant tissue of human healthy periodontal ligament. After the wounding of periodontal ligament cells, the change in expression of heparin-binding epidermal growth factor-like growth factor and epidermal growth factor receptors 1-4 mRNA was assessed. The effects of heparin-binding epidermal growth factor-like growth factor on periodontal ligament cell proliferation and repopulation were assessed in vitro via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and by photographing the injuries, respectively. Extracellular signal-regulated kinase (Erk)1/2, p38 and Akt phosphorylation was characterized via western blotting. Scratch wounding resulted in a significant up-regulation of heparin-binding epidermal growth factor-like growth factor mRNA expression, whereas wounding had no effect on the expression levels of epidermal growth factor receptors 1-4. Interestingly, no expression of epidermal growth factor receptors 2 and 4 was detectable prior to or after wounding. Heparin-binding epidermal growth factor-like growth factor treatment promoted the proliferation and repopulation of periodontal ligament cells. The scratch wounding also stimulated the phosphorylation of Erk1/2 and p38, but not of Akt, in periodontal ligament cells, and heparin-binding epidermal growth factor-like growth factor treatment applied after wounding amplified and extended the activations of Erk1/2 and p38, but not of Akt. Furthermore, Erk1/2 inhibition blocked the process of cell repopulation induced by heparin-binding epidermal growth factor-like growth factor, whereas the inhibition of p38 delayed the process. These results indicate that heparin-binding epidermal growth factor-like growth factor may constitute a critical factor in the wound healing of human periodontal ligament cells by a mechanism that requires the activation of Erk1/2 via specific interaction with epidermal growth factor receptor 1.

Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation.

PubMed

Liu, Yuying; Liang, Xiaoyu; Dong, Wenqian; Fang, Yi; Lv, Jiadi; Zhang, Tianzhen; Fiskesund, Roland; Xie, Jing; Liu, Jinyan; Yin, Xiaonan; Jin, Xun; Chen, Degao; Tang, Ke; Ma, Jingwei; Zhang, Huafeng; Yu, Jing; Yan, Jun; Liang, Huaping; Mo, Siqi; Cheng, Feiran; Zhou, Yabo; Zhang, Haizeng; Wang, Jing; Li, Jingnan; Chen, Yang; Cui, Bing; Hu, Zhuo-Wei; Cao, Xuetao; Xiao-Feng Qin, F; Huang, Bo

2018-03-12

Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 + T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 + T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 + T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications. Copyright © 2018 Elsevier Inc. All rights reserved.

Occurrence of Salmonella serotype Typhimurium DT104 on a commercial swine farm before, during, and after depopulation and repopulation.

PubMed

Erdman, Matthew M; Harris, Isabel T; Torremorell, Montserrat; Wilt, Vincil M; Harris, D L Hank

2005-08-01

To determine whether depopulation-repopulation could be used to eradicate Salmonella serotype Typhimurium DT104 from a commercial swine farm in the midwestern United States. Observational study A commercial swine farm undergoing depopulation-repopulation to eliminate porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae. Pooled fecal samples, tissue samples, and serum samples were collected from pigs on the farm before and after depopulation-repopulation. When there were no pigs on the farm, environmental swab specimens were collected for bacterial culture. Serum was analyzed for anti-Salmonella antibodies with an indirect ELISA. Salmonella isolates obtained by bacterial culture of fecal, tissue, and environmental samples were characterized by means of serotyping, phage typing, pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility testing. 167 Salmonella isolates representing 9 serotypes were recovered from the farm. Results of PFGE and antimicrobial susceptibility testing suggested that S. Typhimurium DT104 strain was not eradicated from the farm. However, seroprevalence of anti-Salmonella antibodies and the percentage of pooled fecal samples positive for Salmonella spp were significantly decreased following repopulation. Results suggested that depopulation-repopulation in conjunction with stringent cleaning and disinfection, attention to biosecurity procedures, control of other diseases, and changes in feed management may reduce the occurrence of, but likely will not eliminate, Salmonella spp in commercial swine herds.

Patterns of hemopoietic reconstitution in nonobese diabetic mice: dichotomy of allogeneic resistance versus competitive advantage of disease-resistant marrow.

PubMed

Kaufman, C L; Li, H; Ildstad, S T

1997-03-01

Complete replacement of the immune system via allogeneic bone marrow transplantation is sufficient to prevent diabetes in the nonobese diabetic (NOD) mouse model. In the present study we examined whether mixed allogeneic reconstitution would be sufficient to interrupt the autoimmune process with respect to occurrence of overt diabetes, as well as preexisting autoimmune insulitis. NOD mice were lethally irradiated and reconstituted with a mixture of NOD and B10.BR marrow. A relative resistance to allogeneic bone marrow engraftment was noted in NOD recipients of the mixed bone marrow inoculum, compared with disease-resistant controls. Moreover, unlike disease-resistant controls, all animals that initially repopulated as mixed donor/host chimeras became predominantly allogeneic by 4 mo, suggesting a competitive advantage for long term engraftment for disease-resistant marrow. All but one mouse in the group that engrafted with allogeneic marrow remained free of diabetes for the entire follow-up period (n = 22). Moreover, in all animals examined, virtually all islets were free of insulitis. In contrast, 74% of NOD mice that received similar conditioning and failed to engraft with donor marrow developed acute diabetes and intra-islet insulitis was present in all animals examined. These data suggest that NOD mice exhibit a relative resistance to engraftment compared with disease-resistant recipients. Conversely, animals that initially repopulated as a mixture of syngeneic and donor marrow become converted to virtually all donor by 4 mo. These data provide additional support that a defective stem cell is responsible for autoimmune diabetes in this experimental model.

Repopulation of calibrations with samples from the target site: effect of the size of the calibration.

NASA Astrophysics Data System (ADS)

Guerrero, C.; Zornoza, R.; Gómez, I.; Mataix-Solera, J.; Navarro-Pedreño, J.; Mataix-Beneyto, J.; García-Orenes, F.

2009-04-01

Near infrared (NIR) reflectance spectroscopy offers important advantages because is a non-destructive technique, the pre-treatments needed in samples are minimal, and the spectrum of the sample is obtained in less than 1 minute without the needs of chemical reagents. For these reasons, NIR is a fast and cost-effective method. Moreover, NIR allows the analysis of several constituents or parameters simultaneously from the same spectrum once it is obtained. For this, a needed steep is the development of soil spectral libraries (set of samples analysed and scanned) and calibrations (using multivariate techniques). The calibrations should contain the variability of the target site soils in which the calibration is to be used. Many times this premise is not easy to fulfil, especially in libraries recently developed. A classical way to solve this problem is through the repopulation of libraries and the subsequent recalibration of the models. In this work we studied the changes in the accuracy of the predictions as a consequence of the successive addition of samples to repopulation. In general, calibrations with high number of samples and high diversity are desired. But we hypothesized that calibrations with lower quantities of samples (lower size) will absorb more easily the spectral characteristics of the target site. Thus, we suspect that the size of the calibration (model) that will be repopulated could be important. For this reason we also studied this effect in the accuracy of predictions of the repopulated models. In this study we used those spectra of our library which contained data of soil Kjeldahl Nitrogen (NKj) content (near to 1500 samples). First, those spectra from the target site were removed from the spectral library. Then, different quantities of samples of the library were selected (representing the 5, 10, 25, 50, 75 and 100% of the total library). These samples were used to develop calibrations with different sizes (%) of samples. We used partial least squares regression, and leave-one-out cross validation as methods of calibration. Two methods were used to select the different quantities (size of models) of samples: (1) Based on Characteristics of Spectra (BCS), and (2) Based on NKj Values of Samples (BVS). Both methods tried to select representative samples. Each of the calibrations (containing the 5, 10, 25, 50, 75 or 100% of the total samples of the library) was repopulated with samples from the target site and then recalibrated (by leave-one-out cross validation). This procedure was sequential. In each step, 2 samples from the target site were added to the models, and then recalibrated. This process was repeated successively 10 times, being 20 the total number of samples added. A local model was also created with the 20 samples used for repopulation. The repopulated, non-repopulated and local calibrations were used to predict the NKj content in those samples from the target site not included in repopulations. For the measurement of the accuracy of the predictions, the r2, RMSEP and slopes were calculated comparing predicted with analysed NKj values. This scheme was repeated for each of the four target sites studied. In general, scarce differences can be found between results obtained with BCS and BVS models. We observed that the repopulation of models increased the r2 of the predictions in sites 1 and 3. The repopulation caused scarce changes of the r2 of the predictions in sites 2 and 4, maybe due to the high initial values (using non-repopulated models r2 >0.90). As consequence of repopulation, the RMSEP decreased in all the sites except in site 2, where a very low RMESP was obtained before the repopulation (0.4 g×kg-1). The slopes trended to approximate to 1, but this value was reached only in site 4 and after the repopulation with 20 samples. In sites 3 and 4, accurate predictions were obtained using the local models. Predictions obtained with models using similar size of samples (similar %) were averaged with the aim to describe the main patterns. The r2 of predictions obtained with models of higher size were not more accurate than those obtained with models of lower size. After repopulation, the RMSEP of predictions using models with lower sizes (5, 10 and 25% of samples of the library) were lower than RMSEP obtained with higher sizes (75 and 100%), indicating that small models can easily integrate the variability of the soils from the target site. The results suggest that calibrations of small size could be repopulated and "converted" in local calibrations. According to this, we can focus most of the efforts in the obtainment of highly accurate analytical values in a reduced set of samples (including some samples from the target sites). The patterns observed here are in opposition with the idea of global models. These results could encourage the expansion of this technique, because very large data based seems not to be needed. Future studies with very different samples will help to confirm the robustness of the patterns observed. Authors acknowledge to "Bancaja-UMH" for the financial support of the project "NIRPROS".

BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells

PubMed Central

Schemionek, Mirle; Elling, Christian; Steidl, Ulrich; Bäumer, Nicole; Hamilton, Ashley; Spieker, Tilmann; Göthert, Joachim R.; Stehling, Martin; Wagers, Amy; Huettner, Claudia S.; Tenen, Daniel G.; Tickenbrock, Lara; Berdel, Wolfgang E.; Serve, Hubert; Holyoake, Tessa L.; Müller-Tidow, Carsten

2010-01-01

In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL+ Lin−Sca-1+c-kit+ (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin−Sca-1−c-kit+), nor mature granulocytes (CD11b+Gr-1+), nor potential stem cell niche cells (CD45−Ter119−) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation. However, prolonged BCR-ABL expression abrogates the potential of LSK cells to induce full-blown disease in secondary recipients and increases the fraction of multipotent progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow. BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development, probably contributing to the reduced LT-HSC frequency within BCR-ABL+ LSK cells. Reversion of BCR-ABL, or treatment with imatinib, eradicates mature cells, whereas leukemic stem cells persist, giving rise to relapsed chronic myeloid leukemia on reinduction of BCR-ABL, or imatinib withdrawal. Our results suggest that BCR-ABL induces differentiation of LT-HSCs and decreases their self-renewal capacity. PMID:20053753

Specific allogeneic unresponsiveness in the adult host: present-day experimental models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rapaport, F.T.; Bachvaroff, R.J.; Cronkite, E.

As part of a long-term intensive effort to apply the induction of adult allogensic unresponsiveness to the transplantation problem, two techniques to control the variability in the persistence of immunologically competent postthymic cells iin the treated host and/or the inoculum of autologous marrow returned to the host after irradiation are described. The first consisted of exposing the peripheral blood of prospective recipients to a 5-week course of extra-corporeal irradiation (ECIB), the other of exposing the stored autologous marrow scheduled to repopulate a given recipient to methyl-prednisolone (MPd) and DNase prior to renifusion into the recipient. Serial analysis of bone marrowmore » cell samples at various intervals before and after treatment was undertaken. The significance of the disappearance of a particular population of nonnuclear cells from the samples, and the association of such disappearance with increased success in the induction of allogeneic unresponsiveness is discussed. (ACR)« less

Hepatic stem/progenitor cells and stem-cell transplantation for the treatment of liver disease.

PubMed

Kakinuma, Sei; Nakauchi, Hiromitsu; Watanabe, Mamoru

2009-01-01

Allogeneic liver transplantation is still the only effective treatment available to patients with liver failure. However, because there is a serious shortage of liver donors, an alternative therapeutic approach is needed. Transplantation of mature hepatocytes has been evaluated in clinical trials, but the long-term efficacy remains unclear and the paucity of donor cells limits this strategy. Stem-cell transplantation is a more promising alternative approach. Several studies have provided information about the mechanism underlying the proliferation and differentiation of hepatic stem/progenitor cells. Moreover, in experimental models of liver disease, transplantation of hepatic stem/progenitor cells or hepatocyte-like cells derived from multipotent stem cells led to donor cell-mediated repopulation of the liver and improved survival rates. However, before stem-cell transplantation can be applied in the clinic to treat liver failure in humans, it will be necessary to overcome several difficulties associated with the technique.

In vitro study of the adverse effect of nicotine and physical strain on human gingival fibroblasts as a model of the healing of wounds commonly found in the military.

PubMed

Dinos, Michael E; Borke, James L; Swiec, Gary D; McPherson, James C; Goodin, Jeremy L; Chuang, Augustine H

2015-03-01

Significant adverse effects on fibroblast growth and metabolism are observed with nicotine. We investigated the synergistic effects of nicotine and cyclical mechanical strain (CMS) on human gingival fibroblasts (HGFs) in a wound-healing model. HGFs were isolated and grown in Dulbecco's modified Eagle's medium. Three-millimeter wounds were created on a confluent cell monolayer grown in a media containing 0, 1, 2, or 4 mM nicotine, with or without CMS. The applied deformation regimen remains constant for 6 days. On days 1, 2, 4, and 6, the cells were stained with hematoxylin and eosin Y for the evaluation of wound repopulation. The application of CMS alone demonstrates a biphasic response, with an initial stimulatory effect on wound repopulation (days 1-2) and less repopulation during the later phase (days 4-6). The addition of nicotine clearly demonstrated a time and inverse dose-dependent relationship on wound repopulation, with no effect during the early phase and reduced wound repopulation during the later phase. Initial treatment of HGF wounds with CMS resulted in faster wound repopulation regardless of nicotine presence. By day 6, wound healing of HGF exposed to both nicotine and CMS is delayed. These findings suggest that CMS and nicotine may affect fibroblasts and delay wound healing at other sites in the body as well. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

Growth promotion of genetically modified hematopoietic progenitors using an antibody/c-Mpl chimera.

PubMed

Kawahara, Masahiro; Chen, Jianhong; Sogo, Takahiro; Teng, Jinying; Otsu, Makoto; Onodera, Masafumi; Nakauchi, Hiromitsu; Ueda, Hiroshi; Nagamune, Teruyuki

2011-09-01

Thrombopoietin is a potent cytokine that exerts proliferation of hematopoietic stem cells (HSCs) through its cognate receptor, c-Mpl. Therefore, mimicry of c-Mpl signaling by a receptor recognizing an artificial ligand would be attractive to attain specific expansion of genetically modified HSCs. Here we propose a system enabling selective expansion of genetically modified cells using an antibody/receptor chimera that can be activated by a specific antigen. We constructed an antibody/c-Mpl chimera, in which single-chain Fv (ScFv) of an anti-fluorescein antibody was tethered to the extracellular D2 domain of the erythropoietin receptor and transmembrane/cytoplasmic domains of c-Mpl. When the chimera was expressed in interleukin (IL)-3-dependent pro-B cell line Ba/F3, genetically modified cells were selectively expanded in the presence of fluorescein-conjugated BSA (BSA-FL) as a specific antigen. Furthermore, highly purified mouse HSCs transduced with the retrovirus carrying antibody/c-Mpl chimera gene proliferated in vitro in response to BSA-FL, and the cells retained in vivo long-term repopulating abilities. These results demonstrate that the antibody/c-Mpl chimera is capable of signal transduction that mimics wild-type c-Mpl signaling. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.

PubMed

Ceronie, Bryan; Jacobs, Benjamin M; Baker, David; Dubuisson, Nicolas; Mao, Zhifeng; Ammoscato, Francesca; Lock, Helen; Longhurst, Hilary J; Giovannoni, Gavin; Schmierer, Klaus

2018-05-01

The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3 + T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.

Monte Carlo radiotherapy simulations of accelerated repopulation and reoxygenation for hypoxic head and neck cancer

PubMed Central

Harriss-Phillips, W M; Bezak, E; Yeoh, E K

2011-01-01

Objective A temporal Monte Carlo tumour growth and radiotherapy effect model (HYP-RT) simulating hypoxia in head and neck cancer has been developed and used to analyse parameters influencing cell kill during conventionally fractionated radiotherapy. The model was designed to simulate individual cell division up to 108 cells, while incorporating radiobiological effects, including accelerated repopulation and reoxygenation during treatment. Method Reoxygenation of hypoxic tumours has been modelled using randomised increments of oxygen to tumour cells after each treatment fraction. The process of accelerated repopulation has been modelled by increasing the symmetrical stem cell division probability. Both phenomena were onset immediately or after a number of weeks of simulated treatment. Results The extra dose required to control (total cell kill) hypoxic vs oxic tumours was 15–25% (8–20 Gy for 5×2 Gy per week) depending on the timing of accelerated repopulation onset. Reoxygenation of hypoxic tumours resulted in resensitisation and reduction in total dose required by approximately 10%, depending on the time of onset. When modelled simultaneously, accelerated repopulation and reoxygenation affected cell kill in hypoxic tumours in a similar manner to when the phenomena were modelled individually; however, the degree was altered, with non-additive results. Simulation results were in good agreement with standard linear quadratic theory; however, differed for more complex comparisons where hypoxia, reoxygenation as well as accelerated repopulation effects were considered. Conclusion Simulations have quantitatively confirmed the need for patient individualisation in radiotherapy for hypoxic head and neck tumours, and have shown the benefits of modelling complex and dynamic processes using Monte Carlo methods. PMID:21933980

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes.

PubMed

Ding, Jianqiang; Yannam, Govardhana R; Roy-Chowdhury, Namita; Hidvegi, Tunda; Basma, Hesham; Rennard, Stephen I; Wong, Ronald J; Avsar, Yesim; Guha, Chandan; Perlmutter, David H; Fox, Ira J; Roy-Chowdhury, Jayanta

2011-05-01

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z-expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%-98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z-expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.

Modelling Potential Consequences of Different Geo-Engineering Treatments for the Baltic Sea Ecosystem

NASA Astrophysics Data System (ADS)

Schrum, C.; Daewel, U.

2017-12-01

From 1950 onwards, the Baltic Sea ecosystem suffered increasingly from eutrophication. The most obvious reason for the eutrophication is the huge amount of nutrients (nitrogen and phosphorus) reaching the Baltic Sea from human activities. However, although nutrient loads have been decreasing since 1980, the hypoxic areas have not decreased accordingly. Thus, geo-engineering projects were discussed and evaluated to artificially ventilate the Baltic Sea deep water and suppress nutrient release from the sediments. Here, we aim at understanding the consequences of proposed geo-engineering projects in the Baltic Sea using long-term scenario modelling. For that purpose, we utilize a 3d coupled ecosystem model ECOSMO E2E, a novel NPZD-Fish model approach that resolves hydrodynamics, biogeochemical cycling and lower and higher trophic level dynamics. We performed scenario modelling that consider proposed geo-engineering projects such as artificial ventilation of Baltic Sea deep waters and phosphorus binding in sediments with polyaluminium chlorides. The model indicates that deep-water ventilation indeed suppresses phosphorus release in the first 1-4 years of treatment. Thereafter macrobenthos repopulates the formerly anoxic bottom regions and nutrients are increasingly recycled in the food web. Consequently, overall system productivity and fish biomass increases and toxic algae blooms decrease. However, deep-water ventilation has no long-lasting effect on the ecosystem: soon after completion of the ventilation process, the system turns back into its original state. Artificial phosphorus binding in sediments in contrast decreases overall ecosystem productivity through permanent removal of phosphorus. As expected it decreases bacterial production and toxic algae blooms, but it also decreases fish production substantially. Contrastingly to deep water ventilation, artificial phosphorus binding show a long-lasting effect over decades after termination of the treatment.

System for tracking transplanted limbal epithelial stem cells in the treatment of corneal stem cell deficiency (Conference Presentation)

NASA Astrophysics Data System (ADS)

Boadi, Joseph; Matcher, Stephen; MacNeil, Sheila; Sangwan, Virender S.

2016-04-01

The prevailing hypothesis for the existence and healing of the avascular corneal epithelium is that this layer of cells are continually produced by stem cells in the limbus and transported onto the cornea to mature into corneal epithelium. In the event that the cornea is damaged and the limbal stem cell population is severely reduced, this condition known as Limbal Stem Cell Deficiency and can lead to blindness. There are numerous treatments but most have high long term failure rates. Most treatment methods include the transplantation of limbal stem cells into damaged limbus with hope of repopulating the region and regenerating at healthy corneal epithelium. Optical Coherence Tomography (OCT) is well known for its high resolution in vivo images. A bespoke OCT has been built to investigate the trajectories of these limbal stem cells after transplantation to see whether if they do repopulate the damaged limbus or not. In the experimentation magneto-labelling was used to track the limbal stem cells. For the magneto-labelling a mixture of limbal stem cells and cornea epithelium are cultured with super paramagnetic iron (Fe3O4) nanoparticles (20-30nm in size) for 24hours, to allow for uptake. The cells are then transplanted onto the denuded cornea. The transplanted cell mixture with the encapsulated magnetic nanoparticles is actuated with an external magnetic field 0.08T leading to a phase modulation on the signal. A Phase sensitive Magneto-motive OCT is used to locate the transplanted cells. The location of the cells with embed SPIOs were located both in 2D and 3D.

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

PubMed Central

Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko; Kuroki, Yoko; Hijikata, Atsushi; Takagi, Masatoshi; Tomizawa, Daisuke; Eguchi, Mariko; Eguchi-Ishimae, Minenori; Kaneko, Akiko; Ono, Rintaro; Sato, Kaori; Suzuki, Nahoko; Fujiki, Saera; Koh, Katsuyoshi; Ishii, Eiichi; Shultz, Leonard D.; Ohara, Osamu; Mizutani, Shuki

2015-01-01

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia. PMID:25538041

Taxonomic and developmental aspects of radiosensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harrison, F.L.; Anderson, S.L.

1996-11-01

Considerable information is available on the effects of radioactivity on adult and early life stages of organisms. The preponderance of data is on mortality after a single irradiation with relatively high doses. Unfortunately, because experiments were carried out under different conditions and for different time periods, the validity of comparing the results from different laxonomic groups is questionable. In general, the conclusions are that there is a relationship (1) between radioresistance to high doses of acute radiation and taxonomy of the organism, primitive forms being more radioresistant than complex vertebrates and (2) between radiosensitivity and developmental stage, early life stagesmore » being more sensitive than later stages. The first conclusion may be related to the capability of the organism to repopulate cells and to differentiate and redifferentiate them; the second to the rate of cellular division and to the degree of differentiation. In question, however, is the relevance of the responses from high levels of acute radiation to that of the responses to long-term exposure to low levels of radiation, which are ecologically of more interest. Data from studies of the effects of acute and chronic exposure on development of gametes and zygotes indicate that, for some fishes and invertebrates, responses at the cellular and molecular levels show effect levels comparable to those observed in some mammals. Acute doses between 0,05 and 0.5Cy and dose rates between 0.02 to 0.2mCy/h appear to define critical ranges in which detrimental effects on fertility are first observed in a variety of radiosensitive organisms. To better understand inherent radiosensitivity, we need more information on the ability of cells to repopulate and differentiate and to prevent or repair damage to biological critical molecules, such as DNA, because these factors may alter significantly organisms` responses to radiation.« less

Combined short-term immunotherapy for experimental autoimmune myasthenia gravis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pestronk, A.; Drachman, D.B.; Teoh, R.

1983-08-01

A therapeutic strategy was designed to eliminate the humoral immune response to acetylcholine receptor (AChR) in ongoing experimental autoimmune myasthenia gravis (EAMG). Rats with EAMG were treated with a protocol consisting of three components: (1) A single high dose of cyclophosphamide (200 mg/kg) was used to produce a rapid and sustained fall in the anti-AChR antibody levels by preferential destruction of antibody-producing B-lymphocytes. ''Memory'' lymphocytes were not eliminated by cyclophosphamide. (2) Irradiation (600 rads) was used to eliminate the ''memory'' cells. It eliminated the anamnestic response to a challenge with the antigen AChR. (3) Bone marrow transplantation was used tomore » repopulate the hematopoietic system after the otherwise lethal dose of cyclophosphamide. We used bone marrow from syngeneic rats with active EAMG to simulate an autologous transplant. Rats with EAMG treated with this combined protocol showed a prompt and sustained fall in the anti-AChR antibody levels and had no anamnestic response to a challenge with AChR. Thus, an affected animal's own marrow could be stored and used later for repopulation after cyclophosphamide-irradiation treatment. This treatment eliminates the animal's ongoing immune responses and reconstitutes the immune system in its original state. The success of this approach suggests that, if their safety could be established, similar ''curative'' strategies might be developed for the treatment of patients with severe antibody-mediated autoimmune disorders, such as myasthenia gravis.« less

Acute effects of alemtuzumab infusion in patients with active relapsing-remitting MS

PubMed Central

Thomas, Katja; Eisele, Judith; Rodriguez-Leal, Francisco Alejandro; Hainke, Undine

2016-01-01

Objective: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cells. Beyond long-term immunologic and clinical data, little is known about acute changes in immunologic and routine laboratory parameters and their clinical relevance during the initial alemtuzumab infusion. Methods: Fifteen patients with highly active MS were recruited. In addition to parameters including heart rate, blood pressure, body temperature, and monitoring of adverse events, complete blood cell count, liver enzymes, kidney function, acute-phase proteins, serum cytokine profile, complement activation, peripheral immune cell distribution, and their potential of cytokine release were investigated prior to and after methylprednisolone and after alemtuzumab on each day of alemtuzumab infusion. Results: After the first alemtuzumab infusion, both the total leukocyte and granulocyte counts markedly increased, whereas lymphocyte counts dramatically decreased. In addition to lymphocyte depletion, cell subtypes important for innate immunity also decreased within the first week after alemtuzumab infusion. Although patients reported feeling well, C-reactive protein and procalcitonin peaked at serum levels consistent with septic conditions. Increases in liver enzymes were detected, although kidney function remained stable. Proinflammatory serum cytokine levels clearly rose after the first alemtuzumab infusion. Alemtuzumab led to impaired cytokine release ex vivo in nondepleted cells. Normal clinical parameters and mild adverse events were presented. Conclusions: Dramatic immunologic effects were observed. Standardized infusion procedure and pretreatment management attenuated infusion-related reactions. Alemtuzumab-mediated effects led to artificially altered parameters in standard blood testing. We recommend clinical decision-making based on primarily clinical symptoms within the first alemtuzumab treatment week. PMID:27213173

Anti-retroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection.

PubMed

Kader, M; Bixler, S; Piatak, M; Lifson, J; Mattapallil, J J

2009-10-01

Human immuno deficiency virus and simian immunodeficiency virus infections are characterized by a severe loss of Th-17 cells (IL-17(+)CD4(+) T cells) that has been associated with disease progression and systemic dissemination of bacterial infections. Anti-retroviral therapy (ART) has led to repopulation of CD4(+) T cells in peripheral tissues with little sustainable repopulation in mucosal tissues. Given the central importance of Th-17 cells in mucosal homeostasis, it is not known if the failure of ART to permanently repopulate mucosal tissues is associated with a failure to restore Th-17 cells that are lost during infection. Dynamics of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood of SIV infected rhesus macaques were evaluated and compared to animals that were treated with ART. The frequency of Th-17 and Tc-17 cells was determined following infection and after therapy. Relative expression of IL-21, IL-23, and TGFbeta was determined using Taqman PCR. Treatment of SIV infected rhesus macaques with anti-retroviral therapy was associated with a substantial repopulation of mucosal homing alpha4(+)beta7(hi)CD4(+) T cells in peripheral blood. This repopulation, however, was not accompanied by a restoration of Th-17 responses. Interestingly, SIV infection was associated with an increase in Tc-17 responses (IL-17(+)CD8(+) T cells) suggesting to a skewing in the ratio of Th-17: Tc-17 cells from a predominantly Th-17 phenotype to a predominantly Tc-17 phenotype. Surprisingly, Tc-17 responses remained high during the course of therapy suggesting that ART failed to correct the imbalance in Th-17 : Tc-17 responses induced following SIV infection. ART was associated with substantial repopulation of alpha4(+)beta7(hi) CD4(+) T cells in peripheral blood with little or no rebound of Th-17 cells. On the other hand, repopulation of alpha4(+)beta7(hi) CD4(+) T cells was accompanied by persistence of high levels of Tc-17 cells in peripheral blood. The dysregulation of Th-17 and Tc-17 responses likely plays a role in disease progression.

Proliferation of multipotent hematopoietic cells controlled by a truncated erythropoietin receptor transgene.

PubMed Central

Kirby, S L; Cook, D N; Walton, W; Smithies, O

1996-01-01

The long-term efficacy of gene therapy using bone marrow transplantation requires the engraftment of genetically altered totipotent hematopoietic stem cells (THSCs). Ex vivo expansion of corrected THSCs is one way to increase the efficiency of the procedure. Similarly, selective in vivo expansion of the therapeutic THSCs rather than the endogenous THSCs could favor the transplant. To test whether a conferred proliferative advantage gene can facilitate the in vitro and in vivo expansion of hematopoietic stem cells, we have generated transgenic mice expressing a truncated receptor for the growth factor erythropoietin. These mice are phenotypically normal, but when treated in vivo with exogenous erythropoietin they exhibit a marked increase in multipotent, clonogenic hematopoietic cells [colony-forming units in the spleen (CFU-S) and CFUs that give rise to granulocytes, erythroid cells, macrophages, and megakaryocytes within the same colony (CFU-GEMM)] in comparison with the wild-type mice. In addition, long-term in vitro culture of tEpoR transgenic bone marrow in the presence of erythropoietin induces exponential expansion of trilineage hematopoietic stem cells not seen with wild-type bone marrow. Thus, the truncated erythropoietin receptor gene shows promise as a means for obtaining cytokine-inducible hematopoietic stem cell proliferation to facilitate the direct targeting of THSCs and to provide a competitive repopulation advantage for transplanted therapeutic stem cells. Images Fig. 3 PMID:8790342

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

PubMed Central

Ding, Jianqiang; Yannam, Govardhana R.; Roy-Chowdhury, Namita; Hidvegi, Tunda; Basma, Hesham; Rennard, Stephen I.; Wong, Ronald J.; Avsar, Yesim; Guha, Chandan; Perlmutter, David H.; Fox, Ira J.; Roy-Chowdhury, Jayanta

2011-01-01

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z–expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%–98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z–expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals. PMID:21505264

Hepatic progenitor cells of biliary origin with liver repopulation capacity

PubMed Central

Boulter, Luke; Tsuchiya, Atsunori; Cole, Alicia M; Hay, Trevor; Guest, Rachel V; Wojtacha, Davina; Man, Tak Yung; Mackinnon, Alison; Ridgway, Rachel A; Kendall, Timothy; Williams, Michael J; Jamieson, Thomas; Raven, Alex; Hay, David C; Iredale, John P; Clarke, Alan R; Sansom, Owen J; Forbes, Stuart J

2015-01-01

Summary Hepatocytes and cholangiocytes self renew following liver injury. Following severe injury hepatocytes are increasingly senescent, whether Hepatic Progenitor Cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where Mdm2 is inducibly deleted in over 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease. PMID:26192438

Microbial Repopulation Following In Situ STAR Remediation

NASA Astrophysics Data System (ADS)

Gerhard, J.; Overbeeke, G.; Edwards, E.; Lomheim, L.; Grant, G.

2016-12-01

STAR (Self-sustaining Treatment for Active Remediation) is an emerging remediation technology that employs a self-sustaining smouldering reaction to destroy nonaqueous phase liquids (NAPLs) in the subsurface. The reaction front travels outwards from an ignition well at approximately 0.5 per day and subjects the soil to temperatures of 400°C-1000°C. The objectives of this work were to monitor re-saturation of the soil over time and quantify the microbial repopulation of the treated zone. STAR is currently being applied as a full scale, in situ remedy for coal tar beneath a former creosol manufacturing facility in New Jersey, USA. This study analyzed soil cores taken at regular intervals following STAR treatment, allowing time for groundwater to re-infiltrate and for microbial populations to potentially reestablish. Soil and groundwater were analyzed for total number of microorganisms via quantitative Polymerase Chain Reaction (qPCR), as well as microbial diversity via amplicon sequencing. Results demonstrate that microbes rapidly repopulated over a 2 month period to 106 gene copies/g of soil. However, concentrations in the treated zone did not rise above this concentration over 6 months post-STAR, indicating a low carrying capacity of the treated soil. To examine the system in more detail and consider the effects of bio-stimulation, a bench top column study using site soil and artificial groundwater explored the rate at which STAR-treated soil is repopulated with naturally occurring microorganisms in the presence and absence of lactate and a terminal electron acceptor. Results demonstrated that biostimulation did not increase the carrying capacity of the STAR treated sol, but rather shifted the microbial community to reflect the TEA provided, in this case, promoting sulfate reducers. Overall, the work illustrates that microbial populations in STAR treated soil do recover via groundwater infiltration but robust communities will take time to naturally establish.

Age-Dependent Netrin-1 Signaling Regulates NG2+ Glial Cell Spatial Homeostasis in Normal Adult Gray Matter

PubMed Central

Birey, Fikri

2015-01-01

Neuron–glial antigen 2-positive (NG2+) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2+ glial cell ablation model in mice, we examined the repopulation dynamics of NG2+ glial cells in the mature and aged mice gray matter. We found that some resident NG2+ glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2+ glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2+ glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2+ glial cell homeostasis that is distinct from its role in myelination. PMID:25926469

Experimental Model for Successful Liver Cell Therapy by Lenti TTR-YapERT2 Transduced Hepatocytes with Tamoxifen Control of Yap Subcellular Location

PubMed Central

Yovchev, Mladen; Jaber, Fadi L.; Lu, Zhonglei; Patel, Shachi; Locker, Joseph; Rogler, Leslie E.; Murray, John W.; Sudol, Marius; Dabeva, Mariana D.; Zhu, Liang; Shafritz, David A.

2016-01-01

Liver repopulation by transplanted hepatocytes has not been achieved previously in a normal liver microenvironment. Here we report that adult rat hepatocytes transduced ex vivo with a lentivirus expressing a human YapERT2 fusion protein (hYapERT2) under control of the hepatocyte-specific transthyretin (TTR) promoter repopulate normal rat liver in a tamoxifen-dependent manner. Transplanted hepatocytes expand very slowly but progressively to produce 10% repopulation at 6 months, showing clusters of mature hepatocytes that are fully integrated into hepatic parenchyma, with no evidence for dedifferentiation, dysplasia or malignant transformation. Thus, we have developed the first vector designed to regulate the growth control properties of Yap that renders it capable of producing effective cell therapy. The level of liver repopulation achieved has significant translational implications, as it is 2-3x the level required to cure many monogenic disorders of liver function that have no underlying hepatic pathology and is potentially applicable to diseases of other tissues and organs. PMID:26763940

Non-viral FoxM1 gene delivery to hepatocytes enhances liver repopulation

PubMed Central

Xiang, D; Liu, C-C; Wang, M-J; Li, J-X; Chen, F; Yao, H; Yu, B; Lu, L; Borjigin, U; Chen, Y-X; Zhong, L; Wangensteen, K J; He, Z-Y; Wang, X; Hu, Y-P

2014-01-01

Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)–/– mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation. PMID:24853430

Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells.

PubMed

Masiuk, Katelyn E; Brown, Devin; Laborada, Jennifer; Hollis, Roger P; Urbinati, Fabrizia; Kohn, Donald B

2017-09-06

Lentiviral vector (LV)-based hematopoietic stem cell (HSC) gene therapy is becoming a promising clinical strategy for the treatment of genetic blood diseases. However, the current approach of modifying 1 × 10 8 to 1 × 10 9 CD34 + cells per patient requires large amounts of LV, which is expensive and technically challenging to produce at clinical scale. Modification of bulk CD34 + cells uses LV inefficiently, because the majority of CD34 + cells are short-term progenitors with a limited post-transplant lifespan. Here, we utilized a clinically relevant, immunomagnetic bead (IB)-based method to purify CD34 + CD38 - cells from human bone marrow (BM) and mobilized peripheral blood (mPB). IB purification of CD34 + CD38 - cells enriched severe combined immune deficiency (SCID) repopulating cell (SRC) frequency an additional 12-fold beyond standard CD34 + purification and did not affect gene marking of long-term HSCs. Transplant of purified CD34 + CD38 - cells led to delayed myeloid reconstitution, which could be rescued by the addition of non-transduced CD38 + cells. Importantly, LV modification and transplantation of IB-purified CD34 + CD38 - cells/non-modified CD38 + cells into immune-deficient mice achieved long-term gene-marked engraftment comparable with modification of bulk CD34 + cells, while utilizing ∼7-fold less LV. Thus, we demonstrate a translatable method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Role of autophagy in the maintenance and function of cancer stem cells.

PubMed

Vitale, Ilio; Manic, Gwenola; Dandrea, Vito; De Maria, Ruggero

2015-01-01

Recent advances in experimental technologies and cancer models have made possible to demonstrate that the tumor is a dynamic system comprising heterogeneous populations of cancer cells organized in a hierarchical fashion with cancer stem cells (CSCs) at the apex. CSCs are immature cells characterized by self-renewal property and long-term repopulation potential. CSCs have been causally linked to cancer initiation, propagation, spreading, recurrence and relapse as well as to resistance to anticancer therapy. A growing body of evidence suggests that the function and physiology of CSCs may be influenced by genetic/epigenetic factors and tumor environment. In this context, macroautophagy is a lysosomal degradative process (herein referred to as autophagy) critical for the adaptive response to stress and the preservation of cellular and tissue homeostasis in all eukaryotes that may have a crucial role of in the origin, maintenance and invasiveness of CSCs. The activation of the autophagic machinery is also considered as an adaptive response of CSCs to perturbation of tumor microenvironment, caused for instance by anticancer therapy. Nevertheless, compelling preclinical and clinical evidence on the cytoprotective role of autophagy for CSCs is still missing. Here, we summarize the results on the contribution of autophagy in CSCs and how it impacts tumorigenesis and tumor progression. We also discuss the therapeutical potential of the modulation of autophagy as a means to eradicate CSCs.

Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.

PubMed

Farace, Francoise; Prestoz, Laetitita; Badaoui, Sabrina; Guillier, Martine; Haond, Celine; Opolon, Paule; Thomas, Jean-Leon; Zalc, Bernard; Vainchenker, William; Turhan, Ali G

2004-02-01

Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation.

The impact of left ventricular stretching in model cultivations with neonatal cardiomyocytes in a whole-heart bioreactor.

PubMed

Hülsmann, Jörn; Aubin, Hug; Wehrmann, Alexander; Lichtenberg, Artur; Akhyari, Payam

2017-05-01

Here, we investigate the impact of integrated three-dimensional (3D) left ventricular (LV) stretching on myocardial maturation in a whole-heart bioreactor setting. Therefore, decellularized rat hearts were selectively repopulated with rodent neonatal cardiomyocytes (5 · 10 6 cells per heart) and cultured over 5 days. Continuous medium perfusion was maintained through the coronary artery system in a customized whole-heart bioreactor system with or without integrated biomechanical stimulation of LV. 3D repopulation effectiveness and cellular vitality were evaluated by repetitive metabolic WST-1 assays and 3D confocal microscopy analysis through fluorescent staining, also assessing cellular organization. Moreover, specific myocardial vitality was verified by detecting spontaneous electrophysiological activity using a multielectrode assay. Western blot analysis of cardiac myosin heavychain (MHC) and quantitative RT-PCR for Connexin 43 was used to analyze cardiomyocyte maturation. Decellularized whole-heart constructs repopulated with neonatal cardiomyocytes (repopWHC) showed vital 3D cell populations throughout the repopulation sites within the LV with a significant increase in metabolic activity (326 ± 113% for stimulated constructs vs. 162 ± 32% for non-stimulated controls after 96 h of continuous cultivation as compared to their state 24 h after injection, directly prior to bioreactor cultivation). Further, bioreactor cultivation under integrated mechanical LV stimulation not only led to a higher degree of cellular organization and an increased MHC content, but also to a significant increase of Cx43 gene expression resulting in a regain of 60 ± 19% of native neonatal hearts expression level in contrast to 20 ± 9% for non-stimulated controls (P = 0.03). Therefore, our study suggests that the integration of LV stretching into whole-heart bioreactor cultivation may enhance cardiac maturation not only by promoting cellular organization but also through adaptive protein and gene expression with particular implications for the formation of the conductive apparatus. Further, this study emphasizes the importance of suitable bioprocessing strategies within sophisticated bioreactor systems as tools for customized stimulation and cultivation of tissue engineered tissues and organs. Biotechnol. Bioeng. 2017;114: 1107-1117. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2.

PubMed

Bugarcic, Andrea; Vetter, Irina; Chalmers, Silke; Kinna, Genevieve; Collins, Brett M; Teasdale, Rohan D

2015-11-01

Retromer is a trimeric complex composed of Vps26, Vps29, and Vps35 and has been shown to be involved in trafficking and sorting of transmembrane proteins within the endosome. The Vps26 paralog, Vps26B, defines a distinct retromer complex (Vps26B-retromer) in vivo and in vitro. Although endosomally associated, Vps26B-retromer does not bind the established retromer transmembrane cargo protein, cation-independent mannose 6-phosphate receptor (CI-M6PR), indicating it has a distinct role to retromer containing the Vps26A paralog. In the present study we use the previously established Vps26B-expressing HEK293 cell model to address the role of Vps26B-retromer in trafficking of the protease activated G-protein coupled receptor PAR-2 to the plasma membrane. In these cells there is no apparent defect in the initial activation of the receptor, as evidenced by release of intracellular calcium, ERK1/2 signaling and endocytosis of activated receptor PAR-2 into degradative organelles. However, we observe a significant delay in plasma membrane repopulation of the protease activated G protein-coupled receptor PAR-2 following stimulation, resulting in a defect in PAR-2 activation after resensitization. Here we propose that PAR-2 plasma membrane repopulation is regulated by Vps26B-retromer, describing a potential novel role for this complex. © 2015 International Federation for Cell Biology.

Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells.

PubMed

Codispoti, Bruna; Rinaldo, Nicola; Chiarella, Emanuela; Lupia, Michela; Spoleti, Cristina Barbara; Marafioti, Maria Grazia; Aloisio, Annamaria; Scicchitano, Stefania; Giordano, Marco; Nappo, Giovanna; Lucchino, Valeria; Moore, Malcolm A S; Zhou, Pengbo; Mesuraca, Maria; Bond, Heather Mandy; Morrone, Giovanni

2017-07-04

Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery.Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes.

Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells

PubMed Central

Codispoti, Bruna; Rinaldo, Nicola; Chiarella, Emanuela; Lupia, Michela; Spoleti, Cristina Barbara; Marafioti, Maria Grazia; Aloisio, Annamaria; Scicchitano, Stefania; Giordano, Marco; Nappo, Giovanna; Lucchino, Valeria; Moore, Malcolm A.S.; Zhou, Pengbo; Mesuraca, Maria

2017-01-01

Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery. Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes. PMID:28187462

Age-Dependent Netrin-1 Signaling Regulates NG2+ Glial Cell Spatial Homeostasis in Normal Adult Gray Matter.

PubMed

Birey, Fikri; Aguirre, Adan

2015-04-29

Neuron-glial antigen 2-positive (NG2(+)) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2(+) glial cell ablation model in mice, we examined the repopulation dynamics of NG2(+) glial cells in the mature and aged mice gray matter. We found that some resident NG2(+) glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2(+) glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2(+) glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2(+) glial cell homeostasis that is distinct from its role in myelination. Copyright © 2015 the authors 0270-6474/15/356946-06$15.00/0.

Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates.

PubMed

Engram, Jessica C; Cervasi, Barbara; Borghans, Jose A M; Klatt, Nichole R; Gordon, Shari N; Chahroudi, Ann; Else, James G; Mittler, Robert S; Sodora, Donald L; de Boer, Rob J; Brenchley, Jason M; Silvestri, Guido; Paiardini, Mirko

2010-08-05

Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4(+) or CD8(+) lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4(+) or CD8(+) T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4(+) and CD8(+) lymphocyte depletions were followed by a largely lineage-specific CD4(+) and CD8(+) T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4(+) T cells than RMs. In addition, in both species CD8(+) T-cell repopulation was faster than that of CD4(+) T cells, with CD8(+) T cells reconstituting a normal pool within 60 days and CD4(+) T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4(+) T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4(+) T-cell destruction is chronic.

Lineage-specific T-cell reconstitution following in vivo CD4+ and CD8+ lymphocyte depletion in nonhuman primates

PubMed Central

Engram, Jessica C.; Cervasi, Barbara; Borghans, Jose A. M.; Klatt, Nichole R.; Gordon, Shari N.; Chahroudi, Ann; Else, James G.; Mittler, Robert S.; Sodora, Donald L.; de Boer, Rob J.; Brenchley, Jason M.; Silvestri, Guido

2010-01-01

Many features of T-cell homeostasis in primates are still unclear, thus limiting our understanding of AIDS pathogenesis, in which T-cell homeostasis is lost. Here, we performed experiments of in vivo CD4+ or CD8+ lymphocyte depletion in 2 nonhuman primate species, rhesus macaques (RMs) and sooty mangabeys (SMs). Whereas RMs develop AIDS after infection with simian immunodeficiency virus (SIV), SIV-infected SMs are typically AIDS-resistant. We found that, in both species, most CD4+ or CD8+ T cells in blood and lymph nodes were depleted after treatment with their respective antibodies. These CD4+ and CD8+ lymphocyte depletions were followed by a largely lineage-specific CD4+ and CD8+ T-cell proliferation, involving mainly memory T cells, which correlated with interleukin-7 plasma levels. Interestingly, SMs showed a faster repopulation of naive CD4+ T cells than RMs. In addition, in both species CD8+ T-cell repopulation was faster than that of CD4+ T cells, with CD8+ T cells reconstituting a normal pool within 60 days and CD4+ T cells remaining below baseline levels up to day 180 after depletion. While this study revealed subtle differences in CD4+ T-cell repopulation in an AIDS-sensitive versus an AIDS-resistant species, such differences may have particular relevance in the presence of active SIV repli cation, where CD4+ T-cell destruction is chronic. PMID:20484087

Inhibiting the Aurora B Kinase Potently Suppresses Repopulation During Fractionated Irradiation of Human Lung Cancer Cell Lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sak, Ali, E-mail: ali.sak@uni-due.de; Stuschke, Martin; Groneberg, Michael

2012-10-01

Purpose: The use of molecular-targeted agents during radiotherapy of non-small-cell lung cancer (NSCLC) is a promising strategy to inhibit repopulation, thereby improving therapeutic outcome. We assessed the combined effectiveness of inhibiting Aurora B kinase and irradiation on human NSCLC cell lines in vitro. Methods and Materials: NSCLC cell lines were exposed to concentrations of AZD1152-hydroxyquinazoline pyrazol anilide (AZD1152-HQPA) inhibiting colony formation by 50% (IC50{sub clone}) in combination with single dose irradiation or different fractionation schedules using multiple 2-Gy fractions per day up to total doses of 4-40 Gy. The total irradiation dose required to control growth of 50% of themore » plaque monolayers (TCD50) was determined. Apoptosis, G2/M progression, and polyploidization were also analyzed. Results: TCD50 values after single dose irradiation were similar for the H460 and H661 cell lines with 11.4 {+-} 0.2 Gy and 10.7 {+-} 0.3 Gy, respectively. Fractionated irradiation using 3 Multiplication-Sign 2 Gy/day, 2 Multiplication-Sign 2 Gy/day, and 1 Multiplication-Sign 2 Gy/day schedules significantly increased TCD50 values for both cell lines grown as plaque monolayers with increasing radiation treatment time. This could be explained by a repopulation effect per day that counteracts 75 {+-} 8% and 27 {+-} 6% of the effect of a 2-Gy fraction in H460 and H661 cells, respectively. AZD1152-HQPA treatment concomitant to radiotherapy significantly decreased the daily repopulation effect (H460: 28 {+-} 5%, H661: 10 {+-} 4% of a 2-Gy fraction per day). Treatment with IC50{sub clone} AZD1152-HPQA did not induce apoptosis, prolong radiation-induced G2 arrest, or delay cell cycle progression before the spindle check point. However, polyploidization was detected, especially in cell lines without functional p53. Conclusions: Inhibition of Aurora B kinase with low AZD1152-HQPA concentrations during irradiation of NSCLC cell lines affects repopulation during radiotherapy. Thus, concomitant Aurora B kinase inhibition and irradiation may be a promising strategy for fast repopulating tumors, which are difficult to cure by dose escalation based on conventional fractionation.« less

Liver repopulation by c-Met-positive stem/progenitor cells isolated from the developing rat liver.

PubMed

Suzuki, Atsushi; Zheng, Yun-wen; Fukao, Katashi; Nakauchi, Hiromitsu; Taniguchi, Hideki

2004-01-01

Self-renewing stem cells responsible for tissue or organ development and regeneration have been recently described. To isolate such cells using flow cytometry, it should be required to find molecules expressing on their cell surfaces. We have previously reported that, on cells fulfilling the criteria for hepatic stem cells, the hepatocyte growth factor receptor c-Met is expressed specifically in the developing mouse liver. In this study, to determine whether c-Met is an essential marker for hepatic stem cells in other animal strains, we examined the potential for in vivo liver-repopulation in sorted fetal rat-derived c-Met+ cells using the retrorsine model. Using flow cytometry and monoclonal antibodies for c-Met and leukocyte common antigen CD45, fetal rat liver cells were fractionated according to the expression of these molecules. Then, cells in each cell subpopulation were sorted and transplanted into the retrorsine-treated adult rats with two-third hepatectomy. At 9 months post transplant, frequency of liver-repopulation was examined by qualitative and quantitative analyses. When we transplanted c-Met+ CD45- sorted cells, many donor-derived cells formed colonies that included mature hepatocytes expressing albumin and containing abundant glycogen in their cytoplasm. In contrast, c-Met- cells and CD45+ cells could not repopulate damaged recipient livers. High enrichment of liver-repopulating cells was conducted by sorting of c-Met+ cells from the developing rat liver. This result suggests that c-Met/HGF interaction plays a crucial role for stem cell growth, differentiation, and self-renewal in rat liver organogenesis. Since the c-Met is also expressed in the fetal mouse-derived hepatic stem cells, this molecule could be expected to be an essential marker for such cell population in the various animal strains, including human.

The impact of MIS-3 climate events at the transition from Neanderthals to modern humans in Europe

NASA Astrophysics Data System (ADS)

Staubwasser, M.; Dragusin, V.; Assonov, S.; Ersek, V.; Hoffmann, D.; Veres, D.; Onac, B. P.

2017-12-01

We report on last glacial stable C and O isotope records from two U-Th dated speleothems from Romania. The southerly record (Ascunsa Cave, South Carpathians) from the Danube region matches the pacing and relative change in amplitude of the Greenland ice temperature record at 30-50 ka BP as well as the abundance of coastal winter sea ice in the Black Sea. The northerly record (Tausoare Cave, East Carpathians) in parts shares the pacing of events with the Greenland or the southern Romanian record, but best matches northern Black Sea summer season temperature change. Heinrich events do not stand out in either record, but the temperature amplitudes of Greenland stadials and Black Sea records are generally reproduced. Based on similarity with the Black Sea we interpret the combined two speleothem records in terms of seasonal temperature change in central Eastern Europe. A climatic influence on the transition from Neanderthals to modern humans has long been suspected. However, the diachronous and spatially complex archaeologic succession across the Middle-Upper Paleolithic (MUPL) in Europe ( 38 - 48 ka) is difficult to reconcile with the millennial-scale pacing of northern hemisphere paleoclimate. Two extreme cold events at 44.0-43.3 recorded and 40.7-39.8 ka in the speleothems bracket the dates of the first known appearance of modern humans - the Aurignacian complex - and the disappearance of Neanderthals from most of Europe. These cold events are coeval with Greenland Stadials GS-12 and GS-10. The speleothem records generally match the paleosol/loess succession from central Europe across the MUPL. The combined record suggests that permafrost advance may have made central Europe uninhabitable at least during winter. The combined paleoclimate and archaeologic records suggest that depopulation-repopulation cycles may have occurred during and after each cold event. Repopulation of central Europe geographically favored the modern human Aurignacians from SE Europe.

Evaluation of stem cell reserve using serial bone marrow transplantation and competitive repopulation in a murine model of chronic hemolytic anemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maggio-Price, L.; Wolf, N.S.; Priestley, G.V.

1988-09-01

Serial transplantation and competitive repopulation were used to evaluate any loss of self-replicative capacity of bone marrow stem cells in a mouse model with increased and persistent hemopoietic demands. Congenic marrows from old control and from young and old mice with hereditary spherocytic anemia (sphha/sphha) were serially transplanted at 35-day intervals into normal irradiated recipients. Old anemic marrow failed or reverted to recipient karyotype at a mean of 3.5 transplants, and young anemic marrow reverted at a mean of 4.0 transplants, whereas controls did so at a mean of 5.0 transplants. In a competitive assay in which a mixture ofmore » anemic and control marrow was transplanted, the anemic marrow persisted to 10 months following transplantation; anemic marrow repopulation was greater if anemic marrow sex matched with the host. It is possible that lifelong stress of severe anemia decreases stem cell reserve in the anemic sphha/sphha mouse marrow. However, marginal differences in serial transplantation number and the maintenance of anemic marrow in a competition assay would suggest that marrow stem cells, under prolonged stress, are capable of exhibiting good repopulating and self-replicating abilities.« less

Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea.

PubMed Central

Stephens, T. C.; Peacock, J. H.

1977-01-01

The relationship between tumour volume response and cell kill in B16 melanoma following treatment in vivo with cyclophosphamide (CY) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated. Tumour volume response, expressed as growth delay, was estimated from measurements of tumour dimensions. Depression of in vitro colony-forming ability of cells from treated tumours was used as the measure of tumour cell kill. The relationship between these parameters was clearly different for the two agents studied. CY produced more growth delay (7.5 days) per decade of tumour cell kill than CCNU (2 to 3.5 days). The possibility that this was due to a technical artefact was rejected in favour of an alternative explanation that different rates of cellular repopulation in tumours treated with CY and CCNU might be responsible. Cellular repopulation was measured directly, by performing cell-survival assays at various times after treatment with doses of CY and CCNU which produced about 3 decades of cell kill. The rate of repopulation by clonogenic cells was much slower after treatment with CY than with CCNU, and this appears to account for the longer duration of the growth delay obtained with CY. PMID:921888

Hematopoietic stem cells with controllable tEpoR transgenes have a competitive advantage in bone marrow transplantation.

PubMed

Kirby, S; Walton, W; Smithies, O

2000-06-15

In a previous study, it was found that a truncated erythropoietin receptor transgene (tEpoR tg) enables multilineage hematopoietic progenitor amplification after treatment with erythropoietin (epo) in vitro and in vivo. This study used competitive bone marrow (BM) repopulation to show that tEpoR tg facilitates transplantation by hematopoietic stem cells (HSC). Individual multilineage colonies, committed myeloid progenitor colonies, and lymphoid colonies (pre-B colony-forming units) were grown from the marrow of animals 6 months after they received a 50/50 mixture of transgene and wild-type BM cells. In epo-treated recipients, the transgene-bearing cells significantly outcompeted the wild-type cells (84%-100% versus 16%-0%, respectively). In recipients treated with phosphate-buffered saline, the repopulation was minimally different from the donor mixture (49%-64% transgene versus 51%-36% wild-type). The epo-induced repopulation advantage is maintained in secondary transplants. In addition, neither accelerated HSC depletion nor uncontrollable proliferation occurred during epo-stimulated serial transplants of transgene-containing BM. Thus, the tEpoR tg functions in a benign fashion in HSC and allows for a significant and controllable repopulation advantage in vivo without excessive HSC depletion relative to wild-type BM. (Blood. 2000;95:3710-3715)

Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice.

PubMed

Liu, Yi; Zhang, Cuiping; Li, Zhenyu; Wang, Chi; Jia, Jianhang; Gao, Tianyan; Hildebrandt, Gerhard; Zhou, Daohong; Bondada, Subbarao; Ji, Peng; St Clair, Daret; Liu, Jinze; Zhan, Changguo; Geiger, Hartmut; Wang, Shuxia; Liang, Ying

2017-04-11

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1) was a potential downstream target with a dramatic downregulation in Lxn-null HSCs. Enforced expression of Thbs1 restored the Lxn inactivation-mediated HSC phenotypes. This study reveals that Lxn plays an important role in the maintenance of homeostatic hematopoiesis, and it may lead to development of safe and effective approaches to manipulate HSCs for clinical benefit. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

The In Vivo PDGF Response During Remyelination in Mouse Spinal Cord Following Murine Hepatitis Virus Strain AS9-Induced Transient Demyelination

DTIC Science & Technology

1998-09-14

repopulation. These and other growth factors interacting with cell adhesion molecules andlor matrix molecules would be expected to mediate oligodendrocyte...oligodendrocyte lineage, along with a closely related CCHC zinc finger, is expressed in developing neurons in the mammalian central nervous system. J...repopulate and remyelinate demyelinated lesions. In vitro studies have shown that platelet- derived growth factor (PDGF) induces proliferation

Long-term hematopoietic stem cell damage in a murine model of the hematopoietic syndrome of the acute radiation syndrome.

PubMed

Chua, Hui Lin; Plett, P Artur; Sampson, Carol H; Joshi, Mandar; Tabbey, Rebeka; Katz, Barry P; MacVittie, Thomas J; Orschell, Christie M

2012-10-01

Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sublethal doses of radiation and time points within a few months of exposure. In this study, the authors examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 mo post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient throughout the study compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSCs is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points.

The Delayed Effects of Acute Radiation Syndrome: Evidence of Long-Term Functional Changes in the Clonogenic Cells of the Small Intestine.

PubMed

Booth, Catherine; Tudor, Gregory L; Katz, Barry P; MacVittie, Thomas J

2015-11-01

Long term or residual damage post-irradiation has been described for many tissues. In hematopoietic stem cells (HSC), this is only revealed when the HSC are stressed and required to regenerate and repopulate a myeloablated host. Such an assay cannot be used to assess the recovery potential of previously irradiated intestinal stem cells (ISC) due to their incompatibility with transplantation. The best approximation to the HSC assay is the crypt microcolony assay, also based on clonogen survival. In the current study, the regenerative capacity of intestinal clonogenic cells in mice that had survived 13 Gy irradiation (with 5% bone marrow shielding to allow survival through the hematopoietic syndrome) and were then aged for 200 d was compared to previously unirradiated age-matched controls. Interestingly, at 200 d following 13 Gy, there remained a statistically significant reduction in crypts present in the various small intestinal regions (illustrating that the gastrointestinal epithelium had not fully recovered despite the 200-d interval). However, upon re-irradiation on day 196, those mice previously irradiated had improved crypt survival and regeneration compared to the age-matched controls. This was evident in all regions of the small intestine following 11-13 Gy re-exposure. Thus, there were either more clonogens per crypt within those previously irradiated and/or those that were present were more radioresistant (possibly because a subpopulation was more quiescent). This is contrary to the popular belief that previously irradiated animals may have an impaired/delayed regenerative response and be more radiosensitive.

Triggered by asphyxia neurogenesis seems not to be an endogenous repair mechanism, gliogenesis more like it.

PubMed

Keilhoff, G; John, R; Langnaese, K; Schweizer, H; Ebmeyer, U

2010-12-15

We analyzed the long-term consequences of asphyxial cardiac arrest for hippocampal cell proliferation in rats to evaluate if the ischaemia-induced degenerated CA1 region may be repopulated by endogenous (stem) cells. Studies were performed in an asphyxial cardiac arrest model with 5 minutes of asphyxiation and three different survival times: 7, 21, and 90 days. Sham-operated non-asphyxiated rats served as control. Cell proliferation was studied by labeling dividing cells with 5-bromo-2'-deoxy-uridine (BrdU). The neurodegenerative/regenerative pattern at single cell levels was monitored by immunohistochemistry. Alterations of gene expression were analyzed by real-time quantitative RT-PCR. Analysis of BrdU-incorporation demonstrated an increase at 7, 21 as well as 90 days after global ischaemia in the hippocampal CA1 pyramidal cell layer. Similar results were found in the dentate gyrus. Differentiation of BrdU-positive cells, investigated by cell phenotype-specific double fluorescent labeling, showed increased neurogenesis only in the dentate gyrus of animals surviving the cardiac arrest for 7 days. The majority of newcomers, especially in the damaged CA1 region, consisted of glial cells. Moreover, asphyxia seemed to be able to induce the migration of microglia and astroglia from adjacent areas into the damaged area and/or the activation of resident cells. In addition, we show microglia proliferation/activation even 90 days after cardiac arrest. This morphological finding was confirmed by PCR analysis. The results indicate that asphyxia triggers cell proliferation in general and gliogenesis in particular - a possible pro-reparative event. Furthermore, from the finding of microglia proliferation up to 90 days after insult we conclude that delayed cell death processes take place which should be considered for further therapy strategies. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Telomerase deficiency in bone marrow-derived cells attenuates angiotensin II-induced abdominal aortic aneurysm formation.

PubMed

Findeisen, Hannes M; Gizard, Florence; Zhao, Yue; Cohn, Dianne; Heywood, Elizabeth B; Jones, Karrie L; Lovett, David H; Howatt, Deborah A; Daugherty, Alan; Bruemmer, Dennis

2011-02-01

Abdominal aortic aneurysms (AAA) are an age-related vascular disease and an important cause of morbidity and mortality. In this study, we sought to determine whether the catalytic component of telomerase, telomerase reverse transcriptase (TERT), modulates angiotensin (Ang) II-induced AAA formation. Low-density lipoprotein receptor-deficient (LDLr-/-) mice were lethally irradiated and reconstituted with bone marrow-derived cells from TERT-deficient (TERT-/-) mice or littermate wild-type mice. Mice were placed on a diet enriched in cholesterol, and AAA formation was quantified after 4 weeks of Ang II infusion. Repopulation of LDLr-/- mice with TERT-/- bone marrow-derived cells attenuated Ang II-induced AAA formation. TERT-deficient recipient mice revealed modest telomere attrition in circulating leukocytes at the study end point without any overt effect of the donor genotype on white blood cell counts. In mice repopulated with TERT-/- bone marrow, aortic matrix metalloproteinase-2 (MMP-2) activity was reduced, and TERT-/- macrophages exhibited decreased expression and activity of MMP-2 in response to stimulation with Ang II. Finally, we demonstrated in transient transfection studies that TERT overexpression activates the MMP-2 promoter in macrophages. TERT deficiency in bone marrow-derived macrophages attenuates Ang II-induced AAA formation in LDLr-/- mice and decreases MMP-2 expression. These results point to a previously unrecognized role of TERT in the pathogenesis of AAA.

Natural Killer Cell Immunotherapy Targeting Cancer Stem Cells

PubMed Central

Luna, Jesus I; Grossenbacher, Steven K.; Murphy, William J; Canter, Robert J

2017-01-01

Introduction Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with “stem-cell” like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. In this report, we review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs. Expert Opinion Unlike cytotoxic cancer treatments, NK cells are able to target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells. PMID:27960589

Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

PubMed Central

Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

2009-01-01

Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

The Culture-Repopulating Ability Assays and Incubation in Low Oxygen: A Simple Way to Test Drugs on Leukaemia Stem or Progenitor Cells

PubMed Central

Cipolleschi, Maria Grazia; Rovida, Elisabetta; Sbarba, Persio Dello

2013-01-01

The Culture-Repopulating Ability (CRA) assays is a method to measure in vitro the bone marrow-repopulating potential of haematopoietic cells. The method was developed in our laboratory in the course of studies based on the use of growth factor-supplemented liquid cultures to study haematopoietic stem/progenitor cell resistance to, and selection at, low oxygen tensions in the incubation atmosphere. These studies led us to put forward the first hypothesis of the existence in vivo of haematopoietic stem cell niches where oxygen tension is physiologically lower than in other bone marrow areas. The CRA assays and incubation in low oxygen were later adapted to the study of leukaemias. Stabilized leukaemia cell lines, ensuring genetically homogeneous cells and enhancing repeatability of results, were found nevertheless phenotypically heterogeneous, comprising cell subsets exhibiting functional phenotypes of stem or progenitor cells. These subsets can be assayed separately, provided an experimental system capable to select one from another (such as different criteria for incubation in low oxygen) is established. On this basis, a two-step procedure was designed, including a primary culture of leukaemia cells in low oxygen for different times, where drug treatment is applied, followed by the transfer of residual cell population (CRA assay) to a drug-free secondary culture incubated at standard oxygen tension, where the expansion of population is allowed. The CRA assays, applied to cell lines first and then to primary cells, represent a simple and relatively rapid, yet accurate and reliable, method for the pre-screening of drugs potentially active on leukaemias which in our opinion could be adopted systematically before they are tested in vivo. PMID:23394087

Effective Hepatocyte Transplantation Using Rat Hepatocytes with Low Asialoglycoprotein Receptor Expression

PubMed Central

Ise, Hirohiko; Nikaido, Toshio; Negishi, Naoki; Sugihara, Nobuhiro; Suzuki, Fumitaka; Akaike, Toshihiro; Ikeda, Uichi

2004-01-01

Development of a reliable method of isolating highly proliferative potential hepatocytes provides information crucial to progress in the field of hepatocyte transplantation. The aim of this study was to develop reliable hepatocyte transplantation using highly proliferative, eg, progenitor-like hepatocytes, based on asialoglycoprotein receptor (ASGPR) expression levels for hepatocyte transplantation. We have previously reported that mouse hepatocytes with low ASGPR expression levels have highly proliferative potential and can be used as progenitor-like hepatocytes. We therefore fractionated F344 male rat hepatocytes expressing low and high levels of ASGPR and determined the liver repopulation capacity of hepatocytes according to low and high ASGPR expression in the liver. Next, 2 × 105 cells of each type were transplanted into female liver regenerative model dipeptidyl peptidase-deficient rats, and we estimated the rate of liver repopulation by the transplanted hepatocytes in the host liver, as determined by recognition of the Sry gene on the Y-chromosome. At 60 days after hepatocyte transplantation, the transplanted hepatocytes occupied ∼76% of the total hepatocyte mass in the case of the transplantation of hepatocytes with low ASGPR expression, but accounted for ∼12% and 17% of the mass in the case of the transplantation of hepatocytes with high ASGPR expression and unfractionated hepatocytes, respectively. In conclusion, these findings suggest that hepatocytes with low ASGPR expression can result in normal liver function and a high repopulation capacity in vivo. These results provide insight into development of a strategy for effective liver repopulation using transplanted hepatocytes. PMID:15277224

Effective hepatocyte transplantation using rat hepatocytes with low asialoglycoprotein receptor expression.

PubMed

Ise, Hirohiko; Nikaido, Toshio; Negishi, Naoki; Sugihara, Nobuhiro; Suzuki, Fumitaka; Akaike, Toshihiro; Ikeda, Uichi

2004-08-01

Development of a reliable method of isolating highly proliferative potential hepatocytes provides information crucial to progress in the field of hepatocyte transplantation. The aim of this study was to develop reliable hepatocyte transplantation using highly proliferative, eg, progenitor-like hepatocytes, based on asialoglycoprotein receptor (ASGPR) expression levels for hepatocyte transplantation. We have previously reported that mouse hepatocytes with low ASGPR expression levels have highly proliferative potential and can be used as progenitor-like hepatocytes. We therefore fractionated F344 male rat hepatocytes expressing low and high levels of ASGPR and determined the liver repopulation capacity of hepatocytes according to low and high ASGPR expression in the liver. Next, 2 x 10(5) cells of each type were transplanted into female liver regenerative model dipeptidyl peptidase-deficient rats, and we estimated the rate of liver repopulation by the transplanted hepatocytes in the host liver, as determined by recognition of the Sry gene on the Y-chromosome. At 60 days after hepatocyte transplantation, the transplanted hepatocytes occupied approximately 76% of the total hepatocyte mass in the case of the transplantation of hepatocytes with low ASGPR expression, but accounted for approximately 12% and 17% of the mass in the case of the transplantation of hepatocytes with high ASGPR expression and unfractionated hepatocytes, respectively. In conclusion, these findings suggest that hepatocytes with low ASGPR expression can result in normal liver function and a high repopulation capacity in vivo. These results provide insight into development of a strategy for effective liver repopulation using transplanted hepatocytes.

Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro

PubMed Central

Havari, Evis; Turner, Michael J; Campos-Rivera, Juanita; Shankara, Srinivas; Nguyen, Tri-Hung; Roberts, Bruce; Siders, William; Kaplan, Johanne M

2014-01-01

Alemtuzumab is a humanized monoclonal antibody specific for the CD52 protein present at high levels on the surface of B and T lymphocytes. In clinical trials, alemtuzumab has shown a clinical benefit superior to that of interferon-β in relapsing–remitting multiple sclerosis patients. Treatment with alemtuzumab leads to the depletion of circulating lymphocytes followed by a repopulation process characterized by alterations in the number, proportions and properties of lymphocyte subsets. Of particular interest, an increase in the percentage of T cells with a regulatory phenotype (Treg cells) has been observed in multiple sclerosis patients after alemtuzumab. Since Treg cells play an important role in the control of autoimmune responses, the effect of alemtuzumab on Treg cells was further studied in vitro. Alemtuzumab effectively mediated complement-dependent cytolysis of human T lymphocytes and the remaining population was enriched in T cells with a regulatory phenotype. The alemtuzumab-exposed T cells displayed functional regulatory characteristics including anergy to stimulation with allogeneic dendritic cells and ability to suppress the allogeneic response of autologous T cells. Consistent with the observed increase in Treg cell frequency, the CD25hi T-cell population was necessary for the suppressive activity of alemtuzumab-exposed T cells. The mechanism of this suppression was found to be dependent on both cell–cell contact and interleukin-2 consumption. These findings suggest that an alemtuzumab-mediated increase in the proportion of Treg cells may play a role in promoting the long-term efficacy of alemtuzumab in patients with multiple sclerosis. PMID:24116901

Mobilization of hematopoietic stem cells with highest self-renewal by G-CSF precedes clonogenic cell mobilization peak.

PubMed

Winkler, Ingrid G; Wiercinska, Eliza; Barbier, Valerie; Nowlan, Bianca; Bonig, Halvard; Levesque, Jean-Pierre

2016-04-01

Harvest of granulocyte colony-stimulating factor (G-CSF)-mobilized hematopoietic stem cells (HSCs) begins at day 5 of G-CSF administration, when most donors have achieved maximal mobilization. This is based on surrogate markers for HSC mobilization, such as CD34(+) cells and colony-forming activity in blood. However, CD34(+) cells or colony-forming units in culture (CFU-C) are heterogeneous cell populations with hugely divergent long-term repopulation potential on transplantation. HSC behavior is influenced by the vascular bed in the vicinity of which they reside. We hypothesized that G-CSF may mobilize sequentially cells proximal and more distal to bone marrow venous sinuses where HSCs enter the blood. We addressed this question with functional serial transplantation assays using blood and bone marrow after specific time points of G-CSF treatment in mice. We found that in mice, blood collected after only 48 hours of G-CSF administration was as enriched in serially reconstituting HSCs as blood collected at 5 days of G-CSF treatment. Similarly, mobilized Lin(-)CD34(+) cells were relatively enriched in more primitive Lin(-)CD34(+)CD38(-) cells at day 2 of G-CSF treatment compared with later points in half of human donors tested (n = 6). This suggests that in both humans and mice, hematopoietic progenitor and stem cells do not mobilize uniformly according to their maturation stage, with most potent HSCs mobilizing as early as day 2 of G-CSF. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Coarse-scale movement patterns of a small-bodied fish inhabiting a desert stream

USGS Publications Warehouse

Dzul, M.C.; Quist, M.C.; Dinsmore, S.J.; Gaines, D.B.; Bower, M.R.

2013-01-01

Located on the floor of Death Valley (CA, USA), Salt Creek harbors a single fish species, the Salt Creek pupfish, Cyprinodon salinus salinus, which has adapted to this extremely harsh environment. Salt Creek is fed by an underground spring and is comprised of numerous pools, runs, and marshes that exhibit substantial variability in temperature, salinity, and dissolved oxygen concentrations. In addition, the wetted area of Salt Creek is reduced throughout the summer months due to high rates of evaporation, with some reaches drying completely. Therefore, it seems logical that short- and long-term movement patterns may play an important role in Salt Creek pupfish population dynamics. The objective of this study was to describe coarse-scale movements of Salt Creek pupfish in Salt Creek during their breeding season from March to May. Sex ratios and length–frequency distributions varied spatially within Salt Creek, suggesting population segregation during the breeding season. Long-distance movements were generally rare, although two fish moved more than 1.2 km. Movement in upstream reaches was rare or absent, in contrast to the greater movement observed in downstream reaches (29% of recaptures). Temporal trends and demographic patterns in movement were not observed. Because the two most downstream habitats dry up in the summer, our results indicate that coarse-scale movements that re-populate downstream reaches likely occur during other times of year. Consequently, the importance of small- and large-scale movements is influenced by season. Further assessment of Salt Creek movement patterns conducted during other times of year may better illuminate long-distance movement patterns and source-sink dynamics.

In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase

PubMed Central

Gori, Jennifer L.; Tian, Xinghui; Swanson, Debra; Gunther, Roland; Shultz, Leonard D.; McIvor, R. Scott; Kaufman, Dan S.

2009-01-01

SUMMARY Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase engraftment of gene-modified hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR – GFP expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rγcnull (NSG) mice after injection of Tyr22-DHFR-derived cells significantly increases human CD34+ and CD45+ cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR-cells in vivo, and provides a novel approach for combined human cell and gene therapy. PMID:19829316

Tree Line Structure and Dynamics at the Northern Limit of the Larch Forest: Anabar Plateau, Siberia, Russia

NASA Technical Reports Server (NTRS)

Kharuk, Viacheslav I.; Ranson, Kenneth J.; Im, Sergey T.; Oskorbin, Pavel A.; Dvinskaya, Maria L.; Ovchinnikov, Dmitriy V.

2013-01-01

The goal of the study was to provide an analysis of climate impact before, during, and after the Little Ice Age (LIA) on the larch (Larix gmelinii) tree line at the northern extreme of Siberian forests. Recent decadal climate change impacts on the tree line, regeneration abundance, and age structure were analyzed. The location of the study area was within the forest-tundra ecotone (elevation range 170-450 m) in the Anabar Plateau, northern Siberia. Field studies were conducted along elevational transects. Tree natality/mortality and radial increment were determined based on dendrochronology analyses. Tree morphology, number of living and subfossil trees, regeneration abundance, and age structure were studied. Locations of pre-LIA, LIA, and post-LIA tree lines and refugia boundaries were established. Long-term climate variables and drought index were included in the analysis. It was found that tree mortality from the 16th century through the beginning of the 19th century caused a downward tree line recession. Sparse larch stands experienced deforestation, transforming into tundra with isolated relict trees. The maximum tree mortality and radial growth decrease were observed to have occurred at the beginning of 18th century. Now larch, at its northern boundary in Siberia, is migrating into tundra areas. Upward tree migration was induced by warming in the middle of the 19th century. Refugia played an important role in repopulation of the forest-tundra ecotone by providing a seed source and shelter for recruitment of larch regeneration. Currently this ecotone is being repopulated mainly by tree cohorts that were established after the 1930s. The last two decades of warming did not result in an acceleration of regeneration recruitment because of increased drought conditions. The regeneration line reached (but did not exceed) the pre-LIA tree line location, although contemporary tree heights and stand densities are comparatively lower than in the pre-LIA period. The mean rate of tree line upward migration has been about 0.35 m/yr (with a range of 0.21-0.58), which translates to a tree line response to temperature of about 55 m/deg C.

Allograft integration in a rabbit transgenic model for anterior cruciate ligament reconstruction.

PubMed

Bachy, M; Sherifi, I; Zadegan, F; Petite, H; Vialle, R; Hannouche, D

2016-04-01

Tissue engineering strategies include both cell-based and cell homing therapies. Ligamentous tissues are highly specialized and constitute vital components of the musculoskeletal system. Their damage causes significant morbidity and loss in function. The aim of this study is to analyze tendinous graft integration, cell repopulation and ligamentization by using GFP+/- allografts in GFP+/- transgenic New Zealand white (NZW) rabbits. Graft implantation was designed to closely mimic anterior cruciate ligament (ACL) repair surgery. Allografts were implanted in 8 NZW rabbits and assessed at 5 days, 3 weeks and 6 weeks through: (1) arthroCT imaging, (2) morphological analysis of the transplanted allograft, (3) histological analysis, (4) collagen type I immunochemistry, and (5) GFP cell tracking. Collagen remodeling was appreciated at 3 and 6 weeks. Graft repopulation with host cells, chondrocyte-like cells at the tendon-bone interface and graft corticalization in the bone tunnels were noticed at 3 weeks. By contrast we noticed a central necrosis aspect in the allografts intra-articularly at 6 weeks with a cell migration towards the graft edge near the synovium. Our study has served to gain a better understanding of tendinous allograft bone integration, ligamentization and allograft repopulation. We believe that both cell-based therapies and cell homing therapies are beneficial in ligament tissue engineering. Future studies may elucidate whether cell repopulation occurs with pre-differentiated or progenitor cells. We believe that both cell-based therapies and cell homing therapies are beneficial in ligament tissue engineering. Level V (animal study). Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Quality of life and physical activity in long-term (≥5 years post-diagnosis) colorectal cancer survivors - systematic review.

PubMed

Eyl, Ruth Elisa; Xie, Kun; Koch-Gallenkamp, Lena; Brenner, Hermann; Arndt, Volker

2018-06-01

Due to the increasing number of long-term (≥5 years post diagnosis) colorectal cancer survivors, long-term quality of life of these patients is highly relevant. Several studies have reported a positive association between physical activity and quality of life in colorectal cancer survivors, however, so far no systematic review has been published which focuses on long-term colorectal cancer survivors. A systematic review was conducted using the databases PubMed, Web of Science, PsychINFO, and CINAHL. Studies which investigated associations between physical activity and quality of life in long-term colorectal cancer survivors were included. Ten articles based on seven studies were identified. Long-term colorectal cancer survivors who were physically active reported better quality of life than long-term survivors who were not physically active. Both, moderate to vigorous physical activity and lower levels like light physical activity were associated with higher quality of life. Most studies assessed the association between physical activity and quality of life cross-sectionally but one prospective study which measured physical activity and quality of life at three different points in time also found associations between physical activity and quality of life. The association between physical activity and quality of life seemed to be stronger among women than among men. The findings of this systematic review support an association between physical activity and quality of life in long-term colorectal cancer survivors. However, the evidence is limited as most studies were based on cross-sectional and observational design.

Loss of Angiotensin-Converting Enzyme 2 Exacerbates Diabetic Retinopathy by Promoting Bone Marrow Dysfunction.

PubMed

Duan, Yaqian; Beli, Eleni; Li Calzi, Sergio; Quigley, Judith L; Miller, Rehae C; Moldovan, Leni; Feng, Dongni; Salazar, Tatiana E; Hazra, Sugata; Al-Sabah, Jude; Chalam, Kakarla V; Le Phuong Trinh, Thao; Meroueh, Marya; Markel, Troy A; Murray, Matthew C; Vyas, Ruchi J; Boulton, Michael E; Parsons-Wingerter, Patricia; Oudit, Gavin Y; Obukhov, Alexander G; Grant, Maria B

2018-05-15

Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin angiotensin system (RAS). We tested the hypothesis that loss of ACE2 would exacerbate diabetic retinopathy by promoting bone marrow dysfunction. ACE2 -/y were crossed with Akita mice, a model of type 1 diabetes. When comparing the bone marrow of the ACE2 -/y -Akita mice to that of Akita mice, we observed a reduction of both short-term and long-term repopulating hematopoietic stem cells, a shift of hematopoiesis towards myelopoiesis, and an impairment of lineage - c-kit + hematopoietic stem/progenitor cell (HS/PC) migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to angiotensin-1-7 (Ang-1-7), the protective peptide generated by ACE2. Over the duration of diabetes examined, ACE2 deficiency led to progressive reduction in electrical responses assessed by electroretinography and to increases in neural infarcts observed by fundus photography. Compared to Akita mice, ACE2 -/y -Akita at 9-months of diabetes showed an increased number of acellular capillaries indicative of more severe diabetic retinopathy. In diabetic and control human subjects, CD34 + cells, a key bone marrow HS/PC population, were assessed for changes in mRNA levels for MAS, the receptor for Ang-1-7. Levels were highest in CD34 + cells from diabetics without retinopathy. Higher serum Ang-1-7 levels predicted protection from development of retinopathy in diabetics. Treatment with Ang-1-7 or alamandine restored the impaired migration function of CD34 + cells from subjects with retinopathy. These data support that activation of the protective RAS within HS/PCs may represent a therapeutic strategy for prevention of diabetic retinopathy. This article is protected by copyright. All rights reserved. © 2018 AlphaMed Press.

Prefrontal θ-Burst Stimulation Disrupts the Organizing Influence of Active Short-Term Retrieval on Episodic Memory.

PubMed

Marin, Bianca M; VanHaerents, Stephen A; Voss, Joel L; Bridge, Donna J

2018-01-01

Dorsolateral prefrontal cortex (DLPFC) is thought to organize items in working memory and this organizational role may also influence long-term memory. To causally test this hypothesized role of DLPFC in long-term memory formation, we used θ-burst noninvasive stimulation (TBS) to modulate DLPFC involvement in a memory task that assessed the influence of active short-term retrieval on later memory. Human subjects viewed three objects on a grid and then either actively retrieved or passively restudied one object's location after a brief delay. Long-term memory for the other objects was assessed after a delay to evaluate the beneficial role of active short-term retrieval on subsequent memory for the entire set of object locations. We found that DLPFC TBS had no significant effects on short-term memory. In contrast, DLPFC TBS impaired long-term memory selectively in the active-retrieval condition but not in the passive-restudy condition. These findings are consistent with the hypothesized contribution of DLPFC to the organizational processes operative during active short-term retrieval that influence long-term memory, although other regions that were not stimulated could provide similar contributions. Notably, active-retrieval and passive-restudy conditions were intermixed, and therefore nonspecific influences of stimulation were well controlled. These results suggest that DLPFC is causally involved in organizing event information during active retrieval to support coherent long-term memory formation.

Prefrontal θ-Burst Stimulation Disrupts the Organizing Influence of Active Short-Term Retrieval on Episodic Memory

PubMed Central

2018-01-01

Abstract Dorsolateral prefrontal cortex (DLPFC) is thought to organize items in working memory and this organizational role may also influence long-term memory. To causally test this hypothesized role of DLPFC in long-term memory formation, we used θ-burst noninvasive stimulation (TBS) to modulate DLPFC involvement in a memory task that assessed the influence of active short-term retrieval on later memory. Human subjects viewed three objects on a grid and then either actively retrieved or passively restudied one object’s location after a brief delay. Long-term memory for the other objects was assessed after a delay to evaluate the beneficial role of active short-term retrieval on subsequent memory for the entire set of object locations. We found that DLPFC TBS had no significant effects on short-term memory. In contrast, DLPFC TBS impaired long-term memory selectively in the active-retrieval condition but not in the passive-restudy condition. These findings are consistent with the hypothesized contribution of DLPFC to the organizational processes operative during active short-term retrieval that influence long-term memory, although other regions that were not stimulated could provide similar contributions. Notably, active-retrieval and passive-restudy conditions were intermixed, and therefore nonspecific influences of stimulation were well controlled. These results suggest that DLPFC is causally involved in organizing event information during active retrieval to support coherent long-term memory formation. PMID:29445769

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aerts-Kaya, Fatima S.F.; Visser, Trudi P.; Arshad, Shazia

Purpose: 5-Androstene-3{beta},17{beta}-diol (5-AED) stimulates recovery of hematopoiesis after exposure to radiation. To elucidate its cellular targets, the effects of 5-AED alone and in combination with (pegylated) granulocyte colony-stimulating factor and thrombopoietin (TPO) on immature hematopoietic progenitor cells were evaluated following total body irradiation. Methods and Materials: BALB/c mice were exposed to radiation delivered as a single or as a fractionated dose, and recovery of bone marrow progenitors and peripheral blood parameters was assessed. Results: BALB/c mice treated with 5-AED displayed accelerated multilineage blood cell recovery and elevated bone marrow (BM) cellularity and numbers of progenitor cells. The spleen colony-forming unitmore » (CFU-S) assay, representing the life-saving short-term repopulating cells in BM of irradiated donor mice revealed that combined treatment with 5-AED plus TPO resulted in a 20.1-fold increase in CFU-S relative to that of placebo controls, and a 3.7 and 3.1-fold increase in comparison to 5-AED and TPO, whereas no effect was seen of Peg-G-CSF with or without 5-AED. Contrary to TPO, 5-AED also stimulated reconstitution of the more immature marrow repopulating (MRA) cells. Conclusions: 5-AED potently counteracts the hematopoietic effects of radiation-induced myelosuppression and promotes multilineage reconstitution by stimulating immature bone marrow cells in a pattern distinct from, but synergistic with TPO.« less

PKA increases in the olfactory bulb act as unconditioned stimuli and provide evidence for parallel memory systems: pairing odor with increased PKA creates intermediate- and long-term, but not short-term, memories.

PubMed

Grimes, Matthew T; Harley, Carolyn W; Darby-King, Andrea; McLean, John H

2012-02-21

Neonatal odor-preference memory in rat pups is a well-defined associative mammalian memory model dependent on cAMP. Previous work from this laboratory demonstrates three phases of neonatal odor-preference memory: short-term (translation-independent), intermediate-term (translation-dependent), and long-term (transcription- and translation-dependent). Here, we use neonatal odor-preference learning to explore the role of olfactory bulb PKA in these three phases of mammalian memory. PKA activity increased normally in learning animals 10 min after a single training trial. Inhibition of PKA by Rp-cAMPs blocked intermediate-term and long-term memory, with no effect on short-term memory. PKA inhibition also prevented learning-associated CREB phosphorylation, a transcription factor implicated in long-term memory. When long-term memory was rescued through increased β-adrenoceptor activation, CREB phosphorylation was restored. Intermediate-term and long-term, but not short-term odor-preference memories were generated by pairing odor with direct PKA activation using intrabulbar Sp-cAMPs, which bypasses β-adrenoceptor activation. Higher levels of Sp-cAMPs enhanced memory by extending normal 24-h retention to 48-72 h. These results suggest that increased bulbar PKA is necessary and sufficient for the induction of intermediate-term and long-term odor-preference memory, and suggest that PKA activation levels also modulate memory duration. However, short-term memory appears to use molecular mechanisms other than the PKA/CREB pathway. These mechanisms, which are also recruited by β-adrenoceptor activation, must operate in parallel with PKA activation.

Investigation of bacterial repopulation after sinus surgery and perioperative antibiotics.

PubMed

Hauser, Leah J; Ir, Diana; Kingdom, Todd T; Robertson, Charles E; Frank, Daniel N; Ramakrishnan, Vijay R

2016-01-01

Endoscopic sinus surgery (ESS) enjoys high success rates, but repopulation with pathogenic bacteria is 1 of the hallmarks of poorer outcomes. There are many hypothesized sources of repopulating bacteria; however, this process remains largely unexplored. This study examined changes in the sinus microbiome after ESS and medical therapies to identify potential sources for postsurgical microbial repopulation. Samples from the anterior nares, ethmoid sinus, and nasopharynx were taken at the time of surgery from 13 subjects undergoing ESS for chronic rhinosinusitis (CRS). Patients were treated postoperatively with 2 weeks of oral antibiotics and saline rinses. The ethmoid sinus was sampled at 2 and 6 weeks postoperatively; microbiota were characterized using quantitative polymerase chain reaction (qPCR) and 16S ribosomal RNA (rRNA) gene sequencing. The Morisita-Horn beta-diversity index (M-H) was used to compare similarity between samples. The bacterial burden of the ethmoid was higher 2 weeks postoperatively than 6 weeks postoperatively (p = 0.01). The 6-week samples most closely represented the anterior nares and ethmoid at surgery (M-H = 0.58 and 0.59, respectively), and were least similar to the nasopharynx (M-H = 0.28). Principal coordinates analysis (PCoA) plots illustrate that the ethmoid microbiota temporarily shifted after surgery and antibiotics but returned toward baseline in many subjects. Bacterial communities colonizing the ethmoid 6 weeks postoperatively were most similar to anterior nasal cavity and pretreatment sinus microbial profiles, indicating a high degree of resilience in the sinonasal microbiome of most subjects. Interestingly, surgery and postoperative antibiotic therapy does not appear to reduce bacterial burden, but rather, shifts the microbial consortia. © 2015 ARS-AAOA, LLC.

Kinetics of depopulation, repopulation and host cell infiltration in the rhabdomyosarcoma R1H after 14 MeV neutron irradiation.

PubMed

Brammer, I; Zywietz, F; Beck-Bornholdt, H P; Jung, H

1992-05-01

The kinetics of depopulation and repopulation of the solid transplantable rhabdomyosarcoma R1H in the rat was studied following irradiation with 5 Gy of 14 MeV neutrons. Several parameters were sequentially measured over a time period of 4 weeks after irradiation: the tumour volume was assessed by in situ caliper measurements; the numerical density of tumour cells was obtained by morphometry; the clonogenic fraction of tumour cells was derived from in vitro colony assay; and the numerical ratio of host to tumour cells was determined by flow cytometry. From these primary parameters the number of clonogenic tumour cells, non-clonogenic tumour cells, and nucleated host cells per tumour, as well as their variation with time, were derived. The results were compared with two sets of data obtained previously for the same tumour exposed to 15 Gy of 200 kVp X-rays. Survival of tumour cells was reduced to 5.5 +/- 0.5% by 5 Gy neutrons and to 4.5 +/- 0.5% by 15 Gy X-rays, i.e. an RBE of close to 3. There was a lag period before the onset of repopulation (4.9 +/- 0.4 days and 4.9 +/- 0.5 days, respectively), followed by a high initial rate of repopulation corresponding to a doubling time of 2.0 +/- 0.2 days for neutrons and 2.1 +/- 0.2 days for X-rays. The rate of depopulation was significantly different for the two treatment modalities; the halving time for the number of non-clonogenic tumour cells was 11 +/- 4 days for neutrons and 2.8 +/- 0.5 days for X-rays.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma

PubMed Central

Budach, W; Paulsen, F; Welz, S; Classen, J; Scheithauer, H; Marini, P; Belka, C; Bamberg, M

2002-01-01

The potential of Mitomycin C in combination with fractionated irradiation to inhibit tumour cell repopulation of a fast growing squamous cell carcinoma after fractionated radiotherapy was investigated in vivo. A rapidly growing human squamous cell carcinoma (FaDudd) was used for the study. For experiments, NMRI (nu/nu) mice with subcutaneously growing tumours were randomly allocated to no treatment, Mitomycin C, fractionated irradiation (ambient: 11x4.5 Gy in 15 days), or fractionated irradiation combined with Mitomycin C. Graded top up doses (clamped blood flow: 0–57 Gy) were given at day 16, 23, 30 or 37. End point of the study was the time to local tumour progression. Data were examined by multiple regression analysis (Cox). Mitomycin C alone resulted in a median time to local tumour progression of 23 (95% confidence limits: 17–43) days, fractionated irradiation in 31 (25–35) days and combined Mitomycin C plus fractionated irradiation in 65 (58–73) days (P=0.02). Mitomycin C decreased the relative risk of local recurrence by 94% (P<<0.001) equivalent to 31.7 Gy top up dose. Repopulation accounted for 1.33 (0.95–1.72) Gy per day top up dose after fractionated irradiation alone and for 0.68 (0.13–1.22) Gy per day after fractionated irradiation+Mitomycin C (P=0.018). Mitomycin C significantly reduces the risk of local recurrence and inhibits tumour cell repopulation in combination with fractionated irradiation in vivo in the tested tumour model. British Journal of Cancer (2002) 86, 470–476. DOI: 10.1038/sj/bjc/6600081 www.bjcancer.com © 2002 The Cancer Research Campaign PMID:11875717

Regenerative periodontal therapy in mucogingival surgery for root coverage.

PubMed

Abitbol, T; Santi, E; Urbani, G

1997-02-01

This article illustrates the potential benefits of regenerative periodontal therapy in mucogingival surgery and esthetic dental treatment. Cases are described in which the treatment of soft-tissue recessions and root exposures are treated with surgical procedures where both clinical soft-tissue augmentation and the regeneration of periodontal attachment are obtained. Cases are also presented to illustrate the clinical application of guided tissue regeneration. Resorbable and nonresorbable barriers are placed over the root surface and bone and covered by the overlying flap, which allows the selective repopulation of the lesion by progenitor cells and the inhibition of a long junctional epithelium. Emphasis is placed on regenerative procedures in soft-tissue augmentation, particularly with respect to rationales, techniques, and indications.

46 CFR 356.43 - Long-term or exclusive sales contracts.

Code of Federal Regulations, 2010 CFR

2010-10-01

... the vessel or the vessel's operation, management and harvesting activities. (b) Provisions of a long... control over the operation, management or harvesting activities of the vessel, vessel owner, or bareboat... DOCUMENTATION Charters, Management Agreements and Exclusive or Long-Term Contracts § 356.43 Long-term or...

Influence of anaesthetics on tumour-cell kill and repopulation in B16 melanoma treated with melphalan.

PubMed Central

Peacock, J. H.; Stephens, T. C.

1978-01-01

The influence of anaesthetics on the in vivo response of B16 melanoma to melphalan was studied using an in vitro cell-survival assay. Three anaesthetics were used, Saffan (Althesin) Sagatal (Nembutal) and Hypnorm. When Saffan was administered to tumour-bearing animals before melphalan there was a significant increase in tumour-cell kill. This effect was not observed with Sagatal or Hypnorm. Maximum increase in tumour-cell kill was achieved when Saffan was administered about 1 h before melphalan, and was dependent on Saffan dose. Clonogenic tumour-cell repopulation after melphalan was rapid (TD - 1 day) and the rate was similar from 2 levels of cell kill. When Saffan was combined with melphalan the repopulation rate was the same as with melphalan alone, and the increased cell kill was reflected in increased growth delay. The in vitro response of B16 melanoma cells to melphalan was unaltered by pretreatment with, or simultaneous exposure to Saffan. The results suggest that the mechanism of the enhanced cell kill in vivo is probably due to an indirect systemic effect, rather than a direct effect on the tumour cells. PMID:743490

Repopulation of interacting tumor cells during fractionated radiotherapy: stochastic modeling of the tumor control probability.

PubMed

Fakir, Hatim; Hlatky, Lynn; Li, Huamin; Sachs, Rainer

2013-12-01

Optimal treatment planning for fractionated external beam radiation therapy requires inputs from radiobiology based on recent thinking about the "five Rs" (repopulation, radiosensitivity, reoxygenation, redistribution, and repair). The need is especially acute for the newer, often individualized, protocols made feasible by progress in image guided radiation therapy and dose conformity. Current stochastic tumor control probability (TCP) models incorporating tumor repopulation effects consider "stem-like cancer cells" (SLCC) to be independent, but the authors here propose that SLCC-SLCC interactions may be significant. The authors present a new stochastic TCP model for repopulating SLCC interacting within microenvironmental niches. Our approach is meant mainly for comparing similar protocols. It aims at practical generalizations of previous mathematical models. The authors consider protocols with complete sublethal damage repair between fractions. The authors use customized open-source software and recent mathematical approaches from stochastic process theory for calculating the time-dependent SLCC number and thereby estimating SLCC eradication probabilities. As specific numerical examples, the authors consider predicted TCP results for a 2 Gy per fraction, 60 Gy protocol compared to 64 Gy protocols involving early or late boosts in a limited volume to some fractions. In sample calculations with linear quadratic parameters α = 0.3 per Gy, α∕β = 10 Gy, boosting is predicted to raise TCP from a dismal 14.5% observed in some older protocols for advanced NSCLC to above 70%. This prediction is robust as regards: (a) the assumed values of parameters other than α and (b) the choice of models for intraniche SLCC-SLCC interactions. However, α = 0.03 per Gy leads to a prediction of almost no improvement when boosting. The predicted efficacy of moderate boosts depends sensitively on α. Presumably, the larger values of α are the ones appropriate for individualized treatment protocols, with the smaller values relevant only to protocols for a heterogeneous patient population. On that assumption, boosting is predicted to be highly effective. Front boosting, apart from practical advantages and a possible advantage as regards iatrogenic second cancers, also probably gives a slightly higher TCP than back boosting. If the total number of SLCC at the start of treatment can be measured even roughly, it will provide a highly sensitive way of discriminating between various models and parameter choices. Updated mathematical methods for calculating repopulation allow credible generalizations of earlier results.

Etanercept blocks inflammatory responses orchestrated by TNF-α to promote transplanted cell engraftment and proliferation in rat liver

PubMed Central

Viswanathan, Preeti; Kapoor, Sorabh; Kumaran, Vinay; Joseph, Brigid; Gupta, Sanjeev

2014-01-01

Engraftment of transplanted cells is critical for liver-directed cell therapy but most transplanted cells are rapidly cleared from liver sinusoids by proinflammatory cytokines/chemokines/receptors after activation of neutrophils or Kupffer cells. To define whether TNF-α served roles in cell-transplantation-induced hepatic inflammation, we used TNF-α antagonist, etanercept, for studies in syngeneic rat hepatocyte transplantation systems. After cell transplantation, multiple cytokines/chemokines/receptors were overexpressed, whereas etanercept prior to cell transplantation essentially normalized these responses. Moreover, ETN downregulated cell transplantation-induced intrahepatic release of secretory cytokines, such as high mobility group box 1. These effects of etanercept decreased cell transplantation-induced activation of neutrophils but not of Kupffer cells. Transplanted cell engraftment improved by several-fold in etanercept-treated animals. These gains in cell engraftment were repeatedly realized after pretreatment of animals with etanercept before multiple cell transplantation sessions. Transplanted cell numbers did not change over time indicating absence of cell proliferation after etanercept alone. By contrast, in animals preconditioned with retrorsine and partial hepatectomy, cell transplantation after etanercept pretreatment significantly accelerated liver repopulation compared with control rats. We concluded that TNF-α played a major role in orchestrating cell transplantation-induced inflammation through regulation of multiple cytokines/chemokines/receptor expression. As TNF-α antagonism by etanercept decreased transplanted cell clearance, improved cell engraftment and accelerated liver repopulation, this pharmacological approach to control hepatic inflammation will help optimize clinical strategies for liver cell therapy. PMID:24844924

BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21

PubMed Central

Lee, Hyemin; Dai, Fangyan; Zhuang, Li; Xiao, Zhen-Dong; Kim, Jongchan; Zhang, Yilei; Ma, Li; You, M. James; Wang, Zhong; Gan, Boyi

2016-01-01

BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology. PMID:26992241

Identification of a population of cells with hematopoietic stem cell properties in mouse aorta-gonad-mesonephros cultures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nobuhisa, Ikuo; Ohtsu, Naoki; Okada, Seiji

The aorta-gonad-mesonephros (AGM) region is a primary source of definitive hematopoietic cells in the midgestation mouse embryo. In cultures of dispersed AGM regions, adherent cells containing endothelial cells are observed first, and then non-adherent hematopoietic cells are produced. Here we report on the characterization of hematopoietic cells that emerge in the AGM culture. Based on the expression profiles of CD45 and c-Kit, we defined three cell populations: CD45{sup low} c-Kit{sup +} cells that had the ability to form hematopoietic cell colonies in methylcellulose media and in co-cultures with stromal cells; CD45{sup low} c-Kit{sup -} cells that showed a granulocyte morphology;more » CD45{sup high} c-Kit{sup low/-} that exhibited a macrophage morphology. In co-cultures of OP9 stromal cells and freshly prepared AGM cultures, CD45{sup low} c-Kit{sup +} cells from the AGM culture had the abilities to reproduce CD45{sup low} c-Kit{sup +} cells and differentiate into CD45{sup low} c-Kit{sup -} and CD45{sup high} c-Kit{sup low/-} cells, whereas CD45{sup low} c-Kit{sup -} and CD45{sup high} c-Kit{sup low/-} did not produce CD45{sup low} c-Kit{sup +} cells. Furthermore, CD45{sup low} c-Kit{sup +} cells displayed a long-term repopulating activity in adult hematopoietic tissue when transplanted into the liver of irradiated newborn mice. These results indicate that CD45{sup low} c-Kit{sup +} cells from the AGM culture have the potential to reconstitute multi-lineage hematopoietic cells.« less

Emv30null NOD-scid mice. An improved host for adoptive transfer of autoimmune diabetes and growth of human lymphohematopoietic cells.

PubMed

Serreze, D V; Leiter, E H; Hanson, M S; Christianson, S W; Shultz, L D; Hesselton, R M; Greiner, D L

1995-12-01

When used as hosts in passive transfer experiments, a stock of NOD/Lt mice congenic for the severe combined immunodeficiency (scid) mutation have provided great insight to the contributions of various T-cell populations in the pathogenesis of autoimmune insulin-dependent diabetes mellitus (IDDM). Moreover, NOD-scid mice support higher levels of human lymphohematopoietic cell growth than the C.B-17-scid strain in which the mutation originated. However, the ability to perform long-term lymphohematopoietic repopulation studies in the NOD-scid stock has been limited by the fact that most of these mice develop lethal thymic lymphomas beginning at 20 weeks of age. These thymic lymphomas are characterized by activation and subsequent genomic reintegrations of Emv30, an endogenous murine ecotropic retrovirus unique to the NOD genome. To test the role of this endogenous retrovirus in thymomagenesis, we produced a stock of Emv30null NOD-scid mice by congenic replacement of the proximal end of chromosome 11 with genetic material derived from the closely related NOR/Lt strain. Thymic lymphomas still initiate in Emv30null NOD-scid females, but their rate of progression is significantly retarded since the frequency of tumors weighing between 170 and 910 mg at 25 weeks of age was reduced to 20.8% vs. 76.2% in Emv30% segregants. The thymic lymphomas that did develop in Emv30null NOD-scid mice were not characterized by a compensatory increase in mink cell focus-forming proviral integrations, which initiate thymomagenesis in other susceptible mouse strains. Significantly, the ability of standard NOD T-cells to transfer IDDM to the Emv30null NOD-scid stock was not impaired.(ABSTRACT TRUNCATED AT 250 WORDS)

Paleoenvironmental recovery from the Chesapeake Bay bolide impact: The benthic foraminiferal record

USGS Publications Warehouse

Poag, C.W.

2009-01-01

The late Eocene Chesapeake Bay bolide impact transformed its offshore target site from an outer neritic, midshelf seafl oor into a bathyal crater basin. To obtain a depositional record from one of the deepest parts of this basin, the U.S. Geological Survey (USGS) and the International Continental Scientifi c Drilling Program (ICDP) drilled a 1.76-km-deep core hole near Eyreville, Virginia. The Eyreville core and eight previously cored boreholes contain a rarely obtainable record of marine deposition and microfossil assemblages that characterize the transition from synimpact to postimpact paleoenvironments inside and near a submarine impact crater. I used depositional style and benthic foraminiferal assemblages to recognize a four-step transitional succession, with emphasis on the Eyreville core. Step 1 is represented by small-scale, silt-rich turbidites, devoid of indigenous microfossils, which lie directly above the crater-fi lling Exmore breccia. Step 2 is represented by very thin, parallel, silt and clay laminae, which accumulated on a relatively tranquil and stagnant seafl oor. This stagnation created a dead zone, which excluded seafl oor biota, and it lasted ~3-5 ka. Step 3 is an interval of marine clay deposition, accompanied by a burst of microfaunal activity, as a species-rich pioneer community of benthic foraminifera repopulated the impact site. The presence of a diagnostic suite of agglutinated foraminifera during step 3 indicates that paleoenvironmental stress related to the impact lasted from ~9 ka to 400 ka at different locations inside the crater. During step 4, the agglutinated assemblage disappeared, and an equilibrium foraminiferal community developed that contained nearly 100% calcareous species. In contrast to intracrater localities, core sites outside and near the crater rim show neither evidence of the agglutinated assemblage, nor other indications of long-term biotic disruption from the bolide impact. 

Exercise mitigates cumulative associations between stress and BMI in girls age 10 to 19.

PubMed

Puterman, Eli; Prather, Aric A; Epel, Elissa S; Loharuka, Sheila; Adler, Nancy E; Laraia, Barbara; Tomiyama, A Janet

2016-02-01

Long-term psychological stress is associated with BMI increases in children as they transition to adulthood, whereas long-term maintenance of physical activity can slow excess weight gain. We hypothesized that in addition to these main effects, long-term physical activity mitigates the relationship between long-term stress and BMI increase. The NHLBI Growth and Health Study enrolled 2,379 10-year-old Black and White girls, following them annually for 10 measurement points. Growth curve modeling captured the dynamics of BMI, measured yearly, and stress and physical activity, measured at varying years. At average levels of activity and stress, with all covariates remaining fixed, average BMI at baseline was 19.74 (SE = 0.38) and increased 0.64 BMI (SE = 0.01, p < .001) units every year. However, this increase in BMI significantly varied as a function of cumulative stress and physical activity. Slower BMI gain occurred in those girls who were less stressed and more active (0.62 BMI units/year, SE = .02, p < .001), whereas the most rapid and largest growth occurred in girls who were more stressed and less active (0.92 BMI units/year, SE = .02, p < .001). Racial identification did not alter these effects. As hypothesized, in girls who maintained long-term activity, BMI growth was mitigated, even when reporting high long-term stress, compared with less physically active girls. This study adds to a converging literature in which physical activity, a modifiable prevention target, functions to potentially limit the damaging health effects of long-term psychological stress. (c) 2016 APA, all rights reserved).

Exercise mitigates cumulative associations between stress and BMI in girls age 10–19

PubMed Central

Prather, Aric A.; Epel, Elissa S.; Loharuka, Sheila; Adler, Nancy E.; Laraia, Barbara

2015-01-01

Objective Long-term psychological stress is associated with BMI increases in children as they transition to adulthood, while long-term maintenance of physical activity can slow excess weight gain. We hypothesized that in addition to these main effects, long-term physical activity mitigates the relationship between long-term stress and BMI increase. Methods The NHLBI Growth and Health Study enrolled 2,379 10-year-old Black and White girls, following them annually for 10 measurement points. Growth curve modeling captured the dynamics of BMI, measured yearly, and stress and physical activity, measured every other year. Results At average levels of activity and stress, with all covariates remaining fixed, average BMI at baseline was 19.74 (SE = 0.38) and increased 0.64 BMI (SE= 0.01, p < .001) units every year. However, this increase in BMI significantly varied as a function of cumulative stress and physical activity. Slower BMI gain occurred in those girls who were less stressed and more active (0.62 BMI units/year, SE= .02, p < .001), whereas the most rapid and largest growth occurred in girls who were the more stressed and less active (0.92 BMI units/year, SE= .02, p < .001). Racial identification did not alter these effects. Conclusions As hypothesized, in girls who maintained long-term activity, BMI growth was mitigated, even when reporting high long-term stress, compared to less physically active girls. This study adds to a converging literature in which physical activity, a modifiable prevention target, functions to potentially limit the damaging health effects of long-term psychological stress. PMID:26301595

[Effects of long-term fertilization on enzyme activities in black soil of Northeast China].

PubMed

Wang, Shu-Qi; Han, Xiao-Zeng; Qiao, Yun-Fa; Wang, Shou-Yu

2008-03-01

In this paper, black soil samples at the depths of 0-20 cm and 20-40 cm were collected from the Hailun Agricultural Ecology Station of Chinese Academy of Sciences to study the effects of long-term fertilization on their urease, invertase, phosphatase and catalase activities and total C and N contents. The results showed that long-term application of chemical fertilizers and organic manure increased the activities of urease, invertase and phosphatase in 0-20 cm and 20-40 cm soil layers in different degree, and the combined application of them increased the activities of the three enzymes significantly, with an increment of 43.6%-113.2%, 25.9%-79.5% and 14.7%-134.4% in 0-20 cm soil layer and 56.1%-127.2%, 14.5%-113.8% and 16.2%-207.2% in 20-40 cm soil layer, respectively. However, long-term application of chemical fertilizers without organic manure had little effects on catalase activity. The activities of urease, invertase and phosphatase decreased with increasing soil depth. Long-term application of N fertilizer increased urease activity, and P fertilization had obvious positive effect on phosphatase activity. Long-term fertilization also had obvious effects on the soil total C and N contents and C/N ratio.

Ethics and Intimate Sexual Activity in Long-Term Care.

PubMed

Metzger, Eran

2017-07-01

A case is presented in which the staff of a long-term care facility discovers that the husband of a resident with dementia is engaged in sexual activity with her. The case illustrates a dilemma for long-term care facilities that create a home-like environment with a goal of maximizing residents' autonomy while ensuring their safety. An approach to assessing capacity to consent to intimate sexual activity is described, followed by guidelines that nursing homes can implement to support residents who wish to engage in sexual activity. Recommendations are also offered for supporting long-term care staff and family members of residents who are interested in intimate sexual activity. © 2017 American Medical Association. All Rights Reserved.

HTR8/SVneo cells display trophoblast progenitor cell-like characteristics indicative of self-renewal, repopulation activity, and expression of "stemness-" associated transcription factors.

PubMed

Weber, Maja; Knoefler, Ilka; Schleussner, Ekkehard; Markert, Udo R; Fitzgerald, Justine S

2013-01-01

JEG3 is a choriocarcinoma--and HTR8/SVneo a transformed extravillous trophoblast--cell line often used to model the physiologically invasive extravillous trophoblast. Past studies suggest that these cell lines possess some stem or progenitor cell characteristics. Aim was to study whether these cells fulfill minimum criteria used to identify stem-like (progenitor) cells. In summary, we found that the expression profile of HTR8/SVneo (CDX2+, NOTCH1+, SOX2+, NANOG+, and OCT-) is distinct from JEG3 (CDX2+ and NOTCH1+) as seen only in human-serum blocked immunocytochemistry. This correlates with HTR8/SVneo's self-renewal capacities, as made visible via spheroid formation and multi-passagability in hanging drops protocols paralleling those used to maintain embryoid bodies. JEG3 displayed only low propensity to form and reform spheroids. HTR8/SVneo spheroids migrated to cover and seemingly repopulate human chorionic villi during confrontation cultures with placental explants in hanging drops. We conclude that HTR8/SVneo spheroid cells possess progenitor cell traits that are probably attained through corruption of "stemness-" associated transcription factor networks. Furthermore, trophoblastic cells are highly prone to unspecific binding, which is resistant to conventional blocking methods, but which can be alleviated through blockage with human serum.

Continuous in vivo infusion of interferon-gamma (IFN-γ) enhances engraftment of syngeneic wild-type cells in Fanca–/– and Fancg–/– mice

PubMed Central

Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J.; Critser, John; Arwert, Fre; Haneline, Laura S.; Clapp, D. Wade

2006-01-01

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc–/– cells to interferon-gamma (IFN-γ), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc–/– mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca–/– and Fancg–/– mice are hypersensitive to IFN-γ and that in vivo infusion of IFN-γ at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-γ conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients. PMID:16946306

Continuous in vivo infusion of interferon-gamma (IFN-gamma) enhances engraftment of syngeneic wild-type cells in Fanca-/- and Fancg-/- mice.

PubMed

Si, Yue; Ciccone, Samantha; Yang, Feng-Chun; Yuan, Jin; Zeng, Daisy; Chen, Shi; van de Vrugt, Henri J; Critser, John; Arwert, Fre; Haneline, Laura S; Clapp, D Wade

2006-12-15

Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.

Lentiviral gene transfer regenerates hematopoietic stem cells in a mouse model for Mpl-deficient aplastic anemia.

PubMed

Heckl, Dirk; Wicke, Daniel C; Brugman, Martijn H; Meyer, Johann; Schambach, Axel; Büsche, Guntram; Ballmaier, Matthias; Baum, Christopher; Modlich, Ute

2011-04-07

Thpo/Mpl signaling plays an important role in the maintenance of hematopoietic stem cells (HSCs) in addition to its role in megakaryopoiesis. Patients with inactivating mutations in Mpl develop thrombocytopenia and aplastic anemia because of progressive loss of HSCs. Yet, it is unknown whether this loss of HSCs is an irreversible process. In this study, we used the Mpl knockout (Mpl(-/-)) mouse model and expressed Mpl from newly developed lentiviral vectors specifically in the physiologic Mpl target populations, namely, HSCs and megakaryocytes. After validating lineage-specific expression in vivo using lentiviral eGFP reporter vectors, we performed bone marrow transplantation of transduced Mpl(-/-) bone marrow cells into Mpl(-/-) mice. We show that restoration of Mpl expression from transcriptionally targeted vectors prevents lethal adverse reactions of ectopic Mpl expression, replenishes the HSC pool, restores stem cell properties, and corrects platelet production. In some mice, megakaryocyte counts were atypically high, accompanied by bone neo-formation and marrow fibrosis. Gene-corrected Mpl(-/-) cells had increased long-term repopulating potential, with a marked increase in lineage(-)Sca1(+)cKit(+) cells and early progenitor populations in reconstituted mice. Transcriptome analysis of lineage(-)Sca1(+)cKit(+) cells in Mpl-corrected mice showed functional adjustment of genes involved in HSC self-renewal.

Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia.

PubMed

Mettananda, Sachith; Fisher, Chris A; Hay, Deborah; Badat, Mohsin; Quek, Lynn; Clark, Kevin; Hublitz, Philip; Downes, Damien; Kerry, Jon; Gosden, Matthew; Telenius, Jelena; Sloane-Stanley, Jackie A; Faustino, Paula; Coelho, Andreia; Doondeea, Jessica; Usukhbayar, Batchimeg; Sopp, Paul; Sharpe, Jacqueline A; Hughes, Jim R; Vyas, Paresh; Gibbons, Richard J; Higgs, Douglas R

2017-09-04

β-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between α- and β-globin chains with an excess of free α-globin chains causing ineffective erythropoiesis and hemolysis. When α-thalassemia is co-inherited with β-thalassemia, excess free α-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 α-globin enhancer and causes α-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in α-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with β-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for β-thalassemia.β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.

Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells.

PubMed

Karpova, Darja; Ritchey, Julie K; Holt, Matthew S; Abou-Ezzi, Grazia; Monlish, Darlene; Batoon, Lena; Millard, Susan; Spohn, Gabriele; Wiercinska, Eliza; Chendamarai, Ezhil; Yang, Wei; Christ, Stephanie; Gehrs, Leah; Schuettpelz, Laura G; Dembowsky, Klaus; Pettit, Allison R; Rettig, Michael P; Bonig, Halvard; DiPersio, John F

2017-05-25

Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool. © 2017 by The American Society of Hematology.

Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells

PubMed Central

Karpova, Darja; Ritchey, Julie K.; Holt, Matthew S.; Abou-Ezzi, Grazia; Monlish, Darlene; Batoon, Lena; Millard, Susan; Spohn, Gabriele; Wiercinska, Eliza; Chendamarai, Ezhil; Yang, Wei; Christ, Stephanie; Gehrs, Leah; Schuettpelz, Laura G.; Dembowsky, Klaus; Pettit, Allison R.; Rettig, Michael P.; Bonig, Halvard

2017-01-01

Interaction between the chemokine receptor CXCR4 and its chief ligand CXCL12 plays a critical role in the retention and migration of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) microenvironment. In this study, qualitative and quantitative effects of long-term pharmacologic inhibition of the CXCR4/CXCL12 axis on the HSPC compartment were investigated by using 3 structurally unrelated small molecule CXCR4 antagonists. A >10-fold increase in mobilization efficiency was achieved by administering the antagonists as a subcutaneous continuous infusion for 2 weeks compared to a single bolus injection. A concurrent increase in self-renewing proliferation leading to a twofold to fourfold expansion of the HSPC pool in the BM was observed. The expanded BM showed a distinct repopulating advantage when tested in serial competitive transplantation experiments. Furthermore, major changes within the HSPC niche associated with previously described HSPC expansion strategies were not detected in bones treated with a CXCR4 antagonist infusion. Our data suggest that prolonged but reversible pharmacologic blockade of the CXCR4/CXCL12 axis represents an approach that releases HSPC with efficiency superior to any other known mobilization strategy and may also serve as an effective method to expand the BM HSPC pool. PMID:28400375

Reduced energy availability: implications for bone health in physically active populations.

PubMed

Papageorgiou, Maria; Dolan, Eimear; Elliott-Sale, Kirsty J; Sale, Craig

2018-04-01

The present review critically evaluates existing literature on the effects of short- and long-term low energy availability (EA) on bone metabolism and health in physically active individuals. We reviewed the literature on the short-term effects of low EA on markers of bone metabolism and the long-term effects of low EA on outcomes relating to bone health (bone mass, microarchitecture and strength, bone metabolic markers and stress fracture injury risk) in physically active individuals. Available evidence indicates that short-term low EA may increase markers of bone resorption and decrease markers of bone formation in physically active women. Bone metabolic marker responses to low EA are less well known in physically active men. Cross-sectional studies investigating the effects of long-term low EA suggest that physically active individuals who have low EA present with lower bone mass, altered bone metabolism (favouring bone resorption), reduced bone strength and increased risk for stress fracture injuries. Reduced EA has a negative influence on bone in both the short- and long-term, and every effort should be made to reduce its occurrence in physically active individuals. Future interventions are needed to explore the effects of long-term reduced EA on bone health outcomes, while short-term low EA studies are also required to give insight into the pathophysiology of bone alterations.

The Longevity of Hippocampus-Dependent Memory Is Orchestrated by the Locus Coeruleus-Noradrenergic System

PubMed Central

2017-01-01

The locus coeruleus is connected to the dorsal hippocampus via strong fiber projections. It becomes activated after arousal and novelty, whereupon noradrenaline is released in the hippocampus. Noradrenaline from the locus coeruleus is involved in modulating the encoding, consolidation, retrieval, and reversal of hippocampus-based memory. Memory storage can be modified by the activation of the locus coeruleus and subsequent facilitation of hippocampal long-term plasticity in the forms of long-term depression and long-term potentiation. Recent evidence indicates that noradrenaline and dopamine are coreleased in the hippocampus from locus coeruleus terminals, thus fostering neuromodulation of long-term synaptic plasticity and memory. Noradrenaline is an inductor of epigenetic modifications regulating transcriptional control of synaptic long-term plasticity to gate the endurance of memory storage. In conclusion, locus coeruleus activation primes the persistence of hippocampus-based long-term memory. PMID:28695015

Effect of aromatherapy massage on elderly patients under long-term hospitalization in Japan.

PubMed

Satou, Tadaaki; Chikama, Mizuki; Chikama, Yoshiko; Hachigo, Masato; Urayama, Haruna; Murakami, Shio; Hayashi, Shinichiro; Koikem, Kazuo

2013-03-01

To verify the effectiveness of aromatherapy massage on elderly patients under long-term hospitalization. Aromatherapy massage was performed twice a week for a total of eight times. Nursing home. Elderly women under long-term hospitalization. Questionnaire and measurement of stress marker levels (salivary amylase activity) before and after the first, fifth, and eighth aromatherapy massages. Questionnaire (Face scale, General Health Questionnaire-12 [GHQ-12]), measurement of salivary amylase activity. A decrease in stress after aromatherapy massage compared to before each massage was confirmed at all measurement times and with the stress marker. No marked reduction was observed in Face scale or saliva amylase activity as a whole over the long term, although decreasing tendencies were seen. Marked reductions in GHQ-12 were observed over the long term. Aroma massage appears likely to prove effective in reducing psychological stress among elderly patients under long-term hospitalization.

Long-Term Habituation of the C-Start Escape Response in Zebrafish Larvae

PubMed Central

Roberts, Adam C.; Pearce, Kaycey C.; Choe, Ronny C.; Alzagatiti, Joseph B.; Yeung, Anthony K.; Bill, Brent R.; Glanzman, David L.

2016-01-01

The cellular and molecular basis of long-term memory in vertebrates remains poorly understood. Knowledge regarding long-term memory has been impeded by the enormous complexity of the vertebrate brain, particularly the mammalian brain, as well as by the relative complexity of the behavioral alterations examined in most studies of long-term memory in vertebrates. Here, we demonstrate a long-term form of nonassociative learning—specifically, long-term habituation (LTH)—of a simple reflexive escape response, the C-start, in zebrafish larvae. The C-start is triggered by the activation of one of a pair of giant neurons in the zebrafish’s hindbrain, the Mauthner cells. We show that LTH of the C-start requires the activity of NMDA receptors and involves macromolecular synthesis. We further show that the long-term habituated reflex can by rapidly dishabituated by a brief tactile stimulus. Our results set the stage for rigorous, mechanistic investigations of the long-term memory for habituation of a reflexive behavioral response, one that is mediated by a relatively simple, neurobiologically tractable, neural circuit. Moreover, the demonstration of NMDAR and transcriptionally dependent LTH in a translucent vertebrate organism should facilitate the use of optical recording, and optogenetic manipulation, of neuronal activity to elucidate the cellular basis of a long-term vertebrate memory. PMID:27555232

A randomized controlled trial of an activity specific exercise program for individuals with Alzheimer disease in long-term care settings.

PubMed

Roach, Kathryn E; Tappen, Ruth M; Kirk-Sanchez, Neva; Williams, Christine L; Loewenstein, David

2011-01-01

To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Randomized, controlled, single-blinded clinical trial. Residents of 7 long-term care facilities. Eighty-two long-term care residents with mild to severe AD. An activity specific exercise program was compared to a walking program and to an attention control. Ability to perform bed mobility and transfers was assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined.

A mechanism of midlatitude noontime foE long-term variations inferred from European observations

NASA Astrophysics Data System (ADS)

Mikhailov, A. V.; Perrone, L.; Nusinov, A. A.

2017-04-01

Manually scaled June noontime monthly median foE values at three European stations Rome, Juliusruh, and Slough/Chilton were used to understand the mechanism of foE long-term variations. The 11 year running mean smoothed foE manifests long-term (for some solar cycles) variations with the rising phase at the end of 1960-1985 and the falling phase after 1985. A close relationship (even in details) between (foEave)11y and (R12)11y variations with the correlation coefficient of 0.996 (absolutely significant according to Fisher F criterion) suggests that the Sun is the source of these (foEave)11y long-term variations. After removing solar activity long-term variations the residual (foEave)11y trend is very small ( 0.029% per decade) being absolutely insignificant. This means that all (foEave)11y variations are removed with one solar activity index, (R12)11y, i.e., this means that long-term variations are fully controlled by solar activity. Theory of midlatitude daytime E region tells us that long-term variations of solar EUV in two lines λ = 977 Å (CIII) and λ = 1025.7 Å (HLyβ) and X-ray radiation with λ < 100 Å (both manifesting the same long-term variations with the rising phase at the end of 1960-1985 and the falling phase after 1985) are responsible for the observed (foEave)11y variations. Therefore, the observed daytime midlatitude foE long-term variations have a natural (not anthropogenic) origin related to long-term variations of solar activity. No peculiarities in relation with the last deep solar minimum in 2008-2009 have been revealed.

Murine bone marrow cells cultured ex vivo in the presence of multiple cytokine combinations lose radioprotective and long-term engraftment potential.

PubMed

Von Drygalski, A; Alespeiti, G; Ren, L; Adamson, J W

2004-02-01

The desire to improve engraftment following transplantation of limited numbers of hematopoietic stem cells (HSC) has spurred the investigation of ex vivo stem cell expansion techniques. While surrogate outcomes, such as an increase in SCID-repopulating cells, suggest successful stem cell expansion in some studies, it is not clear that such assays predict outcomes using a more clinically relevant approach (e.g., myeloablation). We have addressed this by testing three cytokine combinations for their ability to increase the radioprotective and long-term marrow reconstitution capacity of hematopoietic cells cultured ex vivo. Low numbers of light-density (LD) mouse bone marrow (BM) cells or their expanded product were injected into lethally irradiated (9 Gy) congenic recipients. Survival rates and percent donor engraftment were compared at 2, 5, and 7 months post-transplant. The three cytokine combinations used were: (i) kit-ligand (L), thrombopoietin (Tpo), Flt-3 L; (ii) cytokines in (i) plus interleukin-11 (IL-11); (iii) cytokines in (ii) plus IL-3. At 7 months post-transplant, LD cell doses of 10(4), 2-2.5 x 10(4), and 0.5-1.0 x 10(5) gave predictable survivals of 20-30%, 40-70%, and 100%, respectively. Mean percent donor engraftments were 54.9% (SEM 36%), 55.7% (SEM 36%), and 76.3% (SEM 21%), respectively. When cells expanded for 3 or 5-7 days with the various cytokine combinations were transplanted into different groups of mice, survival rates and percent donor engraftment were almost uniformly poorer than results obtained with unmanipulated cells, and cells expanded for 5-7 days led to poorer outcomes than cells expanded for 3 days. Overall, ex vivo expansion of LD BM cells with the cytokine combinations chosen failed to improve transplant outcomes in this model.

Short-term and long-term treatment outcomes with Class III activator

PubMed Central

Ryu, Hyo-kyung; Chong, Hyun-Jeong; An, Ki-Yong

2015-01-01

Objective The purpose of this retrospective study was to investigate short-term and long-term skeletodental outcomes of Class III activator treatment. Methods A Class III activator treatment group (AG) comprised of 22 patients (9 boys, 13 girls) was compared with a Class III control group (CG) comprised of 17 patients (6 boys, 11 girls). The total treatment period was divided into three stages; the initial stage (T1), the post-activator treatment or post-mandibular growth peak stage (T2), and the long-term follow-up stage (T3). Cephalometric changes were evaluated statistically via the Mann-Whitney U-test and the Friedman test. Results The AG exhibited significant increases in the SNA angle, ANB angle, Wits appraisal, A point-N perpendicular, Convexity of A point, and proclination of the maxillary incisors, from T1 to T2. In the long-term follow-up (T1-T3), the AG exhibited significantly greater increases in the ANB angle, Wits appraisal, and Convexity of A point than the CG. Conclusions Favorable skeletal outcomes induced during the Class III activator treatment period were generally maintained until the long-term follow-up period of the post-mandibular growth peak stage. PMID:26445717

Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

PubMed Central

Jenrow, Kenneth A.; Brown, Stephen L.

2014-01-01

To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs. PMID:25324981

Short-term memory and long-term memory are still different.

PubMed

Norris, Dennis

2017-09-01

A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology-the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as "1, 3, 1" where there are 2 tokens of the digit "1" cannot be stored in the correct order simply by activating the representations of the digits "1" and "3" in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Short-Term Memory and Long-Term Memory are Still Different

PubMed Central

2017-01-01

A commonly expressed view is that short-term memory (STM) is nothing more than activated long-term memory. If true, this would overturn a central tenet of cognitive psychology—the idea that there are functionally and neurobiologically distinct short- and long-term stores. Here I present an updated case for a separation between short- and long-term stores, focusing on the computational demands placed on any STM system. STM must support memory for previously unencountered information, the storage of multiple tokens of the same type, and variable binding. None of these can be achieved simply by activating long-term memory. For example, even a simple sequence of digits such as “1, 3, 1” where there are 2 tokens of the digit “1” cannot be stored in the correct order simply by activating the representations of the digits “1” and “3” in LTM. I also review recent neuroimaging data that has been presented as evidence that STM is activated LTM and show that these data are exactly what one would expect to see based on a conventional 2-store view. PMID:28530428

Functional characterization of individual human hematopoietic stem cells cultured at limiting dilution on supportive marrow stromal layers.

PubMed Central

Sutherland, H J; Lansdorp, P M; Henkelman, D H; Eaves, A C; Eaves, C J

1990-01-01

A major goal of current hematopoiesis research is to develop in vitro methods suitable for the measurement and characterization of stem cells with long-term in vivo repopulating potential. Previous studies from several centers have suggested the presence in normal human or murine marrow of a population of very primitive cells that are biologically, physically, and pharmacologically different from cells detectable by short-term colony assays and that can give rise to the latter in long-term cultures (LTCs) containing a competent stromal cell layer. In this report, we show that such cultures can be used to provide a quantitative assay for human "LTC-initiating cells" based on an assessment of the number of clonogenic cells present after 5-8 weeks. Production of derivative clonogenic cells is shown to be absolutely dependent on the presence of a stromal cell feeder. When this requirement is met, the clonogenic cell output (determined by assessment of 5-week-old cultures) is linearly related to the input cell number over a wide range of cell concentrations. Using limiting dilution analysis techniques, we have established the frequency of LTC-initiating cells in normal human marrow to be approximately 1 per 2 X 10(4) cells and in a highly purified CD34-positive subpopulation to be approximately 1 per 50-100 cells. The proliferative capacity exhibited by individual LTC-initiating cells cultured under apparently identical culture conditions was found to be highly variable. Values for the number of clonogenic cells per LTC-initiating cell in 5-week-old cultures ranged from 1 to 30 (the average being 4) with similar levels being detected in positive 8-week-old cultures. Some LTC-initiating cells are multipotent as evidenced by their generation of erythroid as well as granulopoietic progeny. The availability of a system for quantitative analysis of the proliferative and differentiative behavior of this newly defined compartment of primitive human hematopoietic cells should facilitate future studies of specific genetic or microenvironmental parameters involved in the regulation of these cells. Images PMID:2333304

The Association between Physical Activity During the Day and Long-Term Memory Stability.

PubMed

Pontifex, Matthew B; Gwizdala, Kathryn L; Parks, Andrew C; Pfeiffer, Karin A; Fenn, Kimberly M

2016-12-02

Despite positive associations between chronic physical activity and memory; we have little understanding of how best to incorporate physical activity during the day to facilitate the consolidation of information into memory, nor even how time spent physically active during the day relates to memory processes. The purpose of this investigation was to examine the relation between physical activity during the day and long-term memory. Ninety-two young adults learned a list of paired-associate items and were tested on the items after a 12-hour interval during which heart rate was recorded continuously. Although the percentage of time spent active during the day was unrelated to memory, two critical physical activity periods were identified as relating to the maintenance of long-term memory. Engaging in physical activity during the period 1 to 2-hours following the encoding of information was observed to be detrimental to the maintenance of information in long-term memory. In contrast, physical activity during the period 1-hour prior to memory retrieval was associated with superior memory performance, likely due to enhanced retrieval processing. These findings provide initial evidence to suggest that long-term memory may be enhanced by more carefully attending to the relative timing of physical activity incorporated during the day.

Dual-induced multifractality in online viewing activity.

PubMed

Qin, Yu-Hao; Zhao, Zhi-Dan; Cai, Shi-Min; Gao, Liang; Stanley, H Eugene

2018-01-01

Although recent studies have found that the long-term correlations relating to the fat-tailed distribution of inter-event times exist in human activity and that these correlations indicate the presence of fractality, the property of fractality and its origin have not been analyzed. We use both detrended fluctuation analysis and multifractal detrended fluctuation analysis to analyze the time series in online viewing activity separating from Movielens and Netflix. We find long-term correlations at both the individual and communal levels and that the extent of correlation at the individual level is determined by the activity level. These long-term correlations also indicate that there is fractality in the pattern of online viewing. We first find a multifractality that results from the combined effect of the fat-tailed distribution of inter-event times (i.e., the times between successive viewing actions of individuals) and the long-term correlations in online viewing activity and verify this finding using three synthesized series. Therefore, it can be concluded that the multifractality in online viewing activity is caused by both the fat-tailed distribution of inter-event times and the long-term correlations and that this enlarges the generic property of human activity to include not just physical space but also cyberspace.

Fast stack activation procedure and effective long-term storage for high-performance polymer electrolyte membrane fuel cell

NASA Astrophysics Data System (ADS)

Yang, Seung Yong; Seo, Dong-Jun; Kim, Myeong-Ri; Seo, Min Ho; Hwang, Sun-Mi; Jung, Yong-Min; Kim, Beom-Jun; Yoon, Young-Gi; Han, Byungchan; Kim, Tae-Young

2016-10-01

Time-saving stack activation and effective long-term storage are one of most important issues that must be resolved for the commercialization of polymer electrolyte membrane fuel cell (PEMFC). Herein, we developed the cost-effective stack activation method to finish the whole activation within 30 min and the long-term storage method by using humidified N2 without any significant decrease in cell's performance for 30 days. Specifically, the pre-activation step with the direct injection of DI water into the stack and storage at 65 or 80 °C for 2 h increases the distinctive phase separation between the hydrophobic and hydrophilic regions in Nafion membrane, which significantly reduces the total activation time within 30 min. Additionally, the long-term storage with humidified N2 has no effect on the Pt oxidation and drying of Nafion membrane for 30 days due to its exergonic reaction in the cell. As a result, the high water content in Nafion membrane and the decrease of Pt oxidation are the critical factors that have a strong influence on the activation and long-term storage for high-performance PEMFC.

Dual-induced multifractality in online viewing activity

NASA Astrophysics Data System (ADS)

Qin, Yu-Hao; Zhao, Zhi-Dan; Cai, Shi-Min; Gao, Liang; Stanley, H. Eugene

2018-01-01

Although recent studies have found that the long-term correlations relating to the fat-tailed distribution of inter-event times exist in human activity and that these correlations indicate the presence of fractality, the property of fractality and its origin have not been analyzed. We use both detrended fluctuation analysis and multifractal detrended fluctuation analysis to analyze the time series in online viewing activity separating from Movielens and Netflix. We find long-term correlations at both the individual and communal levels and that the extent of correlation at the individual level is determined by the activity level. These long-term correlations also indicate that there is fractality in the pattern of online viewing. We first find a multifractality that results from the combined effect of the fat-tailed distribution of inter-event times (i.e., the times between successive viewing actions of individuals) and the long-term correlations in online viewing activity and verify this finding using three synthesized series. Therefore, it can be concluded that the multifractality in online viewing activity is caused by both the fat-tailed distribution of inter-event times and the long-term correlations and that this enlarges the generic property of human activity to include not just physical space but also cyberspace.

Legislation on Long-Term Care Insurance. Report No. 11.

ERIC Educational Resources Information Center

Wisconsin State Legislative Council, Madison.

This report presents Wisconsin state legislation on long-term care insurance. Part I summarizes key provisions of six 1987 assembly bills concerned with long-term care insurance. Part II describes activities of the Wisconsin State Legislative Council's Special Committee on Long-Term Health Care Insurance. Part III provides background information…

Intensity of recreational physical activity throughout life and later life cognitive functioning in women.

PubMed

Tierney, Mary C; Moineddin, Rahim; Morra, Angela; Manson, Judith; Blake, Jennifer

2010-01-01

Long-term physical activity may affect risk of cognitive impairment but few studies have examined later life cognition in relation to intensity of life-long physical activity. We examined the associations between the intensity of long-term recreational physical activity and neuropsychological functioning in 90 healthy postmenopausal women on tests found to be useful in the early identification of dementia. Information was collected about their participation in strenuous and moderate activities between high school and menopause. Summary measures of long-term strenuous and moderate activity were constructed for each participant. All analyses were adjusted for relevant covariates. The six linear regression analyses showed significant positive associations between moderate activity and Wechsler Adult Intelligence Scale Revised (WAIS-R), Digit Span backward, WAIS-R Digit Symbol, and Trail Making Test Part B. Significant negative relationships were found between strenuous activity and Rey Auditory Verbal Learning Test delayed verbal recall, Complex Figure Test delayed visual memory, WAIS-R Digit Span backward, category fluency, and WAIS-R Digit Symbol. The associations found in the present study suggest that while moderate activity may be protective, long-term strenuous activity before menopause may lower cognitive performance later in life. These results support further investigation of the effects of life-long exercise intensity on cognition in later life.

Protective Properties of Radio-Chemoresistant Glioblastoma Stem Cell Clones Are Associated with Metabolic Adaptation to Reduced Glucose Dependence

PubMed Central

Yamada, Kazunari; Tso, Jonathan L.; Menjivar, Jimmy C.; Tian, Jane Y.; Yong, William H.; Schaue, Dörthe; Mischel, Paul S.; Cloughesy, Timothy F.; Nelson, Stanley F.; Liau, Linda M.; McBride, William; Tso, Cho-Lea

2013-01-01

Glioblastoma stem cells (GSC) are a significant cell model for explaining brain tumor recurrence. However, mechanisms underlying their radiochemoresistance remain obscure. Here we show that most clonogenic cells in GSC cultures are sensitive to radiation treatment (RT) with or without temozolomide (TMZ). Only a few single cells survive treatment and regain their self-repopulating capacity. Cells re-populated from treatment-resistant GSC clones contain more clonogenic cells compared to those grown from treatment-sensitive GSC clones, and repeated treatment cycles rapidly enriched clonogenic survival. When compared to sensitive clones, resistant clones exhibited slower tumor development in animals. Upregulated genes identified in resistant clones via comparative expression microarray analysis characterized cells under metabolic stress, including blocked glucose uptake, impaired insulin/Akt signaling, enhanced lipid catabolism and oxidative stress, and suppressed growth and inflammation. Moreover, many upregulated genes highlighted maintenance and repair activities, including detoxifying lipid peroxidation products, activating lysosomal autophagy/ubiquitin-proteasome pathways, and enhancing telomere maintenance and DNA repair, closely resembling the anti-aging effects of caloric/glucose restriction (CR/GR), a nutritional intervention that is known to increase lifespan and stress resistance in model organisms. Although treatment–introduced genetic mutations were detected in resistant clones, all resistant and sensitive clones were subclassified to either proneural (PN) or mesenchymal (MES) glioblastoma subtype based on their expression profiles. Functional assays demonstrated the association of treatment resistance with energy stress, including reduced glucose uptake, fatty acid oxidation (FAO)-dependent ATP maintenance, elevated reactive oxygen species (ROS) production and autophagic activity, and increased AMPK activity and NAD+ levels accompanied by upregulated mRNA levels of SIRT1/PGC-1α axis and DNA repair genes. These data support the view that treatment resistance may arise from quiescent GSC exhibiting a GR-like phenotype, and suggest that targeting stress response pathways of resistant GSC may provide a novel strategy in combination with standard treatment for glioblastoma. PMID:24260384

Vascular proliferation and enhanced expression of endothelial nitric oxide synthase in human peritoneum exposed to long-term peritoneal dialysis.

PubMed

Combet, S; Miyata, T; Moulin, P; Pouthier, D; Goffin, E; Devuyst, O

2000-04-01

Long-term peritoneal dialysis (PD) is associated with alterations in peritoneal permeability and loss of ultrafiltration. These changes originate from increased peritoneal surface area, but the morphologic and molecular mechanisms involved remain unknown. The hypothesis that modifications of activity and/or expression of nitric oxide synthase (NOS) isozymes might play a role in these modifications, via enhanced local production of nitric oxide, was tested in this study. NOS activities were measured by the L-citrulline assay in peritoneal biopsies from seven control subjects, eight uremic patients immediately before the onset of PD, and 13 uremic patients on short-term (<18 mo, n = 6) or long-term(>18 mo, n = 7) PD. Peritoneal NOS activity is increased fivefold in long-term PD patients compared with control subjects. In uremic patients, NOS activity is positively correlated with the duration of PD. Increased NOS activity is mediated solely by Ca(2+)-dependent NOS and, as shown by immunoblotting, an upregulation of endothelial NOS. The biologic relevance of increased NOS in long-term PD was demonstrated by enhanced nitrotyrosine immunoreactivity and a significant increase in vascular density and endothelial area in the peritoneum. Immunoblotting and immunostaining studies demonstrated an upregulation of vascular endothelial growth factor (VEGF) mostly along the endothelium lining peritoneal blood vessels in long-term PD patients. In the latter, VEGF colocalized with the advanced glycation end product pentosidine deposits. These data provide a morphologic (angiogenesis and increased endothelial area) and molecular (enhanced NOS activity and endothelial NOS upregulation) basis for explaining the permeability changes observed in long-term PD. They also support the implication of local advanced glycation end product deposits and liberation of VEGF in that process.

A Randomized Controlled Trial of an Activity Specific Exercise Program for Individuals With Alzheimer Disease in Long-term Care Settings

PubMed Central

Roach, Kathryn E.; Tappen, Ruth M.; Kirk-Sanchez, Neva; Williams, Christine L.; Loewenstein, David

2011-01-01

Objective To determine whether an activity specific exercise program could improve ability to perform basic mobility activities in long-term care residents with Alzheimer disease (AD). Design Randomized, controlled, single-blinded clinical trial. Setting Residents of 7 long-term care facilities. Participants Eighty-two long-term care residents with mild to severe AD. Intervention An activity specific exercise program was compared to a walking program and to an attention control. Measurements Ability to perform bed mobility and transfers were assessed using the subscales of the Acute Care Index of Function; functional mobility was measured using the 6-Minute Walk test. Results Subjects receiving the activity specific exercise program improved in ability to perform transfers, whereas subjects in the other 2 groups declined. PMID:21937893

Calcium homeostasis and protein kinase/phosphatase balance participate in nicotine-induced memory improvement in passive avoidance task in mice.

PubMed

Michalak, Agnieszka; Biala, Grazyna

2017-01-15

Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca 2+ /calmodulin concentration. LTP results from Ca 2+ influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca 2+ influx, leads to activation of Ca 2+ /calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes. Nicotine, which is one of the most common addictive drugs, manifests its memory effects through nicotinic acetylcholine receptors (nAChRs). Because nAChRs may also gate Ca 2+ , it is suggested that calcium signaling pathways are involved in nicotine-induced memory effects. Within the scope of the study was to evaluate the importance of calcium homeostasis and protein kinase/phosphatase balance in nicotine-induced short- and long-term memory effects. To assess memory function in mice passive avoidance test was used. The presented results confirm that acute nicotine (0.1mg/kg) improves short- and long-term memory. Pretreatment with L-type VGCC blockers (amlodipine, nicardipine verapamil) increased nicotine-induced memory improvement in the context of short- and long-term memory. Pretreatment with FK-506 (a potent CaN inhibitor) enhanced short- but not long-term memory effects of nicotine, while SL-327 (a selective MAPK/ERK kinase inhibitor) attenuated both nicotine-induced short- and long-term memory improvement. Acute nicotine enhances both types of memory via L-type VGCC blockade and via ERK1/2 activation. Only short- but not long-term memory enhancement induced by nicotine is dependent on CaN inhibition. Copyright © 2016 Elsevier B.V. All rights reserved.

A Transcription Factor-Binding Domain of the Coactivator CBP Is Essential for Long-Term Memory and the Expression of Specific Target Genes

ERIC Educational Resources Information Center

Oliveira, Ana M. M.; Brindle, Paul K.; Abel, Ted; Wood, Marcelo A.; Attner, Michelle A.

2006-01-01

Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with…

75 FR 7990 - Use of Community Development Loans by Community Financial Institutions To Secure Advances...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-23

... activities and to allow Banks to make long-term advances to CFI members for purposes of financing community... activities as eligible collateral for advances, to provide that CFI members may use long term advances to... provided that a Bank could make a long-term advance to a member only for the purposes of providing funds to...

Superior Long-Term Synaptic Memory Induced by Combining Dual Pharmacological Activation of PKA and ERK with an Enhanced Training Protocol

ERIC Educational Resources Information Center

Liu, Rong-Yu; Neveu, Curtis; Smolen, Paul; Cleary, Leonard J.; Byrne, John H.

2017-01-01

Developing treatment strategies to enhance memory is an important goal of neuroscience research. Activation of multiple biochemical signaling cascades, such as the protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) pathways, is necessary to induce long-term synaptic facilitation (LTF), a correlate of long-term memory (LTM).…

Long-term solar activity explored with wavelet methods

NASA Astrophysics Data System (ADS)

Lundstedt, H.; Liszka, L.; Lundin, R.; Muscheler, R.

2006-03-01

Long-term solar activity has been studied with a set of wavelet methods. The following indicators of long-term solar activity were used; the group sunspot number, the sunspot number, and the 14C production rate. Scalograms showed the very long-term scales of 2300 years (Hallstat cycle), 900-1000 years, 400-500 years, and 200 years (de Vries cycle). Scalograms of a newly-constructed 14C production rate showed interesting solar modulation during the Maunder minimum. Multi-Resolution Analysis (MRA) revealed the modulation in detail, as well as peaks of solar activity not seen in the sunspot number. In both the group sunspot number scalogram and the 14C production rate scalogram, a process appeared, starting or ending in late 1700. This process has not been discussed before. Its solar origin is unclear.

The group sunspot number ampligram and the sunspot number ampligram showed the Maunder and the Dalton minima, and the period of high solar activity, which already started about 1900 and then decreased again after mid 1990. The decrease starts earlier for weaker components. Also, weak semiperiodic activity was found.

Time Scale Spectra (TSS) showed both deterministic and stochastic processes behind the variability of the long-term solar activity. TSS of the 14C production rate, group sunspot number and Mt. Wilson sunspot index and plage index were compared in an attempt to interpret the features and processes behind the long-term variability.

Analyses of cell surface molecules on hepatic stem/progenitor cells in mouse fetal liver.

PubMed

Kakinuma, Sei; Ohta, Haruhiko; Kamiya, Akihide; Yamazaki, Yuji; Oikawa, Tsunekazu; Okada, Ken; Nakauchi, Hiromitsu

2009-07-01

Hepatic stem/progenitor cells possess active proliferative ability and the capacity for differentiation into hepatic and cholangiocytic lineages. Our group and others have shown that a prospectively defined population in mid-gestational fetal liver contains hepatic stem/progenitor cells. However, the phenotypes of such cells are incompletely elucidated. We analyzed the profile of cell-surface molecules on primary hepatic stem/progenitor cells. Expression of cell surface molecules on primary hepatic stem/progenitor cells in mouse mid-gestational fetal liver was analyzed using flow cytometric multicolor analyses and colony-formation assays. The potential of the cells for liver repopulation was examined by transplantation assay. We found that CD13 (aminopeptidase N) was detected on the cells of the previously reported (Dlk/Pref-1(+)) hepatic stem/progenitor fraction. Colony-formation assays revealed that the CD13(+) fraction, compared with the Dlk(+) fraction, of non-hematopoietic cells in fetal liver was enriched in hepatic stem/progenitor cells. Transplantation assay showed the former fraction exhibited repopulating potential in regenerating liver. Moreover, flow cytometric analysis for over 90 antigens demonstrated enrichment of hepatic stem/progenitor cells using several positive selection markers, including (hitherto unknown) CD13, CD73, CD106, and CD133. Our data indicated that CD13 is a positive selection marker for hepatic stem/progenitor cells in mid-gestational fetal liver.

Endothelial transplantation rejuvenates aged hematopoietic stem cell function

PubMed Central

Poulos, Michael G.; Gutkin, Michael C.; Llanos, Pierre; Gilleran, Katherine; Rabbany, Sina Y.; Butler, Jason M.

2017-01-01

Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens. PMID:29035282

Changing self-reported physical activity using different types of affectively and cognitively framed health messages, in a student population.

PubMed

Morris, Benjamin; Lawton, Rebecca; McEachan, Rosemary; Hurling, Robert; Conner, Mark

2016-01-01

The present research focused upon the power of different messages to increase self-reported physical activity (PA). Five hundered and ninety six participants were randomised to one of five conditions that varied in the content of message: short-term affective, short-term cognitive, long-term affective, long-term cognitive and a no message control. PA was measured at baseline and follow-up (seven days later) was done using the Godin Leisure Time Exercise Questionnaire over the subsequent seven day period. The affective short-term message (ASM) was shown to be equally effective at increasing self-reported PA as a cognitive long-term message. Furthermore, when controlling for baseline activity levels, the ASM emerged as being the message that produced the highest levels of self-reported PA at follow-up. The findings point to the value of distinguishing between health messages in terms of the focus on affective and cognitive outcomes and the temporal nature of the outcomes (short-term or long-term).

Study of stem cell homing & self-renewal marker gene profile of ex vivo expanded human CD34+ cells manipulated with a mixture of cytokines & stromal cell-derived factor 1

PubMed Central

Kode, Jyoti; Khattry, Navin; Bakshi, Ashish; Amrutkar, Vasanti; Bagal, Bhausaheb; Karandikar, Rohini; Rane, Pallavi; Fujii, Nobutaka; Chiplunkar, Shubhada

2017-01-01

Background & objectives: Next generation transplantation medicine aims to develop stimulating cocktail for increased ex vivo expansion of primitive hematopoietic stem and progenitor cells (HSPC). The present study was done to evaluate the cocktail GF (Thrombopoietin + Stem Cell factor + Flt3-ligand) and homing-defining molecule Stromal cell-derived factor 1 (SDF1) for HSPC ex vivo expansion. Methods: Peripheral blood stem cell (n=74) harvests were analysed for CD34hi CD45lo HSPC. Immunomagnetically enriched HSPC were cultured for eight days and assessed for increase in HSPC, colony forming potential in vitro and in vivo engrafting potential by analyzing human CD45+ cells. Expression profile of genes for homing and stemness were studied using microarray analysis. Expression of adhesion/homing markers were validated by flow cytometry/ confocal microscopy. Results: CD34hi CD45lo HSPC expansion cultures with GF+SDF1 demonstrated increased nucleated cells (n=28, P< 0.001), absolute CD34+ cells (n=8, P=0.021) and increased colony forming units (cfu) compared to unstimulated and GF-stimulated HSPC. NOD-SCID mice transplanted with GF+SDF1-HSPC exhibited successful homing/engraftment (n=24, P< 0.001). Microarray analysis of expanded HSPC demonstrated increased telomerase activity and many homing-associated genes (35/49) and transcription factors for stemness/self-renewal (49/56) were significantly upregulated in GF+SDF1 stimulated HSPC when compared to GF-stimulated HSPC. Expression of CD44, CXCR4, CD26, CD14, CD45 and soluble IL-6 in expanded cultures were validated by flow cytometry and confocal microscopy. Interpretation & conclusions: Cocktail of cytokines and SDF1 showed good potential to successfully expand HSPC which exhibited enhanced ability to generate multilineage cells in short-term and long-term repopulation assay. This cocktail-mediated stem cell expansion has potential to obviate the need for longer and large volume apheresis procedure making it convenient for donors. PMID:29168461

The role of short- and long-term cognitive empathy activation in preventing cyberbystander reinforcing cyberbullying behavior.

PubMed

Barlińska, Julia; Szuster, Anna; Winiewski, Mikołaj

2015-04-01

The long- versus short-term effectiveness of empathy activation on reducing bystander behavior reinforcing cyberbullying was tested. The focus was on limiting the frequency of forwarding a message ridiculing a peer. Experimental research on adolescent students was conducted in conditions simulating online contact. The results confirmed the significance of cognitive empathy activated immediately prior to decision making on limiting involvement in reinforcing cyberbullying behavior. The long-term impact of empathy was markedly limited.

Evaluation of long term solar activity effects on GPS derived TEC

NASA Astrophysics Data System (ADS)

Mansoori, Azad A.; Khan, Parvaiz A.; Ahmad, Rafi; Atulkar, Roshni; M, Aslam A.; Bhardwaj, Shivangi; Malvi, Bhupendra; Purohit, P. K.; Gwal, A. K.

2016-10-01

The solar activity hence the solar radiance follows a long term periodic variability with eleven years periodicity, known as solar cycle. This drives the long term variability of the ionosphere. In the present problem we investigate the long term behaviour of the ionosphere with the eleven year cyclic solar activity. Under the present study we characterize the ionospheric variability by Total Electron Content (TEC) using measurements made by Global Positioning System (GPS) and solar cycle variability by various solar activity indices. We make use of five solar activity indices viz. sunspot number (Rz), solar radio Flux (F10.7 cm), EUV Flux (26-34 nm), flare index and CME occurrences. The long term variability of these solar activity indices were then compared and correlated with the variability of ionospheric TEC, at a mid latitude station, Usuda (36.13N, 138.36E), of Japan, during the solar cycle 23 and ascending phase of cycle 24. From our study, we found that long term changes in the ionospheric TEC vary synchronously with corresponding changes in the solar activity indices. The correlation analysis shows that all the solar activity indices exhibit a very strong correlation with TEC (R =0.76 -0.99). Moreover the correlation between the two is stronger in the descending phase of the solar cycle. The correlation is found to be remarkably strongest during the deep minimum of the solar cycle 24 i.e. between 2007- 2009. Also we noticed a hysteresis effect exists with solar radio flux (F10.7 cm) and solar EUV flux (26-34 nm). This effect is absent with other parameters.

PKA and PKC Are Required for Long-Term but Not Short-Term in Vivo Operant Memory in "Aplysia"

ERIC Educational Resources Information Center

Michel, Maximilian; Green, Charity L.; Lyons, Lisa C.

2011-01-01

We investigated the involvement of PKA and PKC signaling in a negatively reinforced operant learning paradigm in "Aplysia", learning that food is inedible (LFI). In vivo injection of PKA or PKC inhibitors blocked long-term LFI memory formation. Moreover, a persistent phase of PKA activity, although not PKC activity, was necessary for long-term…

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

PubMed

Chen, Kang; Neu, Axel; Howard, Allyson L; Földy, Csaba; Echegoyen, Julio; Hilgenberg, Lutz; Smith, Martin; Mackie, Ken; Soltesz, Ivan

2007-01-03

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

Future trends in the prevalence of severe activity limitations among older adults in Europe: a cross-national population study using EU-SILC

PubMed Central

Scherbov, Sergei; Weber, Daniela

2017-01-01

Objective To project the proportion of population 65+ years with severe long-term activity limitations from 2017 to 2047. Design Large population study. Setting Population living in private households of the European Union (EU) and neighbouring countries. Participants Participants from the EU Statistics on Income and Living Conditions aged 55 years and older and living in one of 26 EU and neighbouring countries, who answered the health section of the questionnaire. Outcome measures Prevalence of severe long-term activity limitations of particular subpopulations (ie, 55+, 65+, 75+ and 85+ years) by sex and country. Results We find a huge variation in the prevalence of self-reported severe long-term limitations across Europe for both sexes. However, in 2017, about 20% of the female population aged 65 years and above and about 16% of their male counterparts are expected to report severe long-term activity limitations after accounting for differences in reporting. Accounting for cultural differences in reporting, we expect that European countries will have about 21% (decile 1: 19.5%; decile 9: 22.9%) of female and about 16.8% (decile 1: 15.4%; decile 9: 18.1%) of male 65+ years population with severe long-term activity limitations by 2047. Conclusions Overall, despite the expected increase of life expectancy in European countries, our results suggest almost constant shares of older adults with severe long-term activity limitations within the next 30 years. PMID:29061570

Priming of Short-Term Potentiation and Synaptic Tagging/Capture Mechanisms by Ryanodine Receptor Activation in Rat Hippocampal CA1

ERIC Educational Resources Information Center

Sajikumar, Sreedharan; Li, Qin; Abraham, Wickliffe C.; Xiao, Zhi Cheng

2009-01-01

Activity-dependent changes in synaptic strength such as long-term potentiation (LTP) and long-term depression (LTD) are considered to be cellular mechanisms underlying learning and memory. Strengthening of a synapse for a few seconds or minutes is termed short-term potentiation (STP) and is normally unable to take part in the processes of synaptic…

Craving Responses to Methamphetamine and Sexual Visual Cues in Individuals With Methamphetamine Use Disorder After Long-Term Drug Rehabilitation

PubMed Central

Huang, Shucai; Zhang, Zhixue; Dai, Yuanyuan; Zhang, Changcun; Yang, Cheng; Fan, Lidan; Liu, Jun; Hao, Wei; Chen, Hongxian

2018-01-01

Studies utilizing functional magnetic resonance imaging (fMRI) cue-reactivity paradigms have demonstrated that short-term abstinent or current methamphetamine (MA) users have increased brain activity in the ventral striatum, caudate nucleus and medial frontal cortex, when exposed to MA-related visual cues. However, patterns of brain activity following cue-reactivity in subjects with long-term MA abstinence, especially long-term compulsory drug rehabilitation, have not been well studied. To enrich knowledge in this field, functional brain imaging was conducted during a cue-reactivity paradigm task in 28 individuals with MA use disorder following long-term compulsory drug rehabilitation, and 27 healthy control subjects. The results showed that, when compared with controls, individuals with MA use disorder displayed elevated activity in the bilateral medial prefrontal cortex (mPFC) and right lateral posterior cingulate cortex in response to MA-related images. Additionally, the anterior cingulate region of mPFC activation during the MA-related cue-reactivity paradigm was positively correlated with craving alterations and previous frequency of drug use. No significant differences in brain activity in response to pornographic images were found between the two groups. Compared to MA cues, individuals with MA use disorder had increased activation in the occipital lobe when exposed to pornographic cues. In conclusion, the present study indicates that, even after long-term drug rehabilitation, individuals with MA use disorder have unique brain activity when exposed to MA-related cues. Additionally, our results illustrate that the libido brain response might be restored, and that sexual demand might be more robust than drug demand, in individuals with MA use disorder following long-term drug rehabilitation. PMID:29725310

Craving Responses to Methamphetamine and Sexual Visual Cues in Individuals With Methamphetamine Use Disorder After Long-Term Drug Rehabilitation.

PubMed

Huang, Shucai; Zhang, Zhixue; Dai, Yuanyuan; Zhang, Changcun; Yang, Cheng; Fan, Lidan; Liu, Jun; Hao, Wei; Chen, Hongxian

2018-01-01

Studies utilizing functional magnetic resonance imaging (fMRI) cue-reactivity paradigms have demonstrated that short-term abstinent or current methamphetamine (MA) users have increased brain activity in the ventral striatum, caudate nucleus and medial frontal cortex, when exposed to MA-related visual cues. However, patterns of brain activity following cue-reactivity in subjects with long-term MA abstinence, especially long-term compulsory drug rehabilitation, have not been well studied. To enrich knowledge in this field, functional brain imaging was conducted during a cue-reactivity paradigm task in 28 individuals with MA use disorder following long-term compulsory drug rehabilitation, and 27 healthy control subjects. The results showed that, when compared with controls, individuals with MA use disorder displayed elevated activity in the bilateral medial prefrontal cortex (mPFC) and right lateral posterior cingulate cortex in response to MA-related images. Additionally, the anterior cingulate region of mPFC activation during the MA-related cue-reactivity paradigm was positively correlated with craving alterations and previous frequency of drug use. No significant differences in brain activity in response to pornographic images were found between the two groups. Compared to MA cues, individuals with MA use disorder had increased activation in the occipital lobe when exposed to pornographic cues. In conclusion, the present study indicates that, even after long-term drug rehabilitation, individuals with MA use disorder have unique brain activity when exposed to MA-related cues. Additionally, our results illustrate that the libido brain response might be restored, and that sexual demand might be more robust than drug demand, in individuals with MA use disorder following long-term drug rehabilitation.

Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs.

PubMed

Molina-Estevez, F Javier; Nowrouzi, Ali; Lozano, M Luz; Galy, Anne; Charrier, Sabine; von Kalle, Christof; Guenechea, Guillermo; Bueren, Juan A; Schmidt, Manfred

2015-01-01

Fanconi anemia is a DNA repair-deficiency syndrome mainly characterized by cancer predisposition and bone marrow failure. Trying to restore the hematopoietic function in these patients, lentiviral vector-mediated gene therapy trials have recently been proposed. However, because no insertional oncogenesis studies have been conducted so far in DNA repair-deficiency syndromes such as Fanconi anemia, we have carried out a genome-wide screening of lentiviral insertion sites after the gene correction of Fanca(-/-) hematopoietic stem cells (HSCs), using LAM-PCR and 454-pyrosequencing. Our studies first demonstrated that transduction of Fanca(-/-) HSCs with a lentiviral vector designed for clinical application efficiently corrects the phenotype of Fanconi anemia repopulating cells without any sign of toxicity. The identification of more than 6,500 insertion sites in primary and secondary recipients showed a polyclonal pattern of reconstitution, as well as a continuous turnover of corrected Fanca(-/-) HSC clones, without evidences of selection towards specific common integration sites. Taken together our data show, for the first time in a DNA repair-deficiency syndrome, that lentiviral vector-mediated gene therapy efficiently corrects the phenotype of affected HSCs and promotes a healthy pattern of clonal turnover in vivo. These studies will have a particular impact in the development of new gene therapy trials in patients affected by DNA repair syndromes, particularly in Fanconi anemia.

β-Arrestin2 mediates progression of murine primary myelofibrosis.

PubMed

Rein, Lindsay Am; Wisler, James W; Kim, Jihee; Theriot, Barbara; Huang, LiYin; Price, Trevor; Yang, Haeyoon; Chen, Minyong; Chen, Wei; Sipkins, Dorothy; Fedoriw, Yuri; Walker, Julia Kl; Premont, Richard T; Lefkowitz, Robert J

2017-12-21

Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.

Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells.

PubMed

Kemp, Kevin; Morse, Ruth; Sanders, Kelly; Hows, Jill; Donaldson, Craig

2011-07-01

The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC.

A role for autophagy in long-term spatial memory formation in male rodents.

PubMed

Hylin, Michael J; Zhao, Jing; Tangavelou, Karthikeyan; Rozas, Natalia S; Hood, Kimberly N; MacGowan, Jacalyn S; Moore, Anthony N; Dash, Pramod K

2018-03-01

A hallmark of long-term memory formation is the requirement for protein synthesis. Administration of protein synthesis inhibitors impairs long-term memory formation without influencing short-term memory. Rapamycin is a specific inhibitor of target of rapamycin complex 1 (TORC1) that has been shown to block protein synthesis and impair long-term memory. In addition to regulating protein synthesis, TORC1 also phosphorylates Unc-51-like autophagy activating kinase-1 (Ulk-1) to suppress autophagy. As autophagy can be activated by rapamycin (and rapamycin inhibits long-term memory), our aim was to test the hypothesis that autophagy inhibitors would enhance long-term memory. To examine if learning alters autophagosome number, we used male reporter mice carrying the GFP-LC3 transgene. Using these mice, we observed that training in the Morris water maze task increases the number of autophagosomes, a finding contrary to our expectations. For learning and memory studies, male Long Evans rats were used due to their relatively larger size (compared to mice), making it easier to perform intrahippocampal infusions in awake, moving animals. When the autophagy inhibitors 3-methyladenine (3-MA) or Spautin-1 were administered bilaterally into the hippocampii prior to training in the Morris water maze task, the drugs did not alter learning. In contrast, when memory was tested 24 hours later by a probe trial, significant impairments were observed. In addition, intrahippocampal infusion of an autophagy activator peptide (TAT-Beclin-1) improved long-term memory. These results indicate that autophagy is not necessary for learning, but is required for long-term memory formation. © 2017 Wiley Periodicals, Inc.

Exchange Protein Activated by cAMP Enhances Long-Term Memory Formation Independent of Protein Kinase A

ERIC Educational Resources Information Center

Ma, Nan; Abel, Ted; Hernandez, Pepe J.

2009-01-01

It is well established that cAMP signaling within neurons plays a major role in the formation of long-term memories--signaling thought to proceed through protein kinase A (PKA). However, here we show that exchange protein activated by cAMP (Epac) is able to enhance the formation of long-term memory in the hippocampus and appears to do so…

Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory.

PubMed

Lana, D; Di Russo, J; Mello, T; Wenk, G L; Giovannini, M G

2017-01-01

The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration. Copyright © 2016 Elsevier Inc. All rights reserved.

Rapamycin inhibits mTOR/p70S6K activation in CA3 region of the hippocampus of the rat and impairs long term memory

PubMed Central

Lana, D.; Di Russo, J.; Mello, T.; Wenk, G.L.; Giovannini, M.G.

2016-01-01

The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30 min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object–place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration. PMID:27838442

Short and long-term effects of sham-controlled prefrontal EEG-neurofeedback training in healthy subjects.

PubMed

Engelbregt, H J; Keeser, D; van Eijk, L; Suiker, E M; Eichhorn, D; Karch, S; Deijen, J B; Pogarell, O

2016-04-01

In this study we evaluated long-term effects of frontal beta EEG-neurofeedback training (E-NFT) on healthy subjects. We hypothesized that E-NFT can change frontal beta activity in the long-term and that changes in frontal beta EEG activity are accompanied by altered cognitive performance. 25 healthy subjects were included and randomly assigned to active or sham E-NFT. On average the subjects underwent 15 E-NFT training sessions with a training duration of 45 min. Resting-state EEG was recorded prior to E-NFT training (t1) and in a 3-year follow-up (t3). Compared to sham E-NFT, which was used for the control group, real E-NFT increased beta activity in a predictable way. This increase was maintained over a period of three years post training. However, E-NFT did not result in significantly improved cognitive performance. Based on our results, we conclude that EEG-NFT can selectively modify EEG beta activity both in short and long-term. This is a sham controlled EEG neurofeedback study demonstrating long-term effects in resting state EEG. Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Characterization of slow-cycling cells in the mouse cochlear lateral wall

PubMed Central

Ogawa, Kaoru

2017-01-01

Cochlear spiral ligament fibrocytes (SLFs) play essential roles in the physiology of hearing including ion recycling and the generation of endocochlear potential. In adult animals, SLFs can repopulate after damages, yet little is known about the characteristics of proliferating cells that support SLFs’ self-renewal. Here we report in detail about the characteristics of cycling cells in the spiral ligament (SL). Fifteen P6 mice and six noise-exposed P28 mice were injected with 5-bromo-2′-deoxyuridine (BrdU) for 7 days and we chased BrdU retaining cells for as long as 60 days. Immunohistochemistry revealed that the BrdU positive IB4 (an endotherial marker) negative cells expressed an early SLF marker Pou3f4 but negative for cleaved-Caspase 3. Marker studies revealed that type 3 SLFs displayed significantly higher percentage of BrdU+ cells compared to other subtypes. Notably, the cells retained BrdU until P72, demonstrating they were dividing slowly. In the noise-damaged mice, in contrast to the loss of the other types, the number of type 3 SLFs did not altered and the BrdU incorporating- phosphorylated Histone H3 positive type 3 cells were increased from day 1 to 14 after noise exposure. Furthermore, the cells repopulating type 1 area, where the cells diminished profoundly after damage, were positive for the type 3 SLF markers. Collectively, in the latral wall of the cochlea, type 3 SLFs have the stem cell capacity and may contribute to the endogenous regeneration of lateral wall spiral ligament. Manipulating type 3 cells may be employed for potential regenerative therapies. PMID:28632772

33 CFR 332.7 - Management.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

33 CFR 332.7 - Management.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

33 CFR 332.7 - Management.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

40 CFR 230.97 - Management.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

33 CFR 332.7 - Management.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

40 CFR 230.97 - Management.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

40 CFR 230.97 - Management.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

40 CFR 230.97 - Management.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., the activity causing the authorized impacts. (b) Sustainability. Compensatory mitigation projects... sustainability. Where active long-term management and maintenance are necessary to ensure long-term sustainability (e.g., prescribed burning, invasive species control, maintenance of water control structures...

Fractionated External Beam Radiotherapy as a Suitable Preparative Regimen for Hepatocyte Transplantation After Partial Hepatectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krause, Petra; Wolff, Hendrik A.; Rave-Frank, Margret

2011-07-15

Purpose: Hepatocyte transplantation is strongly considered to be a promising option to correct chronic liver failure through repopulation of the diseased organ. We already reported on extensive liver repopulation by hepatocytes transplanted into rats preconditioned with 25-Gy single dose selective external beam irradiation (IR). Herein, we tested lower radiation doses and fractionated protocols, which would be applicable in clinical use. Methods and Material: Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were preconditioned with partial liver external beam single dose IR at 25 Gy, 8 Gy, or 5 Gy, or fractionated IR at 5 x 5 Gy or 5 x 2 Gy.more » Four days after completion of IR, a partial hepatectomy (PH) was performed to resect the untreated liver section. Subsequently, 12 million wild-type (DPPIV{sup +}) hepatocytes were transplanted via the spleen into the recipient livers. The degree of donor cell integration and liver repopulation was studied 16 weeks after transplantation by means of immunofluorescence and DPPIV-luminescence assay. Results: Donor hepatocyte integration and liver repopulation were more effective in the irradiated livers following pretreatment with the IR doses 1 x 25 Gy and 5 x 5 Gy (formation of large DPPIV-positive cell clusters) than single-dose irradiation at 8 Gy or 5 Gy (DPPIV-positive clusters noticeably smaller and less frequent). Quantitative analysis of extracted DPPIV revealed signals exceeding the control level in all transplanted animals treated with IR and PH. Compared with the standard treatment of 1 x 25 Gy, fractionation with 5 x 5 Gy was equally efficacious, the Mann-Whitney U test disclosing no statistically significant difference (p = 0.146). The lower doses of 1 x 5 Gy, 1 x 8 Gy, and 5 x 2 Gy were significantly less effective with p < 0.05. Conclusion: This study suggests that fractionated radiotherapy in combination with PH is a conceivable pretreatment approach to prime the host liver for hepatocyte transplantation, thus bringing the experimental model a step closer to clinical application.« less

Climate changes and solar cycles recorded at the Holocene Paraná Delta, and their impact on human population.

PubMed

Milana, Juan Pablo; Kröhling, Daniela

2015-08-06

The Paraná delta, growing at a rate of c. 2 km(2) yr(-1) since 6,000 yrs, is one of the most complete records of the Late Holocene in southern South America. The evolution of this 17,400 km(2) delta enclosed in Plata estuary, can be tracked by a series of 343 successive coastal-ridges showing a c.11 years period, in coincidence with sunspot cycle, also found in some North Hemisphere coastal-ridge successions. The Paraná delta shifted from fluvial, to wave-dominated, and back to the present fluvial-dominated delta, in response to climate changes associated with wind activity correlating with South American glacial cycles. The wave-dominated windy period coincides with the activation of the Pampean Sand Sea, suggesting desert conditions prevailed on the Pampas between 5,300 and 1,700 yrs, in coincidence with scarce or absent pre-historic aborigine remains ("archeological silence"). Further warmer and less windy conditions allowed human repopulation. Results suggest that aside the solar forcing, both short and medium term climate changes controlled delta evolution. An important learning is that a slight cooling would turn the highly productive pampas, into that unproductive desert and, given the lack of artificial irrigation systems, changing present-day warmhouse into a cooling cycle might be economically catastrophic for the region.

Climate changes and solar cycles recorded at the Holocene Paraná Delta, and their impact on human population

NASA Astrophysics Data System (ADS)

Milana, Juan Pablo; Kröhling, Daniela

2015-08-01

The Paraná delta, growing at a rate of c. 2 km2 yr-1 since 6,000 yrs, is one of the most complete records of the Late Holocene in southern South America. The evolution of this 17,400 km2 delta enclosed in Plata estuary, can be tracked by a series of 343 successive coastal-ridges showing a c.11 years period, in coincidence with sunspot cycle, also found in some North Hemisphere coastal-ridge successions. The Paraná delta shifted from fluvial, to wave-dominated, and back to the present fluvial-dominated delta, in response to climate changes associated with wind activity correlating with South American glacial cycles. The wave-dominated windy period coincides with the activation of the Pampean Sand Sea, suggesting desert conditions prevailed on the Pampas between 5,300 and 1,700 yrs, in coincidence with scarce or absent pre-historic aborigine remains (“archeological silence”). Further warmer and less windy conditions allowed human repopulation. Results suggest that aside the solar forcing, both short and medium term climate changes controlled delta evolution. An important learning is that a slight cooling would turn the highly productive pampas, into that unproductive desert and, given the lack of artificial irrigation systems, changing present-day warmhouse into a cooling cycle might be economically catastrophic for the region.

Climate changes and solar cycles recorded at the Holocene Paraná Delta, and their impact on human population

PubMed Central

Milana, Juan Pablo; Kröhling, Daniela

2015-01-01

The Paraná delta, growing at a rate of c. 2 km2 yr−1 since 6,000 yrs, is one of the most complete records of the Late Holocene in southern South America. The evolution of this 17,400 km2 delta enclosed in Plata estuary, can be tracked by a series of 343 successive coastal-ridges showing a c.11 years period, in coincidence with sunspot cycle, also found in some North Hemisphere coastal-ridge successions. The Paraná delta shifted from fluvial, to wave-dominated, and back to the present fluvial-dominated delta, in response to climate changes associated with wind activity correlating with South American glacial cycles. The wave-dominated windy period coincides with the activation of the Pampean Sand Sea, suggesting desert conditions prevailed on the Pampas between 5,300 and 1,700 yrs, in coincidence with scarce or absent pre-historic aborigine remains (“archeological silence”). Further warmer and less windy conditions allowed human repopulation. Results suggest that aside the solar forcing, both short and medium term climate changes controlled delta evolution. An important learning is that a slight cooling would turn the highly productive pampas, into that unproductive desert and, given the lack of artificial irrigation systems, changing present-day warmhouse into a cooling cycle might be economically catastrophic for the region. PMID:26246410

Effect of physical activity on frailty and associated negative outcomes: the LIFE randomized trial

USDA-ARS?s Scientific Manuscript database

Background: Limited evidence suggests that physical activity may prevent frailty and associated negative outcomes in older adults. Definitive data from large, long-term, randomized trials are lacking. Objective: To determine whether a long-term structured moderate-intensity physical activity (PA) p...

Differential role of calpain-dependent protein cleavage in intermediate and long-term operant memory in Aplysia.

PubMed

Lyons, Lisa C; Gardner, Jacob S; Lentsch, Cassidy T; Gandour, Catherine E; Krishnan, Harini C; Noakes, Eric J

2017-01-01

In addition to protein synthesis, protein degradation or protein cleavage may be necessary for intermediate (ITM) and long-term memory (LTM) to remove molecular constraints, facilitate persistent kinase activity and modulate synaptic plasticity. Calpains, a family of conserved calcium dependent cysteine proteases, modulate synaptic function through protein cleavage. We used the marine mollusk Aplysia californica to investigate the in vivo role of calpains during intermediate and long-term operant memory formation using the learning that food is inedible (LFI) paradigm. A single LFI training session, in which the animal associates a specific netted seaweed with the failure to swallow, generates short (30min), intermediate (4-6h) and long-term (24h) memory. Using the calpain inhibitors calpeptin and MDL-28170, we found that ITM requires calpain activity for induction and consolidation similar to the previously reported requirements for persistent protein kinase C activity in intermediate-term LFI memory. The induction of LTM also required calpain activity. In contrast to ITM, calpain activity was not necessary for the molecular consolidation of LTM. Surprisingly, six hours after LFI training we found that calpain activity was necessary for LTM, although this is a time at which neither persistent PKC activity nor protein synthesis is required for the maintenance of long-term LFI memory. These results demonstrate that calpains function in multiple roles in vivo during associative memory formation. Copyright © 2016 Elsevier Inc. All rights reserved.

The Baroreflex as a Long-Term Controller of Arterial Pressure

PubMed Central

Iliescu, Radu

2015-01-01

Because of resetting, a role for baroreflexes in long-term control of arterial pressure has been commonly dismissed in the past. However, in recent years, this perspective has changed. Novel approaches for determining chronic neurohormonal and cardiovascular responses to natural variations in baroreceptor activity and to electrical stimulation of the carotid baroreflex indicate incomplete resetting and sustained responses that lead to long-term alterations in sympathetic activity and arterial pressure. PMID:25729060

Treatment with direct-current stimulation against cingulate seizure-like activity induced by 4-aminopyridine and bicuculline in an in vitro mouse model.

PubMed

Chang, Wei-Pang; Lu, Hsiang-Chin; Shyu, Bai-Chuang

2015-03-01

Clinical studies have shown that cathodal transcranial direct-current stimulation (tDCS) application can produce long-term suppressive effects on drug-resistant seizures. Whether this long-term effect produced by cathodal tDCS can counterbalance the enhancement of synaptic transmission during seizures requires further investigation. Our hypothesis was that the long-term effects of DCS on seizure suppression by the application of cathodal DCS occur through a long-term depression (LTD)-like mechanism. We used a thalamocingulate brain slice preparation combined with a multielectrode array and patch recording to investigate the underlying mechanism of the suppressive effect of DCS on anterior cingulate cortex (ACC) seizures. Patch-clamp recordings showed that cathodal DCS significantly decreased spontaneous excitatory postsynaptic currents (EPSCs) and epileptic EPSCs caused by the 4-aminopyridine. Fifteen minutes of DCS application reliably induced LTD, and the synaptic activation frequency was an important factor in LTD formation. The application of DCS alone without continuous synaptic activation did not induce LTD. Direct-current stimulation-induced LTD appeared to be N-methyl-d-aspartate (NMDA)-dependent, in which the application of the NMDA receptor antagonist D-1-2-amino-5-phosphonopentanoic acid (APV) abolished DCS-induced LTD, and the immediate effect remained. Direct-current stimulation-induced LTD and the long-term effects of DCS on seizure-like activities were also abolished by okadaic acid, a protein phosphatase 1 inhibitor. The long-term effects of DCS on seizures were not influenced by the depotentiation blocker FK-506. Therefore, we conclude that the long-term effects of DCS on seizure-like activities in brain slice occur through an LTD-like mechanism. Copyright © 2015 Elsevier Inc. All rights reserved.

Persistent increased PKMζ in long-term and remote spatial memory.

PubMed

Hsieh, Changchi; Tsokas, Panayiotis; Serrano, Peter; Hernández, A Iván; Tian, Dezhi; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2017-02-01

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training. Therefore, if the mechanisms of PKMζ's persistent action in LTP maintenance and long-term memory were similar, persistent increases in PKMζ would last for the duration of the memory, far longer than most other learning-induced gene products. Here we find that spatial conditioning by aversive active place avoidance or appetitive radial arm maze induces PKMζ increases in dorsal hippocampus that persist from 1day to 1month, coinciding with the strength and duration of memory retention. Suppressing the increase by intrahippocampal injections of PKMζ-antisense oligodeoxynucleotides prevents the formation of long-term memory. Thus, similar to LTP maintenance, the persistent increase in the amount of autonomously active PKMζ sustains the kinase's action during long-term and remote spatial memory maintenance. Copyright © 2016. Published by Elsevier Inc.

Long-Term Administration of Conjugated Estrogen and Bazedoxifene Decreased Murine Fecal β-Glucuronidase Activity Without Impacting Overall Microbiome Community.

PubMed

Chen, Karen Lee Ann; Liu, Xiaoji; Zhao, Yiru Chen; Hieronymi, Kadriye; Rossi, Gianluigi; Auvil, Loretta Sue; Welge, Michael; Bushell, Colleen; Smith, Rebecca Lee; Carlson, Kathryn E; Kim, Sung Hoon; Katzenellenbogen, John A; Miller, Michael Joseph; Madak-Erdogan, Zeynep

2018-05-25

Conjugated estrogens (CE) and Bazedoxifene (BZA) combination is used to alleviate menopause-associated symptoms in women. CE+BZA undergo first-pass-metabolism in the liver and deconjugation by gut microbiome via β-glucuronidase (GUS) enzyme inside the distal gut. To date, the impact of long-term exposure to CE+BZA on the gut microbiome or GUS activity has not been examined. Our study using an ovariectomized mouse model showed that CE+BZA administration did not affect the overall cecal or fecal microbiome community except that it decreased the abundance of Akkermansia, which was identified as a fecal biomarker correlated with weight gain. The fecal GUS activity was reduced significantly and was positively correlated with the abundance of Lactobacillaceae in the fecal microbiome. We further confirmed in Escherichia coli K12 and Lactobacillus gasseri ADH that Tamoxifen-, 4-hydroxy-Tamoxifen- and Estradiol-Glucuronides competed for GUS activity. Our study for the first time demonstrated that long-term estrogen supplementation directly modulated gut microbial GUS activity. Our findings implicate that long-term estrogen supplementation impacts composition of gut microbiota and microbial activity, which affects estrogen metabolism in the gut. Thus, it is possible to manipulate such activity to improve the efficacy and safety of long-term administered estrogens for postmenopausal women or breast cancer patients.

Comparative study on short- and long-term behavioral consequences of organophosphate exposure: relationship to AChE mRNA expression.

PubMed

López-Granero, Caridad; Cardona, Diana; Giménez, Estela; Lozano, Rafael; Barril, José; Aschner, Michael; Sánchez-Santed, Fernando; Cañadas, Fernando

2014-01-01

Organophosphates (OPs) affect behavior by inhibiting acetylcholinesterase (AChE). While the cognitive short-term effects may be directly attributed to this inhibition, the mechanisms that underlie OP's long-term cognitive effects remain controversial and poorly understood. Accordingly, two experiments were designed to assess the effects of OPs on cognition, and to ascertain whether both the short- and long-term effects of are AChE-dependent. A single subcutaneous dose of 250 mg/kg chlorpyrifos (CPF), 1.5mg/kg diisopropylphosphorofluoridate (DFP) or 15 mg/kg parathion (PTN) was administered to male Wistar rats. Spatial learning was evaluated 72 h or 23 weeks after exposure, and impulsive choice was tested at 10 and 30 weeks following OPs administration (experiment 1 and 2, respectively). Brain soluble and membrane-bound AChE activity, synaptic AChE-S mRNA, read-through AChE-R mRNA and brain acylpeptide hydrolase (APH) activity (as alternative non-cholinergic target) were analyzed upon completion of the behavioral testing (17 and 37 weeks after OPs exposure). Both short- and long-term CPF treatment caused statistically significant effects on spatial learning, while PTN treatment led only to statistically significant short-term effects. Neither CPF, DFP nor PTN affected the long-term impulsivity response. Long-term exposure to CPF and DFP significantly decreased AChE-S and AChE-R mRNA, while in the PTN treated group only AChE-S mRNA levels were decreased. However, after long-term OP exposure, soluble and membrane-bound AChE activity was indistinguishable from controls. Finally, no changes were noted in brain APH activity in response to OP treatment. Taken together, this study demonstrates long-term effects of OPs on AChE-S and AChE-R mRNA in the absence of changes in AChE soluble and membrane-bound activity. Thus, changes in AChE mRNA expression imply non-catalytic properties of the AChE enzyme. Copyright © 2013 Elsevier Inc. All rights reserved.

Reversing drug resistance of soft tumor-repopulating cells by tumor cell-derived chemotherapeutic microparticles

PubMed Central

Ma, Jingwei; Zhang, Yi; Tang, Ke; Zhang, Huafeng; Yin, Xiaonan; Li, Yong; Xu, Pingwei; Sun, Yanling; Ma, Ruihua; Ji, Tiantian; Chen, Junwei; Zhang, Shuang; Zhang, Tianzhen; Luo, Shunqun; Jin, Yang; Luo, Xiuli; Li, Chengyin; Gong, Hongwei; Long, Zhixiong; Lu, Jinzhi; Hu, Zhuowei; Cao, Xuetao; Wang, Ning; Yang, Xiangliang; Huang, Bo

2016-01-01

Developing novel approaches to reverse the drug resistance of tumor-repopulating cells (TRCs) or stem cell-like cancer cells is an urgent clinical need to improve outcomes of cancer patients. Here we show an innovative approach that reverses drug resistance of TRCs using tumor cell-derived microparticles (T-MPs) containing anti-tumor drugs. TRCs, by virtue of being more deformable than differentiated cancer cells, preferentially take up T-MPs that release anti-tumor drugs after entering cells, which in turn lead to death of TRCs. The underlying mechanisms include interfering with drug efflux and promoting nuclear entry of the drugs. Our findings demonstrate the importance of tumor cell softness in uptake of T-MPs and effectiveness of a novel approach in reversing drug resistance of TRCs with promising clinical applications. PMID:27167569

Biology of high single doses of IORT: RBE, 5 R's, and other biological aspects.

PubMed

Herskind, Carsten; Ma, Lin; Liu, Qi; Zhang, Bo; Schneider, Frank; Veldwijk, Marlon R; Wenz, Frederik

2017-01-19

Intraoperative radiotherapy differs from conventional, fractionated radiotherapy in several aspects that may influence its biological effect. The radiation quality influences the relative biologic effectiveness (RBE), and the role of the five R's of radiotherapy (reassortment, repair, reoxygenation, repopulation, radiosensitivity) is different. Furthermore, putative special biological effects and the small volume receiving a high single dose may be important. The present review focuses on RBE, repair, and repopulation, and gives an overview of the other factors that potentially contribute to the efficacy. The increased RBE should be taken into account for low-energy X-rays while evidence of RBE < 1 for high-energy electrons at higher doses is presented. Various evidence supports a hypothesis that saturation of the primary DNA double-strand break (DSB) repair mechanisms leads to increasing use of an error-prone backup repair system leading to genomic instability that may contribute to inactivate tumour cells at high single doses. Furthermore, the elimination of repopulation of residual tumour cells in the tumour bed implies that some patients are likely to have very few residual tumour cells which may be cured even by low doses to the tumour bed. The highly localised dose distribution of IORT has the potential to inactivate tumour cells while sparing normal tissue by minimising the volume exposed to high doses. Whether special effects of high single doses also contribute to the efficacy will require further experimental and clinical studies.

Improvement of the in vivo cellular repopulation of decellularized cardiovascular tissues by a detergent-free, non-proteolytic, actin-disassembling regimen.

PubMed

Assmann, Alexander; Struß, Marc; Schiffer, Franziska; Heidelberg, Friederike; Munakata, Hiroshi; Timchenko, Elena V; Timchenko, Pavel E; Kaufmann, Tim; Huynh, Khon; Sugimura, Yukiharu; Leidl, Quentin; Pinto, Antonio; Stoldt, Volker R; Lichtenberg, Artur; Akhyari, Payam

2017-12-01

Low immunogenicity and high repopulation capacity are crucial determinants for the functional and structural performance of acellular cardiovascular implants. The present study evaluates a detergent-free, non-proteolytic, actin-disassembling regimen (BIO) for decellularization of heart valve and vessel grafts, particularly focusing on their bio-functionality. Rat aortic conduits (rAoC; n = 89) and porcine aortic valve samples (n = 106) are decellularized using detergents (group DET) or the BIO regimen. BIO decellularization results in effective elimination of cellular proteins and significantly improves removal of DNA as compared with group DET, while the extracellular matrix (ECM) structure as well as mechanical properties are preserved. The architecture of rAoC in group BIO allows for improved bio-functionalization with fibronectin (FN) in a standardized rat implantation model: BIO treatment significantly increases speed and amount of autologous medial cellular repopulation in vivo (p < 0.001) and decreases the formation of hyperplastic intima (p < 0.001) as compared with FN-coated DET-decellularized grafts. Moreover, there are no signs of infiltration with inflammatory cells. The present biological, detergent-free, non-proteolytic regimen balances effective decellularization and ECM preservation in cardiovascular grafts, and provides optimized bio-functionality. Additionally, this study implies that the actin-disassembling regimen may be a promising approach for bioengineering of acellular scaffolds from other muscular tissues, as for example myocardium or intestine. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Bidirectional Retroviral Integration Site PCR Methodology and Quantitative Data Analysis Workflow.

PubMed

Suryawanshi, Gajendra W; Xu, Song; Xie, Yiming; Chou, Tom; Kim, Namshin; Chen, Irvin S Y; Kim, Sanggu

2017-06-14

Integration Site (IS) assays are a critical component of the study of retroviral integration sites and their biological significance. In recent retroviral gene therapy studies, IS assays, in combination with next-generation sequencing, have been used as a cell-tracking tool to characterize clonal stem cell populations sharing the same IS. For the accurate comparison of repopulating stem cell clones within and across different samples, the detection sensitivity, data reproducibility, and high-throughput capacity of the assay are among the most important assay qualities. This work provides a detailed protocol and data analysis workflow for bidirectional IS analysis. The bidirectional assay can simultaneously sequence both upstream and downstream vector-host junctions. Compared to conventional unidirectional IS sequencing approaches, the bidirectional approach significantly improves IS detection rates and the characterization of integration events at both ends of the target DNA. The data analysis pipeline described here accurately identifies and enumerates identical IS sequences through multiple steps of comparison that map IS sequences onto the reference genome and determine sequencing errors. Using an optimized assay procedure, we have recently published the detailed repopulation patterns of thousands of Hematopoietic Stem Cell (HSC) clones following transplant in rhesus macaques, demonstrating for the first time the precise time point of HSC repopulation and the functional heterogeneity of HSCs in the primate system. The following protocol describes the step-by-step experimental procedure and data analysis workflow that accurately identifies and quantifies identical IS sequences.

Short-term Action Intentions Overrule Long-Term Semantic Knowledge

ERIC Educational Resources Information Center

van Elk, M.; van Schie, H.T.; Bekkering, H.

2009-01-01

In the present study, we investigated whether the preparation of an unusual action with an object (e.g. bringing a cup towards the eye) could selectively overrule long-term semantic representations. In the first experiment it was found that unusual action intentions activated short-term semantic goal representations, rather than long-term…

Early remodeling of the neocortex upon episodic memory encoding

PubMed Central

Bero, Adam W.; Meng, Jia; Cho, Sukhee; Shen, Abra H.; Canter, Rebecca G.; Ericsson, Maria; Tsai, Li-Huei

2014-01-01

Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal–hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states. PMID:25071187

Building on a national health information technology strategic plan for long-term and post-acute care: comments by the Long Term Post Acute Care Health Information Technology Collaborative.

PubMed

Alexander, Gregory L; Alwan, Majd; Batshon, Lynne; Bloom, Shawn M; Brennan, Richard D; Derr, John F; Dougherty, Michelle; Gruhn, Peter; Kirby, Annessa; Manard, Barbara; Raiford, Robin; Serio, Ingrid Johnson

2011-07-01

The LTPAC (Long Term Post Acute Care) Health Information Technology (HIT) Collaborative consists of an alliance of long-term services and post-acute care stakeholders. Members of the collaborative are actively promoting HIT innovations in long-term care settings because IT adoption for health care institutions in the United States has become a high priority. One method used to actively promote HIT is providing expert comments on important documents addressing HIT adoption. Recently, the Office of the National Coordinator for HIT released a draft of the Federal Health Information Technology Strategic Plan 2011-2015 for public comment. The following brief is intended to inform about recommendations and comments made by the Collaborative on the strategic plan. Copyright 2011, SLACK Incorporated.

Environmental mutagenesis during the end-Permian ecological crisis

PubMed Central

Visscher, Henk; Looy, Cindy V.; Collinson, Margaret E.; Brinkhuis, Henk; van Konijnenburg-van Cittert, Johanna H. A.; Kürschner, Wolfram M.; Sephton, Mark A.

2004-01-01

During the end-Permian ecological crisis, terrestrial ecosystems experienced preferential dieback of woody vegetation. Across the world, surviving herbaceous lycopsids played a pioneering role in repopulating deforested terrain. We document that the microspores of these lycopsids were regularly released in unseparated tetrads indicative of failure to complete the normal process of spore development. Although involvement of mutation has long been hinted at or proposed in theory, this finding provides concrete evidence for chronic environmental mutagenesis at the time of global ecological crisis. Prolonged exposure to enhanced UV radiation could account satisfactorily for a worldwide increase in land plant mutation. At the end of the Permian, a period of raised UV stress may have been the consequence of severe disruption of the stratospheric ozone balance by excessive emission of hydrothermal organohalogens in the vast area of Siberian Traps volcanism. PMID:15282373

Wound Healing and Cancer Stem Cells: Inflammation as a Driver of Treatment Resistance in Breast Cancer

PubMed Central

Arnold, Kimberly M; Opdenaker, Lynn M; Flynn, Daniel; Sims-Mourtada, Jennifer

2015-01-01

The relationship between wound healing and cancer has long been recognized. The mechanisms that regulate wound healing have been shown to promote transformation and growth of malignant cells. In addition, chronic inflammation has been associated with malignant transformation in many tissues. Recently, pathways involved in inflammation and wound healing have been reported to enhance cancer stem cell (CSC) populations. These cells, which are highly resistant to current treatments, are capable of repopulating the tumor after treatment, causing local and systemic recurrences. In this review, we highlight proinflammatory cytokines and developmental pathways involved in tissue repair, whose deregulation in the tumor microenvironment may promote growth and survival of CSCs. We propose that the addition of anti-inflammatory agents to current treatment regimens may slow the growth of CSCs and improve therapeutic outcomes. PMID:25674014

Biological effects and equivalent doses in radiotherapy: A software solution

PubMed Central

Voyant, Cyril; Julian, Daniel; Roustit, Rudy; Biffi, Katia; Lantieri, Céline

2013-01-01

Background The limits of TDF (time, dose, and fractionation) and linear quadratic models have been known for a long time. Medical physicists and physicians are required to provide fast and reliable interpretations regarding delivered doses or any future prescriptions relating to treatment changes. Aim We, therefore, propose a calculation interface under the GNU license to be used for equivalent doses, biological doses, and normal tumor complication probability (Lyman model). Materials and methods The methodology used draws from several sources: the linear-quadratic-linear model of Astrahan, the repopulation effects of Dale, and the prediction of multi-fractionated treatments of Thames. Results and conclusions The results are obtained from an algorithm that minimizes an ad-hoc cost function, and then compared to an equivalent dose computed using standard calculators in seven French radiotherapy centers. PMID:24936319

Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures.

PubMed

Tardito, Daniela; Gennarelli, Massimo; Musazzi, Laura; Gesuete, Raffaella; Chiarini, Stefania; Barbiero, Valentina Sara; Rydel, Russell E; Racagni, Giorgio; Popoli, Maurizio

2007-09-01

Recent findings suggested a role for soluble amyloid-beta (Abeta) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Abeta(1-40) on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4h) and long-term (5 days) with Abeta(1-40) (1nM-5microM). Abeta did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr(286) phosphorylation. In contrast, long-term treatment (1nM-microM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10nM (three-fold). Up-regulation of activity was associated with increased expression of the alpha-isoform of CaM kinase II, increased phosphorylation at Thr(286) (activator residue) and decreased phosphorylation at Thr(305-306) (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10nM Abeta(1-40). As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Abeta. Short- and long-term Abeta treatment showed opposite effects on CaM kinase II, suggesting that long-term changes are an adaptation to the kinase early down-regulation. The marked effect of Abeta(1-40) on the kinase suggests that semi-physiological and slowly raising peptide concentrations may have a significant impact on synaptic plasticity in the absence of synaptic loss or neuronal cell death.

Forum: Communication Activism Pedagogy. Long-Term Impacts of Communication Activism Pedagogy: Guiding Principles for Future Research

ERIC Educational Resources Information Center

Russell, Vincent; Congdon, Mark, Jr.

2017-01-01

Communication activism pedagogy (CAP) illuminates an array of ways to intervene into oppressive systems to promote just conditions, and CAP's transformative effects on students and communities have been substantively demonstrated (Frey & Palmer 2014). Yet, Frey and Palmer recognize that "social justice issues are long-term, large-scale…

Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection

PubMed Central

Zhang, Zhi-Qiang; Notermans, Daan W.; Sedgewick, Gerald; Cavert, Winston; Wietgrefe, Stephen; Zupancic, Mary; Gebhard, Kristin; Henry, Keith; Boies, Lawrence; Chen, Zongming; Jenkins, Marc; Mills, Roger; McDade, Hugh; Goodwin, Carolyn; Schuwirth, Caspar M.; Danner, Sven A.; Haase, Ashley T.

1998-01-01

Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1. PMID:9448301

Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection.

PubMed

Zhang, Z Q; Notermans, D W; Sedgewick, G; Cavert, W; Wietgrefe, S; Zupancic, M; Gebhard, K; Henry, K; Boies, L; Chen, Z; Jenkins, M; Mills, R; McDade, H; Goodwin, C; Schuwirth, C M; Danner, S A; Haase, A T

1998-02-03

Potent combinations of antiretroviral drugs diminish the turnover of CD4+ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4+ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4+ T cell counts, the CD45RA+ subset, and fractions of proliferating or apoptotic CD4+ T cells. Compared with normal controls, we documented decreased numbers of CD4+ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4+ T and CD45RA+ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA+ CD4+ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4+ T cell populations can be partially restored by control of active replication without eradication of HIV-1.

Modality-specific alpha modulations facilitate long-term memory encoding in the presence of distracters.

PubMed

Jiang, Haiteng; van Gerven, Marcel A J; Jensen, Ole

2015-03-01

It has been proposed that long-term memory encoding is not only dependent on engaging task-relevant regions but also on disengaging task-irrelevant regions. In particular, oscillatory alpha activity has been shown to be involved in shaping the functional architecture of the working brain because it reflects the functional disengagement of specific regions in attention and memory tasks. We here ask if such allocation of resources by alpha oscillations generalizes to long-term memory encoding in a cross-modal setting in which we acquired the ongoing brain activity using magnetoencephalography. Participants were asked to encode pictures while ignoring simultaneously presented words and vice versa. We quantified the brain activity during rehearsal reflecting subsequent memory in the different attention conditions. The key finding was that successful long-term memory encoding is reflected by alpha power decreases in the sensory region of the to-be-attended modality and increases in the sensory region of the to-be-ignored modality to suppress distraction during rehearsal period. Our results corroborate related findings from attention studies by demonstrating that alpha activity is also important for the allocation of resources during long-term memory encoding in the presence of distracters.

Effect of Long-Term Physical Activity Practice after Cardiac Rehabilitation on Some Risk Factors

ERIC Educational Resources Information Center

Freyssin, Celine, Jr.; Blanc, Philippe; Verkindt, Chantal; Maunier, Sebastien; Prieur, Fabrice

2011-01-01

The objective of this study was to evaluate the effects of long-term physical activity practice after a cardiac rehabilitation program on weight, physical capacity and arterial compliance. The Dijon Physical Activity Score was used to identify two groups: sedentary and active. Weight, distance at the 6-min walk test and the small artery elasticity…

76 FR 37824 - Agency Information Collection Activities: Submission for OMB Review; Comment Request, OMB No...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-28

...; FEMA Form 078-0-2A, National Fire Academy (NFA) Long-Term Evaluation Student/Trainee; FEMA Form 078-0-2... Evaluation Student/Trainee; FEMA Form 078-0-2 (Presently FEMA Form 95-58), NFA Long-Term Evaluation...-term Evaluation Form for Supervisors and National Fire Academy Long-term Evaluation Form for Students...

Long-term health benefits of physical activity – a systematic review of longitudinal studies

PubMed Central

2013-01-01

Background The treatment of noncommunicable diseases (NCD), like coronary heart disease or type 2 diabetes mellitus, causes rising costs for the health system. Physical activity is supposed to reduce the risk for these diseases. Results of cross-sectional studies showed that physical activity is associated with better health, and that physical activity could prevent the development of these diseases. The purpose of this review is to summarize existing evidence for the long-term (>5 years) relationship between physical activity and weight gain, obesity, coronary heart disease, type 2 diabetes mellitus, Alzheimer’s disease and dementia. Methods Fifteen longitudinal studies with at least 5-year follow up times and a total of 288,724 subjects (>500 participants in each study), aged between 18 and 85 years, were identified using digital databases. Only studies published in English, about healthy adults at baseline, intentional physical activity and the listed NCDs were included. Results The results of these studies show that physical activity appears to have a positive long-term influence on all selected diseases. Conclusions This review revealed a paucity of long-term studies on the relationship between physical activity and the incidence of NCD. PMID:24010994

Reforming Long-Term Care Funding in Alberta.

PubMed

Crump, R Trafford; Repin, Nadya; Sutherland, Jason M

2015-01-01

Like many provinces across Canada, Alberta is facing growing demand for long-term care. Issues with the mixed funding model used to pay long-term care providers had Alberta Health Services concerned that it was not efficiently meeting the demand for long-term care. Consequently, in 2010, Alberta Health Services introduced the patient/care-based funding (PCBF) model. PCBF is similar to activity-based funding in that it directly ties the complexity and care needs of long-term care residents to the payment received by long-term care providers. This review describes PCBF and discusses some of its strengths and weaknesses. In doing so, this review is intended to inform other provinces faced with similar long-term care challenges and contemplating their own funding reforms.

Hippocampal long term memory: effect of the cholinergic system on local protein synthesis.

PubMed

Lana, Daniele; Cerbai, Francesca; Di Russo, Jacopo; Boscaro, Francesca; Giannetti, Ambra; Petkova-Kirova, Polina; Pugliese, Anna Maria; Giovannini, Maria Grazia

2013-11-01

The present study was aimed at establishing a link between the cholinergic system and the pathway of mTOR and its downstream effector p70S6K, likely actors in long term memory encoding. We performed in vivo behavioral experiments using the step down inhibitory avoidance test (IA) in adult Wistar rats to evaluate memory formation under different conditions, and immunohistochemistry on hippocampal slices to evaluate the level and the time-course of mTOR and p70S6K activation. We also examined the effect of RAPA, inhibitor of mTORC1 formation, and of the acetylcholine (ACh) muscarinic receptor antagonist scopolamine (SCOP) or ACh nicotinic receptor antagonist mecamylamine (MECA) on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition test was performed 30 min after i.c.v. injection of RAPA, a time sufficient for the drug to diffuse to CA1 pyramidal neurons, as demonstrated by MALDI-TOF-TOF imaging. Recall test was performed 1 h, 4 h or 24 h after acquisition. To confirm our results we performed in vitro experiments on live hippocampal slices: we evaluated whether stimulation of the cholinergic system with the cholinergic receptor agonist carbachol (CCh) activated the mTOR pathway and whether the administration of the above-mentioned antagonists together with CCh could revert this activation. We found that (1) mTOR and p70S6K activation in the hippocampus were involved in long term memory formation; (2) RAPA administration caused inhibition of mTOR activation at 1 h and 4 h and of p70S6K activation at 4 h, and long term memory impairment at 24 h after acquisition; (3) scopolamine treatment caused short but not long term memory impairment with an early increase of mTOR/p70S6K activation at 1 h followed by stabilization at longer times; (4) mecamylamine plus scopolamine treatment caused short term memory impairment at 1 h and 4 h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1 h and 4 h; (5) mecamylamine plus scopolamine treatment did not impair long term memory formation; (6) in vitro treatment with carbachol activated mTOR and p70S6K and this effect was blocked by scopolamine and mecamylamine. Taken together our data reinforce the idea that distinct molecular mechanisms are at the basis of the two different forms of memory and are in accordance with data presented by other groups that there exist molecular mechanisms that underlie short term memory, others that underlie long term memories, but some mechanisms are involved in both. Copyright © 2013 Elsevier Inc. All rights reserved.

Accelerometer's position independent physical activity recognition system for long-term activity monitoring in the elderly.

PubMed

Khan, Adil Mehmood; Lee, Young-Koo; Lee, Sungyoung; Kim, Tae-Seong

2010-12-01

Mobility is a good indicator of health status and thus objective mobility data could be used to assess the health status of elderly patients. Accelerometry has emerged as an effective means for long-term physical activity monitoring in the elderly. However, the output of an accelerometer varies at different positions on a subject's body, even for the same activity, resulting in high within-class variance. Existing accelerometer-based activity recognition systems thus require firm attachment of the sensor to a subject's body. This requirement makes them impractical for long-term activity monitoring during unsupervised free-living as it forces subjects into a fixed life pattern and impede their daily activities. Therefore, we introduce a novel single-triaxial-accelerometer-based activity recognition system that reduces the high within-class variance significantly and allows subjects to carry the sensor freely in any pocket without its firm attachment. We validated our system using seven activities: resting (lying/sitting/standing), walking, walking-upstairs, walking-downstairs, running, cycling, and vacuuming, recorded from five positions: chest pocket, front left trousers pocket, front right trousers pocket, rear trousers pocket, and inner jacket pocket. Its simplicity, ability to perform activities unimpeded, and an average recognition accuracy of 94% make our system a practical solution for continuous long-term activity monitoring in the elderly.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats

PubMed Central

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-01-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at −80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs. PMID:29637821

Expansion of Human and Murine Hematopoietic Stem and Progenitor Cells Ex Vivo without Genetic Modification Using MYC and Bcl-2 Fusion Proteins

PubMed Central

Bird, Gregory A.; Polsky, Avital; Estes, Patricia; Hanlon, Teri; Hamilton, Haley; Morton, John J.; Gutman, Jonathan; Jimeno, Antonio

2014-01-01

The long-term repopulating hematopoietic stem cell (HSC) population can self-renew in vivo, support hematopoiesis for the lifetime of the individual, and is of critical importance in the context of bone marrow stem cell transplantation. The mechanisms that regulate the expansion of HSCs in vivo and in vitro remain unclear to date. Since the current set of surface markers only allow for the identification of a population of cells that is highly enriched for HSC activity, we will refer to the population of cells we expand as Hematopoietic Stem and Progenitor cells (HSPCs). We describe here a novel approach to expand a cytokine-dependent Hematopoietic Stem and Progenitor Cell (HSPC) population ex vivo by culturing primary adult human or murine HSPCs with fusion proteins including the protein transduction domain of the HIV-1 transactivation protein (Tat) and either MYC or Bcl-2. HSPCs obtained from either mouse bone marrow, human cord blood, human G-CSF mobilized peripheral blood, or human bone marrow were expanded an average of 87 fold, 16.6 fold, 13.6 fold, or 10 fold, respectively. The expanded cell populations were able to give rise to different types of colonies in methylcellulose assays in vitro, as well as mature hematopoietic populations in vivo upon transplantation into irradiated mice. Importantly, for both the human and murine case, the ex vivo expanded cells also gave rise to a self-renewing cell population in vivo, following initial transplantation, that was able to support hematopoiesis upon serial transplantation. Our results show that a self-renewing cell population, capable of reconstituting the hematopoietic compartment, expanded ex vivo in the presence of Tat-MYC and Tat-Bcl-2 suggesting that this may be an attractive approach to expand human HSPCs ex vivo for clinical use. PMID:25170611

Orthotopic Transplantation of Achilles Tendon Allograft in Rats: With or without Incorporation of Autologous Mesenchymal Stem Cells.

PubMed

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-02-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at -80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.

Do patients with ewing's sarcoma continue with sports activities after limb salvage surgery of the lower extremity?

PubMed

Hobusch, Gerhard Martin; Lang, Nikolaus; Schuh, Reinhard; Windhager, Reinhard; Hofstaetter, Jochen Gerhard

2015-03-01

Limb salvage surgery has evolved to become the standard method of treating sarcomas of the extremities with acceptable oncologic results. However, little information exists relative to the activity level or ability to participate in sports after tumor reconstructions. The aims of the study were to answer the following questions: (1) Which sports activity levels and what types of sports can be expected in the long term after tumor reconstruction? (2) Which frequency durations are patients with Ewing's sarcoma able to perform in long-term followup after local control? (3) Do surgical complications affect sports activity level? Thirty patients (13 females, 17 males; mean age, 18 ± 8 years; range, 2-36 years at diagnosis; mean followup 16 ± 6 years [minimum, 5 years]) were included. Tumors were located in the pelvis, femur, tibia, and fibula. Surgical procedures included surgical resections alone (n = 8), surgical resection with biological reconstruction (n = 9), or endoprosthetic reconstruction (n = 13). We assessed UCLA sports activity levels, kinds of sports as well as the frequency per week and the duration of each training unit at long term (minimum followup, 5 years). In long-term followup 83% patients (25 of 30) were performing athletic activity regularly. The hours/week of sports depended on type of surgery and were highest after resections in the pelvis and femur (5.8) and were lowest after megaprosthetic reconstruction of the pelvis (1.0). Patients undergoing biologic reconstructions were able to perform high-impact sports. UCLA sports activity levels were high after joint-preserving vascularized fibula for tibia reconstruction (7.4) and after megaprosthetic reconstruction of the lower extremity (6.3-6.4) and were low after tumors located in the fibula (4.2). Complications during followup did not significantly influence sports activity in long-term survivors. Long-term survivors can achieve high levels of sports activity in many instances. Tumor sites are associated with the postoperative sports activity levels. This information can help surgeons counsel patients in terms of athletic expectations after limb salvage reconstruction for patients with Ewing's sarcoma. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory

PubMed Central

Maher, Pamela; Akaishi, Tatsuhiro; Abe, Kazuho

2006-01-01

Small molecules that activate signaling pathways used by neurotrophic factors could be useful for treating CNS disorders. Here we show that the flavonoid fisetin activates ERK and induces cAMP response element-binding protein (CREB) phosphorylation in rat hippocampal slices, facilitates long-term potentiation in rat hippocampal slices, and enhances object recognition in mice. Together, these data demonstrate that the natural product fisetin can facilitate long-term memory, and therefore it may be useful for treating patients with memory disorders. PMID:17050681

77 FR 58116 - Commission Information Collection Activities (FERC-732); Comment Request; Extension

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-19

... Rate Schedules and Tariffs: Long-Term Firm Transmission Rights in Organized Electricity Markets. DATES... Tariffs: Long-Term Firm Transmission Rights in Organized Electricity Markets. OMB Control No.:1902-0245... organized electricity markets to make available long-term firm transmission rights that satisfy each of the...

Direct and indirect effects of nutritional status, physical function and cognitive function on activities of daily living in Japanese older adults requiring long-term care.

PubMed

Kamo, Tomohiko; Nishida, Yuusuke

2014-10-01

To identify the direct and indirect effects of nutritional status, physical function, and cognitive function on activities of daily living in Japanese older adults requiring long-term care. In total, 179 participants aged ≥ 65 years who were eligible for long-term care insurance (mean age 85.5 ± 7.8 years) were recruited for this study. Nutritional status (Mini Nutritional Assessment, Short Form) and physical function (Short Physical Performance Battery) were examined. Activities of daily living, cognitive function and frailty were assessed using the Barthel Index, Mini-Mental State Examination and Clinical Frailty Scale, respectively. Path analysis was used to determine relationships between these factors and the activities of daily living. For Japanese older adults requiring long-term care, pathways were modeled for nutritional status, physical function and the activities of daily living. The total effect of nutritional status was 0.516 (P<0.001). The indirect effect of nutritional status through physical function on the activities of daily living was 0.458 (P<0.001). Finally, no significant direct effect of nutritional status on activities of daily living was observed (b=0.058, P=0.258). The present study identified the complex pathway from nutritional status to the activities of daily living through physical function in aged Japanese people requiring long-term care. These findings suggest that maintaining good nutritional status and nutritional support might delay physical function decline, and prolong the activities of daily living. © 2013 Japan Geriatrics Society.

CMS MDS 3.0 Section M Skin Conditions in Long-term Care: Pressure Ulcers, Skin Tears, and Moisture-Associated Skin Damage Data Update.

PubMed

Ayello, Elizabeth A

2017-09-01

The purpose of this learning activity is to provide information about the updates to the Centers for Medicare & Medicaid Services (CMS) MDS 3.0 Section M, Skin Conditions documentation in long-term care. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to:1. Explain the use of the CMS MDS 3.0 tool for documenting skin problems in long-term care.2. Demonstrate examples of proper documentation for specific skin problems. This manuscript reviews some of the key parts of the October 2016 revised Long-term Care Resident Assessment Instrument manual for Minimum Data Set (MDS) 3.0 Section M Skin Conditions. It also reports the Centers for Medicare & Medicaid's publicly reported frequency data in long-term care for selected items on the MDS 3.0 Section M Skin Conditions. Percentages and trends of pressure ulcers/injuries, skin tears, and moisture-associated skin damage are assessed.

Identification of a Functional Connectome for Long-Term Fear Memory in Mice

PubMed Central

Wheeler, Anne L.; Teixeira, Cátia M.; Wang, Afra H.; Xiong, Xuejian; Kovacevic, Natasa; Lerch, Jason P.; McIntosh, Anthony R.; Parkinson, John; Frankland, Paul W.

2013-01-01

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression. PMID:23300432

76 FR 13201 - Agency Information Collection Activities: Proposed Collection; Comment Request, 1660-0039; FEMA...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-10

...-0-2A, National Fire Academy (NFA) Long-Term Evaluation Student/Trainee; FEMA Form 078-0-2, NFA Long... collection; OMB No. 1660-0039; FEMA Form 078-0-2A (Presently FEMA Form 95-59), NFA Long- Term Evaluation Student/Trainee; FEMA Form 078-0-2 (Presently FEMA Form 95-58), NFA Long-Term Evaluation Supervisors...

Long-term surveillance plan for the Green River, Utah, disposal site

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-06-01

The long-term surveillance plan (LTSP) for the Green River, Utah, Uranium Mill Tailings Remedial Action (UMTRA) Project disposal site describes the surveillance activities for the Green River disposal cell. The U.S. Department of Energy (DOE) will carry out these activities to ensure that the disposal cell continues to function as designed. This final LTSP was prepared as a requirement for acceptance under the U.S. Nuclear Regulatory Commission (NRC) general license for custody and long-term care of residual radioactive materials (RRM). This LTSP documents whether the land and interests are owned by the United States or an Indian tribe and detailsmore » how the long-term care of the disposal site will be carried out. The Green River, Utah, LTSP is based on the DOE`s Guidance for Implementing the UMTRA Project Long-term Surveillance Program (DOE, 1992a).« less

Upper limb function in persons with long term paraplegia and implications for independence: Part II.

PubMed

Pentland, W E; Twomey, L T

1994-04-01

Research has shown that wheelchair use in long term paraplegia is associated with upper limb pain and degeneration that interferes with the independent performance of activities of daily living. This paper proposes a model to explain the development of upper limb problems in persons with long term paraplegia, and one that will guide in the prevention and management of this type of long term complication.

New Ligand Design Provides Delocalization and Promotes Strong Absorption throughout the Visible Region in a Ru(II) Complex

DOE PAGES

Whittemore, Tyler J.; White, Travis A.; Turro, Claudia

2017-12-20

The new Ru(II)–anthraquinone complex [Ru(bpy) 2(qdpq)](PF 6) 2 (Ru-qdpq; bpy = 2,2'-bipyridine; qdpq = 2,3-di(2-pyridyl)naphtho[2,3-f]quinoxaline-7,12-quinone) possesses a strong 1MLCT Ru → qdpq absorption with a maximum at 546 nm that tails into the near-IR and is significantly red-shifted relative to that of the related complex [Ru(bpy) 2(qdppz)](PF 6) 2 (Ru-qdppz; qdppz = naphtho[2,3-a]dipyrido[3,2-h:2',3'-f]phenazine-5,18-dione), with λ max = 450 nm. Ru-qdppz possesses electronically isolated proximal and distal qdppz-based excited states; the former is initially generated and decays to the latter, which repopulates the ground state with τ = 362 ps. In contrast, excitation of Ru-qdpq results in the population of amore » relatively long-lived (τ = 19 ns) Ru(dπ) → qdpq(π*) 3MLCT excited state where the promoted electron is delocalized throughout the qdpq ligand. Ultrafast spectroscopy, used together with steady-state absorption, electrochemistry, and DFT calculations, indicates that the unique coordination modes of the qdpq and qdppz ligands impart substantially different electronic communication throughout the quinone-containing ligand, affecting the excited state and electron transfer properties of these molecules. As a result, these observations create a pathway to synthesize complexes with red-shifted absorptions that possess long-lived, redox-active excited states that are useful for various applications, including solar energy conversion and photochemotherapy.« less

New Ligand Design Provides Delocalization and Promotes Strong Absorption throughout the Visible Region in a Ru(II) Complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whittemore, Tyler J.; White, Travis A.; Turro, Claudia

The new Ru(II)–anthraquinone complex [Ru(bpy) 2(qdpq)](PF 6) 2 (Ru-qdpq; bpy = 2,2'-bipyridine; qdpq = 2,3-di(2-pyridyl)naphtho[2,3-f]quinoxaline-7,12-quinone) possesses a strong 1MLCT Ru → qdpq absorption with a maximum at 546 nm that tails into the near-IR and is significantly red-shifted relative to that of the related complex [Ru(bpy) 2(qdppz)](PF 6) 2 (Ru-qdppz; qdppz = naphtho[2,3-a]dipyrido[3,2-h:2',3'-f]phenazine-5,18-dione), with λ max = 450 nm. Ru-qdppz possesses electronically isolated proximal and distal qdppz-based excited states; the former is initially generated and decays to the latter, which repopulates the ground state with τ = 362 ps. In contrast, excitation of Ru-qdpq results in the population of amore » relatively long-lived (τ = 19 ns) Ru(dπ) → qdpq(π*) 3MLCT excited state where the promoted electron is delocalized throughout the qdpq ligand. Ultrafast spectroscopy, used together with steady-state absorption, electrochemistry, and DFT calculations, indicates that the unique coordination modes of the qdpq and qdppz ligands impart substantially different electronic communication throughout the quinone-containing ligand, affecting the excited state and electron transfer properties of these molecules. As a result, these observations create a pathway to synthesize complexes with red-shifted absorptions that possess long-lived, redox-active excited states that are useful for various applications, including solar energy conversion and photochemotherapy.« less

Eradication of Murine Norovirus from a Mouse Barrier Facility

PubMed Central

Kastenmayer, Robin J; Perdue, Kathy A; Elkins, William R

2008-01-01

Murine norovirus (MNV) is a common viral infection of mice in many research facilities. MNV infects hematopoietic cells and alters their cellular morphology. Because of MNV's probable effects on the systemic immune response of infected mice the decision was made to eradicate the virus from 2 rooms containing infected animals in our vivarium. Two different eradication methods were selected. One room, in which most of the indirectly exposed sentinels had antibodies to MNV, was depopulated and thoroughly cleaned prior to repopulation. In the other room, in which only 13% of the sentinels had positive MNV titers, selective testing was used, and MNV-positive animals were removed. Data from surveillance of the sentinel mice exposed to dirty bedding indicate that the test-and-removal method was ineffective in eliminating MNV from the room, whereas sentinel mice in the room that underwent depopulation and cleaning prior to repopulation have not shown any evidence of MNV since December 2006. PMID:18210995

Decellularized human liver as a natural 3D-scaffold for liver bioengineering and transplantation

PubMed Central

Mazza, Giuseppe; Rombouts, Krista; Rennie Hall, Andrew; Urbani, Luca; Vinh Luong, Tu; Al-Akkad, Walid; Longato, Lisa; Brown, David; Maghsoudlou, Panagiotis; Dhillon, Amar P.; Fuller, Barry; Davidson, Brian; Moore, Kevin; Dhar, Dipok; De Coppi, Paolo; Malago, Massimo; Pinzani, Massimo

2015-01-01

Liver synthetic and metabolic function can only be optimised by the growth of cells within a supportive liver matrix. This can be achieved by the utilisation of decellularised human liver tissue. Here we demonstrate complete decellularization of whole human liver and lobes to form an extracellular matrix scaffold with a preserved architecture. Decellularized human liver cubic scaffolds were repopulated for up to 21 days using human cell lines hepatic stellate cells (LX2), hepatocellular carcinoma (Sk-Hep-1) and hepatoblastoma (HepG2), with excellent viability, motility and proliferation and remodelling of the extracellular matrix. Biocompatibility was demonstrated by either omental or subcutaneous xenotransplantation of liver scaffold cubes (5 × 5 × 5 mm) into immune competent mice resulting in absent foreign body responses. We demonstrate decellularization of human liver and repopulation with derived human liver cells. This is a key advance in bioartificial liver development. PMID:26248878

Influence of nandrolone decanoate on the repopulation of the thymus after total body irradiation of mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Plum, J.; Huys, J.; De Scheerder, Y.

1982-10-01

It has been reported that nandrolone decanoate is helpful in overcoming the neutropenic phase following irradiation. In the present study the influence of nandrolone decanoate on the thymus' cellularity after total body irradiation was investigated. In comparison with a placebo-treated group, mice receiving nandrolone decanoate showed a similar pattern of thymus repopulation, but a significantly lower number of thymocytes over the whole period of treatment was found. Nonirradiated mice also had a significantly lower number of thymocytes when treated with nandrolone decanoate. In addition, the number of circulating leukocytes was also evaluated over a period of 1 month after totalmore » body irradiation. On 11 of the 21 days investigated, a significantly higher number of leukocytes was found in the nandrolone decanoate-treated group. We conclude that the action of nandrolone decanoate was not clearly distinct from that of testosterone regarding either granulopoiesis or thymic involution.« less

Hanford immobilized low-activity tank waste performance assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mann, F.M.

1998-03-26

The Hanford Immobilized Low-Activity Tank Waste Performance Assessment examines the long-term environmental and human health effects associated with the planned disposal of the vitrified low-level fraction of waste presently contained in Hanford Site tanks. The tank waste is the by-product of separating special nuclear materials from irradiated nuclear fuels over the past 50 years. This waste has been stored in underground single and double-shell tanks. The tank waste is to be retrieved, separated into low and high-activity fractions, and then immobilized by private vendors. The US Department of Energy (DOE) will receive the vitrified waste from private vendors and plansmore » to dispose of the low-activity fraction in the Hanford Site 200 East Area. The high-level fraction will be stored at Hanford until a national repository is approved. This report provides the site-specific long-term environmental information needed by the DOE to issue a Disposal Authorization Statement that would allow the modification of the four existing concrete disposal vaults to provide better access for emplacement of the immobilized low-activity waste (ILAW) containers; filling of the modified vaults with the approximately 5,000 ILAW containers and filler material with the intent to dispose of the containers; construction of the first set of next-generation disposal facilities. The performance assessment activity will continue beyond this assessment. The activity will collect additional data on the geotechnical features of the disposal sites, the disposal facility design and construction, and the long-term performance of the waste. Better estimates of long-term performance will be produced and reviewed on a regular basis. Performance assessments supporting closure of filled facilities will be issued seeking approval of those actions necessary to conclude active disposal facility operations. This report also analyzes the long-term performance of the currently planned disposal system as a basis to set requirements on the waste form and the facility design that will protect the long-term public health and safety and protect the environment.« less

[Nursing in the framework of long-term care insurance as a basic principle of a specific nursing approach of rehabilitation?].

PubMed

Dangel, Bärbel; Korporal, Johannes

2003-02-01

Activating nursing based on the criteria of the long-term care insurance may be understood as a second specific and nursing approach of rehabilitation beneath medical rehabilitation. Activating nursing is unspecific, characterized by the norms and guidelines of the long-term care insurance, but defined as the general norm of practical nursing. A professional nursing definition for a specific concept is lacking just as funding of nursing science. Adhering to activating nursing as a nursing complement to medical rehabilitation in the framework of long-term care insurance requires professional development and funding. Furthermore, more support of social law is necessary, which depends on professional nursing and nursing science-based indication and the intervention approach. The article develops an approach--based on a study about rehabilitation of people in need for care--and reflects on implementation and acceptance by people in the need of care.

Recreational physical activity and risk of papillary thyroid cancer among women in the California Teachers Study

PubMed Central

Cash, Stephanie Whisnant; Ma, Huiyan; Horn-Ross, Pamela L.; Reynolds, Peggy; Canchola, Alison J.; Sullivan-Halley, Jane; Beresford, Shirley A.A.; Neuhouser, Marian L.; Vaughan, Thomas L.; Heagerty, Patrick J.; Bernstein, Leslie

2012-01-01

Purpose Little is known about the relationship between physical activity and thyroid cancer risk, and few cohort data on this association exist. Thus, the present study aimed to prospectively examine long-term activity and risk of papillary thyroid cancer among women. Methods 116,939 women in the California Teachers Study, aged 22 to 79 years with no history of thyroid cancer at cohort entry, were followed from 1995-1996 through 2009; 275 were diagnosed with invasive papillary thyroid cancer. Cox proportional-hazards regression provided relative risk (RR) estimates and 95% confidence intervals (CI) for associations between thyroid cancer and combined strenuous and moderate recreational physical activity both in the long-term (high school through age 54 years or current age if younger than 54 years) and recently (during the three years prior to joining the cohort). Results Overall, women whose long-term recreational physical activity averaged at least 5.5 MET-hours/week (i.e. were active) had a non-significant 23% lower risk of papillary thyroid cancer than inactive women (RR=0.77, 95% CI: 0.57, 1.04). RR estimates were stronger among normal weight or underweight women (body mass index, BMI<25.0 kg/m2, trend p=0.03) than among overweight or obese women (trend p=0.35; homogeneity-of-trends p=0.03). A similar pattern of risk was observed for recent activity (BMI<25 kg/m2, trend p=0.11; BMI≥25 kg/m2, trend p=0.16; homogeneity-of-trends p=0.04). Associations for long-term activity did not appear to be driven by activity in any particular life period (e.g. youth, adulthood). Conclusions Long-term physical activity may reduce papillary thyroid cancer risk among normal weight and underweight women. PMID:23116823

Benefits and Challenges of the Passport Broadcast Intervention in Long-Term Care

ERIC Educational Resources Information Center

Wittenberg-Lyles, Elaine; Oliver, Debra Parker; Demiris, George; Shaunfield, Sara

2012-01-01

Creative activities are a challenge for long-term care facilities. The Passport intervention uses web-based video technology to provide long-term care residents with a virtual travel experience. Passport broadcasts were conducted and staff and residents were interviewed about the experience. A thematic analysis of interviews was used to discern…

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

PubMed

Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburguères, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernández, Alejandro Iván; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2016-05-17

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.

A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue.

PubMed

Irvine, Karen-Amanda; Blakemore, William F

2007-01-01

This study was designed to investigate whether the residual, dysfunctional oligodendrocyte progenitor cells (OPCs) observed following X-irradiation of the mouse spinal cord [D. M. Chari et al. (2003) Exp. Neurol., 198, 145-153], the presence of which prevented the endogenous repopulation of these areas from normal tissue, reflects a general response of OPCs in the mouse central nervous system (CNS) to X-irradiation. The brains of adult mice were exposed to 40 Gy of X-irradiation and the effect of X-irradiation on the OPCs was assessed up to 4 weeks post-irradiation using anti-NG2 antibodies. X-irradiation resulted in almost complete depletion of OPCs within the telencephalon (cortex, corpus callosum and hippocampus) by 7 days post-irradiation, which was followed by progressive repopulation of OPCs from non-irradiated areas of the cortex. By contrast, within the lower brain centres (the diencephalon and mesencephalon) OPC loss occurred much more slowly so that 26% of the OPCs still remained 4 weeks after X-irradiation. The consequence of this heterogeneous response to X-irradiation was that whereas transplanted and endogenous OPCs rapidly established themselves in the OPC-depleted telencephalon this did not occur in the areas where there was incomplete depletion of endogenous OPCs. Our findings confirm not only the requirement for almost complete OPC depletion in order to establish transplanted OPCs in normal tissue but also highlight a heterogeneity of progenitor populations in different areas of the mouse CNS.

Importance of Sox2 in maintenance of cell proliferation and multipotency of mesenchymal stem cells in low-density culture.

PubMed

Yoon, D S; Kim, Y H; Jung, H S; Paik, S; Lee, J W

2011-10-01

This study has aimed to repopulate 'primitive' cells from late-passage mesenchymal stem cells (MSCs) of poor multipotentiality and low cell proliferation rate, by simply altering plating density. Effects of low density culture compared t high density culture on late-passage bone marrow (BM)-derived MSCs and pluripotency markers of multipotentiality were investigated. Cell proliferation, gene expression, RNA interference and differentiation potential were assayed. We repopulated 'primitive' cells by replating late-passage MSCs at low density (17 cells/cm(2) ) regardless of donor age. Repopulated MSCs from low-density culture were smaller cells with spindle shaped morphology compared to MSCs from high-density culture. The latter had enhanced colony-forming ability, proliferation rate, and adipogenic and chondrogenic potential. Strong expression of osteogenic-related genes (Cbfa1, Dlx5, alkaline phosphatase and type Ι collagen) in late-passage MSCs was reduced by replating at low density, whereas expression of three pluripotency markers (Sox2, Nanog and Oct-4), Osterix and Msx2 reverted to levels of early-passage MSCs. Knockdown of Sox2 and Msx2 but not Nanog, using RNA interference, showed significant decrease in colony-forming ability. Specifically, knockdown of Sox2 significantly inhibited multipotentiality and cell proliferation. Our data suggest that plating density should be considered to be a critical factor for enrichment of 'primitive' cells from heterogeneous BM and that replicative senescence and multipotentiality of MSCs during in vitro expansion may be predominantly regulated through Sox2. © 2011 Blackwell Publishing Ltd.

Relative phase asynchrony and long-range correlation of long-term solar magnetic activity

NASA Astrophysics Data System (ADS)

Deng, Linhua

2017-07-01

Statistical signal processing is one of the most important tasks in a large amount of areas of scientific studies, such as astrophysics, geophysics, and space physics. Phase recurrence analysis and long-range persistence are the two dynamical structures of the underlying processes for the given natural phenomenon. Linear and nonlinear time series analysis approaches (cross-correlation analysis, cross-recurrence plot, wavelet coherent transform, and Hurst analysis) are combined to investigate the relative phase interconnection and long-range correlation between solar activity and geomagnetic activity for the time interval from 1932 January to 2017 January. The following prominent results are found: (1) geomagnetic activity lags behind sunspot numbers with a phase shift of 21 months, and they have a high level of asynchronous behavior; (2) their relative phase interconnections are in phase for the periodic scales during 8-16 years, but have a mixing behavior for the periodic belts below 8 years; (3) both sunspot numbers and geomagnetic activity can not be regarded as a stochastic phenomenon because their dynamical behaviors display a long-term correlation and a fractal nature. We believe that the presented conclusions could provide further information on understanding the dynamical coupling of solar dynamo process with geomagnetic activity variation, and the crucial role of solar and geomagnetic activity in the long-term climate change.

An Initial Evaluation of a Long-Term, Sustainable, Integrated Community-Based Physical Activity Program for Adults with Intellectual Disability

ERIC Educational Resources Information Center

Lante, Kerrie A.; Walkley, Jeff W.; Gamble, Merrilyn; Vassos, Maria V.

2011-01-01

Background: Physical activity (PA) programs for adults with intellectual disability (ID) have positive impacts, at least in the short term. No research has been reported on the effect of long-term engagement in PA programs for adults with ID. This paper explores the physical and psychosocial benefits gained by two individuals with mild ID who…

[Participation as Target of Social Medicine and Nursing Care: - Legal Definition of Long-Term Care Dependency - Strategies to Prevent Long-Term Care Dependency].

PubMed

Nüchtern, Elisabeth; Gansweid, Barbara; Gerber, Hans; von Mittelstaedt, Gert

2017-01-01

Objective: By the "Second Bill to Strengthen Long-Term Care", a new concept of long-term care dependency will be introduced, valid from 2017. Long-term care dependency according to Social Code XI will be defined covering more aspects than today. Therefore, the working group "Nursing Care" of the division "Social Medicine in Practice and Rehabilitation" in the German Society for Social Medicine and Prevention presents their results after working on the social medicine perspective of the definition and prevention of long-term care dependency. Methods: Both the definition and strategies to prevent long-term care dependency are systematically taken into consideration from the point of view of social medicine on the basis of the International Classification of Functioning, Disability and Health (ICF), as long-term care dependency means a defined condition of disability. Results: Both the current and the new concept of long-term care dependency focus activity limitations. The perspective of social medicine considers the interactions of health condition, its effects on daily activities and personal as well as environmental factors. From this point of view approaches for social benefits concerning prevention and rehabilitation can be identified systematically so as to work against the development and progression of long-term care dependency. The reference to the ICF can facilitate the communication between different professions. The new "graduation" of long-term care dependency would allow an international "translation" referring to the ICF. Conclusion: Experts from the field of social medicine as well as those of nursing care, care-givers and nursing researchers have in common the objective that persons in need of nursing care can participate in as many aspects of life of importance to them in an autonomous and self-determined way. The point of view of social medicine on long-term care dependency is fundamental for all occupational groups that are involved and for their successful cooperation. © Georg Thieme Verlag KG Stuttgart · New York.

[Anti-mouse CD122 antibody promotes the hematopoietic repopulating capacity of cord blood CD34⁺ cells in NOD/SCID mice].

PubMed

Sheng, Men-Yao; Shi, Hui; Xing, Wen; Wang, Wen-Jun; Si, Xiao-Hui; Bai, Jie; Yuan, Wei-Ping; Zhou, Yuan; Yang, Feng-Chun

2014-12-01

The study was aimed to investigate the effect of anti-mouse CD122 antibody on the hematopoietic repopulating capacity of cord blood CD34⁺ cells in a humanized murine model-non obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. After sublethal irradiation with γ-ray, NOD/SCID mice were intraperitoneally injected with 200 µg mouse isotype control antibody or anti-mouse CD122 antibody. Human cord blood CD34⁺ cells or phosphate-buffered saline (PBS) were injected via the tail vein at 6-8 hours later. Cohort of the mice injected with anti-mice CD122 antibody or control antibody alone were sacrificed at different time point (at week 2, 3, and 4 weeks) after the injection, and the percentage of NK cells in the peripheral blood was analyzed by flow cytometry. To evaluate the effect of anti-mouse CD122 antibody on the repopulating capacity of cord blood CD34⁺ cells in the recipient mice, phenotype analysis was performed in the bone marrow at 6 and 8 weeks after the transplantation. The results showed that the proportion of NK cells in the peripheral blood were (4.6 ± 0.6)% and (5.7 ± 1.7)% at week 2 and 3 after anti-CD122 antibody injection respectively,which decreased by 60%, compared with the mice injected with isotype control antibody. After 6 and 8 weeks of cord blood CD34⁺ cell transplantation,the percentage of human CD45⁺ in the bone marrow of the recipient mice treated with anti-mice CD122 antibody was (63.0 ± 12.2)% and (53.2 ± 16.3)%,respectively,which were dramatically higher than that in the mice treated with isotype control antibody (7.7 ± 3.6)% and (6.1 ± 2.4)%. Moreover,at 8 weeks after transplantation,human CD34⁺ cells appeared significantly in the recipients treated with anti-CD122 antibody. It is concluded that the anti-mouse CD122 antibody enhances the hematopoietic repopulating capacity of cord blood CD34⁺ cells in the NOD/SCID mice through decreasing the proportion of NK cells.

Formative Evaluation of MyFit: A Curriculum to Promote Self-Regulation of Physical Activity among Middle School Students

ERIC Educational Resources Information Center

Grim, Melissa; Petosa, Rick; Hortz, Brian; Hunt, Laura

2013-01-01

Background: Previous interventions to increase physical activity among middle school students have not produced long-term results. Often, students lack the self-regulation skills needed to support long-term adherence to physical activity. Purpose: The purpose of this study was to conduct a formative evaluation of a self-regulation based physical…

Short- and Long-Term Theory-Based Predictors of Physical Activity in Women Who Participated in a Weight-Management Program

ERIC Educational Resources Information Center

Wasserkampf, A.; Silva, M. N.; Santos, I. C.; Carraça, E. V.; Meis, J. J. M.; Kremers, S. P. J.; Teixeira, P. J.

2014-01-01

This study analyzed psychosocial predictors of the Theory of Planned Behavior (TPB) and Self-Determination Theory (SDT) and evaluated their associations with short- and long-term moderate plus vigorous physical activity (MVPA) and lifestyle physical activity (PA) outcomes in women who underwent a weight-management program. 221 participants (age…

Factors that Influence Physical Activity in Long-Term Care: Perspectives of Residents, Staff, and Significant Others

ERIC Educational Resources Information Center

Benjamin, Kathleen; Edwards, Nancy; Guitard, Paulette; Murray, Mary Ann; Caswell, Wenda; Perrier, Marie Josee

2011-01-01

Physical activity has been linked to positive health outcomes for frail seniors. However, our understanding of factors that influence the physical activity of residents in the long-term care (LTC) setting is limited. This article describes our work with focus groups, one component of a multi-component study that examined factors influencing the…

The Calmodulin-Binding Transcription Activator CAMTA1 Is Required for Long-Term Memory Formation in Mice

ERIC Educational Resources Information Center

Bas-Orth, Carlos; Tan, Yan-Wei; Oliveira, Ana M. M.; Bengtson, C. Peter; Bading, Hilmar

2016-01-01

The formation of long-term memory requires signaling from the synapse to the nucleus to mediate neuronal activity-dependent gene transcription. Synapse-to-nucleus communication is initiated by influx of calcium ions through synaptic NMDA receptors and/or L-type voltage-gated calcium channels and involves the activation of transcription factors by…

Abnormal neural activities of directional brain networks in patients with long-term bilateral hearing loss.

PubMed

Xu, Long-Chun; Zhang, Gang; Zou, Yue; Zhang, Min-Feng; Zhang, Dong-Sheng; Ma, Hua; Zhao, Wen-Bo; Zhang, Guang-Yu

2017-10-13

The objective of the study is to provide some implications for rehabilitation of hearing impairment by investigating changes of neural activities of directional brain networks in patients with long-term bilateral hearing loss. Firstly, we implemented neuropsychological tests of 21 subjects (11 patients with long-term bilateral hearing loss, and 10 subjects with normal hearing), and these tests revealed significant differences between the deaf group and the controls. Then we constructed the individual specific virtual brain based on functional magnetic resonance data of participants by utilizing effective connectivity and multivariate regression methods. We exerted the stimulating signal to the primary auditory cortices of the virtual brain and observed the brain region activations. We found that patients with long-term bilateral hearing loss presented weaker brain region activations in the auditory and language networks, but enhanced neural activities in the default mode network as compared with normally hearing subjects. Especially, the right cerebral hemisphere presented more changes than the left. Additionally, weaker neural activities in the primary auditor cortices were also strongly associated with poorer cognitive performance. Finally, causal analysis revealed several interactional circuits among activated brain regions, and these interregional causal interactions implied that abnormal neural activities of the directional brain networks in the deaf patients impacted cognitive function.

Long-term moderate exercise accelerates the recovery of stress-evoked cardiovascular responses.

PubMed

Hsu, Yuan-Chang; Tsai, Sheng-Feng; Yu, Lung; Chuang, Jih-Ing; Wu, Fong-Sen; Jen, Chauying J; Kuo, Yu-Min

2016-01-01

Psychological stress is an important global health problem. It is well documented that stress increases the incidences of various cardiovascular disorders. Regular exercise is known to reduce resting blood pressure (BP) and heart rate (HR). This study was designed to clarify the effects of long-term exercise on stress-evoked cardiovascular responses and to emphasize post-stress recovery effects. Male Wistar rats underwent 8 weeks of moderate treadmill training, with cardiovascular responses, autonomic nervous system activities and local Fos reactivity changes in the cardiovascular regulation center were monitored before, during and after immobilization stress. A spectral analysis of cardiovascular parameters was used to examine autonomic nervous activities. We found that long-term exercise (i) lowered resting BP, HR and sympathetic activity, but increased resting parasympathetic activity and baroreflex sensitivity (BRS); (ii) accelerated post-stress recovery of stress-evoked cardiovascular and sympathetic responses along with increased BRS and (iii) accelerated post-stress recovery of stress-evoked neuron activations in the paraventricular nucleus, but delayed it in the nucleus of the tractus solitarius. We conclude that, in rats, long-term exercise accelerated recovery of stress-evoked cardiovascular responses differentially altering hypothalamic and medullar neuron activities.

Low-power sensor module for long-term activity monitoring.

PubMed

Leuenberger, Kaspar; Gassert, Roger

2011-01-01

Wearable sensor modules are a promising approach to collecting data on functional motor activities, both for repeated and long-term assessments, as well as to investigate the transfer of therapy to activities of daily living at home, but have so far either had limited sensing capabilities, or were not laid out for long-term monitoring. This paper presents ReSense, a miniature sensor unit optimized for long-term monitoring of functional activity. Inertial MEMS sensors capture accelerations along six degrees of freedom and a barometric pressure sensor serves as a precise altimeter. Data is written to an integrated memory card. The realized module measures Ø25 × 10 mm, weighs 10 g and can record continuously for 27 h at 25 Hz and over 22 h at 100 Hz. The integrated power-management system detects inactivity and extends the operating time by about a factor of two, as shown by initial 24 h recordings on five energetic healthy adults. The integrated barometric pressure sensor allowed to identify activities incorporating a change in altitude, such as going up/down stairs or riding an elevator. By taking into account data from the inertial sensors during the altitude changes, it becomes possible to distinguish between these two activities.

The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory.

PubMed

Giovannini, Maria Grazia; Lana, Daniele; Pepeu, Giancarlo

2015-03-01

The purpose of this review is to summarize the present knowledge on the interplay among the cholinergic system, Extracellular signal-Regulated Kinase (ERK) and Mammalian Target of Rapamycin (mTOR) pathways in the development of short and long term memories during the acquisition and recall of the step-down inhibitory avoidance in the hippocampus. The step-down inhibitory avoidance is a form of associative learning that is acquired in a relatively simple one-trial test through several sensorial inputs. Inhibitory avoidance depends on the integrated activity of hippocampal CA1 and other brain areas. Recall can be performed at different times after acquisition, thus allowing for the study of both short and long term memory. Among the many neurotransmitter systems involved, the cholinergic neurons that originate in the basal forebrain and project to the hippocampus are of crucial importance in inhibitory avoidance processes. Acetylcholine released from cholinergic fibers during acquisition and/or recall of behavioural tasks activates muscarinic and nicotinic acetylcholine receptors and brings about a long-lasting potentiation of the postsynaptic membrane followed by downstream activation of intracellular pathway (ERK, among others) that create conditions favourable for neuronal plasticity. ERK appears to be salient not only in long term memory, but also in the molecular mechanisms underlying short term memory formation in the hippocampus. Since ERK can function as a biochemical coincidence detector in response to extracellular signals in neurons, the activation of ERK-dependent downstream effectors is determined, in part, by the duration of ERK phosphorylation itself. Long term memories require protein synthesis, that in the synapto-dendritic compartment represents a direct mechanism that can produce rapid changes in protein content in response to synaptic activity. mTOR in the brain regulates protein translation in response to neuronal activity, thereby modulating synaptic plasticity and long term memory formation. Some studies demonstrate a complex interplay among the cholinergic system, ERK and mTOR. It has been shown that co-activation of muscarinic acetylcholine receptors and β-adrenergic receptors facilitates the conversion of short term to long term synaptic plasticity through an ERK- and mTOR-dependent mechanism which requires translation initiation. It seems therefore that the complex interplay among the cholinergic system, ERK and mTOR is crucial in the development of new inhibitory avoidance memories in the hippocampus. Copyright © 2015 Elsevier Inc. All rights reserved.

Proteasome expression and activity in cancer and cancer stem cells.

PubMed

Voutsadakis, Ioannis A

2017-03-01

Proteasome is a multi-protein organelle that participates in cellular proteostasis by destroying damaged or short-lived proteins in an organized manner guided by the ubiquitination signal. By being in a central place in the cellular protein complement homeostasis, proteasome is involved in virtually all cell processes including decisions on cell survival or death, cell cycle, and differentiation. These processes are important also in cancer, and thus, the proteasome is an important regulator of carcinogenesis. Cancers include a variety of cells which, according to the cancer stem cell theory, descend from a small percentage of cancer stem cells, alternatively termed tumor-initiating cells. These cells constitute the subsets that have the ability to propagate the whole variety of cancer and repopulate tumors after cytostatic therapies. Proteasome plays a role in cellular processes in cancer stem cells, but it has been found to have a decreased function in them compared to the rest of cancer cells. This article will discuss the transcriptional regulation of proteasome sub-unit proteins in cancer and in particular cancer stem cells and the relationship of the proteasome with the pluripotency that is the defining characteristic of stem cells. Therapeutic opportunities that present from the understanding of the proteasome role will also be discussed.

Planning the Transition to Long-Term Stewardship for the River Corridor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cearlock, C.S.; Lerch, J.A.; Sands, J.P.

2007-07-01

Long-term stewardship refers to all activities necessary to ensure protection of human health and the environment following completion of remediation, disposal, or stabilization of a site or a portion of a site. Efforts to establish the proposed approach and criteria to be met for long-term stewardship in the river corridor of the Hanford Site in Richland, Washington, are currently being established and a draft plan is expected to be completed in mid-2007 to facilitate planning for a smooth and seamless transition to long-term stewardship. Once the initial criteria have been established, supporting information will be gathered as the work proceeds.more » Near the end of cleanup actions under the River Corridor Closure Contract, these criteria will be finalized in a long-term stewardship plan that documents how the criteria have been met. In addition, the final long-term stewardship plan will also contain a proposed Finding of Suitability to Transfer in accordance with Comprehensive Environmental Response, Compensation, and Liability Act of 1980 Section 120(h) [1]. This final long-term stewardship plan will provide the foundation for post-River Corridor Closure Contract and management activities in the river corridor pending actual property transfer from the U.S. Department of Energy. (authors)« less

Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs

PubMed Central

Boyd, Allison L.; Campbell, Clinton J.V.; Hopkins, Claudia I.; Fiebig-Comyn, Aline; Russell, Jennifer; Ulemek, Jelena; Foley, Ronan; Leber, Brian; Xenocostas, Anargyros; Collins, Tony J.

2014-01-01

Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC–niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients. PMID:25180064

β-Arrestin2 mediates progression of murine primary myelofibrosis

PubMed Central

Rein, Lindsay A.M.; Wisler, James W.; Kim, Jihee; Theriot, Barbara; Huang, LiYin; Price, Trevor; Yang, Haeyoon; Chen, Wei; Sipkins, Dorothy; Fedoriw, Yuri; Walker, Julia K.L.; Premont, Richard T.; Lefkowitz, Robert J.

2017-01-01

Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2–/–) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2–/– cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2–/– cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease. PMID:29263312

Gibbon (Hylobates lar) reintroduction success in Phuket, Thailand, and its conservation benefits.

PubMed

Osterberg, Petra; Samphanthamit, Phamon; Maprang, Owart; Punnadee, Suwit; Brockelman, Warren Y

2015-05-01

We summarize the results from a long-term gibbon reintroduction project in Phuket, Thailand, and evaluate its benefits to conservation. Between October 2002 and November 2012, eight breeding families of white-handed gibbons (Hylobates lar) were returned to the wild in Khao Phra Thaew non-hunting area (KPT). Wild gibbons were extirpated from Phuket Island by the early 1980s, but the illegal wildlife trade has continued to bring young gibbons from elsewhere to the island's popular tourist areas as pets and photo props. The Gibbon Rehabilitation Project (GRP) has rescued and rehabilitated confiscated and donated captive gibbons since 1992 and aims to repopulate the island's last sizable forest area. Following unsuccessful early attempts at translocation in the 1990s, GRP has now developed specific methods for gibbon reintroduction that have led to the establishment of a small independent, reproducing population of captive-raised and wild-born gibbons on Phuket. Eleven infants have been born wild within the reintroduced population, including a second generation wild-born gibbon in September 2012. Benefits of the GRP project include restoration of the gibbon population on Phuket, rescue of illegally kept gibbons, public education, training of personnel in gibbon conservation work, and gaining experience which may prove useful in saving more severely threatened species. It is unlikely that gibbon (and other large primate) translocations will make a significant contribution to conservation of the species as a whole, and primate translocation projects should not be judged solely by this criterion. © 2015 Wiley Periodicals, Inc.

Characteristics of a long-term forest soil productivity research site in Missouri

Treesearch

Felix, Jr. Ponder; Nancy M. Mikkelson

1995-01-01

Problems with soil quality and maintenance of soil productivity occur when management activities are improperly planned and carried out. To ensure that Forest Service management practices do not reduce long-term soil productivity (LTSP), a network of coordinated long-term experiments is being established across the United States. The first LTSP study in the Central...

75 FR 76617 - Use of Community Development Loans by Community Financial Institutions To Secure Advances...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-09

... long term advances to CFI members for purposes of financing community development activities. Section... provided that a Bank could make a long-term advance to a member only for the purposes of providing funds to the member for residential housing finance, except that it also allowed long-term advances to CFI...

Evolution of collaboration within the US long term ecological research network

Treesearch

Jeffrey C. Johnson; Robert R. Christian; James W. Brunt; Caleb R. Hickman; Robert B. Waide

2010-01-01

The US Long Term Ecological Research (LTER) program began in 1980 with the mission of addressing long-term ecological phenomena through research at individual sites, as well as comparative and synthetic activities among sites. We applied network science measures to assess how the LTER program has achieved its mission using intersite publications as the measure of...

Environmental mutagenesis during the end-Permian ecological crisis.

PubMed

Visscher, Henk; Looy, Cindy V; Collinson, Margaret E; Brinkhuis, Henk; van Konijnenburg-van Cittert, Johanna H A; Kürschner, Wolfram M; Sephton, Mark A

2004-08-31

During the end-Permian ecological crisis, terrestrial ecosystems experienced preferential dieback of woody vegetation. Across the world, surviving herbaceous lycopsids played a pioneering role in repopulating deforested terrain. We document that the microspores of these lycopsids were regularly released in unseparated tetrads indicative of failure to complete the normal process of spore development. Although involvement of mutation has long been hinted at or proposed in theory, this finding provides concrete evidence for chronic environmental mutagenesis at the time of global ecological crisis. Prolonged exposure to enhanced UV radiation could account satisfactorily for a worldwide increase in land plant mutation. At the end of the Permian, a period of raised UV stress may have been the consequence of severe disruption of the stratospheric ozone balance by excessive emission of hydrothermal organohalogens in the vast area of Siberian Traps volcanism. Copyright 2004 The National Academy of Sciencs of the USA

Short- and long-term theory-based predictors of physical activity in women who participated in a weight-management program.

PubMed

Wasserkampf, A; Silva, M N; Santos, I C; Carraça, E V; Meis, J J M; Kremers, S P J; Teixeira, P J

2014-12-01

This study analyzed psychosocial predictors of the Theory of Planned Behavior (TPB) and Self-Determination Theory (SDT) and evaluated their associations with short- and long-term moderate plus vigorous physical activity (MVPA) and lifestyle physical activity (PA) outcomes in women who underwent a weight-management program. 221 participants (age 37.6 ± 7.02 years) completed a 12-month SDT-based lifestyle intervention and were followed-up for 24 months. Multiple linear regression analyses tested associations between psychosocial variables and self-reported short- and long-term PA outcomes. Regression analyses showed that control constructs of both theories were significant determinants of short- and long-term MVPA, whereas affective and self-determination variables were strong predictors of short- and long-term lifestyle PA. Regarding short-term prediction models, TPB constructs were stronger in predicting MVPA, whereas SDT was more effective in predicting lifestyle PA. For long-term models, both forms of PA were better predicted by SDT in comparison to TPB. These results highlight the importance of comparing health behavior theories to identify the mechanisms involved in the behavior change process. Control and competence constructs are crucial during early adoption of structured PA behaviors, whereas affective and intrinsic sources of motivation are more involved in incidental types of PA, particularly in relation to behavioral maintenance. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Hilbert-Huang transform analysis of long-term solar magnetic activity

NASA Astrophysics Data System (ADS)

Deng, Linhua

2018-04-01

Astronomical time series analysis is one of the hottest and most important problems, and becomes the suitable way to deal with the underlying dynamical behavior of the considered nonlinear systems. The quasi-periodic analysis of solar magnetic activity has been carried out by various authors during the past fifty years. In this work, the novel Hilbert-Huang transform approach is applied to investigate the yearly numbers of polar faculae in the time interval from 1705 to 1999. The detected periodicities can be allocated to three components: the first one is the short-term variations with periods smaller than 11 years, the second one is the mid- term variations with classical periods from 11 years to 50 years, and the last one is the long-term variations with periods larger than 50 years. The analysis results improve our knowledge on the quasi-periodic variations of solar magnetic activity and could be provided valuable constraints for solar dynamo theory. Furthermore, our analysis results could be useful for understanding the long-term variations of solar magnetic activity, providing crucial information to describe and forecast solar magnetic activity indicators.

'Enzyme Test Bench': A biochemical application of the multi-rate modeling

NASA Astrophysics Data System (ADS)

Rachinskiy, K.; Schultze, H.; Boy, M.; Büchs, J.

2008-11-01

In the expanding field of 'white biotechnology' enzymes are frequently applied to catalyze the biochemical reaction from a resource material to a valuable product. Evolutionary designed to catalyze the metabolism in any life form, they selectively accelerate complex reactions under physiological conditions. Modern techniques, such as directed evolution, have been developed to satisfy the increasing demand on enzymes. Applying these techniques together with rational protein design, we aim at improving of enzymes' activity, selectivity and stability. To tap the full potential of these techniques, it is essential to combine them with adequate screening methods. Nowadays a great number of high throughput colorimetric and fluorescent enzyme assays are applied to measure the initial enzyme activity with high throughput. However, the prediction of enzyme long term stability within short experiments is still a challenge. A new high throughput technique for enzyme characterization with specific attention to the long term stability, called 'Enzyme Test Bench', is presented. The concept of the Enzyme Test Bench consists of short term enzyme tests conducted under partly extreme conditions to predict the enzyme long term stability under moderate conditions. The technique is based on the mathematical modeling of temperature dependent enzyme activation and deactivation. Adapting the temperature profiles in sequential experiments by optimum non-linear experimental design, the long term deactivation effects can be purposefully accelerated and detected within hours. During the experiment the enzyme activity is measured online to estimate the model parameters from the obtained data. Thus, the enzyme activity and long term stability can be calculated as a function of temperature. The results of the characterization, based on micro liter format experiments of hours, are in good agreement with the results of long term experiments in 1L format. Thus, the new technique allows for both: the enzyme screening with regard to the long term stability and the choice of the optimal process temperature. The presented article gives a successful example for the application of multi-rate modeling, experimental design and parameter estimation within biochemical engineering. At the same time, it shows the limitations of the methods at the state of the art and addresses the current problems to the applied mathematics community.

A critical review of sex differences in decision-making tasks: focus on the Iowa Gambling Task.

PubMed

van den Bos, Ruud; Homberg, Judith; de Visser, Leonie

2013-02-01

It has been observed that men and women show performance differences in the Iowa Gambling Task (IGT), a task of decision-making in which subjects through exploration learn to differentiate long-term advantageous from long-term disadvantageous decks of cards: men choose more cards from the long-term advantageous decks than women within the standard number of 100 trials. Here, we aim at discussing psychological mechanisms and neurobiological substrates underlying sex differences in IGT-like decision-making. Our review suggests that women focus on both win-loss frequencies and long-term pay-off of decks, while men focus on long-term pay-off. Furthermore, women may be more sensitive to occasional losses in the long-term advantageous decks than men. As a consequence hereof, women need 40-60 trials in addition before they reach the same level of performance as men. These performance differences are related to differences in activity in the orbitofrontal cortex and dorsolateral prefrontal cortex as well as in serotonergic activity and left-right hemispheric activity. Sex differences in orbitofrontal cortex activity may be due to organisational effects of gonadal hormones early in life. The behavioural and neurobiological differences in the IGT between men and women are an expression of more general sex differences in the regulation of emotions. We discuss these findings in the context of sex differences in information processing related to evolutionary processes. Furthermore we discuss the relationship between these findings and real world decision-making. Copyright © 2012 Elsevier B.V. All rights reserved.

Altered neural processing of emotional faces in remitted Cushing's disease.

PubMed

Bas-Hoogendam, Janna Marie; Andela, Cornelie D; van der Werff, Steven J A; Pannekoek, J Nienke; van Steenbergen, Henk; Meijer, Onno C; van Buchem, Mark A; Rombouts, Serge A R B; van der Mast, Roos C; Biermasz, Nienke R; van der Wee, Nic J A; Pereira, Alberto M

2015-09-01

Patients with long-term remission of Cushing's disease (CD) demonstrate residual psychological complaints. At present, it is not known how previous exposure to hypercortisolism affects psychological functioning in the long-term. Earlier magnetic resonance imaging (MRI) studies demonstrated abnormalities of brain structure and resting-state connectivity in patients with long-term remission of CD, but no data are available on functional alterations in the brain during the performance of emotional or cognitive tasks in these patients. We performed a cross-sectional functional MRI study, investigating brain activation during emotion processing in patients with long-term remission of CD. Processing of emotional faces versus a non-emotional control condition was examined in 21 patients and 21 matched healthy controls. Analyses focused on activation and connectivity of two a priori determined regions of interest: the amygdala and the medial prefrontal-orbitofrontal cortex (mPFC-OFC). We also assessed psychological functioning, cognitive failure, and clinical disease severity. Patients showed less mPFC activation during processing of emotional faces compared to controls, whereas no differences were found in amygdala activation. An exploratory psychophysiological interaction analysis demonstrated decreased functional coupling between the ventromedial PFC and posterior cingulate cortex (a region structurally connected to the PFC) in CD-patients. The present study is the first to show alterations in brain function and task-related functional coupling in patients with long-term remission of CD relative to matched healthy controls. These alterations may, together with abnormalities in brain structure, be related to the persisting psychological morbidity in patients with CD after long-term remission. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gold nanoparticles alter parameters of oxidative stress and energy metabolism in organs of adult rats.

PubMed

Ferreira, Gabriela Kozuchovski; Cardoso, Eria; Vuolo, Francieli Silva; Michels, Monique; Zanoni, Elton Torres; Carvalho-Silva, Milena; Gomes, Lara Mezari; Dal-Pizzol, Felipe; Rezin, Gislaine Tezza; Streck, Emilio L; Paula, Marcos Marques da Silva

2015-12-01

This study evaluated the parameters of oxidative stress and energy metabolism after the acute and long-term administration of gold nanoparticles (GNPs, 10 and 30 nm in diameter) in different organs of rats. Adult male Wistar rats received a single intraperitoneal injection or repeated injections (once daily for 28 days) of saline solution, GNPs-10 or GNPs-30. Twenty-four hours after the last administration, the animals were killed, and the liver, kidney, and heart were isolated for biochemical analysis. We demonstrated that acute administration of GNPs-30 increased the TBARS levels, and that GNPs-10 increased the carbonyl protein levels. The long-term administration of GNPs-10 increased the TBARS levels, and the carbonyl protein levels were increased by GNPs-30. Acute administration of GNPs-10 and GNPs-30 increased SOD activity. Long-term administration of GNPs-30 increased SOD activity. Acute administration of GNPs-10 decreased the activity of CAT, whereas long-term administration of GNP-10 and GNP-30 altered CAT activity randomly. Our results also demonstrated that acute GNPs-30 administration decreased energy metabolism, especially in the liver and heart. Long-term GNPs-10 administration increased energy metabolism in the liver and decreased energy metabolism in the kidney and heart, whereas long-term GNPs-30 administration increased energy metabolism in the heart. The results of our study are consistent with other studies conducted in our research group and reinforce the fact that GNPs can lead to oxidative damage, which is responsible for DNA damage and alterations in energy metabolism.

Effects of long-term resveratrol-induced SIRT1 activation on insulin and apoptotic signalling in aged skeletal muscle.

PubMed

Sin, Thomas K; Yu, Angus P; Yung, Benjamin Y; Yip, Shea P; Chan, Lawrence W; Wong, Cesar S; Rudd, John A; Siu, Parco M

2015-12-01

Activation of Foxo1 is known to promote apoptosis and disturbances to insulin signalling. However, their modulating roles in aged skeletal muscle are not clear. The present study tested the hypothesis that long-term (i.e. 8 month) resveratrol supplementation would improve physical traits including exercise capacity and basal voluntary activity of aged mice and modulate insulin/apoptotic signalling in aged skeletal muscle. This study also examined whether these resveratrol-associated alterations would involve orchestration of the SIRT1-Foxo1 signalling axis. Two-month-old SAMP8 mice were randomly assigned to young, aged and aged with resveratrol treatment (AR) groups. The AR mice were supplemented with 4.9 mg(-1) kg(-1) day(-1) resveratrol for 8 months. All animals were subject to endurance capacity test and voluntary motor behaviour assessment. The lateral gastrocnemius muscle tissues were harvested for further analyses. Long-term resveratrol treatment significantly alleviated the age-associated reductions in exercise capacity and voluntary motor behaviour. The protein content, but not the deacetylase activity of SIRT1 was increased with concomitant elevations of p300 acetylase and acetylation of Foxo1 in aged muscle. The aged muscle also manifested signs of impaired insulin signalling including attenuated phosphorylation of Akt, activity of pyruvate dehydrogenase and membrane trafficking of GLUT4 and elevated levels of phosphorylated IRS1 and iNOS and apoptotic activation measured as Bim, p53 and apoptotic DNA fragmentation. Intriguingly, all these age-related adverse changes were mitigated with the activation of SIRT1 deacetylase activity after long-term resveratrol treatment. These data suggest that modulation of the SIRT1-Foxo1 axis by long-term resveratrol treatment enhances physical traits and alleviates the unfavourable changes in insulin and apoptotic signalling in aged muscle.

Beta-Adrenergic Receptor Activation during Distinct Patterns of Stimulation Critically Modulates the PKA-Dependence of LTP in the Mouse Hippocampus

ERIC Educational Resources Information Center

Gelinas, Jennifer N.; Tenorio, Gustavo; Lemon, Neal; Abel, Ted; Nguyen, Peter V.

2008-01-01

Activation of Beta-adrenergic receptors (Beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to Beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms…

Acute myeloid leukemia-targeted toxin activates both apoptotic and necroptotic death mechanisms.

PubMed

Horita, Henrick; Frankel, Arthur E; Thorburn, Andrew

2008-01-01

Acute myelogenous leukemia (AML) is the second most common leukemia with approximately 13,410 new cases and 8,990 deaths annually in the United States. A novel fusion toxin treatment, diphtheria toxin GM-CSF (DT-GMCSF) has been shown to selectively eliminate leukemic repopulating cells that are critical for the formation of AML. We previously showed that DT-GMCSF treatment of U937 cells, an AML cell line, causes activation of caspases and the induction of apoptosis. In this study we further investigate the mechanisms of cell death induced by DT-GMCSF and show that, in addition to the activation of caspase-dependent apoptosis, DT-GMCSF also kills AML cells by simultaneously activating caspase-independent necroptosis. These mechanisms depend on the ability of the targeted toxin to inhibit protein synthesis, and are not affected by the receptor that is targeted or the mechanism through which protein synthesis is blocked. We conclude that fusion toxin proteins may be effective for treating AML cells whether or not they are defective in apoptosis.

Reduced insulin-like growth factor-I serum levels in formerly obese women subjected to laparoscopic-adjustable gastric banding or diet-induced long-term caloric restriction.

PubMed

Mitterberger, Maria C; Mattesich, Monika; Klaver, Elise; Piza-Katzer, Hildegunde; Zwerschke, Werner

2011-11-01

Life-span extension in laboratory rodents induced by long-term caloric restriction correlates with decreased serum insulin-like growth factor-I (IGF-I) levels. Reduced activity of the growth hormone/IGF-I signaling system slows aging and increases longevity in mutant mouse models. In the present study, we show that long-term caloric restriction achieved by two different interventions for 4 years, either laparoscopic-adjustable gastric banding or reducing diet, leads to reduced IGF-I serum levels in formerly obese women relative to normal-weight women eating ad libitum. Moreover, we present evidence that the long-term caloric restriction interventions reduce fasting growth hormone serum levels. The present study indicates that the activity of the growth hormone/IGF-I axis is reduced in long-term calorically restricted formerly obese humans. Furthermore, our findings suggest that the duration and severity of the caloric restriction intervention are important for the outcome on the growth hormone/IGF-I axis in humans.

Forward Inferences: From Activation to Long-Term Memory.

ERIC Educational Resources Information Center

Klin, Celia M.; Murray, John D.; Levine, William H.; Guzman, Alexandria E.

1999-01-01

Investigates the extent to which forward inferences are activated and encoded during reading, as well as their prevalence and their time course. Finds that inferences were encoded and retained in working memory in both high- and low-predictability conditions, and that high-predictability forward inferences were encoded into long-term memory.…

Long-term Variations of The Solar Activity -- Lower Atmosphere Relationship

NASA Astrophysics Data System (ADS)

Zaitseva, S.; Akhremtchik, S.; Pudovkin, M.; Besser, B.; Rijnbeek, R.

Long-term variations of the air temperature in St.Petersburg, Stockholm, Salzburg and English Midlands are considered. There is shown that in the regions under consider- ation the air temperature distinctly depends on the intensity of the lower atmospheric zonal circulation (Blinova index and North Atlantic Oscillation index (NAO)). In turn, the NAO-index is shown to depend on the solar activity. However, this dependence is rather complicated and exhibits long-period variations associated with secular varia- tions of the solar activity. A possible mechanism of this phenomena is discussed.

A systematic review of the evidence regarding efficacy of obesity prevention interventions among adults.

PubMed

Lemmens, V E P P; Oenema, A; Klepp, K I; Henriksen, H B; Brug, J

2008-09-01

In the past, interventions aimed at reducing obesity have mainly targeted at weight loss treatment in obese adults, with limited long-term effects. With the increasing number of people being obese and being at risk for obesity, there has been a shift in focus towards prevention of obesity. We conducted a systematic review of the peer-reviewed literature on the efficacy of obesity prevention interventions in adults in order to identify effective interventions and intervention elements. Pubmed, OVID, and Web of Science databases were searched from January 1996 to June 2006. Interventions aimed at primary prevention of weight gain among adults achieved by focusing on dietary intake, physical activity or the combination of both were included. The outcome measure had to be difference in change in body mass index or body weight between the intervention and the control groups. Nine studies were included, five long-term studies (at least 1 year) and four short-term (3 months to 1 year). Seven studies evaluated an intervention that focused on a combination of diet and physical activity to prevent weight gain, one on diet only and one on physical activity only. One dietary intervention (long-term), and three combined dietary and physical activity interventions (one long-term and two short-term) produced significantly positive results at end of follow-up. The two long-term, effective interventions consisted of intensive and long-term intervention implementation, including groups sessions designed to promote behavioural changes. The current evidence of efficacy of obesity prevention interventions is based on a very small number of studies. Some studies showed a positive impact on body mass index or weight status, but there was too much heterogeneity in terms of study design, theoretical underpinning and target population to draw firm conclusions about which intervention approaches are more effective than others. More research is urgently needed to extend the body of evidence.

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice

PubMed Central

Tsokas, Panayiotis; Hsieh, Changchi; Yao, Yudong; Lesburguères, Edith; Wallace, Emma Jane Claire; Tcherepanov, Andrew; Jothianandan, Desingarao; Hartley, Benjamin Rush; Pan, Ling; Rivard, Bruno; Farese, Robert V; Sajan, Mini P; Bergold, Peter John; Hernández, Alejandro Iván; Cottrell, James E; Shouval, Harel Z; Fenton, André Antonio; Sacktor, Todd Charlton

2016-01-01

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice. DOI: http://dx.doi.org/10.7554/eLife.14846.001 PMID:27187150

A Relationship between Reduced Nucleus Accumbens Shell and Enhanced Lateral Hypothalamic Orexin Neuronal Activation in Long-Term Fructose Bingeing Behavior

PubMed Central

Rorabaugh, Jacki M.; Stratford, Jennifer M.; Zahniser, Nancy R.

2014-01-01

Fructose accounts for 10% of daily calories in the American diet. Fructose, but not glucose, given intracerebroventricularly stimulates homeostatic feeding mechanisms within the hypothalamus; however, little is known about how fructose affects hedonic feeding centers. Repeated ingestion of sucrose, a disaccharide of fructose and glucose, increases neuronal activity in hedonic centers, the nucleus accumbens (NAc) shell and core, but not the hypothalamus. Rats given glucose in the intermittent access model (IAM) display signatures of hedonic feeding including bingeing and altered DA receptor (R) numbers within the NAc. Here we examined whether substituting fructose for glucose in this IAM produces bingeing behavior, alters DA Rs and activates hedonic and homeostatic feeding centers. Following long-term (21-day) exposure to the IAM, rats given 8–12% fructose solutions displayed fructose bingeing but unaltered DA D1R or D2R number. Fructose bingeing rats, as compared to chow bingeing controls, exhibited reduced NAc shell neuron activation, as determined by c-Fos-immunoreactivity (Fos-IR). This activation was negatively correlated with orexin (Orx) neuron activation in the lateral hypothalamus/perifornical area (LH/PeF), a brain region linking homeostatic to hedonic feeding centers. Following short-term (2-day) access to the IAM, rats exhibited bingeing but unchanged Fos-IR, suggesting only long-term fructose bingeing increases Orx release. In long-term fructose bingeing rats, pretreatment with the Ox1R antagonist SB-334867 (30 mg/kg; i.p.) equally reduced fructose bingeing and chow intake, resulting in a 50% reduction in calories. Similarly, in control rats, SB-334867 reduced chow/caloric intake by 60%. Thus, in the IAM, Ox1Rs appear to regulate feeding based on caloric content rather than palatability. Overall, our results, in combination with the literature, suggest individual monosaccharides activate distinct neuronal circuits to promote feeding behavior. Specifically, long-term fructose bingeing activates a hyperphagic circuit composed in part of NAc shell and LH/PeF Orx neurons. PMID:24736531

Uncovering Camouflage: Amygdala Activation Predicts Long-Term Memory of Induced Perceptual Insight

PubMed Central

Ludmer, Rachel; Dudai, Yadin; Rubin, Nava

2012-01-01

What brain mechanisms underlie learning of new knowledge from single events? We studied encoding in long-term memory of a unique type of one-shot experience, induced perceptual insight. While undergoing an fMRI brain scan, participants viewed degraded images of real-world pictures where the underlying objects were hard to recognize (‘camouflage’), followed by brief exposures to the original images (‘solution’), which led to induced insight (“Aha!”). A week later, participants’ memory was tested; a solution image was classified as ‘remembered’ if detailed perceptual knowledge was elicited from the camouflage image alone. During encoding, subsequently remembered images enjoyed higher activity in mid-level visual cortex and medial frontal cortex, but most pronouncedly in the amygdala, whose activity could be used to predict which solutions will remain in long-term memory. Our findings extend the known roles of amygdala in memory to include promoting of long-term memory of the sudden reorganization of internal representations. PMID:21382558

Recent advances in CO2 laser catalysts

NASA Technical Reports Server (NTRS)

Upchurch, B. T.; Schryer, D. R.; Brown, K. G.; Kielin, E. J.; Hoflund, G. B.; Gardner, S. D.

1991-01-01

This paper discusses several recent advances in CO2 laser catalysts including comparisons of the activity of Au/MnO2 to Pt/SnO2 catalysts with possible explanations for observed differences. The catalysts are compared for the effect of test gas composition, pretreatment temperature, isotopic integrity, long term activity, and gold loading effects on the Au/MnO2 catalyst activity. Tests conducted to date include both long-term tests of up to six months continuous operation and short-term tests of one week or more that include isotopic integrity testing.

Physical activity for prevention of osteoporosis in patients with severe haemophilia on long-term prophylaxis.

PubMed

Khawaji, M; Astermark, J; Akesson, K; Berntorp, E

2010-05-01

Physical activity has been considered as an important factor for bone density and as a factor facilitating prevention of osteoporosis. Bone density has been reported to be reduced in haemophilia. To examine the relation between different aspects of physical activity and bone mineral density (BMD) in patients with severe haemophilia on long-term prophylaxis. The study group consisted of 38 patients with severe haemophilia (mean age 30.5 years). All patients received long-term prophylaxis to prevent bleeding. The bone density (BMD g cm(-2)) of the total body, lumbar spine, total hip, femoral neck and trochanter was measured by dual energy X-ray absorptiometry. Physical activity was assessed using the self-report Modifiable Activity Questionnaire, an instrument which collects information about leisure and occupational activities for the prior 12 months. There was only significant correlation between duration and intensity of vigorous physical activity and bone density at lumber spine L1-L4; for duration (r = 0.429 and P = 0.020) and for intensity (r = 0.430 and P = 0.019); whereas no significant correlation between all aspects of physical activity and bone density at any other measured sites. With adequate long-term prophylaxis, adult patients with haemophilia are maintaining bone mass, whereas the level of physical activity in terms of intensity and duration play a minor role. These results may support the proposition that the responsiveness to mechanical strain is probably more important for bone mass development in children and during adolescence than in adults and underscores the importance of early onset prophylaxis.

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation.

PubMed

Nava-Mesa, Mauricio O; Lamprea, Marisol R; Múnera, Alejandro

2013-11-01

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1 mg/kg naltrexone or 3 mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects' dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory. Copyright © 2013 Elsevier Inc. All rights reserved.

T-Cell-Mediated Immune Responses in Patients with Cutaneous or Mucosal Leishmaniasis: Long-Term Evaluation after Therapy

PubMed Central

Da-Cruz, Alda Maria; Bittar, Rita; Mattos, Marise; Oliveira-Neto, Manuel P.; Nogueira, Ricardo; Pinho-Ribeiro, Vanessa; Azeredo-Coutinho, Rilza Beatriz; Coutinho, Sergio G.

2002-01-01

T-cell immune responses in patients with cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML) were studied during the active disease, at the end of therapy, and 1 to 17 years posttherapy (long-term follow-up). Lymphocyte proliferative responses, phenotypic characterization of CD4+ and CD8+ Leishmania-reactive T cells, and cytokine production were assayed. Patients with active ML and CL showed higher proportions of CD4+ than CD8+ T cells. In CL, the healing process was associated with a decrease of CD4+ and an increase of CD8+, leading to similar CD4+ and CD8+ proportions. This pattern was only seen in ML after long-term therapy. Long-term follow-up of patients with CL showed a positive CD4+/CD8+ ratio as observed during the active disease, although the percentages of these T cell subsets were significantly lower. Patients with CL did not show significant differences between gamma interferon (IFN-γ) and interleukin-5 (IL-5) production during the period of study. Patients with active ML presented higher IFN-γ and IL-5 levels compared to patients with active CL. IL-4 was only detected during active disease. Patients long term after cure from ML showed increasing production of IFN-γ, significant decrease of IL-5, and no IL-4 production. Two apparently beneficial immunological parameters were detected in tegumentary leishmaniasis: (i) decreasing proportions of CD4+ Leishmania-reactive T cells in the absence of IL-4 production associated with cure of CL and ML and (ii) decreasing levels of IL-5 long after cure, better detected in patients with ML. The observed T-cell responses maintained for a long period in healed patients could be relevant for immunoprotection against reinfection and used as a parameter for determining the prognosis of patients and selecting future vaccine preparations. PMID:11874860

Effect of long-term industrial waste effluent pollution on soil enzyme activities and bacterial community composition.

PubMed

Subrahmanyam, Gangavarapu; Shen, Ju-Pei; Liu, Yu-Rong; Archana, Gattupalli; Zhang, Li-Mei

2016-02-01

Although numerous studies have addressed the influence of exogenous pollutants on microorganisms, the effect of long-term industrial waste effluent (IWE) pollution on the activity and diversity of soil bacteria was still unclear. Three soil samples characterized as uncontaminated (R1), moderately contaminated (R2), and highly contaminated (R3) receiving mixed organic and heavy metal pollutants for more than 20 years through IWE were collected along the Mahi River basin, Gujarat, western India. Basal soil respiration and in situ enzyme activities indicated an apparent deleterious effect of IWE on microbial activity and soil function. Community composition profiling of soil bacteria using 16S rRNA gene amplification and denaturing gradient gel electrophoresis (DGGE) method indicated an apparent bacterial community shift in the IWE-affected soils. Cloning and sequencing of DGGE bands revealed that the dominated bacterial phyla in polluted soil were affiliated with Firmicutes, Acidobacteria, and Actinobacteria, indicating that these bacterial phyla may have a high tolerance to pollutants. We suggested that specific bacterial phyla along with soil enzyme activities could be used as relevant biological indicators for long-term pollution assessment on soil quality. Graphical Abstract Bacterial community profiling and soil enzyme activities in long-term industrial waste effluent polluted soils.

Examining Long-Term Global Climate Change on the Web.

ERIC Educational Resources Information Center

Huntoon, Jacqueline E.; Ridky, Robert K.

2002-01-01

Describes a web-based, inquiry-oriented activity that enables students to examine long-term global climate change. Supports instruction in other topics such as population growth. (Contains 34 references.) (DDR)

CD8+ lymphocytes are required to maintain virus suppression in SIV-infected macaques treated with short-term antiretroviral therapy

PubMed Central

Cartwright, Emily K.; Spicer, Lori; Smith, S. Abigail; Lee, David; Fast, Randy; Paganini, Sara; Lawson, Benton O.; Nega, Melon; Easley, Kirk; Schmitz, Joern E.; Bosinger, Steven E.; Paiardini, Mirko; Chahroudi, Ann; Vanderford, Thomas H.; Estes, Jacob D.; Lifson, Jeffrey D.; Derdeyn, Cynthia A.; Silvestri, Guido

2016-01-01

Infection with HIV persists despite suppressive antiretroviral therapy (ART) and treatment interruption results in rapid viral rebound. Antibody-mediated CD8+ lymphocyte depletion in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) shows these cells contribute to virus control in untreated animals. However, the contribution of CD8+ lymphocytes to maintaining virus suppression under ART remains unknown. We showed that in SIV-infected RMs treated with short-term ART (i.e., 8-32 weeks), depletion of CD8+ lymphocytes resulted in increased plasma viremia in all animals, and that repopulation of CD8+ T cells was associated with prompt reestablishment of virus control. Although the number of SIV-DNA-positive cells remained unchanged after CD8 depletion and reconstitution, the frequency of SIV-infected CD4+ T cells pre-depletion positively correlated with both peak and area-under-the-curve of viremia post-depletion. These results suggest a role for CD8+ T cells in controlling virus production during ART, thus providing rationale to explore immunotherapeutic approaches in ART-treated HIV-infected individuals. PMID:27653601

Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

NASA Technical Reports Server (NTRS)

Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

2006-01-01

Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low-dose-rate dose to the bone marrow (mean = 2.5 Gy) was consistent with the measured ERR (0.62, 95% Cl =-0.2 to 1.9). Conclusions: An extended, biologically based model for leukemia that includes HSC initiation, inactivation, proliferation, and, uniquely for leukemia, long-range HSC migration predicts, %Kith reasonable accuracy, risks for radiationinduced leukemia associated with exposure to therapeutic doses of radiation.

Mice with chimeric livers are an improved model for human lipoprotein metabolism.

PubMed

Ellis, Ewa C S; Naugler, Willscott Edward; Nauglers, Scott; Parini, Paolo; Mörk, Lisa-Mari; Jorns, Carl; Zemack, Helen; Sandblom, Anita Lövgren; Björkhem, Ingemar; Ericzon, Bo-Göran; Wilson, Elizabeth M; Strom, Stephen C; Grompe, Markus

2013-01-01

Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. FRG [ F ah(-/-) R ag2(-/-)Il2r g (-/-)]) mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL) was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA). Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

Long-term athletic development- part 1: a pathway for all youth.

PubMed

Lloyd, Rhodri S; Oliver, Jon L; Faigenbaum, Avery D; Howard, Rick; De Ste Croix, Mark B A; Williams, Craig A; Best, Thomas M; Alvar, Brent A; Micheli, Lyle J; Thomas, D Phillip; Hatfield, Disa L; Cronin, John B; Myer, Gregory D

2015-05-01

The concept of developing talent and athleticism in youth is the goal of many coaches and sports systems. Consequently, an increasing number of sporting organizations have adopted long-term athletic development models in an attempt to provide a structured approach to the training of youth. It is clear that maximizing sporting talent is an important goal of long-term athletic development models. However, ensuring that youth of all ages and abilities are provided with a strategic plan for the development of their health and physical fitness is also important to maximize physical activity participation rates, reduce the risk of sport- and activity-related injury, and to ensure long-term health and well-being. Critical reviews of independent models of long-term athletic development are already present within the literature; however, to the best of our knowledge, a comprehensive examination and review of the most prominent models does not exist. Additionally, considerations of modern day issues that may impact on the success of any long-term athletic development model are lacking, as are proposed solutions to address such issues. Therefore, within this 2-part commentary, Part 1 provides a critical review of existing models of practice for long-term athletic development and introduces a composite youth development model that includes the integration of talent, psychosocial and physical development across maturation. Part 2 identifies limiting factors that may restrict the success of such models and offers potential solutions.

Participation in Activities Associated With Quality of Life for Long-Term Survivors of Rectal Cancer

PubMed Central

McMullen, Carmit; Liu, Liyan; Bulkley, Joanna E; Hornbrook, Mark C; Wendel, Christopher; Grant, Marcia; Altschuler, Andrea; Temple, Larissa KF; Krouse, Robert S; Herrinton, Lisa

2017-01-01

Context: Cancer patients’ participation in social, recreational, and civic activities is strongly associated with quality of life (QOL), but these activities are not well integrated into cancer survivorship research or interventions. Objective: Test the hypothesis that for long-term (≥ 5 years) survivors of rectal cancer, clinical factors (type of surgery and bowel function) are associated with long-term participation in activities and that participation in activities is associated with long-term QOL. Design: Observational study with longitudinal and cross-sectional components. Main Outcome Measures: Participation in activities and QOL. Tumor registry records were used to identify patients and obtain clinical data; surveys assessed participation and QOL. Using general linear models, we analyzed participation in activities in relation to type of surgery and bowel function after adjustment for potential confounders. We analyzed overall QOL relative to participation in activities after adjustment. Results: A total of 567 rectal cancer survivors completed a mailed questionnaire. Overall response rate was 61%. The type of operation (p < 0.0001), receipt of radiation therapy (p = 0.002), and bowel function (p < 0.0001) were associated with participation in activities. Participation in activities was the strongest predictor of QOL (p < 0.0001), explaining 20% of the variance (R2) in QOL, with all other variables together accounting for another 18% of the variance. Conclusion: The importance of participation in activities on rectal cancer survivors’ QOL is underappreciated. We recommend revising QOL instruments used in cancer care and research to include questions about participation in activities. Interventions should address maintenance of preferred activities and adoption of new, fulfilling activities. PMID:28241904

Participation in Activities Associated With Quality of Life for Long-Term Survivors of Rectal Cancer.

PubMed

Mcmullen, Carmit; Liu, Liyan; Bulkley, Joanna E; Hornbrook, Mark C; Wendel, Christopher; Grant, Marcia; Altschuler, Andrea; Temple, Larissa Kf; Krouse, Robert S; Herrinton, Lisa

2017-01-01

Cancer patients' participation in social, recreational, and civic activities is strongly associated with quality of life (QOL), but these activities are not well integrated into cancer survivorship research or interventions. Test the hypothesis that for long-term (≥ 5 years) survivors of rectal cancer, clinical factors (type of surgery and bowel function) are associated with long-term participation in activities and that participation in activities is associated with long-term QOL. Observational study with longitudinal and cross-sectional components. Participation in activities and QOL. Tumor registry records were used to identify patients and obtain clinical data; surveys assessed participation and QOL. Using general linear models, we analyzed participation in activities in relation to type of surgery and bowel function after adjustment for potential confounders. We analyzed overall QOL relative to participation in activities after adjustment. A total of 567 rectal cancer survivors completed a mailed questionnaire. Overall response rate was 61%. The type of operation (p < 0.0001), receipt of radiation therapy (p = 0.002), and bowel function (p < 0.0001) were associated with participation in activities. Participation in activities was the strongest predictor of QOL (p < 0.0001), explaining 20% of the variance (R 2 ) in QOL, with all other variables together accounting for another 18% of the variance. The importance of participation in activities on rectal cancer survivors' QOL is underappreciated. We recommend revising QOL instruments used in cancer care and research to include questions about participation in activities. Interventions should address maintenance of preferred activities and adoption of new, fulfilling activities.

Few long-term consequences after prolonged maternal separation in female Wistar rats

PubMed Central

Abelson, Klas S. P.; Nylander, Ingrid; Roman, Erika

2017-01-01

Environmental factors during the early-life period are known to have long-term consequences for the adult phenotype. An intimate interplay between genes and environment shape the individual and may affect vulnerability for psychopathology in a sex-dependent manner. A rodent maternal separation model was here used to study the long-term effects of different early-life rearing conditions on adult behavior, HPA axis activity and long-term voluntary alcohol intake in female rats. Litters were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal day 1–21. In adulthood, the behavioral profiles were investigated using the multivariate concentric square field™ (MCSF) test or examined for HPA axis reactivity by cat-odor exposure with subsequent characterization of voluntary alcohol intake and associated changes in HPA axis activity. Adult female MS360 offspring showed mostly no, or only minor, effects on behavior, HPA axis reactivity and long-term alcohol intake relative to MS15. Instead, more pronounced effects were found dependent on changes in the natural hormonal cycle or by the choice of animal supplier. However, changes were revealed in corticosterone load after long-term alcohol access, as females subjected to MS360 had higher concentrations of fecal corticosterone. The present findings are in line with and expand on previous studies on the long-term effects of maternal separation in female rats with regard to behavior, HPA axis activity and voluntary alcohol intake. It can also be a window into further studies detailing how early-life experiences interact with other risk and protective factors to impact the adult phenotype and how possible sex differences play a role. PMID:29267376

Antidepressant-like effects of long-term sarcosine treatment in rats with or without chronic unpredictable stress.

PubMed

Chen, Kuang-Ti; Wu, Ching-Hsiang; Tsai, Mang-Hung; Wu, Ya-Chieh; Jou, Ming-Jia; Huang, Chih-Chia; Wei, I-Hua

2017-01-01

Sarcosine, an N-methyl-d-aspartate receptor enhancer, can improve depression-like behavior in rodent models and depression in humans. We found that a single dose of sarcosine exerted antidepressant-like effects with rapid concomitant increases in the mammalian target of rapamycin (mTOR) signaling pathway activation and enhancement of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR) membrane insertion. Sarcosine may play a crucial role in developing novel therapy for depression. For a detailed understanding of sarcosine, this study examined the effects of long-term sarcosine treatment on the forced swim test (FST), mTOR signaling, and AMPAR membrane insertion in rats. The effects of long-term sarcosine treatment were examined in naive rats and rats exposed to chronic unpredictable stress (CUS). Long-term sarcosine treatment (560mg/kg/d for 21 d) significantly ameliorated the increased immobility induced by CUS in the FST, reaffirming the potential role of sarcosine as an antidepressant for depressed patients. The same long-term treatment exhibited no such effect in naive rats despite increased mTOR activation and AMPAR membrane insertion in both groups. Our findings clearly show CUS-exposed rats are sensitive to long-term sarcosine treatment in FST and the response at the same dose is absent in naïve rats. Nevertheless, the distinct sensitivity to long-term sarcosine treatment in rats with or without CUS is not associated with the activated mTOR signaling pathway or increased AMPAR membrane insertion. Additionally, understanding the behavioral and molecular basis of distinct responses is vital important for developing personalized treatment programs to increase the probability of success when treating depression. Copyright © 2016. Published by Elsevier B.V.

Post-fire logging produces minimal persistent impacts on understory vegetation in northeastern Oregon, USA

Treesearch

David W. Peterson; Erich Dodson

2016-01-01

Post-fire forest management commonly requires accepting some negative ecological impacts from management activities in order to achieve management objectives. Managers need to know, however, whether ecological impacts from post-fire management activities are transient or cause long-term ecosystem degradation. We studied the long-term response of understory vegetation...

Cortical Activation Patterns during Long-Term Memory Retrieval of Visually or Haptically Encoded Objects and Locations

ERIC Educational Resources Information Center

Stock, Oliver; Roder, Brigitte; Burke, Michael; Bien, Siegfried; Rosler, Frank

2009-01-01

The present study used functional magnetic resonance imaging to delineate cortical networks that are activated when objects or spatial locations encoded either visually (visual encoding group, n = 10) or haptically (haptic encoding group, n = 10) had to be retrieved from long-term memory. Participants learned associations between auditorily…

Relationship between Physical Disabilities or Long-Term Health Problems and Health Risk Behaviors or Conditions among US High School Students

ERIC Educational Resources Information Center

Jones, Sherry Everett; Lollar, Donald J.

2008-01-01

Background: This study explores the relationship between self-reported physical disabilities or long-term health problems and health risk behaviors or adverse health conditions (self-reported engagement in violent behaviors, attempted suicide, cigarette smoking, alcohol and other drug use, sexual activity, physical activity, dietary behaviors,…

Exploring Behavioral Markers of Long-Term Physical Activity Maintenance: A Case Study of System Identification Modeling within a Behavioral Intervention

ERIC Educational Resources Information Center

Hekler, Eric B.; Buman, Matthew P.; Poothakandiyil, Nikhil; Rivera, Daniel E.; Dzierzewski, Joseph M.; Aiken Morgan, Adrienne; McCrae, Christina S.; Roberts, Beverly L.; Marsiske, Michael; Giacobbi, Peter R., Jr.

2013-01-01

Efficacious interventions to promote long-term maintenance of physical activity are not well understood. Engineers have developed methods to create dynamical system models for modeling idiographic (i.e., within-person) relationships within systems. In behavioral research, dynamical systems modeling may assist in decomposing intervention effects…

Behavior Change Strategies for Successful Long-Term Weight Loss: Focusing on Dietary and Physical Activity Adherence, Not Weight Loss

ERIC Educational Resources Information Center

Hongu, Nobuko; Kataura, Martha P.; Block, Linda M.

2011-01-01

This article helps Extension professionals guide individuals in a successful long-term weight loss program. A program should focus on behavioral changes (improving eating habits and physical activity), not just weight loss. In order to do this, Extension professionals should implement behavior change strategies that motivate individuals to…

Long-term surveillance plan for the Bodo Canyon Disposal Site, Durango, Colorado

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1994-03-01

This long-term surveillance plan (LTSP) for the Durango, Colorado, Uranium Mill Tailings Remedial Action (UMTRA) Project disposal site describes the surveillance activities for the Durango (Bodo Canyon) disposal site, which will be referred to as the disposal site throughout this document. The US Department of Energy (DOE) will carry out these activities to ensure that the disposal site continues to function as designed. This LTSP was prepared as a requirement for acceptance under the US Nuclear Regulatory Commission (NRC) general license for custody and long-term care of residual radioactive materials (RRM). RRMs include tailings and other uranium ore processing wastesmore » still at the site, which the DOE determines to be radioactive. This LTSP is based on the DOE`s Guidance for Implementing the UMTRA Project Long-term Surveillance Program (DOE, 1992).« less

Calcium/Calmodulin-dependent Protein Kinase II is a Ubiquitous Molecule in Human Long-term Memory Synaptic Plasticity: A Systematic Review

PubMed Central

Ataei, Negar; Sabzghabaee, Ali Mohammad; Movahedian, Ahmad

2015-01-01

Background: Long-term memory is based on synaptic plasticity, a series of biochemical mechanisms include changes in structure and proteins of brain's neurons. In this article, we systematically reviewed the studies that indicate calcium/calmodulin kinase II (CaMKII) is a ubiquitous molecule among different enzymes involved in human long-term memory and the main downstream signaling pathway of long-term memory. Methods: All of the observational, case–control and review studies were considered and evaluated by the search engines PubMed, Cochrane Central Register of Controlled Trials and ScienceDirect Scopus between 1990 and February 2015. We did not carry out meta-analysis. Results: At the first search, it was fined 1015 articles which included “synaptic plasticity” OR “neuronal plasticity” OR “synaptic density” AND memory AND “molecular mechanism” AND “calcium/calmodulin-dependent protein kinase II” OR CaMKII as the keywords. A total of 335 articles were duplicates in the databases and eliminated. A total of 680 title articles were evaluated. Finally, 40 articles were selected as reference. Conclusions: The studies have shown the most important intracellular signal of long-term memory is calcium-dependent signals. Calcium linked calmodulin can activate CaMKII. After receiving information for learning and memory, CaMKII is activated by Glutamate, the most important neurotransmitter for memory-related plasticity. Glutamate activates CaMKII and it plays some important roles in synaptic plasticity modification and long-term memory. PMID:26445635

A framework for supervising lifestyle diseases using long-term activity monitoring.

PubMed

Han, Yongkoo; Han, Manhyung; Lee, Sungyoung; Sarkar, A M Jehad; Lee, Young-Koo

2012-01-01

Activity monitoring of a person for a long-term would be helpful for controlling lifestyle associated diseases. Such diseases are often linked with the way a person lives. An unhealthy and irregular standard of living influences the risk of such diseases in the later part of one's life. The symptoms and the initial signs of these diseases are common to the people with irregular lifestyle. In this paper, we propose a novel healthcare framework to manage lifestyle diseases using long-term activity monitoring. The framework recognizes the user's activities with the help of the sensed data in runtime and reports the irregular and unhealthy activity patterns to a doctor and a caregiver. The proposed framework is a hierarchical structure that consists of three modules: activity recognition, activity pattern generation and lifestyle disease prediction. We show that it is possible to assess the possibility of lifestyle diseases from the sensor data. We also show the viability of the proposed framework.

Activities and sources of income after a period of long-term sick leave--a population-based prospective cohort study.

PubMed

Wikman, Anders; Wiberg, Michael; Marklund, Staffan; Alexanderson, Kristina

2012-09-06

There is limited knowledge about what happens to people after long-term sick leave. The aim of this report was to conduct a prospective study of individuals who were on prolonged sick leave during a particular year, considering their activities and sources of income during subsequent years. To enable comparison of different time periods, we used three cohorts of individuals with different starting years. Using data from national registers, three separate cohorts were constructed that included all people living in Sweden who were 20-64 years of age (>5 million) in the years 1995, 2000 and 2005, respectively. The individual members of the cohorts were classified into the following groups based on their main source of income and activity in 1995-2008: on long-term sick leave, employed, old-age pensioner, long-term unemployed, disability pensioner, on parental leave, social assistance recipient, student allowance recipient, deceased, or emigrated. Most individuals on long-term (> 6 months) sick leave in 1995 were not employed 13 years later. Only 11% of the women and 13% of the men were primarily in employment after 13 years. Instead, a wide range of alternatives existed, for example, many had been granted disability pension, and about 10% of the women and 17% of the men had died during the follow-up period. A larger proportion of those with long-term sick leave were back in employment when 2005 was the starting year for the follow-up. The low future employment rates for people on long-term sick leave may seem surprising. There are several possible explanations for the finding: The disorders these people may have, might have entailed longstanding difficulties on the labor market. Besides, long-term absence from work, no matter what its causes were, might have worsen the chances of further employment. The economic cycles may also have been of importance. The improving labor market during later years seems to have improved the chances for employment among those earlier on long-term sick leave.

Chemotherapeutic tumor microparticles combining low-dose irradiation reprogram tumor-promoting macrophages through a tumor-repopulating cell-curtailing pathway

PubMed Central

Sun, Yanling; Zheng, Zu'an; Zhang, Huafeng; Yu, Yuandong; Ma, Jingwei; Tang, Ke; Xu, Pingwei; Ji, Tiantian; Liang, Xiaoyu; Chen, Degao; Jin, Xun; Zhang, Tianzhen; Long, Zhixiong; Liu, Yuying; Huang, Bo

2017-01-01

ABSTRACT Stem cell-like tumor-repopulating cells (TRCs) have a critical role in establishing a tumor immunosuppressive microenvironment. However, means to enhance antitumor immunity by disrupting TRCs are absent. Our previous studies have shown that tumor cell-derived microparticles (T-MPs) preferentially abrogate TRCs by delivering antitumor drugs into nuclei of TRCs. Here, we show that low dose irradiation (LDI) enhances the effect of cisplatin-packaging T-MPs (Cis-MPs) on TRCs, leading to inhibiting tumor growth in different tumor models. This antitumor effect is not due to the direct killing of tumor cells but is T cell-dependent and relies on macrophages for their efficacy. The underlying mechanism is involved in therapeutic reprograming macrophages from tumor-promotion to tumor-inhibition by disrupting TRCs and curtailing their vicious education on macrophages. These findings provide a novel strategy to reset macrophage polarization and confer their function more like M1 than M2 types with highly promising potential clinical applications. PMID:28680743

The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.

PubMed

van Galen, Peter; Kreso, Antonija; Mbong, Nathan; Kent, David G; Fitzmaurice, Timothy; Chambers, Joseph E; Xie, Stephanie; Laurenti, Elisa; Hermans, Karin; Eppert, Kolja; Marciniak, Stefan J; Goodall, Jane C; Green, Anthony R; Wouters, Bradly G; Wienholds, Erno; Dick, John E

2014-06-12

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells.

Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation

PubMed Central

Iliescu, Radu

2012-01-01

Device-based therapy for resistant hypertension by electrical activation of the carotid baroreflex is currently undergoing active clinical investigation, and initial findings from clinical trials have been published. The purpose of this mini-review is to summarize the experimental studies that have provided a conceptual understanding of the mechanisms that account for the long-term lowering of arterial pressure with baroreflex activation. The well established mechanisms mediating the role of the baroreflex in short-term regulation of arterial pressure by rapid changes in peripheral resistance and cardiac function are often extended to long-term pressure control, and the more sluggish actions of the baroreflex on renal excretory function are often not taken into consideration. However, because clinical, experimental, and theoretical evidence indicates that the kidneys play a dominant role in long-term control of arterial pressure, this review focuses on the mechanisms that link baroreflex-mediated reductions in central sympathetic outflow with increases in renal excretory function that lead to sustained reductions in arterial pressure. PMID:22797307

Platelet-activating factor and group I metabotropic glutamate receptors interact for full development and maintenance of long-term potentiation in the rat medial vestibular nuclei.

PubMed

Grassi, S; Francescangeli, E; Goracci, G; Pettorossi, V E

1999-01-01

In rat brainstem slices, we investigated the interaction between platelet-activating factor and group I metabotropic glutamate receptors in mediating long-term potentiation within the medial vestibular nuclei. We analysed the N1 field potential wave evoked in the ventral portion of the medial vestibular nuclei by primary vestibular afferent stimulation. The group I metabotropic glutamate receptor antagonist, (R,S)-1-aminoindan-1,5-dicarboxylic acid, prevented long-term potentiation induced by a platelet-activating factor analogue [1-O-hexadecyl-2-O-(methylcarbamyl)-sn-glycero-3-phosphocholine], as well as the full development of potentiation, induced by high-frequency stimulation under the blocking agent for synaptosomal platelet-activating factor receptors (ginkolide B), at drug washout. However, potentiation directly induced by the group I glutamate metabotropic receptor agonist, (R,S)-3,5-dihydroxyphenylglycine, was reduced by ginkolide B. These findings suggest that platelet-activating factor, whether exogenous or released following potentiation induction, exerts its effect through presynaptic group I metabotropic glutamate receptors, mediating the increase of glutamate release. In addition, we found that this mechanism, which led to full potentiation through presynaptic group I metabotropic glutamate receptor activation, was inactivated soon after application of potentiation-inducing stimulus. In fact, the long-lasting block of the platelet-activating factor and metabotropic glutamate receptors prevented the full potentiation development and the induced potentiation progressively declined to null. Moreover, ginkolide B, given when high-frequency-dependent potentiation was established, only reduced it within 5 min after potentiation induction. We conclude that to fully develop vestibular long-term potentiation requires presynaptic events. Platelet-activating factor, released after the activation of postsynaptic mechanisms which induce potentiation, is necessary for coupling postsynaptic and presynaptic phenomena, through the activation of group I metabotropic glutamate receptors, and its action lasts only for a short period. If this coupling does not occur, a full and long-lasting potentiation cannot develop.

Short- and long-term effectiveness of a three-month individualized need-supportive physical activity counseling intervention at the workplace.

PubMed

Arrogi, Anass; Schotte, Astrid; Bogaerts, An; Boen, Filip; Seghers, Jan

2017-01-09

The objective of the present study was to evaluate the short- and long-term intervention and mediation effects of a 3-month individualized need-supportive physical activity (PA) counseling intervention on employees' PA and sedentary behavior. Insufficiently active employees (n = 300; mean age 42 ± 9 years; 78% female) were recruited from a large pharmaceutical company in Flanders, Belgium. A quasi-experimental design was used in which the intervention group (N = 246) was recruited separately from the reference group (N = 54). Intervention group participants received a 3-month behavioral support intervention, which consisted of two one-hour face-to-face counseling sessions and three follow-up counseling contacts by e-mail or telephone at weeks three, six and nine. PA counseling, delivered by qualified PA counselors, aimed to satisfy participants' basic psychological needs for autonomy, competence, and relatedness. Reference group participants did not receive individualized PA counseling. Outcome measures included objectively assessed and self-reported PA and sedentary time and psychological need satisfaction. Assessments were held at baseline, immediately after the intervention (short-term) and 6 months post-intervention (long-term). Mixed model analyses and bootstrapping analyses were used to determine intervention and mediation effects, respectively. The intervention group increased weekday daily steps both in the short- and long-term, while the reference group showed reductions in daily step count (ES = .65 and ES = .48 in the short- and long-term, respectively). In the short-term, weekday moderate-to-vigorous PA increased more pronouncedly in the intervention group compared to the reference group (ES = .34). Moreover, the intervention group demonstrated reductions in self-reported sitting time during weekends both in the short- and long-term, whereas the reference group reported increased sitting time (ES = .44 and ES = .32 in the short- and long-term, respectively). Changes in perceived autonomy and competence need satisfaction mediated the long-term intervention effects on daily step count. A 3-month individualized need-supportive PA counseling intervention among employees resulted in significant and sustained improvements in weekday daily step count and in decreased self-reported sitting during weekends. Our findings contribute to the growing evidence of the long-term effectiveness of need-supportive PA counseling. ClinicalTrials.gov NCT01759927 . Registered December 30, 2012.

Importance of punishment frequency in the Iowa gambling task: an fMRI study.

PubMed

Ma, Shuangye; Zang, Yufeng; Cheung, Vinci; Chan, Chetwyn C H

2015-12-01

It has been widely found that in the Iowa Gambling Task (IGT; Bechara et al. Cognition, 50(1), 7-15 1994) normal subjects would gradually learn to prefer obtaining rewards for long-term benefits than seeking immediate rewards to maximize the overall profit. The current study aimed to gain an understanding of how punishment frequency in the IGT would be processed and its association with subjects' reward preferences. In this study, we employed the clinical version of the IGT, in which response options are not only different in the long-term outcome, but also associated with different punishment frequencies. Event-related functional Magnetic Resonance Imaging (fMRI) was used to capture the subjects' brain activity when performing the IGT. A total of 24 male subjects (mean age = 21.7 years, SD = 1.8 years), who were university students, participated in the experiment. It is found that subjects learned to select more from the decks that were advantageous in the long-term, but they were more sensitive to the effect of long-term outcome under the condition of high punishment frequency. The corresponding brain activation showed that the Anterior Cingulate Cortex (ACC) had significantly higher activation during the disadvantageous choices than the advantageous choices. Such activity difference between the two conditions of long-term outcome was more prominent with high punishment frequency than low punishment frequency; and this brain activity difference was significantly correlated with the behavioral performance under the condition of high punishment frequency. The results suggested that only in the context with high punishment frequency, there would be increased neural activity in ACC when subjects intended to select from the disadvantageous choices so that these choices would be inhibited and advantageous choices would be selected.

Long-term stable active mount for reflective optics

NASA Astrophysics Data System (ADS)

Reinlein, C.; Brady, A.; Damm, C.; Mohaupt, M.; Kamm, A.; Lange, N.; Goy, M.

2016-07-01

We report on the development of an active mount with an orthogonal actuator matrix offering a stable shape optimization for gratings or mirrors. We introduce the actuator distribution and calculate the accessible Zernike polynomials from their actuator influence function. Experimental tests show the capability of the device to compensate for aberrations of grating substrates as we report measurements of a 110x105 mm2 and 220x210 mm2 device With these devices, we evaluate the position depending aberrations, long-term stability shape results, and temperature-induced shape variations. Therewith we will discuss potential applications in space telescopes and Earth-based facilities where long-term stability is mandatory.

Successful Establishment of Plasmids R1 and pMV158 in a New Host Requires the Relief of the Transcriptional Repression of Their Essential rep Genes

PubMed Central

Ruiz-Masó, José Á.; Luengo, Luis M.; Moreno-Córdoba, Inmaculada; Díaz-Orejas, Ramón; del Solar, Gloria

2017-01-01

Although differing in size, encoded traits, host range, and replication mechanism, both narrow-host-range theta-type conjugative enterobacterial plasmid R1 and promiscuous rolling-circle-type mobilizable streptococcal plasmid pMV158 encode a transcriptional repressor protein, namely CopB in R1 and CopG in pMV158, involved in replication control. The gene encoding CopB or CopG is cotranscribed with a downstream gene that encodes the replication initiator Rep protein of the corresponding plasmid. However, whereas CopG is an auto-repressor that inhibits transcription of the entire copG-repB operon, CopB is expressed constitutively and represses a second, downstream promoter that directs transcription of repA. As a consequence of the distinct regulatory pathways implied by CopB and CopG, these repressor proteins play a different role in control of plasmid replication during the steady state: while CopB has an auxiliary role by keeping repressed the regulated promoter whenever the plasmid copy number is above a low threshold, CopG plays a primary role by acting coordinately with RNAII. Here, we have studied the role of the regulatory circuit mediated by these transcriptional repressors during the establishment of these two plasmids in a new host cell, and found that excess Cop repressor molecules in the recipient cell result in a severe decrease in the frequency and/or the velocity of appearance of transformant colonies for the cognate plasmid but not for unrelated plasmids. Using the pMV158 replicon as a model system, together with highly sensitive real-time qPCR and inverse PCR methods, we have also analyzed the effect of CopG on the kinetics of repopulation of the plasmid in Streptococcus pneumoniae. We show that, whereas in the absence of CopG pMV158 repopulation occurs mainly during the first 45 min following plasmid transfer, the presence of the transcriptional repressor in the recipient cell severely impairs the replicon repopulation and makes the plasmid replicate at approximately the same rate as the chromosome at any time after transformation, which results in maximal plasmid loss rate in the absence of selection. Overall, these findings indicate that unrepressed activity of the Cop-regulated promoter is crucial for the successful colonization of the recipient bacterial cells by the plasmid. PMID:29250051

Long-term potentiation and depression after unilateral labyrinthectomy in the medial vestibular nucleus of rats.

PubMed

Pettorossi, Vito Enrico; Dutia, Mayank; Frondaroli, Adele; Dieni, Cristina; Grassi, Silvarosa

2003-01-01

We previously demonstrated in rat brainstem slices that high-frequency stimulation (HFS) of the vestibular afferents induces long-term potentiation (LTP) in the ventral part (Vp) of the medial vestibular nucleus (MVN) and long-term depression (LTD) in the dorsal part (Dp). Both LTP and LTD depend on N-methyl-D-aspartate receptor activation, which increases synaptic efficacy; however, in the Dp, LTP reverses to LTD because of the activation of gamma-aminobutyric acid-ergic neurons. Here we show that the probability of inducing long-term effects in the MVN of rat brainstem slices is altered after unilateral labyrinthectomy (UL). In fact, LTP occurs less frequently in the ventral contra-lesional side compared with sham-operated rats. In the dorsal ipsi-lesional side, LTD is reduced and LTP enhanced, while the opposite occurs in the dorsal contra-lesional side. These changes in synaptic plasticity may be useful for re-balancing the tonic discharge of the MVN of the two sides during vestibular compensation, and for enhancing the dynamic responses of the deafferented MVN neurons in the long term.

Protective Role of Recent and Past Long-Term Physical Activity on Age-Related Cognitive Decline: The Moderating Effect of Sex.

PubMed

Lopez-Fontana, Iréné; Castanier, Carole; Le Scanff, Christine; Perrot, Alexandra

2018-06-13

This study aimed to investigate if the impact of both recent and long-term physical activity on age-related cognitive decline would be modified by sex. One-hundred thirty-five men (N = 67) and women (N = 68) aged 18 to 80 years completed the Modifiable Activity Questionnaire and the Historical Leisure Activity Questionnaire. A composite score of cognitive functions was computed from five experimental tasks. Hierarchical regression analyses performed to test the moderating effect of recent physical activity on age-cognition relationship had not revealed significant result regardless of sex. Conversely, past long-term physical activity was found to slow down the age-related cognitive decline among women (β = 0.22, p = .03), but not men. The findings support a lifecourse approach in identifying determinants of cognitive aging and the importance of taking into account the moderating role of sex. This article presented potential explanations for these moderators and future avenues to explore.

Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix.

PubMed

Bravarenko, N I; Onufriev, M V; Stepanichev, M Yu; Ierusalimsky, V N; Balaban, P M; Gulyaeva, N V

2006-01-01

Although caspase activity in the nervous system of mollusks has not been described before, we suggested that these cysteine proteases might be involved in the phenomena of neuroplasticity in mollusks. We directly measured caspase-3 (DEVDase) activity in the Helix lucorum central nervous system (CNS) using a fluorometrical approach and showed that the caspase-3-like immunoreactivity is present in the central neurons of Helix. Western blots revealed the presence of caspase-3-immunoreactive proteins with a molecular mass of 29 kDa. Staurosporin application, routinely used to induce apoptosis in mammalian neurons through the activating cleavage of caspase-3, did not result in the appearance of a smaller subunit corresponding to the active caspase in the snail. However, it did increase the enzyme activity in the snail CNS. This suggests differences in the regulation of caspase-3 activity in mammals and snails. In the snail CNS, the caspase homolog seems to possess an active center without activating cleavage typical for mammals. In electrophysiological experiments with identified snail neurons, selective blockade of the caspase-3 with the irreversible and cell-permeable inhibitor of caspase-3 N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp-(OMe)-fluoro-methylketone prevented development of the long-term stage of synaptic input sensitization, suggesting that caspase is necessary for normal synaptic plasticity in snails. The results of our study give the first direct evidence that the caspase-3-like activity is essential for long-term plasticity in the invertebrate neurons. This activity is presumably involved in removing inhibitory constraints on the storage of long-term memory.

Synaptic Plasticity Enables Adaptive Self-Tuning Critical Networks

PubMed Central

Stepp, Nigel; Plenz, Dietmar; Srinivasa, Narayan

2015-01-01

During rest, the mammalian cortex displays spontaneous neural activity. Spiking of single neurons during rest has been described as irregular and asynchronous. In contrast, recent in vivo and in vitro population measures of spontaneous activity, using the LFP, EEG, MEG or fMRI suggest that the default state of the cortex is critical, manifested by spontaneous, scale-invariant, cascades of activity known as neuronal avalanches. Criticality keeps a network poised for optimal information processing, but this view seems to be difficult to reconcile with apparently irregular single neuron spiking. Here, we simulate a 10,000 neuron, deterministic, plastic network of spiking neurons. We show that a combination of short- and long-term synaptic plasticity enables these networks to exhibit criticality in the face of intrinsic, i.e. self-sustained, asynchronous spiking. Brief external perturbations lead to adaptive, long-term modification of intrinsic network connectivity through long-term excitatory plasticity, whereas long-term inhibitory plasticity enables rapid self-tuning of the network back to a critical state. The critical state is characterized by a branching parameter oscillating around unity, a critical exponent close to -3/2 and a long tail distribution of a self-similarity parameter between 0.5 and 1. PMID:25590427

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

PubMed Central

Tao, Xiaoxiao; Lin, Mike T.; Thorington, Glyne U.; Wilson, Sean M.; Longo, Lawrence D.

2015-01-01

Acclimatization to high-altitude, long-term hypoxia (LTH) reportedly alters cerebral artery contraction-relaxation responses associated with changes in K+ channel activity. We hypothesized that to maintain oxygenation during LTH, basilar arteries (BA) in the ovine adult and near-term fetus would show increased large-conductance Ca2+ activated potassium (BK) channel activity. We measured BK channel activity, expression, and cell surface distribution by use of patch-clamp electrophysiology, flow cytometry, and confocal microscopy, respectively, in myocytes from normoxic control and LTH adult and near-term fetus BA. Electrophysiological data showed that BK channels in LTH myocytes exhibited 1) lowered Ca2+ set points, 2) left-shifted activation voltages, and 3) longer dwell times. BK channels in LTH myocytes also appeared to be more dephosphorylated. These differences collectively make LTH BK channels more sensitive to activation. Studies using flow cytometry showed that the LTH fetus exhibited increased BK β1 subunit surface expression. In addition, in both fetal groups confocal microscopy revealed increased BK channel clustering and colocalization to myocyte lipid rafts. We conclude that increased BK channel activity in LTH BA occurred in association with increased channel affinity for Ca2+ and left-shifted voltage activation. Increased cerebrovascular BK channel activity may be a mechanism by which LTH adult and near-term fetal sheep can acclimatize to long-term high altitude hypoxia. Our findings suggest that increasing BK channel activity in cerebral myocytes may be a therapeutic target to ameliorate the adverse effects of high altitude in adults or of intrauterine hypoxia in the fetus. PMID:25599571

Visual working memory buffers information retrieved from visual long-term memory.

PubMed

Fukuda, Keisuke; Woodman, Geoffrey F

2017-05-16

Human memory is thought to consist of long-term storage and short-term storage mechanisms, the latter known as working memory. Although it has long been assumed that information retrieved from long-term memory is represented in working memory, we lack neural evidence for this and need neural measures that allow us to watch this retrieval into working memory unfold with high temporal resolution. Here, we show that human electrophysiology can be used to track information as it is brought back into working memory during retrieval from long-term memory. Specifically, we found that the retrieval of information from long-term memory was limited to just a few simple objects' worth of information at once, and elicited a pattern of neurophysiological activity similar to that observed when people encode new information into working memory. Our findings suggest that working memory is where information is buffered when being retrieved from long-term memory and reconcile current theories of memory retrieval with classic notions about the memory mechanisms involved.

Visual working memory buffers information retrieved from visual long-term memory

PubMed Central

Fukuda, Keisuke; Woodman, Geoffrey F.

2017-01-01

Human memory is thought to consist of long-term storage and short-term storage mechanisms, the latter known as working memory. Although it has long been assumed that information retrieved from long-term memory is represented in working memory, we lack neural evidence for this and need neural measures that allow us to watch this retrieval into working memory unfold with high temporal resolution. Here, we show that human electrophysiology can be used to track information as it is brought back into working memory during retrieval from long-term memory. Specifically, we found that the retrieval of information from long-term memory was limited to just a few simple objects’ worth of information at once, and elicited a pattern of neurophysiological activity similar to that observed when people encode new information into working memory. Our findings suggest that working memory is where information is buffered when being retrieved from long-term memory and reconcile current theories of memory retrieval with classic notions about the memory mechanisms involved. PMID:28461479

Long-term potentiation and long-term depression: a clinical perspective

PubMed Central

Bliss, Timothy V.P.; Cooke, Sam F

2011-01-01

Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke. PMID:21779718

Radioprotection of mice by a single subcutaneous injection of heat-killed Lactobacillus casei after irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nomoto, K.; Yokokura, T.; Tsuneoka, K.

1991-03-01

Treatment of whole-body gamma-irradiated mice with a preparation of Lactobacillus casei (LC 9018) immediately after irradiation caused a sustained increase in serum colony-stimulating activity which was followed by an enhanced repopulation of granulocyte-macrophage colony-forming cells in the femoral marrow and spleen. Numbers of blood leukocytes, erythrocytes, and platelets were increased earlier in the treated mice than in the controls, and the survival rate was elevated significantly. The radioprotective effect was dependent on the dose of LC 9018 as well as on the dose of radiation. These results demonstrate the value of LC 9018 for the treatment of myelosuppression after radiotherapymore » or radiation accidents.« less

Two Long-Term Intermittent Pulsars Discovered in the PALFA Survey

NASA Astrophysics Data System (ADS)

Lyne, A. G.; Stappers, B. W.; Freire, P. C. C.; Hessels, J. W. T.; Kaspi, V. M.; Allen, B.; Bogdanov, S.; Brazier, A.; Camilo, F.; Cardoso, F.; Chatterjee, S.; Cordes, J. M.; Crawford, F.; Deneva, J. S.; Ferdman, R. D.; Jenet, F. A.; Knispel, B.; Lazarus, P.; van Leeuwen, J.; Lynch, R.; Madsen, E.; McLaughlin, M. A.; Parent, E.; Patel, C.; Ransom, S. M.; Scholz, P.; Seymour, A.; Siemens, X.; Spitler, L. G.; Stairs, I. H.; Stovall, K.; Swiggum, J.; Wharton, R. S.; Zhu, W. W.

2017-01-01

We report the discovery of two long-term intermittent radio pulsars in the ongoing Pulsar Arecibo L-Band Feed Array survey. Following discovery with the Arecibo Telescope, extended observations of these pulsars over several years at Jodrell Bank Observatory have revealed the details of their rotation and radiation properties. PSRs J1910+0517 and J1929+1357 show long-term extreme bimodal intermittency, switching between active (ON) and inactive (OFF) emission states and indicating the presence of a large, hitherto unrecognized underlying population of such objects. For PSR J1929+1357, the initial duty cycle was fON = 0.008, but two years later, this changed quite abruptly to fON = 0.16. This is the first time that a significant evolution in the activity of an intermittent pulsar has been seen, and we show that the spin-down rate of the pulsar is proportional to the activity. The spin-down rate of PSR J1929+1357 is increased by a factor of 1.8 when it is in active mode, similar to the increase seen in the other three known long-term intermittent pulsars. These discoveries increase the number of known pulsars displaying long-term intermittency to five. These five objects display a remarkably narrow range of spin-down power (\\dot{E} ˜ {10}32 {erg} {{{s}}}-1) and accelerating potential above their polar caps. If confirmed by further discoveries, this trend might be important for understanding the physical mechanisms that cause intermittency.

Long-term Effects of Shrub Encroachment and Grazing on Soil Microbial Composition and Function

NASA Astrophysics Data System (ADS)

Gallery, R. E.; O'Shea, C.; Kwiecien, A.; Predick, K.; Archer, S. R.

2014-12-01

Drylands account for ca. 35% of terrestrial net primary productivity and thus play a significant role in global water and biogeochemical cycles. Replacement of grasses by shrubs has been widespread in these systems and has altered rates of erosion and native plant biodiversity and productivity. The net effect of these changes on biogeochemical cycling is not well understood. Projected warmer and drier conditions may further alter the function and stability of these ecosystems and soil resources through direct effects on soil microbiota and plant-microbe interactions. We quantified microbial community responses to long-term livestock grazing and shrub encroachment in a Sonoran Desert grassland. We sought to characterize tipping points where biotic controls over ecosystem processes shift from being 'grass-driven' to 'shrub-driven.' We asked: How do livestock grazing (the predominant land use in dryland ecosystems) and shrub invasion (a predominant land cover change) interact to influence microbial biomass and the relative abundance of bacteria, archaea, and fungi and their extracellular enzyme activities? Surface soil from bare-ground patches, native and invasive grass rhizospheres, and bole and canopy dripline locations in patches of mature mesquite trees in long-term grazed and long-term (70+ y) protected pastures were collected and analyzed for microbial community composition, biomass, potential exoenzyme activities, and a suite of biogeochemical characteristics. We found no differences in microbial communities or the soils associated with native vs. exotic grasses. Overall, mesquite bole patches differed from other patches in all soil characteristics except potential enzyme activity: soil temperature was significantly lower, and total carbon (C) and soil moisture were significantly higher. Potential activities were lowest for bare ground and highest at shrub dripline patches for all seven exoenzymes tested. Mean potential activities for C and phosphorous (P) hydrolyzing enzymes in long-term protected pastures (C: 21.4 ug activity g-1 h-1 ± 2.3; P: 29.8 ug activity g-1 h-1 ± 3.5) were significantly higher than those in grazed pastures (C: 16.6 ug activity g-1 h-1 ± 2.1; P: 15.8 ug activity g-1 h-1 ± 2.5), suggesting long-term effects of past land use on current soil microbial populations.

Motivation and placebos: do different mechanisms occur in different contexts?

PubMed

Hyland, Michael E

2011-06-27

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic-pituitary-adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state.

Motivation and placebos: do different mechanisms occur in different contexts?

PubMed Central

Hyland, Michael E.

2011-01-01

This paper challenges the common assumption that the mechanisms underlying short-term placebo paradigms (where there is no motivation for health improvement) and long-term placebo paradigms (where patients value improvement in their health) are the same. Three types of motivational theory are reviewed: (i) classical placebo motivation theory that the placebo response results from the desire for therapeutic improvement; (ii) goal activation model that expectancy-driven placebo responses are enhanced when the placebo response satisfies an activated goal; and (iii) motivational concordance model that the placebo response is the consequence of concordance between the placebo ritual and significant intrinsic motives. It is suggested that current data are consistent with the following theory: response expectancy, conditioning and goal activation are responsible for short-term placebo effects but long-term therapeutic change is achieved through the effects of goal satisfaction and affect on the inflammatory response system and hypothalamic–pituitary–adrenal axis. Empirical predictions of this new theory are outlined, including ways in which placebo effects can be combined with other psychologically mediated effects on short-term and long-term psychological and physiological state. PMID:21576140

Short Meditation Trainings Enhance Non-REM Sleep Low-Frequency Oscillations.

PubMed

Dentico, Daniela; Ferrarelli, Fabio; Riedner, Brady A; Smith, Richard; Zennig, Corinna; Lutz, Antoine; Tononi, Giulio; Davidson, Richard J

2016-01-01

We have recently shown higher parietal-occipital EEG gamma activity during sleep in long-term meditators compared to meditation-naive individuals. This gamma increase was specific for NREM sleep, was present throughout the entire night and correlated with meditation expertise, thus suggesting underlying long-lasting neuroplastic changes induced through prolonged training. The aim of this study was to explore the neuroplastic changes acutely induced by 2 intensive days of different meditation practices in the same group of practitioners. We also repeated baseline recordings in a meditation-naive cohort to account for time effects on sleep EEG activity. High-density EEG recordings of human brain activity were acquired over the course of whole sleep nights following intervention. Sound-attenuated sleep research room. Twenty-four long-term meditators and twenty-four meditation-naïve controls. Two 8-h sessions of either a mindfulness-based meditation or a form of meditation designed to cultivate compassion and loving kindness, hereafter referred to as compassion meditation. We found an increase in EEG low-frequency oscillatory activities (1-12 Hz, centered around 7-8 Hz) over prefrontal and left parietal electrodes across whole night NREM cycles. This power increase peaked early in the night and extended during the third cycle to high-frequencies up to the gamma range (25-40 Hz). There was no difference in sleep EEG activity between meditation styles in long-term meditators nor in the meditation naïve group across different time points. Furthermore, the prefrontal-parietal changes were dependent on meditation life experience. This low-frequency prefrontal-parietal activation likely reflects acute, meditation-related plastic changes occurring during wakefulness, and may underlie a top-down regulation from frontal and anterior parietal areas to the posterior parietal and occipital regions showing chronic, long-lasting plastic changes in long-term meditators.

Durability of Anti-Infective Effect of Long-Term Silicone Sheath Catheters Impregnated with Antimicrobial Agents

PubMed Central

Tcholakian, Robert K.; Raad, Issam I.

2001-01-01

This study was performed to test the long-term antimicrobial efficacy of impregnated silicone catheters comprising an antimicrobial layer sandwiched between an external surface sheath and a luminal surface silicone sheath. The design of the catheter permits the introduction of various antimicrobials in addition to anticoagulants or antifibrins in the antimicrobial layer and allows their gradual release over a period of months after insertion. The in vitro data presented show that the catheter can provide antimicrobial activity for 90 days, after being replated for 15 7-day cycles of replating. When the catheters were immersed in human serum and incubated at 37°C, they demonstrated significant antimicrobial activity after more than 325 days of incubation. The significant long-term in vitro antimicrobial activity observed may imply effective in vivo activity for almost 1 year after insertion and could serve as a cost-effective alternative to surgically implantable silicone catheters. PMID:11408213

Temporal Activity Modulation of Deep Very Low Frequency Earthquakes in Shikoku, Southwest Japan

NASA Astrophysics Data System (ADS)

Baba, Satoru; Takeo, Akiko; Obara, Kazushige; Kato, Aitaro; Maeda, Takuto; Matsuzawa, Takanori

2018-01-01

We investigated long-term changes in the activity of deep very low frequency earthquakes (VLFEs) in western Shikoku, southwest part of the Nankai subduction zone in Japan for 13 years by the matched-filter technique. VLFE activity is expected to be a proxy of interplate slips. In the Bungo channel, where long-term slow slip events (SSEs) occurred frequently, the cumulative number of detected VLFEs increased rapidly in 2010 and 2014, which were modulated by long-term SSEs. In the neighboring inland region near the Bungo channel, the cumulative number increased steeply every 6 months. This stepwise change was accompanied by episodic tremors and slips. Deep VLFE activity in western Shikoku has been low since the latter half of 2014. This decade-scale quiescence may be attributed to the change in interplate coupling strength in the Nankai subduction zone.

Activity Analyses for Solar-type Stars Observed with Kepler. II. Magnetic Feature versus Flare Activity

NASA Astrophysics Data System (ADS)

He, Han; Wang, Huaning; Zhang, Mei; Mehrabi, Ahmad; Yan, Yan; Yun, Duo

2018-05-01

The light curves of solar-type stars present both periodic fluctuation and flare spikes. The gradual periodic fluctuation is interpreted as the rotational modulation of magnetic features on the stellar surface and is used to deduce magnetic feature activity properties. The flare spikes in light curves are used to derive flare activity properties. In this paper, we analyze the light curve data of three solar-type stars (KIC 6034120, KIC 3118883, and KIC 10528093) observed with Kepler space telescope and investigate the relationship between their magnetic feature activities and flare activities. The analysis shows that: (1) both the magnetic feature activity and the flare activity exhibit long-term variations as the Sun does; (2) unlike the Sun, the long-term variations of magnetic feature activity and flare activity are not in phase with each other; (3) the analysis of star KIC 6034120 suggests that the long-term variations of magnetic feature activity and flare activity have a similar cycle length. Our analysis and results indicate that the magnetic features that dominate rotational modulation and the flares possibly have different source regions, although they may be influenced by the magnetic field generated through a same dynamo process.

A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML

PubMed Central

Alsuliman, Abdullah; Muftuoglu, Muharrem; Khoder, Ahmad; Ahn, Yong-Oon; Basar, Rafet; Verneris, Michael R.; Muranski, Pawel; Barrett, A. John; Liu, Enli; Li, Li; Stringaris, Kate; Armstrong-James, Darius; Shaim, Hila; Kondo, Kayo; Imahashi, Nobuhiko; Andersson, Borje; Marin, David; Champlin, Richard E.; Shpall, Elizabeth J.

2017-01-01

The establishment of long-lived pathogen-specific T cells is a fundamental property of the adaptive immune response. However, the mechanisms underlying long-term persistence of antigen-specific CD4+ T cells are not well-defined. Here we identify a subset of memory CD4+ T cells capable of effluxing cellular toxins, including rhodamine (Rho), through the multidrug efflux protein MDR1 (also known as P-glycoprotein and ABCB1). Drug-effluxing CD4+ T cells were characterized as CD161+CD95+CD45RA−CD127hiCD28+CD25int cells with a distinct chemokine profile and a Th1-polarized pro-inflammatory phenotype. CD4+CD161+Rho-effluxing T cells proliferated vigorously in response to stimulation with anti-CD3/CD28 beads and gave rise to CD161− progeny in vitro. These cells were also capable of self-renewal and maintained their phenotypic and functional characteristics when cultured with homeostatic cytokines. Multidrug-effluxing CD4+CD161+ T cells were enriched within the viral-specific Th1 repertoire of healthy donors and patients with acute myeloid leukemia (AML) and survived exposure to daunorubicin chemotherapy in vitro. Multidrug-effluxing CD4+CD161+ T cells also resisted chemotherapy-induced cytotoxicity in vivo and underwent significant expansion in AML patients rendered lymphopenic after chemotherapy, contributing to the repopulation of anti-CMV immunity. Finally, after influenza vaccination, the proportion of influenza-specific CD4+ T cells coexpressing CD161 was significantly higher after 2 years compared with 4 weeks after immunization, suggesting CD161 is a marker for long-lived antigen-specific memory T cells. These findings suggest that CD4+CD161+ T cells with rapid efflux capacity contribute to the maintenance of viral-specific memory T cells. These data provide novel insights into mechanisms that preserve antiviral immunity in patients undergoing chemotherapy and have implications for the development of novel immunotherapeutic approaches. PMID:27821506

Increased mitochondrial energy efficiency in skeletal muscle after long-term fasting: its relevance to animal performance.

PubMed

Bourguignon, Aurore; Rameau, Anaïs; Toullec, Gaëlle; Romestaing, Caroline; Roussel, Damien

2017-07-01

In the final stage of fasting, skeletal muscle mass and protein content drastically decrease when the maintenance of efficient locomotor activity becomes crucial for animals to reactivate feeding behaviour and survive a very long period of starvation. As mitochondrial metabolism represents the main physiological link between the endogenous energy store and animal performance, the aim of this study was to determine how a very long, natural period of fasting affected skeletal muscle mitochondrial bioenergetics in king penguin ( Aptenodytes patagonicus ) chicks. Rates of mitochondrial oxidative phosphorylation were measured in pectoralis permeabilized fibres and isolated mitochondria. Mitochondrial ATP synthesis efficiency and the activities of respiratory chain complexes were measured in mitochondria isolated from pectoralis muscle. Results from long-term (4-5 months) naturally fasted chicks were compared with those from short-term (10 day) fasted birds. The respiratory activities of muscle fibres and isolated mitochondria were reduced by 60% and 45%, respectively, on average in long-term fasted chicks compared with short-term fasted birds. Oxidative capacity and mitochondrial content of pectoralis muscle were lowered by long-term fasting. Bioenergetic analysis of pectoralis muscle also revealed that mitochondria were, on average, 25% more energy efficient in the final stage of fasting (4-5 months) than after 10 days of fasting (short-term fasted birds). These results suggest that the strong reduction in respiratory capacity of pectoralis muscle was partly alleviated by increased mitochondrial ATP synthesis efficiency. Such oxidative phosphorylation optimization can impact animal performance, e.g. the metabolic cost of locomotion or the foraging efficiency. © 2017. Published by The Company of Biologists Ltd.

Effects of using nursing home residents to serve as group activity leaders: lessons learned from the RAP project.

PubMed

Skrajner, Michael J; Haberman, Jessica L; Camp, Cameron J; Tusick, Melanie; Frentiu, Cristina; Gorzelle, Gregg

2014-03-01

Previous research has demonstrated that persons with early to moderate stage dementia are capable of leading small group activities for persons with more advanced dementia. In this study, we built upon this previous work by training residents in long-term care facilities to fill the role of group activity leaders using a Resident-Assisted Programming (RAP) training regimen. There were two stages to the program. In the first stage, RAP training was provided by researchers. In the second stage, RAP training was provided to residents by activities staff members of long-term care facilities who had been trained by researchers. We examine the effects of RAP implemented by researchers and by activities staff member on long-term care resident with dementia who took part in these RAP activities. We also examined effects produced by two types of small group activities: two Montessori-based activities and an activity which focuses on persons with more advanced dementia, based on the work of Jitka Zgola. Results demonstrate that levels of positive engagement seen in players during RAP (resident-led activities) were typically higher than those observed during standard activities programming led by site staff. In general, Montessori-Based Dementia Programming® produced more constructive engagement than Zgola-based programming (ZBP), though ZBP did increase a positive form of engagement involving observing activities with interest. In addition, RAP implemented by activities staff members produced effects that were, on the whole, similar to those produced when RAP was implemented by researchers. Implications of these findings for providing meaningful social roles for persons with dementia residing in long-term care, and suggestions for further research in this area, are discussed.

77 FR 24701 - Agency Information Collection Activities; Submission to OMB for Review and Approval; Comment...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-25

... Backwash Recycling Rule (FBRR), Long Term 1 Enhanced Surface Water Treatment Rule (LT1ESWTR), Long Term 2... review instructions; develop, acquire, install, and utilize technology and systems for the purposes of...

How Chunks, Long-Term Working Memory and Templates Offer a Cognitive Explanation for Neuroimaging Data on Expertise Acquisition: A Two-Stage Framework

ERIC Educational Resources Information Center

Guida, Alessandro; Gobet, Fernand; Tardieu, Hubert; Nicolas, Serge

2012-01-01

Our review of research on PET and fMRI neuroimaging of experts and expertise acquisition reveals two apparently discordant patterns in working-memory-related tasks. When experts are involved, studies show activations in brain regions typically activated during long-term memory tasks that are not observed with novices, a result that is compatible…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kleiner, J.B.; Amiel, D.; Harwood, F.L.

A rabbit model for anterior cruciate ligament (ACL) reconstruction using autogenous patellar tendon was utilized to study the early events of autograft cellular dynamics. Biochemical, autoradiographic, histological, and vascular injection techniques demonstrated that the native autograft cell population rapidly necroses. This repopulation occurs without a vascular contribution; cells entering the autograft are reliant upon synovial fluid nutrition.

Platelet recruitment promotes keratocyte repopulation following corneal epithelial abrasion in the mouse

USDA-ARS?s Scientific Manuscript database

Corneal abrasion not only damages the epithelium but also induces stromal keratocyte death at the site of injury. While a coordinated cascade of inflammatory cell recruitment facilitates epithelial restoration, it is unclear if this cascade is necessary for keratocyte recovery. Since platelet and ne...

Effect of long-term bedrest on lower leg muscle activation patterns during quiet standing.

PubMed

Miyoshi, T; Sato, T; Sekiguchi, H; Yamanaka, K; Miyazaki, M; Igawa, S; Komeda, T; Nakazawa, K; Yano, H

2001-07-01

It has been well known that balance instabilities after long-term exposure to microgravity (e.g., Anderson et al. 1986) or bedrest (BR) can be related to alterations and/or adaptations to postural control strategies. Little is known, however, how the reduced muscular activity affects the activation pattern of the lower limb muscles during quiet standing (QS). The purpose of this study was to investigate whether or not any changes in the lower limb muscle activation patterns during QS would occur after BR.

Montessori-based activities for long-term care residents with advanced dementia: effects on engagement and affect.

PubMed

Orsulic-Jeras, S; Judge, K S; Camp, C J

2000-02-01

Sixteen residents in long-term care with advanced dementia (14 women; average age = 88) showed significantly more constructive engagement (defined as motor or verbal behaviors in response to an activity), less passive engagement (defined as passively observing an activity), and more pleasure while participating in Montessori-based programming than in regularly scheduled activities programming. Principles of Montessori-based programming, along with examples of such programming, are presented. Implications of the study and methods for expanding the use of Montessori-based dementia programming are discussed.

On policies to regulate long-term risks from hazardous waste disposal sites under both intergenerational equity and intragenerational equity

NASA Astrophysics Data System (ADS)

Shu, Zhongbin

In recent years, it has been recognized that there is a need for a general philosophic policy to guide the regulation of societal activities that involve long-term and very long-term risks. Theses societal activities not only include the disposal of high-level radioactive wastes and global warming, but also include the disposal of non-radioactive carcinogens that never decay, such as arsenic, nickel, etc. In the past, attention has been focused on nuclear wastes. However, there has been international recognition that large quantities of non-radioactive wastes are being disposed of with little consideration of their long-term risks. The objectives of this dissertation are to present the significant long-term risks posed by non-radioactive carcinogens through case studies; develop the conceptual decision framework for setting the long-term risk policy; and illustrate that certain factors, such as discount rate, can significantly influence the results of long-term risk analysis. Therefore, the proposed decision-making framework can be used to systematically study the important policy questions on long-term risk regulations, and then subsequently help the decision-maker to make informed decisions. Regulatory disparities between high-level radioactive wastes and non-radioactive wastes are summarized. Long-term risk is rarely a consideration in the regulation of disposal of non-radioactive hazardous chemicals; and when it is, the matter has been handled in a somewhat perfunctory manner. Case studies of long-term risks are conducted for five Superfund sites that are contaminated with one or more non-radioactive carcinogens. Under the same assumptions used for the disposal of high-level radioactive wastes, future subsistence farmers would be exposed to significant individual risks, in some cases with lifetime fatality risk equal to unity. The important policy questions on long-term risk regulation are identified, and the conceptual decision-making framework to regulate long-term risk is presented. The results of decision tree analysis of cleanup alternatives for the Crystal Chemical site indicate that discount rate has profound impact on the results of the analysis and significant implication with regard to intergenerational equity. It is expected that other policy factors could have similar impacts. There is a need to use the proposed decision-making framework to systemically study those factors and make rational policy decisions accordingly.

Could the Geminid meteoroid stream be the result of long-term thermal fracture?

NASA Astrophysics Data System (ADS)

Ryabova, G.

2015-01-01

The previous models by Ryabova have shown that the Geminid meteoroid stream has a cometary origin, so asteroid (3200) Phaethon (the Geminids' parent body) is probably a dead comet. Recently (in 2009 and 2012) some weak activity was observed (Jewitt and Li, 2010, 2013), but it was not a cometary activity. Recurrent brightening of Phaethon at perihelion could be the result of thermal fracture and decomposition. In this study we model the long term dust release from Phaethon based on this mechanism. It is unlikely that the Geminid meteoroid stream (or its low-active wide component) was generated by long-time thermal fracture.

Short- and long-term antidepressant effects of ketamine in a rat chronic unpredictable stress model.

PubMed

Jiang, Yinghong; Wang, Yiqiang; Sun, Xiaoran; Lian, Bo; Sun, Hongwei; Wang, Gang; Du, Zhongde; Li, Qi; Sun, Lin

2017-08-01

This research was aimed to evaluate the behaviors of short- or long-term antidepressant effects of ketamine in rats exposed to chronic unpredictable stress (CUS). Ketamine, a glutamate noncompetitive NMDA receptor antagonist, regulates excitatory amino acid functions, such as anxiety disorders and major depression, and plays an important role in synaptic plasticity and learning and memory. After 42 days of CUS model, male rats received either a single injection of ketamine (10 mg/kg; day 43) or 15 daily injections (days 43-75). The influence of ketamine on behavioral reactivity was assessed 24 hr (short-term) or 7 weeks after ketamine treatment (long-term). Behavioral tests used to assess the effects of these treatments included the sucrose preference (SP), open field (OF), elevated plus maze (EPM), forced swimming (FS), and water maze (WM) to detect anxiety-like behavior (OF and EPM), forced swimming (FS), and water maze (WM). Results: Short-term ketamine administration resulted in increases of body weight gain, higher sensitivity to sucrose, augmented locomotor activity in the OF, more entries into the open arms of the EPM, along increased activity in the FS test; all responses indicative of reductions in depression/despair in anxiety-eliciting situations. No significant differences in these behaviors were obtained under conditions of long-term ketamine administration ( p  > .05). The CUS + Ketamine group showed significantly increased activity as compared with the CUS + Vehicle group for analysis of the long-term effects of ketamine (* p  < .05). Nor were significant differences obtained in learning and memory performance in rats receiving ketamine ( p  > .05). Taken together these findings demonstrate that a short-term administration of ketamine induced rapid antidepressant-like effects in adult male rats exposed to CUS conditions, effects that were not observed in response to the long-term treatment regime.

Effects of long-term cryopreservation on peripheral blood progenitor cells.

PubMed

Vosganian, Gregory S; Waalen, Jill; Kim, Kevin; Jhatakia, Sejal; Schram, Ethan; Lee, Tracey; Riddell, Dan; Mason, James R

2012-11-01

The long-term stability of cryopreserved peripheral blood progenitor cells is an important issue for patients experiencing disease relapse. However, there is no consensus on how to evaluate the long-term effects of cryopreservation. We describe the effect of cryopreservation on viability and progenitor colony activity from 87 individual samples processed at the Scripps Green Hospital Stem Cell Processing Center (La Jolla, CA, USA). We randomly selected 87 peripheral blood hematopoietic stem cell (PBHSC) samples from 60 patients and evaluated the effect of cryopreservation on sample viability and red and white cell colony activity after < 24 h and 7, 10 and 15 years of cryopreservation. Viability was assayed via trypan blue dye exclusion and activity was measured following 14 days of culture. An age at collection older than 50 years may result in suboptimal activity and viability following long-term cryopreservation, while gender and disease status had no effect. Cryopreservation did not significantly affect white or red cell activity following 10 years of cryopreservation. However, for samples stored longer than 10 years, viability and activity significantly decreased. We noted a positive association between higher pre-cryopreservation %CD34 count and colony activity. Cryopreservation of peripheral blood progenitor cells for up to 10 years results in no loss of clonogenic capacity, as determined by culture activity, although longer durations of storage may affect activity. Until validated methods are developed, cryopreserved grafts should be evaluated based on pre-freeze CD34(+) cell counts as assayed by flow cytometry, and post-thaw sample evaluation should be reserved for patients identified as poor mobilizers.

Long term mechanical properties of alkali activated slag

NASA Astrophysics Data System (ADS)

Zhu, J.; Zheng, W. Z.; Xu, Z. Z.; Leng, Y. F.; Qin, C. Z.

2018-01-01

This article reports a study on the microstructural and long-term mechanical properties of the alkali activated slag up to 180 days, and cement paste is studied as the comparison. The mechanical properties including compressive strength, flexural strength, axis tensile strength and splitting tensile strength are analyzed. The results showed that the alkali activated slag had higher compressive and tensile strength, Slag is activated by potassium silicate (K2SiO3) and sodium hydroxide (NaOH) solutions for attaining silicate modulus of 1 using 12 potassium silicate and 5.35% sodium hydroxide. The volume dosage of water is 35% and 42%. The results indicate that alkali activated slag is a kind of rapid hardening and early strength cementitious material with excellent long-term mechanical properties. Single row of holes block compressive strength, single-hole block compressive strength and standard solid brick compressive strength basically meet engineering requirements. The microstructures of alkali activated slag are studied by X-ray diffraction (XRD). The hydration products of alkali-activated slag are assured as hydrated calcium silicate and hydrated calcium aluminate.

Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter.

PubMed

Armstrong, Regina C; Le, Tuan Q; Frost, Emma E; Borke, Rosemary C; Vana, Adam C

2002-10-01

This study takes advantage of fibroblast growth factor 2 (FGF2) knock-out mice to determine the contribution of FGF2 to the regeneration of oligodendrocytes in the adult CNS. The role of FGF2 during spontaneous remyelination was examined using two complementary mouse models of experimental demyelination. The murine hepatitis virus strain A59 (MHV-A59) model produces focal areas of spinal cord demyelination with inflammation. The cuprizone neurotoxicant model causes extensive corpus callosum demyelination without a lymphocytic cell response. In both models, FGF2 expression is upregulated in areas of demyelination in wild-type mice. Surprisingly, in both models, oligodendrocyte repopulation of demyelinated white matter was significantly increased in FGF2 -/- mice compared with wild-type mice and even surpassed the oligodendrocyte density of nonlesioned mice. This dramatic result indicated that the absence of FGF2 promoted oligodendrocyte regeneration, possibly by enhancing oligodendrocyte progenitor proliferation and/or differentiation. FGF2 -/- and +/+ mice had similar oligodendrocyte progenitor densities in normal adult CNS, as well as similar progenitor proliferation and accumulation during demyelination. To directly analyze progenitor differentiation, glial cultures from spinal cords of wild-type mice undergoing remyelination after MHV-A59 demyelination were treated for 3 d with either exogenous FGF2 or an FGF2 neutralizing antibody. Elevating FGF2 favored progenitor proliferation, whereas attenuating endogenous FGF2 activity promoted the differentiation of progenitors into oligodendrocytes. These in vitro results are consistent with enhanced progenitor differentiation in FGF2 -/- mice. These studies demonstrate that the FGF2 genotype regulates oligodendrocyte regeneration and that FGF2 appears to inhibit oligodendrocyte lineage differentiation during remyelination.

Pre-differentiation of human neural stem cells into GABAergic neurons prior to transplant results in greater repopulation of the damaged brain and accelerates functional recovery after transient ischemic stroke.

PubMed

Abeysinghe, Hima C S; Bokhari, Laita; Quigley, Anita; Choolani, Mahesh; Chan, Jerry; Dusting, Gregory J; Crook, Jeremy M; Kobayashi, Nao R; Roulston, Carli L

2015-09-29

Despite attempts to prevent brain injury during the hyperacute phase of stroke, most sufferers end up with significant neuronal loss and functional deficits. The use of cell-based therapies to recover the injured brain offers new hope. In the current study, we employed human neural stem cells (hNSCs) isolated from subventricular zone (SVZ), and directed their differentiation into GABAergic neurons followed by transplantation to ischemic brain. Pre-differentiated GABAergic neurons, undifferentiated SVZ-hNSCs or media alone were stereotaxically transplanted into the rat brain (n=7/group) 7 days after endothelin-1 induced stroke. Neurological outcome was assessed by neurological deficit scores and the cylinder test. Transplanted cell survival, cellular phenotype and maturation were assessed using immunohistochemistry and confocal microscopy. Behavioral assessments revealed accelerated improvements in motor function 7 days post-transplant in rats treated with pre-differentiated GABAergic cells in comparison to media alone and undifferentiated hNSC treated groups. Histopathology 28 days-post transplant indicated that pre-differentiated cells maintained their GABAergic neuronal phenotype, showed evidence of synaptogenesis and up-regulated expression of both GABA and calcium signaling proteins associated with neurotransmission. Rats treated with pre-differentiated cells also showed increased neurogenic activity within the SVZ at 28 days, suggesting an additional trophic role of these GABAergic cells. In contrast, undifferentiated SVZ-hNSCs predominantly differentiated into GFAP-positive astrocytes and appeared to be incorporated into the glial scar. Our study is the first to show enhanced exogenous repopulation of a neuronal phenotype after stroke using techniques aimed at GABAergic cell induction prior to delivery that resulted in accelerated and improved functional recovery.

TH-E-BRF-01: Exploiting Tumor Shrinkage in Split-Course Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unkelbach, J; Craft, D; Hong, T

2014-06-15

Purpose: In split-course radiotherapy, a patient is treated in several stages separated by weeks or months. This regimen has been motivated by radiobiological considerations. However, using modern image-guidance, it also provides an approach to reduce normal tissue dose by exploiting tumor shrinkage. In this work, we consider the optimal design of split-course treatments, motivated by the clinical management of large liver tumors for which normal liver dose constraints prohibit the administration of an ablative radiation dose in a single treatment. Methods: We introduce a dynamic tumor model that incorporates three factors: radiation induced cell kill, tumor shrinkage, and tumor cellmore » repopulation. The design of splitcourse radiotherapy is formulated as a mathematical optimization problem in which the total dose to the liver is minimized, subject to delivering the prescribed dose to the tumor. Based on the model, we gain insight into the optimal administration of radiation over time, i.e. the optimal treatment gaps and dose levels. Results: We analyze treatments consisting of two stages in detail. The analysis confirms the intuition that the second stage should be delivered just before the tumor size reaches a minimum and repopulation overcompensates shrinking. Furthermore, it was found that, for a large range of model parameters, approximately one third of the dose should be delivered in the first stage. The projected benefit of split-course treatments in terms of liver sparing depends on model assumptions. However, the model predicts large liver dose reductions by more than a factor of two for plausible model parameters. Conclusion: The analysis of the tumor model suggests that substantial reduction in normal tissue dose can be achieved by exploiting tumor shrinkage via an optimal design of multi-stage treatments. This suggests taking a fresh look at split-course radiotherapy for selected disease sites where substantial tumor regression translates into reduced target volumes.« less

Newfoundland and Labrador: 80/20 staffing model pilot in a long-term care facility.

PubMed

Stuckless, Trudy; Power, Margaret

2012-03-01

This project, based in Newfoundland and Labrador's Central Regional Health Authority, is the first application of an 80/20 staffing model to a long-term care facility in Canada. The model allows nurse participants to spend 20% of their paid time pursuing a professional development activity instead of providing direct patient care. Newfoundland and Labrador has the highest aging demographic in Canada owing, in part, to the out-migration of younger adults. Recruiting and retaining nurses to work in long-term care in the province is difficult; at the same time, the increasing acuity of long-term care residents and their complex care needs mean that nurses must assume greater leadership roles in these facilities. This project set out to increase capacity for registered nurse (RN) leadership, training and support and to enhance the profile of long-term care as a place to work. Six RNs and one licensed practical nurse (LPN) participated and engaged in a range of professional development activities. Several of the participants are now pursuing further nursing educational activities. Central Health plans to continue a 90/10 model for one RN and one LPN per semester, with the timeframe to be determined. The model will be evaluated and, if it is deemed successful, the feasibility of implementing it in other sites throughout the region will be explored.

Long commuting time, extensive overtime, and sympathodominant state assessed in terms of short-term heart rate variability among male white-collar workers in the Tokyo megalopolis.

PubMed

Kageyama, T; Nishikido, N; Kobayashi, T; Kurokawa, Y; Kaneko, T; Kabuto, M

1998-07-01

To investigate the possible effects of long commuting time and extensive overtime on daytime cardiac autonomic activity, the short-term heart rate variability (HRV) both at supine rest and at standing rest of 223 male white-collar workers in the Tokyo Megalopolis was examined. Workers with a one-way commute of 90 min or more exhibited decreased vagal activity at supine rest and increased sympathetic activity regardless of posture, and those doing overtime of 60 h/month or more exhibited decreased vagal activity and increased sympathetic activity at standing rest. These findings suggest that chronic stress or fatigue resulting from long commuting time or extensive overtime caused these individuals to be in a sympathodominant state. Although these shifts in autonomic activities are not direct indicators of disease, it can be hypothesized that they can induce cardiovascular abnormalities or dysfunctions related to the onset of heart disease. Assessment of the daily and weekly variations in HRV as a function of daily life activities (such as working, commuting, sleeping, and exercising) among workers in Asia-Pacific urban areas might be one way of studying the possible effects of long commuting time, and extensive overtime, on health.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garland, Sid; Brown, Sally; Sims, Lynn

Long-term stewardship is the set of activities necessary to return contaminated land to safe and beneficial use. The activities include physical and legal controls to prevent inappropriate exposure to contamination left in place at a site. It is the longest phase of the Department of Energy's Environmental Management Program and ensures the protection of human health and the environment for varied end uses. At the Department of Energy's Oak Ridge Reservation an automated program has been developed and implemented that tracks the multitude of long-term stewardship activities. The Oak Ridge Reservation is a large site that currently has over 50more » actions requiring long-term stewardship activities. The Oak Ridge Reservation consists primarily of three plant sites, and long-term stewardship will enable these sites to be leased to private entities (East Tennessee Technology Park), modernized for an evolving national security mission (Y-12 National Security Complex), and revitalized to continue multi-disciplinary research (Oak Ridge National Laboratory). The varied site end uses of the individual plant sites coupled with the multitude of controls required by leaving waste in place presents challenges. A single remedial action may include surveillance and maintenance activities, media monitoring, property record notices as well as physical controls such as fences and signs. Thus, the array of long-term stewardship activities is complex and intermingled (over 200 inspections each year at various frequencies are required currently) and requires an effective tracking program, termed the Land Use Manager. The Land Use Manager is a web-based data management application for use by personnel responsible for implementing, maintaining, and verifying engineering and land use controls on the Oak Ridge Reservation. The program is a data entry and tracking tool, as well as a notification tool. The status and performance of engineering and land use controls are checked annually for evaluation in the required Remediation Effectiveness Report, and the automated Land Use Manager collects, maintains, tracks, notifies, monitors, and manages the information necessary to perform this evaluation. Land Use Manager tracks site information including type of contamination, regulatory requirements, locates land use controls; provides information on inspections, certification, and reporting; and provides reports. Most data access features, e.g., view, print, query, and download, are available to all users; however, data input, updating, and editing are restricted to the personnel directly responsible for monitoring and inspection. The Land Use Manager application was developed for the Department of Energy Oak Ridge Office by URS - CH2M Oak Ridge LLC, Restoration Services Incorporated, and MIJARA Corporation to meet the specific needs of long-term stewardship tracking on the Oak Ridge Reservation. The successful implementation of long-term stewardship enables the future government and private activities being planned on the Oak Ridge Reservation to proceed. (authors)« less

Study of the Role of CREB, BDNF, and VGF Neuropeptide in Long Term Antidepressant Activity of Crocin in the Rat Cerebellum

PubMed Central

Razavi, Bibi Marjan; Sadeghi, Mahdieh; Abnous, Khalil; Vahdati Hasani, Faezeh; Hosseinzadeh, Hossein

2017-01-01

Antidepressant activity of crocin, saffron main component, has been established before. Based on previous study, it is suggested that elevation in the levels of BDNF (brain-derived neurotrophic factor), CREB (cAMP response element binding) and VGF neuropeptide could be considered as one probable molecular mechanisms involved in antidepressant activity of long term crocin administration in the rat hippocampus. In this study we further investigated whether the antidepressant activity of crocin in long term administration was associated with alteration in these factors in the rat cerebellum. Crocin (12.5, 25 and 50 mg/kg/day) and imipramine (10 mg/kg/day) were administered interaperitoneally for 21 days to rats. At the end of experiment, animals were sacrificed and cerebellums were dissected. BDNF, VGF, CREB, and phospho-CREB (P-CREB) protein and mRNA levels in the rat cerebellum were evaluated using Western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). In the current study significant increases in mRNA and protein levels of VGF, CREB and (BDNF) in long term crocin treatment were not observed in the rat cerebellum. Although a slight increase was observed in protein level of P-CREB compared to normal saline, but it was not significant. It is concluded that antidepressant activity of crocin might be partially mediated to CREB. Moreover, other factors rather than BDNF and VGF neuropeptides may alter following long term crocin treatment in the cerebellum. To understand the precise mechanism of crocin antidepressant effects in the cerebellum, longer duration of crocin treatment in further studies is recommended. PMID:29552054

Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors.

PubMed

Chung, Woosuk; Park, Saegeun; Hong, Jiso; Park, Sangil; Lee, Soomin; Heo, Junyoung; Kim, Daesoo; Ko, Youngkwon

2015-10-01

To examine whether neonatal exposure to sevoflurane induces autism-like behaviors in mice. There are continuing reports regarding the potential negative effects of anesthesia on the developing brain. Recently, several studies suggest that neurotoxicity caused by anesthesia may lead to neurodevelopmental impairments. However, unlike reports focusing on learning and memory, there are only a few animal studies focusing on neurodevelopmental disorders after general anesthesia. Therefore, we have focused on autism, a representative neurodevelopmental disorder. Neonatal mice (P6-7) were exposed to a titrated dose of sevoflurane for 6 h. Apoptosis was evaluated by assessing the expression level of cleaved (activated) caspase-3. Autism-like behaviors, general activity, anxiety level, and long-term memory were evaluated with multiple behavioral assays. Western blotting confirmed that neonatal exposure to sevoflurane increased the expression level of activated caspase-3, indicative of apoptosis. Mice exposed to sevoflurane also showed impaired long-term memory in fear tests. However, sevoflurane-exposed mice did not exhibit autism-like features in all of the following assays: social interaction (three-chamber test, caged social interaction), social communication (ultrasonic vocalization test), or repetitive behavior (self-grooming test, digging). There were also no differences in general activity (open field test, home cage activity) and anxiety (open field test, light-dark box) after sevoflurane exposure. Our results confirm previous studies that neonatal sevoflurane exposure causes neurodegeneration and long-term memory impairment in mice. However, sevoflurane did not induce autism-like features. Our study suggests that mice are more vulnerable to long-term memory deficits than autism-like behaviors after exposure to sevoflurane. © 2015 John Wiley & Sons Ltd.

Dopaminergic tone persistently regulates voltage-gated ion current densities through the D1R-PKA axis, RNA polymerase II transcription, RNAi, mTORC1, and translation

PubMed Central

Krenz, Wulf-Dieter C.; Parker, Anna R.; Rodgers, Edmund W.; Baro, Deborah J.

2014-01-01

Long-term intrinsic and synaptic plasticity must be coordinated to ensure stability and flexibility in neuronal circuits. Coordination might be achieved through shared transduction components. Dopamine (DA) is a well-established participant in many forms of long-term synaptic plasticity. Recent work indicates that DA is also involved in both activity-dependent and -independent forms of long-term intrinsic plasticity. We previously examined DA-enabled long-term intrinsic plasticity in a single identified neuron. The lateral pyloric (LP) neuron is a component of the pyloric network in the crustacean stomatogastric nervous system (STNS). LP expresses type 1 DA receptors (D1Rs). A 1 h bath application of 5 nM DA followed by washout produced a significant increase in the maximal conductance (Gmax) of the LP transient potassium current (IA) that peaked ~4 h after the start of DA application; furthermore, if a change in neuronal activity accompanied the DA application, then a persistent increase in the LP hyperpolarization activated current (Ih) was also observed. Here, we repeated these experiments with pharmacological and peptide inhibitors to determine the cellular processes and signaling proteins involved. We discovered that the persistent, DA-induced activity-independent (IA) and activity-dependent (Ih) changes in ionic conductances depended upon many of the same elements that enable long-term synaptic plasticity, including: the D1R-protein kinase A (PKA) axis, RNA polymerase II transcription, RNA interference (RNAi), and mechanistic target of rapamycin (mTOR)-dependent translation. We interpret the data to mean that increasing the tonic DA concentration enhances expression of a microRNA(s) (miRs), resulting in increased cap-dependent translation of an unidentified protein(s). PMID:24596543

Different Phases of Long-Term Memory Require Distinct Temporal Patterns of PKA Activity after Single-Trial Classical Conditioning

ERIC Educational Resources Information Center

Michel, Maximilian; Kemenes, Ildiko; Muller, Uli; Kemenes, Gyorgy

2008-01-01

The cAMP-dependent protein kinase (PKA) is known to play a critical role in both transcription-independent short-term or intermediate-term memory and transcription-dependent long-term memory (LTM). Although distinct phases of LTM already have been demonstrated in some systems, it is not known whether these phases require distinct temporal patterns…

10 CFR 40.27 - General license for custody and long-term care of residual radioactive material disposal sites.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 1 2011-01-01 2011-01-01 false General license for custody and long-term care of residual... residual radioactive material disposal sites. (a) A general license is issued for the custody of and long... water characterization and any necessary ground water protection activities or strategies. This...

Long-term prehypertension treatment with losartan effectively prevents brain damage and stroke in stroke-prone spontaneously hypertensive rats.

PubMed

He, De-Hua; Zhang, Liang-Min; Lin, Li-Ming; Ning, Ruo-Bing; Wang, Hua-Jun; Xu, Chang-Sheng; Lin, Jin-Xiu

2014-02-01

Prehypertension has been associated with adverse cerebrovascular events and brain damage. The aims of this study were to investigate ⅰ) whether short‑ and long-term treatments with losartan or amlodipine for prehypertension were able to prevent blood pressure (BP)-linked brain damage, and ⅱ) whether there is a difference in the effectiveness of treatment with losartan and amlodipine in protecting BP-linked brain damage. In the present study, prehypertensive treatment with losartan and amlodipine (6 and 16 weeks treatment with each drug) was performed on 4-week‑old stroke-prone spontaneously hypertensive rats (SHRSP). The results showed that long-term (16 weeks) treatment with losartan is the most effective in lowering systolic blood pressure in the long term (up to 40 weeks follow-up). Additionally, compared with the amlodipine treatment groups, the short‑ and long-term losartan treatments protected SHRSP from stroke and improved their brains structurally and functionally more effectively, with the long-term treatment having more benefits. Mechanistically, the short‑ and long-term treatments with losartan reduced the activity of the local renin-angiotensin-aldosterone system (RAAS) in a time-dependent manner and more effectively than their respective counterpart amlodipine treatment group mainly by decreasing AT1R levels and increasing AT2R levels in the cerebral cortex. By contrast, the amlodipine treatment groups inhibited brain cell apoptosis more effectively as compared with the losartan treatment groups mainly through the suppression of local oxidative stress. Taken together, the results suggest that long-term losartan treatment for prehypertension effectively protects SHRSP from stroke-induced brain damage, and this protection is associated with reduced local RAAS activity than with brain cell apoptosis. Thus, the AT1R receptor blocker losartan is a good candidate drug that may be used in the clinic for long-term treatment on prehypertensive populations in order to prevent BP-linked brain damage.

[Health promotion for long-term unemployed. Effects on motivation for a healthy lifestyle].

PubMed

Horns, K; Seeger, K; Heinmüller, M; Limm, H; Waldhoff, H-P; Salman, R; Gündel, H; Angerer, P

2012-05-01

Among the long-term unemployed ill health is often a hindrance to successful reintegration in the job market. In a quasi-experimental controlled study we examined the effects of a health promotion intervention program tailored to the specific needs of the long-term unemployed combining individual sessions based on motivational interviewing and participatory group sessions including physical activity. Over a period of 3 months the participants of the intervention group (n = 179) showed more improvement compared to the control group (n = 108) in terms of motivation for lifestyle changes towards more physical activity and healthier nutrition. Participants of the intervention group developed an intention to act significantly more often (active lifestyle: odds ratio 4.44; 95% CI: 2.00-9.83; healthy nutrition: odds ratio 3.94; 95% CI: 1.55-10.00) and actually implemented a behavior change significantly more often (active lifestyle: odds ratio 2.77; 95% CI: 1.35-5.71; healthy nutrition: odds ratio 4.34; 95% CI: 1.92-9.78). In terms of smoking and alcohol consumption no significant intervention effects were detected. The results of the study show the effectiveness of the described health promotion program regarding a lifestyle change towards more healthy nutrition and more physical activity.

Patient activation in older people with long-term conditions and multimorbidity: correlates and change in a cohort study in the United Kingdom.

PubMed

Blakemore, Amy; Hann, Mark; Howells, Kelly; Panagioti, Maria; Sidaway, Mark; Reeves, David; Bower, Peter

2016-10-18

Patient Activation is defined as the knowledge, skill, and confidence a patient has in managing their health. Higher levels of patient activation are associated with better self-management, better health outcomes, and lower healthcare costs. Understanding the drivers of patient activation can allow better tailoring of patient support and interventions. There are few data on patient activation in UK patients with long-term conditions. A prospective cohort design was used. Questionnaires were mailed to 12,989 patients over the age of 65 years with at least one long-term condition in Salford, UK. They completed the Patient Activation Measure and self-report measures of: depression, health literacy, social support, health-related quality of life, and impact of multimorbidity. We report descriptive data on baseline activation and change over time, and use multivariate regression to model associations with patient activation at baseline and predictors of change in Activation over 6 months. The cohort included 4377 (33.6 %) older people, of whom 4225 were mailed a further questionnaire at 6 months; 3390 returned it complete (80.2 %). At baseline, 15 % self-reported PAM level 1, 16 % level 2, 45 % level 3, and 25 % level 4. Across all patients, depression had the strongest association with patient activation. Other important factors were: older age, being retired, poor health literacy, health-related quality of life, and social support. Total number of self-reported comorbidities and the perceived impact of comorbidities were also important for patients with more than one long-term condition. Patient activation scores were reasonably enduring over time (r = 0.43 between baseline and at six months), although nearly half changed 'levels' of activation over that time. Few variables predicted change in activation over 6 months. This is the first large scale assessment of patient activation in the UK. Our data may be useful in identifying patients who need support with patient activation, and allow interventions (such as health coaching) to be tailored to better support older patients with long-term conditions who have symptoms of depression, poor social support and impaired health literacy. Further analyses of longitudinal studies will be necessary to better understand the causal relationships between patient activation and variables such as depression.

Is Life better after motor cortex stimulation for pain control? Results at long-term and their prediction by preoperative rTMS.

PubMed

André-Obadia, Nathalie; Mertens, Patrick; Lelekov-Boissard, Taïssia; Afif, Afif; Magnin, Michel; Garcia-Larrea, Luis

2014-01-01

A positive effect of motor cortex stimulation (MCS) (defined as subjective estimations of pain relief ≥ 30%) has been reported in 55 - 64% of patients. Repetitive magnetic cortical stimulation (rTMS) is considered a predictor of MCS effect. These figures are, however, mostly based on subjective reports of pain intensity, and have not been confirmed in the long-term. This study assessed long-term pain relief (2 - 9 years) after epidural motor cortex stimulation and its pre-operative prediction by rTMS, using both intensity and Quality of Life (QoL) scales. Analysis of the long-term evolution of pain patients treated by epidural motor cortex stimulation, and predictive value of preoperative response to rTMS. University Neurological Hospital Pain Center. Twenty patients suffering chronic pharmaco-resistant neuropathic pain. All patients received first randomized sham vs. active 20 Hz-rTMS, before being submitted to MCS surgery. Postoperative pain relief was evaluated at 6 months and then up to 9 years post-MCS (average 6.1 ± 2.6 y) using (i) pain numerical rating scores (NRS); (ii) a combined assessment (CPA) including NRS, drug intake, and subjective quality of life; and (iii) a short questionnaire (HowRu) exploring discomfort, distress, disability, and dependence. Pain scores were significantly reduced by active (but not sham) rTMS and by subsequent MCS. Ten out of 20 patients kept a long-term benefit from MCS, both on raw pain scores and on CPA. The CPA results were strictly comparable when obtained by the surgeon or by a third-party on telephonic survey (r = 0.9). CPA scores following rTMS and long-term MCS were significantly associated (Fisher P = 0.02), with 90% positive predictive value and 67% negative predictive value of preoperative rTMS over long-term MCS results. On the HowRu questionnaire, long-term MCS-related improvement concerned "discomfort" (physical pain) and "dependence" (autonomy for daily activities), whereas "disability" (work, home, and leisure activities) and "distress" (anxiety, stress, depression) did not significantly improve. Limited cohort of patients with inhomogeneous pain etiology. Subjectivity of the reported items by the patient after a variable and long delay after surgery. Predictive evaluation based on a single rTMS session compared to chronic MCS. Half of the patients still retain a significant benefit after 2 - 9 years of continuous MCS, and this can be reasonably predicted by preoperative rTMS. Adding drug intake and QoL estimates to raw pain scores allows a more realistic assessment of long-term benefits and enhance the rTMS predictive value. The aims of this study and its design were approved by the local ethics committee (University Hospitals St Etienne and Lyon, France).

rhEPO Enhances Cellular Anti-oxidant Capacity to Protect Long-Term Cultured Aging Primary Nerve Cells.

PubMed

Wang, Huqing; Fan, Jiaxin; Chen, Mengyi; Yao, Qingling; Gao, Zhen; Zhang, Guilian; Wu, Haiqin; Yu, Xiaorui

2017-08-01

Erythropoietin (EPO) may protect the nervous system of animals against aging damage, making it a potential anti-aging drug for the nervous system. However, experimental evidence from natural aging nerve cell models is lacking, and the efficacy of EPO and underlying mechanism of this effect warrant further study. Thus, the present study used long-term cultured primary nerve cells to successfully mimic the natural aging process of nerve cells. Starting on the 11th day of culture, cells were treated with different concentrations of recombinant human erythropoietin (rhEPO). Using double immunofluorescence labeling, we found that rhEPO significantly improved the morphology of long-term cultured primary nerve cells and increased the total number of long-term cultured primary cells. However, rhEPO did not improve the ratio of nerve cells. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to measure nerve cell activity and showed that rhEPO significantly improved the activity of long-term cultured primary nerve cells. Moreover, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) double immunofluorescence labeling flow cytometry revealed that rhEPO reduced the apoptotic rate of long-term cultured primary nerve cells. Senescence-associated β-galactosidase (SA-β-gal) immunohistochemistry staining showed that rhEPO significantly reduced the aging rate of long-term cultured primary nerve cells. Immunochemistry revealed that rhEPO enhanced intracellular superoxide dismutase (SOD) activity and glutathione (GSH) abundance and reduced the intracellular malondialdehyde (MDA) level. In addition, this effect depended on the dose, was maximized at a dose of 100 U/ml and was more pronounced than that of vitamin E. In summary, this study finds that rhEPO protects long-term cultured primary nerve cells from aging in a dose-dependent manner. The mechanism of this effect may be associated with the enhancement of the intracellular anti-oxidant capacity. These findings provide a theoretical basis to further the anti-aging mechanism of EPO in the nervous system, and they provide experimental evidence at the cellular level for the clinical application of EPO to protect the nervous system from aging.

The influence of a tilt training programme on the renin-angiotensin-aldosterone system activity in patients with vasovagal syncope.

PubMed

Gajek, Jacek; Zyśko, Dorota; Krzemińska, Sylwia; Mazurek, Walentyna

2009-08-01

We assessed the influence of short-term and long-term tilt training on the activity of the renin-angiotensin-aldosterone system (RAAS) in vasovagal patients. Thirty-nine patients (28 F, 11 M) aged 39.7 +/- 11.2 years with a history of vasovagal syncope and a positive head-up tilt test (HUT) were studied. Blood samples for plasma renin activity (PRA) and aldosterone (ALDO) concentration were drawn at the baseline, immediately after HUT and 10 min after HUT, during the diagnostic, the negative short-term (2-5 days) follow-up HUT and long-term (1-3 months) follow-up HUT. Tilt training was started after diagnostic HUT. In diagnostic HUT, PRA increased significantly immediately after HUT comparing to the baseline, during recovery the values did not change. ALDO concentration increased after HUT comparing to baseline and further increased during recovery. After short-term tilt training, PRA and ALDO concentrations did not significantly change compared to their corresponding values in diagnostic HUT. After long-term tilt training, PRA did not significantly change compared to the values in the diagnostic and short-term follow-up HUT. ALDO concentration also did not change significantly at the baseline and immediately after HUT, and 10 min after HUT ALDO concentration was significantly lower than after diagnostic HUT. Tilt training changes the response of RAAS to the prolonged orthostasis in vasovagal patients. The coupling between PRA and ALDO after diagnostic HUT has been found to be altered and the physiological relationship was restored after long-term tilt training. The beneficial effect of tilt training depends partially on changed RAAS activation.

The integration of brain dissection within the medical neuroscience laboratory enhances learning.

PubMed

Rae, Guenevere; Cork, R John; Karpinski, Aryn C; Swartz, William J

2016-11-01

The purpose of this study was to design a one-hour brain dissection protocol for a medical neuroscience course and evaluate the short and long-term effects of its implementation on medical students. First-year medical students (n = 166) participated in a brain dissection activity that included dissection of the basal nuclei and associated deep brain structures. Short-term retention was assessed by administering identical pre- and post-activity tests involving identification of brain structures. Following the brain dissection, the students' posttest scores were significantly higher (68.8% ± 17.8%; mean percent score ± SD) than their pretest scores (35.8% ± 20.0%) (P ≤ 0.0001). Long-term retention was evaluated by conducting an identical assessment five months after completion of the course. Students who participated in the dissection activity (n = 80) had significantly higher scores (46.6% ± 23.8%) than the students who did not participate in the dissection activity (n = 85) (38.1% ± 23.9%) (P ≤ 0.05). In addition to the long-term retention assessment, the NBME ® Subject Examination scores of students who participated in the dissection activity were significantly higher than the students who did not participate in the dissection activity (P ≤ 0.01). Results suggest that this succinct brain dissection activity may be a practical addition to an undergraduate medical neuroscience course for increasing the effectiveness of neuroanatomy training. This effect may have long-term benefits on knowledge retention and may be correlated with higher performance levels on standardized subject examinations. Anat Sci Educ 9: 565-574. © 2016 American Association of Anatomists. © 2016 American Association of Anatomists.

A Portable Dynamic Laser Speckle System for Sensing Long-Term Changes Caused by Treatments in Painting Conservation.

PubMed

Pérez, Alberto J; González-Peña, Rolando J; Braga, Roberto; Perles, Ángel; Pérez-Marín, Eva; García-Diego, Fernando J

2018-01-11

Dynamic laser speckle (DLS) is used as a reliable sensor of activity for all types of materials. Traditional applications are based on high-rate captures (usually greater than 10 frames-per-second, fps). Even for drying processes in conservation treatments, where there is a high level of activity in the first moments after the application and slower activity after some minutes or hours, the process is based on the acquisition of images at a time rate that is the same in moments of high and low activity. In this work, we present an alternative approach to track the drying process of protective layers and other painting conservation processes that take a long time to reduce their levels of activity. We illuminate, using three different wavelength lasers, a temporary protector (cyclododecane) and a varnish, and monitor them using a low fps rate during long-term drying. The results are compared to the traditional method. This work also presents a monitoring method that uses portable equipment. The results present the feasibility of using the portable device and show the improved sensitivity of the dynamic laser speckle when sensing the long-term process for drying cyclododecane and varnish in conservation.

Disability in long-term care residents explained by prevalent geriatric syndromes, not long-term care home characteristics: a cross-sectional study.

PubMed

Lane, Natasha E; Wodchis, Walter P; Boyd, Cynthia M; Stukel, Thérèse A

2017-02-10

Self-care disability is dependence on others to conduct activities of daily living, such as bathing, eating and dressing. Among long-term care residents, self-care disability lowers quality of life and increases health care costs. Understanding the correlates of self-care disability in this population is critical to guide clinical care and ongoing research in Geriatrics. This study examines which resident geriatric syndromes and chronic conditions are associated with residents' self-care disability and whether these relationships vary across strata of age, sex and cognitive status. It also describes the proportion of variance in residents' self-care disability that is explained by residents' geriatric syndromes versus long-term care home characteristics. We conducted a cross-sectional study using a health administrative cohort of 77,165 long-term care home residents residing in 614 Ontario long-term care homes. Eligible residents had their self-care disability assessed using the RAI-MDS 2.0 activities of daily living long-form score (range: 0-28) within 90 days of April 1st, 2011. Hierarchical multivariable regression models with random effects for long-term care homes were used to estimate the association between self-care disability and resident geriatric syndromes, chronic conditions and long-term care home characteristics. Differences in findings across strata of sex, age and cognitive status (cognitively intact versus cognitively impaired) were examined. Geriatric syndromes were much more strongly associated with self-care disability than chronic conditions in multivariable models. The direction and size of some of these effects were different for cognitively impaired versus cognitively intact residents. Residents' geriatric syndromes explained 50% of the variation in their self-care disability scores, while characteristics of long-term care homes explained an additional 2% of variation. Differences in long-term care residents' self-care disability are largely explained by prevalent geriatric syndromes. After adjusting for resident characteristics, there is little variation in self-care disability associated with long-term care home characteristics. This suggests that residents' geriatric syndromes-not the homes in which they live-may be the appropriate target of interventions to reduce self-care disability, and that such interventions may need to differ for cognitively impaired versus unimpaired residents.

GH Mediates Exercise-Dependent Activation of SVZ Neural Precursor Cells in Aged Mice

PubMed Central

Blackmore, Daniel G.; Vukovic, Jana; Waters, Michael J.; Bartlett, Perry F.

2012-01-01

Here we demonstrate, both in vivo and in vitro, that growth hormone (GH) mediates precursor cell activation in the subventricular zone (SVZ) of the aged (12-month-old) brain following exercise, and that GH signaling stimulates precursor activation to a similar extent to exercise. Our results reveal that both addition of GH in culture and direct intracerebroventricular infusion of GH stimulate neural precursor cells in the aged brain. In contrast, no increase in neurosphere numbers was observed in GH receptor null animals following exercise. Continuous infusion of a GH antagonist into the lateral ventricle of wild-type animals completely abolished the exercise-induced increase in neural precursor cell number. Given that the aged brain does not recover well after injury, we investigated the direct effect of exercise and GH on neural precursor cell activation following irradiation. This revealed that physical exercise as well as infusion of GH promoted repopulation of neural precursor cells in irradiated aged animals. Conversely, infusion of a GH antagonist during exercise prevented recovery of precursor cells in the SVZ following irradiation. PMID:23209615

A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System.

PubMed

Qin, Yan; Garrison, Brian S; Ma, Wenjiang; Wang, Rui; Jiang, Aiping; Li, Jing; Mistry, Meeta; Bronson, Roderick T; Santoro, Daria; Franco, Charlotte; Robinton, Daisy A; Stevens, Beth; Rossi, Derrick J; Lu, Chafen; Springer, Timothy A

2018-06-12

Extracellular proTGF-β is covalently linked to "milieu" molecules in the matrix or on cell surfaces and is latent until TGF-β is released by integrins. Here, we show that LRRC33 on the surface of microglia functions as a milieu molecule and enables highly localized, integrin-αVβ8-dependent TGF-β activation. Lrrc33 -/- mice lack CNS vascular abnormalities associated with deficiency in TGF-β-activating integrins but have microglia with a reactive phenotype and after 2 months develop ascending paraparesis with loss of myelinated axons and death by 5 months. Whole bone marrow transplantation results in selective repopulation of Lrrc33 -/- brains with WT microglia and halts disease progression. The phenotypes of WT and Lrrc33 -/- microglia in the same brain suggest that there is little spreading of TGF-β activated from one microglial cell to neighboring microglia. Our results suggest that interactions between integrin-bearing cells and cells bearing milieu molecule-associated TGF-β provide localized and selective activation of TGF-β. Copyright © 2018 Elsevier Inc. All rights reserved.

Cost-Effectiveness of a Long-Term Internet-Delivered Worksite Health Promotion Programme on Physical Activity and Nutrition: A Cluster Randomized Controlled Trial

ERIC Educational Resources Information Center

Robroek, Suzan J. W.; Polinder, Suzanne; Bredt, Folef J.; Burdorf, Alex

2012-01-01

This study aims to evaluate the cost-effectiveness of a long-term workplace health promotion programme on physical activity (PA) and nutrition. In total, 924 participants enrolled in a 2-year cluster randomized controlled trial, with departments (n = 74) within companies (n = 6) as the unit of randomization. The intervention was compared with a…

Prior Activation of Inositol 1,4,5-Trisphosphate Receptors Suppresses the Subsequent Induction of Long-Term Potentiation in Hippocampal CA1 Neurons

ERIC Educational Resources Information Center

Fujii, Satoshi; Yamazaki, Yoshihiko; Goto, Jun-Ichi; Fujiwara, Hiroki; Mikoshiba, Katsuhiko

2016-01-01

We investigated the role of inositol 1,4,5-trisphosphate receptors (IP3Rs) activated by preconditioning low-frequency afferent stimulation (LFS) in the subsequent induction of long-term potentiation (LTP) in CA1 neurons in hippocampal slices from mature guinea pigs. Induction of LTP in the field excitatory postsynaptic potential or the population…

Long-term surveillance plan for the Bodo Canyon Disposal Site, Durango, Colorado. Revision 1

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1995-11-01

This long-term surveillance plan (LTSP) for the Uranium Mill Tailings Remedial Act on (UMTRA) Project Bodo Canyon disposal site at Durango, Colorado, describes the surveillance activities for the disposal site. The US Department of Energy (DOE) will carry out these activities to ensure that the disposal call continues to function as designed This LTSP was prepared as a requirement for DOE acceptance under the US Nuclear Regulatory Commission (NRC) general license for custody and long-term care of residual radioactive materials (RRM) from processing uranium ore. This LTSP documents that the land and interests are owned by the United States andmore » details how long-term care of the disposal site will be carried out. It is based on the DOE`s Guidance for Implementing the UMTRA Project Long-term Surveillance Program (DOE, 1992a). Following the introduction, contents of this report include the following: site final condition; site drawings and photographs; permanent site surveillance features; ground water monitoring; annual site inspections; unscheduled inspections; custodial maintenance; corrective action; record keeping and reporting requirements; emergency notification and reporting; quality assurance; personal health and safety; list of contributions; and references.« less

The requirement for enhanced CREB1 expression in consolidation of long-term synaptic facilitation and long-term excitability in sensory neurons of Aplysia

PubMed Central

Liu, Rong-Yu; Cleary, Leonard J.; Byrne, John H.

2011-01-01

Accumulating evidence suggests that the transcriptional activator CREB1 is important for serotonin (5-HT)-induced long-term facilitation (LTF) of the sensorimotor synapse in Aplysia. Moreover, creb1 is among the genes activated by CREB1, suggesting a role for this protein beyond the induction phase of LTF. The time course of the requirement for CREB1 synthesis in the consolidation of long-term facilitation was examined using RNA interference (RNAi) techniques in sensorimotor co-cultures. Injection of CREB1 small-interfering RNA (siRNA) immediately or 10 h after 5-HT treatment blocked LTF when measured at 24 h and 48 h after treatment. In contrast, CREB1 siRNA did not block LTF when injected 16 h after 5-HT treatment. These results demonstrate that creb1 expression must be sustained for a relatively long time in order to support the consolidation of LTF. In addition, LTF is also accompanied by a long-term increase in the excitability (LTE) of sensory neurons (SNs). Because LTE was observed in the isolated SN after 5-HT treatment, this long-term change was intrinsic to that element of the circuit. LTE was blocked when CREB1 siRNA was injected into isolated SNs immediately after 5-HT treatment. These data suggest that 5-HT-induced CREB1 synthesis is required for consolidation of both LTF and LTE. PMID:21543617

Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease.

PubMed

Monday, Hannah R; Younts, Thomas J; Castillo, Pablo E

2018-04-25

Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats

PubMed Central

Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

2015-01-01

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes. PMID:26716991

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats.

PubMed

Favaro, Vanessa Manchim; Yonamine, Maurício; Soares, Juliana Carlota Kramer; Oliveira, Maria Gabriela Menezes

2015-01-01

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.

Long-term three-dimensional perfusion culture of human adult bone marrow mononuclear cells in bioreactors.

PubMed

Schmelzer, Eva; Finoli, Anthony; Nettleship, Ian; Gerlach, Jörg C

2015-04-01

The construction and long-term maintenance of three-dimensional in vitro bone marrow models is of great interest but still quite challenging. Here we describe the use of a multi-compartment hollow-fiber membrane based three-dimensional perfusion bioreactor for long-term culture of whole human bone marrow mononuclear cells. We also investigated bioreactors with incorporated open-porous foamed hydroxyapatite scaffolds, mimicking the in vivo bone matrix. Cells in bioreactors with and without scaffolds were cultured to 6 weeks and compared to Petri dish controls. Cells were analyzed for gene expression, surface markers by flow cytometry, metabolic activity, hematopoietic potential, viability, and attachment by immunocytochemistry. Cells in bioreactors were metabolic active during long-term culture. The percentages of hematopoietic stem cell and mature endothelial cell fractions were maintained in bioreactors. The expression of most of the analyzed genes stabilized and increased after long-term culture of 6 weeks. Compared to Petri dish culture controls, bioreactor perfusion culture improved in both the short and long-term, the colony formation unit capacity of hematopoietic progenitors. Cells attached to the ample surface area provided by hydroxyapatite scaffolds. The implementation of a hydroxyapatite scaffold did not influence colony formation capacity, percentages of cell type specific fractions, gene expression, cell viability or metabolic turnover when compared to control cells cultured in bioreactors without scaffolds. In conclusion, three-dimensional perfusion bioreactor culture enables long-term maintenance of primary human bone marrow cells, with hydroxyapatite scaffolds providing an in vivo-like scaffold for three-dimensional culture. © 2015 Wiley Periodicals, Inc.

Role of nitric oxide in long-term potentiation of the rat medial vestibular nuclei.

PubMed

Grassi, S; Pettorossi, V E

2000-01-01

In rat brainstem slices, we investigated the role of nitric oxide in long-term potentiation induced in the ventral portion of the medial vestibular nuclei by high-frequency stimulation of the primary vestibular afferents. The nitric oxide scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide ] and the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester were administered before and after induction of potentiation. Both drugs completely prevented long-term potentiation, whereas they did not impede the potentiation build-up, or affect the already established potentiation. These results demonstrate that the induction, but not the maintenance of vestibular long-term potentiation, depends on the synthesis and release into the extracellular medium of nitric oxide. In addition, we analysed the effect of the nitric oxide donor sodium nitroprusside on vestibular responses. Sodium nitroprusside induced long-term potentiation, as evidenced through the field potential enhancement and unit peak latency decrease. This potentiation was impeded by D, L-2-amino-5-phosphonopentanoic acid, and was reduced under blockade of synaptosomal platelet-activating factor receptors by ginkgolide B and group I metabotropic glutamate receptors by (R,S)-1-aminoindan-1, 5-dicarboxylic acid. When reduced, potentiation fully developed following the washout of antagonist, demonstrating an involvement of platelet-activating factor and group I metabotropic glutamate receptors in its full development. Potentiation induced by sodium nitroprusside was also associated with a decrease in the paired-pulse facilitation ratio, which persisted under ginkgolide B, indicating that nitric oxide increases glutamate release independently of platelet-activating factor-mediated presynaptic events. We suggest that nitric oxide, released after the activation of N-methyl-D-aspartate receptors, acts as a retrograde messenger leading to an enhancement of glutamate release to a sufficient level for triggering potentiation. Once the synaptic efficacy has changed, it becomes a long-lasting phenomenon only through a subsequent action of platelet-activating factor.

Chronic ethanol intake induces partial microglial activation that is not reversed by long-term ethanol withdrawal in the rat hippocampal formation.

PubMed

Cruz, Catarina; Meireles, Manuela; Silva, Susana M

2017-05-01

Neuroinflammation has been implicated in the pathogenesis of several disorders. Activation of microglia leads to the release of pro-inflammatory mediators and microglial-mediated neuroinflammation has been proposed as one of the alcohol-induced neuropathological mechanisms. The present study aimed to examine the effect of chronic ethanol exposure and long-term withdrawal on microglial activation and neuroinflammation in the hippocampal formation. Male rats were submitted to 6 months of ethanol treatment followed by a 2-month withdrawal period. Stereological methods were applied to estimate the total number of microglia and activated microglia detected by CD11b immunohistochemistry in the hippocampal formation. The expression levels of the pro-inflammatory cytokines TNF-α, COX-2 and IL-15 were measured by qRT-PCR. Alcohol consumption was associated with an increase in the total number of activated microglia but morphological assessment indicated that microglia did not exhibit a full activation phenotype. These data were supported by functional evidence since chronic alcohol consumption produced no changes in the expression of TNF-α or COX-2. The levels of IL-15 a cytokine whose expression is increased upon activation of both astrocytes and microglia, was induced by chronic alcohol treatment. Importantly, the partial activation of microglia induced by ethanol was not reversed by long-term withdrawal. This study suggests that chronic alcohol exposure induces a microglial phenotype consistent with partial activation without significant increase in classical cytokine markers of neuroinflammation in the hippocampal formation. Furthermore, long-term cessation of alcohol intake is not sufficient to alter the microglial partial activation phenotype induced by ethanol. Copyright © 2017 Elsevier B.V. All rights reserved.

Brain Angiotensin II AT1 receptors are involved in the acute and long-term amphetamine-induced neurocognitive alterations.

PubMed

Marchese, Natalia Andrea; Artur de laVillarmois, Emilce; Basmadjian, Osvaldo Martin; Perez, Mariela Fernanda; Baiardi, Gustavo; Bregonzio, Claudia

2016-03-01

Angiotensin II, by activation of its brain AT1-receptors, plays an active role as neuromodulator in dopaminergic transmission. These receptors participate in the development of amphetamine-induced behavioral and dopamine release sensitization. Dopamine is involved in cognitive processes and provides connectivity between brain areas related to these processes. Amphetamine by its mimetic activity over dopamine neurotransmission elicits differential responses after acute administration or after re-exposure following long-term withdrawal periods in different cognitive processes. The purpose of this study is to evaluate the AT1-receptor involvement in the acute and long-term amphetamine-induced alterations in long-term memory and in cellular-related events. Male Wistar rats (250-300 g) were used in this study. Acute effects: Amphetamine (0.5/2.5 mg/kg i.p.) was administered after post-training in the inhibitory avoidance (IA) response. The AT1-receptor blocker Losartan was administered i.c.v. before a single dose of amphetamine (0.5 mg/kg i.p.). Long-term effects: The AT1-receptors blocker Candesartan (3 mg/kg p.o.) was administered for 5 days followed by 5 consecutive days of amphetamine (2.5 mg/kg/day, i.p.). The neuroadaptive changes were evidenced after 1 week of withdrawal by an amphetamine challenge (0.5 mg/kg i.p.). The IA response, the neuronal activation pattern, and the hippocampal synaptic transmission were evaluated. The impairing effect in the IA response of post-training acute amphetamine was partially prevented by Losartan. The long-term changes induced by repeated amphetamine (resistance to acute amphetamine interference in the IA response, neurochemical altered response, and increased hippocampal synaptic transmission) were prevented by AT1-receptors blockade. AT1-receptors are involved in the acute alterations and in the neuroadaptations induced by repeated amphetamine associated with neurocognitive processes.

Mechanism underlying the effect of long-term exposure to low dose of pesticides on DNA integrity.

PubMed

Alleva, Renata; Manzella, Nicola; Gaetani, Simona; Bacchetti, Tiziana; Bracci, Massimo; Ciarapica, Veronica; Monaco, Federica; Borghi, Battista; Amati, Monica; Ferretti, Gianna; Tomasetti, Marco

2018-04-01

Pesticides, including herbicides, insecticides and fungicides, are widely used in intensive agriculture. Recently, the long-term effects of pesticide exposure were found to be associated with many diseases. In this study, we evaluated the long-term effect of low-level exposure to a mixture of pesticides on DNA damage response (DDR) in relation to individual detoxifying variability. A residential population chronically exposed to pesticides was enrolled, biological/environmental pesticide levels; paroxonase 1 (PON-1) activity and 192 Q/R polymorphism and DDR were evaluated at three different periods of pesticide exposure. OGG1-dependent DNA repair activity was decreased in relation to pesticide exposure. The increase of DNA lesions and pesticide levels in the intensive pesticide-spraying period was independent on PON-1 activity. Next, human bronchial epithelial and neuronal cells were used as a model for in vitro evaluation of the mechanistic effect of pesticides. Pesticides induced mitochondrial dysfunction leading to ROS formation. ROS from mitochondria induced DNA damage, which in turn induced OGG1-dependent DNA repair activity through 8-oxoguanine DNA glycosylase 1 (OGG1) expression and activation. Even though OGG1 was overexpressed, an inhibition of its activity, associated with DNA lesion accumulation, was found at prolonged pesticide-exposure. A post-translational regulation of OGG1 by pesticide may be postulated. Taken together, long-term exposure to low-levels of pesticides affects DDR resulting in accumulation of DNA lesions that eventually may lead to cancer or neurological disorders. © 2018 Wiley Periodicals, Inc.

Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies

PubMed Central

Finsterwald, Charles; Alberini, Cristina M.

2013-01-01

A proper response against stressors is critical for survival. In mammals, the stress response is primarily mediated by secretion of glucocorticoids via the hypothalamic-pituitaryadrenocortical (HPA) axis and release of catecholamines through adrenergic neurotransmission. Activation of these pathways results in a quick physical response to the stress and, in adaptive conditions, mediates long-term changes in the brain that lead to the formation of long-term memories of the experience. These long-term memories are an essential adaptive mechanism that allows an animal to effectively face similar demands again. Indeed, a moderate stress level has a strong positive effect on memory and cognition, as a single arousing or moderately stressful event can be remembered for up to a lifetime. Conversely, exposure to extreme, traumatic, or chronic stress can have the opposite effect and cause memory loss, cognitive impairments, and stress-related psychopathologies such as anxiety disorders, depression and post-traumatic stress disorder (PTSD). While more effort has been devoted to the understanding of the effects of the negative effects of chronic stress, much less has been done thus far on the identification of the mechanisms engaged in the brain when stress promotes long-term memory formation. Understanding these mechanisms will provide critical information for use in ameliorating memory processes in both normal and pathological conditions. Here, we will review the role of glucocorticoids and glucocorticoid receptors (GRs) in memory formation and modulation. Furthermore, we will discuss recent findings on the molecular cascade of events underlying the effect of GR activation in adaptive levels of stress that leads to strong, long-lasting memories. Our recent data indicate that the positive effects of GR activation on memory consolidation critically engage the brain-derived neurotrophic factor (BDNF) pathway. We propose and will discuss the hypothesis that stress promotes the formation of strong long-term memories because the activation of hippocampal GRs after learning is coupled to the recruitment of the growth and pro-survival BDNF/cAMP response element-binding protein (CREB) pathway, which is well-know to be a general mechanism required for long-term memory formation. We will then speculate about how these results may explain the negative effects of traumatic or chronic stress on memory and cognitive functions. PMID:24113652

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

The Office of Natural Gas and Petroleum Import and Export Activities prepares quarterly reports showing natural gas import and export activity. Companies are required to file quarterly reports. Attachments show the percentage of takes to maximum firm contract levels and the weighted average per unit price for each of the long-term importers during the 5 most recent quarters, volumes and prices of gas purchased by long-term importers and exporters during the past 12 months, volume and price data for gas imported on a short-term or spot market basis, and the gas exported on a short-term or spot market basis tomore » Canada and Mexico.« less

The Histone Deacetylase HDAC4 Regulates Long-Term Memory in Drosophila

PubMed Central

Fitzsimons, Helen L.; Schwartz, Silvia; Given, Fiona M.; Scott, Maxwell J.

2013-01-01

A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. Here, we investigate the role of HDAC4 in long-term memory formation in Drosophila. We show that overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, resulted in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. We found that overexpression of HDAC4 resulted in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, we also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory, therefore we demonstrate that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation. PMID:24349558

Short-term and long-term effects of protein kinase C on the trafficking and stability of human organic anion transporter 3

PubMed Central

Zhang, Qiang; Suh, Wonmo; Pan, Zui; You, Guofeng

2012-01-01

Human organic anion transporter 3 (hOAT3) belongs to a family of organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. In the current study, we investigated the short-term and long-term regulation of hOAT3 by protein kinase C (PKC). We showed that short-term activation of PKC by phobol 12-Myristate 13-Acetate (PMA) inhibited hOAT3 activity through accelerating its internalization from cell surface to intracellular recycling endosomes. The colocalization of hOAT3 with EEA1-positive recycling endosomes was demonstrated by immunolocalization with confocal microscopy. Furthermore, we showed that long-term activation of PKC resulted in the enhanced degradation of cell surface hOAT3. The pathways for hOAT3 degradation were further examined using proteasomal and lysosomal inhibitors. Our results showed that both proteasomal inhibitors and the lysosomal inhibitors significantly blocked hOAT3 degradation. These results demonstrate that PKC plays critical roles in the trafficking and the stability of hOAT3. PMID:22773962

Chromosome Aberrations in Astronauts

NASA Technical Reports Server (NTRS)

George, Kerry A.; Durante, M.; Cucinotta, Francis A.

2007-01-01

A review of currently available data on in vivo induced chromosome damage in the blood lymphocytes of astronauts proves that, after protracted exposure of a few months or more to space radiation, cytogenetic biodosimetry analyses of blood collected within a week or two of return from space provides a reliable estimate of equivalent radiation dose and risk. Recent studies indicate that biodosimetry estimates from single spaceflights lie within the range expected from physical dosimetry and biophysical models, but very large uncertainties are associated with single individual measurements and the total sample population remains low. Retrospective doses may be more difficult to estimate because of the fairly rapid time-dependent loss of "stable" aberrations in blood lymphocytes. Also, biodosimetry estimates from individuals who participate in multiple missions, or very long (interplanetary) missions, may be complicated by an adaptive response to space radiation and/or changes in lymphocyte survival and repopulation. A discussion of published data is presented and specific issues related to space radiation biodosimetry protocols are discussed.

Electron shuttling in phosphorus donor qubit systems

NASA Astrophysics Data System (ADS)

Jacobson, N. Tobias; Gamble, John King; Nielsen, Erik; Muller, Richard P.; Witzel, Wayne M.; Montano, Ines; Carroll, Malcolm S.

2014-03-01

Phosphorus donors in silicon are a promising qubit architecture, due in large part to their long nuclear coherence times and the recent development of atomically precise fabrication methods. Here, we investigate issues related to implementing qubits with phosphorus donors in silicon, employing an effective mass theory that non-phenomenologically takes into account inter-valley coupling. We estimate the significant sources of decoherence and control errors in this system to compute the fidelity of primitive gates and gate timescales. We include the effects of valley repopulation during the process of shuttling an electron between a donor and nearby interface or between neighboring donors, evaluating the control requirements for ensuring adiabaticity with respect to the valley sector. This work was supported in part by the LDRD program at Sandia National Labs, a multi-program laboratory managed and operated by Sandia Corp, a wholly owned subsidiary of Lockheed Martin Corp, for the U.S. DOE NNSA under contract DE-AC04-94AL85000.

76 FR 17419 - Agency Information Collection Activities; Proposed Collection; Comment Request; Extension of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-29

... Title III and Minor Revisions to the Certification of Long-Term Care Ombudsman Program Expenditures... Certification of Long-Term Care Ombudsman Program Expenditures provides statutorily required information... DEPARTMENT OF HEALTH AND HUMAN SERVICES Administration on Aging Agency Information Collection...

ALTERED PHOSPHORYLATION OF MAP KINASE AFTER ACUTE EXPOSURE TO PCB153.

EPA Science Inventory

Long-term potentiation (LTP) is a model of synaptic plasticity believed to encompass the physiological substrate of memory. The mitogen-activated protein kinase (ERK1/2) signalling cascade contributes to synaptic plasticity and to long-term memory formation. Learning and LTP st...

Implantable fiber-optic interface for parallel multisite long-term optical dynamic brain interrogation in freely moving mice

PubMed Central

Doronina-Amitonova, L. V.; Fedotov, I. V.; Ivashkina, O. I.; Zots, M. A.; Fedotov, A. B.; Anokhin, K. V.; Zheltikov, A. M.

2013-01-01

Seeing the big picture of functional responses within large neural networks in a freely functioning brain is crucial for understanding the cellular mechanisms behind the higher nervous activity, including the most complex brain functions, such as cognition and memory. As a breakthrough toward meeting this challenge, implantable fiber-optic interfaces integrating advanced optogenetic technologies and cutting-edge fiber-optic solutions have been demonstrated, enabling a long-term optogenetic manipulation of neural circuits in freely moving mice. Here, we show that a specifically designed implantable fiber-optic interface provides a powerful tool for parallel long-term optical interrogation of distinctly separate, functionally different sites in the brain of freely moving mice. This interface allows the same groups of neurons lying deeply in the brain of a freely behaving mouse to be reproducibly accessed and optically interrogated over many weeks, providing a long-term dynamic detection of genome activity in response to a broad variety of pharmacological and physiological stimuli. PMID:24253232

Involvement of melatonin metabolites in the long-term inhibitory effect of the hormone on rat spinal nociceptive transmission.

PubMed

Mondaca, Mauricio; Hernández, Alejandro; Valladares, Luis; Sierralta, Walter; Noseda, Rodrigo; Soto-Moyano, Rubén

2004-02-01

There is evidence that melatonin and its metabolites could bind to nuclear sites in neurones, suggesting that this hormone is able to exert long-term functional effects in the central nervous system via genomic mechanisms. This study was designed to investigate (i) whether systemically administered melatonin can exert long-term effects on spinal cord windup activity, and (ii) whether blockade of melatonin degradation with eserine could prevent this effect. Rats receiving melatonin (10 mg/kg ip), the same dose of melatonin plus eserine (0.5 mg/kg ip), or saline were studied. Seven days after administration of the drugs or saline, spinal windup of rats was assessed in a C-fiber reflex response paradigm. Results show that rats receiving melatonin exhibited a reduction in spinal windup activity. This was not observed in the animals receiving melatonin plus eserine or saline, suggesting a role for melatonin metabolites in long-term changes of nociceptive transmission in the rat spinal cord.

Long-Term Spectral Variability of the Spotted Star IN Com

NASA Astrophysics Data System (ADS)

Alekseev, I. Yu.; Kozlova, O. V.; Gorda, S. Yu.; Avvakumova, E. A.; Kozhevnikova, A. V.

2017-06-01

We present long-term (2004-2016) spectral observations (R = 20000) of IN Com in the regions of Hα, Hβ and He I 5876 Å lines. The unique feature of the stellar spectrum is the presence of the extended two-component emission with limits up to ± 400 km s-1 in the Hα line. Emission parameters show the rotation modulation with the stellar rotation period and a significant variability on the long-term scale. Similar emission is also observed in Hβ and He I 5876 Å lines. Our results allow us to conclude that observational emission profiles are formed in optically thin hot gas. It is a result of presence of a circumstellar gas disk around IN Com. Its size is not exceed several stellar radii. The matter for the disk is supported by stellar wind. Detected variability of Hα emission parameters shows evident relation with UBVRI photometric activity of the star. This fact allowed us to link the long-term spectral variability with cycles of stellar activity of IN Com.

Implantable fiber-optic interface for parallel multisite long-term optical dynamic brain interrogation in freely moving mice

NASA Astrophysics Data System (ADS)

Doronina-Amitonova, L. V.; Fedotov, I. V.; Ivashkina, O. I.; Zots, M. A.; Fedotov, A. B.; Anokhin, K. V.; Zheltikov, A. M.

2013-11-01

Seeing the big picture of functional responses within large neural networks in a freely functioning brain is crucial for understanding the cellular mechanisms behind the higher nervous activity, including the most complex brain functions, such as cognition and memory. As a breakthrough toward meeting this challenge, implantable fiber-optic interfaces integrating advanced optogenetic technologies and cutting-edge fiber-optic solutions have been demonstrated, enabling a long-term optogenetic manipulation of neural circuits in freely moving mice. Here, we show that a specifically designed implantable fiber-optic interface provides a powerful tool for parallel long-term optical interrogation of distinctly separate, functionally different sites in the brain of freely moving mice. This interface allows the same groups of neurons lying deeply in the brain of a freely behaving mouse to be reproducibly accessed and optically interrogated over many weeks, providing a long-term dynamic detection of genome activity in response to a broad variety of pharmacological and physiological stimuli.

mTORC2 controls actin polymerization required for consolidation of long-term memory

PubMed Central

Huang, Wei; Zhu, Ping Jun; Zhang, Shixing; Zhou, Hongyi; Stoica, Loredana; Galiano, Mauricio; Krnjević, Krešimir; Roman, Gregg; Costa-Mattioli, Mauro

2013-01-01

A major goal of biomedical research has been the identification of molecular mechanisms that can enhance memory. Here we report a novel signaling pathway that regulates the conversion from short- to long-term memory. The mTOR complex 2 (mTORC2), which contains the key regulatory protein Rictor (Rapamycin-Insensitive Companion of mTOR), was discovered only recently, and little is known about its physiological role. We show that conditional deletion of rictor in the postnatal murine forebrain greatly reduces mTORC2 activity and selectively impairs both long-term memory (LTM) and the late (but not the early) phase of hippocampal long-term potentiation (LTP). Actin polymerization is reduced in the hippocampus of mTORC2-deficient mice and its restoration rescues both L-LTP and LTM. More importantly, a compound that selectively promotes mTORC2 activity converts early-LTP into late-LTP and enhances LTM. These findings indicate that mTORC2 could be a novel therapeutic target for the treatment of cognitive dysfunction. PMID:23455608

Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization

PubMed Central

Uzarski, Joseph S.; Bijonowski, Brent M.; Wang, Bo; Ward, Heather H.; Wandinger-Ness, Angela

2015-01-01

Analysis of perfusion-based bioreactors for organ engineering and a detailed evaluation of physical and biochemical parameters that measure dynamic changes within maturing cell-laden scaffolds are critical components of ex vivo tissue development that remain understudied topics in the tissue and organ engineering literature. Intricately designed bioreactors that house developing tissue are critical to properly recapitulate the in vivo environment, deliver nutrients within perfused media, and monitor physiological parameters of tissue development. Herein, we provide an in-depth description and analysis of two dual-purpose perfusion bioreactors that improve upon current bioreactor designs and enable comparative analyses of ex vivo scaffold recellularization strategies and cell growth performance during long-term maintenance culture of engineered kidney or liver tissues. Both bioreactors are effective at maximizing cell seeding of small-animal organ scaffolds and maintaining cell survival in extended culture. We further demonstrate noninvasive monitoring capabilities for tracking dynamic changes within scaffolds as the native cellular component is removed during decellularization and model human cells are introduced into the scaffold during recellularization and proliferate in maintenance culture. We found that hydrodynamic pressure drop (ΔP) across the retained scaffold vasculature is a noninvasive measurement of scaffold integrity. We further show that ΔP, and thus resistance to fluid flow through the scaffold, decreases with cell loss during decellularization and correspondingly increases to near normal values for whole organs following recellularization of the kidney or liver scaffolds. Perfused media may be further sampled in real time to measure soluble biomarkers (e.g., resazurin, albumin, or kidney injury molecule-1) that indicate degree of cellular metabolic activity, synthetic function, or engraftment into the scaffold. Cell growth within bioreactors is validated for primary and immortalized cells, and the design of each bioreactor is scalable to accommodate any three-dimensional scaffold (e.g., synthetic or naturally derived matrix) that contains conduits for nutrient perfusion to deliver media to growing cells and monitor noninvasive parameters during scaffold repopulation, broadening the applicability of these bioreactor systems. PMID:25929317

Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization.

PubMed

Uzarski, Joseph S; Bijonowski, Brent M; Wang, Bo; Ward, Heather H; Wandinger-Ness, Angela; Miller, William M; Wertheim, Jason A

2015-10-01

Analysis of perfusion-based bioreactors for organ engineering and a detailed evaluation of physical and biochemical parameters that measure dynamic changes within maturing cell-laden scaffolds are critical components of ex vivo tissue development that remain understudied topics in the tissue and organ engineering literature. Intricately designed bioreactors that house developing tissue are critical to properly recapitulate the in vivo environment, deliver nutrients within perfused media, and monitor physiological parameters of tissue development. Herein, we provide an in-depth description and analysis of two dual-purpose perfusion bioreactors that improve upon current bioreactor designs and enable comparative analyses of ex vivo scaffold recellularization strategies and cell growth performance during long-term maintenance culture of engineered kidney or liver tissues. Both bioreactors are effective at maximizing cell seeding of small-animal organ scaffolds and maintaining cell survival in extended culture. We further demonstrate noninvasive monitoring capabilities for tracking dynamic changes within scaffolds as the native cellular component is removed during decellularization and model human cells are introduced into the scaffold during recellularization and proliferate in maintenance culture. We found that hydrodynamic pressure drop (ΔP) across the retained scaffold vasculature is a noninvasive measurement of scaffold integrity. We further show that ΔP, and thus resistance to fluid flow through the scaffold, decreases with cell loss during decellularization and correspondingly increases to near normal values for whole organs following recellularization of the kidney or liver scaffolds. Perfused media may be further sampled in real time to measure soluble biomarkers (e.g., resazurin, albumin, or kidney injury molecule-1) that indicate degree of cellular metabolic activity, synthetic function, or engraftment into the scaffold. Cell growth within bioreactors is validated for primary and immortalized cells, and the design of each bioreactor is scalable to accommodate any three-dimensional scaffold (e.g., synthetic or naturally derived matrix) that contains conduits for nutrient perfusion to deliver media to growing cells and monitor noninvasive parameters during scaffold repopulation, broadening the applicability of these bioreactor systems.

[The education and training of manpower in elderly & long-term care].

PubMed

Chen, Huey-Tzy

2008-08-01

With the rapid expansion of the aged population, elderly & long-term care has become a significant issue in Taiwan, as in many developed countries, such as Japan. Service resources in long-term care have benefitted profoundly from investment and development in the past 15 years in Taiwan, but the education and training of manpower in long-term care has only recently begun to be addressed. The purpose of this article is to describe the education and training of nursing manpower in long-term care in Taiwan and in other countries. Three recommendations are also made: (1) To integrate Gerontology Nursing & Practicum into the nursing curriculum to cultivate nursing students with competency in providing direct care and competency in accountability. (2) To prepare RN-BSN students with secondary competency in management/information & communication/activities design. (3) To incorporate faculty from across disciplines in the running of gerontology & long-term care programs in order to develop students' competency in transdisciplinary team work.

Politics, Religion and Morals: The Symbolism of Public Schooling for the Urban Middle-Class Identity

ERIC Educational Resources Information Center

Rowe, Emma E.

2016-01-01

Research points to sections of the middle-class repopulating the "ordinary" urban public school and whilst there are key differences in how they are navigating public school choices, from "seeking a critical mass" to resisting traditional methods of choice and going "against-the-grain", or collectively campaigning for…

National Strength and Conditioning Association Position Statement on Long-Term Athletic Development.

PubMed

Lloyd, Rhodri S; Cronin, John B; Faigenbaum, Avery D; Haff, G Gregory; Howard, Rick; Kraemer, William J; Micheli, Lyle J; Myer, Gregory D; Oliver, Jon L

2016-06-01

There has recently been a growing interest in long-term athletic development for youth. Because of their unique physical, psychological, and social differences, children and adolescents should engage in appropriately prescribed exercise programs that promote physical development to prevent injury and enhance fitness behaviors that can be retained later in life. Irrespective of whether a child is involved in organized sport or engages in recreational physical activity, there remains a need to adopt a structured, logical, and evidence-based approach to the long-term development of athleticism. This is of particular importance considering the alarmingly high number of youth who fail to meet global physical activity recommendations and consequently present with negative health profiles. However, appropriate exercise prescription is also crucial for those young athletes who are physically underprepared and at risk of overuse injury because of high volumes of competition and an absence of preparatory conditioning. Whether the child accumulates insufficient or excessive amounts of exercise, or falls somewhere between these opposing ends of the spectrum, it is generally accepted that the young bodies of modern day youth are often ill-prepared to tolerate the rigors of sports or physical activity. All youth should engage in regular physical activity and thus should be viewed as "athletes" and afforded the opportunity to enhance athleticism in an individualized, holistic, and child-centered manner. Because of emerging interest in long-term athletic development, an authorship team was tasked on behalf of the National Strength and Conditioning Association (NSCA) to critically synthesize existing literature and current practices within the field and to compose a relevant position statement. This document was subsequently reviewed and formally ratified by the NSCA Board of Directors. A list of 10 pillars of successful long-term athletic development are presented, which summarize the key recommendations detailed within the position statement. With these pillars in place, it is believed that the NSCA can (a) help foster a more unified and holistic approach to long-term athletic development, (b) promote the benefits of a lifetime of healthy physical activity, and (c) prevent and/or minimize injuries from sports participation for all boys and girls.

Functional performance and exercise of older adults in long-term care settings.

PubMed

Resnick, B

2000-03-01

Performing functional activities and exercising are important for older adults living in long-term care settings. Participation in these activities not only improves and maintains function in older adults but also can improve physical and emotional health and quality of life. The purpose of this study was to explore the variables that influence functional performance and exercise activity in a group of nursing home residents. Participants included 59 residents in a long-term care facility. The mean age of participants was 88 +/- 6.9, and the majority were women (76%), White (97%), and unmarried (76%). Residents participated in a single face-to-face interview. Chart reviews for demographic and health information also were performed. Based on stepwise multiple regression analyses, upper and lower extremity contractures and cognitive status were the only variables that significantly influenced functional performance and accounted for 49% of the variance in function. Self-efficacy and outcome expectations were the only variables to significantly influence exercise behavior and accounted for 57% of the variance in this behavior. These findings can be used to help develop and implement effective restorative nursing care programs in long-term care settings.

Optimizing autologous cell grafts to improve stem cell gene therapy.

PubMed

Psatha, Nikoletta; Karponi, Garyfalia; Yannaki, Evangelia

2016-07-01

Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically engineered hematopoietic stem cells are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels posttransplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by reduced-intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing megadoses of genetically modified CD34(+) cells into conditioned patients or by transplanting hematopoietic stem cells hematopoietic stem cells with high engrafting and repopulating potential. On the basis of the lessons gained from cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of hematopoietic stem cells for transplantation or/and their engraftability, as a platform toward the optimization of engineered stem cell grafts. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Biochemical Changes in Erythrocytes as a Molecular Marker of Cell Damage during Long-Term Simvastatin Treatment.

PubMed

Mikashinovich, Z I; Belousova, E S

2016-08-01

Long-term administration of simvastatin to rats, irrespective of the baseline cholesterol levels, induced biochemical changes in erythrocytes attesting to hypoxic damage (accumulation of lactate and 2,3-diphosphoglycerate), disturbances in ATP-dependent mechanisms of ion homeostasis regulation (decrease in total ATPase and Ca(2+)-ATPase activities), and antioxidant enzymes system imbalance. These changes can be considered as a sensitive indicator and molecular basis of cell damage during long-term administration of statins.

The Benefits of Continuous Leisure Participation in Relocation Adjustment Among Residents of Long-Term Care Facilities.

PubMed

Lin, Li-Jung; Yen, Hsin-Yen

2018-03-19

The rising population of older adults is transforming Taiwan society. Although many long-term care facilities now operate for older adults, the transition from the home environment to long-term facilities may cause multiple issues, including relocation stress syndrome, for new residents. Autonomy is a critical element of the human experience. Leisure, as an expression of autonomy, has been shown to enhance self-image and promote feelings of competence and mastery. The aim of this study was to assess the relationship between participation in leisure activities and adjustment to residential care using the continuity theory. One hundred sixty-three qualified individuals from 11 long-term care institutions were recruited and completed the questionnaire. The sampling criteria for the study were age (55+ years), appropriate cognitive skills, and residency (less than 5 years). Interviews conducted by trained interviewers were used to collect data. Measured outcomes included leisure participation; physical, psychological, and social adjustments; and background information. Cluster analysis, descriptive analysis, multivariate analysis of variance, and least significant difference test were used in analysis. Type of admission (voluntary/mandated) and type of leisure participation significantly affected the level of relocation adjustment success. Four leisure behavior categories were identified, including reduced participation, expanded participation, active participation, and continuing participation. The participants in the active and continuing participation categories had significantly higher psychological adjustment than their peers in the reduced participation category. Moreover, the continuing participation category had a significantly better level of social adjustment than their expanded participation category peers. Continuous and active participation categories had a beneficial outcome in relocation adjustment. The findings support that, in general, residents of long-term care facilities who participate continuously in leisure activities adjust better psychologically and socially to their new life in these facilities than individuals in the other participation categories. As continuity of participation in leisure activities is important for successful aging, institutions should facilitate the continuing leisure behavior of new residents.

Physical Activity and Function in Older, Long-term Colorectal Cancer Survivors

PubMed Central

Johnson, Brent L.; Trentham-Dietz, Amy; Koltyn, Kelli F.; Colbert, Lisa H.

2009-01-01

Objective Increasing age and cancer history are related to impaired physical function. Since physical activity has been shown to ameliorate age-related functional declines, we evaluated the association between physical activity and function in older, long-term colorectal cancer survivors. Methods In 2006–2007, mailed surveys were sent to colorectal cancer survivors, aged ≥65 years when diagnosed during 1995 – 2000, and identified through a state cancer registry. Information on physical activity, physical function and relevant covariates was obtained and matched to registry data. Analysis of covariance and linear regression were used to compare means and trends in physical function across levels of activity in the final analytic sample of 843 cases. Results A direct, dose-dependent association between physical activity and function was observed (ptrend <.001), with higher SF-36 physical function subscores in those reporting high vs. low activity levels (65.0 ± 1.7 vs. 42.7 ± 1.7 (mean ± standard error)). Walking, gardening, housework, and exercise activities were all independently related to better physical function. Moderate-vigorous intensity activity (ptrend <.001) was associated with function, but light activity (ptrend =0.39) was not. Conclusion Results from this cross-sectional study indicate significant associations between physical activity and physical function in older, long-term colorectal cancer survivors. PMID:19123055

[Long-term physical activity after a myocardial infarction : a permanent challenge].

PubMed

Tessitore, Elena; Sigaud, Philippe; Meyer, Philippe; Mach, François

2017-05-24

Cardiac rehabilitation is a well-defined multidisciplinary program with the objective to reduce mortality and morbidity, while also improving the exercise capacity and quality of life of the patient following a myocardial infarction. Despite the fact that a cardiovascular rehabilitation program is now recommended by international guidelines for all patients who have suffered from an acute coronary syndrome, only half of all patients actually participate to such a program in Switzerland. Even worse, especially when taking into consideration the population in Geneva, less than 5 % of patients follow a long-term cardiac maintenance program (phase III). Since 2015, our project has been to encourage patients who have completed a phase II cardiac rehabilitation program, to resume regular physical activity in the long term.

DNA Methyltransferase Activity is Required for Memory- Related Neural Plasticity in the Lateral Amygdala

PubMed Central

Maddox, Stephanie A.; Watts, Casey S.; Schafe, Glenn E.

2014-01-01

We have previously shown that auditory Pavlovian fear conditioning is associated with an increase in DNA methyltransferase (DNMT) expression in the lateral amygdala (LA) and that intra-LA infusion or bath application of an inhibitor of DNMT activity impairs the consolidation of an auditory fear memory and long-term potentiation (LTP) at thalamic and cortical inputs to the LA, in vitro. In the present study, we use awake behaving neurophysiological techniques to examine the role of DNMT activity in memory-related neurophysiological changes accompanying fear memory consolidation and reconsolidation in the LA, in vivo. We show that auditory fear conditioning results in a training-related enhancement in the amplitude of short-latency auditory-evoked field potentials (AEFPs) in the LA. Intra-LA infusion of a DNMT inhibitor impairs both fear memory consolidation and, in parallel, the consolidation of training-related neural plasticity in the LA; that is, short-term memory (STM) and short-term training-related increases in AEFP amplitude in the LA are intact, while long-term memory (LTM) and long-term retention of training-related increases in AEFP amplitudes are impaired. In separate experiments, we show that intra-LA infusion of a DNMT inhibitor following retrieval of an auditory fear memory has no effect on post-retrieval STM or short-term retention of training-related changes in AEFP amplitude in the LA, but significantly impairs both post-retrieval LTM and long-term retention of AEFP amplitude changes in the LA. These findings are the first to demonstrate the necessity of DNMT activity in the consolidation and reconsolidation of memory-associated neural plasticity, in vivo. PMID:24291571

Long-term Optical Activity of the Hard X-ray Flaring Star DG CVn

NASA Astrophysics Data System (ADS)

Šimon, V.

2017-04-01

DG CVn is a young late-type star which displayed an X-ray and optical superflare in 2014. This paper presents an analysis of the long-term activity of this object in the optical band. I used the photographic data from DASCH (Digital Access to a Sky Century @ Harvard). These measurements from the years 1895-1989 cover the blue spectral region. CCD V-band ASAS data were used for several UV Cet-type stars to place the activity of DG CVn in the context of flaring stars. I show that three large brightenings (flares) of DG CVn by more than 1 mag were detected on the DASCH plates. The character of the long-term activity (regarding the histogram of brightness) of DG CVn is compatible with those of flaring stars UV Cet and V371 Ori. The flares brighter than ˜ 0.4 mag represent less than 1 percent of the observed data in all three objects

Short-term and long-term clinostat and vibration-induced biochemical changes in dwarf Marigold stems

NASA Astrophysics Data System (ADS)

Siegel, S. M.; Siegel, B. Z.

Stems of 21-day dwarf Marigold plants cultivated on the clinostat were compared with plants cultivated on vertical axis rotators (``vibrational controls'') and stationary controls for long-term changes in cell wall composition. Stems of 21-day plants grown under stationary conditions and subsequently exposed to the clinostat for 24 hours were also analyzed. Among the long-term markers, calcium, lignin, and protein-bound hemicellulose (possibly cell wall glycoprotein) clearly differentiated the effects of vibration from those of the clinostat. Short-term differential responses included rate of ethylene production, nastic movement and peroxidase activity of the cell wall, but not of the protoplast.

Short-term and long-term clinostat and vibration-induced biochemical changes in dwarf marigold stems

NASA Technical Reports Server (NTRS)

Siegel, S. M.; Siegel, B. Z.

1983-01-01

Stems of 21-day dwarf marigold plants cultivated on the clinostat were compared with plants cultivated on vertical axis rotators ('vibrational controls') and stationary controls for long-term changes in cell wall composition. Stems of 21-day plants grown under stationary conditions and subsequently exposed to the clinostat for 24 hours were also analyzed. Among the long-term markers, calcium, lignin, and protein-bound hemicellulose (possibly cell wall glycoprotein) clearly differentiated the effects of vibration from those of the clinostat. Short-term differential responses included rate of ethylene production, nastic movement and peroxidase activity of the cell wall, but not of the protoplast.

Falling Leaves Inspired ZnO Nanorods-Nanoslices Hierarchical Structure for Implant Surface Modification with Two Stage Releasing Features.

PubMed

Liao, Hang; Miao, Xinxin; Ye, Jing; Wu, Tianlong; Deng, Zhongbo; Li, Chen; Jia, Jingyu; Cheng, Xigao; Wang, Xiaolei

2017-04-19

Inspired from falling leaves, ZnO nanorods-nanoslices hierarchical structure (NHS) was constructed to modify the surfaces of two widely used implant materials: titanium (Ti) and tantalum (Ta), respectively. By which means, two-stage release of antibacterial active substances were realized to address the clinical importance of long-term broad-spectrum antibacterial activity. At early stages (within 48 h), the NHS exhibited a rapid releasing to kill the bacteria around the implant immediately. At a second stage (over 2 weeks), the NHS exhibited a slow releasing to realize long-term inhibition. The excellent antibacterial activity of ZnO NHS was confirmed once again by animal test in vivo. According to the subsequent experiments, the ZnO NHS coating exhibited the great advantage of high efficiency, low toxicity, and long-term durability, which could be a feasible manner to prevent the abuse of antibiotics on implant-related surgery.

Zscan4 restores the developmental potency of embryonic stem cells

PubMed Central

Amano, Tomokazu; Hirata, Tetsuya; Falco, Geppino; Monti, Manuela; Sharova, Lioudmila V.; Amano, Misa; Sheer, Sarah; Hoang, Hien G.; Piao, Yulan; Stagg, Carole A.; Yamamizu, Kohei; Akiyama, Tomohiko; Ko, Minoru S.H.

2013-01-01

The developmental potency of mouse embryonic stem (ES) cells, which is the ability to contribute to a whole embryo is known to deteriorate during long-term cell culture. Previously we have shown that ES cells oscillate between Zscan4- and Zscan4+ states, and the transient activation of Zscan4 is required for the maintenance of telomeres and genome stability of ES cells. Here we show that increasing the frequency of Zscan4 activation in mouse ES cells restores and maintains their developmental potency in long-term cell culture. Injection of a single ES cell with such increased potency into a tetraploid blastocyst gives rise to an entire embryo with a higher success rate. These results not only provide a means to rejuvenate ES cells by manipulating Zscan4 expression, but also indicate the active roles of Zscan4 in the long-term maintenance of ES cell potency. PMID:23739662

Cognitive Control Network Contributions to Memory-Guided Visual Attention

PubMed Central

Rosen, Maya L.; Stern, Chantal E.; Michalka, Samantha W.; Devaney, Kathryn J.; Somers, David C.

2016-01-01

Visual attentional capacity is severely limited, but humans excel in familiar visual contexts, in part because long-term memories guide efficient deployment of attention. To investigate the neural substrates that support memory-guided visual attention, we performed a set of functional MRI experiments that contrast long-term, memory-guided visuospatial attention with stimulus-guided visuospatial attention in a change detection task. Whereas the dorsal attention network was activated for both forms of attention, the cognitive control network (CCN) was preferentially activated during memory-guided attention. Three posterior nodes in the CCN, posterior precuneus, posterior callosal sulcus/mid-cingulate, and lateral intraparietal sulcus exhibited the greatest specificity for memory-guided attention. These 3 regions exhibit functional connectivity at rest, and we propose that they form a subnetwork within the broader CCN. Based on the task activation patterns, we conclude that the nodes of this subnetwork are preferentially recruited for long-term memory guidance of visuospatial attention. PMID:25750253

Planning as a Precursor to Scheduling for Space Station Payload Operations

NASA Technical Reports Server (NTRS)

Howell, Eric; Maxwell, Theresa

1995-01-01

Contemporary schedulers attempt to solve the problem of best fitting a set of activities into an available timeframe while still satisfying the necessary constraints. This approach produces results which are optimized for the region of time the scheduler is able to process, satisfying the near term goals of the operation. In general the scheduler is not able to reason about the activities which precede or follow the window into which it is inputs to scheduling so that the intermediate placing activities. This creates a problem for operations which are composed of many activities spanning long durations (which exceed the scheduler's reasoning horizon) such as the continuous operations environment for payload operations on the Space Station. Not only must the near term scheduling objectives be met, but somehow the results of near term scheduling must be made to support the attainment of long term goals.

A study to assess the long-term stability of the ionization chamber reference system in the LNMRI

NASA Astrophysics Data System (ADS)

Trindade Filho, O. L.; Conceição, D. A.; da Silva, C. J.; Delgado, J. U.; de Oliveira, A. E.; Iwahara, A.; Tauhata, L.

2018-03-01

Ionization chambers are used as secondary standard in order to maintain the calibration factors of radionuclides in the activity measurements in metrology laboratories. Used as radionuclide calibrator in nuclear medicine clinics to control dose in patients, its long-term performance is not evaluated systematically. A methodology for long-term evaluation for its stability is monitored and checked. Historical data produced monthly of 2012 until 2017, by an ionization chamber, electrometer and 226Ra, were analyzed via control chart, aiming to follow the long-term performance. Monitoring systematic errors were consistent within the limits of control, demonstrating the quality of measurements in compliance with ISO17025.

Getting a Bigger Bang for Your Buck: A Collaborative Approach to Enhancing Dementia Education Planning in Long-Term Care Homes

PubMed Central

McAiney, Carrie A.; Hillier, Loretta M.; Ringland, Margaret; Cooper, Nancy

2009-01-01

A collaborative of Ontario-based long-term care associations, researchers, clinicians and educators representing various education initiatives related to dementia care and challenging behaviours used existing research evidence on adult learning principles, knowledge transfer and performance improvement to develop an evidence-based approach to support practice change and improvement in long-term care. The collaborative was led by the two provincial long-term care associations with no external funds to support its activities. This effort illustrates how people with common challenges, visions and goals can work together to share their intellectual and physical resources to address pervasive problems. PMID:21037817

HDAC3 and the Molecular Brake Pad Hypothesis

PubMed Central

McQuown, Susan C.; Wood, Marcelo A.

2011-01-01

Successful transcription of specific genes required for long-term memory processes involves the orchestrated effort of not only transcription factors, but also very specific enzymatic protein complexes that modify chromatin structure. Chromatin modification has been identified as a pivotal molecular mechanism underlying certain forms of synaptic plasticity and memory. The best-studied form of chromatin modification in the learning and memory field is histone acetylation, which is regulated by histone acetyltransferases and histone deacetylases (HDACs). HDAC inhibitors have been shown to strongly enhance long-term memory processes, and recent work has aimed to identify contributions of individual HDACs. In this review, we focus on HDAC3 and discuss its recently defined role as a negative regulator of long-term memory formation. HDAC3 is part of a corepressor complex and has direct interactions with class II HDACs that may be important for its molecular and behavioral consequences. And last, we propose the “molecular brake pad” hypothesis of HDAC function. The HDACs and associated corepressor complexes may function in neurons, in part, as “molecular brake pads.” HDACs are localized to promoters of active genes and act as a persistent clamp that requires strong activity-dependent signaling to temporarily release these complexes (or brake pads) to activate gene expression required for long-term memory formation. Thus, HDAC inhibition removes the “molecular brake pads” constraining the processes necessary for long-term memory and results in strong, persistent memory formation. PMID:21521655

Oxygen Therapy for Patients With COPD

PubMed Central

Stoller, James K.; Panos, Ralph J.; Krachman, Samuel; Doherty, Dennis E.

2010-01-01

Long-term use of supplemental oxygen improves survival in patients with COPD and severe resting hypoxemia. However, the role of oxygen in symptomatic patients with COPD and more moderate hypoxemia at rest and desaturation with activity is unclear. The few long-term reports of supplemental oxygen in this group have been of small size and insufficient to demonstrate a survival benefit. Short-term trials have suggested beneficial effects other than survival in patients with COPD and moderate hypoxemia at rest. In addition, supplemental oxygen appeared to improve exercise performance in small short-term investigations of patients with COPD and moderate hypoxemia at rest and desaturation with exercise, but long-term trials evaluating patient-reported outcomes are lacking. This article reviews the evidence for long-term use of supplemental oxygen therapy and provides a rationale for the National Heart, Lung, and Blood Institute Long-term Oxygen Treatment Trial. The trial plans to enroll subjects with COPD with moderate hypoxemia at rest or desaturation with exercise and compare tailored oxygen therapy to no oxygen therapy. PMID:20605816

[Status of aortic valve reconstruction and Ross operation in aortic valve diseases].

PubMed

Sievers, Hans H

2002-08-01

At first glance the aortic valve is a relative simple valve mechanism connecting the left ventricle and the ascending aorta. Detailed analysis of the different components of the aortic valve including the leaflets and sinuses revealed a complex motion of each part leading to a perfect durable valve mechanism at rest and during exercise. Theoretically, the reconstruction or imitation of these structures in patients with aortic valve disease should lead to optimal results. Prerequisite is the exact knowledge of the important functional characteristics of the aortic valve. The dynamic behavior of the aortic root closely harmonizing with the leaflets not only warrants stress minimizing and valve durability, but also optimizes coronary flow, left ventricular function and aortic impedance. The newly discovered contractile capacity of the leaflets and the root components are important for tuning the dynamics. Isolated reconstruction of the aortic valve such as decalcification, commissurotomy, plication of ring or leaflets of a tricuspid aortic valve and cusp extension are seldom indicated in contrast to the reconstruction of the bicuspid insufficient valve. Proper indication and skilled techniques lead to excellent hemodynamic and clinical intermediate-term result up to 7 years after reconstruction. Latest follow-up revealed a mean aortic insufficiency of 0.7, maximal pressure gradient of 11.4 +/- 8.5 mm Hg with zero hospital or late mortality, reoperation or thromboembolic events in 22 patients. The reconstructive techniques for aortic root aneurysm and/or type A dissection according to David or Yacoub have become routine procedures in the last 10 years. The hemodynamic and clinical results are excellent with low reoperation rate and very low risk of thromboembolism. Generally, a maximal diameter of the root of 5 cm is indicative for performing the operation. In patients with Marfan's syndrome the reconstruction should be advanced even with smaller diameters especially if these are progressive and combined with aortic insufficiency. ROSS-OPERATION: The Ross-Operation includes the replacement of the diseased aortic valve with the pulmonary autograft and reconstruction of the right ventricular outflow tract using a homograft. The hemodynamic results are excellent regarding the autograft and also the clinical results with very low thromboembolic risk and acceptable reoperation rate. This method is especially indicated for active young patients, women, who desire children, athletes and patients in general, who like to avoid long-term anticoagulation. In some cases the homograft may develop a dysfunction predominantly a pulmonary stenosis requiring reoperation. In the author's series of 245 Ross-operations in 12 years the homograft had to be replaced in 4 cases without letality. Innovative, decellularized homografts with the potential to repopulate with autologeous cells show promising results after 1 year of clinical implantation without signs of antibody development. Probably these tissue-engineered modification may improve the homograft results. The reconstructive techniques of the aortic valve and the Ross-operation have a certain risk of reoperation that must be weighed against the advantages of very low hospital and late valve related death, excellent hemodynamics, very low risk of macro- and microembolism as well as bleeding, lack of long-term anticoagulation and unrestricted life-style.

Dimerization of the EphA1 Receptor Tyrosine Kinase Transmembrane Domain: Insights into the Mechanism of Receptor Activation

PubMed Central

2014-01-01

EphA1 is a receptor tyrosine kinase (RTK) that plays a key role in developmental processes, including guidance of the migration of axons and cells in the nervous system. EphA1, in common with other RTKs, contains an N-terminal extracellular domain, a single transmembrane (TM) α-helix, and a C-terminal intracellular kinase domain. The TM helix forms a dimer, as seen in recent NMR studies. We have modeled the EphA1 TM dimer using a multiscale approach combining coarse-grain (CG) and atomistic molecular dynamics (MD) simulations. The one-dimensional potential of mean force (PMF) for this system, based on interhelix separation, has been calculated using CG MD simulations. This provides a view of the free energy landscape for helix–helix interactions of the TM dimer in a lipid bilayer. The resulting PMF profiles suggest two states, consistent with a rotation-coupled activation mechanism. The more stable state corresponds to a right-handed helix dimer interacting via an N-terminal glycine zipper motif, consistent with a recent NMR structure (2K1K). A second metastable state corresponds to a structure in which the glycine zipper motif is not involved. Analysis of unrestrained CG MD simulations based on representative models from the PMF calculations or on the NMR structure reveals possible pathways of interconversion between these two states, involving helix rotations about their long axes. This suggests that the interaction of TM helices in EphA1 dimers may be intrinsically dynamic. This provides a potential mechanism for signaling whereby extracellular events drive a shift in the repopulation of the underlying TM helix dimer energy landscape. PMID:25286141

Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function.

PubMed

Romero-Moya, Damia; Bueno, Clara; Montes, Rosa; Navarro-Montero, Oscar; Iborra, Francisco J; López, Luis Carlos; Martin, Miguel; Menendez, Pablo

2013-07-01

The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34(+) hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34(+) cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34(+) cells with high (CD34(+) Mito(High)) versus low (CD34(+) Mito(Low)) mitochondrial mass. The CD34(+) Mito(Low) fraction contained 6-fold more CD34(+)CD38(-) primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34(+) Mito(High) fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34(+) Mito(Low) cells was significantly delayed as compared to that of CD34(+) Mito(High) cells. The eventual complete differentiation of CD34(+) Mito(Low) cells, which coincided with a robust expansion of the CD34(-) differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34(+) cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell differentiation and proliferation of lineage-committed CD34(-) cells.

In vitro investigation of head and neck cancer stem cell proportions and their changes following X-ray irradiation as a function of HPV status.

PubMed

Reid, Paul; Wilson, Puthenparampil; Li, Yanrui; Marcu, Loredana G; Staudacher, Alexander H; Brown, Michael P; Bezak, Eva

2017-01-01

Some head and neck squamous cell carcinomas (HNSCC) have a distinct aetiology, which depends on the presence of oncogenic human papilloma virus (HPV). Also, HNSCC contains cancer stem cells (CSCs) that have greater radioresistance and capacity to change replication dynamics in response to irradiation compared to non-clonogenic cells. Since there is limited data on CSCs in HNSCC as a function of HPV status, better understanding of their radiobiology may enable improved treatment outcome. Baseline and post-irradiation changes in CSC proportions were investigated by flow cytometry in a HPV-negative (UM-SCC-1) and a HPV-positive (UM-SCC-47) HNSCC cell line, using fluorescent staining with CD44/ALDH markers. CSC proportions in both irradiated and unirradiated cultures were compared for the two cell lines at various times post-irradiation. To assess repopulation of CSCs, untreated cultures were depleted of CD44+/ALDH+ cells and re-cultured for 3 weeks before flow cytometry analysis. CSC proportions in untreated cell lines were 0.57% (UM-SCC-1) and 2.87% (UM-SCC-47). Untreated cell lines depleted of CD44+/ALDH+ repopulated this phenotype to a mean of 0.15% (UM-SCC-1) and 6.76% (UM-SCC-47). All UM-SCC-47 generations showed elevated CSC proportions after irradiation, with the most significant increase at 2 days post-irradiation. The highest elevation in UM-SCC-1 CSCs was observed at 1 day post-irradiation in the 2nd generation and at 3 days after irradiation in the 3rd generation. When measured after 10 days, only the 3rd generation of UM-SCC-1 showed elevated CSCs. CSC proportions in both cell lines were elevated after exposure and varied with time post irradiation. UM-SCC-47 displayed significant plasticity in repopulating the CSC phenotype in depleted cultures, which was not seen in UM-SCC-1.

Decellularized aortic conduits: could their cryopreservation affect post-implantation outcomes? A morpho-functional study on porcine homografts.

PubMed

Gallo, Michele; Bonetti, Antonella; Poser, Helen; Naso, Filippo; Bottio, Tomaso; Bianco, Roberto; Paolin, Adolfo; Franci, Paolo; Busetto, Roberto; Frigo, Anna Chiara; Buratto, Edward; Spina, Michele; Marchini, Maurizio; Ortolani, Fulvia; Iop, Laura; Gerosa, Gino

2016-11-01

Decellularized porcine aortic valve conduits (AVCs) implanted in a Vietnamese Pig (VP) experimental animal model were matched against decellularized and then cryopreserved AVCs to assess the effect of cryopreservation on graft hemodynamic performance and propensity to in vivo repopulation by host's cells. VPs (n = 12) underwent right ventricular outflow tract substitution using AVC allografts and were studied for 15-month follow-up. VPs were randomized into two groups, receiving AVCs treated with decellularization alone (D; n = 6) or decellularization/cryopreservation (DC; n = 6), respectively. Serial echocardiography was carried out to follow up hemodynamic function. All explanted AVCs were processed for light and electron microscopy. No signs of dilatation, progressive stenosis, regurgitation, and macroscopic calcification were echocardiographically observed in both D and DC groups. Explanted D grafts exhibited near-normal features, whereas the presence of calcification, inflammatory infiltrates, and disarray of elastic lamellae occurred in some DC grafts. In the unaltered regions of AVCs from both groups, almost complete re-endothelialization was observed for both valve cusps and aorta walls. In addition, side-by-side repopulation by recipient's fibroblasts, myofibroblasts, and smooth muscle cells was paralleled by ongoing tissue remodeling, as revealed by the ultrastructural identification of typical canals of collagen fibrillogenesis and elastogenesis-related features. Incipient neo-vascularization and re-innervation of medial and adventitial tunicae of grafted aortic walls were also detected for both D and DC groups. Cryopreservation did not affect post-implantation AVC hemodynamic behavior and was topically propensive to cell repopulation and tissue renewal, although graft deterioration including calcification was present in several areas. Thus, these preliminary data provide essential information on feasibility of decellularization and cryopreservation coupling in the perspective of treatment optimization and subsequent clinical trials using similarly treated human allografts as innovative heart valve substitutes.

Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain.

PubMed

Reeve, Rachel L; Yammine, Samantha Z; Morshead, Cindi M; van der Kooy, Derek

2017-09-01

Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP) - Oct4 + cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self-renew or give rise to GFAP + NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)-green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3-5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4 fl/fl ;Sox1 Cre (Oct4 CKO ), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP + dNSCs, in these Oct4 CKO mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine β-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP + dNSCs allows them to repopulate a depleted neural lineage. Stem Cells 2017;35:2071-2082. © 2017 AlphaMed Press.

Superior long-term activity for a Pt-Re alloy compared to Pt in methanol oxidation reactions

NASA Astrophysics Data System (ADS)

Duke, Audrey S.; Xie, Kangmin; Monnier, John R.; Chen, Donna A.

2017-03-01

Pt-Re bimetallic catalysts have shown enhanced activity compared to pure Pt for reactions involving oxidation, but the origins of this improved activity are not fully understood. Methanol oxidation on a Pt-Re alloy surface and pure Pt foil was studied in a microreactor coupled to an ultrahigh vacuum chamber. For reaction at 60 °C, the Pt-Re alloy surface exhibits superior long-term activity over a 24 h reaction period compared to pure Pt. The initial activity of Pt is 10-15% higher than on Pt-Re; however, the Pt surface gradually loses activity after 10 h online, whereas the activity of Pt-Re does not diminish. Post-reaction XPS shows that more carbon accumulates on the Pt than on Pt-Re, and the improved long-term activity is attributed to a greater ability of Pt-Re to oxidize the carbonaceous intermediates that eventually poison active sites. Both Pt and Pt-Re surfaces have almost no activity for methanol oxidation until a minimum coverage of oxygen is achieved from O2 dissociation. A comparison with methanol oxidation studies on Pt and Pt-Re in a pressure regime that is 150 times lower than in this work demonstrates that more carbon and less oxygen accumulate on the surfaces during reaction at the lower pressures.

A self-determination theory approach to adults' healthy body weight motivation: A longitudinal study focussing on food choices and recreational physical activity.

PubMed

Hartmann, Christina; Dohle, Simone; Siegrist, Michael

2015-01-01

This study focuses on body weight motivation based on self-determination theory. The impact of body weight motivation on longitudinal changes in food choices, recreational physical activity and body mass index was explored. A sample of adults (N = 2917, 47% men), randomly selected from the telephone book, completed a questionnaire in two consecutive years (2012, 2013), self-reporting food choices, recreational physical activity and body weight motivation. Types of body weight motivation at T1 (autonomous regulation, introjected regulation, and external regulation) were tested with regard to their predictive potential for changes in food choices, recreational physical activity and body mass index (BMI). Autonomous motivation predicted improvements in food choices and long-term adherence to vigorous recreational physical activity in both genders. Introjected motivation predicted long-term adherence to vigorous recreational physical activity only in women. External motivation predicted negative changes in food choices; however, the type of body weight motivation had no impact on BMI in overweight adults in the long term. Autonomous goal-setting regarding body weight seems to be substantial for healthy food choices and adherence to recreational physical activity.

Effects of Developmental Activation of the Aryl Hydrocarbon Receptor by 2,3,7,8-Tetrachlorodibenzo-p-dioxin on Long-term Self-renewal of Murine Hematopoietic Stem Cells.

PubMed

Laiosa, Michael D; Tate, Everett R; Ahrenhoerster, Lori S; Chen, Yuhong; Wang, Demin

2016-07-01

Human epidemiological and animal studies suggest that developmental exposure to contaminants that activate the aryl hydrocarbon receptor (AHR) lead to suppression of immune system function throughout life. The persistence of immune deficiency throughout life suggests that the cellular target of AHR activation is a fetal hematopoietic progenitor or stem cell. The aim of this study was to identify the effects of transplacental exposure to an AHR agonist on long-term self-renewal of fetal hematopoietic stem cells. Pregnant C57BL/6 or AHR+/- mice were exposed to the AHR agonist, 2,3,7,8-tetra-​chlorodibenzo-p-dioxin (TCDD). On day 14 of gestation, hematopoietic progenitors from wild-type or AHR-deficient fetuses were placed into in vitro T-lymphocyte differentiation cultures to identify the effects of transplacental TCDD on AHR activation in the fetus. We next analyzed the fetal hematopoietic progenitor cells for changes in reactive oxygen species (ROS). Finally, hematopoietic progenitors from fetuses exposed transplacentally to TCDD were mixed 1:1 with cells from congenic controls and used to reconstitute lethally irradiated recipients for analysis of long-term self-renewal potential. Our findings suggested that the effects of TCDD on the developing hematopoietic system were mediated by direct AHR activation in the fetus. Furthermore, developmental AHR activation by TCDD increased ROS in the fetal hematopoietic stem cells, and the elevated ROS was associated with a reduced capacity of the TCDD-exposed fetal cells to compete with control cells in a mixed competitive irradiation/reconstitution assay. Our findings indicate that AHR activation by TCDD in the fetus during pregnancy leads to impairment of long-term self-renewal of hematopoietic stem cells. Laiosa MD, Tate ER, Ahrenhoerster LS, Chen Y, Wang D. 2016. Effects of developmental activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-dioxin on long-term self-renewal of murine hematopoietic stem cells. Environ Health Perspect 124:957-965; http://dx.doi.org/10.1289/ehp.1509820.

Socially supportive activity inventory: reliability and validity of a social activity instrument for long-term care institutions.

PubMed

Hsu, Ya-Chuan

2011-09-01

: Diverse social and recreational activities in elder care institutions have been provided to enrich a person's mental well-being amidst what is a relatively monotonous life. However, few instruments that measure the social activities of long-term care residents are available. : This study was designed to develop a culturally sensitive instrument (Socially Supportive Activity Inventory, SSAI) to assess quantity and quality of social activities for long-term care institutions and validate the instrument's psychometric properties. : The SSAI was developed on the basis of the social support theory, a synthesis of literature, and Taiwanese cultural mores. The instrument was rigorously subjected to a two-stage process to evaluate its reliability and validity. In Stage 1, six experts from diverse backgrounds were recruited to evaluate instrument items and estimate the content validity of the instrument using a content validity questionnaire. Items were modified and refined on the basis of the responses of the expert panel and a set of criteria. After obtaining approval from a university institutional review board, in the second stage of evaluating test-retest reliability, a convenience sample of 10 Taiwanese institutionalized elders in a pilot study, recruited from a nursing home, completed the revised instrument at two separate times over 2 weeks. : Results showed a content validity of .96. Test-retest reliability from a sample of 10 participants yielded stability coefficients of .76-1.00. The stability coefficient was 1.00 for the component of frequency, .76-1.00 for the component of meaningfulness, and .78-1.00 for the component of enjoyment. : The SSAI is a highly relevant and reliable culturally based instrument that can measure social activity in long-term care facilities. Because of the pilot nature of this study, future directions include further exploration of the SSAI instrument's psychometric properties. This should be done by enlarging the sample size to include more long-term care facilities and individual participants. Future studies can utilize diverse measures of social activity for comparison and validation of the SSAI.

Modulation of working memory updating: Does long-term memory lexical association matter?

PubMed

Artuso, Caterina; Palladino, Paola

2016-02-01

The aim of the present study was to investigate how working memory updating for verbal material is modulated by enduring properties of long-term memory. Two coexisting perspectives that account for the relation between long-term representation and short-term performance were addressed. First, evidence suggests that performance is more closely linked to lexical properties, that is, co-occurrences within the language. Conversely, other evidence suggests that performance is linked more to long-term representations which do not entail lexical/linguistic representations. Our aim was to investigate how these two kinds of long-term memory associations (i.e., lexical or nonlexical) modulate ongoing working memory activity. Therefore, we manipulated (between participants) the strength of the association in letters based on either frequency of co-occurrences (lexical) or contiguity along the sequence of the alphabet (nonlexical). Results showed a cost in working memory updating for strongly lexically associated stimuli only. Our findings advance knowledge of how lexical long-term memory associations between consonants affect working memory updating and, in turn, contribute to the study of factors which impact the updating process across memory systems.

Short Meditation Trainings Enhance Non-REM Sleep Low-Frequency Oscillations

PubMed Central

Dentico, Daniela; Ferrarelli, Fabio; Riedner, Brady A.; Smith, Richard; Zennig, Corinna; Lutz, Antoine; Tononi, Giulio; Davidson, Richard J.

2016-01-01

Study Objectives We have recently shown higher parietal-occipital EEG gamma activity during sleep in long-term meditators compared to meditation-naive individuals. This gamma increase was specific for NREM sleep, was present throughout the entire night and correlated with meditation expertise, thus suggesting underlying long-lasting neuroplastic changes induced through prolonged training. The aim of this study was to explore the neuroplastic changes acutely induced by 2 intensive days of different meditation practices in the same group of practitioners. We also repeated baseline recordings in a meditation-naive cohort to account for time effects on sleep EEG activity. Design High-density EEG recordings of human brain activity were acquired over the course of whole sleep nights following intervention. Setting Sound-attenuated sleep research room. Patients or Participants Twenty-four long-term meditators and twenty-four meditation-naïve controls. Interventions Two 8-h sessions of either a mindfulness-based meditation or a form of meditation designed to cultivate compassion and loving kindness, hereafter referred to as compassion meditation. Measurements and Results We found an increase in EEG low-frequency oscillatory activities (1–12 Hz, centered around 7–8 Hz) over prefrontal and left parietal electrodes across whole night NREM cycles. This power increase peaked early in the night and extended during the third cycle to high-frequencies up to the gamma range (25–40 Hz). There was no difference in sleep EEG activity between meditation styles in long-term meditators nor in the meditation naïve group across different time points. Furthermore, the prefrontal-parietal changes were dependent on meditation life experience. Conclusions This low-frequency prefrontal-parietal activation likely reflects acute, meditation-related plastic changes occurring during wakefulness, and may underlie a top-down regulation from frontal and anterior parietal areas to the posterior parietal and occipital regions showing chronic, long-lasting plastic changes in long-term meditators. PMID:26900914

End-task versus in-task feedback to increase procedural learning retention during spinal anaesthesia training of novices.

PubMed

Lean, Lyn Li; Hong, Ryan Yee Shiun; Ti, Lian Kah

2017-08-01

Communication of feedback during teaching of practical procedures is a fine balance of structure and timing. We investigate if continuous in-task (IT) or end-task feedback (ET) is more effective in teaching spinal anaesthesia to medical students. End-task feedback was hypothesized to improve both short-term and long-term procedural learning retention as experiential learning promotes active learning after encountering errors during practice. Upon exposure to a 5-min instructional video, students randomized to IT or ET feedbacks were trained using a spinal simulator mannequin. A blinded expert tested the students using a spinal anaesthesia checklist in the short term (immediate) and long-term (average 4 months). Sixty-five students completed the training and testing. There were no differences in demographics of age or gender within IT or ET distributions. Both short-term and long-term learning retention of spinal anaesthesia ET feedback proved to be better (P < 0.01) than IT feedback. The time taken for ET students was shorter at long-term testing. End-task feedback improves both short-term and long-term procedural learning retention.

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation.

PubMed

Latorre, Eva; Layunta, Elena; Grasa, Laura; Castro, Marta; Pardo, Julián; Gomollón, Fernando; Alcalde, Ana I; Mesonero, José E

2016-01-01

TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.

Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation

PubMed Central

Layunta, Elena; Grasa, Laura; Castro, Marta; Pardo, Julián; Gomollón, Fernando; Mesonero, José E.

2016-01-01

TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT) has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT) activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system. PMID:28033388

AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seo, Arnold Y.; Lau, Pick -Wei; Feliciano, Daniel

Dietary restriction increases the longevity of many organisms, but the cell signaling and organellar mechanisms underlying this capability are unclear. We demonstrate that to permit long-term survival in response to sudden glucose depletion, yeast cells activate lipid-droplet (LD) consumption through micro-lipophagy (µ-lipophagy), in which fat is metabolized as an alternative energy source. AMP-activated protein kinase (AMPK) activation triggered this pathway, which required Atg14p. More gradual glucose starvation, amino acid deprivation or rapamycin did not trigger µ-lipophagy and failed to provide the needed substitute energy source for long-term survival. During acute glucose restriction, activated AMPK was stabilized from degradation and interactedmore » with Atg14p. This prompted Atg14p redistribution from ER exit sites onto liquid-ordered vacuole membrane domains, initiating µ-lipophagy. Our findings that activated AMPK and Atg14p are required to orchestrate µ-lipophagy for energy production in starved cells is relevant for studies on aging and evolutionary survival strategies of different organisms.« less

AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation

DOE PAGES

Seo, Arnold Y.; Lau, Pick -Wei; Feliciano, Daniel; ...

2017-04-10

Dietary restriction increases the longevity of many organisms, but the cell signaling and organellar mechanisms underlying this capability are unclear. We demonstrate that to permit long-term survival in response to sudden glucose depletion, yeast cells activate lipid-droplet (LD) consumption through micro-lipophagy (µ-lipophagy), in which fat is metabolized as an alternative energy source. AMP-activated protein kinase (AMPK) activation triggered this pathway, which required Atg14p. More gradual glucose starvation, amino acid deprivation or rapamycin did not trigger µ-lipophagy and failed to provide the needed substitute energy source for long-term survival. During acute glucose restriction, activated AMPK was stabilized from degradation and interactedmore » with Atg14p. This prompted Atg14p redistribution from ER exit sites onto liquid-ordered vacuole membrane domains, initiating µ-lipophagy. Our findings that activated AMPK and Atg14p are required to orchestrate µ-lipophagy for energy production in starved cells is relevant for studies on aging and evolutionary survival strategies of different organisms.« less

Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis.

PubMed

Constantinescu, R; Krýsl, D; Bergquist, F; Andrén, K; Malmeström, C; Asztély, F; Axelsson, M; Menachem, E B; Blennow, K; Rosengren, L; Zetterberg, H

2016-04-01

Clinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity and to predict long-term outcome. The value of cerebrospinal fluid (CSF) markers of neuronal [neurofilament light chain protein (NFL), and total tau protein (T-tau)] and glial cell [glial fibrillary acidic protein (GFAP)] damage in patients with autoimmune encephalitis was investigated. Demographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for 1 year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. The acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement 1 year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased but did not change significantly later on. Final outcome (disability at 1 year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at 3 ± 1 months. This correlation remained significant after age adjustment for CSF-NFL and T-tau but not for GFAP. In autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability. © 2016 EAN.

Decrease in calcitonin and parathyroid hormone mRNA levels and hormone secretion under long-term hypervitaminosis D3 in rats.

PubMed

Fernández-Santos, J M; Utrilla, J C; Conde, E; Hevia, A; Loda, M; Martín-Lacave, I

2001-04-01

In calcium homeostasis, vitamin D3 is a potent serum calcium-raising agent which in vivo regulates both calcitonin (CT) and parathyroid hormone (PTH) gene expression. Serum calcium is the major secretagogue for CT, a hormone product whose biosynthesis is the main biological activity of thyroid C-cells. Taking advantage of this regulatory mechanism, long-term vitamin D3-induced hypercalcemia has been extensively used as a model to produce hyperactivation, hyperplasia and even proliferative lesions of C-cells, supposedly to reduce the sustained high calcium serum concentrations. We have recently demonstrated that CT serum levels did not rise after long-term hypervitaminosis D3. Moreover, C-cells did not have a proliferative response, rather a decrease in CT-producing C-cell number was observed. In order to confirm the inhibitory effect of vitamin D3 on C-cells, Wistar rats were administered vitamin D3 chronically (25,000 IU/d) with or without calcium chloride (CaCl2). Under these long-term vitamin D3-hypercalcemic conditions, calcium, active metabolites of vitamin D3, CT and PTH serum concentrations were determined by RIA; CT and PTH mRNA levels were analysed by Northern blot and in situ hybridization; and, finally, the ultrastructure of calciotrophic hormone-producing cells was analysed by electron microscopy. Our results show, that, in rats, long term administration of vitamin D3 results in a decrease in hormone biosynthetic activities of both PTH and CT-producing cells, albeit at different magnitudes. Based upon these results, we conclude that hypervitaminosis D3-based methods do not stimulate C-cell activity and can not be used to induce proliferative lesions of calcitonin-producing cells.

Gill Na+,K+-ATPase of Atlantic salmon smolts in freshwater is not a predictor of long-term growth in seawater

USGS Publications Warehouse

Zydlewski, Gayle B.; Zydlewski, Joseph D.

2012-01-01

Gill Na+,K+-ATPase activity is a widely used measure of osmoregulatory preparedness in salmonid smolts. The degree to which this measure may predict long term performance is uncertain. In order to assess the relationship of this enzyme to long term growth and ion homeostasis, a cohort of Atlantic salmon hatchery smolts was used in a controlled environment with no salinity perturbations. In May 2006, gill Na+,K+-ATPase activity from 940 individually PIT tagged, Penobscot River smolts (USFWS, Green Lake National Fish Hatchery, Maine, United States) was measured immediately prior to isothermal transfer from freshwater to 32 ppt seawater. From the observed range of activities, individuals were classified as having “low”, “middle”, or “high” enzyme activity levels. Individual size (fork length and mass) was recorded on days 0, 1, 3, and 14 and monthly for four months. Growth rates over four time periods were calculated for individual fish maintained until the end of the experiment. Gill Na+,K+-ATPase activities were also measured from a subset of sampled fish. All groups effectively osmoregulated as evidenced by minor perturbations in plasma osmolyte levels. Apart from initial weight loss on transfer, fish grew throughout the experiment, however, there were no differences (fish size, growth rate, and gill Na+,K+-ATPase activity in seawater) among groups with initially different gill Na+,K+-ATPase activities (prior to seawater entry). While gill Na+,K+-ATPase activity may be predictive of performance during the acute phase of acclimation (first few days), typical variation in this enzyme, expressed in freshwater at the peak of smolting, does not appear to be predictive of long-term growth in seawater.

Determining the amount of physical activity needed for long-term weight control

NASA Technical Reports Server (NTRS)

Wier, L. T.; Ayers, G. W.; Jackson, A. S.; Rossum, A. C.; Poston, W. S.; Foreyt, J. P.

2001-01-01

OBJECTIVE: To evaluate prospectively the influence of habitual physical activity on body weight of men and women and to develop a model that defines the role of physical activity on longitudinal weight change. DESIGN AND SETTING: Occupational cohort study conducted for a mean of 5.5 y. SUBJECTS: A total of 496 (341 male and 155 female) NASA/Johnson Space Center employees who completed the 3 month education component of the employee health-related fitness program and remained involved for a minimum of 2 y. MEASUREMENTS: Body weights were measured at baseline (T1) and follow-up (T2), and habitual physical activity was obtained from the mean of multiple ratings of the 11-point (0-10) NASA Activity Scale (NAS) recorded quarterly between T1 and T2. Other measures included age, gender, VO(2 max) obtained from maximal treadmill testing, body mass index (BMI), and body fat percentage. RESULTS: Multiple regression demonstrated that mean NAS, T1 weight, aging and gender all influence long-term T2 weight. T1 age was significant for the men only. Independently, each increase in mean NAS significantly (P<0.01) reduced T2 weight in men (b=-0.91 kg; 95% CI:-1.4 to-0.42 kg) and women (b=-2.14 kg; 95% CI:-2.93 to-1.35 kg). Mean NAS had a greater effect on T2 weight as T1 weight increased, and the relationship was dose-dependent. CONCLUSIONS: Habitual physical activity is a significant source of long-term weight change. The use of self-reported activity level is helpful in predicting long-term weight changes and may be used by health care professionals when counseling patients about the value of physical activity for weight control.

Protein synthesis during acquisition of long-term facilitation is needed for the persistent loss of regulatory subunits of the Aplysia cAMP-dependent protein kinase.

PubMed Central

Bergold, P J; Sweatt, J D; Winicov, I; Weiss, K R; Kandel, E R; Schwartz, J H

1990-01-01

Depending on the number or the length of exposure, application of serotonin can produce either short-term or long-term presynaptic facilitation of Aplysia sensory-to-motor synapses. The cAMP-dependent protein kinase, a heterodimer of two regulatory and two catalytic subunits, has been shown to become stably activated only during long-term facilitation. Both acquisition of long-term facilitation and persistent activation of the kinase is blocked by anisomycin, an effective, reversible, and specific inhibitor of protein synthesis in Aplysia. We report here that 2-hr exposure of pleural sensory cells to serotonin lowers the concentration of regulatory subunits but does not change the concentration of catalytic subunits, as assayed 24 hr later; 5-min exposure to serotonin has no effect on either type of subunit. Increasing intracellular cAMP with a permeable analog of cAMP together with the phosphodiesterase inhibitor isobutyl methylxanthine also decreased regulatory subunits, suggesting that cAMP is the second messenger mediating serotonin action. Anisomycin blocked the loss of regulatory subunits only when applied with serotonin; application after the 2-hr treatment with serotonin had no effect. In the Aplysia accessory radula contractor muscle, prolonged exposure to serotonin or to the peptide transmitter small cardioactive peptide B, both of which produce large increases in intracellular cAMP, does not decrease regulatory subunits. This mechanism of regulating the cAMP-dependent protein kinase therefore may be specific to the nervous system. We conclude that during long-term facilitation, new protein is synthesized in response to the facilitatory stimulus, which changes the ratio of subunits of the cAMP-dependent protein kinase. This alteration in ratio could persistently activate the kinase and produce the persistent phosphorylation seen in long-term facilitated sensory cells. Images PMID:1692622

Current prevention and control of health care-associated infections in long-term care facilities for the elderly in Japan.

PubMed

Kariya, Naoko; Sakon, Naomi; Komano, Jun; Tomono, Kazunori; Iso, Hiroyasu

2018-05-01

Residents of long-term care facilities for the elderly are vulnerable to health care-associated infections. However, compared to medical institutions, long-term care facilities for the elderly lag behind in health care-associated infection control and prevention. We conducted a epidemiologic study to clarify the current status of infection control in long-term care facilities for the elderly in Japan. A questionnaire survey on the aspects of infection prevention and control was developed according to SHEA/APIC guidelines and was distributed to 617 long-term care facilities for the elderly in the province of Osaka during November 2016 and January 2017. The response rate was 16.9%. The incidence rates of health care-associated infection outbreaks and residents with health care-associated infections were 23.4 per 100 facility-years and 0.18 per 1,000 resident-days, respectively. Influenza and acute gastroenteritis were reported most frequently. Active surveillance to identify the carrier of multiple drug-resistant organisms was not common. The overall compliance with 21 items selected from the SHEA/APIC guidelines was approximately 79.2%. All facilities had infection control manuals and an assigned infection control professional. The economic burdens of infection control were approximately US$ 182.6 per resident-year during fiscal year 2015. Importantly, these data implied that physicians and nurses were actively contributed to higher SHEA/APIC guideline compliance rates and the advancement of infection control measures in long-term care facilities for the elderly. Key factors are discussed to further improve the infection control in long-term care facilities for the elderly, particularly from economic and social structural standpoints. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Long-term exercise adherence after public health training in at-risk adults.

PubMed

Saida, Trine Gro Riktrup Hansen; Juul Sørensen, Tina; Langberg, Henning

2017-07-01

Sustainment of healthy exercise behavior is essential in preventing cardiovascular disease and diabetes. Few studies have explored long-term exercise adherence after an exercise referral scheme. The objective of this study was to examine 12-month exercise adherence after an exercise intervention program. This was a pragmatic follow-up study in at-risk people performed between June 2012 and January 2014. The main outcome measure was self-reported single-item exercise adherence. Secondary outcomes were change in exercise level, quality of life rated on a visual analog scale and self-rated health. Predictors of long-term exercise adherence were assessed by logistic regression, estimating crude odds-ratios (OR) and 95% confidence intervals (95% CIs) and adjusting for age, gender, education, smoking, moderate and vigorous exercise. In total, 214 adults (mean age 58.8±11.97 years, 71% women) participated in the study and received a 12-week training intervention: 62% had hypertension, 64% dyslipidemia and 15% impaired glucose tolerance. Attrition rate was 84% (n=179). During the 12-month follow-up, 48% (n=85) reported long-term exercise adherence. The main predictors of long-term exercise adherence were participation in sport activities at baseline (adjusted odds-ratio [aOR] 4.22, 95% CI 1.72-10.40), self-rated health (aOR 2.60, 1.00-6.75) and quality of life (aOR 2.39, 1.03-5.54). Long-term non-adherence was associated with low education (<10 years; aOR 3.27, 1.14-9.43) and age<50 years (aOR 3.53, 1.32-9.43). In this pragmatic study, long-term exercise adherence was associated with participation in sport activities and self-rated health at baseline. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Mucosal Healing Is Associated With Improved Long-term Outcomes of Patients With Ulcerative Colitis: A Systematic Review and Meta-analysis.

PubMed

Shah, Shailja C; Colombel, Jean-Frederic; Sands, Bruce E; Narula, Neeraj

2016-09-01

The paradigm for treatment for ulcerative colitis (UC) is shifting from resolving symptoms toward objective measures such as mucosal healing (MH). However, it is unclear whether MH is associated with improved long-term outcomes. We performed a systematic review and meta-analysis to identify and analyze studies comparing long-term outcomes of patients with MH with those without MH. We performed a systematic search of 3 large databases to identify prospective studies of patients with active UC that included outcomes of patients found to have MH at the first endoscopic evaluation after initiation of UC therapy (MH1) compared with those without MH1. The primary outcome was clinical remission after at least 52 weeks. Secondary outcomes included proportions of patients who were free of colectomy or corticosteroids and rate of MH after at least 52 weeks. We analyzed 13 studies comprising 2073 patients with active UC. Patients with MH1 had pooled odds ratio of 4.50 for achieving long-term (after at least 52 weeks) clinical remission (95% confidence interval [CI], 2.12-9.52), 4.15 for remaining free of colectomy (95% CI, 2.53-6.81), 8.40 for achieving long-term MH (95% CI, 3.13-22.53), and 9.70 for achieving long-term corticosteroid-free clinical remission (95% CI, 0.94-99.67), compared with patients without MH1. We found no difference in outcomes if patients achieved MH1 while receiving biologic versus non-biologic therapy. In a meta-analysis, we associated MH with long-term clinical remission, avoidance of colectomy, and corticosteroid-free clinical remission. MH is therefore appropriate goal of UC therapy. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Nitrifying moving bed biofilm reactor (MBBR) biofilm and biomass response to long term exposure to 1 °C.

PubMed

Hoang, V; Delatolla, R; Abujamel, T; Mottawea, W; Gadbois, A; Laflamme, E; Stintzi, A

2014-02-01

This study aims to investigate moving bed biofilm reactor (MBBR) nitrification rates, nitrifying biofilm morphology, biomass viability as well as bacterial community shifts during long-term exposure to 1 °C. Long-term exposure to 1 °C is the key operational condition for potential ammonia removal upgrade units to numerous northern region treatment systems. The average laboratory MBBR ammonia removal rate after long-term exposure to 1 °C was measured to be 18 ± 5.1% as compared to the average removal rate at 20 °C. Biofilm morphology and specifically the thickness along with biomass viability at various depths in the biofilm were investigated using variable pressure electron scanning microscope (VPSEM) imaging and confocal laser scanning microscope (CLSM) imaging in combination with viability live/dead staining. The biofilm thickness along with the number of viable cells showed significant increases after long-term exposure to 1 °C. Hence, this study observed nitrifying bacteria with higher activities at warm temperatures and a slightly greater quantity of nitrifying bacteria with lower activities at cold temperatures in nitrifying MBBR biofilms. Using DNA sequencing analysis, Nitrosomonas and Nitrosospira (ammonia oxidizers) as well as Nitrospira (nitrite oxidizer) were identified and no population shift was observed between 20 °C and after long-term exposure to 1 °C. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Falls and fractures among older adults living in long-term care].

PubMed

Del Duca, Giovâni Firpo; Antes, Danielle Ledur; Hallal, Pedro Curi

2013-03-01

To investigate the prevalence of falls and fractures over the past 12 months and associated factors among older adults living in long-term care. Census of all long-term care located in the city of Pelotas, Brazil, in 2008. Falls over the past 12 months were assessed using the following question: "Over the last 12 months, have you fallen?" For those who replied positively, another question was asked: "In any of these falls, have you fractured a bone?" Sex, age, schooling, disability relating to basic activities of daily living, type of financing of the long-term care and hospital admissions were the independent variables. We used chi-square tests for heterogeneity and linear trend in the unadjusted analysis, and Poisson regression with robust variance in the adjusted one. Within the 24 long-term care studied, we collected data for 466 individuals. The prevalence of falls in the past year was 38.9% (95%CI 34.5; 43.4). Among those who have fallen, 19.2% had fractures. Femur (hip) was the most frequent site fractured (43.4%), followed by wrist (10%). In the adjusted analysis, older age, disability for 1-5 basic activities of daily living, living in public institutions and hospital admissions in the last year were associated with higher risk of falls. The high prevalence of falls and fractures highlights the fragility of the individuals living in long-term care. Special attention should be paid to older adults and those with hospital admissions in the last year.

Statewide ITS development and deployment plan

DOT National Transportation Integrated Search

2002-10-01

This plan was developed to create a means to implement the ongoing, short-term and long-term activities identified in the Statewide ITS Action Plan. As part of the process for organizing the approximately seventy-five Action Plan activities, these we...

A Model of Bidirectional Synaptic Plasticity: From Signaling Network to Channel Conductance

ERIC Educational Resources Information Center

Castellani, Gastone C.; Quinlan, Elizabeth M.; Bersani, Ferdinando; Cooper, Leon N.; Shouval, Harel Z.

2005-01-01

In many regions of the brain, including the mammalian cortex, the strength of synaptic transmission can be bidirectionally regulated by cortical activity (synaptic plasticity). One line of evidence indicates that long-term synaptic potentiation (LTP) and long-term synaptic depression (LTD), correlate with the phosphorylation/dephosphorylation of…

Speaking up and Speaking Out? Long-Term Impact of Critical Multicultural Pedagogy

ERIC Educational Resources Information Center

Flynn, Jill Ewing

2017-01-01

This study explores the long-term effects of critical multicultural pedagogy on seven adolescents. Four years later, participants continued to demonstrate awareness of privilege and racism, yet few were actively engaged in antiracist work. Participants also expressed disillusionment and lamented the lack of productive discussions of critical…

Progesterone Regulation of Synaptic Transmission and Plasticity in Rodent Hippocampus

ERIC Educational Resources Information Center

Foy, Michael R.; Akopian, Garnik; Thompson, Richard F.

2008-01-01

Ovarian hormones influence memory formation by eliciting changes in neural activity. The effects of various concentrations of progesterone (P4) on synaptic transmission and plasticity associated with long-term potentiation (LTP) and long-term depression (LTD) were studied using in vitro hippocampal slices. Extracellular studies show that the…

Long-term Bat Monitoring on Islands, Offshore Structures, and Coastal Sites in the Gulf of Maine, mid-Atlantic, and Great Lakes—Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, Trevor; Pelletier, Steve; Giovanni, Matt

This report summarizes results of a long-term regional acoustic survey of bat activity at remote islands, offshore structures, and coastal sites in the Gulf of Maine, Great Lakes, and mid-Atlantic coast.

Socioeconomic Factors Affecting Local Support for Black Bear Recovery Strategies

NASA Astrophysics Data System (ADS)

Morzillo, Anita T.; Mertig, Angela G.; Hollister, Jeffrey W.; Garner, Nathan; Liu, Jianguo

2010-06-01

There is global interest in recovering locally extirpated carnivore species. Successful efforts to recover Louisiana black bear in Louisiana have prompted interest in recovery throughout the species’ historical range. We evaluated support for three potential black bear recovery strategies prior to public release of a black bear conservation and management plan for eastern Texas, United States. Data were collected from 1,006 residents living in proximity to potential recovery locations, particularly Big Thicket National Preserve. In addition to traditional logistic regression analysis, we used conditional probability analysis to statistically and visually evaluate probabilities of public support for potential black bear recovery strategies based on socioeconomic characteristics. Allowing black bears to repopulate the region on their own (i.e., without active reintroduction) was the recovery strategy with the greatest probability of acceptance. Recovery strategy acceptance was influenced by many socioeconomic factors. Older and long-time local residents were most likely to want to exclude black bears from the area. Concern about the problems that black bears may cause was the only variable significantly related to support or non-support across all strategies. Lack of personal knowledge about black bears was the most frequent reason for uncertainty about preferred strategy. In order to reduce local uncertainty about possible recovery strategies, we suggest that wildlife managers focus outreach efforts on providing local residents with general information about black bears, as well as information pertinent to minimizing the potential for human-black bear conflict.

Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

PubMed

McCabe, Amanda; Smith, Julianne N P; Costello, Angelica; Maloney, Jackson; Katikaneni, Divya; MacNamara, Katherine C

2018-05-17

Severe aplastic anemia results from profound hematopoietic stem cell loss. T cells and interferon gamma have long been associated with severe aplastic anemia, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of severe aplastic anemia, we demonstrate that interferon gamma-dependent hematopoietic stem cell loss required macrophages. Interferon gamma was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating interferon gamma signaling specifically in macrophages did not impair T cell activation or interferon gamma production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of interferon gamma in severe aplastic anemia and rather act as sensors of interferon gamma. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, severe aplastic anemia induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis demonstrating a novel role for macrophages as sensors of interferon gamma, thus illustrating an important role for the microenvironment in pathogenesis of severe aplastic anemia. Copyright © 2018, Ferrata Storti Foundation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohi, J.

Supporting analysis and assessments can provide a sound analytic foundation and focus for program planning, evaluation, and coordination, particularly if issues of hydrogen production, distribution, storage, safety, and infrastructure can be analyzed in a comprehensive and systematic manner. The overall purpose of this activity is to coordinate all key analytic tasks-such as technology and market status, opportunities, and trends; environmental costs and benefits; and regulatory constraints and opportunities-within a long-term and systematic analytic foundation for program planning and evaluation. Within this context, the purpose of the project is to help develop and evaluate programmatic pathway options that incorporate near andmore » mid-term strategies to achieve the long-term goals of the Hydrogen Program. In FY 95, NREL will develop a comprehensive effort with industry, state and local agencies, and other federal agencies to identify and evaluate programmatic pathway options to achieve the long-term goals of the Program. Activity to date is reported.« less

A Portable Dynamic Laser Speckle System for Sensing Long-Term Changes Caused by Treatments in Painting Conservation

PubMed Central

Pérez, Alberto J.; Braga, Roberto; Perles, Ángel; Pérez–Marín, Eva; García-Diego, Fernando J.

2018-01-01

Dynamic laser speckle (DLS) is used as a reliable sensor of activity for all types of materials. Traditional applications are based on high-rate captures (usually greater than 10 frames-per-second, fps). Even for drying processes in conservation treatments, where there is a high level of activity in the first moments after the application and slower activity after some minutes or hours, the process is based on the acquisition of images at a time rate that is the same in moments of high and low activity. In this work, we present an alternative approach to track the drying process of protective layers and other painting conservation processes that take a long time to reduce their levels of activity. We illuminate, using three different wavelength lasers, a temporary protector (cyclododecane) and a varnish, and monitor them using a low fps rate during long-term drying. The results are compared to the traditional method. This work also presents a monitoring method that uses portable equipment. The results present the feasibility of using the portable device and show the improved sensitivity of the dynamic laser speckle when sensing the long-term process for drying cyclododecane and varnish in conservation. PMID:29324692

Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia

PubMed Central

Michael, Dan; Martin, Kelsey C.; Seger, Rony; Ning, Ming-Ming; Baston, Rene; Kandel, Eric R.

1998-01-01

Long-term facilitation of the connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia requires five repeated pulses of serotonin (5-HT). The repeated pulses of 5-HT initiate a cascade of gene activation that leads ultimately to the growth of new synaptic connections. Several genes in this process have been identified, including the transcriptional regulators apCREB-1, apCREB-2, apC/EBP, and the cell adhesion molecule apCAM, which is thought to be involved in the formation of new synaptic connections. Here we report that the transcriptional regulators apCREB-2 and apC/EBP, as well as a peptide derived from the cytoplasmic domain of apCAM, are phosphorylated in vitro by Aplysia mitogen-activated protein kinase (apMAPK). We have cloned the cDNA encoding apMAPK and show that apMAPK activity is increased in sensory neurons treated with repeated pulses of 5-HT and by the cAMP pathway. These results suggest that apMAPK may participate with cAMP-dependent protein kinase during long-term facilitation in sensory cells by modifying some of the key elements involved in the consolidation of short- to long-lasting changes in synaptic strength. PMID:9465108

Persistent negative illness perceptions despite long-term biochemical control of acromegaly: novel application of the drawing test.

PubMed

Tiemensma, Jitske; Pereira, Alberto M; Romijn, Johannes A; Broadbent, Elizabeth; Biermasz, Nienke R; Kaptein, Adrian A

2015-05-01

Patients with acromegaly have persistent complaints despite long-term biochemical control. Drawings can be used to assess patients' perceptions about their disease. We aimed to explore the utility of the drawing test and its relation to illness perceptions and quality of life (QoL) in patients after long-term remission of acromegaly. A cross-sectional study was conducted to evaluate the utility of the drawing test. A total of 50 patients after long-term remission (mean±s.e.m., 16±1.2 years) of acromegaly were included in this study. Patients completed the drawing test (two retrospective drawings of their body perception before acromegaly and during the active phase of acromegaly, and one drawing on the current condition after long-term remission), Illness Perception Questionnaire-Revised, Physical Symptom Checklist, EuroQoL-5D, and AcroQoL. Patients perceived a dramatic change in body size during the active state of the disease compared with the healthy state before the awareness of acromegaly. Patients reported that their body did not completely return to the original proportions after long-term remission. In addition, larger drawings indicated more negative consequences (P<0.05), a higher score on emotional representations (P<0.05), and more perceived symptoms that were attributed to acromegaly (P<0.01). Larger drawings also indicated more impaired QoL, especially disease-specific QoL (all P<0.05). There are strong correlations among the drawing test, illness perceptions, and QoL. The drawing test appears to be a novel and relatively easy tool to assess the perception of patients after long-term remission of acromegaly. The assessment of drawings may enable health care providers to appreciate the perceptions of patients with long-term remission of acromegaly, and enable discussion of symptoms and remission. © 2015 European Society of Endocrinology.

Exploration of life experiences of positive growth in long-term childhood cancer survivors.

PubMed

Kim, Yoonjung

2017-10-01

The aim of this study was to explore experiences of positive growth in long-term childhood cancer survivors, from their perspective. Fifteen long-term survivors of childhood cancer provided descriptions of their experiences. Data were collected through face-to-face interviews and the analysis was based on Giorgi's phenomenological research method. The analysis of positive growth experienced by long-term childhood cancer survivors revealed three themes: self-directed life, normalcy in life, and inner maturity. Long-term survivors defined positive growth as a successful transition to a self-satisfactory life based on motivation acquired through their cancer experience and on subjective goal-setting, as well as becoming cancer-free and living a normal life within society. They seemed to have acquired optimistic, flexible, active attitudes toward life while demonstrating profound gratefulness and consideration of people around them, as well as prudent approaches to health. The findings of this study verified that long-term survivors of childhood cancer have grown positively due to their negative past experience. We expect these findings to contribute to the development of programs that promote positive growth in long-term childhood cancer survivors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Understanding causality and uncertainty in volcanic observations: An example of forecasting eruptive activity on Soufrière Hills Volcano, Montserrat

NASA Astrophysics Data System (ADS)

Sheldrake, T. E.; Aspinall, W. P.; Odbert, H. M.; Wadge, G.; Sparks, R. S. J.

2017-07-01

Following a cessation in eruptive activity it is important to understand how a volcano will behave in the future and when it may next erupt. Such an assessment can be based on the volcano's long-term pattern of behaviour and insights into its current state via monitoring observations. We present a Bayesian network that integrates these two strands of evidence to forecast future eruptive scenarios using expert elicitation. The Bayesian approach provides a framework to quantify the magmatic causes in terms of volcanic effects (i.e., eruption and unrest). In October 2013, an expert elicitation was performed to populate a Bayesian network designed to help forecast future eruptive (in-)activity at Soufrière Hills Volcano. The Bayesian network was devised to assess the state of the shallow magmatic system, as a means to forecast the future eruptive activity in the context of the long-term behaviour at similar dome-building volcanoes. The findings highlight coherence amongst experts when interpreting the current behaviour of the volcano, but reveal considerable ambiguity when relating this to longer patterns of volcanism at dome-building volcanoes, as a class. By asking questions in terms of magmatic causes, the Bayesian approach highlights the importance of using short-term unrest indicators from monitoring data as evidence in long-term forecasts at volcanoes. Furthermore, it highlights potential biases in the judgements of volcanologists and identifies sources of uncertainty in terms of magmatic causes rather than scenario-based outcomes.

Protein kinase M ζ and the maintenance of long-term memory.

PubMed

Zhang, Yang; Zong, Wei; Zhang, Lei; Ma, Yuanye; Wang, Jianhong

2016-10-01

Although various molecules have been found to mediate the processes of memory acquisition and consolidation, the molecular mechanism to maintain memory still remains elusive. In recent years, a molecular pathway focusing on protein kinase Mζ (PKMζ) has become of interest to researchers because of its potential role in long-term memory maintenance. PKMζ is an isoform of protein kinase C (PKC) and has a related structure that influences its function in maintaining memory. Considerable evidence has been gathered on PKMζ activity, including loss of function studies using PKMζ inhibitors, such as PKMζ inhibitory peptide (ZIP), suggesting PKMζ plays an important role in long-term memory maintenance. This review provides an overview of the role of PKMζ in long-term memory and outlines the molecular structure of PKMζ, the molecular mechanism of PKMζ in long-term memory maintenance and future directions of PKMζ research. Copyright © 2016 Elsevier Ltd. All rights reserved.

Natural gas imports and exports, first quarter report 2000

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

The Office of Natural Gas and Petroleum Import and Export Activities prepares quarterly reports showing natural gas import and export activity. Companies are required to file quarterly reports. Attachments show the percentage of takes to maximum firm contract levels and the weighted average per unit price for each of the long-term importers during the 5 most recent reporting quarters, volumes and prices of gas purchased by long-term importers and exporters during the past 12 months, volume and price data for gas imported on a short-term or spot market basis, and the gas exported on a short-term or spot market basismore » to Canada and Mexico.« less

Natural gas imports and exports, fourth quarter report 1999

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

The Office of Natural Gas and Petroleum Import and Export Activities prepares quarterly reports showing natural gas import and export activity. Companies are required to file quarterly reports. Attachments show the percentage of takes to maximum firm contract levels and the weighted average per unit price for each of the long-term importers during the five most recent quarters, volumes and prices of gas purchased by long-term importers and exporters during the past 12 months, volume and price data for gas imported on a short-term or spot market basis, and the gas exported on a short-term or spot market basis tomore » Canada and Mexico.« less

Microglial activation as a measure of stress in mouse brains exposed acutely (60 minutes) and long-term (2 years) to mobile telephone radiofrequency fields.

PubMed

Finnie, John W; Cai, Zhao; Manavis, Jim; Helps, Stephen; Blumbergs, Peter C

2010-02-01

To determine whether acute or long-term exposure of the brain to mobile telephone radiofrequency (RF) fields produces activation of microglia, which normally respond rapidly to any change in their microenvironment. Using a purpose designed exposure system at 900 MHz, mice were given a single, far-field whole body exposure at a specific absorption rate (SAR) of 4 W/kg for 60 min (acute) or on five successive days per week for 104 weeks (long-term). Control mice were sham-exposed or freely mobile in a cage to control for any stress caused by immobilisation in the exposure module. Positive control brains subjected to a stab wound were also included to confirm the ability of microglia to react to any neural stress. Brains were perfusion-fixed with 4% paraformaldehyde and representative regions of the cerebral cortex and hippocampus immunostained for ionised calcium binding adaptor molecule (Iba1), a specific microglial marker. There was no increase in microglial Iba1 expression in brains short or long-term exposed to mobile telephony microwaves compared to control (sham-exposed or freely moving caged mice) brains, while substantial microglial activation occurred in damaged positive control neural tissue. Acute (60 minutes) or longer duration (2 years) exposure of murine brains to mobile telephone RF fields did not produce any microglial activation detectable by Iba1 immunostaining.

Identifying Feasible Physical Activity Programs for Long-Term Care Homes in the Ontario Context

PubMed Central

Shakeel, Saad; Newhouse, Ian; Malik, Ali; Heckman, George

2015-01-01

Background Structured exercise programs for frail institutionalized seniors have shown improvement in physical, functional, and psychological health of this population. However, the ‘feasibility’ of implementation of such programs in real settings is seldom discussed. The purpose of this systematic review was to gauge feasibility of exercise and falls prevention programs from the perspective of long-term care homes in Ontario, given the recent changes in funding for publically funded physiotherapy services. Method Six electronic databases were searched by two independent researchers for randomized controlled trials that targeted long-term care residents and included exercise as an independent component of the intervention. Results A total of 39 studies were included in this review. A majority of these interventions were led by physiotherapist(s), carried out three times per week for 30–45 minutes per session. However, a few group-based interventions that were led by long-term care staff, volunteers, or trained non-exercise specialists were identified that also required minimal equipment. Conclusion This systematic review has identified ‘feasible’ physical activity and falls prevention programs that required minimal investment in staff and equipment, and demonstrated positive outcomes. Implementation of such programs represents cost-effective means of providing long-term care residents with meaningful gains in physical, psychological, and social health. PMID:26180563

Lazy workers are necessary for long-term sustainability in insect societies

PubMed Central

Hasegawa, Eisuke; Ishii, Yasunori; Tada, Koichiro; Kobayashi, Kazuya; Yoshimura, Jin

2016-01-01

Optimality theory predicts the maximization of productivity in social insect colonies, but many inactive workers are found in ant colonies. Indeed, the low short-term productivity of ant colonies is often the consequence of high variation among workers in the threshold to respond to task-related stimuli. Why is such an inefficient strategy among colonies maintained by natural selection? Here, we show that inactive workers are necessary for the long-term sustainability of a colony. Our simulation shows that colonies with variable thresholds persist longer than those with invariable thresholds because inactive workers perform the critical function of replacing active workers when they become fatigued. Evidence of the replacement of active workers by inactive workers has been found in ant colonies. Thus, the presence of inactive workers increases the long-term persistence of the colony at the expense of decreasing short-term productivity. Inactive workers may represent a bet-hedging strategy in response to environmental stochasticity. PMID:26880339

Long-term effect of set potential on biocathodes in microbial fuel cells: electrochemical and phylogenetic characterization.

PubMed

Xia, Xue; Sun, Yanmei; Liang, Peng; Huang, Xia

2012-09-01

The long-term effect of set potential on oxygen reducing biocathodes was investigated in terms of electrochemical and biological characteristics. Three biocathodes were poised at 200, 60 and -100 mV vs. saturated calomel electrode (SCE) for 110 days, including the first 17 days for startup. Electrochemical analyses showed that 60 mV was the optimum potential during long-term operation. The performance of all the biocathodes kept increasing after startup, suggesting a period longer than startup time needed to make potential regulation more effective. The inherent characteristics without oxygen transfer limitation were studied. Different from short-term regulation, the amounts of biomass were similar while the specific electrochemical activity was significantly influenced by potential. Moreover, potential showed a strong selection for cathode bacteria. Clones 98% similar with an uncultured Bacteroidetes bacterium clone CG84 accounted for 75% to 80% of the sequences on the biocathodes that showed higher electrochemical activity (60 and -100 mV). Copyright © 2012 Elsevier Ltd. All rights reserved.

Replicating annual North Atlantic hurricane activity 1878-2012 from environmental variables

NASA Astrophysics Data System (ADS)

Saunders, Mark A.; Klotzbach, Philip J.; Lea, Adam S. R.

2017-06-01

Statistical models can replicate annual North Atlantic hurricane activity from large-scale environmental field data for August and September, the months of peak hurricane activity. We assess how well the six environmental fields used most often in contemporary statistical modeling of seasonal hurricane activity replicate North Atlantic hurricane numbers and Accumulated Cyclone Energy (ACE) over the 135 year period from 1878 to 2012. We find that these fields replicate historical hurricane activity surprisingly well, showing that contemporary statistical models and their seasonal physical links have long-term robustness. We find that August-September zonal trade wind speed over the Caribbean Sea and the tropical North Atlantic is the environmental field which individually replicates long-term hurricane activity the best and that trade wind speed combined with the difference in sea surface temperature between the tropical Atlantic and the tropical mean is the best multi-predictor model. Comparing the performance of the best single-predictor and best multi-predictor models shows that they exhibit little difference in hindcast skill for predicting long-term ACE but that the best multipredictor model offers improved skill for predicting long-term hurricane numbers. We examine whether replicated real-time prediction skill 1983-2012 increases as the model training period lengthens and find evidence that this happens slowly. We identify a dropout in hurricane replication centered on the 1940s and show that this is likely due to a decrease in data quality which affects all data sets but Atlantic sea surface temperatures in particular. Finally, we offer insights on the implications of our findings for seasonal hurricane prediction.

Linear and nonlinear measures of fetal heart rate patterns evaluated on very short fetal magnetocardiograms.

PubMed

Moraes, Eder Rezende; Murta, Luiz Otavio; Baffa, Oswaldo; Wakai, Ronald T; Comani, Silvia

2012-10-01

We analyzed the effectiveness of linear short- and long-term variability time domain parameters, an index of sympatho-vagal balance (SDNN/RMSSD) and entropy in differentiating fetal heart rate patterns (fHRPs) on the fetal heart rate (fHR) series of 5, 3 and 2 min duration reconstructed from 46 fetal magnetocardiograms. Gestational age (GA) varied from 21 to 38 weeks. FHRPs were classified based on the fHR standard deviation. In sleep states, we observed that vagal influence increased with GA, and entropy significantly increased (decreased) with GA (SDNN/RMSSD), demonstrating that a prevalence of vagal activity with autonomous nervous system maturation may be associated with increased sleep state complexity. In active wakefulness, we observed a significant negative (positive) correlation of short-term (long-term) variability parameters with SDNN/RMSSD. ANOVA statistics demonstrated that long-term irregularity and standard deviation of normal-to-normal beat intervals (SDNN) best differentiated among fHRPs. Our results confirm that short- and long-term variability parameters are useful to differentiate between quiet and active states, and that entropy improves the characterization of sleep states. All measures differentiated fHRPs more effectively on very short HR series, as a result of the fMCG high temporal resolution and of the intrinsic timescales of the events that originate the different fHRPs.

The neural substrates of recognition memory for verbal information: spanning the divide between short- and long-term memory.

PubMed

Buchsbaum, Bradley R; Padmanabhan, Aarthi; Berman, Karen Faith

2011-04-01

One of the classic categorical divisions in the history of memory research is that between short-term and long-term memory. Indeed, because memory for the immediate past (a few seconds) and memory for the relatively more remote past (several seconds and beyond) are assumed to rely on distinct neural systems, more often than not, memory research has focused either on short- (or "working memory") or on long-term memory. Using an auditory-verbal continuous recognition paradigm designed for fMRI, we examined how the neural signatures of recognition memory change across an interval of time (from 2.5 to 30 sec) that spans this hypothetical division between short- and long-term memory. The results revealed that activity during successful auditory-verbal item recognition in inferior parietal cortex and the posterior superior temporal lobe was maximal for early lags, whereas, conversely, activity in the left inferior frontal gyrus increased as a function of lag. Taken together, the results reveal that as the interval between item repetitions increases, there is a shift in the distribution of memory-related activity that moves from posterior temporo-parietal cortex (lags 1-4) to inferior frontal regions (lags 5-10), indicating that as time advances, the burden of recognition memory is increasingly placed on top-down retrieval mechanisms that are mediated by structures in inferior frontal cortex.

The Role of Actin Cytoskeleton in Dendritic Spines in the Maintenance of Long-Term Memory.

PubMed

Basu, Sreetama; Lamprecht, Raphael

2018-01-01

Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such alterations induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. This is especially intriguing as the half-life of most of the proteins that underlie such changes is usually in the range of hours to days and these proteins may change their location over time. In this review we describe studies that indicate the involvement of dendritic spines in memory formation and its maintenance. These studies show that learning leads to changes in the number and morphology of spines. Disruption in spines morphology or manipulations that lead to alteration in their number after consolidation are associated with impairment in memory maintenance. We further ask how changes in dendritic spines morphology, induced by learning and reputed to encode memory, are maintained to preserve long-term memory. We propose a mechanism, based on studies described in the review, whereby the actin cytoskeleton and its regulatory proteins involved in the initial alteration in spine morphology induced by learning are also essential for spine structural stabilization that maintains long-term memory. In this model glutamate receptors and other synaptic receptors activation during learning leads to the creation of new actin cytoskeletal scaffold leading to changes in spines morphology and memory formation. This new actin cytoskeletal scaffold is preserved beyond actin and its regulatory proteins turnover and dynamics by active stabilization of the level and activity of actin regulatory proteins within these memory spines.