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Sample records for aav-bmal1 rescued mice

  1. Necrostatin-1 rescues mice from lethal irradiation.

    PubMed

    Huang, Zhentai; Epperly, Michael; Watkins, Simon C; Greenberger, Joel S; Kagan, Valerian E; Bayır, Hülya

    2016-04-01

    There is an emerging need in new medical products that can mitigate and/or treat the short- and long-term consequences of radiation exposure after a radiological or nuclear terroristic event. The direct effects of ionizing radiation are realized primarily via apoptotic death pathways in rapidly proliferating cells within the initial 1-2days after the exposure. However later in the course of the radiation disease necrotic cell death may ensue via direct and indirect pathways from increased generation of pro-inflammatory cytokines. Here we evaluated radiomitigative potential of necrostatin-1 after total body irradiation (TBI) and the contribution of necroptosis to cell death induced by radiation. Circulating TNFα levels were increased starting on d1 after TBI and associated with increased plasmalemma permeability in ileum of irradiated mice. Necrostatin-1 given iv. 48h after 9.5Gy TBI attenuated radiation-induced receptor interacting protein kinase 3 (RIPK3) serine phosphorylation in ileum and improved survival vs. vehicle. Utilizing apoptosis resistant cytochrome c(-/-) cells, we showed that radiation can induce necroptosis, which is attenuated by RNAi knock down of RIPK1 and RIPK3 or by treatment with necrostatin-1 or -1s whereas 1-methyl-L-tryptophan, an indoleamine-2,3-dioxygenase inhibitor, did not exhibit radiomitigative effect. This suggests that the beneficial effect of necrostatin-1 is likely through inhibition of RIPK1-mediated necroptotic pathway. Overall, our data indicate that necroptosis, a form of programmed necrosis, may play a significant role in cell death contributing to radiation disease and mortality. This study provides a proof of principle that necrostatin-1 and perhaps other RIPK1 inhibitors are promising therapeutic agents for radiomitigation after TBI. PMID:26802452

  2. Rescue of NGF-deficient mice I: transgenic expression of NGF in skin rescues mice lacking endogenous NGF.

    PubMed

    Harrison, Susan M W; Davis, Brian M; Nishimura, Merry; Albers, Kathryn M; Jones, Marc E; Phillips, Heidi S

    2004-03-30

    Mice lacking a functional NGF gene (ngf-/- mice) have less than one third of the normal complement of sensory neurons, few sympathetic postganglionic neurons and die shortly after birth. We report here that transgenic expression of NGF under control of the K14 keratin promoter can rescue some elements of the peripheral nervous system and restore normal growth and viability to ngf-/- mice. While hybrid transgenic-ngf-/- mice (ngfTKOs) displayed marginal rescue of trigeminal ganglion neurons, the percentage of CGRP-positive neurons was restored to normal. Restoration of CGRP-positive terminals in skin and spinal cord was also found and accompanied by recovery of behavioral responses to noxious stimuli. ngfTKO mice displayed a normal number of superior cervical ganglion neurons and recovery of sympathetic innervation of skin. These results demonstrate that substitution of a functional NGF locus by a transgene directing expression largely to skin can result in normal growth and viability. Thus, the most vital functions of NGF are not dependent on faithful recapitulation of the normal spatiotemporal pattern of gene expression. PMID:15010204

  3. Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

    PubMed Central

    Liu, Xiaoli; Hall, Sean R. R.; Wang, Zhihong; Huang, He; Ghanta, Sailaja; Di Sante, Moises; Leri, Annarosa; Anversa, Piero; Perrella, Mark A.

    2015-01-01

    Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg−/− mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg−/− foetal hearts. CPCs harvested from Speg−/− mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg−/− mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg−/− mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases. PMID:26593099

  4. Laminin γ2 knockout mice rescued with the human protein exhibit enamel maturation defects.

    PubMed

    Wazen, Rima M; Viegas-Costa, Luiz C; Fouillen, Aurélien; Moffatt, Pierre; Adair-Kirk, Tracy L; Senior, Robert M; Nanci, Antonio

    2016-01-01

    The epithelial ameloblasts are separated from the maturing enamel by an atypical basement membrane (BM) that is enriched in laminin 332 (LM-332). This heterotrimeric protein (α3, ß3 and γ2 chains) provides structural integrity to BMs and influences various epithelial cell processes including cell adhesion and differentiation. Mouse models that lack expression of individual LM-332 chains die shortly after birth. The lethal phenotype of laminin γ2 knockout mice can be rescued by human laminin γ2 (LAMC2) expressed using a doxycycline-inducible (Tet-on) cytokeratin 14 promoter-rtTA. These otherwise normal-looking rescued mice exhibit white spot lesions on incisors. We therefore investigated the effect of rescue with human LAMC2 on enamel maturation and structuring of the atypical BM. The maturation stage enamel organ in transgenic mice was severely altered as compared to wild type controls, a structured BM was no longer discernible, dystrophic matrix appeared in the maturing enamel layer, and there was residual enamel matrix late into the maturation stage. Microtomographic scans revealed excessive wear of occlusal surfaces on molars, chipping of enamel on incisor tips, and hypomineralization of the enamel layer. No structural alterations were observed at other epithelial sites, such as skin, palate and tongue. These results indicate that while this humanized mouse model is capable of rescue in various epithelial tissues, it is unable to sustain structuring of a proper BM at the interface between ameloblasts and maturing enamel. This failure may be related to the atypical composition of the BM in the maturation stage and reaffirms that the atypical BM is essential for enamel maturation. PMID:26956061

  5. Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice

    PubMed Central

    Escobedo, Noelia; Proulx, Steven T.; Karaman, Sinem; Dillard, Miriam E.; Johnson, Nicole; Detmar, Michael; Oliver, Guillermo

    2016-01-01

    Prox1 heterozygous mice have a defective lymphatic vasculature and develop late-onset obesity. Chyle abnormally leaks from those vessels, accumulates in the surrounding tissues, and causes an increase in adipose tissue. We characterized the lymphatics of Prox1+/− mice to determine whether the extent of obesity correlated with the severity of lymphatic defects. The lymphatic vasculature in Prox1+/− mice exhibited reduced tracer clearance from the ear skin, dysfunctional perfusion of the lower legs, and reduced tracer uptake into the deep lymphatic collectors during mechanostimulation prior to the onset of obesity. Ear lymphatic vessels and leg collectors in Prox1+/− mice were disorganized and irregular, further confirming that defective lymphatic vessels are associated with obesity in Prox1+/− mice. We now provide conclusive in vivo evidence that demonstrates that leaky lymphatics mediate obesity in Prox1+/− mice, as restoration of lymphatic vasculature function was sufficient to rescue the obesity features in Prox1+/− mice. Finally, depth-lipomic profiling of lymph contents showed that free fatty acids induce adipogenesis in vitro. PMID:26973883

  6. Strategies to Rescue the Consequences of Inducible Arginase-1 Deficiency in Mice

    PubMed Central

    Ballantyne, Laurel L.; Sin, Yuan Yan; St. Amand, Tim; Si, Joshua; Goossens, Steven; Haenebalcke, Lieven; Haigh, Jody J.; Kyriakopoulou, Lianna; Schulze, Andreas; Funk, Colin D.

    2015-01-01

    Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken β-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies. PMID:25938595

  7. Object recognition impairment and rescue by a dopamine D2 antagonist in hyperdopaminergic mice.

    PubMed

    França, Arthur S C; Muratori, Larissa; Nascimento, George Carlos; Pereira, Catia Mendes; Ribeiro, Sidarta; Lobão-Soares, Bruno

    2016-07-15

    Genetically-modified mice without the dopamine transporter (DAT) are hyperdopaminergic, and serve as models for studies of addiction, mania and hyperactive disorders. Here we investigated the capacity for object recognition in mildly hyperdopaminergic mice heterozygous for DAT (DAT +/-), with synaptic dopaminergic levels situated between those shown by DAT -/- homozygous and wild-type (WT) mice. We used a classical dopamine D2 antagonist, haloperidol, to modulate the levels of dopaminergic transmission in a dose-dependent manner, before or after exploring novel objects. In comparison with WT mice, DAT +/- mice showed a deficit in object recognition upon subsequent testing 24h later. This deficit was compensated by a single 0.05mg/kg haloperidol injection 30min before training. In all mice, a 0.3mg/kg haloperidol injected immediately after training impaired object recognition. The results indicate that a mild enhancement of dopaminergic levels can be detrimental to object recognition, and that this deficit can be rescued by a low dose of a D2 dopamine receptor antagonist. This suggests that novel object recognition is optimal at intermediate levels of D2 receptor activity. PMID:27059337

  8. Targeting macrophages rescues age-related immune deficiencies in C57BL/6J geriatric mice.

    PubMed

    Jackaman, Connie; Radley-Crabb, Hannah G; Soffe, Zoe; Shavlakadze, Tea; Grounds, Miranda D; Nelson, Delia J

    2013-06-01

    Changes to innate cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), during aging in healthy or tumor-bearing hosts are not well understood. We compared macrophage subpopulations and MDSCs from healthy young (6-8 weeks) C57BL/6J mice to those from healthy geriatric (24-28 months) mice. Spleens, lymph nodes, and bone marrow of geriatric hosts contained significantly more M2 macrophages and MDSCs than their younger counterparts. Peritoneal macrophages from geriatric, but not young, mice co-expressed CD40 and CX3CR1 that are usually mutually exclusively expressed by M1 or M2 macrophages. Nonetheless, macrophages from geriatric mice responded to M1 or M2 stimuli similarly to macrophages from young mice, although they secreted higher levels of TGF-β in response to IL-4. We mimicked conditions that may occur within tumors by exposing macrophages from young vs. geriatric mice to mesothelioma or lung carcinoma tumor cell-derived supernatants. While both supernatants skewed macrophages toward the M2-phenotype regardless of age, only geriatric-derived macrophages produced IL-4, suggesting a more immunosuppressive tumor microenvironment will be established in the elderly. Both geriatric- and young-derived macrophages induced allogeneic T-cell proliferation, regardless of the stimuli used, including tumor supernatant. However, only macrophages from young mice induced T-cell IFN-γ production. We examined the potential of an IL-2/agonist anti-CD40 antibody immunotherapy that eradicates large tumors in young hosts to activate macrophages from geriatric mice. IL-2-/CD40-activated macrophages rescued T-cell production of IFN-γ in geriatric mice. Therefore, targeting macrophages with IL-2/anti-CD40 antibody may improve innate and T-cell immunity in aging hosts. PMID:23442123

  9. Bone marrow-derived cells rescue salivary gland function in mice with head and neck irradiation

    PubMed Central

    Sumita, Yoshinori; Liu, Younan; Khalili, Saeed; Maria, Ola M.; Xia, Dengsheng; Key, Sharon; Cotrim, Ana P.; Mezey, Eva; Tran, Simon D.

    2012-01-01

    Treatment for most patients with head and neck cancers includes ionizing radiation. A consequence of this treatment is irreversible damage to salivary glands (SGs), which is accompanied by a loss of fluid-secreting acinar-cells and a considerable decrease of saliva output. While there are currently no adequate conventional treatments for this condition, cell-based therapies are receiving increasing attention to regenerate SGs. In this study, we investigated whether bone marrow-derived cells (BMDCs) can differentiate into salivary epithelial cells and restore SG function in head and neck irradiated mice. BMDCs from male mice were transplanted into the tail-vein of 18 Gy-irradiated female mice. Salivary output was increased in mice that received BMDCs transplantation at week 8 and 24 post-irradiation. At 24 weeks after irradiation (IR), harvested SGs (submandibular and parotid glands) of BMDC-treated mice had greater weights than those of non-treated mice. Histological analysis shows that SGs of treated mice demonstrated an increased level of tissue regenerative activity such as blood vessel formation and cell proliferation, while apoptotic activity was increased in non-transplanted mice. The expression of stem cell markers (Sca-1 or c-kit) was detected in BMDC-treated SGs. Finally, we detected an increased ratio of acinar-cell area and approximately 9% of Y-chromosome-positive (donor-derived) salivary epithelial cells in BMDC-treated mice. We propose here that cell therapy using BMDCs can rescue the functional damage of irradiated SGs by direct differentiation of donor BMDCs into salivary epithelial cells. PMID:20933096

  10. Rescue of NGF-deficient mice II: basal forebrain cholinergic projections require NGF for target innervation but not guidance.

    PubMed

    Phillips, Heidi S; Nishimura, Merry; Armanini, Mark P; Chen, Karen; Albers, Kathryn M; Davis, Brian M

    2004-04-29

    Basal forebrain cholinergic (BFC) neurons are an important substrate of cognitive function and are hypothesized to require the presence of nerve growth factor (NGF) for survival and target innervation. NGF-deficient mice develop BFC neurons that extend projections into telencephalic targets, but the mice perish before innervation is fully established. Rescue of NGF-deficient mice by transgenic expression of NGF under the keratin promoter yields viable mice with disrupted CNS expression of NGF. In the current study, rescued NGF-deficient mice contain normal numbers of septal cholinergic neurons yet reveal severe compromise of cholinergic innervation of both cortex and hippocampus. Surprisingly, intracerebroventricular infusion of NGF into juvenile mice can induce an essentially normal pattern of cholinergic innervation of the hippocampus. These results indicate that NGF is required for induction of proper innervation by BFC neurons, but that the cellular pattern of expression of this factor is not critical for specifying the distribution of axon terminals. PMID:15093680

  11. Cardiac dysfunction in Pkd1-deficient mice with phenotype rescue by galectin-3 knockout.

    PubMed

    Balbo, Bruno E; Amaral, Andressa G; Fonseca, Jonathan M; de Castro, Isac; Salemi, Vera M; Souza, Leandro E; Dos Santos, Fernando; Irigoyen, Maria C; Qian, Feng; Chammas, Roger; Onuchic, Luiz F

    2016-09-01

    Alterations in myocardial wall texture stand out among ADPKD cardiovascular manifestations in hypertensive and normotensive patients. To elucidate their pathogenesis, we analyzed the cardiac phenotype in Pkd1(cond/cond)Nestin(cre) (CYG+) cystic mice exposed to increased blood pressure, at 5 to 6 and 20 to 24 weeks of age, and Pkd1(+/-) (HTG+) noncystic mice at 5-6 and 10-13 weeks. Echocardiographic analyses revealed decreased myocardial deformation and systolic function in CYG+ and HTG+ mice, as well as diastolic dysfunction in older CYG+ mice, compared to their Pkd1(cond/cond) and Pkd1(+/+) controls. Hearts from CYG+ and HTG+ mice presented reduced polycystin-1 expression, increased apoptosis, and mild fibrosis. Since galectin-3 has been associated with heart dysfunction, we studied it as a potential modifier of the ADPKD cardiac phenotype. Double-mutant Pkd1(cond/cond):Nestin(cre);Lgals3(-/-) (CYG-) and Pkd1(+/-);Lgals3(-/-) (HTG-) mice displayed improved cardiac deformability and systolic parameters compared to single-mutants, not differing from the controls. CYG- and HTG- showed decreased apoptosis and fibrosis. Analysis of a severe cystic model (Pkd1(V/V); VVG+) showed that Pkd1(V/V);Lgals3(-/-) (VVG-) mice have longer survival, decreased cardiac apoptosis and improved heart function compared to VVG+. CYG- and VVG- animals showed no difference in renal cystic burden compared to CYG+ and VVG+ mice. Thus, myocardial dysfunction occurs in different Pkd1-deficient models and suppression of galectin-3 expression rescues this phenotype. PMID:27475230

  12. Running rescues a fear-based contextual discrimination deficit in aged mice

    PubMed Central

    Wu, Melody V.; Luna, Victor M.; Hen, René

    2015-01-01

    Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG) of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed on a fear-based contextual discrimination task. Aged mice showed a profound impairment in contextual discrimination compared to young animals. Voluntary exercise rescued this deficit to such an extent that behavioral pattern separation of aged-run mice was now similar to young animals. Running also resulted in a significant increase in the number of immature neurons with tertiary dendrites in aged mice. Despite this, neurogenesis levels in aged-run mice were still considerably lower than in young animals. Thus, mechanisms other than DG neurogenesis likely play significant roles in improving behavioral pattern separation elicited by exercise in aged animals. PMID:26321926

  13. Premature skin aging features rescued by inhibition of NADPH oxidase activity in XPC-deficient mice.

    PubMed

    Hosseini, Mohsen; Mahfouf, Walid; Serrano-Sanchez, Martin; Raad, Houssam; Harfouche, Ghida; Bonneu, Marc; Claverol, Stephane; Mazurier, Frederic; Rossignol, Rodrigue; Taieb, Alain; Rezvani, Hamid Reza

    2015-04-01

    Xeroderma pigmentosum type C (XP-C) is characterized mostly by a predisposition to skin cancers and accelerated photoaging, but little is known about premature skin aging in this disease. By comparing young and old mice, we found that the level of progerin and p16(INK4a) expression, β-galactosidase activity, and reactive oxygen species, which increase with age, were higher in young Xpc(-/-) mice than in young Xpc(+/+) ones. The expression level of mitochondrial complexes and mitochondrial functions in the skin of young Xpc(-/-) was as low as in control aged Xpc(+/+)animals. Furthermore, the metabolic profile in young Xpc(-/-) mice resembled that found in aged Xpc(+/+) mice. Furthermore, premature skin aging features in young Xpc(-/-) mice were mostly rescued by inhibition of nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1) activity by using a NOX1 peptide inhibitor, suggesting that the continuous oxidative stress due to overactivation of NOX1 has a causative role in the underlying pathophysiology. PMID:25437426

  14. Multiple Renal Cyst Development but Not Situs Abnormalities in Transgenic RNAi Mice against Inv::GFP Rescue Gene

    PubMed Central

    Kamijho, Yuki; Shiozaki, Yayoi; Sakurai, Eiki; Hanaoka, Kazunori; Watanabe, Daisuke

    2014-01-01

    In this study we generated RNA interference (RNAi)-mediated gene knockdown transgenic mice (transgenic RNAi mice) against the functional Inv gene. Inv mutant mice show consistently reversed internal organs (situs inversus), multiple renal cysts and neonatal lethality. The Inv::GFP-rescue mice, which introduced the Inv::GFP fusion gene, can rescue inv mutant mice phenotypes. This indicates that the Inv::GFP gene is functional in vivo. To analyze the physiological functions of the Inv gene, and to demonstrate the availability of transgenic RNAi mice, we introduced a short hairpin RNA expression vector against GFP mRNA into Inv::GFP-rescue mice and analyzed the gene silencing effects and Inv functions by examining phenotypes. Transgenic RNAi mice with the Inv::GFP-rescue gene (Inv-KD mice) down-regulated Inv::GFP fusion protein and showed hypomorphic phenotypes of inv mutant mice, such as renal cyst development, but not situs abnormalities or postnatal lethality. This indicates that shRNAi-mediated gene silencing systems that target the tag sequence of the fusion gene work properly in vivo, and suggests that a relatively high level of Inv protein is required for kidney development in contrast to left/right axis determination. Inv::GFP protein was significantly down-regulated in the germ cells of Inv-KD mice testis compared with somatic cells, suggesting the existence of a testicular germ cell-specific enhanced RNAi system that regulates germ cell development. The Inv-KD mouse is useful for studying Inv gene functions in adult tissue that are unable to be analyzed in inv mutant mice showing postnatal lethality. In addition, the shRNA-based gene silencing system against the tag sequence of the fusion gene can be utilized as a new technique to regulate gene expression in either in vitro or in vivo experiments. PMID:24586938

  15. Pathogenic Profiles and Molecular Signatures of Antinuclear Autoantibodies Rescued from NZM2410 Lupus Mice

    PubMed Central

    Liang, Zhiyan; Xie, Chun; Chen, Cui; Kreska, Desi; Hsu, Kelvin; Li, Liunan; Zhou, Xin J.; Mohan, Chandra

    2004-01-01

    Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs. PMID:14757744

  16. Environmental enrichment rescues memory in mice deficient for the polysialytransferase ST8SiaIV.

    PubMed

    Zerwas, Meike; Trouche, Stéphanie; Richetin, Kevin; Escudé, Timothé; Halley, Hélène; Gerardy-Schahn, Rita; Verret, Laure; Rampon, Claire

    2016-04-01

    The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and post-natal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired long-term but not short-term memory in both, spatial and non-spatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus. PMID:25596866

  17. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.

    PubMed

    Sztainberg, Yehezkel; Chen, Hong-mei; Swann, John W; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Wan, Ying-Wooi; Liu, Zhandong; Rigo, Frank; Zoghbi, Huda Y

    2015-12-01

    Copy number variations have been frequently associated with developmental delay, intellectual disability and autism spectrum disorders. MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical-pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question that we addressed was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders, including loss of MeCP2 in Rett syndrome, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we propose that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. By generating and characterizing a conditional Mecp2-overexpressing mouse model, here we show that correction of MeCP2 levels largely reverses the behavioural, molecular and electrophysiological deficits. We also reduced MeCP2 using an antisense oligonucleotide strategy, which has greater translational potential. Antisense oligonucleotides are small, modified nucleic acids that can selectively hybridize with messenger RNA transcribed from a target gene and silence it, and have been successfully used to correct deficits in different mouse models. We find that antisense oligonucleotide treatment induces a broad phenotypic rescue in adult

  18. Transgenic expression of Dspp partially rescued the long bone defects of Dmp1-null mice.

    PubMed

    Jani, Priyam H; Gibson, Monica P; Liu, Chao; Zhang, Hua; Wang, Xiaofang; Lu, Yongbo; Qin, Chunlin

    2016-01-01

    Dentin matrix protein 1 (DMP1) and dentin sialophosphoprotein (DSPP) belong to the Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) family. In addition to the features common to all SIBLING members, DMP1 and DSPP share several unique similarities in chemical structure, proteolytic activation and tissue localization. Mutations in, or deletion of DMP1, cause autosomal recessive hypophosphatemic rickets along with dental defects; DSPP mutations or its ablation are associated with dentinogenesis imperfecta. While the roles and functional mechanisms of DMP1 in osteogenesis have been extensively studied, those of DSPP in long bones have been studied only to a limited extent. Previous studies by our group revealed that transgenic expression of Dspp completely rescued the dentin defects of Dmp1-null (Dmp1(-/-)) mice. In this investigation, we assessed the effects of transgenic Dspp on osteogenesis by analyzing the formation and mineralization of the long bones in Dmp1(-/-) mice that expresses a transgene encoding full-length DSPP driven by a 3.6-kb rat Col1a1 promoter (referred as "Dmp1(-/-);Dspp-Tg mice"). We characterized the long bones of the Dmp1(-/-);Dspp-Tg mice at different ages and compared them with those from Dmp1(-/-) and Dmp1(+/-) (normal control) mice. Our analyses showed that the long bones of Dmp1(-/-);Dspp-Tg mice had a significant increase in cortical bone thickness, bone volume and mineral density along with a remarkable restoration of trabecular thickness compared to those of the Dmp1(-/-) mice. The long bones of Dmp1(-/-);Dspp-Tg mice underwent a dramatic reduction in the amount of osteoid, significant improvement of the collagen fibrillar network, and better organization of the lacunocanalicular system, compared to the Dmp1(-/-) mice. The elevated levels of biglycan, bone sialoprotein and osteopontin in Dmp1(-/-) mice were also noticeably corrected by the transgenic expression of Dspp. These findings suggest that DSPP and DMP1 may function

  19. Rescue from dominant follicle atresia by follicle-stimulating hormone in mice.

    PubMed

    Zhou, X L; Teng, Y; Cao, R; Fu, H; Xiong, K; Sun, W X; Zhu, C C; Huang, X J; Xiao, P; Liu, H L

    2013-01-01

    We investigated the effects of follicle-stimulating hormone (FSH) on atresia of the dominant follicle and changes in relevant apoptosis genes in granulosa cells of dominant follicles regulated by FSH in vivo. Four-week-old mice were administered FSH by intraperitoneal injection to induce follicular maturation. Granulosa cells of dominant follicles were collected at 48, 72, and 96 h after the first FSH injection. Phosphate-buffered saline was injected as a control. The mRNA levels of relevant granulosa cell apoptosis genes were examined by real-time quantitative polymerase chain reaction, and apoptosis of granulosa cells in dominant ovarian follicles was determined by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Apoptosis in granulosa cells of dominant follicles was almost TUNEL-negative at 48, 72-66, 72, and 96-90 h after the first FSH injection, but granulosa cell apoptosis in dominant follicles was clearly detected at 96, 102, and 102-96 h by TUNEL. The BIM, caspase-3, and caspase-9 mRNA expression levels were significantly lower after FSH treatment at 72-66 and 96-90 h, compared with that at 72 and 96 h (P < 0.05). Caspase-8 and FasL mRNA expressions did not respond to FSH. FSH rescued granulosa cells from apoptosis when the relevant apoptosis genes were upregulated in early atretic follicles. FSH did not rescue granulosa cells from apoptosis if the DNA was cut into fragments by endonucleases. Thus, the rescue by FSH of granulosa cells from apoptosis and dominant follicle atresia may be accomplished by inhibition of apoptosis in mitochondria. PMID:24065650

  20. Human cathepsin L rescues the neurodegeneration and lethality incathepsin B/L double deficient mice

    SciTech Connect

    Sevenich, Lisa; Pennacchio, Len A.; Peters, Christoph; Reinheckel, Thomas

    2006-01-09

    Cathepsin B (CTSB) and cathepsin L (CTSL) are two widelyexpressed cysteine proteases thought to predominantly reside withinlysosomes. Functional analysis of CTSL in humans is complicated by theexistence of two CTSL-like homologues (CTSL and CTSL2), in contrast tomice which contain only one CTSL enzyme. Thus transgenic expression ofhuman CTSL in CTSL deficient mice provides an opportunity to study the invivo functions of this human protease without interference by its highlyrelated homologue. While mice with single gene deficiencies for murineCTSB or CTSL survive without apparent neuromuscular impairment, murineCTSB/CTSL double deficient mice display degeneration of cerebellarPurkinje cells and neurons of the cerebral cortex, resulting in severehypotrophy, motility defects, and lethality during their third to fourthweek of life. Here we show that expression of human CTSL through agenomic transgene results in widespread expression of human CTSL in themouse which is capable of rescuing the lethality found in CTSB/CTSLdouble-deficient animals. Human CTSL is expressed in the brain of thesecompound mutants predominantly in neurons of the cerebral cortex and inPurkinje cells of the cerebellum, where it appears to prevent neuronalcell death.

  1. Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

    PubMed Central

    Mochizuki, Takatoshi; Arrigoni, Elda; Marcus, Jacob N.; Clark, Erika L.; Yamamoto, Mihoko; Honer, Michael; Borroni, Edilio; Lowell, Bradford B.; Elmquist, Joel K.; Scammell, Thomas E.

    2011-01-01

    Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets. PMID:21368172

  2. Nature vs. nurture: can enrichment rescue the behavioural phenotype of BDNF heterozygous mice?

    PubMed

    Chourbaji, Sabine; Brandwein, Christiane; Vogt, Miriam A; Dormann, Christof; Hellweg, Rainer; Gass, Peter

    2008-10-10

    In earlier experiments we have demonstrated that group-housing in a rather impoverished "standard" environment can be a crucial stress factor in male C57Bl/6 mice. The present study aimed at investigating the effect of combining a probable genetic vulnerability--postulated by the "Neurotrophin Hypothesis of Depression"--with the potentially modulating influence of a stressful environment such as "impoverished" standard housing conditions. For that purpose mice with a partial deletion of brain-derived neurotrophic factor (BDNF) were group-housed under standard and enriched housing conditions and analysed in a well-established test battery for emotional behaviours. Standard group-housing affected emotional behaviour in male and female BDNF heterozygous mice, causing an increase in anxiety, changes in exploration as well as nociception. Providing the animals' cages with supplementary enrichment, however, led to a rescue of emotional alterations, which emphasises the significance of external factors and their relevance for a valid investigation of genetic aspects in these mutants as well as others, which may be examined in terms of stress-responsiveness or emotionality. PMID:18538870

  3. Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice

    PubMed Central

    Dupree, Jeffrey L.; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia

    2016-01-01

    Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. SIGNIFICANCE STATEMENT Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under

  4. Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.

    PubMed

    Sun, Miao-Kun; Hongpaisan, Jarin; Alkon, Daniel L

    2016-05-01

    Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults. PMID:26941170

  5. Clemastine Enhances Myelination in the Prefrontal Cortex and Rescues Behavioral Changes in Socially Isolated Mice.

    PubMed

    Liu, Jia; Dupree, Jeffrey L; Gacias, Mar; Frawley, Rebecca; Sikder, Tamjeed; Naik, Payal; Casaccia, Patrizia

    2016-01-20

    Altered myelin structure and oligodendrocyte function have been shown to correlate with cognitive and motor dysfunction and deficits in social behavior. We and others have previously demonstrated that social isolation in mice induced behavioral, transcriptional, and ultrastructural changes in oligodendrocytes of the prefrontal cortex (PFC). However, whether enhancing myelination and oligodendrocyte differentiation could be beneficial in reversing such changes remains unexplored. To test this hypothesis, we orally administered clemastine, an antimuscarinic compound that has been shown to enhance oligodendrocyte differentiation and myelination in vitro, for 2 weeks in adult mice following social isolation. Clemastine successfully reversed social avoidance behavior in mice undergoing prolonged social isolation. Impaired myelination was rescued by oral clemastine treatment, and was associated with enhanced oligodendrocyte progenitor differentiation and epigenetic changes. Clemastine induced higher levels of repressive histone methylation (H3K9me3), a marker for heterochromatin, in oligodendrocytes, but not neurons, of the PFC. This was consistent with the capability of clemastine in elevating H3K9 histone methyltransferases activity in cultured primary mouse oligodendrocytes, an effect that could be antagonized by cotreatment with muscarine. Our data suggest that promoting adult myelination is a potential strategy for reversing depressive-like social behavior. Significance statement: Oligodendrocyte development and myelination are highly dynamic processes influenced by experience and neuronal activity. However, whether enhancing myelination and oligodendrocyte differentiation is beneficial to treat depressive-like behavior has been unexplored. Mice undergoing prolonged social isolation display impaired myelination in the prefrontal cortex. Clemastine, a Food and Drug Administration-approved antimuscarinic compound that has been shown to enhance myelination under

  6. Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice.

    PubMed

    Pietropaolo, Susanna; Goubran, Mina G; Joffre, Corinne; Aubert, Agnes; Lemaire-Mayo, Valerie; Crusio, Wim E; Layé, Sophie

    2014-11-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to critically influence brain development and functions. Dietary supplementation with n-3 PUFAs has been suggested as a non-pharmacological therapy for a number of developmental disorders, e.g., autistic spectrum disorders (ASD), but human studies so far have led to conflicting results. Furthermore, it has been hypothesized that the therapeutic impact of n-3 PUFAs on these disorders might be explained by their anti-inflammatory properties and their promoting effects on synaptic function and plasticity, but no clear evidence has been produced in this direction. We evaluated the impact of n-3 PUFA dietary supplementation in a mouse model of fragile X syndrome (FXS), i.e., a major developmental disease and the most frequent monogenic cause of ASD. Fmr1-KO and wild-type mice were provided with a diet enriched or not with n-3 PUFAs from weaning until adulthood when they were tested for multiple FXS-like behaviors. The brain expression of several cytokines and of brain-derived neurotrophic factor (BDNF) was concomitantly assessed as inflammatory and synaptic markers. n-3 PUFA supplementation rescued most of the behavioral abnormalities displayed by Fmr1-KO mice, including alterations in emotionality, social interaction and non-spatial memory, although not their deficits in social recognition and spatial memory. n-3 PUFAs also rescued most of the neuroinflammatory imbalances of KOs, but had a limited impact on their BDNF deficits. These results demonstrate that n-3 PUFAs dietary supplementation, although not a panacea, has a considerable therapeutic value for FXS and potentially for ASD, suggesting a major mediating role of neuroinflammatory mechanisms. PMID:25080404

  7. Rescue of the mature B cell compartment in BAFF-deficient mice by treatment with recombinant Fc-BAFF.

    PubMed

    Swee, Lee Kim; Tardivel, Aubry; Schneider, Pascal; Rolink, Antonius

    2010-06-15

    BAFF deficiency in mice impairs B cell development beyond the transitional stage 1 in the spleen and thus severely reduces the size of follicular and marginal zone B cell compartments. Moreover, humoral immune responses in these mice are dramatically impaired. We now addressed the question whether the decrease in mature B cell numbers and the reduced humoral immune responses in BAFF-deficient mice could be overcome by the injection of recombinant BAFF. We therefore engineered a recombinant protein containing the human IgG1 Fc moiety fused to receptor-binding domain of human BAFF (Fc-BAFF). At 1 week after the second injection of this fusion protein a complete rescue of the marginal zone B cell compartment and a 50% rescue of the follicular B cell compartment was observed. Moreover these mice mounted a T cell-dependent humoral immune response indistinguishable from wild-type mice. By day 14 upon arrest of Fc-BAFF treatment mature B cell numbers in the blood dropped by 50%, indicating that the life span of mature B cells in the absence of BAFF is 14 days or less. Collectively these findings demonstrate that injection of Fc-BAFF in BAFF-deficient mice results in a temporary rescue of a functional mature B cell compartment. PMID:20350570

  8. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia.

    PubMed

    Bär, Christian; Povedano, Juan Manuel; Serrano, Rosa; Benitez-Buelga, Carlos; Popkes, Miriam; Formentini, Ivan; Bobadilla, Maria; Bosch, Fatima; Blasco, Maria A

    2016-04-01

    Aplastic anemia is a fatal bone marrow disorder characterized by peripheral pancytopenia and marrow hypoplasia. The disease can be hereditary or acquired and develops at any stage of life. A subgroup of the inherited form is caused by replicative impairment of hematopoietic stem and progenitor cells due to very short telomeres as a result of mutations in telomerase and other telomere components. Abnormal telomere shortening is also described in cases of acquired aplastic anemia, most likely secondary to increased turnover of bone marrow stem and progenitor cells. Here, we test the therapeutic efficacy of telomerase activation by using adeno-associated virus (AAV)9 gene therapy vectors carrying the telomeraseTertgene in 2 independent mouse models of aplastic anemia due to short telomeres (Trf1- andTert-deficient mice). We find that a high dose of AAV9-Terttargets the bone marrow compartment, including hematopoietic stem cells. AAV9-Terttreatment after telomere attrition in bone marrow cells rescues aplastic anemia and mouse survival compared with mice treated with the empty vector. Improved survival is associated with a significant increase in telomere length in peripheral blood and bone marrow cells, as well as improved blood counts. These findings indicate that telomerase gene therapy represents a novel therapeutic strategy to treat aplastic anemia provoked or associated with short telomeres. PMID:26903545

  9. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligos

    PubMed Central

    Sztainberg, Yehezkel; Chen, Hong-mei; Swann, John W.; Hao, Shuang; Tang, Bin; Wu, Zhenyu; Tang, Jianrong; Wan, Ying-Wooi; Liu, Zhandong; Rigo, Frank; Zoghbi, Huda Y.

    2015-01-01

    Copy number variations have been frequently associated with developmental delay, intellectual disability, and autism spectrum disorders1. MECP2 duplication syndrome is one of the most common genomic rearrangements in males2 and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections, and early death3–5. The broad range of deficits caused by methyl-CpG-binding protein 2 (MeCP2) overexpression poses a daunting challenge to traditional biochemical pathway-based therapeutic approaches. Accordingly, we sought strategies that directly target MeCP2 and are amenable to translation into clinical therapy. The first question, however, was whether the neurological dysfunction is reversible after symptoms set in. Reversal of phenotypes in adult symptomatic mice has been demonstrated in some models of monogenic loss-of-function neurological disorders6–8, including loss of MeCP2 in Rett syndrome9, indicating that, at least in some cases, the neuroanatomy may remain sufficiently intact so that correction of the molecular dysfunction underlying these disorders can restore healthy physiology. Given the absence of neurodegeneration in MECP2 duplication syndrome, we hypothesized that restoration of normal MeCP2 levels in MECP2 duplication adult mice would rescue their phenotype. Therefore, we first generated and characterized a conditional Mecp2-overexpressing mouse model and showed that correction of MeCP2 levels largely reversed the behavioral, molecular, and electrophysiological deficits. Next, we sought a translational strategy to reduce MeCP2 and turned to antisense oligonucleotides (ASOs). ASOs are small modified nucleic acids that can selectively hybridize with mRNA transcribed from a target gene and silence it10,11, and have been successfully used to correct deficits in different mouse models12–18. We found that ASO treatment induced a broad phenotypic rescue in adult symptomatic transgenic MECP2

  10. Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice.

    PubMed

    Kwon, H J E; Park, E K; Jia, S; Liu, H; Lan, Y; Jiang, R

    2015-08-01

    Tooth organogenesis depends on genetically programmed sequential and reciprocal inductive interactions between the dental epithelium and neural crest-derived mesenchyme. Previous studies showed that the Msx1 and Runx2 transcription factors are required for activation of odontogenic signals, including Bmp4 and Fgf3, in the early tooth mesenchyme to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 acts downstream of Msx1 to activate Fgf3 expression. Recent studies identified Osr2 as a repressor of tooth development and showed that inactivation of Osr2 rescued molar tooth morphogenesis in the Msx1(-/-) mutant mice as well as in mice with neural crest-specific inactivation of Bmp4. Here we show that Runx2 expression is expanded in the tooth bud mesenchyme in Osr2(-/-) mutant mouse embryos and is partially restored in the tooth mesenchyme in Msx1(-/-)Osr2(-/-) mutants in comparison with Msx1(-/-) and wild-type embryos. Whereas mandibular molar development arrested at the bud stage and maxillary molar development arrested at the bud-to-cap transition in Runx2(-/-) mutant mice, both mandibular and maxillary molar tooth germs progressed to the early bell stage, with rescued expression of Msx1 and Bmp4 in the dental papilla as well as expression of Bmp4, p21, and Shh in the primary enamel knot in the Osr2(-/-)Runx2(-/-) compound mutants. In contrast to the Msx1(-/-)Osr2(-/-) compound mutants, which exhibit nearly normal first molar morphogenesis, the Osr2(-/-)Runx2(-/-) compound mutant embryos failed to activate the expression of Fgf3 and Fgf10 in the dental papilla and exhibited significant deficit in cell proliferation in both the dental epithelium and mesenchyme in comparison with the control embryos. These data indicate that Runx2 synergizes with Msx1 to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 controls continued tooth growth and morphogenesis beyond the cap stage through activation of Fgf3 and Fgf10 expression

  11. Conditional expression of human β-hexosaminidase in the neurons of Sandhoff disease rescues mice from neurodegeneration but not neuroinflammation

    PubMed Central

    2012-01-01

    This study evaluated whether GM2 ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB−/− mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB−/− mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB−/− mice from GM2 neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM2 presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored. PMID:22863301

  12. A Cysteine Protease Inhibitor Rescues Mice from a Lethal Cryptosporidium parvum Infection

    PubMed Central

    Nath-Chowdhury, Milli; Sajid, Mohammed; Marcus, Victoria; Mashiyama, Susan T.; Sakanari, Judy; Chow, Eric; Mackey, Zachary; Land, Kirkwood M.; Jacobson, Matthew P.; Kalyanaraman, Chakrapani; McKerrow, James H.; Arrowood, Michael J.; Caffrey, Conor R.

    2013-01-01

    Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium parvum, can stunt infant growth and can be lethal in immunocompromised individuals. The most widely used drugs for treating cryptosporidiosis are nitazoxanide and paromomycin, although both exhibit limited efficacy. To investigate an alternative approach to therapy, we demonstrate that the clan CA cysteine protease inhibitor N-methyl piperazine-Phe-homoPhe-vinylsulfone phenyl (K11777) inhibits C. parvum growth in mammalian cell lines in a concentration-dependent manner. Further, using the C57BL/6 gamma interferon receptor knockout (IFN-γR-KO) mouse model, which is highly susceptible to C. parvum, oral or intraperitoneal treatment with K11777 for 10 days rescued mice from otherwise lethal infections. Histologic examination of untreated mice showed intestinal inflammation, villous blunting, and abundant intracellular parasite stages. In contrast, K11777-treated mice (210 mg/kg of body weight/day) showed only minimal inflammation and no epithelial changes. Three putative protease targets (termed cryptopains 1 to 3, or CpaCATL-1, -2, and -3) were identified in the C. parvum genome, but only two are transcribed in infected mammals. A homology model predicted that K11777 would bind to cryptopain 1. Recombinant enzymatically active cryptopain 1 was successfully targeted by K11777 in a competition assay with a labeled active-site-directed probe. K11777 exhibited no toxicity in vitro and in vivo, and surviving animals remained free of parasites 3 weeks after treatment. The discovery that a cysteine protease inhibitor provides potent anticryptosporidial activity in an animal model of infection encourages the investigation and development of this biocide class as a new, and urgently needed, chemotherapy for cryptosporidiosis. PMID:24060869

  13. Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

    PubMed

    Cubells, Joseph F; Schroeder, Jason P; Barrie, Elizabeth S; Manvich, Daniel F; Sadee, Wolfgang; Berg, Tiina; Mercer, Kristina; Stowe, Taylor A; Liles, L Cameron; Squires, Katherine E; Mezher, Andrew; Curtin, Patrick; Perdomo, Dannie L; Szot, Patricia; Weinshenker, David

    2016-01-01

    Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a "C" or a "T" at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency

  14. Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice

    PubMed Central

    Cubells, Joseph F.; Schroeder, Jason P.; Barrie, Elizabeth S.; Manvich, Daniel F.; Sadee, Wolfgang; Berg, Tiina; Mercer, Kristina; Stowe, Taylor A.; Liles, L. Cameron; Squires, Katherine E.; Mezher, Andrew; Curtin, Patrick; Perdomo, Dannie L.; Szot, Patricia; Weinshenker, David

    2016-01-01

    Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a “C” or a “T” at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh

  15. Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert−/− mice

    PubMed Central

    Zhou, Q-G; Wu, H-Y; Zhou, H; Liu, M-Y; Lee, H-W; Liu, X; Devkota, S; Ro, E J; Zhu, D-Y; Suh, H

    2016-01-01

    The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert−/− mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert−/− mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert−/− mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert−/− mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert−/− mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert−/− mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control. PMID:27300262

  16. Reactivation of Tert in the medial prefrontal cortex and hippocampus rescues aggression and depression of Tert(-/-) mice.

    PubMed

    Zhou, Q-G; Wu, H-Y; Zhou, H; Liu, M-Y; Lee, H-W; Liu, X; Devkota, S; Ro, E J; Zhu, D-Y; Suh, H

    2016-01-01

    The role of telomerase reverse transcriptase (TERT) has been extensively investigated in the contexts of aging and cancer. Interestingly, Tert(-/-) mice exhibit additional but unexpected aggressive and depressive behaviors, implying the potential involvement of TERT function in mood control. Our conditional rescue experiments revealed that the depressive and aggressive behaviors of Tert(-/-) mice originate from Tert deficiency in two distinct brain structures. Reactivation of Tert in the hippocampus was sufficient to normalize the depressive but not the aggressive behaviors of Tert(-/-) mice. Conversely, re-expression of Tert in the medial prefrontal cortex (mPFC) reversed the aggressive but not the depressive behavior of Tert(-/-) mice. Mechanistically, decreased serotonergic signaling and increased nitric oxide (NO) transmission in the hippocampus transduced Tert deficiency into depression as evidenced by our observation that the infusion of a pharmacological agonist for serotonin receptor 1a (5-HTR1A) and a selective antagonist for neuronal NO synthase into the hippocampus successfully normalized the depressive behavior of Tert(-/-) mice. In addition, increased serotonergic transmission by the 5-HTR1A agonist in the mPFC was sufficient to rescue the aggressive behavior of Tert(-/-) mice. Thus, our studies revealed a novel function of TERT in the pathology of depression and aggression in a brain structure-specific manner, providing direct evidence for the contribution of TERT to emotional control. PMID:27300262

  17. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.

    PubMed

    Hao, Shuang; Tang, Bin; Wu, Zhenyu; Ure, Kerstin; Sun, Yaling; Tao, Huifang; Gao, Yan; Patel, Akash J; Curry, Daniel J; Samaco, Rodney C; Zoghbi, Huda Y; Tang, Jianrong

    2015-10-15

    Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT. PMID:26469053

  18. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice

    PubMed Central

    Hao, Shuang; Tang, Bin; Wu, Zhenyu; Ure, Kerstin; Sun, Yaling; Tao, Huifang; Gao, Yan; Patel, Akash J.; Curry, Daniel J.; Samaco, Rodney C.; Zoghbi, Huda Y.; Tang, Jianrong

    2016-01-01

    Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnestic rats have demonstrated that DBS targeted to the fimbria-fornix1-3, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory3-5. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder (IDD). IDDs are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We hypothesized that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett Syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP26, RTT appears by the second year of life, causing profound impairment in cognitive, motor, and social skills along with an array of neurological features7; RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity8-11. Here we show that forniceal DBS in RTT mice rescued contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restored in vivo hippocampal long-term potentiation (LTP) and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT. PMID:26469053

  19. Silencing Mutant Ataxin-3 Rescues Motor Deficits and Neuropathology in Machado-Joseph Disease Transgenic Mice

    PubMed Central

    Onofre, Isabel; Albuquerque, David; Hirai, Hirokazu; Déglon, Nicole; de Almeida, Luís Pereira

    2013-01-01

    Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein – ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy

  20. Riluzole rescues alterations in rapid glutamate transients in the hippocampus of rTg4510 mice.

    PubMed

    Hunsberger, Holly C; Hickman, James E; Reed, Miranda N

    2016-06-01

    Those at risk for Alzheimer's disease (AD) often exhibit hippocampal hyperexcitability in the years preceding diagnosis. Our previous work with the rTg(TauP301L)4510 tau mouse model of AD suggests that this increase in hyperexcitability is likely mediated by an increase in depolarization-evoked glutamate release and a decrease in glutamate uptake, alterations of which correlate with learning and memory deficits. Treatment with riluzole restored glutamate regulation and rescued memory deficits in the TauP301L model. Here, we used enzyme-based ceramic microelectrode array technology to measure real-time phasic glutamate release and uptake events in the hippocampal subregions of TauP301L mice. For the first time, we demonstrate that perturbations in glutamate transients (rapid, spontaneous bursts of glutamate) exist in a tau mouse model of AD mouse model and that riluzole mitigates these alterations. These results help to inform our understanding of how glutamate signaling is altered in the disease process and also suggest that riluzole may serve as a clinically applicable therapeutic approach in AD. PMID:26744018

  1. Modulation of Rho GTPases rescues brain mitochondrial dysfunction, cognitive deficits and aberrant synaptic plasticity in female mice modeling Rett syndrome.

    PubMed

    De Filippis, Bianca; Valenti, Daniela; Chiodi, Valentina; Ferrante, Antonella; de Bari, Lidia; Fiorentini, Carla; Domenici, Maria Rosaria; Ricceri, Laura; Vacca, Rosa Anna; Fabbri, Alessia; Laviola, Giovanni

    2015-06-01

    Rho GTPases are molecules critically involved in neuronal plasticity and cognition. We have previously reported that modulation of brain Rho GTPases by the bacterial toxin CNF1 rescues the neurobehavioral phenotype in MeCP2-308 male mice, a model of Rett syndrome (RTT). RTT is a rare X-linked neurodevelopmental disorder and a genetic cause of intellectual disability, for which no effective therapy is available. Mitochondrial dysfunction has been proposed to be involved in the mechanism of the disease pathogenesis. Here we demonstrate that modulation of Rho GTPases by CNF1 rescues the reduced mitochondrial ATP production via oxidative phosphorylation in the brain of MeCP2-308 heterozygous female mice, the condition which more closely recapitulates that of RTT patients. In RTT mouse brain, CNF1 also restores the alterations in the activity of the mitochondrial respiratory chain (MRC) complexes and of ATP synthase, the molecular machinery responsible for the majority of cell energy production. Such effects were achieved through the upregulation of the protein content of those MRC complexes subunits, which were defective in RTT mouse brain. Restored mitochondrial functionality was accompanied by the rescue of deficits in cognitive function (spatial reference memory in the Barnes maze), synaptic plasticity (long-term potentiation) and Tyr1472 phosphorylation of GluN2B, which was abnormally enhanced in the hippocampus of RTT mice. Present findings bring into light previously unknown functional mitochondrial alterations in the brain of female mice modeling RTT and provide the first evidence that RTT brain mitochondrial dysfunction can be rescued by modulation of Rho GTPases. PMID:25890884

  2. Partial rescue of mucopolysaccharidosis type VII mice with a lifelong engraftment of allogeneic stem cells in utero.

    PubMed

    Ihara, Norimasa; Akihiro, Umezawa; Onami, Naoko; Tsumura, Hideki; Inoue, Eisuke; Hayashi, Satoshi; Sago, Haruhiko; Mizutani, Shuki

    2015-02-01

    In utero hematopoietic cell transplantation (IUHCT) has been performed in Mucopolysaccharidosis Type VII (MPSVII) mice, but a lifelong engraftment of allogeneic donor cells has not been achieved. In this study, we sought to confirm a lifelong engraftment of allogeneic donor cells immunologically matched to the mother and to achieve partial rescue of phenotypes in the original MPSVII strain through IUHCT by intravenous injection. We performed in vitro fertilization in a MPSVII murine model and transferred affected embryos to ICR/B6-GFP surrogate mothers in cases where fetuses receiving IUHCT were all homozygous. Lineage-depleted cells from ICR/B6-GFP mice were injected intravenously at E14.5. Chimerism was confirmed by flow cytometry at 4 weeks after birth, and β-glucuronidase activity in serum and several phenotypes were assessed at 8 weeks of age or later. Donor cells in chimeric mice from ICR/B6-GFP mothers were detected at death, and were confirmed in several tissues including the brains of sacrificed chimeric mice. Although the serum enzyme activity of chimeric mice was extremely low, the engraftment rate of donor cells correlated with enzyme activity. Furthermore, improvement of bone structure and rescue of reproductive ability were confirmed in our limited preclinical study. We confirmed the lifelong engraftment of donor cells in an original immunocompetent MPSVII murine model using intravenous IUHCT with cells immunologically matched to the mother without myeloablation, and the improvement of several phenotypes. PMID:25421592

  3. Partial rescue of mucopolysaccharidosis type VII mice with a lifelong engraftment of allogeneic stem cells in utero

    PubMed Central

    Ihara, Norimasa; Akihiro, Umezawa; Onami, Naoko; Tsumura, Hideki; Inoue, Eisuke; Hayashi, Satoshi; Sago, Haruhiko; Mizutani, Shuki

    2015-01-01

    In utero hematopoietic cell transplantation (IUHCT) has been performed in Mucopolysaccharidosis Type VII (MPSVII) mice, but a lifelong engraftment of allogeneic donor cells has not been achieved. In this study, we sought to confirm a lifelong engraftment of allogeneic donor cells immunologically matched to the mother and to achieve partial rescue of phenotypes in the original MPSVII strain through IUHCT by intravenous injection. We performed in vitro fertilization in a MPSVII murine model and transferred affected embryos to ICR/B6-GFP surrogate mothers in cases where fetuses receiving IUHCT were all homozygous. Lineage-depleted cells from ICR/B6-GFP mice were injected intravenously at E14.5. Chimerism was confirmed by flow cytometry at 4 weeks after birth, and β-glucuronidase activity in serum and several phenotypes were assessed at 8 weeks of age or later. Donor cells in chimeric mice from ICR/B6-GFP mothers were detected at death, and were confirmed in several tissues including the brains of sacrificed chimeric mice. Although the serum enzyme activity of chimeric mice was extremely low, the engraftment rate of donor cells correlated with enzyme activity. Furthermore, improvement of bone structure and rescue of reproductive ability were confirmed in our limited preclinical study. We confirmed the lifelong engraftment of donor cells in an original immunocompetent MPSVII murine model using intravenous IUHCT with cells immunologically matched to the mother without myeloablation, and the improvement of several phenotypes. PMID:25421592

  4. Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.

    PubMed

    Itzhak, Yossef; Anderson, Karen L; Kelley, Jonathan B; Petkov, Martin

    2012-05-01

    Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice. PMID:22452925

  5. Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background

    PubMed Central

    Tu, Qisheng; Pi, Min; Karsenty, Gerard; Simpson, Leigh; Liu, Shiguang; Quarles, L. Darryl

    2003-01-01

    To understand the role of the calcium-sensing receptor (CasR) in the skeleton, we used a genetic approach to ablate parathyroid glands and remove the confounding effects of elevated parathyroid hormone (PTH) in CasR-deficient mice. CasR deficiency was transferred onto the glial cells missing 2–deficient (Gcm2-deficient) background by intercrossing CasR- and Gcm2-deficient mice. Superimposed Gcm2 deficiency rescued the perinatal lethality in CasR-deficient mice in association with ablation of the parathyroid glands and correction of the severe hyperparathyroidism. In addition, the double homozygous CasR- and Gcm2-deficient mice demonstrated healing of the abnormal mineralization of cartilage and bone associated with CasR deficiency, indicating that rickets and osteomalacia in CasR-deficient mice are not due to an independent function of CasR in bone and cartilage but to the effect of severe hyperparathyroidism in the neonate. Analysis of the skeleton of 6-week-old homozygous CasR- and Gcm2-deficient mice also failed to identify any essential, nonredundant role for CasR in regulating chondrogenesis or osteogenesis, but further studies are needed to establish the function of CasR in the skeleton. In contrast, concomitant Gcm2 and CasR deficiency failed to rescue the hypocalciuria in CasR-deficient mice, consistent with direct regulation of urinary calcium excretion by CasR in the kidney. Double Gcm2- and CasR-deficient mice provide an important model for evaluating the extraparathyroid functions of CasR. PMID:12671052

  6. The testicular form of hormone-sensitive lipase HSLtes confers rescue of male infertility in HSL-deficient mice.

    PubMed

    Vallet-Erdtmann, Virginie; Tavernier, Geneviève; Contreras, Juan Antonio; Mairal, Aline; Rieu, Cécile; Touzalin, Anne-Marie; Holm, Cecilia; Jégou, Bernard; Langin, Dominique

    2004-10-01

    Inactivation of the hormone-sensitive lipase gene (HSL) confers male sterility with a major defect in spermatogenesis. Several forms of HSL are expressed in testis. HSLtes mRNA and protein are found in early and elongated spermatids, respectively. The other forms are expressed in diploid germ cells and interstitial cells of the testis. To determine whether the absence of the testis-specific form of HSL, HSLtes, was responsible for the infertility in HSL-null mice, we generated transgenic mice expressing HSLtes under the control of its own promoter. The transgenic animals were crossed with HSL-null mice to produce mice deficient in HSL in nongonadal tissues but expressing HSLtes in haploid germ cells. Cholesteryl ester hydrolase activity was almost completely blunted in HSL-deficient testis. Mice with one allele of the transgene showed an increase in enzymatic activity and a small elevation in the production of spermatozoa. The few fertile hemizygous male mice produced litters of very small to small size. The presence of the two alleles led to a doubling in cholesteryl ester hydrolase activity, which represented 25% of the wild type values associated with a qualitatively normal spermatogenesis and a partial restoration of sperm reserves. The fertility of these mice was totally restored with normal litter sizes. In line with the importance of the esterase activity, HSLtes transgene expression reversed the cholesteryl ester accumulation observed in HSL-null mice. Therefore, expression of HSLtes and cognate cholesteryl ester hydrolase activity leads to a rescue of the infertility observed in HSL-deficient male mice. PMID:15292223

  7. Gata3 Hypomorphic Mutant Mice Rescued with a Yeast Artificial Chromosome Transgene Suffer a Glomerular Mesangial Cell Defect.

    PubMed

    Moriguchi, Takashi; Yu, Lei; Otsuki, Akihito; Ainoya, Keiko; Lim, Kim-Chew; Yamamoto, Masayuki; Engel, James Douglas

    2016-09-01

    GATA3 is a zinc finger transcription factor that plays a crucial role in embryonic kidney development, while its precise functions in the adult kidney remain largely unexplored. Here, we demonstrate that GATA3 is specifically expressed in glomerular mesangial cells and plays a critical role in the maintenance of renal glomerular function. Newly generated Gata3 hypomorphic mutant mice exhibited neonatal lethality associated with severe renal hypoplasia. Normal kidney size was restored by breeding the hypomorphic mutant with a rescuing transgenic mouse line bearing a 662-kb Gata3 yeast artificial chromosome (YAC), and these animals (termed G3YR mice) survived to adulthood. However, most of the G3YR mice showed degenerative changes in glomerular mesangial cells, which deteriorated progressively during postnatal development. Consequently, the G3YR adult mice suffered severe renal failure. We found that the 662-kb Gata3 YAC transgene recapitulated Gata3 expression in the renal tubules but failed to direct sufficient GATA3 activity to mesangial cells. Renal glomeruli of the G3YR mice had significantly reduced amounts of platelet-derived growth factor receptor (PDGFR), which is known to participate in the development and maintenance of glomerular mesangial cells. These results demonstrate a critical role for GATA3 in the maintenance of mesangial cells and its absolute requirement for prevention of glomerular disease. PMID:27296697

  8. Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice.

    PubMed

    Gusmão, Isabela D; Monteiro, Brisa M M; Cornélio, Guilherme O S; Fonseca, Cristina S; Moraes, Márcio F D; Pereira, Grace S

    2012-03-17

    Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction. PMID:22226622

  9. Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract

    SciTech Connect

    Park, Sun Hong; Roh, Eunmiri; Kim, Hyun Soo; Baek, Seung-Il; Choi, Nam Song; Kim, Narae; Hwang, Bang Yeon; Han, Sang-Bae; Kim, Youngsoo

    2013-12-13

    Highlights: •Lonicerae flos extract (HS-23) is a clinical candidate, Phase I for sepsis treatment. •Here, HS-23 or its major constituents rescued LPS-induced septic mortality in mice. •As a mechanism, they directly inhibited IRAK-4-catalyzed kinase activity. •Thus, they suppressed LPS-induced expression of NF-κB/AP-1-target inflammatory genes. -- Abstract: Lonicerae flos extract (HS-23) is a clinical candidate currently undergoing Phase I trial in lipopolysaccharide (LPS)-injected healthy human volunteers, but its molecular basis remains to be defined. Here, we investigated protective effects of HS-23 or its major constituents on Escherichia coli LPS-induced septic mortality in mice. Intravenous treatment with HS-23 rescued LPS-intoxicated C57BL/6J mice under septic conditions, and decreased the levels of cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and high-mobility group box-1 (HMGB-1) in the blood. Chlorogenic acid (CGA) and its isomers were assigned as major constituents of HS-23 in the protection against endotoxemia. As a molecular mechanism, HS-23 or CGA isomers inhibited endotoxin LPS-induced autophosphorylation of the IL-1 receptor-associated kinase 4 (IRAK-4) in mouse peritoneal macrophages as well as the kinase activity of IRAK-4 in cell-free reactions. HS-23 consequently suppressed downstream pathways critical for LPS-induced activation of nuclear factor (NF)-κB or activating protein 1 (AP-1) in the peritoneal macrophages. HS-23 also inhibited various toll-like receptor agonists-induced nitric oxide (NO) production, and down-regulated LPS-induced expression of NF-κB/AP-1-target inflammatory genes in the cells. Taken together, HS-23 or CGA isomers exhibited anti-inflammatory therapy against LPS-induced septic mortality in mice, at least in part, mediated through the inhibition of IRAK-4.

  10. Partial rescue of taste responses of alpha-gustducin null mice by transgenic expression of alpha-transducin.

    PubMed

    He, Wei; Danilova, Vicktoria; Zou, Shiying; Hellekant, Göran; Max, Marianna; Margolskee, Robert F; Damak, Sami

    2002-10-01

    The transduction of responses to bitter and sweet compounds utilizes guanine nucleotide binding proteins (G proteins) and their coupled receptors. Alpha-gustducin, a transducin-like G protein alpha-subunit, and rod alpha-transducin are expressed in taste receptor cells. Alpha-gustducin knockout mice have profoundly diminished behavioral and electrophysiological responses to many bitter and sweet compounds, although these mice retain residual responses to these compounds. Alpha-gustducin and rod alpha-transducin are biochemically indistinguishable in their in vitro interactions with retinal phosphodiesterase, rhodopsin and G protein betagamma-subunits. To determine if alpha-transducin can function in taste receptor cells and to compare the function of alpha-gustducin versus alpha-transducin in taste transduction in vivo, we generated transgenic mice that express alpha-transducin under the control of the alpha-gustducin promoter in the alpha-gustducin null background. Immunohistochemistry showed that the alpha-transducin transgene was expressed in about two-thirds of the alpha-gustducin lineage of taste receptor cells. Two-bottle preference tests showed that transgenic expression of rod alpha-transducin partly rescued responses to denatonium benzoate, sucrose and the artificial sweetener SC45647, but not to quinine sulfate. Gustatory nerve recordings showed a partial rescue by the transgene of the response to sucrose, SC45647 and quinine, but not to denatonium. These results demonstrate that alpha-transducin can function in taste receptor cells and transduce some taste cell responses. Our results also suggest that alpha-transducin and alpha-gustducin may differ, at least in part, in their function in these cells, although this conclusion must be qualified because of the limited fidelity of the transgene expression. PMID:12379596

  11. PKR Inhibition Rescues Memory Deficit and ATF4 Overexpression in ApoE ε4 Human Replacement Mice.

    PubMed

    Segev, Yifat; Barrera, Iliana; Ounallah-Saad, Hadile; Wibrand, Karin; Sporild, Ida; Livne, Adva; Rosenberg, Tali; David, Orit; Mints, Meshi; Bramham, Clive R; Rosenblum, Kobi

    2015-09-23

    Sporadic Alzheimer's disease (AD) is an incurable neurodegenerative disease with clear pathological hallmarks, brain dysfunction, and unknown etiology. Here, we tested the hypothesis that there is a link between genetic risk factors for AD, cellular metabolic stress, and transcription/translation regulation. In addition, we aimed at reversing the memory impairment observed in a mouse model of sporadic AD. We have previously demonstrated that the most prevalent genetic risk factor for AD, the ApoE4 allele, is correlated with increased phosphorylation of the translation factor eIF2α. In the present study, we tested the possible involvement of additional members of the eIF2α pathway and identified increased mRNA expression of negative transcription factor ATF4 (aka CREB2) both in human and a mouse model expressing the human ApoE4 allele. Furthermore, injection of a PKR inhibitor rescued memory impairment and attenuated ATF4 mRNA increased expression in the ApoE4 mice. The results propose a new mechanism by which ApoE4 affects brain function and further suggest that inhibition of PKR is a way to restore ATF4 overexpression and memory impairment in early stages of sporadic AD. Significance statement: ATF4 mRNA relative quantities are elevated in ApoE4 allele carriers compared with noncarrier controls. This is true also for the ApoE ε4 human replacement mice. ApoE4 mice injected with PKR inhibitor (PKRi) demonstrate a significant reduction in ATF4 expression levels 3 h after one injection of PKRi. Treatment of ApoE4 human replacement mice with the PKRi before learning rescues the memory impairment of the ApoE4 AD model mice. We think that these results propose a new mechanism by which ApoE4 affects brain function and suggest that inhibition of PKR is a way to restore memory impairment in early stages of sporadic AD. PMID:26400930

  12. Functional Rescue of Dopaminergic Neuron Loss in Parkinson's Disease Mice After Transplantation of Hematopoietic Stem and Progenitor Cells.

    PubMed

    Altarche-Xifro, Wassim; di Vicino, Umberto; Muñoz-Martin, Maria Isabel; Bortolozzi, Analía; Bové, Jordi; Vila, Miquel; Cosma, Maria Pia

    2016-06-01

    Parkinson's disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinson's disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinson's disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinson's disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach. PMID:27428421

  13. Rescue of Calcineurin Aα−/− Mice Reveals a Novel Role for the α Isoform in the Salivary Gland

    PubMed Central

    Reddy, Ramesh N.; Pena, Juan A.; Roberts, Brian R.; Williams, Stephen R.; Price, S. Russ; Gooch, Jennifer L.

    2011-01-01

    Calcineurin is an important signal transduction mediator in T cells, neurons, the heart, and kidneys. Recent evidence points to unique actions of the two main isoforms of the catalytic subunit. Although the β isoform is required for T-cell development, α is important in the brain and kidney. In addition, mice lacking α but not β suffer from failure to thrive and early mortality. The purpose of this study was to identify the cause of postnatal death of calcineurin α null (CnAα−/−) mice and to determine the mechanism of α activity that contributes to the phenotype. CnAα−/− mice and wild-type littermate controls were fed a modified diet and then salivary gland function and histology were examined. In vitro studies were performed to identify the mechanism of α action. Data show that calcineurin is required for normal submandibular gland function and secretion of digestive enzymes. Loss of α does not impair nuclear factor of activated T-cell activity or expression but results in impaired protein trafficking downstream of the inositol trisphosphate receptor. These findings show a novel function of calcineurin in digestion and protein trafficking. Significantly, these data also provide a mechanism to rescue to adulthood a valuable animal model of calcineurin inhibitor-mediated neuronal and renal toxicities. PMID:21435446

  14. Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR−/− mice

    PubMed Central

    Ostedgaard, Lynda S.; Meyerholz, David K.; Vermeer, Daniel W.; Karp, Philip H.; Schneider, Lindsey; Sigmund, Curt D.; Welsh, Michael J.

    2011-01-01

    Gene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV size constraints, we recently developed a shortened CFTR missing the N-terminal portion of the R domain (residues 708–759, CFTRΔR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRΔR could correct in vivo defects, we generated CFTR−/− mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRΔR in the intestine (CFTR−/−;TgΔR). We found that intestinal crypts of CFTR−/−;TgΔR mice expressed CFTRΔR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRΔR transgene produced CFTR Cl− currents and rescued the CFTR−/− intestinal phenotype. These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRΔR may have utility for AAV-mediated gene transfer in CF. PMID:21285372

  15. Cystic fibrosis transmembrane conductance regulator with a shortened R domain rescues the intestinal phenotype of CFTR-/- mice.

    PubMed

    Ostedgaard, Lynda S; Meyerholz, David K; Vermeer, Daniel W; Karp, Philip H; Schneider, Lindsey; Sigmund, Curt D; Welsh, Michael J

    2011-02-15

    Gene transfer could provide a novel therapeutic approach for cystic fibrosis (CF), and adeno-associated virus (AAV) is a promising vector. However, the packaging capacity of AAV limits inclusion of the full-length cystic fibrosis transmembrane conductance regulator (CFTR) cDNA together with other regulatory and structural elements. To overcome AAV size constraints, we recently developed a shortened CFTR missing the N-terminal portion of the R domain (residues 708-759, CFTRΔR) and found that it retained regulated anion channel activity in vitro. To test the hypothesis that CFTRΔR could correct in vivo defects, we generated CFTR(-/-) mice bearing a transgene with a fatty acid binding protein promoter driving expression of human CFTRΔR in the intestine (CFTR(-/-);TgΔR). We found that intestinal crypts of CFTR(-/-);TgΔR mice expressed CFTRΔR and the intestine appeared histologically similar to that of WT mice. Moreover, like full-length CFTR transgene, the CFTRΔR transgene produced CFTR Cl(-) currents and rescued the CFTR(-/-) intestinal phenotype. These results indicate that the N-terminal part of the CFTR R domain is dispensable for in vivo intestinal physiology. Thus, CFTRΔR may have utility for AAV-mediated gene transfer in CF. PMID:21285372

  16. A high‐calcium diet failed to rescue an osteopenia phenotype in claudin‐18 knockout mice

    PubMed Central

    Alshbool, Fatima Z.; Alarcon, Catrina; Wergedal, Jon; Mohan, Subburaman

    2014-01-01

    Abstract We have recently demonstrated that mice with disruption of claudin‐18 (Cldn‐18) gene exhibited osteopenia due to increased bone resorption (BR). In this study, we found that gastric pH was significantly higher in Cldn‐18 knockout (KO) mice compared to heterozygous control mice at 10 weeks of age. To test the possibility that the increased BR in the Cldn‐18 KO mice fed a normal‐Ca diet is a consequence of decreased Ca absorption caused by increased stomach pH, we subjected KO and control mice to a normal‐Ca and high‐Ca diet at birth. Serum Ca levels were significantly lower in Cldn‐18 KO mice compared to control mice at a normal‐Ca diet but not at high‐Ca diet. Dual energy X‐ray absorptiometry revealed that a high‐Ca diet significantly increased lumbar bone mineral density (BMD), but had no effect on femur/tibia BMD in both Cldn‐18 KO and control mice compared to a normal‐Ca diet. While a high‐Ca diet did not affect volumetric BMD, trabecular, and cortical parameters of the lumbar vertebra (LV) as measured by μCT, the size of the LV did increase, in both genotypes due to reduced BR. Comparison of the skeletal phenotype of high‐Ca Cldn‐18 KO and control mice revealed that an osteopenia phenotype seen at a normal‐Ca diet was still maintained at different skeletal sites in the KO mice till 10 weeks of age. In conclusion, our findings suggest that increased BR is likely caused by direct effects of a lack of Cldn‐18 on osteoclasts rather than gastric pH changes. PMID:24744879

  17. A mutation in dynein rescues axonal transport defects and extends the life span of ALS mice

    PubMed Central

    Kieran, Dairin; Hafezparast, Majid; Bohnert, Stephanie; Dick, James R.T.; Martin, Joanne; Schiavo, Giampietro; Fisher, Elizabeth M.C.; Greensmith, Linda

    2005-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterized by motoneuron degeneration and muscle paralysis. Although the precise pathogenesis of ALS remains unclear, mutations in Cu/Zn superoxide dismutase (SOD1) account for ∼20–25% of familial ALS cases, and transgenic mice overexpressing human mutant SOD1 develop an ALS-like phenotype. Evidence suggests that defects in axonal transport play an important role in neurodegeneration. In Legs at odd angles (Loa) mice, mutations in the motor protein dynein are associated with axonal transport defects and motoneuron degeneration. Here, we show that retrograde axonal transport defects are already present in motoneurons of SOD1G93A mice during embryonic development. Surprisingly, crossing SOD1G93A mice with Loa/+ mice delays disease progression and significantly increases life span in Loa/SOD1G93A mice. Moreover, there is a complete recovery in axonal transport deficits in motoneurons of these mice, which may be responsible for the amelioration of disease. We propose that impaired axonal transport is a prime cause of neuronal death in neurodegenerative disorders such as ALS. PMID:15911875

  18. Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate.

    PubMed

    Bondulich, Marie K; Guo, Tong; Meehan, Christopher; Manion, John; Rodriguez Martin, Teresa; Mitchell, Jacqueline C; Hortobagyi, Tibor; Yankova, Natalia; Stygelbout, Virginie; Brion, Jean-Pierre; Noble, Wendy; Hanger, Diane P

    2016-08-01

    Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies. PMID:27297240

  19. Transducible P11-CNTF rescues the learning and memory impairments induced by amyloid-beta peptide in mice.

    PubMed

    Qu, Heng Yan; Zhang, Ting; Li, Xu Ling; Zhou, Jian Ping; Zhao, Bao Quan; Li, Qian; Sun, Man Ji

    2008-10-10

    Alzheimer's disease is a progressive brain disorder with the loss of memory and other intellectual abilities. Amyloid species and neurofibrillary tangles are the prime suspects in damaging and killing nerve cells. Abnormal accumulation of Amyloid-beta peptide (Abeta) may cause synaptic dysfunction and degeneration of neurons. Drugs that can prevent its formation and accumulation or stimulate its clearance might ultimately be of therapeutic benefit. Ciliary neurotrophic factor (CNTF), a neurotrophic cytokine, promotes the survival of various neurons in brain. However, the blood-brain barrier hinders the systemic delivery of CNTF to brain. Recently the 11-amino acid of protein transduction domain TAT has successfully assisted the delivery of many macromolecules to treat preclinical models of human disease. The present study aimed to evaluate whether P11-CNTF fusion protein (P11-CNTF) is protective against the Abeta25-35-induced dementia in mice. Immunofluorescence experiments showed that P11 effectively carried CNTF to the SH-SY5Y cells in vitro, and to the brains of mice in vivo. The learning and memory impairments of mice induced by Abeta were substantially rescued by supplement with the P11-CNTF. Furthermore, mRNAs of enzymes involved in the Abeta metabolism, e.g. neprilysin (NEP), endothelin-converting enzyme 1 (ECE-1) and insulin degrading enzyme (IDE), increased in the P11-CNTF treated dementia mice, accompanied by the proliferation of nestin- and choline acetyltransferase (ChAT)-positive cells in hippocampus. It implies that the delivery of P11-CNTF may be a novel treatment for Alzheimer's disease. PMID:18644361

  20. Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate

    PubMed Central

    Bondulich, Marie K.; Guo, Tong; Meehan, Christopher; Manion, John; Rodriguez Martin, Teresa; Mitchell, Jacqueline C.; Hortobagyi, Tibor; Yankova, Natalia; Stygelbout, Virginie; Brion, Jean-Pierre; Noble, Wendy

    2016-01-01

    Human neurodegenerative tauopathies exhibit pathological tau aggregates in the brain along with diverse clinical features including cognitive and motor dysfunction. Post-translational modifications including phosphorylation, ubiquitination and truncation, are characteristic features of tau present in the brain in human tauopathy. We have previously reported an N-terminally truncated form of tau in human brain that is associated with the development of tauopathy and is highly phosphorylated. We have generated a new mouse model of tauopathy in which this human brain-derived, 35 kDa tau fragment (Tau35) is expressed in the absence of any mutation and under the control of the human tau promoter. Most existing mouse models of tauopathy overexpress mutant tau at levels that do not occur in human neurodegenerative disease, whereas Tau35 transgene expression is equivalent to less than 10% of that of endogenous mouse tau. Tau35 mice recapitulate key features of human tauopathies, including aggregated and abnormally phosphorylated tau, progressive cognitive and motor deficits, autophagic/lysosomal dysfunction, loss of synaptic protein, and reduced life-span. Importantly, we found that sodium 4-phenylbutyrate (Buphenyl®), a drug used to treat urea cycle disorders and currently in clinical trials for a range of neurodegenerative diseases, reverses the observed abnormalities in tau and autophagy, behavioural deficits, and loss of synapsin 1 in Tau35 mice. Our results show for the first time that, unlike other tau transgenic mouse models, minimal expression of a human disease-associated tau fragment in Tau35 mice causes a profound and progressive tauopathy and cognitive changes, which are rescued by pharmacological intervention using a clinically approved drug. These novel Tau35 mice therefore represent a highly disease-relevant animal model in which to investigate molecular mechanisms and to develop novel treatments for human tauopathies. PMID:27297240

  1. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

    PubMed Central

    Tomatsu, Shunji; Montaño, Adriana M.; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S.

    2014-01-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology (1). To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250 units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in liver and spleen, with detectable activity in bone and brain. Second, newborn ERT was conducted after tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th week were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mouse. PMID:24953405

  2. Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

    PubMed Central

    Simmons, Danielle A.; Rex, Christopher S.; Palmer, Linda; Pandyarajan, Vijay; Fedulov, Vadim; Gall, Christine M.; Lynch, Gary

    2009-01-01

    Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD. PMID:19264961

  3. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice

    PubMed Central

    Bittolo, Tamara; Raminelli, Carlo Antonio; Deiana, Chiara; Baj, Gabriele; Vaghi, Valentina; Ferrazzo, Sara; Bernareggi, Annalisa; Tongiorgi, Enrico

    2016-01-01

    Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome. PMID:26806603

  4. Pharmacological treatment with mirtazapine rescues cortical atrophy and respiratory deficits in MeCP2 null mice.

    PubMed

    Bittolo, Tamara; Raminelli, Carlo Antonio; Deiana, Chiara; Baj, Gabriele; Vaghi, Valentina; Ferrazzo, Sara; Bernareggi, Annalisa; Tongiorgi, Enrico

    2016-01-01

    Loss of MeCP2 (Methyl CpG binding protein 2) in Rett syndrome (RTT) causes brain weight decrease, shrinkage of the cortex with reduced dendritic arborization, behavioral abnormalities, seizures and cardio-respiratory complications. The observed monoamine neurotransmitters reduction in RTT suggested antidepressants as a possible therapy. We treated MeCP2-null mice from postnatal-day 28 for two weeks with desipramine, already tested in RTT, or mirtazapine, an antidepressant with limited side-effects, known to promote GABA release. Mirtazapine was more effective than desipramine in restoring somatosensory cortex thickness by fully rescuing pyramidal neurons dendritic arborization and spine density. Functionally, mirtazapine treatment normalized heart rate, breath rate, anxiety levels, and eliminated the hopping behavior observed in MeCP2-null mice, leading to improved phenotypic score. These morphological and functional effects of mirtazapine were accompanied by reestablishment of the GABAergic and glutamatergic receptor activity recorded in cortex and brainstem tissues. Thus, mirtazapine can represent a new potential pharmacological treatment for the Rett syndrome. PMID:26806603

  5. Longitudinal Attentional Engagement Rescues Mice from Age-Related Cognitive Declines and Cognitive Inflexibility

    ERIC Educational Resources Information Center

    Matzel, Louis D.; Light, Kenneth R.; Wass, Christopher; Colas-Zelin, Danielle; Denman-Brice, Alexander; Waddel, Adam C.; Kolata, Stefan

    2011-01-01

    Learning, attentional, and perseverative deficits are characteristic of cognitive aging. In this study, genetically diverse CD-1 mice underwent longitudinal training in a task asserted to tax working memory capacity and its dependence on selective attention. Beginning at 3 mo of age, animals were trained for 12 d to perform in a dual radial-arm…

  6. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

    PubMed Central

    Charbel Issa, Peter; Barnard, Alun R.; Herrmann, Philipp; Washington, Ilyas; MacLaren, Robert E.

    2015-01-01

    Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D3-vitamin A) impedes the dimerization rate of vitamin A—by approximately fivefold for the vitamin A dimer A2E—and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D3-vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D3-vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina. PMID:26106163

  7. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization.

    PubMed

    Charbel Issa, Peter; Barnard, Alun R; Herrmann, Philipp; Washington, Ilyas; MacLaren, Robert E

    2015-07-01

    Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D3-vitamin A) impedes the dimerization rate of vitamin A--by approximately fivefold for the vitamin A dimer A2E--and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D3-vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D3-vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina. PMID:26106163

  8. Peptide Nucleic Acid Promotes Systemic Dystrophin Expression and Functional Rescue in Dystrophin-deficient mdx Mice

    PubMed Central

    Gao, Xianjun; Shen, Xiaoyong; Dong, Xue; Ran, Ning; Han, Gang; Cao, Limin; Gu, Ben; Yin, HaiFang

    2015-01-01

    Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise for Duchenne muscular dystrophy (DMD) patients. However, recent failure with drisapersen, an AO candidate drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable biological activity of peptide nucleic acid (PNA) AOs in restoring dystrophin expression in dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective therapeutics without the associated toxicity. PMID:26440599

  9. Peptide Nucleic Acid Promotes Systemic Dystrophin Expression and Functional Rescue in Dystrophin-deficient mdx Mice.

    PubMed

    Gao, Xianjun; Shen, Xiaoyong; Dong, Xue; Ran, Ning; Han, Gang; Cao, Limin; Gu, Ben; Yin, HaiFang

    2015-01-01

    Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise for Duchenne muscular dystrophy (DMD) patients. However, recent failure with drisapersen, an AO candidate drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable biological activity of peptide nucleic acid (PNA) AOs in restoring dystrophin expression in dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective therapeutics without the associated toxicity. PMID:26440599

  10. Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

    PubMed Central

    Rachel, Rivka A.; May-Simera, Helen L.; Veleri, Shobi; Gotoh, Norimoto; Choi, Byung Yoon; Murga-Zamalloa, Carlos; McIntyre, Jeremy C.; Marek, Jonah; Lopez, Irma; Hackett, Alice N.; Brooks, Matthew; den Hollander, Anneke I.; Beales, Philip L.; Li, Tiansen; Jacobson, Samuel G.; Sood, Raman; Martens, Jeffrey R.; Liu, Paul; Friedman, Thomas B.; Khanna, Hemant; Koenekoop, Robert K.; Kelley, Matthew W.; Swaroop, Anand

    2012-01-01

    Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy Bardet-Biedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290rd16 and Mkksko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies. PMID:22446187

  11. Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibition.

    PubMed

    Ohsawa, Yutaka; Hagiwara, Hiroki; Nakatani, Masashi; Yasue, Akihiro; Moriyama, Keiji; Murakami, Tatsufumi; Tsuchida, Kunihiro; Noji, Sumihare; Sunada, Yoshihide

    2006-11-01

    Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-beta superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients. PMID:17039257

  12. Modulation of lipid metabolic defects rescues cleft palate in Tgfbr2 mutant mice.

    PubMed

    Iwata, Junichi; Suzuki, Akiko; Pelikan, Richard C; Ho, Thach-Vu; Sanchez-Lara, Pedro A; Chai, Yang

    2014-01-01

    Mutations in transforming growth factor beta (TGFβ) receptor type II (TGFBR2) cause Loeys-Dietz syndrome, characterized by craniofacial and cardiovascular abnormalities. Mice with a deletion of Tgfbr2 in cranial neural crest cells (Tgfbr2(fl/fl);Wnt1-Cre mice) develop cleft palate as the result of abnormal TGFβ signaling activation. However, little is known about metabolic processes downstream of TGFβ signaling during palatogenesis. Here, we show that Tgfbr2 mutant palatal mesenchymal cells spontaneously accumulate lipid droplets, resulting from reduced lipolysis activity. Tgfbr2 mutant palatal mesenchymal cells failed to respond to the cell proliferation stimulator sonic hedgehog, derived from the palatal epithelium. Treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor or telmisartan, a modulator of p38 MAPK activation and lipid metabolism, blocked abnormal TGFβ-mediated p38 MAPK activation, restoring lipid metabolism and cell proliferation activity both in vitro and in vivo. Our results highlight the influence of alternative TGFβ signaling on lipid metabolic activities, as well as how lipid metabolic defects can affect cell proliferation and adversely impact palatogenesis. This discovery has broader implications for the understanding of metabolic defects and potential prevention of congenital birth defects. PMID:23975680

  13. A Soluble Adenylyl Cyclase Form Targets to Axonemes and Rescues Beat Regulation in Soluble Adenylyl Cyclase Knockout Mice

    PubMed Central

    Chen, Xi; Baumlin, Nathalie; Buck, Jochen; Levin, Lonny R.; Fregien, Nevis

    2014-01-01

    Ciliary beating is important for effective mucociliary clearance. Soluble adenylyl cyclase (sAC) regulates ciliary beating, and a roughly 50-kD sAC variant is expressed in axonemes. Normal human bronchial epithelial (NHBE) cells express multiple sAC splice variants: full-length sAC; variants with catalytic domain 1 (C1) deletions; and variants with partial C1. One variant, sACex5v2-ex12v2, contains two alternative splices creating new exons 5 (ex5v2) and 12 (ex12v2), encoding a roughly 45-kD protein. It is therefore similar in size to ciliary sAC. The variant increases in expression upon ciliogenesis during differentiation at the air–liquid interface. When expressed in NHBE cells, this variant was targeted to cilia. Exons 5v2–7 were important for ciliary targeting, whereas exons 2–4 prevented it. In vitro, cytoplasmic sACex2-ex12v2 (containing C1 and C2) was the only variant producing cAMP. Ciliary sACex5v2-ex12v2 was not catalytically active. Airway epithelial cells isolated from wild-type mice revealed sAC-dependent ciliary beat frequency (CBF) regulation, analogous to NHBE cells: CBF rescue from HCO3−/CO2–mediated intracellular acidification was sensitive to the sAC inhibitor, KH7. Compared with wild type, sAC C2 knockout (KO) mice revealed lower CBF baseline, and the HCO3−/CO2–mediated CBF decrease was not inhibited by KH7, confirming lack of functional sAC. Human sACex5v2-ex12v2 was targeted to cilia and sACex2-ex12v2 to the cytoplasm in these KO mice. Introduction of the ciliary sACex5v2-ex12v2 variant, but not the cytoplasmic sACex2-ex12v2, restored functional sAC activity in C2 KO mice. Thus, we show, for the first time, a mammalian axonemal targeting sequence that localizes a sAC variant to cilia to regulate CBF. PMID:24874272

  14. In vivo structure-function studies of human hepatic lipase: the catalytic function rescues the lean phenotype of HL-deficient (hl−/−) mice

    PubMed Central

    Chen, Jeffrey; Kaiyala, Karl J; Lam, Jennifer; Agrawal, Nalini; Nguyen, Lisa; Ogimoto, Kayoko; Spencer, Dean; Morton, Gregory J; Schwartz, Michael W; Dichek, Helén L

    2015-01-01

    The lean body weight phenotype of hepatic lipase (HL)–deficient mice (hl−/−) suggests that HL is required for normal weight gain, but the underlying mechanisms are unknown. HL plays a unique role in lipoprotein metabolism performing bridging as well as catalytic functions, either of which could participate in energy homeostasis. To determine if both the catalytic and bridging functions or the catalytic function alone are required for the effect of HL on body weight, we studied (hl−/−) mice that transgenically express physiologic levels of human (h)HL (with catalytic and bridging functions) or a catalytically-inactive (ci)HL variant (with bridging function only) in which the catalytic Serine 145 was mutated to Alanine. As expected, HL activity in postheparin plasma was restored to physiologic levels only in hHL-transgenic mice (hl−/−hHL). During high-fat diet feeding, hHL-transgenic mice exhibited increased body weight gain and body adiposity relative to hl−/−ciHL mice. A similar, albeit less robust effect was observed in female hHL-transgenic relative to hl−/−ciHL mice. To delineate the basis for this effect, we determined cumulative food intake and measured energy expenditure using calorimetry. Interestingly, in both genders, food intake was 5–10% higher in hl−/−hHL mice relative to hl−/−ciHL controls. Similarly, energy expenditure was ∼10% lower in HL-transgenic mice after adjusting for differences in total body weight. Our results demonstrate that (1) the catalytic function of HL is required to rescue the lean body weight phenotype of hl−/− mice; (2) this effect involves complementary changes in both sides of the energy balance equation; and (3) the bridging function alone is insufficient to rescue the lean phenotype of hl−/−ciHL mice. PMID:25862097

  15. Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice

    PubMed Central

    Quinn, Malgorzata E.; Haaning, Allison; Ware, Stephanie M.

    2012-01-01

    Limb anomalies are important birth defects that are incompletely understood genetically and mechanistically. GLI3, a mediator of hedgehog signaling, is a genetic cause of limb malformations including pre- and postaxial polydactyly, Pallister–Hall syndrome and Greig cephalopolysyndactyly. A closely related Gli (glioma-associated oncogene homolog)-superfamily member, ZIC3, causes X-linked heterotaxy syndrome in humans but has not been investigated in limb development. During limb development, post-translational processing of Gli3 from activator to repressor antagonizes and posteriorly restricts Sonic hedgehog (Shh). We demonstrate that Zic3 and Gli3 expression overlap in developing limbs and that Zic3 converts Gli3 from repressor to activator in vitro. In Gli3 mutant mice, Zic3 loss of function abrogates ectopic Shh expression in anterior limb buds, limits overexpression in the zone of polarizing activity and normalizes aberrant Gli3 repressor/Gli3 activator ratios observed in Gli3+/− embryos. Zic3 null;Gli3+/− neonates show rescue of the polydactylous phenotype seen in Gli3+/− animals. These studies identify a previously unrecognized role for Zic3 in regulating limb digit number via its modifying effect on Gli3 and Shh expression levels. Together, these results indicate that two Gli superfamily members that cause disparate human congenital malformation syndromes interact genetically and demonstrate the importance of Zic3 in regulating Shh pathway in developing limbs. PMID:22234993

  16. Serotonin Deficiency Rescues Lactation on Day 1 in Mice Fed a High Fat Diet.

    PubMed

    Weaver, Samantha R; Bohrer, Justin C; Prichard, Allan S; Perez, Paola K; Streckenbach, Liana J; Olson, Jake M; Cook, Mark E; Hernandez, Laura L

    2016-01-01

    Obesity is an inflammatory state associated with delayed lactogenesis stage II and altered mammary gland morphology. Serotonin mediates inflammation and mammary gland involution. The objective of this study was to determine if a genetic deficiency of tryptophan hydroxylase 1, the rate-limiting enzyme in peripheral serotonin synthesis, would result in an improved ability to lactate in dams fed a high fat diet. Twenty-six female mice were fed a high (HFD) or low fat (LFD) diet throughout pregnancy and lactation. Fourteen mice were genetically deficient for Tph1 (Tph1-/-), and twelve were wild type. Milk yield, pup mortality, and dam weights were recorded and milk samples were collected. On day 10 of lactation, dams were sacrificed and mammary glands were harvested for RT-PCR and histological evaluation. HFD dams weighed more than LFD dams at the onset of lactation. WT HFD dams were unable to lactate on day 1 of lactation and exhibited increased pup mortality relative to all other treatments, including Tph1-/- HFD dams. mRNA expression of immune markers C-X-C motif chemokine 5 and tumor necrosis factor alpha were elevated in WT HFD mammary glands. Mammary gland histology showed a reduced number of alveoli in WT compared to Tph1-/- dams, regardless of diet, and the alveoli of HFD dams were smaller than those of LFD dams. Finally, fatty acid profile in milk was dynamic in both early and peak lactation, with reduced de novo synthesis of fatty acids on day 10 of lactation in the HFD groups. Administration of a HFD to C57BL/6 dams produced an obese phenotype in the mammary gland, which was alleviated by a genetic deficiency of Tph1. Serotonin may modulate the effects of obesity on the mammary gland, potentially contributing to the delayed onset of lactogenesis seen in obese women. PMID:27603698

  17. Photodynamic therapy with a cationic functionalized fullerene rescues mice from fatal wound infections

    PubMed Central

    Lu, Zongshun; Dai, Tianhong; Huang, Liyi; Kurup, Divya B; Tegos, George P; Jahnke, Ashlee; Wharton, Tim; Hamblin, Michael R

    2011-01-01

    Aims Fullerenes are under intensive study for potential biomedical applications. We have previously reported that a C60 fullerene functionalized with three dimethylpyrrolidinium groups (BF6) is a highly active broad-spectrum antimicrobial photosensitizer in vitro when combined with white-light illumination. We asked whether this high degree of in vitro activity would translate into an in vivo therapeutic effect in two potentially lethal mouse models of infected wounds. Materials & methods We used stable bioluminescent bacteria and a low light imaging system to follow the progress of the infection noninvasively in real time. An excisional wound on the mouse back was contaminated with one of two bioluminescent Gram-negative species, Proteus mirabilis (2.5 × 107 cells) and Pseudomonas aeruginosa (5 × 106 cells). A solution of BF6 was placed into the wound followed by delivery of up to 180 J/cm2 of broadband white light (400–700 nm). Results In both cases there was a light-dose-dependent reduction of bioluminescence from the wound not observed in control groups (light alone or BF6 alone). Fullerene-mediated photodynamic therapy of mice infected with P. mirabilis led to 82% survival compared with 8% survival without treatment (p < 0.001). Photodynamic therapy of mice infected with highly virulent P. aeruginosa did not lead to survival, but when photodynamic therapy was combined with a suboptimal dose of the antibiotic tobramycin (6 mg/kg for 1 day) there was a synergistic therapeutic effect with a survival of 60% compared with a survival of 20% with tobramycin alone (p < 0.01). Conclusion These data suggest that cationic fullerenes have clinical potential as an antimicrobial photosensitizer for superficial infections where red light is not needed to penetrate tissue. PMID:21143031

  18. Rescuing the duty to rescue.

    PubMed

    Rulli, Tina; Millum, Joseph

    2016-04-01

    Clinicians and health researchers frequently encounter opportunities to rescue people. Rescue cases can generate a moral duty to aid those in peril. As such, bioethicists have leveraged a duty to rescue for a variety of purposes. Yet, despite its broad application, the duty to rescue is underanalysed. In this paper, we assess the state of theorising about the duty to rescue. There are large gaps in bioethicists' understanding of the force, scope and justification of the two most cited duties to rescue-the individual duty of easy rescue and the institutional rule of rescue. We argue that the duty of easy rescue faces unresolved challenges regarding its force and scope, and the rule of rescue is indefensible. If the duty to rescue is to help solve ethical problems, these theoretical gaps must be addressed. We identify two further conceptions of the duty to rescue that have received less attention-an institutional duty of easy rescue and the professional duty to rescue. Both provide guidance in addressing force and scope concerns and, thereby, traction in answering the outstanding problems with the duty to rescue. We conclude by proposing research priorities for developing accounts of duties to rescue in bioethics. PMID:24790055

  19. Slow and continuous delivery of a low dose of nimodipine improves survival and electrocardiogram parameters in rescue therapy of mice with experimental cerebral malaria

    PubMed Central

    2013-01-01

    Background Human cerebral malaria (HCM) is a life-threatening complication caused by Plasmodium falciparum infection that continues to be a major global health problem despite optimal anti-malarial treatment. In the experimental model of cerebral malaria (ECM) by Plasmodium berghei ANKA, bolus administration of nimodipine at high doses together with artemether, increases survival of mice with ECM. However, the dose and administration route used is associated with cardiovascular side effects such as hypotension and bradycardia in humans and mice, which could preclude its potential use as adjunctive treatment in HCM. Methods In the present study, alternative delivery systems for nimodipine during late-stage ECM in association with artesunate were searched to define optimal protocols to achieve maximum efficacy in increasing survival in rescue therapy while causing the least cardiac side effects. The baseline electrocardiogram (ECG) and arterial pressure characteristics of uninfected control animals and of mice with ECM and its response upon rescue treatment with artesunate associated or not with nimodipine is also analysed. Results Nimodipine, given at 0.5 mg/kg/day via a slow and continuous delivery system by osmotic pumps, increases survival of mice with ECM when used as adjunctive treatment to artesunate. Mice with ECM showed hypotension and ECG changes, including bradycardia and increases in PR, QRS, QTc and ST interval duration. ECM mice also show increased QTc dispersion, heart rate variability (HRV), RMSSD, low frequency (LF) and high frequency (HF) bands of the power spectrum. Both sympathetic and parasympathetic inputs to the heart were increased, but there was a predominance of sympathetic tone as demonstrated by an increased LF/HF ratio. Nimodipine potentiated bradycardia when given by bolus injection, but not when via osmotic pumps. In addition, nimodipine shortened PR duration and improved HRV, RMSSD, LF and HF powers in mice with ECM. In addition

  20. Adeno-associated Virus-mediated Rescue of Neonatal Lethality in Argininosuccinate Synthetase-deficient Mice

    PubMed Central

    Kok, Cindy Y; Cunningham, Sharon C; Carpenter, Kevin H; Dane, Allison P; Siew, Susan M; Logan, Grant J; Kuchel, Philip W; Alexander, Ian E

    2013-01-01

    Viral vectors based on adeno-associated virus (AAV) are showing exciting promise in gene therapy trials targeting the adult liver. A major challenge in extending this promise to the pediatric liver is the loss of episomal vector genomes that accompanies hepatocellular proliferation during liver growth. Hence maintenance of sufficient transgene expression will be critical for success in infants and children. We therefore set out to explore the therapeutic efficacy and durability of liver-targeted gene transfer in the challenging context of a neonatal lethal urea cycle defect, using the argininosuccinate synthetase deficient mouse. Lethal neonatal hyperammonemia was prevented by prenatal and early postnatal vector delivery; however, hyperammonemia subsequently recurred limiting survival to no more than 33 days despite vector readministration. Antivector antibodies acquired in milk from vector-exposed dams were subsequently shown to be blocking vector readministration, and were avoided by crossfostering vector-treated pups to vector-naive dams. In the absence of passively acquired antivector antibodies, vector redelivery proved efficacious with mice surviving to adulthood without recurrence of significant hyperammonemia. These data demonstrate the potential of AAV vectors in the developing liver, showing that vector readministration can be used to counter growth-associated loss of transgene expression provided the challenge of antivector humoral immunity is addressed. PMID:23817206

  1. Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

    PubMed Central

    Krakauer, Teresa; Buckley, Marilyn

    2012-01-01

    Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window. PMID:23105977

  2. DNA nanoparticle-mediated ABCA4 delivery rescues Stargardt dystrophy in mice.

    PubMed

    Han, Zongchao; Conley, Shannon M; Makkia, Rasha S; Cooper, Mark J; Naash, Muna I

    2012-09-01

    Mutations in the photoreceptor-specific flippase ABCA4 are associated with Stargardt disease and many other forms of retinal degeneration that currently lack curative therapies. Gene replacement is a logical strategy for ABCA4-associated disease, particularly given the current success of traditional viral-mediated gene delivery, such as with adeno-associated viral (AAV) vectors. However, the large size of the ABCA4 cDNA (6.8 kbp) has hampered progress in the development of genetic treatments. Nonviral DNA nanoparticles (NPs) can accommodate large genes, unlike traditional viral vectors, which have capacity limitations. We utilized an optimized DNA NP technology to subretinally deliver ABCA4 to Abca4-deficient mice. We detected persistent ABCA4 transgene expression for up to 8 months after injection and found marked correction of functional and structural Stargardt phenotypes, such as improved recovery of dark adaptation and reduced lipofuscin granules. These data suggest that DNA NPs may be an excellent, clinically relevant gene delivery approach for genes too large for traditional viral vectors. PMID:22886305

  3. Completely Humanizing Prolactin Rescues Infertility in Prolactin Knockout Mice and Leads to Human Prolactin Expression in Extrapituitary Mouse Tissues

    PubMed Central

    Christensen, Heather R.; Murawsky, Michael K.; Horseman, Nelson D.; Willson, Tara A.

    2013-01-01

    A variety of fundamental differences have evolved in the physiology of the human and rodent prolactin (PRL) systems. The PRL gene in humans and other primates contains an alternative promoter, 5.8 kbp upstream of the pituitary transcription start site, which drives expression of PRL in “extrapituitary” tissues, where PRL is believed to exert local, or paracrine, actions. Several of these extrapituitary PRL tissues serve a reproductive function (eg, mammary gland, decidua, prostate, etc), consistent with the hypothesis that local PRL production may be involved in, and required for, normal reproductive physiology in primates. Rodent research models have generated significant findings regarding the role of PRL in reproduction. Specifically, disruption (knockout) of either the PRL gene or its receptor causes profound female reproductive defects at several levels (ovaries, preimplantation endometrium, mammary glands). However, the rodent PRL gene differs significantly from the human, most notably lacking the alternative promoter. Understanding of the physiological regulation and function of extrapituitary PRL has been limited by the absence of a readily accessible experimental model, because the rodent PRL gene does not contain the alternative promoter. To overcome these limitations, we have generated mice that have been “humanized” with regard to the structural gene and tissue expression of PRL. Here, we present the characterization of these animals, demonstrating that the human PRL transgene is responsive to known physiological regulators both in vitro and in vivo. More importantly, the expression of the human PRL transgene is able to rescue the reproductive defects observed in mouse PRL knockout (mPRL−) females, validating their usefulness in studying the function or regulation of this hormone in a manner that is relevant to human physiology. PMID:24029242

  4. Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

    PubMed Central

    Vannoy, Charles H.; Xu, Lei; Keramaris, Elizabeth; Lu, Pei; Xiao, Xiao

    2014-01-01

    Abstract Multiple genes (e.g., POMT1, POMT2, POMGnT1, ISPD, GTDC2, B3GALNT2, FKTN, FKRP, and LARGE) are known to be involved in the glycosylation pathway of α-dystroglycan (α-DG). Mutations of these genes result in muscular dystrophies with wide phenotypic variability. Abnormal glycosylation of α-DG with decreased extracellular ligand binding activity is a common biochemical feature of these genetic diseases. While it is known that LARGE overexpression can compensate for defects in a few aforementioned genes, it is unclear whether it can also rescue defects in FKRP function. We examined adeno-associated virus (AAV)-mediated LARGE or FKRP overexpression in two dystrophic mouse models with loss-of-function mutations: (1) Largemyd (LARGE gene) and (2) FKRPP448L (FKRP gene). The results agree with previous findings that overexpression of LARGE can ameliorate the dystrophic phenotypes of Largemyd mice. In addition, LARGE overexpression in the FKRPP448L mice effectively generated functional glycosylation (hyperglycosylation) of α-DG and improved dystrophic pathologies in treated muscles. Conversely, FKRP transgene overexpression failed to rescue the defect in glycosylation and improve the phenotypes of the Largemyd mice. Our findings suggest that AAV-mediated LARGE gene therapy may still be a viable therapeutic strategy for dystroglycanopathies with FKRP deficiency. PMID:24635668

  5. Partial rescue of epithelial phenotype in integrin beta4 null mice by a keratin-5 promoter driven human integrin beta4 transgene.

    PubMed

    van der Neut, R; Cachaço, A S; Thorsteinsdóttir, S; Janssen, H; Prins, D; Bulthuis, J; van der Valk, M; Calafat, J; Sonnenberg, A

    1999-11-01

    Integrin beta4 null mice exhibit extensive epidermal detachment, reminiscent of the human skin blistering disease junctional epidermolysis bullosa associated with pyloric atresia. Hemidesmosomes, the stable adhesion structures of squamous epithelia, are not formed in the absence of alpha6beta4. Null mutant mice die shortly after birth, but apart from their striking epithelial phenotype, no obvious developmental defects have been observed. To elucidate the cause of death in these mice, we generated transgenic mice with a heterologous construct consisting of the squamous epithelial-specific keratin-5 promoter and a human integrin beta4 subunit cDNA. The transgene was not expressed in the presence of endogenous beta4, probably as a result of competition for a limited pool of alpha6 subunits. In a beta4 null background, however, the transgene was expressed, and its expression pattern followed that of squamous epithelial-specific keratins. These rescued pups appeared healthy and ultrastructural analysis revealed that the interspecies heterodimer alpha6(mouse)/beta4(human) was sufficient to trigger the assembly of hemidesmosomes. After a variable period of up to 48 hours after birth these animals began to exhibit haemorrhages at the plantar and palmar areas. We observed the formation of small blisters and found that the transgene was not detectably expressed in this region, which is devoid of hair follicles. The rescued neonates became increasingly cyanotic and died soon after the onset of this phenomenon. We performed a developmental study of the expression of beta4 in the complete respiratory tract, but we found no correlation between the spatiotemporal distribution of beta4 and the onset of the respiratory insufficiency. It became clear, however, that there was a gradual detachment of squamous epithelia in the oral and nasal cavities which led to obstruction of the respiratory tract, suggesting that in beta4 null and rescued mice, neonatal death was a direct

  6. Leptin gene therapy attenuates neuronal damages evoked by amyloid-β and rescues memory deficits in APP/PS1 mice.

    PubMed

    Pérez-González, R; Alvira-Botero, M X; Robayo, O; Antequera, D; Garzón, M; Martín-Moreno, A M; Brera, B; de Ceballos, M L; Carro, E

    2014-03-01

    There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricular administration to APP/PS1 transgenic model of AD. Three months after intra-cerebroventricular administration of HIV-leptin, brain Aβ accumulation was reduced. By electron microscopy, we found that APP/PS1 mice exhibited deficits in synaptic density, which were partially rescued by HIV-leptin treatment. Synaptic deficits in APP/PS1 mice correlated with an enhancement of caspase-3 expression, and a reduction in synaptophysin levels in synaptosome preparations. Notably, HIV-leptin therapy reverted these dysfunctions. Moreover, leptin modulated neurite outgrowth in primary neuronal cultures, and rescued them from Aβ42-induced toxicity. All the above changes suggest that leptin may affect multiple aspects of the synaptic status, and correlate with behavioral improvements. Our data suggest that leptin gene delivery has a therapeutic potential for Aβ-targeted treatment of mouse model of AD. PMID:24430238

  7. Space Rescue

    NASA Technical Reports Server (NTRS)

    Muratore, John F.

    2007-01-01

    Space Rescue has been a topic of speculation for a wide community of people for decades. Astronauts, aerospace engineers, diplomats, medical and rescue professionals, inventors and science fiction writers have all speculated on this problem. Martin Caidin's 1964 novel Marooned dealt with the problems of rescuing a crew stranded in low earth orbit. Legend at the Johnson Space Center says that Caidin's portrayal of a Russian attempt to save the American crew played a pivotal role in convincing the Russians to join the real joint Apollo-Soyuz mission. Space Rescue has been a staple in science fiction television and movies portrayed in programs such as Star Trek, Stargate-SG1 and Space 1999 and movies such as Mission To Mars and Red Planet. As dramatic and as difficult as rescue appears in fictional accounts, in the real world it has even greater drama and greater difficulty. Space rescue is still in its infancy as a discipline and the purpose of this chapter is to describe the issues associated with space rescue and the work done so far in this field. For the purposes of this chapter, the term space rescue will refer to any system which allows for rescue or escape of personnel from situations which endanger human life in a spaceflight operation. This will span the period from crew ingress prior to flight through crew egress postlanding. For the purposes of this chapter, the term primary system will refer to the spacecraft system that a crew is either attempting to escape from or from which an attempt is being made to rescue the crew.

  8. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish.

    PubMed

    Gros-Louis, Francois; Kriz, Jasna; Kabashi, Edor; McDearmid, Jonathan; Millecamps, Stéphanie; Urushitani, Makoto; Lin, Li; Dion, Patrick; Zhu, Qinzhang; Drapeau, Pierre; Julien, Jean-Pierre; Rouleau, Guy A

    2008-09-01

    Recessive ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2 encoded protein, we generated Als2 knock-out (KO) mice and zAls2 knock-down zebrafish. The Als2(-/-) mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, northern and western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild-type littermates and some rescued the zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2 KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients. PMID:18558633

  9. A human FSHB transgene encoding the double N-glycosylation mutant (Asn(7Δ) Asn(24Δ)) FSHβ subunit fails to rescue Fshb null mice.

    PubMed

    Wang, Huizhen; Butnev, Vladimir; Bousfield, George R; Kumar, T Rajendra

    2016-05-01

    Follicle-stimulating hormone (FSH) is a gonadotrope-derived heterodimeric glycoprotein. Both the common α- and hormone-specific β subunits contain Asn-linked N-glycan chains. Recently, macroheterogeneous FSH glycoforms consisting of β-subunits that differ in N-glycan number were identified in pituitaries of several species and subsequently the recombinant human FSH glycoforms biochemically characterized. Although chemical modification and in vitro site-directed mutagenesis studies defined the roles of N-glycans on gonadotropin subunits, in vivo functional analyses in a whole-animal setting are lacking. Here, we have generated transgenic mice with gonadotrope-specific expression of either an HFSHB(WT) transgene that encodes human FSHβ WT subunit or an HFSHB(dgc) transgene that encodes a human FSHβ(Asn7Δ 24Δ) double N-glycosylation site mutant subunit, and separately introduced these transgenes onto Fshb null background using a genetic rescue strategy. We demonstrate that the human FSHβ(Asn7Δ 24Δ) double N-glycosylation site mutant subunit, unlike human FSHβ WT subunit, inefficiently combines with the mouse α-subunit in pituitaries of Fshb null mice. FSH dimer containing this mutant FSHβ subunit is inefficiently secreted with very low levels detectable in serum. Fshb null male mice expressing HFSHB(dgc) transgene are fertile and exhibit testis tubule size and sperm number similar to those of Fshb null mice. Fshb null female mice expressing the mutant, but not WT human FSHβ subunit-containing FSH dimer are infertile, demonstrate no evidence of estrus cycles, and many of the FSH-responsive genes remain suppressed in their ovaries. Thus, HFSHB(dgc) unlike HFSHB(WT) transgene does not rescue Fshb null mice. Our genetic approach provides direct in vivo evidence that N-linked glycans on FSHβ subunit are essential for its efficient assembly with the α-subunit to form FSH heterodimer in pituitary. Our studies also reveal that N-glycans on FSHβ subunit are

  10. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2-/y) Mice by Rolipram

    PubMed Central

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W.

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2-/y mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2-/y mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2-/y mice. This weaker potentiation in Mecp2-/y mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (Ih) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2-/y mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2-/y mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  11. Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2(-/y) ) Mice by Rolipram.

    PubMed

    Balakrishnan, Saju; Niebert, Marcus; Richter, Diethelm W

    2016-01-01

    Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2(-/y) mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2(-/y) mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2(-/y) mice. This weaker potentiation in Mecp2 (-/) (y) mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (I h) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2 (-/) (y) mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2 (-/) (y) mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect. PMID:26869885

  12. Compound danshen tablet ameliorated aβ25-35-induced spatial memory impairment in mice via rescuing imbalance between cytokines and neurotrophins

    PubMed Central

    2014-01-01

    mice by rescuing imbalance between cytokines and neurotrophins. PMID:24422705

  13. Pulsed focused ultrasound pretreatment improves mesenchymal stem cell efficacy in preventing and rescuing established acute kidney injury in mice

    PubMed Central

    Burks, Scott R.; Nguyen, Ben A.; Tebebi, Pamela A.; Kim, Saejeong J.; Bresler, Michele N.; Ziadloo, Ali; Street, Jonathan M.; Yuen, Peter S. T.; Star, Robert A.; Frank, Joseph A.

    2014-01-01

    Animal studies have shown that mesenchymal stem cell (MSC) infusions improve acute kidney injury (AKI) outcomes when administered early after ischemic/reperfusion injury or within 24hr after cisplatin administration. These findings have spurred several human clinical trials to prevent AKI. However, no specific therapy effectively treats clinically obvious AKI or rescues renal function once advanced injury is established. We investigated if noninvasive image-guided pulsed focused ultrasound (pFUS) could alter the kidney microenvironment to enhance homing of subsequently infused MSC. To examine the efficacy of pFUS-enhanced cell homing in disease, we targeted pFUS to kidneys to enhance MSC homing after cisplatin-induced AKI. We found that pFUS enhanced MSC homing at 1 day post-cisplatin, prior to renal functional deficits, and that enhanced homing improved outcomes of renal function, tubular cell death, and regeneration at 5 days post-cisplatin compared to MSC alone. We then investigated whether pFUS+MSC therapy could rescue established AKI. MSC alone at 3 days post-cisplatin, after renal functional deficits were obvious, significantly improved 7-day survival of animals. Survival was further improved using pFUS+MSC. MSC, alone or with pFUS, changed kidney macrophage phenotypes from M1 to M2. This study shows pFUS is a neoadjuvant approach to improve MSC homing to diseased organs. pFUS with MSC better prevents AKI than MSC alone and allows rescue therapy in established AKI, which currently has no meaningful therapeutic options. PMID:25640064

  14. Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

    SciTech Connect

    Wang, Dongxu; Wang, Yijun; Wan, Xiaochun; Yang, Chung S.; Zhang, Jinsong

    2015-02-15

    (−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at

  15. Long-Term Rescue of Retinal Structure and Function by Rhodopsin RNA Replacement with a Single Adeno-Associated Viral Vector in P23H RHO Transgenic Mice

    PubMed Central

    Mao, Haoyu; Gorbatyuk, Marina S.; Rossmiller, Brian; Hauswirth, William W.

    2012-01-01

    Abstract Many mutations in the human rhodopsin gene (RHO) cause autosomal dominant retinitis pigmentosa (ADRP). Our previous studies with a P23H (proline-23 substituted by histidine) RHO transgenic mouse model of ADRP demonstrated significant improvement of retinal function and preservation of retinal structure after transfer of wild-type rhodopsin by AAV. In this study we demonstrate long-term rescue of retinal structure and function by a single virus expressing both RHO replacement cDNA and small interfering RNA (siRNA) to digest mouse Rho and human P23H RHO mRNA. This combination should prevent overexpression of rhodopsin, which can be deleterious to photoreceptors. On the basis of the electroretinogram (ERG) response, degeneration of retinal function was arrested at 2 months postinjection, and the response was maintained at this level until termination at 9 months. Preservation of the ERG response in P23H RHO mice reflected survival of photoreceptors: both the outer nuclear layer (ONL) and outer segments of photoreceptor cells maintained the same thickness as in nontransgenic mice, whereas the control injected P23H eyes exhibited severe thinning of the ONL and outer segments. These findings suggest that delivery of both a modified cDNA and an siRNA by a single adeno-associated viral vector provided long-term rescue of ADRP in this model. Because the siRNA targets human as well as mouse rhodopsin mRNAs, the combination vector may be useful for the treatment of human disease. PMID:22289036

  16. Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading strand deprotection.

    PubMed

    Zhang, S; Matsunaga, S; Lin, Y-F; Sishc, B; Shang, Z; Sui, J; Shih, H-Y; Zhao, Y; Foreman, O; Story, M D; Chen, D J; Chen, B P C

    2016-07-28

    Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs(3A/3A) mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs(3A/3A) mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs(3A/3A) skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs(3A/3A) cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development. PMID:26616856

  17. Experience-dependent reduction of soluble β-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome.

    PubMed

    Sansevero, Gabriele; Begenisic, Tatjana; Mainardi, Marco; Sale, Alessandro

    2016-09-01

    Down syndrome (DS) is the most diffused genetic cause of intellectual disability and, after the age of forty, is invariantly associated with Alzheimer's disease (AD). In the last years, the prolongation of life expectancy in people with DS renders the need for intervention paradigms aimed at improving mental disability and counteracting AD pathology particularly urgent. At present, however, there are no effective therapeutic strategies for DS and concomitant AD in mid-life people. The most intensively studied mouse model of DS is the Ts65Dn line, which summarizes the main hallmarks of the DS phenotype, included severe learning and memory deficits and age-dependent AD-like pathology. Here we report for the first time that middle-age Ts65Dn mice display a marked increase in soluble Aβ oligomer levels in their hippocampus. Moreover, we found that long-term exposure to environmental enrichment (EE), a widely used paradigm that increases sensory-motor stimulation, reduces Aβ oligomers and rescues spatial memory abilities in trisomic mice. Our findings underscore the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes in DS subjects. PMID:27288239

  18. Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.

    PubMed

    Jafar-Nejad, Paymaan; Ward, Christopher S; Richman, Ronald; Orr, Harry T; Zoghbi, Huda Y

    2011-02-01

    Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3ε levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3ε haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3ε haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis. PMID:21245341

  19. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

    PubMed Central

    Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa; Chen, Fang; Zhuo, Jia L

    2015-01-01

    The role of Na+/H+ exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3−/−) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3+/+) and tgNhe3−/− mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3−/− mice (P < 0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na+ excretion, urinary K+ excretion, and urinary Cl− excretion were significantly lower in tgNhe3−/− mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na+/HCO3 cotransporter, the α1 subunit isoform of Na+/K+-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3−/− mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3+/+, as expected, but all of these responses to ANG II were attenuated in tgNhe3−/− mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension. PMID:26564064

  20. Maternal transcription of non-protein coding RNAs from the PWS-critical region rescues growth retardation in mice.

    PubMed

    Rozhdestvensky, Timofey S; Robeck, Thomas; Galiveti, Chenna R; Raabe, Carsten A; Seeger, Birte; Wolters, Anna; Gubar, Leonid V; Brosius, Jürgen; Skryabin, Boris V

    2016-01-01

    Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by loss of paternally expressed genes on chromosome 15q11-q13. The PWS-critical region (PWScr) contains an array of non-protein coding IPW-A exons hosting intronic SNORD116 snoRNA genes. Deletion of PWScr is associated with PWS in humans and growth retardation in mice exhibiting ~15% postnatal lethality in C57BL/6 background. Here we analysed a knock-in mouse containing a 5'HPRT-LoxP-Neo(R) cassette (5'LoxP) inserted upstream of the PWScr. When the insertion was inherited maternally in a paternal PWScr-deletion mouse model (PWScr(p-/m5'LoxP)), we observed compensation of growth retardation and postnatal lethality. Genomic methylation pattern and expression of protein-coding genes remained unaltered at the PWS-locus of PWScr(p-/m5'LoxP) mice. Interestingly, ubiquitous Snord116 and IPW-A exon transcription from the originally silent maternal chromosome was detected. In situ hybridization indicated that PWScr(p-/m5'LoxP) mice expressed Snord116 in brain areas similar to wild type animals. Our results suggest that the lack of PWScr RNA expression in certain brain areas could be a primary cause of the growth retardation phenotype in mice. We propose that activation of disease-associated genes on imprinted regions could lead to general therapeutic strategies in associated diseases. PMID:26848093

  1. Maternal transcription of non-protein coding RNAs from the PWS-critical region rescues growth retardation in mice

    PubMed Central

    Rozhdestvensky, Timofey S.; Robeck, Thomas; Galiveti, Chenna R.; Raabe, Carsten A.; Seeger, Birte; Wolters, Anna; Gubar, Leonid V.; Brosius, Jürgen; Skryabin, Boris V.

    2016-01-01

    Prader-Willi syndrome (PWS) is a neurogenetic disorder caused by loss of paternally expressed genes on chromosome 15q11-q13. The PWS-critical region (PWScr) contains an array of non-protein coding IPW-A exons hosting intronic SNORD116 snoRNA genes. Deletion of PWScr is associated with PWS in humans and growth retardation in mice exhibiting ~15% postnatal lethality in C57BL/6 background. Here we analysed a knock-in mouse containing a 5′HPRT-LoxP-NeoR cassette (5′LoxP) inserted upstream of the PWScr. When the insertion was inherited maternally in a paternal PWScr-deletion mouse model (PWScrp−/m5′LoxP), we observed compensation of growth retardation and postnatal lethality. Genomic methylation pattern and expression of protein-coding genes remained unaltered at the PWS-locus of PWScrp−/m5′LoxP mice. Interestingly, ubiquitous Snord116 and IPW-A exon transcription from the originally silent maternal chromosome was detected. In situ hybridization indicated that PWScrp−/m5′LoxP mice expressed Snord116 in brain areas similar to wild type animals. Our results suggest that the lack of PWScr RNA expression in certain brain areas could be a primary cause of the growth retardation phenotype in mice. We propose that activation of disease-associated genes on imprinted regions could lead to general therapeutic strategies in associated diseases. PMID:26848093

  2. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy

    PubMed Central

    Lawlor, Michael W.; Armstrong, Dustin; Viola, Marissa G.; Widrick, Jeffrey J.; Meng, Hui; Grange, Robert W.; Childers, Martin K.; Hsu, Cynthia P.; O'Callaghan, Michael; Pierson, Christopher R.; Buj-Bello, Anna; Beggs, Alan H.

    2013-01-01

    No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1δ4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1δ4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM. PMID:23307925

  3. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice.

    PubMed

    Zhou, Haiyan; Janghra, Narinder; Mitrpant, Chalermchai; Dickinson, Rachel L; Anthony, Karen; Price, Loren; Eperon, Ian C; Wilton, Stephen D; Morgan, Jennifer; Muntoni, Francesco

    2013-03-01

    In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27), and PMO20 (-10, -29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 μg/g and 2-fold at 40 μg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-μg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo-Morpholino and have potential for future SMA clinical applications. PMID:23339722

  4. Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits

    PubMed Central

    Pei, Ju-Chun; Liu, Chih-Min; Lai, Wen-Sung

    2014-01-01

    Accumulating evidence suggests that neuregulin 1 (NRG1) might be involved in the neurodevelopment, neural plasticity, GABAergic neurotransmission, and pathogenesis of schizophrenia. NRG1 is abundantly expressed in the hippocampus, and emerging studies have begun to reveal the link between NRG1 signaling and cognitive deficits in schizophrenic patients. Because the transmembrane domain of NRG1 is vital for both forward and reverse signaling cascades, new Nrg1-deficient mice that carry a truncation of the transmembrane domain of the Nrg1 gene were characterized and used in this study to test a NRG1 loss-of-function hypothesis for schizophrenia. Both male and female Nrg1 heterozygous mutant mice and their wild-type littermates were used in a series of 4 experiments to characterize the impact of Nrg1 on behavioral phenotypes and to determine the importance of Nrg1 in the regulation of hippocampal neuromorphology and local GABAergic interneurons. First, a comprehensive battery of behavioral tasks indicated that male Nrg1-deficient mice exhibited significant impairments in cognitive functions. Second, pharmacological challenges were conducted and revealed that Nrg1 haploinsufficiency altered GABAergic activity in males. Third, although no genotype-specific neuromorphological alterations were found in the hippocampal CA1 pyramidal neurons, significant reductions in the hippocampal expressions of GAD67 and parvalbumin were revealed in the Nrg1-deficient males. Fourth, chronic treatment with valproate rescued the observed behavioral deficits and hippocampal GAD67 reduction in Nrg1-deficient males. Collectively, these results indicate the potential therapeutic effect of valproate and the importance of Nrg1 in the regulation of cognitive functions and hippocampal GABAergic interneurons, especially in males. PMID:24782733

  5. Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects.

    PubMed

    Santos, Rosaysela; Kawauchi, Shimako; Jacobs, Russell E; Lopez-Burks, Martha E; Choi, Hojae; Wikenheiser, Jamie; Hallgrimsson, Benedikt; Jamniczky, Heather A; Fraser, Scott E; Lander, Arthur D; Calof, Anne L

    2016-09-01

    Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form. PMID:27606604

  6. Stem cell factor rescues dark epidermal pigmentation in discreet anatomic locations in albino and fair-skinned mice

    PubMed Central

    Vanover, Jillian C.; Spry, Malinda L.; Hamilton, Laura; Wakamatsu, Kazumasa; Ito, Shosuke; D’Orazio, John A.

    2016-01-01

    We previously reported a transgenic animal model of variant pigmentation based on epidermal expression of stem cell factor (SCF) and well-characterized coat color genes bred into the C57Bl/6 background. In this system, constitutive expression of SCF by epidermal keratinocytes results in the maintenance of epidermal melanocytes in the interfollicular basal epidermal layer and subsequent pigmentation of the epidermis itself. In this report, we describe extending this animal model by developing a compound mutant transgenic amelanotic animal defective at both the melanocortin 1 receptor (Mc1r) and tyrosinase (Tyr) loci. We have observed SCF-dependent pigment deposition in specific anatomic regions regardless of tyrosinase (Tyr) or Mc1r genetic status. Thus, in the presence of K14-Scf, tyrosinase-null animals (previously thought incapable of synthesizing melanin) exhibited progressive robust epidermal pigmentation with age in the ears and tails. Furthermore, in the presence of the K14-Scf transgene, Tyr-defective animals demonstrated tyrosinase activity, suggesting that the c2j Tyr promoter defect is leaky and that Tyr expression can be rescued in part by SCF in the ears and tail. Lastly, we found that UV sensitivity of K14-Scf congenic animals differing only at the Mc1r or Tyr loci depended mainly on the amount of eumelanin present in the skin. These findings suggest that c-kit signaling can overcome the c2j Tyr promoter mutation in the ears and tails of aging animals but that UV resistance depends on accumulation of epidermal eumelanin. PMID:19682281

  7. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice

    PubMed Central

    Akamatsu, Megumi; Yamashita, Takenari; Hirose, Naoki; Teramoto, Sayaka; Kwak, Shin

    2016-01-01

    Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca2+-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca2+ influx by AMPA receptor antagonists may be a potential ALS therapy. Here, we showed that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice. Given that perampanel is an approved anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial. PMID:27350567

  8. Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer.

    PubMed

    Cordier, L; Hack, A A; Scott, M O; Barton-Davis, E R; Gao, G; Wilson, J M; McNally, E M; Sweeney, H L

    2000-02-01

    In humans, a subset of cases of Limb-girdle muscular dystrophy (LGMD) arise from mutations in the genes encoding one of the sarcoglycan (alpha, beta, gamma, or delta) subunits of the dystrophin-glycoprotein complex. While adeno-associated virus (AAV) is a potential gene therapy vector for these dystrophies, it is unclear if AAV can be used if a diseased muscle is undergoing rapid degeneration and necrosis. The skeletal muscles of mice lacking gamma-sarcoglycan (gsg-/- mice) differ from the animal models that have been evaluated to date in that the severity of the skeletal muscle pathology is much greater and more representative of that of humans with muscular dystrophy. Following direct muscle injection of a recombinant AAV [in which human gamma-sarcoglycan expression is driven by a truncated muscle creatine kinase (MCK) promoter/enhancer], we observed significant numbers of muscle fibers expressing gamma-sarcoglycan and an overall improvement of the histologic pattern of dystrophy. However, these results could be achieved only if injections into the muscle were prior to the development of significant fibrosis in the muscle. The results presented in this report show promise for AAV gene therapy for LGMD, but underscore the need for intervention early in the time course of the disease process. PMID:10933922

  9. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.

    PubMed

    Akamatsu, Megumi; Yamashita, Takenari; Hirose, Naoki; Teramoto, Sayaka; Kwak, Shin

    2016-01-01

    Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca(2+)-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca(2+) influx by AMPA receptor antagonists may be a potential ALS therapy. Here, we showed that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice. Given that perampanel is an approved anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial. PMID:27350567

  10. Loss of Hif-2α Rescues the Hif-1α Deletion Phenotype of Neonatal Respiratory Distress In Mice

    PubMed Central

    Saini, Yogesh; Proper, Steven P.; Dornbos, Peter; Greenwood, Krista K.; Kopec, Anna K.; Lynn, Scott G.; Grier, Elizabeth; Burgoon, Lyle D.; Zacharewski, Timothy R.; Thomas, Russell S.; Harkema, Jack R.; LaPres, John J.

    2015-01-01

    Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1α in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1α, Hif-2α is also expressed in the developing lung, although the overlapping roles of Hif-1α and Hif-2α in this context are not fully understood. To further investigate the independent role of Hif-2α in lung epithelium and its ability to alter Hif-1α-mediated lung maturation, we generated two additional lung-specific inducible Hif-α knockout models (Hif-2α and Hif-1α+Hif-2α). The intrauterine loss of Hif-2α in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1α and Hif-2α suggests that the loss of Hif-2α is capable of rescuing the neonatal RDS phenotype seen in Hif-1α-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retlnγ, and Il-1r2, which are differentially regulated by the two HIF-α isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-κB, C/EBPα, and c-MYC signaling are central to HIF-mediated changes in lung development. PMID:26422241

  11. Bone marrow cells other than stem cells seed the bone marrow after rescue transfusion of fatally irradiated mice

    SciTech Connect

    Cronkite, E.P.; Inoue, T.; Bullis, J.E.

    1987-12-01

    In a previous publication, iodinated deoxyuridine (/sup 125/IUdR) incorporation data were interpreted as indicating that spleen colony-forming units (CFU-S) in DNA synthesis preferentially seeded bone marrow. In the present studies, the CFU-S content of marrow from irradiated, bone-marrow transfused mice was directly determined. Pretreatment of the transfused cells with cytocidal tritiated thymidine resulted in an insignificant diminution in CFU-S content when compared with nontritiated thymidine pretreatment, implying that there is no preferential seeding. The /sup 125/IUdR incorporation data have been reinterpreted as being a result of the proliferation of other progenitor cells present that have seeded the bone marrow.

  12. Blue Light Rescues Mice from Potentially Fatal Pseudomonas aeruginosa Burn Infection: Efficacy, Safety, and Mechanism of Action

    PubMed Central

    Dai, Tianhong; Gupta, Asheesh; Huang, Ying-Ying; Yin, Rui; Murray, Clinton K.; Vrahas, Mark S.; Sherwood, Margaret E.; Tegos, George P.

    2013-01-01

    Blue light has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. However, the use of blue light for wound infections has not been established yet. In this study, we demonstrated the efficacy of blue light at 415 nm for the treatment of acute, potentially lethal Pseudomonas aeruginosa burn infections in mice. Our in vitro studies demonstrated that the inactivation rate of P. aeruginosa cells by blue light was approximately 35-fold higher than that of keratinocytes (P = 0.0014). Transmission electron microscopy revealed blue light-mediated intracellular damage to P. aeruginosa cells. Fluorescence spectroscopy suggested that coproporphyrin III and/or uroporphyrin III are possibly the intracellular photosensitive chromophores associated with the blue light inactivation of P. aeruginosa. In vivo studies using an in vivo bioluminescence imaging technique and an area-under-the-bioluminescence-time-curve (AUBC) analysis showed that a single exposure of blue light at 55.8 J/cm2, applied 30 min after bacterial inoculation to the infected mouse burns, reduced the AUBC by approximately 100-fold in comparison with untreated and infected mouse burns (P < 0.0001). Histological analyses and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays indicated no significant damage in the mouse skin exposed to blue light at the effective antimicrobial dose. Survival analyses revealed that blue light increased the survival rate of the infected mice from 18.2% to 100% (P < 0.0001). In conclusion, blue light therapy might offer an effective and safe alternative to conventional antimicrobial therapy for P. aeruginosa burn infections. PMID:23262998

  13. Blue light rescues mice from potentially fatal Pseudomonas aeruginosa burn infection: efficacy, safety, and mechanism of action.

    PubMed

    Dai, Tianhong; Gupta, Asheesh; Huang, Ying-Ying; Yin, Rui; Murray, Clinton K; Vrahas, Mark S; Sherwood, Margaret E; Tegos, George P; Hamblin, Michael R

    2013-03-01

    Blue light has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. However, the use of blue light for wound infections has not been established yet. In this study, we demonstrated the efficacy of blue light at 415 nm for the treatment of acute, potentially lethal Pseudomonas aeruginosa burn infections in mice. Our in vitro studies demonstrated that the inactivation rate of P. aeruginosa cells by blue light was approximately 35-fold higher than that of keratinocytes (P = 0.0014). Transmission electron microscopy revealed blue light-mediated intracellular damage to P. aeruginosa cells. Fluorescence spectroscopy suggested that coproporphyrin III and/or uroporphyrin III are possibly the intracellular photosensitive chromophores associated with the blue light inactivation of P. aeruginosa. In vivo studies using an in vivo bioluminescence imaging technique and an area-under-the-bioluminescence-time-curve (AUBC) analysis showed that a single exposure of blue light at 55.8 J/cm(2), applied 30 min after bacterial inoculation to the infected mouse burns, reduced the AUBC by approximately 100-fold in comparison with untreated and infected mouse burns (P < 0.0001). Histological analyses and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays indicated no significant damage in the mouse skin exposed to blue light at the effective antimicrobial dose. Survival analyses revealed that blue light increased the survival rate of the infected mice from 18.2% to 100% (P < 0.0001). In conclusion, blue light therapy might offer an effective and safe alternative to conventional antimicrobial therapy for P. aeruginosa burn infections. PMID:23262998

  14. Rescue Equipment

    NASA Technical Reports Server (NTRS)

    1995-01-01

    The Lifeshear cutter, a rescue tool for freeing accident victims from wreckage, was developed under the Clinton Administration's Technology Reinvestment Program. Prior cutting equipment was cumbersome and expensive; the new cutter is 50 percent lighter and 70 percent cheaper. The cutter is pyrotechnically-actuated, using a miniature version of the power cartridges used for separation devices on the Space Shuttle and other NASA spacecraft. Hi-Shear Technology Corporation developed the cutter with the Jet Propulsion Laboratory and input from the City of Torrance (California) Fire Department.

  15. Drosophila atonal fully rescues the phenotype of Math1 null mice: new functions evolve in new cellular contexts

    NASA Technical Reports Server (NTRS)

    Wang, Vincent Y.; Hassan, Bassem A.; Bellen, Hugo J.; Zoghbi, Huda Y.

    2002-01-01

    Many genes share sequence similarity between species, but their properties often change significantly during evolution. For example, the Drosophila genes engrailed and orthodenticle and the onychophoran gene Ultrabithorax only partially substitute for their mouse or Drosophila homologs. We have been analyzing the relationship between atonal (ato) in the fruit fly and its mouse homolog, Math1. In flies, ato acts as a proneural gene that governs the development of chordotonal organs (CHOs), which serve as stretch receptors in the body wall and joints and as auditory organs in the antennae. In the fly CNS, ato is important not for specification but for axonal arborization. Math1, in contrast, is required for the specification of cells in both the CNS and the PNS. Furthermore, Math1 serves a role in the development of secretory lineage cells in the gut, a function that does not parallel any known to be served by ato. We wondered whether ato and Math1 might be more functionally homologous than they appear, so we expressed Math1 in ato mutant flies and ato in Math1 null mice. To our surprise, the two proteins are functionally interchangeable.

  16. Curcumin rescues high fat diet-induced obesity and insulin sensitivity in mice through regulating SREBP pathway.

    PubMed

    Ding, Lili; Li, Jinmei; Song, Baoliang; Xiao, Xu; Zhang, Binfeng; Qi, Meng; Huang, Wendong; Yang, Li; Wang, Zhengtao

    2016-08-01

    Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance. PMID:27208389

  17. Prenatal minocycline treatment alters synaptic protein expression, and rescues reduced mother call rate in oxytocin receptor-knockout mice.

    PubMed

    Miyazaki, Shinji; Hiraoka, Yuichi; Hidema, Shizu; Nishimori, Katsuhiko

    2016-04-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired communication, difficulty in companionship, repetitive behaviors and restricted interests. Recent studies have shown amelioration of ASD symptoms by intranasal administration of oxytocin and demonstrated the association of polymorphisms in the oxytocin receptor (Oxtr) gene with ASD patients. Deficient pruning of synapses by microglial cells in the brain has been proposed as potential mechanism of ASD. Other researchers have shown specific activation of microglial cells in brain regions related to sociality in patients with ASD. Although the roles of Oxtr and microglia in ASD are in the spotlight, the relationship between them remains to be elucidated. In this study, we found abnormal activation of microglial cells and a reduction of postsynaptic density protein PSD95 expression in the Oxtr-deficient brain. Moreover, pharmacological inhibition of microglia during development can alter the expression of PSD95 and ameliorate abnormal mother-infant communication in Oxtr-deficient mice. Our results suggest that microglial abnormality is a potential mechanism of the development of Oxt/Oxtr mediated ASD-like phenotypes. PMID:26926566

  18. Diets Containing α-Linolenic (ω3) or Oleic (ω9) Fatty Acids Rescues Obese Mice From Insulin Resistance.

    PubMed

    Oliveira, V; Marinho, R; Vitorino, D; Santos, G A; Moraes, J C; Dragano, N; Sartori-Cintra, A; Pereira, L; Catharino, R R; da Silva, A S R; Ropelle, E R; Pauli, J R; De Souza, C T; Velloso, L A; Cintra, D E

    2015-11-01

    Subclinical systemic inflammation is a hallmark of obesity and insulin resistance. The results obtained from a number of experimental studies suggest that targeting different components of the inflammatory machinery may result in the improvement of the metabolic phenotype. Unsaturated fatty acids exert antiinflammatory activity through several distinct mechanisms. Here, we tested the capacity of ω3 and ω9 fatty acids, directly from their food matrix, to exert antiinflammatory activity through the G protein-coupled receptor (GPR)120 and GPR40 pathways. GPR120 was activated in liver, skeletal muscle, and adipose tissues, reverting inflammation and insulin resistance in obese mice. Part of this action was also mediated by GPR40 on muscle, as a novel mechanism described. Pair-feeding and immunoneutralization experiments reinforced the pivotal role of GPR120 as a mediator in the response to the nutrients. The improvement in insulin sensitivity in the high-fat substituted diets was associated with a marked reduction in tissue inflammation, decreased macrophage infiltration, and increased IL-10 levels. Furthermore, improved glucose homeostasis was accompanied by the reduced expression of hepatic gluconeogenic enzymes and reduced body mass. Thus, our data indicate that GPR120 and GPR40 play a critical role as mediators of the beneficial effects of dietary unsaturated fatty acids in the context of obesity-induced insulin resistance. PMID:26280128

  19. SLC26A4 Targeted to the Endolymphatic Sac Rescues Hearing and Balance in Slc26a4 Mutant Mice

    PubMed Central

    Li, Xiangming; Sanneman, Joel D.; Harbidge, Donald G.; Zhou, Fei; Ito, Taku; Nelson, Raoul; Picard, Nicolas; Chambrey, Régine; Eladari, Dominique; Miesner, Tracy; Griffith, Andrew J.; Marcus, Daniel C.; Wangemann, Philine

    2013-01-01

    Mutations of SLC26A4 are a common cause of human hearing loss associated with enlargement of the vestibular aqueduct. SLC26A4 encodes pendrin, an anion exchanger expressed in a variety of epithelial cells in the cochlea, the vestibular labyrinth and the endolymphatic sac. Slc26a4 Δ/Δ mice are devoid of pendrin and develop a severe enlargement of the membranous labyrinth, fail to acquire hearing and balance, and thereby provide a model for the human phenotype. Here, we generated a transgenic mouse line that expresses human SLC26A4 controlled by the promoter of ATP6V1B1. Crossing this transgene into the Slc26a4 Δ/Δ line restored protein expression of pendrin in the endolymphatic sac without inducing detectable expression in the cochlea or the vestibular sensory organs. The transgene prevented abnormal enlargement of the membranous labyrinth, restored a normal endocochlear potential, normal pH gradients between endolymph and perilymph in the cochlea, normal otoconia formation in the vestibular labyrinth and normal sensory functions of hearing and balance. Our study demonstrates that restoration of pendrin to the endolymphatic sac is sufficient to restore normal inner ear function. This finding in conjunction with our previous report that pendrin expression is required for embryonic development but not for the maintenance of hearing opens the prospect that a spatially and temporally limited therapy will restore normal hearing in human patients carrying a variety of mutations of SLC26A4. PMID:23874234

  20. Combination Antisense Treatment for Destructive Exon Skipping of Myostatin and Open Reading Frame Rescue of Dystrophin in Neonatal mdx Mice.

    PubMed

    Lu-Nguyen, Ngoc B; Jarmin, Susan A; Saleh, Amer F; Popplewell, Linda; Gait, Michael J; Dickson, George

    2015-08-01

    The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD. PMID:25959011

  1. X11β rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice

    PubMed Central

    Mitchell, Jacqueline C.; Ariff, Belall B.; Yates, Darran M.; Lau, Kwok-Fai; Perkinton, Michael S.; Rogelj, Boris; Stephenson, John D.; Miller, Christopher C.J.; McLoughlin, Declan M.

    2009-01-01

    Increased production and deposition of amyloid β-protein (Aβ) are believed to be key pathogenic events in Alzheimer's disease. As such, routes for lowering cerebral Aβ levels represent potential therapeutic targets for Alzheimer's disease. X11β is a neuronal adaptor protein that binds to the intracellular domain of the amyloid precursor protein (APP). Overexpression of X11β inhibits Aβ production in a number of experimental systems. However, whether these changes to APP processing and Aβ production induced by X11β overexpression also induce beneficial effects to memory and synaptic plasticity are not known. We report here that X11β-mediated reduction in cerebral Aβ is associated with normalization of both cognition and in vivo long-term potentiation in aged APPswe Tg2576 transgenic mice that model the amyloid pathology of Alzheimer's disease. Overexpression of X11β itself has no detectable adverse effects upon mouse behaviour. These findings support the notion that modulation of X11β function represents a therapeutic target for Aβ-mediated neuronal dysfunction in Alzheimer's disease. PMID:19744962

  2. Combination antisense treatment for destructive exon skipping of myostatin and open reading frame rescue of dystrophin in neonatal mdx mice

    PubMed Central

    Lu-Nguyen, Ngoc B.; Jarmin, Susan A.; Saleh, Amer F.; Popplewell, Linda; Gait, Michael J.; Dickson, George

    2015-01-01

    The fatal X-linked Duchenne muscular dystrophy (DMD), characterized by progressive muscle wasting and muscle weakness, is caused by mutations within the DMD gene. The use of antisense oligonucleotides (AOs) modulating pre-mRNA splicing to restore the disrupted dystrophin reading frame, subsequently generating a shortened but functional protein has emerged as a potential strategy in DMD treatment. AO therapy has recently been applied to induce out-of-frame exon skipping of myostatin pre-mRNA, knocking-down expression of myostatin protein, and such an approach is suggested to enhance muscle hypertrophy/hyperplasia and to reduce muscle necrosis. Within this study, we investigated dual exon skipping of dystrophin and myostatin pre-mRNAs using phosphorodiamidate morpholino oligomers conjugated with an arginine-rich peptide (B-PMOs). Intraperitoneal administration of B-PMOs was performed in neonatal mdx males on the day of birth, and at weeks 3 and 6. At week 9, we observed in treated mice (as compared to age-matched, saline-injected controls) normalization of muscle mass, a recovery in dystrophin expression, and a decrease in muscle necrosis, particularly in the diaphragm. Our data provide a proof of concept for antisense therapy combining dystrophin restoration and myostatin inhibition for the treatment of DMD. PMID:25959011

  3. Rescue Manual. Module 8.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The eighth of 10 modules contains 6 chapters: (1) trench rescue; (2) shoring and tunneling techniques; (3) farm accident rescue; (4) wilderness search and rescue; (5) aircraft rescue; and (6) helicopter information. Key points, an…

  4. Rescue Manual. Module 9.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The ninth of 10 modules contains 7 chapters: (1) ice characteristics; (2) river characteristics and tactics for rescue; (3) water rescue techniques; (4) water rescue/recovery operations; (5) dive operations; (6) water rescue equipment; and…

  5. Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development.

    PubMed

    Perucho, Juan; Gómez, Ana; Muñoz, María Paz; de Yébenes, Justo García; Mena, María Ángeles; Casarejos, María José

    2016-07-01

    The pathological hallmark of Huntington disease (HD) is the intracellular aggregation of mutant huntingtin (mHTT) in striatal neurons and glia associated with the selective loss of striatal medium-sized spiny neurons. Up to the present, the role of glia in HD is poorly understood and has been classically considered secondary to neuronal disorder. Trehalose is a disaccharide known to possess many pharmacological properties, acting as an antioxidant, a chemical chaperone, and an inducer of autophagy. In this study, we analyzed at an early postnatal development stage the abnormalities observed in striatal glial cell cultures of postnatal R6/1 mice (HD glia), under baseline and stressing conditions and the protective effects of trehalose. Our data demonstrate that glial HD alterations already occur at early stages of postnatal development. After 20 postnatal days in vitro, striatal HD glia cultures showed more reactive astrocytes with increased expression of glial fibrillary acidic protein (GFAP) but with less replication capacity, less A2B5(+) glial progenitors and more microglia than wild-type (WT) cultures. HD glia had lower levels of intracellular glutathione (GSH) and was more susceptible to H2O2 and epoxomicin insults. The amount of expressed GDNF and secreted mature-BDNF by HD astrocytes were much lower than by WT astrocytes. In addition, HD glial cultures showed a deregulation of the major proteolytic systems, the ubiquitin-proteasomal system (UPS), and the autophagic pathway. This produces a defective protein quality control, indicated by the elevated levels of ubiquitination and p62 protein. Interestingly, we show that trehalose, through its capacity to induce autophagy, inhibited p62/SQSTM1 accumulation and facilitated the degradation of cytoplasmic aggregates from mHTT and α-synuclein proteins. Trehalose also reduced microglia activation and reversed the disrupted cytoskeleton of astrocytes accompanied with an increase in the replication capacity. In

  6. Inhibition of GSK-3β Rescues the Impairments in Bone Formation and Mechanical Properties Associated with Fracture Healing in Osteoblast Selective Connexin 43 Deficient Mice

    PubMed Central

    Loiselle, Alayna E.; Lloyd, Shane A. J.; Paul, Emmanuel M.; Lewis, Gregory S.; Donahue, Henry J.

    2013-01-01

    Connexin 43 (Cx43) is the most abundant gap junction protein in bone and is required for osteoblastic differentiation and bone homeostasis. During fracture healing, Cx43 is abundantly expressed in osteoblasts and osteocytes, while Cx43 deficiency impairs bone formation and healing. In the present study we selectively deleted Cx43 in the osteoblastic lineage from immature osteoblasts through osteocytes and tested the hypothesis that Cx43 deficiency results in delayed osteoblastic differentiation and impaired restoration of biomechanical properties due to attenuated β-catenin expression relative to wild type littermates. Here we show that Cx43 deficiency results in alterations in the mineralization and remodeling phases of healing. In Cx43 deficient fractures the mineralization phase is marked by delayed expression of osteogenic genes. Additionally, the decrease in the RankL/ Opg ratio, osteoclast number and osteoclast size suggest decreased osteoclast bone resorption and remodeling. These changes in healing result in functional deficits as shown by a decrease in ultimate torque at failure. Consistent with these impairments in healing, β-catenin expression is attenuated in Cx43 deficient fractures at 14 and 21 days, while Sclerostin (Sost) expression, a negative regulator of bone formation is increased in Cx43cKO fractures at 21 days, as is GSK-3β, a key component of the β-catenin proteasomal degradation complex. Furthermore, we show that alterations in healing in Cx43 deficient fractures can be rescued by inhibiting GSK-3β activity using Lithium Chloride (LiCl). Treatment of Cx43 deficient mice with LiCl restores both normal bone formation and mechanical properties relative to LiCl treated WT fractures. This study suggests that Cx43 is a potential therapeutic target to enhance fracture healing and identifies a previously unknown role for Cx43 in regulating β-catenin expression and thus bone formation during fracture repair. PMID:24260576

  7. Rescue Manual. Module 6.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The sixth of 10 modules contains 4 chapters: (1) industrial rescue; (2) rescue from a confined space; (3) extrication from heavy equipment; and (4) rescue operations involving elevators. Key points, an introduction, and conclusion accompany…

  8. Rescue Manual. Module 4.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The fourth of 10 modules contains 8 chapters: (1) construction and characteristics of rescue rope; (2) knots, bends, and hitches; (3) critical angles; (4) raising systems; (5) rigging; (6) using the brake-bar rack for rope rescue; (7) rope…

  9. Rescue Skills and Techniques.

    ERIC Educational Resources Information Center

    Defense Civil Preparedness Agency (DOD), Washington, DC.

    The guide has been prepared for use as a textbook in rescue training courses at DCPA (Defense Civil Preparedness Agency) approved training schools and is to be used in rescue training programs of State and local governments. The document explains the various types of rescue missions, command structure, the personnel of the operating unit,…

  10. Enhanced Rescue Lift Capability

    NASA Technical Reports Server (NTRS)

    Young, Larry A.

    2007-01-01

    The evolving and ever-increasing demands of emergency response and disaster relief support provided by rotorcraft dictate, among other things, the development of enhanced rescue lift capability for these platforms. This preliminary analysis is first-order in nature but provides considerable insight into some of the challenges inherent in trying to effect rescue using a unique form of robotic rescue device deployed and operated from rotary-wing aerial platforms.

  11. Forebrain-specific Expression of Monoamine Oxidase A Reduces Neurotransmitter Levels, Restores the Brain Structure, and Rescues Aggressive Behavior in Monoamine Oxidase A-deficient Mice*

    PubMed Central

    Chen, Kevin; Cases, Olivier; Rebrin, Igor; Wu, Weihua; Gallaher, Timothy K.; Seif, Isabelle; Shih, Jean Chen

    2010-01-01

    Previous studies have established that abrogation of monoamine oxidase (MAO) A expression leads to a neurochemical, morphological, and behavioral specific phenotype with increased levels of serotonin (5-HT), norepinephrine, and dopamine, loss of barrel field structure in mouse somatosensory cortex, and an association with increased aggression in adults. Forebrain-specific MAO A transgenic mice were generated from MAO A knock-out (KO) mice by using the promoter of calcium-dependent kinase IIα (CaMKIIα). The presence of human MAO A transgene and its expression were verified by PCR of genomic DNA and reverse transcription-PCR of mRNA and Western blot, respectively. Significant MAO A catalytic activity, autoradiographic labeling of 5-HT, and immunocytochemistry of MAO A were found in the frontal cortex, striatum, and hippocampus but not in the cerebellum of the forebrain transgenic mice. Also, compared with MAO A KO mice, lower levels of 5-HT, norepinephrine, and DA and higher levels of MAO A metabolite 5-hydroxyin-doleacetic acid were found in the forebrain regions but not in the cerebellum of the transgenic mice. These results suggest that MAO A is specifically expressed in the forebrain regions of transgenic mice. This forebrain-specific differential expression resulted in abrogation of the aggressive phenotype. Furthermore, the disorganization of the somatosensory cortex barrel field structure associated with MAO A KO mice was restored and became morphologically similar to wild type. Thus, the lack of MAO A in the forebrain of MAO A KO mice may underlie their phenotypes. PMID:17090537

  12. Partial rescue of a lethal phenotype of fragile bones in transgenic mice with a chimeric antisense gene directed against a mutated collagen gene.

    PubMed Central

    Khillan, J S; Li, S W; Prockop, D J

    1994-01-01

    Previously, transgenic mice were prepared that developed a lethal phenotype of fragile bones because they expressed an internally deleted mini-gene for the pro alpha 1(I) chain of human type I procollagen. The shortened pro alpha 1(I) chains synthesized from the human transgene bound to and produced degradation of normal pro alpha 1(I) chains synthesized from the normal mouse alleles. Here we assembled an antisense gene that was similar to the internally deleted COL1A1 minigene but the 3' half of the gene was inverted so as to code for an antisense RNA. Transgenic mice expressing the antisense gene had a normal phenotype, apparently because the antisense gene contained human sequences instead of mouse sequences. Two lines of mice expressing the antisense gene were bred to two lines of transgenic mice expressing the mini-gene. In mice that inherited both genes, the incidence of the lethal fragile bone phenotype was reduced from 92% to 27%. The effects of the antisense gene were directly demonstrated by an increase in the ratio of normal mouse pro alpha 1(I) chains to human mini-pro alpha 1(I) chains in tissues from mice that inherited both genes and had a normal phenotype. The results raise the possibility that chimeric gene constructs that contain intron sequences and in which only the second half of a gene is inverted may be particularly effective as antisense genes. Images PMID:8022775

  13. Levofloxacin Rescues Mice from Lethal Intra-nasal Infections with Virulent Francisella tularensis and Induces Immunity and Production of Protective Antibody

    PubMed Central

    Klimpel, Gary R.; Eaves-Pyles, Tonyia; Moen, Scott T.; Taormina, Joanna; Peterson, Johnny W.; Chopra, Ashok K.; Niesel, David W.; Carness, Paige; Haithcoat, Judith L.; Kirtley, Michelle; Ben Nasr, Abdelhakim

    2009-01-01

    The ability to protect mice against respiratory infections with virulent Francisella tularensis has been problematic and the role of antibody-versus-cell-mediated immunity controversial. In this study, we tested the hypothesis that protective immunity can develop in mice that were given antibiotic therapy following infection via the respiratory tract with Francisella tularensis SCHU S4. We show that mice infected with a lethal dose of SCHU S4, via an intra-nasal challenge, could be protected with levofloxacin treatment. This protection was evident even when levofloxacin treatment was delayed 72 hours post-infection. At early time points after levofloxacin treatment, significant numbers of bacteria could be recovered from the lungs and spleens of mice, which was followed by a dramatic disappearance of bacteria from these tissues. Mice successfully treated with levofloxacin were later shown to be almost completely resistant to rechallenge with SCHU S4 by the intra-nasal route. Serum antibody appeared to play an important role in this immunity. Normal mice, when given sera from animals protected by levofloxacin treatment, were solidly protected from a lethal intra-nasal challenge with SCHU S4. The protective antiserum contained high titers of SCHU S4 specific IgG2a, indicating that a strong Th1 response was induced following levofloxacin treatment. Thus, this study describes a potentially valuable animal model for furthering our understanding of respiratory tularemia and provides suggestive evidence that antibody can protect against respiratory infections with virulent F. tularensis. PMID:18930100

  14. Levofloxacin rescues mice from lethal intra-nasal infections with virulent Francisella tularensis and induces immunity and production of protective antibody.

    PubMed

    Klimpel, Gary R; Eaves-Pyles, Tonyia; Moen, Scott T; Taormina, Joanna; Peterson, Johnny W; Chopra, Ashok K; Niesel, David W; Carness, Paige; Haithcoat, Judith L; Kirtley, Michelle; Nasr, Abdelhakim Ben

    2008-12-01

    The ability to protect mice against respiratory infections with virulent Francisella tularensis has been problematic and the role of antibody-versus-cell-mediated immunity controversial. In this study, we tested the hypothesis that protective immunity can develop in mice that were given antibiotic therapy following infection via the respiratory tract with F. tularensis SCHU S4. We show that mice infected with a lethal dose of SCHU S4, via an intra-nasal challenge, could be protected with levofloxacin treatment. This protection was evident even when levofloxacin treatment was delayed 72h post-infection. At early time points after levofloxacin treatment, significant numbers of bacteria could be recovered from the lungs and spleens of mice, which was followed by a dramatic disappearance of bacteria from these tissues. Mice successfully treated with levofloxacin were later shown to be almost completely resistant to re-challenge with SCHU S4 by the intra-nasal route. Serum antibody appeared to play an important role in this immunity. Normal mice, when given sera from animals protected by levofloxacin treatment, were solidly protected from a lethal intra-nasal challenge with SCHU S4. The protective antiserum contained high titers of SCHU S4-specific IgG2a, indicating that a strong Th1 response was induced following levofloxacin treatment. Thus, this study describes a potentially valuable animal model for furthering our understanding of respiratory tularemia and provides suggestive evidence that antibody can protect against respiratory infections with virulent F. tularensis. PMID:18930100

  15. EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques.

    PubMed

    Kim, Hye Yun; Kim, Hyunjin Vincent; Jo, Seonmi; Lee, C Justin; Choi, Seon Young; Kim, Dong Jin; Kim, YoungSoo

    2015-01-01

    Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD. PMID:26646366

  16. EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques

    PubMed Central

    Kim, Hye Yun; Kim, Hyunjin Vincent; Jo, Seonmi; Lee, C. Justin; Choi, Seon Young; Kim, Dong Jin; Kim, YoungSoo

    2015-01-01

    Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD. PMID:26646366

  17. A retinoic acid receptor agonist Am80 rescues neurons, attenuates inflammatory reactions, and improves behavioral recovery after intracerebral hemorrhage in mice.

    PubMed

    Matsushita, Hideaki; Hijioka, Masanori; Hisatsune, Akinori; Isohama, Yoichiro; Shudo, Koichi; Katsuki, Hiroshi

    2011-01-01

    Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH. PMID:20551971

  18. A retinoic acid receptor agonist Am80 rescues neurons, attenuates inflammatory reactions, and improves behavioral recovery after intracerebral hemorrhage in mice

    PubMed Central

    Matsushita, Hideaki; Hijioka, Masanori; Hisatsune, Akinori; Isohama, Yoichiro; Shudo, Koichi; Katsuki, Hiroshi

    2011-01-01

    Am80 (tamibarotene) is a retinoic acid receptor (RAR) agonist clinically available for treatment of acute promyelocytic leukemia. As intracerebral hemorrhage (ICH) accompanies inflammatory reactions in the brain and also because retinoids may suppress activation of microglia, we investigated the effect of Am80 on collagenase-induced experimental model of ICH in adult mice. Daily oral administration of Am80 (5 mg/kg) starting from 1 day before or from up to 6 hours after intrastriatal injection of collagenase significantly inhibited the decrease in the number of striatal neurons at 3 days after the insult. Am80 showed no significant effect on the hematoma size and the extent of edema associated with hemorrhage. Prominent expression of RARα was observed in activated microglia/macrophages, and the number of activated microglia/macrophages in the perihematoma region was lower in Am80-treated mice than in vehicle-treated mice. Am80 treatment also reduced areas affected by hemorrhage-associated oxidative stress as indicated by nitrotyrosine immunoreactivity, and attenuated heme oxygenase-1 expression in activated microglia/macrophages. Moreover, Am80-treated mice exhibited better recovery from hemorrhage-induced neurologic deficits than vehicle-treated mice. These results suggest that RAR is a promising target of neuroprotective therapy for ICH. PMID:20551971

  19. Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice.

    PubMed

    Liu, Yan; Sun, Jiandong; Wang, Yubin; Lopez, Dulce; Tran, Jennifer; Bi, Xiaoning; Baudry, Michel

    2016-08-01

    Calpain-1 (CANP1) has been shown to play a critical role in synaptic plasticity and learning and memory, as its deletion in mice results in impairment in theta-burst stimulation- (TBS) induced LTP and various forms of learning and memory. Likewise, PHLPP1 (aka SCOP) has also been found to participate in learning and memory, as PHLPP1 overexpression impairs hippocampus-dependent learning. We previously showed that TBS-induced LTP was associated with calpain-1 mediated truncation of PHLPP1.To better understand the roles of these 2 genes in synaptic plasticity and learning and memory, we generated a double knockout (DKO) mouse by crossing the parent strains. Surprisingly, DKO mice exhibit normal TBS-induced LTP, and the learning impairments in fear conditioning and novel object or novel location recognition were absent in the DKO mice. Moreover, TBS-induced ERK activation in field CA1 of hippocampal slices, which is impaired in both single deletion mice, was restored in the DKO mice. These results further strengthen the roles of both CANP1 and PHLPP1 in synaptic plasticity and learning and memory, and illustrate the complexities of the interactions between multiple pathways participating in synaptic plasticity. PMID:27421891

  20. Rescue Manual. Module 2.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The second of 10 modules contains 5 chapters: (1) patient care and handling techniques; (2) rescue carries and drags; (3) emergency vehicle operations; (4) self-contained breathing apparatus; and (5) protective clothing. Key points, an…

  1. Rescuing neurons in prion disease.

    PubMed

    Verity, Nicholas C; Mallucci, Giovanna R

    2011-01-01

    One of the major current challenges to both medicine and neuroscience is the treatment of neurodegenerative diseases, which pose an ever-increasing medical, social and economic burden in the developed world. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases, and the rarer prion diseases, are separate entities clinically but have common features, including aggregates of misfolded proteins and varying patterns of neurodegeneration. A key barrier to effective treatment is that patients present clinically with advanced, irreversible, neuronal loss. Critically, mechanisms of neurotoxicity are poorly understood. Prevention of neuronal loss, ideally by targeting underlying pathogenic mechanisms, must be the aim of therapy. The present review describes the rationale and experimental approaches that have allowed such prevention, rescuing neurons in mice with prion disease. This rescue cured animals of a rapidly fatal neurodegenerative condition, resulting in symptom-free survival for their natural lifespan. Early pathological changes were reversed; behavioural, cognitive and neurophysiological deficits were recovered; and there was no neuronal loss. This was achieved by targeting the central pathogenic process in prion disease rather than the presumed toxic species, first by proof-of-principle experiments in transgenic mice and then by treatment using RNA interference for gene knockdown. The results have been a new therapeutic target for prion disease, further insight into mechanisms of prion neurotoxicity and the discovery of a window of reversibility in neuronal damage. Furthermore, the work gives rise to new concepts for treatment strategies for other neurodegenerative disorders, and highlights the need for clinical detection of early neuronal dysfunction, so that similar early rescue can also be achieved for these disorders. PMID:21158739

  2. Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice.

    PubMed

    Cheatham, Mary Ann; Edge, Roxanne M; Homma, Kazuaki; Leserman, Emily L; Dallos, Peter; Zheng, Jing

    2015-01-01

    A knockin (KI) mouse expressing mutated prestinV499G/Y501H (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs were normal in stiffness and longer than OHCs lacking prestin, accelerated OHC death was unexpectedly observed relative to that documented in prestin knockout (KO) mice. These observations imply an additional role of prestin in OHC maintenance besides its known requirement for mammalian cochlear amplification. In order to gain mechanistic insights into prestin-associated OHC loss, we implemented several interventions to improve survival. First, 499 prestin KI's were backcrossed to Bak KO mice, which lack the mitochondrial pro-apoptotic gene Bak. Because oxidative stress is implicated in OHC death, another group of 499 prestin KI mice was fed the antioxidant diet, Protandim. 499 KI mice were also backcrossed onto the FVB murine strain, which retains excellent high-frequency hearing well into adulthood, to reduce the compounding effect of age-related hearing loss associated with the original 499 prestin KIs. Finally, a compound heterozygous (chet) mouse expressing one copy of 499 prestin and one copy of KO prestin was also created to reduce quantities of 499 prestin protein. Results show reduction in OHC death in chets, and in 499 prestin KIs on the FVB background, but only a slight improvement in OHC survival for mice receiving Protandim. We also report that improved OHC survival in 499 prestin KIs had little effect on hearing phenotype, reaffirming the original contention about the essential role of prestin's motor function in cochlear amplification. PMID:26682723

  3. Prestin-Dependence of Outer Hair Cell Survival and Partial Rescue of Outer Hair Cell Loss in PrestinV499G/Y501H Knockin Mice

    PubMed Central

    Cheatham, Mary Ann; Edge, Roxanne M.; Homma, Kazuaki; Leserman, Emily L.; Dallos, Peter; Zheng, Jing

    2015-01-01

    A knockin (KI) mouse expressing mutated prestinV499G/Y501H (499 prestin) was created to study cochlear amplification. Recordings from isolated outer hair cells (OHC) in this mutant showed vastly reduced electromotility and, as a consequence, reduced hearing sensitivity. Although 499 prestin OHCs were normal in stiffness and longer than OHCs lacking prestin, accelerated OHC death was unexpectedly observed relative to that documented in prestin knockout (KO) mice. These observations imply an additional role of prestin in OHC maintenance besides its known requirement for mammalian cochlear amplification. In order to gain mechanistic insights into prestin-associated OHC loss, we implemented several interventions to improve survival. First, 499 prestin KI’s were backcrossed to Bak KO mice, which lack the mitochondrial pro-apoptotic gene Bak. Because oxidative stress is implicated in OHC death, another group of 499 prestin KI mice was fed the antioxidant diet, Protandim. 499 KI mice were also backcrossed onto the FVB murine strain, which retains excellent high-frequency hearing well into adulthood, to reduce the compounding effect of age-related hearing loss associated with the original 499 prestin KIs. Finally, a compound heterozygous (chet) mouse expressing one copy of 499 prestin and one copy of KO prestin was also created to reduce quantities of 499 prestin protein. Results show reduction in OHC death in chets, and in 499 prestin KIs on the FVB background, but only a slight improvement in OHC survival for mice receiving Protandim. We also report that improved OHC survival in 499 prestin KIs had little effect on hearing phenotype, reaffirming the original contention about the essential role of prestin’s motor function in cochlear amplification. PMID:26682723

  4. Behavioral deficits induced by third-trimester equivalent alcohol exposure in male C57BL/6J mice are not associated with reduced adult hippocampal neurogenesis but are still rescued with voluntary exercise.

    PubMed

    Hamilton, G F; Bucko, P J; Miller, D S; DeAngelis, R S; Krebs, C P; Rhodes, J S

    2016-11-01

    Prenatal alcohol exposure can produce permanent alterations in brain structure and profound behavioral deficits. Mouse models can help discover mechanisms and identify potentially useful interventions. This study examined long-term influences of either a single or repeated alcohol exposure during the third-trimester equivalent on survival of new neurons in the hippocampus, behavioral performance on the Passive avoidance and Rotarod tasks, and the potential role of exercise as a therapeutic intervention. C57BL/6J male mice received either saline or 5g/kg ethanol split into two s.c. injections, two hours apart, on postnatal day (PD)7 (Experiment 1) or on PD5, 7 and 9 (Experiment 2). All mice were weaned on PD21 and received either a running wheel or remained sedentary from PD35-PD80/81. From PD36-45, mice received i.p. injections of 50mg/kg bromodeoxyuridine (BrdU) to label dividing cells. Behavioral testing occurred between PD72-79. Number of surviving BrdU+ cells and immature neurons (doublecortin; DCX+) was measured at PD80-81. Alcohol did not affect number of BrdU+ or DCX+ cells in either experiment. Running significantly increased number of BrdU+ and DCX+ cells in both treatment groups. Alcohol-induced deficits on Rotarod performance and acquisition of the Passive avoidance task (Day 1) were evident only in Experiment 2 and running rescued these deficits. These data suggest neonatal alcohol exposure does not result in long-term impairments in adult hippocampal neurogenesis in the mouse model. Three doses of ethanol were necessary to induce behavioral deficits. Finally, the mechanisms by which exercise ameliorated the neonatal alcohol induced behavioral deficits remain unknown. PMID:27491590

  5. Transgenic overexpression of laminin alpha1 chain in laminin alpha2 chain-deficient mice rescues the disease throughout the lifespan.

    PubMed

    Gawlik, Kinga I; Durbeej, Madeleine

    2010-07-01

    Several approaches to treat laminin alpha2 chain-deficient congenital muscular dystrophy (MDC1A) in mouse models have been undertaken. Most have shown promising results in young animals. However, older animals have only been characterized to some extent. Herein we analyze the lifespan of laminin alpha2 chain-deficient mice with transgenic overexpression of laminin alpha1 chain. Further outcome measures included internalized myonuclei, heart fibrosis, grip strength, and serum creatine kinase activity. We show that laminin alpha2-chain-deficient animals that overexpress laminin alpha1 chain survive to up to 1.5-2 years of age. Furthermore, they displayed improved skeletal and heart muscle morphology, near-normal muscle strength, and normalized creatine kinase levels. Such an improvement of the dystrophic phenotype that persists to old age has not been previously demonstrated in mice. Our findings hold promise with regard to the efficient treatment of MDC1A patients in the future. PMID:20544910

  6. Rescue of Obesity-Induced Infertility in Female Mice due to a Pituitary-Specific Knockout of the Insulin Receptor (IR)

    PubMed Central

    Brothers, Kathryn J.; Wu, Sheng; DiVall, Sara A.; Messmer, Marcus R.; Kahn, C. Ronald; Miller, Ryan S.; Radovick, Sally; Wondisford, Fredric E.; Wolfe, Andrew

    2010-01-01

    Summary Obesity is associated with insulin resistance in metabolic tissues such as adipose, liver, and muscle, but it is unclear whether non-classical target tissues, such as those of the reproductive axis, are also insulin resistant. To determine if the reproductive axis maintains insulin sensitivity in obesity in vivo, murine models of diet-induced obesity with and without intact insulin signaling in pituitary gonadotrophs were created. Diet-induced obese wild type female mice (WT DIO) were infertile and experienced a robust increase in luteinizing hormone (LH) after gonadotropin releasing hormone (GnRH) or insulin stimulation. By contrast, both lean and obese mice with a pituitary-specific knockout of the insulin receptor (PitIRKO) exhibited reproductive competency, indicating that insulin signaling in the pituitary is required for the reproductive impairment seen in diet-induced obesity and that the gonadotroph maintains insulin sensitivity in a setting of peripheral insulin resistance. PMID:20816095

  7. Lipoprotein-based nanoparticles rescue the memory loss of mice with Alzheimer's disease by accelerating the clearance of amyloid-beta.

    PubMed

    Song, Qingxiang; Huang, Meng; Yao, Lei; Wang, Xiaolin; Gu, Xiao; Chen, Juan; Chen, Jun; Huang, Jialin; Hu, Quanyin; Kang, Ting; Rong, Zhengxing; Qi, Hong; Zheng, Gang; Chen, Hongzhuan; Gao, Xiaoling

    2014-03-25

    Amyloid-beta (Aβ) accumulation in the brain is believed to play a central role in Alzheimer's disease (AD) pathogenesis, and the common late-onset form of AD is characterized by an overall impairment in Aβ clearance. Therefore, development of nanomedicine that can facilitate Aβ clearance represents a promising strategy for AD intervention. However, previous work of this kind was concentrated at the molecular level, and the disease-modifying effectiveness of such nanomedicine has not been investigated in clinically relevant biological systems. Here, we hypothesized that a biologically inspired nanostructure, apolipoprotein E3-reconstituted high density lipoprotein (ApoE3-rHDL), which presents high binding affinity to Aβ, might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance. Surface plasmon resonance, transmission electron microscopy, and co-immunoprecipitation analysis showed that ApoE3-rHDL demonstrated high binding affinity to both Aβ monomer and oligomer. It also accelerated the microglial, astroglial, and liver cell degradation of Aβ by facilitating the lysosomal transport. One hour after intravenous administration, about 0.4% ID/g of ApoE3-rHDL gained access to the brain. Four-week daily treatment with ApoE3-rHDL decreased Aβ deposition, attenuated microgliosis, ameliorated neurologic changes, and rescued memory deficits in an AD animal model. The findings here provided the direct evidence of a biomimetic nanostructure crossing the blood-brain barrier, capturing Aβ and facilitating its degradation by glial cells, indicating that ApoE3-rHDL might serve as a novel nanomedicine for disease modification in AD by accelerating Aβ clearance, which also justified the concept that nanostructures with Aβ-binding affinity might provide a novel nanoplatform for AD therapy. PMID:24527692

  8. Countries renew rescue agreement

    NASA Astrophysics Data System (ADS)

    Bush, Susan M.

    To insure long-term continuity for the international satellite search and rescue system, COSPAS/SARSAT, an intergovernmental agreement binding the four sponsoring nations to cooperate was signed July 1 in Paris. According to Russell Vollmers of the National Oceanic and Atmospheric Administration, the agreement is binding for 15 years, with an automatic extension.The system marked the fifth anniversary of its first rescue last year, when on September 10, 1982, three persons were rescued. Begun in the 1970s by NASA as an experiment, COSPAS/SARSAT (a Russian-English acronym) is now a cooperative project among the United States, Canada, France, and the Soviet Union. Its goal is to reduce the time required to rescue air and maritime distress victims and also to locate victims who otherwise may not be found, thus using the satellite system as a life-saving device.

  9. Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-α2 chain-null congenital muscular dystrophy mice.

    PubMed

    Aoki, Yoshitsugu; Nagata, Tetsuya; Yokota, Toshifumi; Nakamura, Akinori; Wood, Matthew J A; Partridge, Terence; Takeda, Shin'ichi

    2013-12-15

    Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is among the more promising approaches to the treatment of several neuromuscular disorders including Duchenne muscular dystrophy. The main weakness of this approach arises from the low efficiency and sporadic nature of the delivery of charge-neutral PMO into muscle fibers, the mechanism of which is unknown. In this study, to test our hypothesis that muscle fibers take up PMO more efficiently during myotube formation, we induced synchronous muscle regeneration by injection of cardiotoxin into the tibialis anterior muscle of Dmd exon 52-deficient mdx52 and wild-type mice. Interestingly, by in situ hybridization, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibers. In addition, we showed that PMO or 2'-O-methyl phosphorothioate is taken up efficiently into C2C12 myotubes when transfected 24-72 h after the induction of differentiation but is poorly taken up into undifferentiated C2C12 myoblasts suggesting efficient uptake of PMO in the early stages of C2C12 myotube formation. Next, we tested the therapeutic potential of PMO for laminin-α2 chain-null dy(3K)/dy(3K) mice: a model of merosin-deficient congenital muscular dystrophy (MDC1A) with active muscle regeneration. We confirmed the recovery of laminin-α2 chain and slightly prolonged life span following skipping of the mutated exon 4 in dy(3K)/dy(3K) mice. These findings support the idea that PMO entry into fibers is dependent on a developmental stage in myogenesis rather than on dystrophinless muscle membranes and provide a platform for developing PMO-mediated therapies for a variety of muscular disorders, such as MDC1A, that involve active muscle regeneration. PMID:23882132

  10. Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice.

    PubMed

    Zhang, Tan; Pereyra, Andrea S; Wang, Zhong-Min; Birbrair, Alexander; Reisz, Julie A; Files, Daniel Clark; Purcell, Lina; Feng, Xin; Messi, Maria L; Feng, Hanzhong; Chalovich, Joseph; Jin, Jian-Ping; Furdui, Cristina; Delbono, Osvaldo

    2016-06-01

    Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca(2+) channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice. PMID:26892246

  11. Airborne rescue system

    NASA Technical Reports Server (NTRS)

    Haslim, Leonard A. (Inventor)

    1991-01-01

    The airborne rescue system includes a boom with telescoping members for extending a line and collar to a rescue victim. The boom extends beyond the tip of the helicopter rotor so that the victim may avoid the rotor downwash. The rescue line is played out and reeled in by winch. The line is temporarily retained under the boom. When the boom is extended, the rescue line passes through clips. When the victim dons the collar and the tension in the line reaches a predetermined level, the clips open and release the line from the boom. Then the rescue line can form a straight line between the victim and the winch, and the victim can be lifted to the helicopter. A translator is utilized to push out or pull in the telescoping members. The translator comprises a tape and a rope. Inside the telescoping members the tape is curled around the rope and the tape has a tube-like configuration. The tape and rope are provided from supply spools.

  12. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice.

    PubMed

    Lecca, Salvatore; Pelosi, Assunta; Tchenio, Anna; Moutkine, Imane; Lujan, Rafael; Hervé, Denis; Mameli, Manuel

    2016-03-01

    The lateral habenula (LHb) encodes aversive signals, and its aberrant activity contributes to depression-like symptoms. However, a limited understanding of the cellular mechanisms underlying LHb hyperactivity has precluded the development of pharmacological strategies to ameliorate depression-like phenotypes. Here we report that an aversive experience in mice, such as foot-shock exposure (FsE), induces LHb neuronal hyperactivity and depression-like symptoms. This occurs along with increased protein phosphatase 2A (PP2A) activity, a known regulator of GABAB receptor (GABABR) and G protein-gated inwardly rectifying potassium (GIRK) channel surface expression. Accordingly, FsE triggers GABAB1 and GIRK2 internalization, leading to rapid and persistent weakening of GABAB-activated GIRK-mediated (GABAB-GIRK) currents. Pharmacological inhibition of PP2A restores both GABAB-GIRK function and neuronal excitability. As a consequence, PP2A inhibition ameliorates depression-like symptoms after FsE and in a learned-helplessness model of depression. Thus, GABAB-GIRK plasticity in the LHb represents a cellular substrate for aversive experience. Furthermore, its reversal by PP2A inhibition may provide a novel therapeutic approach to alleviate symptoms of depression in disorders that are characterized by LHb hyperactivity. PMID:26808347

  13. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice

    PubMed Central

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  14. A surge of late-occurring meiotic double-strand breaks rescues synapsis abnormalities in spermatocytes of mice with hypomorphic expression of SPO11.

    PubMed

    Faieta, Monica; Di Cecca, Stefano; de Rooij, Dirk G; Luchetti, Andrea; Murdocca, Michela; Di Giacomo, Monica; Di Siena, Sara; Pellegrini, Manuela; Rossi, Pellegrino; Barchi, Marco

    2016-06-01

    Meiosis is the biological process that, after a cycle of DNA replication, halves the cellular chromosome complement, leading to the formation of haploid gametes. Haploidization is achieved via two successive rounds of chromosome segregation, meiosis I and II. In mammals, during prophase of meiosis I, homologous chromosomes align and synapse through a recombination-mediated mechanism initiated by the introduction of DNA double-strand breaks (DSBs) by the SPO11 protein. In male mice, if SPO11 expression and DSB number are reduced below heterozygosity levels, chromosome synapsis is delayed, chromosome tangles form at pachynema, and defective cells are eliminated by apoptosis at epithelial stage IV at a spermatogenesis-specific endpoint. Whether DSB levels produced in Spo11 (+/-) spermatocytes represent, or approximate, the threshold level required to guarantee successful homologous chromosome pairing is unknown. Using a mouse model that expresses Spo11 from a bacterial artificial chromosome, within a Spo11 (-/-) background, we demonstrate that when SPO11 expression is reduced and DSBs at zygonema are decreased (approximately 40 % below wild-type level), meiotic chromosome pairing is normal. Conversely, DMC1 foci number is increased at pachynema, suggesting that under these experimental conditions, DSBs are likely made with delayed kinetics at zygonema. In addition, we provide evidences that when zygotene-like cells receive enough DSBs before chromosome tangles develop, chromosome synapsis can be completed in most cells, preventing their apoptotic elimination. PMID:26440409

  15. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice.

    PubMed

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi; Jung, Ji-Yeon; Kim, Won-Jae

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  16. SAFER Rescue System Tested

    NASA Technical Reports Server (NTRS)

    1994-01-01

    Astronauts Carl J. Meade and Mark C. Lee (red strip on suit) test the new Simplified Aid for EVA Rescue (SAFER) system some 130 nautical miles above Earth. The pair was actually performing an in-space rehearsal or demonstration of a contingency rescue using never-before flown hardware. Meade, who here wears the small back-pack unit with its complementary chest-mounted control unit, and Lee anchored to the Space Shuttle Discovery's Remote Manipulator System (RMS) robot arm, took turns using the SAFER hardware during their shared space walk.

  17. Escape and rescue model

    NASA Astrophysics Data System (ADS)

    Alvord, D.; Nelson, H. E.

    The Escape and Rescue model is a discrete-event simulation program written in Simscript. It was developed to simulate the emergency movement involved in escape and/or rescue of people from a Board and Care Home housing a group of persons with varying degrees of physical or mental disabilities along with a small live-in staff. It may, however, be used in a much more general setting. It can reasonably handle a building with up to 100 residents and 100 rooms.

  18. Close Call: Unwanted Rescue.

    ERIC Educational Resources Information Center

    Journal of Adventure Education and Outdoor Leadership, 1991

    1991-01-01

    Describes incident where group engaged in training exercise was almost "rescued" by Coast Guard, although Coast Guard had been alerted that training exercise would be taking place. On another occasion Coast Guard did not react to actual report, thinking it was training group. Group was studying grey seal breeding colonies in Pembrokeshire. (KS)

  19. Operation Rescue. Final Report.

    ERIC Educational Resources Information Center

    McKee, Neena; Crawford, Georgette

    The Operation Rescue project was designed to develop a classroom setting for the delivery of comprehensive educational services to "at risk" young adolescents. The classroom was established as part of the pre-existing Jonesboro Alternative School, and it utilized the basic academic and social program developed by this entity over 12 years of work…

  20. Rescue Manual. Module 5.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The fifth of 10 modules contains information on hazardous materials. Key points, an introduction, and conclusion accompany substantive material in this module. In addition, the module contains a Department of Transportation guide chart on…

  1. Collectivizing rescue obligations in bioethics.

    PubMed

    Garrett, Jeremy R

    2015-01-01

    Bioethicists invoke a duty to rescue in a wide range of cases. Indeed, arguably, there exists an entire medical paradigm whereby vast numbers of medical encounters are treated as rescue cases. The intuitive power of the rescue paradigm is considerable, but much of this power stems from the problematic way that rescue cases are conceptualized-namely, as random, unanticipated, unavoidable, interpersonal events for which context is irrelevant and beneficence is the paramount value. In this article, I critique the basic assumptions of the rescue paradigm, reframe the ethical landscape in which rescue obligations are understood, and defend the necessity and value of a wider social and institutional view. Along the way, I move back and forth between ethical theory and a concrete case where the duty to rescue has been problematically applied: the purported duty to regularly return incidental findings and individual research results in genomic and genetic research. PMID:25674948

  2. Inflatable rescue device

    NASA Technical Reports Server (NTRS)

    Swan, Scott A. (Inventor)

    1995-01-01

    This invention discloses, in one aspect, a personal rescue device for use in outer space which has an inflatable flexible tube with a shaper apparatus herein. Gas under pressure flows through the shaper apparatus and into the flexible tube. The flexible tube is mounted to the shaper so that as it inflates it expands and deploys lengthwise away from the shaper. In one embodiment a housing contains the shaper and the flexible tube and the housing is designed to facilitate movement of the expanding tube from the housing so the expanding tube does not bunch up in the housing.

  3. Hybridization facilitates evolutionary rescue

    PubMed Central

    Stelkens, Rike B; Brockhurst, Michael A; Hurst, Gregory D D; Greig, Duncan

    2014-01-01

    The resilience of populations to rapid environmental degradation is a major concern for biodiversity conservation. When environments deteriorate to lethal levels, species must evolve to adapt to the new conditions to avoid extinction. Here, we test the hypothesis that evolutionary rescue may be enabled by hybridization, because hybridization increases genetic variability. Using experimental evolution, we show that interspecific hybrid populations of Saccharomyces yeast adapt to grow in more highly degraded environments than intraspecific and parental crosses, resulting in survival rates far exceeding those of their ancestors. We conclude that hybridization can increase evolutionary responsiveness and that taxa able to exchange genes with distant relatives may better survive rapid environmental change. PMID:25558281

  4. [Importance of helicopter rescue].

    PubMed

    Hofer, G; Voelckel, W G

    2014-03-01

    Helicopter emergency medical service (HEMS) have become a main part of prehospital emergency medical services over the last 40 years. Recently, an ongoing discussion about financial shortage and personal shortcomings question the role of cost-intensive air rescue. Thus, the value of HEMS must be examined and discussed appropriately. Since the number of physician-staffed ground ambulances may decrease due to the limited availability of qualified physicians, HEMS may fill the gap. In addition patient transfer to specialized hospitals will require an increasing number of air transports in order to minimize prehospital time. The higher risk ratio for HEMS missions when compared with ground rescue requires a rigorous quality management system. When it comes to missions in remote and exposed areas, the scope of medical treatment must be adjusted to the individual situation. Medical competence is key in order to balance guideline compliant or maximal care versus optimal care characterized as a mission-specific, individualized emergency care concept. Although, medical decision making and treatment is typically based on the best scientific evidence, personal skills, competence, and the mission scenario will determine the scope of interventions suitable to improve outcome. Thus, the profile of requirements for the HEMS medical crew is high. PMID:24618925

  5. Psychological Factors in Wilderness Rescue.

    ERIC Educational Resources Information Center

    Ogilvie, Bruce C.

    This presentation provides wilderness rescue workers with an overview of the psychological reactions of victims of accidents and natural disasters and suggested responses for rescuers and caregivers. A personal account of rescue and death in a drowning accident illustrates how the rescuer can also be traumatized by such an incident and may suffer…

  6. Locate and rescue system components

    NASA Technical Reports Server (NTRS)

    1976-01-01

    Two types of search and rescue systems not involving satellites are studied; one using a network radio communications link and the other a characteristic beacon signal. Line of slight limitation of VHF radio and beacon signals limit the range (approximately 25 miles) between the origin of the distress signal and the mobile rescue unit.

  7. How competition affects evolutionary rescue

    PubMed Central

    Osmond, Matthew Miles; de Mazancourt, Claire

    2013-01-01

    Populations facing novel environments can persist by adapting. In nature, the ability to adapt and persist will depend on interactions between coexisting individuals. Here we use an adaptive dynamic model to assess how the potential for evolutionary rescue is affected by intra- and interspecific competition. Intraspecific competition (negative density-dependence) lowers abundance, which decreases the supply rate of beneficial mutations, hindering evolutionary rescue. On the other hand, interspecific competition can aid evolutionary rescue when it speeds adaptation by increasing the strength of selection. Our results clarify this point and give an additional requirement: competition must increase selection pressure enough to overcome the negative effect of reduced abundance. We therefore expect evolutionary rescue to be most likely in communities which facilitate rapid niche displacement. Our model, which aligns to previous quantitative and population genetic models in the absence of competition, provides a first analysis of when competitors should help or hinder evolutionary rescue. PMID:23209167

  8. Electronic search and rescue aids

    NASA Technical Reports Server (NTRS)

    Trudell, B. J.

    1980-01-01

    There are two elements to the basic electronic search and rescue problem: a means for immediately alerting potential rescuers and an effective method to guide the rescue forces to the scene of the emergency. An Emergency Locator Transmitter (ELT) used by aircraft or an Emergency Position Indicating Radio Beacon (EPIRB) used by maritime vessels has the capability of providing for both an immediate alert and a homing signal to assist rescue forces in locating the site of the distress. This paper describes the development of ELT/EPIRB systems. Emphasis is placed on the SARSAT project, the COSPAS/SARSAT project, and an experimental 406 MHz ELT/EPIRB system.

  9. Community rescue in experimental metacommunities.

    PubMed

    Low-Décarie, Etienne; Kolber, Marcus; Homme, Paige; Lofano, Andrea; Dumbrell, Alex; Gonzalez, Andrew; Bell, Graham

    2015-11-17

    The conditions that allow biodiversity to recover following severe environmental degradation are poorly understood. We studied community rescue, the recovery of a viable community through the evolutionary rescue of many populations within an evolving community, in metacommunities of soil microbes adapting to a herbicide. The metacommunities occupied a landscape of crossed spatial gradients of the herbicide (Dalapon) and a resource (glucose), whereas their constituent communities were either isolated or connected by dispersal. The spread of adapted communities across the landscape and the persistence of communities when that landscape was degraded were strongly promoted by dispersal, and the capacity to adapt to lethal stress was also related to community size and initial diversity. After abrupt and lethal stress, community rescue was most frequent in communities that had previously experienced sublethal levels of stress and had been connected by dispersal. Community rescue occurred through the evolutionary rescue of both initially common taxa, which remained common, and of initially rare taxa, which grew to dominate the evolved community. Community rescue may allow productivity and biodiversity to recover from severe environmental degradation. PMID:26578777

  10. Community rescue in experimental metacommunities

    PubMed Central

    Low-Décarie, Etienne; Kolber, Marcus; Homme, Paige; Lofano, Andrea; Dumbrell, Alex; Gonzalez, Andrew; Bell, Graham

    2015-01-01

    The conditions that allow biodiversity to recover following severe environmental degradation are poorly understood. We studied community rescue, the recovery of a viable community through the evolutionary rescue of many populations within an evolving community, in metacommunities of soil microbes adapting to a herbicide. The metacommunities occupied a landscape of crossed spatial gradients of the herbicide (Dalapon) and a resource (glucose), whereas their constituent communities were either isolated or connected by dispersal. The spread of adapted communities across the landscape and the persistence of communities when that landscape was degraded were strongly promoted by dispersal, and the capacity to adapt to lethal stress was also related to community size and initial diversity. After abrupt and lethal stress, community rescue was most frequent in communities that had previously experienced sublethal levels of stress and had been connected by dispersal. Community rescue occurred through the evolutionary rescue of both initially common taxa, which remained common, and of initially rare taxa, which grew to dominate the evolved community. Community rescue may allow productivity and biodiversity to recover from severe environmental degradation. PMID:26578777

  11. 46 CFR 180.210 - Rescue boats.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Rescue boats. 180.210 Section 180.210 Shipping COAST...) LIFESAVING EQUIPMENT AND ARRANGEMENTS Number and Type of Survival Craft § 180.210 Rescue boats. (a) A vessel... that the vessel itself cannot serve as an adequate rescue craft. (c) In general, a rescue boat must...

  12. 46 CFR 180.210 - Rescue boats.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Rescue boats. 180.210 Section 180.210 Shipping COAST...) LIFESAVING EQUIPMENT AND ARRANGEMENTS Number and Type of Survival Craft § 180.210 Rescue boats. (a) A vessel... that the vessel itself cannot serve as an adequate rescue craft. (c) In general, a rescue boat must...

  13. 46 CFR 180.210 - Rescue boats.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Rescue boats. 180.210 Section 180.210 Shipping COAST...) LIFESAVING EQUIPMENT AND ARRANGEMENTS Number and Type of Survival Craft § 180.210 Rescue boats. (a) A vessel... that the vessel itself cannot serve as an adequate rescue craft. (c) In general, a rescue boat must...

  14. Joseph Conrad's tormented Rescue (fantasy).

    PubMed

    Freedman, William

    2014-02-01

    Joseph Conrad was a notoriously tormented writer for whom the creative act was often a punishment severe enough to drive him into paralyzing depressions that delayed the completion of his novels, sometimes for years. By far the most agonizing of these projects was The Rescue, a novel he began in 1898, abandoned a year later, tried unsuccessfully to continue several times over the next two decades, but was only able to resume in 1918 and to complete, after another tortured two-year struggle, in 1920. An explanation for this incapacity, that is powerfully suggested by the novel's evocative title and perhaps unintentionally ironic subtitle (A Romance of the Shallows) has not yet been explored. Using Freud's 1910 essay on the rescue fantasy, "Contributions to the Psychology of Love: A Special Type of Choice of Object Made by Men," and Emanuel Berman's instructive revision and expansion of the concept in his 2003 American Imago essay, "Ferenczi, Rescue, and Utopia," I argue that a substantial explanation for Conrad's tormented history with The Rescue is ascribable to its quite remarkably faithful treatment of a rescue fantasy with deep and disabling resonance for its author. More specifically, the difficulty was compounded by the novel's dramatization of the soul-crushing conflict between two such fantasies: one in the service of the masculine ideal of unflinching dedication to a heroic purpose, the other promising satisfaction to the equally potent demands of emotional and sexual desire. Features of Conrad's narrative fit so tightly and consistently with the theory as Freud (and Abraham) proposed and as Berman elaborated it that The Rescue offers itself as one of those rare and reinforcing instances wherein the literary text seems to validate the psychoanalytic theory at least as persuasively as the theory "understands" the text. PMID:24555549

  15. Rotorcraft and Enabling Robotic Rescue

    NASA Technical Reports Server (NTRS)

    Young, Larry A.

    2010-01-01

    This paper examines some of the issues underlying potential robotic rescue devices (RRD) in the context where autonomous or manned rotorcraft deployment of such robotic systems is a crucial attribute for their success in supporting future disaster relief and emergency response (DRER) missions. As a part of this discussion, work related to proof-of-concept prototyping of two notional RRD systems is summarized.

  16. Rescues conducted by surfers on Australian beaches.

    PubMed

    Attard, Anna; Brander, Robert W; Shaw, Wendy S

    2015-09-01

    This study describes the demographics, occurrence, location, primary hazards and outcomes involved in rescues performed by surfers on Australian beaches. Conservative estimates suggest that the number of rescues conducted by Australian surfers each year is on par with the number conducted by volunteer surf lifesavers. Surfers perform a considerable number of serious rescues in both lifesaver/lifeguard patrolled (45%) and unpatrolled (53%) beach locations. Rip currents represent the major physical hazard leading to rescue (75%) and the dominant emotional response of people rescued is one of panic (85%). Most surfer rescue events occur during conditions of moderate waves and sunny, fine weather with the highest proportion of rescues occurring on quiet beaches with few people around (26%). Swimming is the activity associated with most rescue events (63%), followed by board riding (25%). Males aged 18-29 represent the largest demographic of people rescued. Surfers with prior water-safety training are more likely to perform a higher number of rescues, however ability to perform rescues is not associated with formal training, but rather number of years' experience surfing. Seventy-eight percent of surfers were happy to help, while 28% expressed feelings of annoyance or inconvenience, generally towards unwary swimmers. Results of this research suggest that 63% of surfers feel they have saved a life. This value may be enhanced through improved training of surfers in basic water safety rescue techniques. PMID:26056968

  17. Rescue fantasies and the secret benefactor.

    PubMed

    Gillman, R D

    1992-01-01

    The concept of rescue fantasies is traced from Freud's earliest idea of the rescue of the mother as the fallen woman to later ideas of ambivalent rescue of the father, siblings, and children. Clinical vignettes from work with children and adults illustrate these points as well as reparative rescue fantasies in response to trauma and narcissistic hurt. The contemporary family romance myth of the secret benefactor as rescuer is described. An analytic case presentation explores the narcissistic-masochistic and the positive and negative oedipal meanings of the secret benefactor rescue fantasy. Application to countertransference enactments in the analyst is suggested. PMID:1289936

  18. Toward a behavioral ecology of rescue behavior.

    PubMed

    Hollis, Karen L; Nowbahari, Elise

    2013-01-01

    Although the study of helping behavior has revolutionized the field of behavioral ecology, scientific examination of rescue behavior remains extremely rare, except perhaps in ants, having been described as early as 1874. Nonetheless, recent work in our laboratories has revealed several new patterns of rescue behavior that appear to be much more complex than previously studied forms. This precisely-directed rescue behavior bears a remarkable resemblance to what has been labeled empathy in rats, and thus raises numerous philosophical and theoretical questions: How should rescue behavior (or empathy) be defined? What distinguishes rescue from other forms of altruism? In what ways is rescue behavior in ants different from, and similar to, rescue in other non-human animals? What selection pressures dictate its appearance? In this paper, we review our own experimental studies of rescue in both laboratory and field, which, taken together, begin to reveal some of the behavioral ecological conditions that likely have given rise to rescue behavior in ants. Against this background, we also address important theoretical questions involving rescue, including those outlined above. In this way, we hope not only to encourage further experimental analysis of rescue behavior, but also to highlight important similarities and differences in very distant taxa. PMID:23864298

  19. Hermes rescue strategies during launch

    NASA Astrophysics Data System (ADS)

    Cledassou, Rodelphe

    Safety and rescue strategies during the launch of Hermes space plane by Ariane 5 are discussed. Before solid booster separation, the pilots must be ejected by seats which are later recovered. After solid booster separation it becomes possible to extract the plane, which can perform a reentry leading to an available landing site or to sea recovery. When there is no useful landing site, the plane can be injected on a downgraded orbit.

  20. Lunar mission safety and rescue: Escape/rescue analysis and plan

    NASA Technical Reports Server (NTRS)

    1971-01-01

    The results are presented of the technical analysis of escape/rescue/survival situations, crew survival techniques, alternate escape/rescue approaches and vehicles, and the advantages and disadvantages of each for advanced lunar exploration. Candidate escape/rescue guidelines are proposed and elements of a rescue plan developed. The areas of discussions include the following: lunar arrival/departure operations, lunar orbiter operations, lunar surface operations, lunar surface base escape/rescue analysis, lander tug location operations, portable airlock, emergency pressure suit, and the effects of no orbiting lunar station, no lunar surface base, and no foreign lunar orbit/surface operations on the escape/rescue plan.

  1. The Data Rescue @ Home Project

    NASA Astrophysics Data System (ADS)

    Stickler, A.; Allan, R.; Valente, M. A.; Tinz, B.; Brönnimann, S.

    2012-04-01

    Climate science as a whole as well as reanalyses as a special case can significantly profit from the recovery, imaging and digitisation of historical observations. The importance of this fact is reflected in large, global data rescue projects and initiatives such as the Atmospheric Circulation Reconstructions over the Earth (ACRE, www.met-acre.org) or the EU FP7 ERA-CLIM project (www.era-clim.eu). From the time before 1957, there are still large amounts of surface data e.g. from former colonies and from overseas territories of European countries )e.g. Portugal, France and Germany) that need to be rescued. Also in case of the very early upper-air observations before the 1930s, even Europe and North America still hold an important quantity of data to be recovered in digital form. Here, we present the web platform "Data Rescue @ Home" (www.data-rescue-at-home.org), which has been developed at ETH Zurich and Oeschger Centre for Climate Change Research, and which has been designed to take advantage of the voluntary assistance of the thousands of people on the web who are interested in climate or old weather data. On the website, these volunteers can enter meteorological data shown on digital images into entry masks that resemble the original. By registering, the users get access to their personal digitisation statistics and help optimising the project. At the moment, 4 digitisation projects are online: One project is dealing with German upper-air data from the Second World War period. In a second project, station data from Tulagi (Solomon Islands) is being digitised. Finally, two collaborative projects have been included: One in cooperation with the Instituto Dom Luiz (Univ. Lisbon, Portugal), where Portuguese station data from Angra (Azores) is digitised, and a further one in cooperation with the German Meteorological Service (DWD), in which precipitation data from former German colonies is being digitised. On our poster, we will report on the status of the projects

  2. Lightweight Boom For Rescue Helicopter

    NASA Technical Reports Server (NTRS)

    Haslim, Leonard A.

    1993-01-01

    Telescoping boom and associated mechanisms attached to helicopter aid rescue operations by extending lifeline beyond sweep of main rotor. Pilot observes rescuee and control position of helicopter more effectively than if rescuee directly below and hidden from pilot's view. Rescuee outside downdraft of rotor, which is often powerful enough to blow away or submerge someone in water. Used for marine or land operations. Boom thin and lightweight because it need not support weight of rescuee. Lifeline pulls away from boom after secured around rescuee, who is lifted directly into cabin by winch. Potential application for in situ erection of telescopic space structures.

  3. Drug storage temperatures in rescue vehicles.

    PubMed

    DuBois, W C

    2000-04-01

    This study was conducted to determine storage temperatures of drugs carried on rescue vehicles. Recording thermometers were placed inside drug boxes carried on rescue vehicles. Those temperatures were compared with ambient air temperatures, temperatures inside mechanically cooled compartments of the rescue vehicles, and USP-recommended drug storage temperatures. The results indicate that drug storage temperatures in some prehospital rescue vehicles exceed USP guidelines. Mechanical cooling of the storage compartment results in drug storage temperatures within the USP guidelines. Mechanical cooling of drug storage compartments on vehicles is technologically and financially possible. PMID:10729674

  4. Rescue coronary stenting in acute myocardial infarction

    NASA Astrophysics Data System (ADS)

    Barbieri, Enrico; Meneghetti, Paolo; Molinari, Gionata; Zardini, Piero

    1996-01-01

    Failed rescue coronary angioplasty is a high risk situation because of high mortality. Coronary stent has given us the chance of improving and maintaining the patency of the artery. We report our preliminary experience of rescue stenting after unsuccessful coronary angioplasty.

  5. Fire Service Training. Rescue Practices. (Revised).

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Community Colleges, Raleigh.

    One of a set of fourteen instructional outlines for use in a course to train novice firemen, this guide covers the topic of rescue operations. Two types of rescue functions are recognized: the primary one consists of locating and saving trapped victims, and the secondary one of recovering bodies and making the area safe for other workers and…

  6. 46 CFR 169.517 - Rescue boat.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Rescue boat. 169.517 Section 169.517 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) NAUTICAL SCHOOLS SAILING SCHOOL VESSELS Lifesaving and Firefighting Equipment Primary Lifesaving Equipment § 169.517 Rescue boat. All vessels certificated for exposed or partially protected...

  7. Teaching Holocaust Rescue: A Problematic Pedagogy

    ERIC Educational Resources Information Center

    Lindquist, David H.

    2008-01-01

    Determining how to teach about rescue during the Holocaust presents many dilemmas to teachers as they plan Holocaust curricula. Rescue is often overemphasized, and faulty perspectives about rescuers and their actions may cause students to develop distorted views about this aspect of Holocaust history. This article explores several factors that…

  8. Simplified Aid For Crew Rescue (SAFR)

    NASA Technical Reports Server (NTRS)

    Fisher, H. Thomas

    1990-01-01

    Viewgraphs and discussion of a Crew Emergency Rescue System (CERS) are presented. Topics covered include: functional description; operational description; interfaces with other subsystems/elements; simplified aid for crew rescue (SACR) characteristics; potential resource requirements; logistics, repair, and resupply; potential performance improvements; and automation impact.

  9. Satellite search and rescue analysis

    NASA Astrophysics Data System (ADS)

    Bailey, J. T.

    The success of rescue operations in the case of the survivors of aircraft crashes depends crucially on the rapid detection of the aircraft location. Similar considerations apply in the case of marine distress. For this reason, the U.S. is currently participating in a program called Cospas/Sarsat, an international cooperative humanitarian effort designed to assist in saving the lives of aviators and mariners in distress. The other original participants in the program include France, Canada, and the Soviet Union. The program began as an experiment with the launch of the first spacecraft, Cospas I, in June 1982. The Cospas/Sarsat partners are engaged in work concerning a second experiment, involving a new generation distress beacon operating on a frequency of 406 MHz. Details regarding the Cospas/Sarsat constellation are discussed, and attention is given to the immediate and the long-term outlook.

  10. Is genetic rescue of cystinosis an achievable treatment goal?

    PubMed Central

    Cherqui, Stephanie

    2014-01-01

    Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS, which encodes the lysosomal cystine transporter, cystinosin. Cystine accumulates in all tissues and leads to organ damage including end-stage renal disease. In this review, we outline the studies that support that genetic rescue of cystinosis could be an achievable goal, even though cystinosis is a multi-compartmental disease and cystinosin an intracellular transmembrane protein. Using the mouse model of cystinosis, the Ctns−/− mice, we showed that transplanted hematopoietic stem cells (HSCs) were able to act as vehicles for the delivery of a functional Ctns gene to the different organs and led to the significant decrease of the tissue cystine content and tissue preservation. Ex vivo gene-modified Ctns−/− HSC transplantation using a lentiviral vector containing CTNS complementary DNA (cDNA) was also successful in the Ctns−/− mice and built the foundations for a clinical trial for autologous HSC transplantation for cystinosis. The capacity of HSCs for rescuing non-hematopoietic disease is controversial, and new insights into regenerative medicine could be gained from unraveling the underlying mechanism of action. PMID:23861466

  11. Hubble Space Telescope Crew Rescue Analysis

    NASA Technical Reports Server (NTRS)

    Hamlin, Teri L.; Canga, Michael; Boyer, Roger; Thigpen, Eric

    2009-01-01

    In the aftermath of the 2003 Columbia accident NASA removed the Hubble Space Telescope (HST) Servicing Mission 4 (SM4) from the Space Shuttle manifest. Reasons cited included concerns that the risk of flying the mission would be too high. There was at the time no viable technique to repair the orbiter s thermal protection system if it were to be damaged by debris during ascent. Furthermore in the event of damage, since the mission was not to the International Space Station, there was no safe haven for the crew to wait for an extended period of time for a rescue. The HST servicing mission was reconsidered because of improvements in the ascent debris environment, the development of techniques for the astronauts to perform on orbit repairs to damage thermal protection, and the development of a strategy to provide a crew rescue capability. However, leading up to the launch of servicing mission, the HST crew rescue capability was a recurring topic. For HST there was a limited amount of time available to perform a crew rescue because of the limited consumables available on the Orbiter. The success of crew rescue depends upon several factors including when a problem is identified, when and to what extent power down procedures are begun, and where the rescue vehicle is in its ground processing cycle. Severe power downs maximize crew rescue success but would eliminate the option for the orbiter servicing the HST to attempt a landing. Therefore, crew rescue success needed to be weighed against preserving the ability of the orbiter to have landing option in case there was a problem with the rescue vehicle. This paper focuses on quantification of the HST mission loss of crew rescue capability using Shuttle historical data and various power down capabilities. That work supported NASA s decision to proceed with the HST service mission, which was successfully completed on May 24th 2009.

  12. Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation

    PubMed Central

    McFarland, Hugh I.; Berkson, Julia D.; Lee, Jay P.; Elkahloun, Abdel G.; Mason, Karen P.; Rosenberg, Amy S.

    2015-01-01

    Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (Dd) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic “signature of rescue” identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated Dd skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic Dd expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation. PMID:26122582

  13. A New Antibiotic to the Rescue?

    MedlinePlus

    ... gov/medlineplus/news/fullstory_159417.html A New Antibiotic to the Rescue? Experimental drug shows promise against ... THURSDAY, June 16, 2016 (HealthDay News) -- An experimental antibiotic has shown promise against a dangerous drug-resistant ...

  14. Fire and Rescue Technology. Resources in Technology.

    ERIC Educational Resources Information Center

    Valesey, Brigitte G.

    1997-01-01

    Provides occupational information about fire and rescue operations personnel, such as fire science, fire protection engineering, emergency medical technicians, and firefighters. Provides information about organizations in these fields. (JOW)

  15. A New Antibiotic to the Rescue?

    MedlinePlus

    ... to the Rescue? Experimental drug shows promise against MRSA superbug in animal trials To use the sharing ... treated animals infected with the so-called "superbug" MRSA -- methicillin-resistant staphylococcus aureus . The results are "important ...

  16. NASA's Search-and-Rescue Technology

    NASA Video Gallery

    This animation depicts the next-generation search and rescue system, the DASS. Under this system, instruments used to relay emergency beacon signals will be installed on GPS satellites. When one em...

  17. GATA factor transgenes under GATA-1 locus control rescue germline GATA-1 mutant deficiencies.

    PubMed

    Takahashi, S; Shimizu, R; Suwabe, N; Kuroha, T; Yoh, K; Ohta, J; Nishimura, S; Lim, K C; Engel, J D; Yamamoto, M

    2000-08-01

    GATA-1 germline mutation in mice results in embryonic lethality due to defective erythroid cell maturation, and thus other hematopoietic GATA factors do not compensate for the loss of GATA-1. To determine whether the obligate presence of GATA-1 in erythroid cells is due to its distinct biochemical properties or spatiotemporal patterning, we attempted to rescue GATA-1 mutant mice with hematopoietic GATA factor complementary DNAs (cDNAs) placed under the transcriptional control of the GATA-1 gene. We found that transgenic expression of a GATA-1 cDNA fully abrogated the GATA-1-deficient phenotype. Surprisingly, GATA-2 and GATA-3 factors expressed from the same regulatory cassette also rescued the embryonic lethal phenotype of the GATA-1 mutation. However, adult mice rescued with the latter transgenes developed anemia, while GATA-1 transgenic mice did not. These results demonstrate that the transcriptional control dictating proper GATA-1 accumulation is the most critical determinant of GATA-1 activity during erythropoiesis. The results also show that there are biochemical distinctions among the hematopoietic GATA proteins and that during adult hematopoiesis the hematopoietic GATA factors are not functionally equivalent. PMID:10910904

  18. Renal rescue of dopamine D2 receptor function reverses renal injury and high blood pressure

    PubMed Central

    Konkalmatt, Prasad R.; Asico, Laureano D.; Zhang, Yanrong; Yang, Yu; Drachenberg, Cinthia; Zheng, Xiaoxu; Han, Fei; Jose, Pedro A.; Armando, Ines

    2016-01-01

    Dopamine D2 receptor (DRD2) deficiency increases renal inflammation and blood pressure in mice. We show here that long-term renal-selective silencing of Drd2 using siRNA increases renal expression of proinflammatory and profibrotic factors and blood pressure in mice. To determine the effects of renal-selective rescue of Drd2 expression in mice, the renal expression of DRD2 was first silenced using siRNA and 14 days later rescued by retrograde renal infusion of adeno-associated virus (AAV) vector with DRD2. Renal Drd2 siRNA treatment decreased the renal expression of DRD2 protein by 55%, and DRD2 AAV treatment increased the renal expression of DRD2 protein by 7.5- to 10-fold. Renal-selective DRD2 rescue reduced the expression of proinflammatory factors and kidney injury, preserved renal function, and normalized systolic and diastolic blood pressure. These results demonstrate that the deleterious effects of renal-selective Drd2 silencing on renal function and blood pressure were rescued by renal-selective overexpression of DRD2. Moreover, the deleterious effects of 45-minute bilateral ischemia/reperfusion on renal function and blood pressure in mice were ameliorated by a renal-selective increase in DRD2 expression by the retrograde ureteral infusion of DRD2 AAV immediately after the induction of ischemia/reperfusion injury. Thus, 14 days after ischemia/reperfusion injury, the renal expression of profibrotic factors, serum creatinine, and blood pressure were lower in mice infused with DRD2 AAV than in those infused with control AAV. These results indicate an important role of renal DRD2 in limiting renal injury and preserving normal renal function and blood pressure. PMID:27358912

  19. Hubble Space Telescope Crew Rescue Analysis

    NASA Technical Reports Server (NTRS)

    Hamlin, Teri L.; Canga, Michael A.; Cates, Grant R.

    2010-01-01

    In the aftermath of the 2003 Columbia accident, NASA removed the Hubble Space Telescope (HST) Servicing Mission 4 (SM4) from the Space Shuttle manifest. Reasons cited included concerns that the risk of flying the mission would be too high. The HST SM4 was subsequently reinstated and flown as Space Transportation System (STS)-125 because of improvements in the ascent debris environment, the development of techniques for astronauts to perform on orbit repairs to damaged thermal protection, and the development of a strategy to provide a viable crew rescue capability. However, leading up to the launch of STS-125, the viability of the HST crew rescue capability was a recurring topic. For STS-125, there was a limited amount of time available to perform a crew rescue due to limited consumables (power, oxygen, etc.) available on the Orbiter. The success of crew rescue depended upon several factors, including when a problem was identified; when and what actions, such as powering down, were begun to conserve consumables; and where the Launch on Need (LON) vehicle was in its ground processing cycle. Crew rescue success also needed to be weighed against preserving the Orbiter s ability to have a landing option in case there was a problem with the LON vehicle. This paper focuses on quantifying the HST mission loss of crew rescue capability using Shuttle historical data and various power down strategies. Results from this effort supported NASA s decision to proceed with STS-125, which was successfully completed on May 24th 2009.

  20. Factors influencing mine rescue team behaviors.

    PubMed

    Jansky, Jacqueline H; Kowalski-Trakofler, K M; Brnich, M J; Vaught, C

    2016-01-01

    A focus group study of the first moments in an underground mine emergency response was conducted by the National Institute for Occupational Safety and Health (NIOSH), Office for Mine Safety and Health Research. Participants in the study included mine rescue team members, team trainers, mine officials, state mining personnel, and individual mine managers. A subset of the data consists of responses from participants with mine rescue backgrounds. These responses were noticeably different from those given by on-site emergency personnel who were at the mine and involved with decisions made during the first moments of an event. As a result, mine rescue team behavior data were separated in the analysis and are reported in this article. By considering the responses from mine rescue team members and trainers, it was possible to sort the data and identify seven key areas of importance to them. On the basis of the responses from the focus group participants with a mine rescue background, the authors concluded that accurate and complete information and a unity of purpose among all command center personnel are two of the key conditions needed for an effective mine rescue operation. PMID:26963229

  1. 30 CFR 49.15 - Mine rescue station.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Mine rescue station. 49.15 Section 49.15 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.15 Mine rescue station. (a) Every...

  2. 30 CFR 49.5 - Mine rescue station.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Mine rescue station. 49.5 Section 49.5 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.5 Mine rescue station. (a)...

  3. 30 CFR 49.5 - Mine rescue station.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Mine rescue station. 49.5 Section 49.5 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.5 Mine rescue station. (a)...

  4. 30 CFR 49.15 - Mine rescue station.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Mine rescue station. 49.15 Section 49.15 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.15 Mine rescue station. (a) Every...

  5. 30 CFR 49.15 - Mine rescue station.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mine rescue station. 49.15 Section 49.15 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.15 Mine rescue station. (a) Every...

  6. 30 CFR 49.15 - Mine rescue station.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Mine rescue station. 49.15 Section 49.15 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.15 Mine rescue station. (a) Every...

  7. 30 CFR 49.5 - Mine rescue station.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Mine rescue station. 49.5 Section 49.5 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.5 Mine rescue station. (a)...

  8. 30 CFR 49.15 - Mine rescue station.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Mine rescue station. 49.15 Section 49.15 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.15 Mine rescue station. (a) Every...

  9. Amorphous silicon bolometer for fire/rescue

    NASA Astrophysics Data System (ADS)

    Francisco, Glenn L.

    2001-03-01

    Thermal imaging sensors have completely changed the way the world views fire and rescue applications. Recently, in the uncooled infrared camera and microbolometer detector areas, major strides have been made in manufacturing personal fire and rescue sensors. A family of new amorphous silicon microbolometers are being produced utilizing low cost, low weight, ultra low power, small size, high volume vacuum packaged silicon wafer-level focal plane array technologies. These bolometers contain no choppers or thermoelectric coolers, require no manual calibration and use readily available commercial off-the-shelf components. Manufacturing and packaging discoveries have allowed infrared sensitive silicon arrays to be produced with the same methods that have driven the rapidly advancing digital wireless telecommunications industries. Fire and rescue professionals are now able to conduct minimum time thermal imaging penetration, surveillance, detection, recognition, rescue and egress while maintaining situational awareness in a manner consistent with the modern technological applications. The purpose of this paper is to describe an uncooled micro bolometer infrared camera approach for meeting fire/rescue wants, needs and requirements, with application of recent technology advancements. This paper also details advances in bolometric focal plane arrays, optical and circuit card technologies, while providing a glimpse into the future of micro sensor growth. Technical barriers are addressed in light of constraints and lessons learned around this technology.

  10. Rescue Medicine for Epilepsy in Education Settings.

    PubMed

    Hartman, Adam L; Devore, Cynthia Di Laura; Doerrer, Sarah C

    2016-01-01

    Children and adolescents with epilepsy may experience prolonged seizures in school-associated settings (eg, during transportation, in the classroom, or during sports activities). Prolonged seizures may evolve into status epilepticus. Administering a seizure rescue medication can abort the seizure and may obviate the need for emergency medical services and subsequent care in an emergency department. In turn, this may save patients from the morbidity of more invasive interventions and the cost of escalated care. There are significant variations in prescribing practices for seizure rescue medications, partly because of inconsistencies between jurisdictions in legislation and professional practice guidelines among potential first responders (including school staff). There also are potential liability issues for prescribers, school districts, and unlicensed assistive personnel who might administer the seizure rescue medications. This clinical report highlights issues that providers may consider when prescribing seizure rescue medications and creating school medical orders and/or action plans for students with epilepsy. Collaboration among prescribing providers, families, and schools may be useful in developing plans for the use of seizure rescue medications. PMID:26712862

  11. [Air rescue: current significance and practical issues].

    PubMed

    Schellhaaß, A; Popp, E

    2014-12-01

    Germany has a nationwide and powerful helicopter emergency medical services system (HEMS), which executes primary rescue missions and interhospital transfer of intensive care patients. In recent years the range of HEMS missions has become modified due to demographic changes and structural changes in the healthcare system. Furthermore, the number of HEMS missions is steadily increasing. If reasonably used air rescue contributes to desired reductions in overall preclinical time. Moreover, it facilitates prompt transport of patients to a hospital suitable for definitive medical care and treatment can be initiated earlier which is a particular advantage for severely injured and critically ill patients. Because of complex challenges during air rescue missions the qualifications of the HEMS personnel have to be considerably higher in comparison with ground based emergency medical services. PMID:25430664

  12. RESCU: A real space electronic structure method

    NASA Astrophysics Data System (ADS)

    Michaud-Rioux, Vincent; Zhang, Lei; Guo, Hong

    2016-02-01

    In this work we present RESCU, a powerful MATLAB-based Kohn-Sham density functional theory (KS-DFT) solver. We demonstrate that RESCU can compute the electronic structure properties of systems comprising many thousands of atoms using modest computer resources, e.g. 16 to 256 cores. Its computational efficiency is achieved from exploiting four routes. First, we use numerical atomic orbital (NAO) techniques to efficiently generate a good quality initial subspace which is crucially required by Chebyshev filtering methods. Second, we exploit the fact that only a subspace spanning the occupied Kohn-Sham states is required, and solving accurately the KS equation using eigensolvers can generally be avoided. Third, by judiciously analyzing and optimizing various parts of the procedure in RESCU, we delay the O (N3) scaling to large N, and our tests show that RESCU scales consistently as O (N2.3) from a few hundred atoms to more than 5000 atoms when using a real space grid discretization. The scaling is better or comparable in a NAO basis up to the 14,000 atoms level. Fourth, we exploit various numerical algorithms and, in particular, we introduce a partial Rayleigh-Ritz algorithm to achieve efficiency gains for systems comprising more than 10,000 electrons. We demonstrate the power of RESCU in solving KS-DFT problems using many examples running on 16, 64 and/or 256 cores: a 5832 Si atoms supercell; a 8788 Al atoms supercell; a 5324 Cu atoms supercell and a small DNA molecule submerged in 1713 water molecules for a total 5399 atoms. The KS-DFT is entirely converged in a few hours in all cases. Our results suggest that the RESCU method has reached a milestone of solving thousands of atoms by KS-DFT on a modest computer cluster.

  13. Spatiotemporal rescue of memory dysfunction in Drosophila.

    PubMed

    McGuire, Sean E; Le, Phuong T; Osborn, Alexander J; Matsumoto, Kunihiro; Davis, Ronald L

    2003-12-01

    We have developed a method for temporal and regional gene expression targeting (TARGET) in Drosophila and show the simultaneous spatial and temporal rescue of a memory defect. The transient expression of the rutabaga-encoded adenylyl cyclase in the mushroom bodies of the adult brain was necessary and sufficient to rescue the rutabaga memory deficit, which rules out a developmental brain defect in the etiology of this deficit and demonstrates an acute role for rutabaga in memory formation in these neurons. The TARGET system offers general utility in simultaneously addressing issues of when and where gene products are required. PMID:14657498

  14. Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A

    PubMed Central

    Guedj, Fayçal; Sébrié, Catherine; Rivals, Isabelle; Ledru, Aurelie; Paly, Evelyne; Bizot, Jean C.; Smith, Desmond; Rubin, Edward; Gillet, Brigitte; Arbones, Mariona; Delabar, Jean M.

    2009-01-01

    Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) — a member of a natural polyphenols family, found in great amount in green tea leaves — is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice. PMID:19242551

  15. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.

    PubMed

    Guedj, Fayçal; Sébrié, Catherine; Rivals, Isabelle; Ledru, Aurelie; Paly, Evelyne; Bizot, Jean C; Smith, Desmond; Rubin, Edward; Gillet, Brigitte; Arbones, Mariona; Delabar, Jean M

    2009-01-01

    Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) - a member of a natural polyphenols family, found in great amount in green tea leaves - is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice. PMID:19242551

  16. EMERGENCY VICTIM CARE AND RESCUE, INSTRUCTOR'S MANUAL.

    ERIC Educational Resources Information Center

    MORANDO, ROCCO V.; STOVER, WILBUR F.

    DEVELOPED AT THE STATE LEVEL BY SQUADMEN AND TRADE AND INDUSTRIAL PERSONNEL, THIS MANUAL IS FOR USE BY A QUALIFIED SQUADMAN IN TEACHING FULL-TIME AND VOLUNTEER EMERGENCY AND RESCUE WORKERS IN AN EMERGENCY SQUAD STATION OR TRAINING CENTER. TEACHING GUIDES ARE PROVIDED FOR A 30-HOUR COURSE ON EMERGENCY VICTIM CARE AND A 20-HOUR COURSE ON VICTIM…

  17. REM sleep rescues learning from interference.

    PubMed

    McDevitt, Elizabeth A; Duggan, Katherine A; Mednick, Sara C

    2015-07-01

    Classical human memory studies investigating the acquisition of temporally-linked events have found that the memories for two events will interfere with each other and cause forgetting (i.e., interference; Wixted, 2004). Importantly, sleep helps consolidate memories and protect them from subsequent interference (Ellenbogen, Hulbert, Stickgold, Dinges, & Thompson-Schill, 2006). We asked whether sleep can also repair memories that have already been damaged by interference. Using a perceptual learning paradigm, we induced interference either before or after a consolidation period. We varied brain states during consolidation by comparing active wake, quiet wake, and naps with either non-rapid eye movement sleep (NREM), or both NREM and REM sleep. When interference occurred after consolidation, sleep and wake both produced learning. However, interference prior to consolidation impaired memory, with retroactive interference showing more disruption than proactive interference. Sleep rescued learning damaged by interference. Critically, only naps that contained REM sleep were able to rescue learning that was highly disrupted by retroactive interference. Furthermore, the magnitude of rescued learning was correlated with the amount of REM sleep. We demonstrate the first evidence of a process by which the brain can rescue and consolidate memories damaged by interference, and that this process requires REM sleep. We explain these results within a theoretical model that considers how interference during encoding interacts with consolidation processes to predict which memories are retained or lost. PMID:25498222

  18. Emergency Medical Rescue in a Radiation Environment

    SciTech Connect

    Briesmeister, L.; Ellington, Y.; Hollis, R.; Kunzman, J.; McNaughton, M.; Ramsey, G.; Somers, B.; Turner, A.; Finn, J.

    1999-09-14

    Previous experience with emergency medical rescues in the presence of radiation or contamination indicates that the training provided to emergency responders is not always appropriate. A new course developed at Los Alamos includes specific procedures for emergency response in a variety of radiological conditions.

  19. 78 FR 39531 - Mine Rescue Teams

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-01

    ... July 1, 2013 Part V Department of Labor Mine Safety and Health Administration 30 CFR Part 49 Mine... and Regulations#0;#0; ] DEPARTMENT OF LABOR Mine Safety and Health Administration 30 CFR Part 49 Mine... Miner Act Requirements for Underground Coal Mine Operators and Mine Rescue Teams Type of mine...

  20. Rescue Fantasies in Homicide-Suicide

    ERIC Educational Resources Information Center

    Selkin, James

    1976-01-01

    Homicide-suicides (N=13), events in which an individual murders one or more persons and kills himself immediately afterward, were studied, The results are interpreted to suggest that persons who commit homicide-suicide are acting out a three-party rescue fantasy in an attempt to resolve unbearable stress. (Author)

  1. Summary of prior grain entrapment rescue strategies.

    PubMed

    Roberts, M J; Deboy, G R; Field, W E; Maier, D E

    2011-10-01

    Entrapment in flowable agricultural material continues to be a relevant problem facing both farmers and employees of commercial grain storage and handling operations. While considerable work has been done previously on the causes of entrapment in grain and possible preventative measures, there is little research on the efficacy of current first response or extrication techniques. With the recent introduction of new grain rescue equipment and training programs, it was determined that the need exists to document and summarize prior grain rescue strategies with a view to develop evidence-based recommendations that would enhance the efficacy of the techniques used and reduce the risks to both victims and first responders. Utilizing the Purdue University Agricultural Entrapment Database, all data were queried for information related to extrication of victims from grain entrapments documented over the period 1964-2006. Also analyzed were data from other sources, including public records related to entrapments and information from onsite investigations. Significant findings of this study include the following: (1) between 1964 and 2006, the number of entrapments averaged 16 per year, with the frequency increasing over the last decade; (2) of all cases documented, about 45% resulted in fatality; (3) no less than 44% of entrapments occurred in shelled corn; (4) fatality was the result in 82% of cases where victims were submerged beneath the grain surface, while fatality occurred in 10% of cases where victims were only partially engulfed; (5) the majority of rescues were reported to have been conducted by untrained personnel who were at the scene at the time of entrapment; and (6) in those cases where the rescue strategies were known, 56% involved cutting or punching holes in the side walls of the storage structure, 19% involved utilizing onsite fabricated grain retaining walls to extricate partially entrapped victims, and the use of grain vacuum machines as a rescue

  2. ISS Update: Orion Recovery and Rescue Lead Tom Walker

    NASA Video Gallery

    NASA Public Affairs Officer Brandi Dean talks with Tom Walker, Orion Recovery and Rescue Lead, about how the Neutral Buoyancy Laboratory (NBL) is being used to train rescue and recovery personnel f...

  3. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome.

    PubMed

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-Jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-01-01

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2(+/-) mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome. PMID:27328321

  4. Point-of-care ultrasonography during rescue operations on board a Polish Medical Air Rescue helicopter.

    PubMed

    Darocha, Tomasz; Gałązkowski, Robert; Sobczyk, Dorota; Żyła, Zbigniew; Drwiła, Rafał

    2014-12-01

    Point-of-care ultrasound examination has been increasingly widely used in pre-hospital care. The use of ultrasound in rescue medicine allows for a quick differential diagnosis, identification of the most important medical emergencies and immediate introduction of targeted treatment. Performing and interpreting a pre-hospital ultrasound examination can improve the accuracy of diagnosis and thus reduce mortality. The authors' own experiences are presented in this paper, which consist in using a portable, hand-held ultrasound apparatus during rescue operations on board a Polish Medical Air Rescue helicopter. The possibility of using an ultrasound apparatus during helicopter rescue service allows for a full professional evaluation of the patient's health condition and enables the patient to be brought to a center with the most appropriate facilities for their condition. PMID:26674604

  5. Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition.

    PubMed

    Tamura, Makoto; Mukai, Jun; Gordon, Joshua A; Gogos, Joseph A

    2016-03-01

    While the genetic basis of schizophrenia is increasingly well characterized, novel treatments will require establishing mechanistic relationships between specific risk genes and core phenotypes. Rare, highly penetrant risk genes such as the 22q11.2 microdeletion are promising in this regard. Df(16)A(+/-) mice, which carry a homologous microdeletion, have deficits in hippocampal-prefrontal connectivity that correlate with deficits in spatial working memory. These mice also have deficits in axonal development that are accompanied by dysregulated Gsk3β signaling and can be rescued by Gsk3 antagonists. Here we show that developmental inhibition of Gsk3 rescues deficits in hippocampal-prefrontal connectivity, task-related neural activity, and spatial working memory behavior in Df(16)A(+/-) mice. Taken together, these results provide mechanistic insight into how the microdeletion results in cognitive deficits, and they suggest possible targets for novel therapies. PMID:26898776

  6. Titration of mitochondrial fusion rescues Mff-deficient cardiomyopathy

    PubMed Central

    Chen, Hsiuchen; Ren, Shuxun; Clish, Clary; Jain, Mohit; Mootha, Vamsi; McCaffery, J. Michael

    2015-01-01

    Defects in mitochondrial fusion or fission are associated with many pathologies, raising the hope that pharmacological manipulation of mitochondrial dynamics may have therapeutic benefit. This approach assumes that organ physiology can be restored by rebalancing mitochondrial dynamics, but this concept remains to be validated. We addressed this issue by analyzing mice deficient in Mff, a protein important for mitochondrial fission. Mff mutant mice die at 13 wk as a result of severe dilated cardiomyopathy leading to heart failure. Mutant tissue showed reduced mitochondrial density and respiratory chain activity along with increased mitophagy. Remarkably, concomitant deletion of the mitochondrial fusion gene Mfn1 completely rescued heart dysfunction, life span, and respiratory chain function. Our results show for the first time that retuning the balance of mitochondrial fusion and fission can restore tissue integrity and mitochondrial physiology at the whole-organ level. Examination of liver, testis, and cerebellum suggest, however, that the precise balance point of fusion and fission is cell type specific. PMID:26598616

  7. Minimum-fuel rescue trajectories for the Extravehicular Excursion Unit

    NASA Technical Reports Server (NTRS)

    Fowler, W. T.; Neff, J. M.

    1991-01-01

    The problem of determining minimum-fuel trajectories for rescuing astronauts or equipment which become separated from a Space Station is addressed. Using the Clohessy-Wiltshire equations of relative motion and assuming impulsive Delta-Vs, the minimum-fuel rescue problem is shown to be a parameter optimization problem. Minimum-fuel rescue trajectories are found for seventeen test cases using a recursive quadratic programming algorithm. The results are analyzed and general rules for astronaut rescue and equipment retrieval are developed.

  8. A Space Station crew rescue and equipment retrieval system

    NASA Technical Reports Server (NTRS)

    Adornato, Rudolph J.; Bo, Ronald A.

    1988-01-01

    This paper studies the possible use of a Space Station crew rescue and equipment retrieval system as a safeguard against the inadvertent separation of crew or equipment from the Space Station. The time to effect rescue and retrieval and the problem of crew separation are discussed. Alternate rescue/retrieval systems are evaluated. It is concluded that telerobotic vehicles provide the lowest cost rescue capability.

  9. Resource Guide for Search and Rescue Training Materials.

    ERIC Educational Resources Information Center

    LaValla, Patrick

    The bibliography about search and rescue training materials lists booklets, books, manuals, films, papers, periodicals, and pamphlets that treat many aspects of search and rescue situations: general, cave, disaster, and mountain rescues; strategy tactics; communications; knots and ropes; outdoor living; dogs; tracking; map and compass; survival;…

  10. 30 CFR 49.5 - Mine rescue station.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Mine rescue station. 49.5 Section 49.5 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.5 Mine rescue station. (a) Except where alternative compliance is permitted, every...

  11. 30 CFR 49.2 - Availability of mine rescue teams.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Availability of mine rescue teams. 49.2 Section 49.2 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.2...

  12. 30 CFR 49.8 - Training for mine rescue teams.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Training for mine rescue teams. 49.8 Section 49.8 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.8 Training...

  13. 30 CFR 49.8 - Training for mine rescue teams.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Training for mine rescue teams. 49.8 Section 49.8 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.8 Training...

  14. 30 CFR 49.12 - Availability of mine rescue teams.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Availability of mine rescue teams. 49.12 Section 49.12 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.12 Availability of mine...

  15. 30 CFR 49.8 - Training for mine rescue teams.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Training for mine rescue teams. 49.8 Section 49.8 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.8 Training for mine rescue teams. (a) Prior to serving on a mine...

  16. 30 CFR 49.12 - Availability of mine rescue teams.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Availability of mine rescue teams. 49.12 Section 49.12 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.12 Availability of mine...

  17. 30 CFR 49.18 - Training for mine rescue teams.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Training for mine rescue teams. 49.18 Section 49.18 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.18 Training for mine...

  18. 30 CFR 49.18 - Training for mine rescue teams.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Training for mine rescue teams. 49.18 Section 49.18 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.18 Training for mine...

  19. 30 CFR 49.18 - Training for mine rescue teams.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Training for mine rescue teams. 49.18 Section 49.18 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.18 Training for mine...

  20. 30 CFR 49.8 - Training for mine rescue teams.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Training for mine rescue teams. 49.8 Section 49.8 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.8 Training for mine rescue teams. (a) Prior to serving on a mine...

  1. 30 CFR 49.8 - Training for mine rescue teams.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Training for mine rescue teams. 49.8 Section 49.8 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.8 Training...

  2. 30 CFR 49.18 - Training for mine rescue teams.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Training for mine rescue teams. 49.18 Section 49.18 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.18 Training for mine...

  3. 30 CFR 49.2 - Availability of mine rescue teams.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Availability of mine rescue teams. 49.2 Section 49.2 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.2 Availability of mine rescue teams. (a) Except where...

  4. 30 CFR 49.12 - Availability of mine rescue teams.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Availability of mine rescue teams. 49.12 Section 49.12 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.12 Availability of mine...

  5. 30 CFR 49.12 - Availability of mine rescue teams.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Availability of mine rescue teams. 49.12 Section 49.12 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.12 Availability of mine...

  6. 30 CFR 49.2 - Availability of mine rescue teams.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Availability of mine rescue teams. 49.2 Section 49.2 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.2 Availability of mine rescue teams. (a) Except where...

  7. 30 CFR 49.5 - Mine rescue station.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Mine rescue station. 49.5 Section 49.5 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.5 Mine rescue station. (a) Except where alternative compliance is permitted, every...

  8. 30 CFR 49.2 - Availability of mine rescue teams.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Availability of mine rescue teams. 49.2 Section 49.2 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.2...

  9. 30 CFR 49.2 - Availability of mine rescue teams.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Availability of mine rescue teams. 49.2 Section 49.2 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines § 49.2...

  10. 30 CFR 49.12 - Availability of mine rescue teams.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Availability of mine rescue teams. 49.12 Section 49.12 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.12 Availability of mine...

  11. 30 CFR 49.18 - Training for mine rescue teams.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Training for mine rescue teams. 49.18 Section 49.18 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines § 49.18 Training for mine...

  12. Rescue Effects and Underlying Mechanisms of Intragland Shh Gene Delivery on Irradiation-Induced Hyposalivation.

    PubMed

    Hai, Bo; Zhao, Qingguo; Qin, Lizheng; Rangaraj, Dharanipathy; Gutti, Veera R; Liu, Fei

    2016-05-01

    Irreversible hypofunction of salivary glands is common in head and neck cancer survivors treated with radiotherapy and can only be temporarily relieved with current treatments. We found in an inducible sonic hedgehog (Shh) transgenic mouse model that transient activation of the Hedgehog pathway after irradiation rescued salivary gland function in males by preserving salivary stem/progenitor cells and parasympathetic innervation. To translate these findings into feasible clinical application, we evaluated the effects of Shh gene transfer to salivary glands of wild-type mice on irradiation-induced hyposalivation. Shh or control GFP gene was delivered by noninvasive retrograde ductal instillation of corresponding adenoviral vectors. In both male and female mice, Shh gene delivery efficiently activated Hedgehog/Gli signaling, and significantly improved stimulated saliva secretion and preserved saliva-producing acinar cells after irradiation. In addition to preserving parasympathetic innervation through induction of neurotrophic factors, Shh gene delivery also alleviated the irradiation damage of the microvasculature, likely via inducing angiogenic factors, but did not expand the progeny of cells responsive to Hedgehog/Gli signaling. These data indicate that transient activation of the Hedgehog pathway by gene delivery is promising to rescue salivary function after irradiation in both sexes, and the Hedgehog/Gli pathway may function mainly in cell nonautonomous manners to achieve the rescue effect. PMID:27021743

  13. Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

    PubMed Central

    Chen, Tao; Lu, Jing-Shan; Song, Qian; Liu, Ming-Gang; Koga, Kohei; Descalzi, Giannina; Li, Yun-Qing; Zhuo, Min

    2014-01-01

    Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/channels within the cingulate circuit and is typically detected in ∼75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients. PMID:24553731

  14. Issues in intelligent robots for search and rescue

    NASA Astrophysics Data System (ADS)

    Casper, Jennifer L.; Micire, Mark; Murphy, Robin R.

    2000-07-01

    Since the 1995 Oklahoma City bombing and Kobe, Japan, earthquake, robotics researchers have been considering search and rescue as a humanitarian research domain. The recent devastation in Turkey and Taiwan, compounded with the new Robocup Rescue and AAAI Urban Search and Rescue robot competition, may encourage more research. However, roboticists generally go not have access to domain experts: the emergency workers or first providers. This paper shares our understanding of urban search and rescue, based on our active research in this area and training sessions with rescue workers from the Hillsborough County (Florida) Fire Departments. The paper is intended to be a stepping stone for roboticists entering the field.

  15. Medical considerations in the use of helicopters in mountain rescue.

    PubMed

    Tomazin, Iztok; Kovacs, Tim

    2003-01-01

    The outcome of patient care can be dramatically improved by bringing rapid rescue and medical care to the mountain rescue scene and by rapid transport to a medical facility. The use of a helicopter for these purposes is common. It is necessary when it has clear advantages for victims in comparison with ground rescue and transport. Helicopters should work within the existing emergency medical system and must be staffed by appropriate mountain rescue and medically trained personnel. Activation time should be as short as possible. Activation of a helicopter for a mountain rescue should primarily include indication and assessment of flight and safety conditions. No other mediators or delaying factors should be permitted. The main safety criteria are appropriate mountain rescue and flight training, competence of air and ground crews, radio communication between the air and ground crews, and mission briefing before the rescue. Criteria for a helicopter used for mountain rescue are proper medical and rescue equipment, load capacity, adequate space, and others. There are two main groups of indications for use of a helicopter for mountain rescue: the patient's condition and the circumstances at the site of the accident. All persons responsible for the activation of the helicopter rescue operation should be aware of specific problems in the mountains or wilderness. PMID:14672551

  16. Lidar techniques for search and rescue

    SciTech Connect

    Cabral, W.L.

    1985-01-01

    Four techniques for using LIDAR in Search and Rescue Operations will be discussed. The topic will include laser retroreflection, laser-induced fluorescence in the visible, laser-induced fluorescence during daylight hours, and laser-induced fluorescence in the uv. These techniques use high-repetition rate lasers at a variety of frequencies to induce either fluorescence in dye markers or retroreflection from plastic corner cubes on life preservers and other emergency markers.

  17. Skylab rescue space vehicle flight readiness test

    NASA Technical Reports Server (NTRS)

    Jevitt, S. J.

    1973-01-01

    A Skylab Rescue Space Vehicle flight readiness test is described which ensures that space vehicle systems are in a state of flight readiness and are compatible with associated ground support equipment. The functions of propellant loading, umbilical ejection, ignition, holddown arm release, liftoff, and service arm and tail service mast retraction are simulated. The test outline is presented along with a list of references, intercommunications information, operations interface control chart, and flight test.

  18. Monte Carlo simulations within avalanche rescue

    NASA Astrophysics Data System (ADS)

    Reiweger, Ingrid; Genswein, Manuel; Schweizer, Jürg

    2016-04-01

    Refining concepts for avalanche rescue involves calculating suitable settings for rescue strategies such as an adequate probing depth for probe line searches or an optimal time for performing resuscitation for a recovered avalanche victim in case of additional burials. In the latter case, treatment decisions have to be made in the context of triage. However, given the low number of incidents it is rarely possible to derive quantitative criteria based on historical statistics in the context of evidence-based medicine. For these rare, but complex rescue scenarios, most of the associated concepts, theories, and processes involve a number of unknown "random" parameters which have to be estimated in order to calculate anything quantitatively. An obvious approach for incorporating a number of random variables and their distributions into a calculation is to perform a Monte Carlo (MC) simulation. We here present Monte Carlo simulations for calculating the most suitable probing depth for probe line searches depending on search area and an optimal resuscitation time in case of multiple avalanche burials. The MC approach reveals, e.g., new optimized values for the duration of resuscitation that differ from previous, mainly case-based assumptions.

  19. Psychological Distress in Chimpanzees Rescued From Laboratories.

    PubMed

    Lopresti-Goodman, Stacy M; Bezner, Jocelyn; Ritter, Chelsea

    2015-01-01

    The United States is one of the last countries allowing invasive research on chimpanzees. Biomedical research on chimpanzees commonly involves maternal deprivation, social isolation, intensive confinement, and repetitive invasive procedures. These physically harmful and psychologically traumatic experiences cause many chimpanzees to develop symptoms of psychopathology that persist even after relocation from laboratories to sanctuaries. Through semistructured interviews with chimpanzee caregivers, direct behavioral observations, and consultation of laboratory records, we were interested in qualitatively analyzing symptoms of psychological distress in a sample of 253 chimpanzees rescued from biomedical research now residing at an accredited chimpanzee sanctuary. We present the results of this analysis and include an illustrative case study of one rescued chimpanzee who engages in self-injurious behaviors and meets modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for posttraumatic stress disorder. We discuss our results in light of recent policy changes regarding the use of chimpanzees in biomedical research in the United States and their implications for those involved in the rescue and rehabilitation of chimpanzees from biomedical research. PMID:25893315

  20. Avalanche Survival After Rescue With the RECCO Rescue System: A Case Report.

    PubMed

    Grasegger, Katharina; Strapazzon, Giacomo; Procter, Emily; Brugger, Hermann; Soteras, Inigo

    2016-06-01

    We report a case of survival of a completely buried avalanche victim after being located with the radar-based RECCO Rescue System. In the winter of 2015, 2 off-piste skiers were completely buried in an avalanche near the secured ski area in Baqueira Beret, Spain. The first victim was located with the RECCO Rescue System in less than 35 minutes and was alive and conscious at extrication. This system emits radio waves and requires a specific reflector. It is a portable device that is used by more than 600 rescue organizations worldwide, especially in secured ski areas. The device should be brought to the avalanche site together with electronic avalanche transceivers, a probing team, and avalanche dogs. In the hands of experienced professionals, the device may allow rapid location of victims not carrying an electronic avalanche transceiver. Although it is not the first successful extrication of a victim with the RECCO Rescue System, it is the first case published in the medical literature and is intended to encourage data collection and to increase our understanding of the effectiveness of this device in avalanche rescue. PMID:27116920

  1. Recombinant EDA or Sonic Hedgehog rescue the branching defect in Ectodysplasin A pathway mutant salivary glands in vitro.

    PubMed

    Wells, K L; Mou, C; Headon, D J; Tucker, A S

    2010-10-01

    Hypohidrotic ectodermal dysplasia (HED) is characterized by defective ectodermal organ development. This includes the salivary glands (SGs), which have an important role in lubricating the oral cavity. In humans and mice, HED is caused by mutations in Ectodysplasin A (Eda) pathway genes. Various phenotypes of the mutant mouse Eda(Ta/Ta), which lacks the ligand Eda, can be rescued by maternal injection or in vitro culture supplementation with recombinant EDA. However, the response of the SGs to this treatment has not been investigated. Here, we show that the submandibular glands (SMGs) of Eda(Ta/Ta) mice exhibit impaired branching morphogenesis, and that supplementation of Eda(Ta/Ta) SMG explants with recombinant EDA rescues the defect. Supplementation of Edar(dlJ/dlJ) SMGs with recombinant Sonic hedgehog (Shh) also rescues the defect, whereas treatment with recombinant Fgf8 does not. This work is the first to test the ability of putative Eda target molecules to rescue Eda pathway mutant SMGs. PMID:20803597

  2. A High Fat Diet and NAD+ Rescue Premature Aging in Cockayne Syndrome

    PubMed Central

    Scheibye-Knudsen, Morten; Mitchell, Sarah J.; Fang, Evandro F.; Iyama, Teruaki; Ward, Theresa; Wang, James; Dunn, Christopher A.; Singh, Nagendra; Veith, Sebastian; Hasan, M. Mahdi; Mangerich, Aswin; Wilson, Mark A.; Mattson, Mark P.; Bergersen, Linda H.; Cogger, Victoria C.; Warren, Alessandra; Le Couteur, David G.; Moaddel, Ruin; Wilson, David M.; Croteau, Deborah L.; de Cabo, Rafael; Bohr, Vilhelm A.

    2014-01-01

    Summary Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in the genes encoding the DNA repair proteins CSA or CSB. Csbm/m mice were given a high fat, caloric restricted or resveratrol supplemented diet. The high fat diet rescued the phenotype of Csbm/m mice at the metabolic, transcriptomic and behavioral levels. Additional analysis suggests that the premature aging seen in CS mice, nematodes and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high fat diet; and β-hydroxybutyrate, PARP inhibition, or NAD+ supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB is able to displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD+, through the deacetylase SIRT1 and suggests possible interventions for CS. PMID:25440059

  3. Survey of space escape/rescue/survivability capabilities.

    NASA Technical Reports Server (NTRS)

    Fleisig, R.; Bolger, P. H.; Heath, G. W.

    1971-01-01

    Discussion of preventive or remedial systems to achieve safer space flight operations. Escape, rescue, and survival systems are defined by categories: on board, prepositioned aid, and earth-launched concepts. The survey considers separable escape or survival capsules; standby escape or rescue systems; and earth-launched manned and unmanned rescue systems. Reports covering such systems are listed, and the contents are classified as to scope of investigation, space mission, and design approach. Mission classes considered are earth orbit, lunar, and interplanetary. Results of the space escape, rescue, and survivability investigations are summarized in terms of system features and performance, including apparent voids or limitations in rescue capability. Recovery requirements and resources for space rescue are discussed.

  4. Multiple Rescue Factors Within a Wolbachia Strain

    PubMed Central

    Zabalou, Sofia; Apostolaki, Angeliki; Pattas, Savvas; Veneti, Zoe; Paraskevopoulos, Charalampos; Livadaras, Ioannis; Markakis, George; Brissac, Terry; Merçot, Hervé; Bourtzis, Kostas

    2008-01-01

    Wolbachia-induced cytoplasmic incompatibility (CI) is expressed when infected males are crossed with either uninfected females or females infected with Wolbachia of different CI specificity. In diploid insects, CI results in embryonic mortality, apparently due to the the loss of the paternal set of chromosomes, usually during the first mitotic division. The molecular basis of CI has not been determined yet; however, several lines of evidence suggest that Wolbachia exhibits two distinct sex-dependent functions: in males, Wolbachia somehow “imprints” the paternal chromosomes during spermatogenesis (mod function), whereas in females, the presence of the same Wolbachia strain(s) is able to restore embryonic viability (resc function). On the basis of the ability of Wolbachia to induce the modification and/or rescue functions in a given host, each bacterial strain can be classified as belonging in one of the four following categories: mod+ resc+, mod− resc+, mod− resc−, and mod+ resc−. A so-called “suicide” mod+ resc− strain has not been found in nature yet. Here, a combination of embryonic cytoplasmic injections and introgression experiments was used to transfer nine evolutionary, distantly related Wolbachia strains (wYak, wTei, wSan, wRi, wMel, wHa, wAu, wNo, and wMa) into the same host background, that of Drosophila simulans (STCP strain), a highly permissive host for CI expression. We initially characterized the modification and rescue properties of the Wolbachia strains wYak, wTei, and wSan, naturally present in the yakuba complex, upon their transfer into D. simulans. Confocal microscopy and multilocus sequencing typing (MLST) analysis were also employed for the evaluation of the CI properties. We also tested the compatibility relationships of wYak, wTei, and wSan with all other Wolbachia infections. So far, the cytoplasmic incompatibility properties of different Wolbachia variants are explained assuming a single pair of modification and rescue

  5. Lipid rescue in children: The prompt decision.

    PubMed

    Eizaga Rebollar, Ramón; García Palacios, María V; Morales Guerrero, Javier; Torres Morera, Luis M

    2016-08-01

    We report the case of a 17-month-old child who underwent laparotomy under general anesthesia and caudal block. Electrocardiogram ST-T changes were observed after local anesthetic injection. The prompt use of Intralipid 30% was successful in normalizing ECG alterations. Our experience is consistent with previous literature, mainly carried out in adults. Thereby, we conduct a brief review of the subject in pediatrics. As a major conclusion, we strongly recommend the "fast-track" lipid rescue as soon as this severe complication is detected. PMID:27290983

  6. Post-disaster medical rescue strategy in tropical regions

    PubMed Central

    Li, Xiang-hui; Hou, Shi-ke; Zheng, Jing-chen; Fan, Hao-jun; Song, Jian-qi

    2012-01-01

    BACKGROUND: Earthquakes, floods, droughts, storms, mudslides, landslides, and forest wild fires are serious threats to human lives and properties. The present study aimed to study the environmental characteristics and pathogenic traits, recapitulate experiences, and augment applications of medical reliefs in tropical regions. METHODS: Analysis was made on work and projects of emergency medical rescue, based on information and data collected from 3 emergency medical rescue missions of China International Search and Rescue Team to overseas earthquakes and tsunamis aftermaths in tropical disaster regions — Indonesia-Aceh, Indonesia-Yogyakarta, and Haiti-Port au Prince. RESULTS: Shock, infection and heat stroke were frequently encountered in addition to outbreaks of infectious diseases, skin diseases, and diarrhea during post-disaster emergency medical rescue in tropical regions. CONCLUSIONS: High temperature, high humidity, and proliferation of microorganisms and parasites are the characteristics of tropical climate that impose strict requirements on the preparation of rescue work including selective team members suitable for a particular rescue mission and the provisioning of medical equipment and life support materials. The overseas rescue mission itself needs a scientific, efficient, simple workflow for providing efficient emergency medical assistance. Since shock and infection are major tasks in post-disaster treatment of severely injured victims in tropical regions, the prevention and diagnosis of hyperthermia, insect-borne infectious diseases, tropic skin diseases, infectious diarrhea, and pest harms of disaster victims and rescue team staff should be emphasized during the rescue operations. PMID:25215034

  7. Evolutionary rescue in vertebrates: evidence, applications and uncertainty

    PubMed Central

    Vander Wal, E.; Garant, D.; Festa-Bianchet, M.; Pelletier, F.

    2013-01-01

    The current rapid rate of human-driven environmental change presents wild populations with novel conditions and stresses. Theory and experimental evidence for evolutionary rescue present a promising case for species facing environmental change persisting via adaptation. Here, we assess the potential for evolutionary rescue in wild vertebrates. Available information on evolutionary rescue was rare and restricted to abundant and highly fecund species that faced severe intentional anthropogenic selective pressures. However, examples from adaptive tracking in common species and genetic rescues in species of conservation concern provide convincing evidence in favour of the mechanisms of evolutionary rescue. We conclude that low population size, long generation times and limited genetic variability will result in evolutionary rescue occurring rarely for endangered species without intervention. Owing to the risks presented by current environmental change and the possibility of evolutionary rescue in nature, we suggest means to study evolutionary rescue by mapping genotype → phenotype → demography → fitness relationships, and priorities for applying evolutionary rescue to wild populations. PMID:23209171

  8. The Pain and the Gain of Rescuing Historic Science Data: The Nimbus Data Rescue Project

    NASA Astrophysics Data System (ADS)

    Gallaher, D. W.; Campbell, G. G.

    2015-12-01

    While technology of our satellite systems have greatly improved the quality of observations over the past 50 years, it is the legacy of the first global coverage environment satellites, the Nimbus systems launched by NASA in the mid-1960s, that marks the beginning of a unique perspective from space. Such early data can extend our climate record and provide important context in longer-term climate changes. Unfortunately, the Nimbus data nearly disappeared before its value was recognized and attempts to recover the data were undertaken. While the Nimbus data was never truly lost, it was in a form that could not be read and was not organized in a way that could be accessed with modern computer systems. The rescue and recovery of the Nimbus data began in 2007 with an initiative by the NASA Goddard Space Flight Center. Without the Goddard efforts, the early Nimbus data might be forever dark. The Nimbus Rescue Project has just completed processing and archival of the Nimbus 4 visible and infrared observations from 1970 and 1971. This adds to our rescue efforts from Nimbus 1, 2 and 3 for 1964, 1966 and 1969. The procedures to recover the Nimbus data, from both film and tape, could be used by other data rescue projects, however the algorithms presented will tend to be Nimbus specific. The compositing of the mapped minimum brightness over weekly intervals resulted in never before seen views of the Polar Regions, such as a visible light view of the Antarctic ice extent from October 1970 (Figure 1). The Nimbus data recovery and reprocessing into modern formats was important, however it was the utility of the data as a part of the satellite climate record that made it valuable. Data rescue projects are often both difficult and time consuming but the data they bring back to the science community makes these efforts worthwhile.

  9. Leadership lessons from the Chilean mine rescue.

    PubMed

    Rashid, Faaiza; Edmondson, Amy C; Leonard, Herman B

    2013-01-01

    Three years ago, when a cave-in at the San José mine in Chile trapped 33 men under 700,000 metric tons of rock, experts estimated the probability of getting them out alive at less than 1%. Yet, after spending a record 69 days underground, all 33 were hoisted up to safety. The inspiring story of their rescue is a case study in how to lead in situations where the stakes, risk, and uncertainty are incredibly high and time pressure is intense. Today executives often find themselves in similar straits. When they do, many feel torn. Should they be directive, taking charge and commanding action? Or should they be empowering, enabling innovation and experimentation? As the successful example of André Sougarret, the chief of the mine rescue operation, shows, the answer is yes--to both. The choice is a false dichotomy. Implementing this dual approach involves three key tasks. Each has directive and enabling components. The first task is envisioning, which requires instilling both realism and hope. The second task is enrolling, which means setting clear boundaries for who is on and off the team, but inviting in helpful collaborators. The third task is engaging--leading disciplined execution while encouraging innovation and experimentation. The authors of this article describe how Sougarret ably juggled all of these tasks, orchestrating the efforts of hundreds of people from different organizations, areas of expertise, and countries in an extraordinary mission that overcame impossible odds. PMID:24730174

  10. [Anaesthesia under unfavorable conditions - rescue helicopter].

    PubMed

    Knacke, Peer G; Gehring, Hartmut; Saur, Petra

    2011-03-01

    Rescue helicopters are used for emergency care and transport of emergency patients. The dimension of the cabin is clearly limited. A transport is carried out under spatial narrowness and high noise levels. Acoustic alarms or noises caused by the patient are hardly to be perceived, so that the view at optical alarms is necessary. Environmental conditions affect the concentration on the patient. Rearrangement maneuvers represent the most critical phases. Always the whole apparative monitoring and respirator must be in the field of view of the emergency doctor, drugs to the care must be handy to be quickly administered, the quantity of oxygen has to be observed. Infusions and option of airway management are ready to set in advance. Standardized work with the aid of algorithms and knowledge of treatment recommendations and guidelines help to prevent errors. To optimize the care of emergency patients, special training courses for the crew of rescue helicopters are offered. A training simulator to practice different scenarios and the establishment of a CIRS system are recommended. PMID:21400396

  11. BH3 domain-independent apolipoprotein L1 toxicity rescued by BCL2 prosurvival proteins.

    PubMed

    Heneghan, J F; Vandorpe, D H; Shmukler, B E; Giovinazzo, J A; Giovinnazo, J A; Raper, J; Friedman, D J; Pollak, M R; Alper, S L

    2015-09-01

    The potent trypanolytic properties of human apolipoprotein L1 (APOL1) can be neutralized by the trypanosome variant surface antigen gene product known as serum resistance-associated protein. However, two common APOL1 haplotypes present uniquely in individuals of West African ancestry each encode APOL1 variants resistant to serum resistance-associated protein, and each confers substantial resistance to human African sleeping sickness. In contrast to the dominantly inherited anti-trypanosomal activity of APOL1, recessive inheritance of these two trypanoprotective APOL1 alleles predisposes to kidney disease. Proposed mechanisms of APOL1 toxicity have included BH3 domain-dependent autophagy and/or ion channel activity. We probed these potential mechanisms by expressing APOL1 in Xenopus laevis oocytes. APOL1 expression in oocytes increased ion permeability and caused profound morphological deterioration (toxicity). Coexpression of BCL2 family members rescued APOL1-associated oocyte toxicity in the order MCL1 ∼ BCLW > BCLXL ∼ BCL2A1 ≫ BCL2. Deletion of nine nominal core BH3 domain residues abolished APOL1-associated toxicity, but missense substitution of the same residues abolished neither oocyte toxicity nor its rescue by coexpressed MCL1. The APOL1 BH3 domain was similarly dispensable for the ability of APOL1 to rescue intact mice from lethal trypanosome challenge. Replacement of most extracellular Na(+) by K(+) also reduced APOL1-associated oocyte toxicity, allowing demonstration of APOL1-associated increases in Ca(2+) and Cl(-) fluxes and oocyte ion currents, which were similarly reduced by MCL1 coexpression. Thus APOL1 toxicity in Xenopus oocytes is BH3-independent, but can nonetheless be rescued by some BCL2 family proteins. PMID:26108665

  12. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease.

    PubMed

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie; Li, Xiaojie; Chandler-Militello, Devin; Mauceri, Joseph; Burm, Hayley B; Toner, Michael; Osipovitch, Mikhail; Jim Xu, Qiwu; Ding, Fengfei; Wang, Fushun; Kang, Ning; Kang, Jian; Curtin, Paul C; Brunner, Daniela; Windrem, Martha S; Munoz-Sanjuan, Ignacio; Nedergaard, Maiken; Goldman, Steven A

    2016-01-01

    The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder. PMID:27273432

  13. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

    PubMed Central

    Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie; Li, Xiaojie; Chandler-Militello, Devin; Mauceri, Joseph; Burm, Hayley B.; Toner, Michael; Osipovitch, Mikhail; Jim Xu, Qiwu; Ding, Fengfei; Wang, Fushun; Kang, Ning; Kang, Jian; Curtin, Paul C.; Brunner, Daniela; Windrem, Martha S.; Munoz-Sanjuan, Ignacio; Nedergaard, Maiken; Goldman, Steven A.

    2016-01-01

    The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder. PMID:27273432

  14. Defects and rescue of the minor salivary glands in Eda pathway mutants.

    PubMed

    Wells, K L; Mou, C; Headon, D J; Tucker, A S

    2011-01-15

    Despite their importance to oral health, the mechanisms of minor salivary gland (SG) development are largely unexplored. Here we present in vivo and in vitro analyses of developing minor SGs in wild type and mutant mice. Eda, Shh and Fgf signalling pathway genes are expressed in these glands from an early stage of development. Developing minor SGs are absent in Eda pathway mutant embryos, and these mice exhibit a dysplastic circumvallate papilla with disrupted Shh expression. Supplementation of Eda pathway mutant minor SG explants with recombinant EDA rescues minor SG induction. Supplementation with Fgf8 or Shh, previously reported targets of Eda signalling, leads to induction of gland like structures in a few cases, but these fail to develop into minor SGs. PMID:20969842

  15. Emotional Reactions of Rescue Workers Following a Tornado.

    ERIC Educational Resources Information Center

    McCammon, Susan L.; And Others

    Rescue and medical workers may be at risk for negative emotional experience following intervention efforts in disaster situations. To examine this possibility, 120 rescue and hospital personnel responded to a survey of their emotional reactions and coping behaviors 3 months after a devastating tornado. Twenty-eight subjects had been involved in…

  16. 30 CFR 57.4362 - Underground rescue and firefighting operations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Underground rescue and firefighting operations... MINES Fire Prevention and Control Firefighting Procedures/alarms/drills § 57.4362 Underground rescue and firefighting operations. Following evacuation of a mine in a fire emergency, only persons wearing and...

  17. 30 CFR 56.4330 - Firefighting, evacuation, and rescue procedures.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Firefighting, evacuation, and rescue procedures... Fire Prevention and Control Firefighting Procedures/alarms/drills § 56.4330 Firefighting, evacuation, and rescue procedures. (a) Mine operators shall establish emergency firefighting, evacuation,...

  18. 30 CFR 56.4330 - Firefighting, evacuation, and rescue procedures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Firefighting, evacuation, and rescue procedures... Fire Prevention and Control Firefighting Procedures/alarms/drills § 56.4330 Firefighting, evacuation, and rescue procedures. (a) Mine operators shall establish emergency firefighting, evacuation,...

  19. 30 CFR 57.4362 - Underground rescue and firefighting operations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Underground rescue and firefighting operations... MINES Fire Prevention and Control Firefighting Procedures/alarms/drills § 57.4362 Underground rescue and firefighting operations. Following evacuation of a mine in a fire emergency, only persons wearing and...

  20. 49 CFR 238.114 - Rescue access windows.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Rescue access windows. 238.114 Section 238.114 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PASSENGER EQUIPMENT SAFETY STANDARDS Safety Planning and General Requirements § 238.114 Rescue access windows....

  1. 77 FR 39745 - General Aviation Search and Rescue

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-05

    ... SAFETY BOARD General Aviation Search and Rescue The National Transportation Safety Board (NTSB) will convene a 2- day forum focused on general aviation search and rescue operations on July 17 and 18, 2012. In the United States, following the crash of a general aviation airplane, inland searches for...

  2. 46 CFR 133.140 - Stowage of rescue boats.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... survival craft at any other launching station. (b) Each rescue boat must be provided a means for recharging the rescue boat batteries from the OSV's power supply at a supply voltage not exceeding 50 volts. (c... Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OFFSHORE SUPPLY VESSELS...

  3. 46 CFR 108.565 - Stowage of rescue boats.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... operation of any survival craft at any other launching station. (4) Each rescue boat that is also a lifeboat... rescue boat batteries from the unit's power supply at a supply voltage not exceeding 50 volts. (c) Each... Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS...

  4. 29 CFR 553.215 - Ambulance and rescue service employees.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Protection and Law Enforcement Employees of Public Agencies Exemption Requirements § 553.215 Ambulance and rescue service employees. (a) Ambulance and rescue service employees of a public agency other than a fire... activities, the applicable standard is the one which applies to the activity in which the employee spends...

  5. Project Rescue: So Close and yet so Far

    ERIC Educational Resources Information Center

    Laster, Stephen

    2011-01-01

    This is the third installment in a four-part series that follows the exploits of Gene, a well-established CIO of a sizable IT organization at a top-100 university. Gene has been working with his team to regain the trust of the campus through Project Rescue, a 30-day turnaround plan focused on demonstrating IT's value. Project Rescue has two…

  6. Nitric oxide rescues thalidomide mediated teratogenicity

    PubMed Central

    Siamwala, Jamila H.; Veeriah, Vimal; Priya, M. Krishna; Rajendran, Saranya; Saran, Uttara; Sinha, Swaraj; Nagarajan, Shunmugam; T, Pradeep; Chatterjee, Suvro

    2012-01-01

    Thalidomide, a sedative drug given to pregnant women, unfortunately caused limb deformities in thousands of babies. Recently the drug was revived because of its therapeutic potential; however the search is still ongoing for an antidote against thalidomide induced limb deformities. In the current study we found that nitric oxide (NO) rescues thalidomide affected chick (Gallus gallus) and zebrafish (Danio rerio) embryos. This study confirms that NO reduced the number of thalidomide mediated limb deformities by 94% and 80% in chick and zebrafish embryos respectively. NO prevents limb deformities by promoting angiogenesis, reducing oxidative stress and inactivating caspase-3 dependent apoptosis. We conclude that NO secures angiogenesis in the thalidomide treated embryos to protect them from deformities. PMID:22997553

  7. Apollo 16 Crew Aboard Rescue Ship

    NASA Technical Reports Server (NTRS)

    1962-01-01

    The Apollo 16 Command Module splashed down in the Pacific Ocean on April 27, 1972 after an 11-day moon exploration mission. The 3-man crew is shown here aboard the rescue ship, USS Horton. From left to right are: Mission Commander John W. Young, Lunar Module pilot Charles M. Duke, and Command Module pilot Thomas K. Mattingly II. The sixth manned lunar landing mission, the Apollo 16 (SA-511) lifted off on April 16, 1972. The Apollo 16 mission continued the broad-scale geological, geochemical, and geophysical mapping of the Moon's crust, begun by the Apollo 15, from lunar orbit. This mission marked the first use of the Moon as an astronomical observatory by using the ultraviolet camera/spectrograph which photographed ultraviolet light emitted by Earth and other celestial objects. The Lunar Roving Vehicle, developed by the Marshall Space Flight Center, was also used.

  8. Air and sea rescue via satellite systems

    NASA Astrophysics Data System (ADS)

    Scales, W. C.; Swanson, R.

    1984-03-01

    Two approaches to a satellite system for air and sea rescue to be put into use by the 1990s, one employing polar-orbiting satellites and the other using fixed geosynchronous satellites over the equator, are discussed. A battery-powered transmitter on a ship or aircraft would be activated in an accident to emit a low-power omnidirectional signal that would be relayed by a satellite to an earth station. The polar-orbiting approach, now being evaluated on a small-scale with the Cospas-Sarsat system, allows complete coverage of the earth, including the poles, and provides a fix on the origin of the distress signals by means of the Doppler shift. A parallel effort for the testing of geostationary satellites to measure system sensitivity to various interference sources, to optimize design, and to measure land and sea performance is reviewed.

  9. Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: role of M1 muscarinic receptors

    PubMed Central

    Maltese, M.; Martella, G.; Madeo, G.; Fagiolo, I.; Tassone, A.; Ponterio, G.; Sciamanna, G.; Burbaud, P.; Conn, P.J.; Bonsi, P.; Pisani, A.

    2014-01-01

    Background Broad spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. Methods We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a+/Δgag) mice heterozygous for ΔE-torsinA and their controls (Tor1a+/+ mice). Results Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1-preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the non-selective antagonists orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1-dependent potentiation of NMDA current recorded from striatal neurons. Conclusions Our study demonstrate that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. PMID:25195914

  10. Protein dynamics associated with failed and rescued learning in the Ts65Dn mouse model of Down syndrome.

    PubMed

    Ahmed, Md Mahiuddin; Dhanasekaran, A Ranjitha; Block, Aaron; Tong, Suhong; Costa, Alberto C S; Stasko, Melissa; Gardiner, Katheleen J

    2015-01-01

    Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials

  11. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons.

    PubMed

    Ourednik, Jitka; Ourednik, Václav; Lynch, William P; Schachner, Melitta; Snyder, Evan Y

    2002-11-01

    We investigated the hypothesis that neural stem cells (NSCs) possess an intrinsic capacity to "rescue" dysfunctional neurons in the brains of aged mice. The study focused on a neuronal cell type with stereotypical projections that is commonly compromised in the aged brain-the dopaminergic (DA) neuron. Unilateral implantation of murine NSCs into the midbrains of aged mice, in which the presence of stably impaired but nonapoptotic DA neurons was increased by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was associated with bilateral reconstitution of the mesostriatal system. Functional assays paralleled the spatiotemporal recovery of tyrosine hydroxylase (TH) and dopamine transporter (DAT) activity, which, in turn, mirrored the spatiotemporal distribution of donor-derived cells. Although spontaneous conversion of donor NSCs to TH(+) cells contributed to nigral reconstitution in DA-depleted areas, the majority of DA neurons in the mesostriatal system were "rescued" host cells. Undifferentiated donor progenitors spontaneously expressing neuroprotective substances provided a plausible molecular basis for this finding. These observations suggest that host structures may benefit not only from NSC-derived replacement of lost neurons but also from the "chaperone" effect of some NSC-derived progeny. PMID:12379867

  12. Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness.

    PubMed

    Lentz, Jennifer J; Jodelka, Francine M; Hinrich, Anthony J; McCaffrey, Kate E; Farris, Hamilton E; Spalitta, Matthew J; Bazan, Nicolas G; Duelli, Dominik M; Rigo, Frank; Hastings, Michelle L

    2013-03-01

    Hearing impairment is the most common sensory disorder, with congenital hearing impairment present in approximately 1 in 1,000 newborns. Hereditary deafness is often mediated by the improper development or degeneration of cochlear hair cells. Until now, it was not known whether such congenital failures could be mitigated by therapeutic intervention. Here we show that hearing and vestibular function can be rescued in a mouse model of human hereditary deafness. An antisense oligonucleotide (ASO) was used to correct defective pre-mRNA splicing of transcripts from the USH1C gene with the c.216G>A mutation, which causes human Usher syndrome, the leading genetic cause of combined deafness and blindness. Treatment of neonatal mice with a single systemic dose of ASO partially corrects Ush1c c.216G>A splicing, increases protein expression, improves stereocilia organization in the cochlea, and rescues cochlear hair cells, vestibular function and low-frequency hearing in mice. These effects were sustained for several months, providing evidence that congenital deafness can be effectively overcome by treatment early in development to correct gene expression and demonstrating the therapeutic potential of ASOs in the treatment of deafness. PMID:23380860

  13. PDE-4 Inhibition Rescues Aberrant Synaptic Plasticity in Drosophila and Mouse Models of Fragile X Syndrome

    PubMed Central

    Choi, Catherine H.; Schoenfeld, Brian P.; Weisz, Eliana D.; Bell, Aaron J.; Chambers, Daniel B.; Hinchey, Joseph; Choi, Richard J.; Hinchey, Paul; Kollaros, Maria; Gertner, Michael J.; Ferrick, Neal J.; Terlizzi, Allison M.; Yohn, Nicole; Koenigsberg, Eric; Liebelt, David A.; Zukin, R. Suzanne; Woo, Newton H.; Tranfaglia, Michael R.; Louneva, Natalia; Arnold, Steven E.; Siegel, Steven J.

    2015-01-01

    Fragile X syndrome (FXS) is the leading cause of both intellectual disability and autism resulting from a single gene mutation. Previously, we characterized cognitive impairments and brain structural defects in a Drosophila model of FXS and demonstrated that these impairments were rescued by treatment with metabotropic glutamate receptor (mGluR) antagonists or lithium. A well-documented biochemical defect observed in fly and mouse FXS models and FXS patients is low cAMP levels. cAMP levels can be regulated by mGluR signaling. Herein, we demonstrate PDE-4 inhibition as a therapeutic strategy to ameliorate memory impairments and brain structural defects in the Drosophila model of fragile X. Furthermore, we examine the effects of PDE-4 inhibition by pharmacologic treatment in the fragile X mouse model. We demonstrate that acute inhibition of PDE-4 by pharmacologic treatment in hippocampal slices rescues the enhanced mGluR-dependent LTD phenotype observed in FXS mice. Additionally, we find that chronic treatment of FXS model mice, in adulthood, also restores the level of mGluR-dependent LTD to that observed in wild-type animals. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of FXS is an important advance, in that this identifies and validates PDE-4 inhibition as potential therapeutic intervention for the treatment of individuals afflicted with FXS. PMID:25568131

  14. 46 CFR 160.056-4 - Approval tests of prototype rescue boat.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... tests of prototype rescue boat. (a) Drop test. The rescue boat, fully equipped, shall be dropped, in a... unserviceable shall result from this drop. (b) Stability and freeboard test. The rescue boat shall...

  15. 46 CFR 160.056-4 - Approval tests of prototype rescue boat.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... tests of prototype rescue boat. (a) Drop test. The rescue boat, fully equipped, shall be dropped, in a... unserviceable shall result from this drop. (b) Stability and freeboard test. The rescue boat shall...

  16. 46 CFR 160.156-7 - Design, construction and performance of rescue boats and fast rescue boats.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 CFR part 164, subpart 164.120. (B) Glass reinforcement. Any glass reinforcement used must have... the type of rescue boat; (3) 46 CFR part 159; and (4) This subpart. (b) Each rescue boat must meet the... recognized by the Commandant in accordance with 46 CFR 8.220, the U.S. Navy, or the national body where...

  17. 46 CFR 160.156-7 - Design, construction and performance of rescue boats and fast rescue boats.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 CFR part 164, subpart 164.120. (B) Glass reinforcement. Any glass reinforcement used must have... the type of rescue boat; (3) 46 CFR part 159; and (4) This subpart. (b) Each rescue boat must meet the... recognized by the Commandant in accordance with 46 CFR 8.220, the U.S. Navy, or the national body where...

  18. 46 CFR 160.156-7 - Design, construction and performance of rescue boats and fast rescue boats.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 CFR part 164, subpart 164.120. (B) Glass reinforcement. Any glass reinforcement used must have... the type of rescue boat; (3) 46 CFR part 159; and (4) This subpart. (b) Each rescue boat must meet the... recognized by the Commandant in accordance with 46 CFR 8.220, the U.S. Navy, or the national body where...

  19. Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein.

    PubMed

    Gaffin, Robert D; Peña, James R; Alves, Marco S L; Dias, Fernando A L; Chowdhury, Shamim A K; Heinrich, Lynley S; Goldspink, Paul H; Kranias, Evangelia G; Wieczorek, David F; Wolska, Beata M

    2011-11-01

    We have recently shown that a temporary increase in sarcoplasmic reticulum (SR) cycling via adenovirus-mediated overexpression of sarcoplasmic reticulum ATPase (SERCA2) transiently improves relaxation and delays hypertrophic remodeling in a familial hypertrophic cardiomyopathy (FHC) caused by a mutation in the thin filament protein, tropomyosin (i.e., α-TmE180G or Tm180). In this study, we sought to permanently alter calcium fluxes via phospholamban (PLN) gene deletion in Tm180 mice in order to sustain long-term improvements in cardiac function and adverse cardiac remodeling/hypertrophy. While similar work has been done in FHCs resulting from mutations in thick myofilament proteins, no one has studied these effects in an FHC resulting from a thin filament protein mutation. Tm180 transgenic (TG) mice were crossbred with PLN knockout (KO) mice and four groups were studied in parallel: 1) non-TG (NTG), 2) Tm180, 3) PLNKO/NTG and 4) PLNKO/Tm180. Tm180 mice exhibit increased heart weight/body weight and hypertrophic gene markers compared to NTG mice, but levels in PLNKO/Tm180 mice were similar to NTG. Tm180 mice also displayed altered function as assessed via in situ pressure-volume analysis and echocardiography at 3-6 months and one year; however, altered function in Tm180 mice was rescued back to NTG levels in PLNKO/Tm180 mice. Collagen deposition, as assessed by Picrosirius Red staining, was increased in Tm180 mice but was similar in NTG and in PLNKO/Tm180 mice. Extracellular signal-regulated kinase (ERK1/2) phosphorylation increased in Tm180 mice while levels in PLNKO/Tm180 mice were similar to NTGs. The present study shows that by modulating SR calcium cycling, we were able to rescue many of the deleterious aspects of FHC caused by a mutation in the thin filament protein, Tm. PMID:21840315

  20. p53 Suppresses Tetraploid Development in Mice

    PubMed Central

    Horii, Takuro; Yamamoto, Masamichi; Morita, Sumiyo; Kimura, Mika; Nagao, Yasumitsu; Hatada, Izuho

    2015-01-01

    Mammalian tetraploid embryos die in early development because of defects in the epiblast. Experiments with diploid/tetraploid chimeric mice, obtained via the aggregation of embryonic stem cells, clarified that while tetraploid cells are excluded from epiblast derivatives, diploid embryos with tetraploid extraembryonic tissues can develop to term. Today, this method, known as tetraploid complementation, is usually used for rescuing extraembryonic defects or for obtaining completely embryonic stem (ES) cell-derived pups. However, it is still unknown why defects occur in the epiblast during mammalian development. Here, we demonstrated that downregulation of p53, a tumour suppressor protein, rescued tetraploid development in the mammalian epiblast. Tetraploidy in differentiating epiblast cells triggered p53-dependent cell-cycle arrest and apoptosis, suggesting the activation of a tetraploidy checkpoint during early development. Finally, we found that p53 downregulation rescued tetraploid embryos later in gestation. PMID:25752699

  1. Bax inactivation in lurcher mutants rescues cerebellar granule cells but not purkinje cells or inferior olivary neurons.

    PubMed

    Selimi, F; Vogel, M W; Mariani, J

    2000-07-15

    Lurcher is a gain-of-function mutation in the delta2 glutamate receptor gene (Grid2) that turns the receptor into a leaky ion channel. The expression of the Lurcher gene in heterozygous (Grid2(Lc/+)) mutants induces the death of almost all Purkinje cells starting from the second postnatal week. Ninety percent of the granule cells and 60-75% of the inferior olivary neurons die because of the loss of their target neurons, the Purkinje cells. The apoptotic nature of the neurodegeneration has been demonstrated previously by the presence of activated caspase-3 and DNA fragmentation. Bax, a pro-apoptotic gene of the Bcl-2 family, has been shown to be involved in developmental neuronal death. To study the role of Bax in Grid2(Lc/+) neurodegeneration, double mutants with Grid2(Lc/)+ mice and Bax knock-out mice (Bax-/-) were generated. Bax deletion had no effect on the death of Purkinje cells and inferior olivary neurons, although a temporary rescue of some Purkinje cells could be detected in P15 Grid2(Lc/)+;Bax-/- animals. From postnatal day 15 (P15) to P60, the number of granule cells in Grid2(Lc/)+;Bax-/-mice did not significantly change and was significantly increased compared with the number found in Grid2(Lc/)+;Bax+/+ mice. Granule cell number in P60 Grid2(Lc/)+;Bax-/- mice corresponded to 70% of the number found in wild-type mice. Our results show that Bax inactivation in Grid2(Lc/+) mice does not rescue intrinsic Purkinje cell death or the target-related cell death of olivary neurons, but Bax inactivation does inhibit persistently target-related cell death in cerebellar granule cells. PMID:10884318

  2. Medical rescue of naval combat: challenges and future.

    PubMed

    Jin, Hai; Hou, Li-Jun; Fu, Xiao-Bing

    2015-01-01

    There has been no large-scale naval combat in the last 30 years. With the rapid development of battleships, weapons manufacturing and electronic technology, naval combat will present some new characteristics. Additionally, naval combat is facing unprecedented challenges. In this paper, we discuss the topic of medical rescue at sea: what challenges we face and what we could do. The contents discussed in this paper contain battlefield self-aid buddy care, clinical skills, organized health services, medical training and future medical research programs. We also discuss the characteristics of modern naval combat, medical rescue challenges, medical treatment highlights and future developments of medical rescue at sea. PMID:26309738

  3. Space shuttle search and rescue experiment using synthetic aperture radar

    NASA Technical Reports Server (NTRS)

    Sivertson, W. E., Jr.; Larson, R. W.; Zelenka, J. S.

    1977-01-01

    The feasibility of a synthetic aperture radar for search and rescue applications was demonstrated with aircraft experiments. One experiment was conducted using the ERIM four-channel radar and several test sites in the Michigan area. In this test simple corner-reflector targets were successfully imaged. Results from this investigation were positive and indicate that the concept can be used to investigate new approaches focused on the development of a global search and rescue system. An orbital experiment to demonstrate the application of synthetic aperture radar to search and rescue is proposed using the space shuttle.

  4. Artist's concept illustrating cutaway view of Skylab Rescue Command Module

    NASA Technical Reports Server (NTRS)

    1973-01-01

    An artist's concept illustrating a cutaway view of the general arrangement of the Skylab Rescue Command Module (CM). The standard Skylab CM accommodates a crew of three with storage lockers on the aft bulkhead for resupply of experiment film and other equipment as well as the return of exposed film, data tapes and experiment samples. To convert the standard CM to a rescue vehicle, the storage lockers are removed and replaced with two crew couches in order to seat five crewmen. The rescue CM would then be launched with a crew of two.

  5. Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment

    PubMed Central

    Zhao, Hui-Jun; Sun, Tian-Tian; Chen, Hui-Min; Chen, Hao-Yan; An, Hui-Fang; Weng, Yu-Rong; Yu, Jun; Li, Min; Qin, Wen-Xin; Ma, Xiong; Shen, Nan; Hong, Jie; Fang, Jing-Yuan

    2015-01-01

    Background Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. Methods 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. Results The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone. Conclusions F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways. PMID:26397137

  6. Rescuing failed oral implants via Wnt activation

    PubMed Central

    Yin, Xing; Li, Jingtao; Chen, Tao; Mouraret, Sylvain; Dhamdhere, Girija; Brunski, John B.; Zou, Shujuan; Helms, Jill A.

    2016-01-01

    Aim Implant osseointegration is not always guaranteed and once fibrous encapsulation occurs clinicians have few options other than implant removal. Our goal was to test whether a WNT protein therapeutic could rescue such failed implants. Material and Methods Titanium implants were placed in over-sized murine oral osteotomies. A lack of primary stability was verified by mechanical testing. Interfacial strains were estimated by finite element modelling and histology coupled with histomorphometry confirmed the lack of peri-implant bone. After fibrous encapsulation was established peri-implant injections of a liposomal formulation of WNT3A protein (L-WNT3A) or liposomal PBS (L-PBS) were then initiated. Quantitative assays were employed to analyse the effects of L-WNT3A treatment. Results Implants in gap-type interfaces exhibited high interfacial strains and no primary stability. After verification of implant failure, L-WNT3A or L-PBS injections were initiated. L-WNT3A induced a rapid, significant increase in Wnt responsiveness in the peri-implant environment, cell proliferation and osteogenic protein expression. The amount of peri-implant bone and bone in contact with the implant were significantly higher in L-WNT3A cases. Conclusions These data demonstrate L-WNT3A can induce peri-implant bone formation even in cases where fibrous encapsulation predominates. PMID:26718012

  7. Rescuing the intracluster medium of NGC 5813

    NASA Astrophysics Data System (ADS)

    Soker, Noam; Hillel, Shlomi; Sternberg, Assaf

    2016-06-01

    We use recent X-ray observations of the intracluster medium (ICM) of the galaxy group NGC 5813 to confront theoretical studies of ICM thermal evolution with the newly derived ICM properties. We argue that the ICM of the cooling flow in the galaxy group NGC 5813 is more likely to be heated by mixing of post-shock gas from jets residing in hot bubbles with the ICM, than by shocks or turbulent-heating. Shocks thermalize only a small fraction of their energy in the inner regions of the cooling flow; in order to adequately heat the inner part of the ICM, they would overheat the outer regions by a large factor, leading to its ejection from the group. Heating by mixing, which was found to be much more efficient than turbulent-heating and shocks-heating, hence, rescues the outer ICM of NGC 5813 from its predestined fate according to cooling flow feedback scenarios that are based on heating by shocks.

  8. Equipment of medical backpacks in mountain rescue.

    PubMed

    Elsensohn, Fidel; Soteras, Inigo; Resiten, Oliver; Ellerton, John; Brugger, Hermann; Paal, Peter

    2011-01-01

    We conducted a survey of equipment in medical backpacks for mountain rescuers and mountain emergency physicians. The aim was to investigate whether there are standards for medical equipment in mountain rescue organizations associated with the International Commission for Mountain Emergency Medicine (ICAR MEDCOM). A questionnaire was completed by 18 member organizations from 14 countries. Backpacks for first responders are well equipped to manage trauma, but deficiencies in equipment to treat medical emergencies were found. Paramedic and physicians' backpacks were well equipped to provide advanced life support and contained suitable drugs. We recommend that medical backpacks should be equipped in accordance with national laws, the medical emergencies in a given region, and take into account the climate, geography, medical training of rescuers, and funding of the organization. Automated external defibrillator provision should be improved. The effects of temperature on the drugs and equipment should be considered. Standards for training in the use and maintenance of medical tools should be enforced. First responders and physicians should only use familiar tools and drugs. PMID:22206560

  9. Line drawing illustrating Skylab crew rescue mission profile

    NASA Technical Reports Server (NTRS)

    1971-01-01

    A line drawing by North American Rockwell Space Division artist illustrating Skylab crew rescue mission profile. The standard Command Module converts from a three-seater to accommodate five astronauts for the return trip.

  10. Space shuttle search and rescue experiment using synthetic aperture radar

    NASA Technical Reports Server (NTRS)

    Sivertson, W. E., Jr.; Larson, R. W.; Zelenka, J. S.

    1977-01-01

    Langley Research Center, NASA, is developing a concept for using a spaceborne synthetic aperture radar with passive reflectors for search and rescue applications. The feasibility of a synthetic aperture radar for search and rescue applications has been demonstrated with aircraft experiments. One experiment was conducted using the ERIM four-channel radar and several test sites in the Michigan area. In this test simple corner-reflector targets were successfully imaged. Results from this investigation were positive and indicate that the concept can be used to investigate new approaches focused on the development of a global search and rescue system. An orbital experiment to demonstrate the application of synthetic aperture radar to search and rescue is proposed using the space shuttle.

  11. 33 CFR 127.1505 - Emergency response and rescue.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... furnished to those personnel. Training and equipment that meets 29 CFR 1910.120, hazardous-waste operations... and rescue pending the arrival of resources for firefighting or pollution control. Response and...

  12. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens.

    PubMed

    White, André O; Kramár, Enikö A; López, Alberto J; Kwapis, Janine L; Doan, John; Saldana, David; Davatolhagh, M Felicia; Alaghband, Yasaman; Blurton-Jones, Mathew; Matheos, Dina P; Wood, Marcelo A

    2016-01-01

    Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations. PMID:27226355

  13. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens

    PubMed Central

    White, André O.; Kramár, Enikö A.; López, Alberto J.; Kwapis, Janine L.; Doan, John; Saldana, David; Davatolhagh, M. Felicia; Alaghband, Yasaman; Blurton-Jones, Mathew; Matheos, Dina P.; Wood, Marcelo A.

    2016-01-01

    Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations. PMID:27226355

  14. Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene

    PubMed Central

    Pitcher, Meagan R.; Herrera, José A.; Buffington, Shelly A.; Kochukov, Mikhail Y.; Merritt, Jonathan K.; Fisher, Amanda R.; Schanen, N. Carolyn; Costa-Mattioli, Mauro; Neul, Jeffrey L.

    2015-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2R255X). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2R255X mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2R255X allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2R255X embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein. PMID:25634563

  15. Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene.

    PubMed

    Pitcher, Meagan R; Herrera, José A; Buffington, Shelly A; Kochukov, Mikhail Y; Merritt, Jonathan K; Fisher, Amanda R; Schanen, N Carolyn; Costa-Mattioli, Mauro; Neul, Jeffrey L

    2015-05-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder that is usually caused by mutations in Methyl-CpG-binding Protein 2 (MECP2). Four of the eight common disease causing mutations in MECP2 are nonsense mutations and are responsible for over 35% of all cases of RTT. A strategy to overcome disease-causing nonsense mutations is treatment with nonsense mutation suppressing drugs that allow expression of full-length proteins from mutated genes with premature in-frame stop codons. To determine if this strategy is useful in RTT, we characterized a new mouse model containing a knock-in nonsense mutation (p.R255X) in the Mecp2 locus (Mecp2(R255X)). To determine whether the truncated gene product acts as a dominant negative allele and if RTT-like phenotypes could be rescued by expression of wild-type protein, we genetically introduced an extra copy of MECP2 via an MECP2 transgene. The addition of MECP2 transgene to Mecp2(R255X) mice abolished the phenotypic abnormalities and resulted in near complete rescue. Expression of MECP2 transgene Mecp2(R255X) allele also rescued mTORC1 signaling abnormalities discovered in mice with loss of function and overexpression of Mecp2. Finally, we treated Mecp2(R255X) embryonic fibroblasts with the nonsense mutation suppressing drug gentamicin and we were able to induce expression of full-length MeCP2 from the mutant p.R255X allele. These data provide proof of concept that the p.R255X mutation of MECP2 is amenable to the nonsense suppression therapeutic strategy and provide guidelines for the extent of rescue that can be expected by re-expressing MeCP2 protein. PMID:25634563

  16. Intraovarian Transplantation of Female Germline Stem Cells Rescue Ovarian Function in Chemotherapy-Injured Ovaries.

    PubMed

    Xiong, Jiaqiang; Lu, Zhiyong; Wu, Meng; Zhang, Jinjin; Cheng, Jing; Luo, Aiyue; Shen, Wei; Fang, Li; Zhou, Su; Wang, Shixuan

    2015-01-01

    Early menopause and infertility often occur in female cancer patients after chemotherapy (CTx). For these patients, oocyte/embryo cryopreservation or ovarian tissue cryopreservation is the current modality for fertility preservation. However, the above methods are limited in the long-term protection of ovarian function, especially for fertility preservation (very few females with cancer have achieved pregnancy with cryopreserved ovarian tissue or eggs until now). In addition, the above methods are subject to their scope (females with no husband or prepubertal females with no mature oocytes). Thus, many females who suffer from cancers would not adopt the above methods pre- and post-CTx due to their uncertainty, safety and cost-effectiveness. Therefore, millions of women have achieved long-term survival after thorough CTx treatment and have desired to rescue their ovarian function and fertility with economic, durable and reliable methods. Recently, some studies showed that mice with infertility caused by CTx can produce normal offspring through intraovarian injection of exogenous female germline stem cells (FGSCs). Though exogenous FGSC can be derived from mice without immune rejection in the same strain, it is difficult to obtain human female germline stem cells (hFGSCs), and immune rejection could occur between different individuals. In this study, infertility in mice was caused by CTx, and the ability of FGSCs to restore ovarian function or even produce offspring was assessed. We had successfully isolated and purified the FGSCs from adult female mice two weeks after CTx. After infection with GFP-carrying virus, the FGSCs were transplanted into ovaries of mice with infertility caused by CTx. Finally, ovarian function was restored and the recipients produced offspring long-term. These findings showed that mice with CTx possessed FGSCs, restoring ovarian function and avoiding immune rejection from exogenous germline stem cells. PMID:26431320

  17. Intraovarian Transplantation of Female Germline Stem Cells Rescue Ovarian Function in Chemotherapy-Injured Ovaries

    PubMed Central

    Wu, Meng; Zhang, Jinjin; Cheng, Jing; Luo, Aiyue; Shen, Wei; Fang, Li; Zhou, Su; Wang, Shixuan

    2015-01-01

    Early menopause and infertility often occur in female cancer patients after chemotherapy (CTx). For these patients, oocyte/embryo cryopreservation or ovarian tissue cryopreservation is the current modality for fertility preservation. However, the above methods are limited in the long-term protection of ovarian function, especially for fertility preservation (very few females with cancer have achieved pregnancy with cryopreserved ovarian tissue or eggs until now). In addition, the above methods are subject to their scope (females with no husband or prepubertal females with no mature oocytes). Thus, many females who suffer from cancers would not adopt the above methods pre- and post-CTx due to their uncertainty, safety and cost-effectiveness. Therefore, millions of women have achieved long-term survival after thorough CTx treatment and have desired to rescue their ovarian function and fertility with economic, durable and reliable methods. Recently, some studies showed that mice with infertility caused by CTx can produce normal offspring through intraovarian injection of exogenous female germline stem cells (FGSCs). Though exogenous FGSC can be derived from mice without immune rejection in the same strain, it is difficult to obtain human female germline stem cells (hFGSCs), and immune rejection could occur between different individuals. In this study, infertility in mice was caused by CTx, and the ability of FGSCs to restore ovarian function or even produce offspring was assessed. We had successfully isolated and purified the FGSCs from adult female mice two weeks after CTx. After infection with GFP-carrying virus, the FGSCs were transplanted into ovaries of mice with infertility caused by CTx. Finally, ovarian function was restored and the recipients produced offspring long-term. These findings showed that mice with CTx possessed FGSCs, restoring ovarian function and avoiding immune rejection from exogenous germline stem cells. PMID:26431320

  18. Rescue Effects: Irradiated Cells Helped by Unirradiated Bystander Cells

    PubMed Central

    Lam, R. K. K.; Fung, Y. K.; Han, W.; Yu, K. N.

    2015-01-01

    The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed. PMID:25625514

  19. Rescue effects: irradiated cells helped by unirradiated bystander cells.

    PubMed

    Lam, R K K; Fung, Y K; Han, W; Yu, K N

    2015-01-01

    The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed. PMID:25625514

  20. 30 CFR Appendix to Subpart B - Optional Form for Certifying Mine Rescue Teams

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Optional Form for Certifying Mine Rescue Teams... EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines Pt. 49, Subpt. B, App. Appendix to Subpart B—Optional Form for Certifying Mine Rescue Teams ER08FE08.000 ER08FE08.001...

  1. 75 FR 28200 - Safety Zone; Washington State Department of Transportation Ferries Division Marine Rescue...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-20

    ... Transportation Ferries Division Marine Rescue Response (M2R) Full-Scale Exercise for a Mass Rescue Incident (MRI... Madison. This training exercise will simulate a mass rescue incident (MRI) and will involve an abandon... Department of Transportation Ferries Division Marine Rescue Response (M2R) Full-Scale Exercise for a...

  2. Rescuing Loading Induced Bone Formation at Senescence

    PubMed Central

    Srinivasan, Sundar; Ausk, Brandon J.; Prasad, Jitendra; Threet, Dewayne; Bain, Steven D.; Richardson, Thomas S.; Gross, Ted S.

    2010-01-01

    The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential. PMID:20838577

  3. Defectors Can Create Conditions That Rescue Cooperation.

    PubMed

    Waite, Adam James; Cannistra, Caroline; Shou, Wenying

    2015-12-01

    Cooperation based on the production of costly common goods is observed throughout nature. This is puzzling, as cooperation is vulnerable to exploitation by defectors which enjoy a fitness advantage by consuming the common good without contributing fairly. Depletion of the common good can lead to population collapse and the destruction of cooperation. However, population collapse implies small population size, which, in a structured population, is known to favor cooperation. This happens because small population size increases variability in cooperator frequency across different locations. Since individuals in cooperator-dominated locations (which are most likely cooperators) will grow more than those in defector-dominated locations (which are most likely defectors), cooperators can outgrow defectors globally despite defectors outgrowing cooperators in each location. This raises the possibility that defectors can lead to conditions that sometimes rescue cooperation from defector-induced destruction. We demonstrate multiple mechanisms through which this can occur, using an individual-based approach to model stochastic birth, death, migration, and mutation events. First, during defector-induced population collapse, defectors occasionally go extinct before cooperators by chance, which allows cooperators to grow. Second, empty locations, either preexisting or created by defector-induced population extinction, can favor cooperation because they allow cooperator but not defector migrants to grow. These factors lead to the counterintuitive result that the initial presence of defectors sometimes allows better survival of cooperation compared to when defectors are initially absent. Finally, we find that resource limitation, inducible by defectors, can select for mutations adaptive to resource limitation. When these mutations are initially present at low levels or continuously generated at a moderate rate, they can favor cooperation by further reducing local population size

  4. Defectors Can Create Conditions That Rescue Cooperation

    PubMed Central

    Waite, Adam James; Cannistra, Caroline; Shou, Wenying

    2015-01-01

    Cooperation based on the production of costly common goods is observed throughout nature. This is puzzling, as cooperation is vulnerable to exploitation by defectors which enjoy a fitness advantage by consuming the common good without contributing fairly. Depletion of the common good can lead to population collapse and the destruction of cooperation. However, population collapse implies small population size, which, in a structured population, is known to favor cooperation. This happens because small population size increases variability in cooperator frequency across different locations. Since individuals in cooperator-dominated locations (which are most likely cooperators) will grow more than those in defector-dominated locations (which are most likely defectors), cooperators can outgrow defectors globally despite defectors outgrowing cooperators in each location. This raises the possibility that defectors can lead to conditions that sometimes rescue cooperation from defector-induced destruction. We demonstrate multiple mechanisms through which this can occur, using an individual-based approach to model stochastic birth, death, migration, and mutation events. First, during defector-induced population collapse, defectors occasionally go extinct before cooperators by chance, which allows cooperators to grow. Second, empty locations, either preexisting or created by defector-induced population extinction, can favor cooperation because they allow cooperator but not defector migrants to grow. These factors lead to the counterintuitive result that the initial presence of defectors sometimes allows better survival of cooperation compared to when defectors are initially absent. Finally, we find that resource limitation, inducible by defectors, can select for mutations adaptive to resource limitation. When these mutations are initially present at low levels or continuously generated at a moderate rate, they can favor cooperation by further reducing local population size

  5. RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR*

    PubMed Central

    Trzcińska-Daneluti, Agata M.; Chen, Anthony; Nguyen, Leo; Murchie, Ryan; Jiang, Chong; Moffat, Jason; Pelletier, Lawrence; Rotin, Daniela

    2015-01-01

    Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins. We identified 20 novel suppressors of ΔF508-CFTR maturation, including the FGFR1. These were subsequently validated by measuring channel activity by the YFP halide-sensitive assay following shRNA-mediated knockdown, immunoblotting for the mature (band C) ΔF508-CFTR and measuring the amount of surface ΔF508-CFTR by ELISA. The role of FGFR signaling on ΔF508-CFTR trafficking was further elucidated by knocking down FGFRs and their downstream signaling proteins: Erk1/2, Akt, PLCγ-1, and FRS2. Interestingly, inhibition of FGFR1 with SU5402 administered to intestinal organoids (mini-guts) generated from the ileum of ΔF508-CFTR homozygous mice resulted in a robust ΔF508-CFTR rescue. Moreover, combination of SU5402 and VX-809 treatments in cells led to an additive enhancement of ΔF508-CFTR rescue, suggesting these compounds operate by different mechanisms. Chaperone array analysis on human bronchial epithelial cells harvested from ΔF508/ΔF508-CFTR transplant patients treated with SU5402 identified altered expression of several chaperones, an effect validated by their overexpression or knockdown experiments. We propose that FGFR signaling regulates specific chaperones that control ΔF508-CFTR maturation, and suggest that FGFRs may serve as important targets for therapeutic intervention for the treatment of CF. PMID:25825526

  6. p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

    PubMed Central

    Caprio, Cinzia; Baldini, Antonio

    2014-01-01

    T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbx1. We found that Gbx2 expression is down-regulated in Tbx1+/− embryos and is restored to normal levels in Tbx1+/−;Trp53+/− embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1+/−;Trp53+/− embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically. PMID:25197075

  7. A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome.

    PubMed

    Scheibye-Knudsen, Morten; Mitchell, Sarah J; Fang, Evandro F; Iyama, Teruaki; Ward, Theresa; Wang, James; Dunn, Christopher A; Singh, Nagendra; Veith, Sebastian; Hasan-Olive, Md Mahdi; Mangerich, Aswin; Wilson, Mark A; Mattson, Mark P; Bergersen, Linda H; Cogger, Victoria C; Warren, Alessandra; Le Couteur, David G; Moaddel, Ruin; Wilson, David M; Croteau, Deborah L; de Cabo, Rafael; Bohr, Vilhelm A

    2014-11-01

    Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS. PMID:25440059

  8. Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells

    PubMed Central

    Ferdaoussi, Mourad; Dai, Xiaoqing; Jensen, Mette V.; Wang, Runsheng; Peterson, Brett S.; Huang, Chao; Ilkayeva, Olga; Smith, Nancy; Miller, Nathanael; Hajmrle, Catherine; Spigelman, Aliya F.; Wright, Robert C.; Plummer, Gregory; Suzuki, Kunimasa; Mackay, James P.; van de Bunt, Martijn; Gloyn, Anna L.; Ryan, Terence E.; Norquay, Lisa D.; Brosnan, M. Julia; Trimmer, Jeff K.; Rolph, Timothy P.; Kibbey, Richard G.; Manning Fox, Jocelyn E.; Colmers, William F.; Shirihai, Orian S.; Neufer, P. Darrell; Yeh, Edward T.H.; Newgard, Christopher B.; MacDonald, Patrick E.

    2015-01-01

    Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D. PMID:26389676

  9. Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model.

    PubMed

    Whittle, Nigel; Schmuckermair, Claudia; Gunduz Cinar, Ozge; Hauschild, Markus; Ferraguti, Francesco; Holmes, Andrew; Singewald, Nicolas

    2013-01-01

    Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'. PMID:22722028

  10. Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model

    PubMed Central

    Whittle, Nigel; Schmuckermair, Claudia; Gunduz Cinar, Ozge; Hauschild, Markus; Ferraguti, Francesco; Holmes, Andrew; Singewald, Nicolas

    2013-01-01

    Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. PMID:22722028

  11. Cyclin D2 rescues size and function of GATA4 haplo-insufficient hearts

    PubMed Central

    Yamak, Abir; Temsah, Rana; Maharsy, Wael; Caron, Sophie; Paradis, Pierre; Aries, Anne

    2012-01-01

    Transcription factor GATA4 is a key regulator of cardiomyocyte growth, and differentiation and 50% reduction in GATA4 levels results in hypoplastic hearts. Search for GATA4 targets/effectors revealed cyclin D2 (CD2), a member of the D-type cyclins (D1, D2, and D3) that play a vital role in cell growth and differentiation as a direct transcriptional target and a mediator of GATA4 growth in postnatal cardiomyocytes. GATA4 associates with the CD2 promoter in cardiomyocytes and is sufficient to induce endogenous CD2 transcription and to dose-dependently activate the CD2 promoter in heterologous cells. Cardiomyocyte-specific overexpression of CD2 results in enhanced postnatal cardiac growth because of increased cardiomyocyte proliferation. When these transgenic mice are crossed with Gata4 heterozygote mice, they rescue the hypoplastic cardiac phenotype of Gata4+/− mice and enhance cardiomyocyte survival and heart function. The data uncover a role for CD2 in the postnatal heart as an effector of GATA4 in myocyte growth and survival. The finding that postnatal upregulation of a cell-cycle gene in GATA4 haplo-insufficient hearts may be protective opens new avenues for maintaining or restoring cardiac function in GATA4-dependent cardiac disease. PMID:22923619

  12. Genetic p53 deficiency partially rescues the adrenocortical dysplasia (acd) phenotype at the expense of increased tumorigenesis

    PubMed Central

    Else, Tobias; Trovato, Alessia; Kim, Alex C.; Wu, Yipin; Ferguson, David O.; Kuick, Rork D.; Lucas, Peter C.; Hammer, Gary D.

    2009-01-01

    Summary Telomere dysfunction and shortening induce chromosomal instability and tumorigenesis. In this study, we analyze the adrenocortical dysplasia (acd) mouse, harboring a mutation in Tpp1/Acd. Additional loss of p53 dramatically rescues the acd phenotype in an organ-specific manner, including skin hyperpigmentation and adrenal morphology, but not germ cell atrophy. Survival to weaning age is significantly increased in Acdacd/acd p53−/− mice. On the contrary p53−/− and p53+/− mice with the Acdacd/acd genotype show a decreased tumor free survival compared to Acd+/+ mice. Tumors from Acdacd/acd p53+/− mice show a striking switch from the classical spectrum of p53−/− mice towards carcinomas. The acd mouse model provides further support for an in vivo role of telomere deprotection in tumorigenesis. Significance Critically shortened dysfunctional telomeres of the Terc−/− mice have been shown to impact tissue development and maintenance and lead to the occurrence of a pro-cancer genome. The present study examines the contribution of telomere shortening vs. telomere deprotection to the development of genetic instability and cancer. By studying the acd mouse, we show that telomere deprotection without significant telomere shortening is sufficient to induce tumor formation in the context of p53 absence. It also raises the possibility that telomere deprotection contributes to the high prevalence of carcinomas in humans. PMID:19477426

  13. Rescue of Brain Function Using Tunneling Nanotubes Between Neural Stem Cells and Brain Microvascular Endothelial Cells.

    PubMed

    Wang, Xiaoqing; Yu, Xiaowen; Xie, Chong; Tan, Zijian; Tian, Qi; Zhu, Desheng; Liu, Mingyuan; Guan, Yangtai

    2016-05-01

    Evidence indicates that neural stem cells (NSCs) can ameliorate cerebral ischemia in animal models. In this study, we investigated the mechanism underlying one of the neuroprotective effects of NSCs: tunneling nanotube (TNT) formation. We addressed whether the control of cell-to-cell communication processes between NSCs and brain microvascular endothelial cells (BMECs) and, particularly, the control of TNT formation could influence the rescue function of stem cells. In an attempt to mimic the cellular microenvironment in vitro, a co-culture system consisting of terminally differentiated BMECs from mice in a distressed state and NSCs was constructed. Additionally, engraftment experiments with infarcted mouse brains revealed that control of TNT formation influenced the effects of stem cell transplantation in vivo. In conclusion, our findings provide the first evidence that TNTs exist between NSCs and BMECs and that regulation of TNT formation alters cell function. PMID:26041660

  14. Development of a Mine Rescue Drilling System (MRDS) :

    SciTech Connect

    Raymond, David W.; Gaither, Katherine N.; Polsky, Yarom; Knudsen, Steven D.; Broome, Scott Thomas; Su, Jiann-Cherng; Blankenship, Douglas A.; Costin, Laurence S.

    2014-06-01

    Sandia National Laboratories (Sandia) has a long history in developing compact, mobile, very high-speed drilling systems and this technology could be applied to increasing the rate at which boreholes are drilled during a mine accident response. The present study reviews current technical approaches, primarily based on technology developed under other programs, analyzes mine rescue specific requirements to develop a conceptual mine rescue drilling approach, and finally, proposes development of a phased mine rescue drilling system (MRDS) that accomplishes (1) development of rapid drilling MRDS equipment; (2) structuring improved web communication through the Mine Safety & Health Administration (MSHA) web site; (3) development of an improved protocol for employment of existing drilling technology in emergencies; (4) deployment of advanced technologies to complement mine rescue drilling operations during emergency events; and (5) preliminary discussion of potential future technology development of specialized MRDS equipment. This phased approach allows for rapid fielding of a basic system for improved rescue drilling, with the ability to improve the system over time at a reasonable cost.

  15. Rescue of newborn ants by older Cataglyphis cursor adult workers.

    PubMed

    Nowbahari, Elise; Amirault, Céline; Hollis, Karen L

    2016-05-01

    Cataglyphis cursor worker ants are capable of highly sophisticated rescue behaviour in which individuals are able to identify what has trapped a nestmate and to direct their behaviour towards that obstacle. Nonetheless, rescue behaviour is constrained by workers' subcaste: whereas foragers, the oldest workers, are able both to give and to receive the most help, the youngest workers, inactives, neither give nor receive any help whatsoever; nurses give and receive intermediate levels of aid, reflecting their intermediate age. Such differences in rescue behaviour across subcastes suggest that age and experience play a critical role. In this species, as in many others in which a sensitive period for nestmate recognition exists, newly enclosed ants, called callows, are adopted by ants belonging not only to different colonies but also to different species; foreign callows receive nearly the same special care provided to resident newborns. Because callows are younger than inactives, which are incapable of soliciting rescue, we wondered whether entrapped callows would receive such aid. In the present study, we artificially ensnared individual callows from their own colony (homocolonial), from a different colony (heterocolonial), and from a different species (heterospecific), and tested each one with groups of five potential C. cursor rescuers, either all foragers or all nurses. Our results show that all three types of callows are able to elicit rescue behaviour from both foragers and nurses. Nonetheless, nurse rescuers are better able to discriminate between the three types of callow victims than are foragers. PMID:26846232

  16. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

    PubMed Central

    Ure, Kerstin; Lu, Hui; Wang, Wei; Ito-Ishida, Aya; Wu, Zhenyu; He, Ling-jie; Sztainberg, Yehezkel; Chen, Wu; Tang, Jianrong; Zoghbi, Huda Y

    2016-01-01

    The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome. DOI: http://dx.doi.org/10.7554/eLife.14198.001 PMID:27328321

  17. Repeated beta-2 adrenergic receptor agonist therapy attenuates the response to rescue bronchodilation in a hyperoxic newborn mouse model

    PubMed Central

    Raffay, Thomas; Kc, Prabha; Reynolds, James; Di Fiore, Juliann; MacFarlane, Peter; Martin, Richard

    2014-01-01

    Background Preterm infants with neonatal lung injury are prone to wheezing and are often treated with beta-2 adrenergic receptor (β-AR) agonists although any benefits of β-AR agonists may be lost with chronic use. Objective To investigate if repeated β-AR agonist exposures would down-regulate β-ARs in the immature lung resulting in a decreased response to bronchodilator rescue and whether hyperoxic exposure would aggravate this response. Methods Newborn mice were raised for 21 days in 60% or 21% oxygen and received daily aerosols of formoterol or saline. Respiratory system resistance (Rrs) and compliance (Crs) were measured in response to methacholine challenge and rescue bronchodilation with levalbuterol. Western blot analysis quantified the relative amount of lung β-ARs. Results Hyperoxia increased airway reactivity to methacholine. Animals raised in hyperoxia that received daily formoterol were most sensitive to methacholine and exhibited a blunted response to levalbuterol bronchodilation. Hyperoxia exposed animals receiving daily formoterol vs saline showed a significant decrease in the relative amount of lung β-ARs. Conclusions In this hyperoxia exposed neonatal mouse model, repeated β-AR agonist treatments increased airway reactivity and attenuated the response to a rescue bronchodilator. The blunted bronchodilator response could be explained by a reduced quantity of lung β-ARs. Our findings may account for a time-dependent decrease in therapeutic benefit of β-AR agonists in preterm infants with neonatal lung injury, which may have clinical consequences for patients already prone to airway hyperreactivity. PMID:24969536

  18. An unmanned search and rescue mission

    NASA Astrophysics Data System (ADS)

    Novaro Mascarello, Laura; Quagliotti, Fulvia; Bertini, Mario

    2016-04-01

    The Remotely Piloted Aircraft Systems (RPAS) are becoming more and more powerful and innovative and they have an increased interest in civil applications, in particular, after natural hazard phenomena. The RPAS is useful in search and rescue missions in high mountain where scenarios are unfriendly and the use of helicopters is often not profitable. First, the unmanned configuration is safer because there is no hazards for human life that is not on board. Moreover, it is cheaper due to the use of electric propulsion instead of internal combustion engine and to its small dimensions and weights. Finally, the use of the RPAS is faster while the helicopter is often not available because is involved in other missions or it cannot be used if the search mission is in impervious scenario, such as forests with thick vegetation. For instance, the RPAS can be used after an avalanche when victims have little time to be saved before the death by hypothermia. In most conditions, the body maintains a healthy temperature. However, if it is exposed to cold temperatures, especially with a high cooling factor from wind and high humidity, for extended periods, the control mechanisms of the body may not be able to maintain a normal body temperature. When you lose more heat than the body can generate, it takes over hypothermia, defined as a body temperature below 35° C. Wet clothing, fall into cold water or not adequately cover themselves during the cold season, are all factors that can increase the chances of hypothermia. Signs and symptoms (tremor, slurred speech, breathing abnormally slow, cold and pale skin, loss of coordination, fatigue, lethargy or apathy, confusion or memory loss) usually develop slowly. People with hypothermia typically experience a gradual loss of mental acuity and physical capacity, and realize that you have need of emergency medical care. For these reasons, the use of an RPAS could be crucial for the survival of disappeared people in high mountain. In

  19. Structures of oncogenic, suppressor and rescued p53 core-domain variants: mechanisms of mutant p53 rescue

    SciTech Connect

    Wallentine, Brad D.; Wang, Ying; Tretyachenko-Ladokhina, Vira; Tan, Martha; Senear, Donald F.; Luecke, Hartmut

    2013-10-01

    X-ray crystallographic structures of four p53 core-domain variants were determined in order to gain insights into the mechanisms by which certain second-site suppressor mutations rescue the function of a significant number of cancer mutations of the tumor suppressor protein p53. To gain insights into the mechanisms by which certain second-site suppressor mutations rescue the function of a significant number of cancer mutations of the tumor suppressor protein p53, X-ray crystallographic structures of four p53 core-domain variants were determined. These include an oncogenic mutant, V157F, two single-site suppressor mutants, N235K and N239Y, and the rescued cancer mutant V157F/N235K/N239Y. The V157F mutation substitutes a smaller hydrophobic valine with a larger hydrophobic phenylalanine within strand S4 of the hydrophobic core. The structure of this cancer mutant shows no gross structural changes in the overall fold of the p53 core domain, only minor rearrangements of side chains within the hydrophobic core of the protein. Based on biochemical analysis, these small local perturbations induce instability in the protein, increasing the free energy by 3.6 kcal mol{sup −1} (15.1 kJ mol{sup −1}). Further biochemical evidence shows that each suppressor mutation, N235K or N239Y, acts individually to restore thermodynamic stability to V157F and that both together are more effective than either alone. All rescued mutants were found to have wild-type DNA-binding activity when assessed at a permissive temperature, thus pointing to thermodynamic stability as the critical underlying variable. Interestingly, thermodynamic analysis shows that while N239Y demonstrates stabilization of the wild-type p53 core domain, N235K does not. These observations suggest distinct structural mechanisms of rescue. A new salt bridge between Lys235 and Glu198, found in both the N235K and rescued cancer mutant structures, suggests a rescue mechanism that relies on stabilizing the

  20. The evolving role of rescue therapy for acute myocardial infarction.

    PubMed

    Tadros, George M; Iliadis, Elias A; Wilson, Robert F; Henry, Timothy D

    2005-07-01

    Coronary reperfusion for acute ST-elevation myocardial infarction can be accomplished with fibrinolytic therapy or with percutaneous coronary intervention (PCI). Primary PCI provides more effective and sustained early reperfusion than fibrinolytic therapy, but is only available in a minority of hospitals worldwide. There is a lack of a definite method for identification of patients who have inadequate reperfusion after fibrinolysis. Transfer of patients after fibrinolysis for diagnostic angiography and possible rescue therapy is safe and feasible. Rescue PCI with the use of stents and antiplatelet therapy decreases cardiovascular mortality and morbidity compared with conservative therapy. Increasing use of primary PCI and forming networks to transfer patients to centers that offer primary PCI may decrease the need for rescue therapy in the future. PMID:19804147

  1. Rescue of recombinant Newcastle disease virus from cDNA.

    PubMed

    Ayllon, Juan; García-Sastre, Adolfo; Martínez-Sobrido, Luis

    2013-01-01

    Newcastle disease virus (NDV), the prototype member of the Avulavirus genus of the family Paramyxoviridae(1), is a non-segmented, negative-sense, single-stranded, enveloped RNA virus (Figure 1) with potential applications as a vector for vaccination and treatment of human diseases. In-depth exploration of these applications has only become possible after the establishment of reverse genetics techniques to rescue recombinant viruses from plasmids encoding their complete genomes as cDNA(2-5). Viral cDNA can be conveniently modified in vitro by using standard cloning procedures to alter the genotype of the virus and/or to include new transcriptional units. Rescue of such genetically modified viruses provides a valuable tool to understand factors affecting multiple stages of infection, as well as allows for the development and improvement of vectors for the expression and delivery of antigens for vaccination and therapy. Here we describe a protocol for the rescue of recombinant NDVs. PMID:24145366

  2. Synthetic Aperture Radar: The NCCS Enables Search and Rescue

    NASA Technical Reports Server (NTRS)

    2002-01-01

    For as long as planes have gone down, dedicated men and women have used ever-improving technologies to aid their search for survivors. Nearly 2,000 general aviation crashes occur each year in U.S.-and many, like the Montana incident, occur without witnesses. On average, every day in the U.S. one airplane is reported missing. The Air Force Rescue Coordination Center (AFRCC) organizes search missions for about 100 aircraft each year. Some of these are not found before the searches called off, and are discovered only by chance long after the crash. In some cases, the crash site is never found. NASA Search and Rescue Mission is using NCCS rescues to develop tools for processing radar data that can help these effort

  3. Urban search and rescue medical teams: FEMA Task Force System.

    PubMed

    Barbera, J A; Lozano, M

    1993-01-01

    Recent national and international disasters involving collapsed structures and trapped casualties (Mexico City; Armenia; Iran; Philippines; Charleston, South Carolina; Loma Prieta, California; and others) have provoked a heightened national concern for the development of an adequate capability to respond quickly and effectively to this type of calamity. The Federal Emergency Management Agency (FEMA) has responded to this need by developing an Urban Search and Rescue (US&R) Response System, a national system of multi-disciplinary task forces for rapid deployment to the site of a collapsed structure incident. Each 56-person task force includes a medical team capable of providing advanced emergency medical care both for task force members and for victims located and reached by the sophisticated search, rescue, and technical components of the task force. This paper reviews the background and development of urban search and rescue, and describes the make-up and function of the Federal Emergency Management Agency (FEMA) Task Force medical teams. PMID:10155479

  4. Design and implementation of fishery rescue data mart system

    NASA Astrophysics Data System (ADS)

    Pan, Jun; Huang, Haiguang; Liu, Yousong

    A novel data mart based system for fishery rescue field was designed and implemented. The system runs ETL process to deal with original data from various databases and data warehouses, and then reorganized the data into the fishery rescue data mart. Next, online analytical processing (OLAP) are carried out and statistical reports are generated automatically. Particularly, quick configuration schemes are designed to configure query dimensions and OLAP data sets. The configuration file will be transformed into statistic interfaces automatically through a wizard-style process. The system provides various forms of reporting files, including crystal reports, flash graphical reports, and two-dimensional data grids. In addition, a wizard style interface was designed to guide users customizing inquiry processes, making it possible for nontechnical staffs to access customized reports. Characterized by quick configuration, safeness and flexibility, the system has been successfully applied in city fishery rescue department.

  5. Rescue of Recombinant Newcastle Disease Virus from cDNA

    PubMed Central

    Ayllon, Juan; García-Sastre, Adolfo; Martínez-Sobrido, Luis

    2013-01-01

    Newcastle disease virus (NDV), the prototype member of the Avulavirus genus of the family Paramyxoviridae1, is a non-segmented, negative-sense, single-stranded, enveloped RNA virus (Figure 1) with potential applications as a vector for vaccination and treatment of human diseases. In-depth exploration of these applications has only become possible after the establishment of reverse genetics techniques to rescue recombinant viruses from plasmids encoding their complete genomes as cDNA2-5. Viral cDNA can be conveniently modified in vitro by using standard cloning procedures to alter the genotype of the virus and/or to include new transcriptional units. Rescue of such genetically modified viruses provides a valuable tool to understand factors affecting multiple stages of infection, as well as allows for the development and improvement of vectors for the expression and delivery of antigens for vaccination and therapy. Here we describe a protocol for the rescue of recombinant NDVs. PMID:24145366

  6. [Air rescue missions at night: Data analysis of primary and secondary missions by the DRF air rescue service in 2014].

    PubMed

    Aschenbrenner, U; Neppl, S; Ahollinger, F; Schweigkofler, U; Weigt, J O; Frank, M; Zimmermann, M; Braun, J

    2015-06-01

    The advantages that are inherent to the air ambulance service are shown in a reduction in mortality of critically ill or injured patients. The air ambulance service ensures quick and efficient medical care to a patient as well as the immediate transport of patients to a suitable hospital. In addition, primary air rescue has proved to be effective as a support for the standard ground-based ambulance services in some regions of Germany during the night. Under certain conditions, such as the strict adherence to established, practiced and coordinated procedures, air rescue at night does not have a significantly higher risk compared to operations in daytime. Particular requirements should be imposed for air rescue operations at night: a strict indication system for alerting, 4-man helicopter crews solely during the night as well as pilots (and copilots) with the correct qualifications and experience in dealing with night vision devices on a regular basis. Moreover, the helicopters need to be suitable and approved for night flying including cabin upgrades and the appropriate medical technology equipment. To increase the benefits of air rescue for specific diseases and injuries, a nationwide review of the processes is needed to further develop the primary air rescue service. PMID:26013391

  7. 46 CFR 12.615 - Requirements to qualify for an STCW endorsement in proficiency in survival craft and rescue boats...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... proficiency in survival craft and rescue boats other than lifeboats and fast rescue boats-limited (PSC-limited... lifeboats and fast rescue boats-limited (PSC-limited). (a) To qualify for an STCW endorsement in proficiency in survival craft and rescue boats other than lifeboats and fast rescue boats-limited...

  8. 46 CFR 12.613 - Requirements to qualify for an STCW endorsement in proficiency in survival craft and rescue boats...

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... proficiency in survival craft and rescue boats other than fast rescue boats (PSC). 12.613 Section 12.613... STCW endorsement in proficiency in survival craft and rescue boats other than fast rescue boats (PSC... fast rescue boats (PSC), the applicant must— (1) Be at least 18 years of age; (2) Meet the...

  9. The general rescue subsystem-adaptation and structure at sea

    SciTech Connect

    Skyttner, L.

    1992-12-31

    The existence of a general rescue subsystem in higher organisms, as part of the GLS theory and the GAS syndrome, is asserted. Working principle for the system and its existence throughout higher system levels are presented. Among important processes demonstrated are the adaptation of the system to special threats at sea and the storage of the system knowledge and organization in the sea-safety convention. Recursiveness of the rescue subsystem within all higher system levels was found to be a basic requisite for individual survival, especially at sea. Finally, the most serious threat to lives on board ships at sea, was found to be system morality failures. 12 refs.

  10. A Practice of Rescue Robot Contest in Junior High Schools

    NASA Astrophysics Data System (ADS)

    Kawada, Kazuo; Nagamatsu, Masayasu; Yamamoto, Toru

    The rescue robot contest for junior high school students was created to give students an opportunity to design a robot to rescue the victims under large scale disasters. The activity was not only intended as an humanitarian project but also aiming at students to : (1) take the role of victims and imagining the situation from his or her perspective, (2) enhance thinking skills, creativity through the problem solving processes and, (3) work cooperatively in groups. From results of questionnaire for the participated students, important factors for further implementation as curriculum of technology education are implied.

  11. Rescue of retinal function by BDNF in a mouse model of glaucoma.

    PubMed

    Domenici, Luciano; Origlia, Nicola; Falsini, Benedetto; Cerri, Elisa; Barloscio, Davide; Fabiani, Carlotta; Sansò, Marco; Giovannini, Luca

    2014-01-01

    Vision loss in glaucoma is caused by progressive dysfunction of retinal ganglion cells (RGCs) and optic nerve atrophy. Here, we investigated the effectiveness of BDNF treatment to preserve vision in a glaucoma experimental model. As an established experimental model, we used the DBA/2J mouse, which develops chronic intraocular pressure (IOP) elevation that mimics primary open-angle glaucoma (POAG). IOP was measured at different ages in DBA/2J mice. Visual function was monitored using the steady-state Pattern Electroretinogram (P-ERG) and visual cortical evoked potentials (VEP). RGC alterations were assessed using Brn3 immunolabeling, and confocal microscope analysis. Human recombinant BDNF was dissolved in physiological solution (0.9% NaCl); the effects of repeated intravitreal injections and topical eye BDNF applications were independently evaluated in DBA/2J mice with ocular hypertension. BDNF level was measured in retinal homogenate by ELISA and western blot. We found a progressive decline of P-ERG and VEP responses in DBA/2J mice between 4 and 7 months of age, in relationship with the development of ocular hypertension and the reduction of Brn3 immunopositive RGCs. Conversely, repeated intravitreal injections (BDNF concentration = 2 µg/µl, volume = 1 µl, for each injection; 1 injection every four days, three injections over two weeks) and topical eye application of BDNF eye-drops (12 µg/µl, 5 µl eye-drop every 48 h for two weeks) were able to rescue visual responses in 7 month DBA/2J mice. In particular, BDNF topical eye treatment recovered P-ERG and VEP impairment increasing the number of Brn3 immunopositive RGCs. We showed that BDNF effects were independent of IOP reduction. Thus, topical eye treatment with BDNF represents a promisingly safe and feasible strategy to preserve visual function and diminish RGC vulnerability to ocular hypertension. PMID:25536045

  12. Docosahexaenoic Acid Rescues Synaptogenesis Impairment and Long-Term Memory Deficits Caused by Postnatal Multiple Sevoflurane Exposures.

    PubMed

    Tao, Guorong; Luo, Yan; Xue, Qingsheng; Li, Guohui; Tan, Yongchang; Xiao, Jinglei; Yu, Buwei

    2016-01-01

    Sevoflurane exposures were demonstrated to induce neurotoxicity in the developing brain in both human and animal studies. However, there is no effective approach to reverse it. The present study aimed to evaluate the feasibility of utilizing docosahexaenoic acid (DHA) to prevent sevoflurane-induced neurotoxicity. P6 (postnatal 6 days) mice were administrated DHA after exposure to 3% sevoflurane for two hours daily in three consecutive days. Molecular expressions of synaptic makers (PSD95, synaptophysin) and synaptic morphological changes were investigated by Western blot analysis and transmission electron microscopy, respectively. Meanwhile, Morris water maze test was used to assess spatial memory of mice at P31 (postnatal 31 days). DHA restored sevoflurane-induced decreased level of PSD95 and synaptophysin expressions and increased PSD areas and also improved long-term spatial memory. These results suggest that DHA could rescue synaptogenesis impairment and long-term memory deficits in postnatal caused by multiple sevoflurane exposures. PMID:27597963

  13. Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria.

    PubMed

    Liu, Baohua; Ghosh, Shrestha; Yang, Xi; Zheng, Huiling; Liu, Xinguang; Wang, Zimei; Jin, Guoxiang; Zheng, Bojian; Kennedy, Brian K; Suh, Yousin; Kaeberlein, Matt; Tryggvason, Karl; Zhou, Zhongjun

    2012-12-01

    Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria. PMID:23217256

  14. Docosahexaenoic Acid Rescues Synaptogenesis Impairment and Long-Term Memory Deficits Caused by Postnatal Multiple Sevoflurane Exposures

    PubMed Central

    Tao, Guorong; Luo, Yan; Xue, Qingsheng; Li, Guohui; Tan, Yongchang

    2016-01-01

    Sevoflurane exposures were demonstrated to induce neurotoxicity in the developing brain in both human and animal studies. However, there is no effective approach to reverse it. The present study aimed to evaluate the feasibility of utilizing docosahexaenoic acid (DHA) to prevent sevoflurane-induced neurotoxicity. P6 (postnatal 6 days) mice were administrated DHA after exposure to 3% sevoflurane for two hours daily in three consecutive days. Molecular expressions of synaptic makers (PSD95, synaptophysin) and synaptic morphological changes were investigated by Western blot analysis and transmission electron microscopy, respectively. Meanwhile, Morris water maze test was used to assess spatial memory of mice at P31 (postnatal 31 days). DHA restored sevoflurane-induced decreased level of PSD95 and synaptophysin expressions and increased PSD areas and also improved long-term spatial memory. These results suggest that DHA could rescue synaptogenesis impairment and long-term memory deficits in postnatal caused by multiple sevoflurane exposures. PMID:27597963

  15. Endothelial Restoration of Receptor Activity-Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy.

    PubMed

    Kechele, Daniel O; Dunworth, William P; Trincot, Claire E; Wetzel-Strong, Sarah E; Li, Manyu; Ma, Hong; Liu, Jiandong; Caron, Kathleen M

    2016-09-01

    RAMPs (receptor activity-modifying proteins) serve as oligomeric modulators for numerous G-protein-coupled receptors, yet elucidating the physiological relevance of these interactions remains complex. Ramp2 null mice are embryonic lethal, with cardiovascular developmental defects similar to those observed in mice null for canonical adrenomedullin/calcitonin receptor-like receptor signaling. We aimed to genetically rescue the Ramp2(-/-) lethality in order to further delineate the spatiotemporal requirements for RAMP2 function during development and thereby enable the elucidation of an expanded repertoire of RAMP2 functions with family B G-protein-coupled receptors in adult homeostasis. Endothelial-specific expression of Ramp2 under the VE-cadherin promoter resulted in the partial rescue of Ramp2(-/-) mice, demonstrating that endothelial expression of Ramp2 is necessary and sufficient for survival. The surviving Ramp2(-/-) Tg animals lived to adulthood and developed spontaneous hypotension and dilated cardiomyopathy, which was not observed in adult mice lacking calcitonin receptor-like receptor. Yet, the hearts of Ramp2(-/-) Tg animals displayed dysregulation of family B G-protein-coupled receptors, including parathyroid hormone and glucagon receptors, as well as their downstream signaling pathways. These data suggest a functional requirement for RAMP2 in the modulation of additional G-protein-coupled receptor pathways in vivo, which is critical for sustained cardiovascular homeostasis. The cardiovascular importance of RAMP2 extends beyond the endothelium and canonical adrenomedullin/calcitonin receptor-like receptor signaling, in which future studies could elucidate novel and pharmacologically tractable pathways for treating cardiovascular diseases. PMID:27402918

  16. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.

    PubMed

    Pons-Espinal, Meritxell; Martinez de Lagran, Maria; Dierssen, Mara

    2013-12-01

    Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS. PMID:23969234

  17. Search and Rescue. Auxiliary Operational Specialty Course. Student Text.

    ERIC Educational Resources Information Center

    Coast Guard, Washington, DC.

    This text, based on the National Search and Rescue (SAR) Plan, was prepared to provide a course of study on common procedures for SAR operations so that any basically qualified person in the U.S. Coast Guard Auxiliary can effectively accomplish a SAR mission and act as on-scene commander if required. There are 13 chapters: Introduction to Search…

  18. EMERGENCY VICTIM CARE AND RESCUE, TEXTBOOK FOR SQUADMEN.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Education, Columbus. Trade and Industrial Education Service.

    DESIGNED FOR TRAINING EMERGENCY SQUAD PERSONNEL IN RESCUE PROCEDURES AND VICTIM CARE BEYOND BASIC FIRST AID, THIS TEXTBOOK WAS DEVELOPED BY A COMMITTEE OF SQUADMEN, DOCTORS, NURSES, FIREMEN, AND STATE TRADE AND INDUSTRIAL PERSONNEL TO BE USED IN ADULT TRAINING CLASSES OF FULL-TIME OR VOLUNTEER SQUADMEN. THE INSTRUCTIONAL MATERIAL INCLUDES 26…

  19. First steps towards rescuing Las-infected citrus germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Huanglongbing (HLB) disease is having significant impact on the USDA citrus breeding program as it has shown up in a number of trees which exist only in a virtually irreplaceable collection of diverse citrus types. It is critical that we rescue HLB-free budwood from elite germplasm that is HLB-patho...

  20. Synthetic aperture radar processing system for search and rescue

    NASA Astrophysics Data System (ADS)

    Huxtable, Barton D.; Jackson, Christopher R.; Mansfield, Arthur W.; Rais, Houra

    1997-06-01

    Synthetic aperture radar (SAR) is uniquely suited to help solve the search and rescue problem since it can be utilized either day or night and through both dense fog or thick cloud cover. This paper describes the search and rescue data processing system (SARDPS) developed at Goddard Space Flight Center. SARDPS was developed for the Search and Rescue Mission Office in order to conduct research, development, and technology demonstration of SAR to quickly locate small aircraft which have crashed in remote areas. In order to effectively apply SAR to the detection of crashed aircraft several technical challenges needed to be overcome. These include full resolution SAR image formation using low frequency radar appropriate for foliage penetration, the application of autofocusing for SAR motion compensation in the processing system, and the development of sophisticated candidate crash site detection algorithms. In addition, the need to dispatch rescue teams to specific locations requires precise SAR image georectification and map registration techniques. The final end-to-end processing system allows for raw SAR phase history data to be quickly converted to georeferenced map/image products with candidate crash site locations identified.

  1. Eco-evolutionary feedbacks, adaptive dynamics and evolutionary rescue theory

    PubMed Central

    Ferriere, Regis; Legendre, Stéphane

    2013-01-01

    Adaptive dynamics theory has been devised to account for feedbacks between ecological and evolutionary processes. Doing so opens new dimensions to and raises new challenges about evolutionary rescue. Adaptive dynamics theory predicts that successive trait substitutions driven by eco-evolutionary feedbacks can gradually erode population size or growth rate, thus potentially raising the extinction risk. Even a single trait substitution can suffice to degrade population viability drastically at once and cause ‘evolutionary suicide’. In a changing environment, a population may track a viable evolutionary attractor that leads to evolutionary suicide, a phenomenon called ‘evolutionary trapping’. Evolutionary trapping and suicide are commonly observed in adaptive dynamics models in which the smooth variation of traits causes catastrophic changes in ecological state. In the face of trapping and suicide, evolutionary rescue requires that the population overcome evolutionary threats generated by the adaptive process itself. Evolutionary repellors play an important role in determining how variation in environmental conditions correlates with the occurrence of evolutionary trapping and suicide, and what evolutionary pathways rescue may follow. In contrast with standard predictions of evolutionary rescue theory, low genetic variation may attenuate the threat of evolutionary suicide and small population sizes may facilitate escape from evolutionary traps. PMID:23209163

  2. Instructional Alternatives: Rescue Strategies for At-Risk Students.

    ERIC Educational Resources Information Center

    Wircenski, Jerry L.; And Others

    1990-01-01

    An instructional plan to rescue at-risk students must be based on a curriculum intended to serve all students. The creation of a functional curriculum, the promotion of employability skills, and an emphasis on improving study skills are instructional patterns that seem to be effective in reducing the number of student dropouts. Two alternatives…

  3. The role of "rescue saccades" in tracking objects through occlusions.

    PubMed

    Zelinsky, Gregory J; Todor, Andrei

    2010-01-01

    We hypothesize that our ability to track objects through occlusions is mediated by timely assistance from gaze in the form of "rescue saccades"-eye movements to tracked objects that are in danger of being lost due to impending occlusion. Observers tracked 2-4 target sharks (out of 9) for 20 s as they swam through a rendered 3D underwater scene. Targets were either allowed to enter into occlusions (occlusion trials) or not (no occlusion trials). Tracking accuracy with 2-3 targets was ≥ 92% regardless of target occlusion but dropped to 74% on occlusion trials with four targets (no occlusion trials remained accurate; 83%). This pattern was mirrored in the frequency of rescue saccades. Rescue saccades accompanied approximatlely 50% of the Track 2-3 target occlusions, but only 34% of the Track 4 occlusions. Their frequency also decreased with increasing distance between a target and the nearest other object, suggesting that it is the potential for target confusion that summons a rescue saccade, not occlusion itself. These findings provide evidence for a tracking system that monitors for events that might cause track loss (e.g., occlusions) and requests help from the oculomotor system to resolve these momentary crises. As the number of crises increase with the number of targets, some requests for help go unsatisfied, resulting in degraded tracking. PMID:21191133

  4. "Denmark 1943": Using Music to Teach Holocaust Rescue

    ERIC Educational Resources Information Center

    Lindquist, David H.

    2007-01-01

    Addressing the topic of rescue efforts poses particular challenges for teachers planning Holocaust curricula. While the issue leads many students to develop an engaged empathy with rescuers, teachers must avoid overemphasizing what was a limited occurrence within the overall Holocaust. This article presents a plan for using music to teach about…

  5. Beaconless search and rescue overview: history, development, and achievements

    NASA Astrophysics Data System (ADS)

    Wallace, Ronald G.; Affens, David W.; Rais, Houra

    1997-06-01

    The NASA Search and Rescue Mission at Goddard Space Flight Center (GSFC) is carrying out a technology development project intended to complement the COSPAS-SARSAT satellite-based distress alerting and locating system. This system is based on emergency radio beacons and cannot function when beacons fail to operate. The beaconless search and rescue concept utilizes an airborne or spaceborne remote sensing instrument, such as a synthetic aperture radar (SAR), to aid in searching for downed aircraft in remote regions when no beacon is present. Compared with conventional visual search, a radar-based system would be capable of dramatically improving crash site detection due to its wide area coverage and foliage penetration. Moreover, the performance of this system is unaffected by weather conditions and ambient light level and hence it offers quick response time which is vital to the survival of crash victims. The Search and Rescue Mission has conducted a series of field experiments using the Jet Propulsion Laboratory's airborne SAR system (AIRSAR) which has demonstrated the technical feasibility of using SAR. The SAR data processing software (SARDPS) developed at GSFC is used to produce high-quality SAR images for post-processing and analysis. Currently various elements of an operational system are being investigated, including a SAR designed specifically to meet search and rescue needs, real-time or near-real time on-board SAR processing, and processing algorithms for advanced automatic crash site detection, image geo- rectification and map registration.

  6. 78 FR 58567 - Criteria to Certify Coal Mine Rescue Teams

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-24

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF LABOR Mine Safety and Health Administration Criteria to Certify Coal Mine Rescue Teams AGENCY: Mine Safety and Health Administration, Labor. ACTION: Notice of availability; request for comments. SUMMARY: The...

  7. 78 FR 79010 - Criteria to Certify Coal Mine Rescue Teams

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-27

    ... training. MSHA published a notice in the Federal Register (78 FR 58567) announcing the availability of the... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF LABOR Mine Safety and Health Administration Criteria to Certify Coal Mine Rescue Teams AGENCY: Mine Safety...

  8. Organization and implementation of mass medical rescue after an earthquake.

    PubMed

    Zhang, Yan-Ling

    2014-01-01

    On May 12, 2008, an 8.0-magnitude earthquake occurred in Wenchuan, Sichuan Province. In this disaster, 69,000 people were killed, 18,000 people were reported missing, and 37,000 people were injured, including more than 10,000 who were seriously injured. Trauma was the most commonly observed type of injury, with fractures accounting for 74% of all injury cases. On April 14, 2010, a 7.1-magnitude earthquake occurred in Yushu of Qinghai Province. In this disaster, 2,698 people were killed, 270 people were reported missing, and 11,000 people were injured, including more than 3,100 who were seriously injured. Fracture injury accounted for 58.4% of all injury cases. After each earthquake, the Chinese Army Medical Services responded promptly, according to the previously established guidelines, and sent out elite forces to the disaster areas, with the objectives of organizing, coordinating and participating in an efficient and evidence-based medical rescue effort. After the Wenchuan earthquake, 397 mobile medical service teams including 7,061 health workers were sent to the disaster areas. A total of 69,000 casualties were treated, and 22,000 surgeries were performed. After the Yushu earthquake, 25 mobile medical service teams involving 2,025 health workers were sent. They performed 1,635 surgeries and created an astounding outcome of "zero deaths" in the aftermath of the earthquake during their treatment of casualties in a high-altitude region. Within a week after each earthquake, the military teams rescued approximately 60% of the total number of rescued casualties and evacuated approximately 80% of the total number of evacuated sick or wounded victims, playing a critical role and making invaluable contributions to earthquake relief. The experience and lessons learned from the rescue efforts of the Chinese military after the two earthquakes have highlighted several key aspects in emergency medical rescue: (1) medical rescue theories must be updated; (2) military

  9. An evaluation of coordination relationships during earthquake emergency rescue using entropy theory.

    PubMed

    Rong, Huang; Xuedong, Liang; Guizhi, Zeng; Yulin, Ye; Da, Wang

    2015-05-01

    Emergency rescue after an earthquake is complex work which requires the participation of relief and social organizations. Studying earthquake emergency coordination efficiency can not only help rescue organizations to define their own rescue missions, but also strengthens inter-organizational communication and collaboration tasks, improves the efficiency of emergency rescue, and reduces loss. In this paper, collaborative entropy is introduced to study earthquake emergency rescue operations. To study the emergency rescue coordination relationship, collaborative matrices and collaborative entropy functions are established between emergency relief work and relief organizations, and the collaborative efficiency of the emergency rescue elements is determined based on this entropy function. Finally, the Lushan earthquake is used as an example to evaluate earthquake emergency rescue coordination efficiency. PMID:26083170

  10. CD4 T Cell Depletion Substantially Augments the Rescue Potential of PD-L1 Blockade for Deeply Exhausted CD8 T Cells

    PubMed Central

    Penaloza-MacMaster, Pablo; Provine, Nicholas M.; Blass, Eryn

    2015-01-01

    In various models of chronic infections and cancers, blockade of the inhibitory programmed cell death-1 (PD-1) pathway has been shown to be promising at restoring immune function. However, there is not a complete understanding of the factors that influence responsiveness to programmed death-ligand 1 (PD-L1) blockade. In particular, it is currently unclear whether the efficacy of PD-L1 blockade is dependent on the stage of disease. In a model of chronic lymphocytic choriomeningitis virus infection in mice, we show that exhausted CD8 T cells during the late stage of infection are refractory to rescue by PD-L1 blockade. Interestingly, PD-L1 blockade during the late stage of infection resulted in a biased expansion of PD-1+ CTLA-4+ regulatory T cells (Tregs) over antiviral CD8 T cells. Although previous studies have shown that Treg ablation can enhance the immune rescue by PD-L1 blockade, this regimen may induce lethal autoimmunity. In this report, we show that PD-L1 blockade together with CD4 T cell depletion effectively rescued deeply exhausted CD8 T cells and enhanced antiviral control during the late stage of chronic infection without any associated mortality. These data demonstrate the pleiotropic effects of anti–PD-L1 therapy on both virus-specific CD8 T cells and Tregs, and suggest a novel strategy for effectively rescuing deeply exhausted CD8 T cells. PMID:26116499

  11. Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer's disease.

    PubMed

    Born, Heather A; Kim, Ji-Yoen; Savjani, Ricky R; Das, Pritam; Dabaghian, Yuri A; Guo, Qinxi; Yoo, Jong W; Schuler, Dorothy R; Cirrito, John R; Zheng, Hui; Golde, Todd E; Noebels, Jeffrey L; Jankowsky, Joanna L

    2014-03-12

    Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology. PMID:24623762

  12. Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis Enteropathica

    PubMed Central

    Geiser, Jim; De Lisle, Robert C.; Finkelstein, David; Adlard, Paul A.; Bush, Ashley I.; Andrews, Glen K.

    2013-01-01

    Background Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed. Methods/Principal Findings Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4intest KO phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver. Conclusions These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells. PMID:24015258

  13. Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease

    PubMed Central

    Born, Heather A.; Kim, Ji-Yoen; Savjani, Ricky R.; Das, Pritam; Dabaghian, Yuri A.; Guo, Qinxi; Yoo, Jong W.; Schuler, Dorothy R.; Cirrito, John R.; Zheng, Hui; Golde, Todd E.; Noebels, Jeffrey L.

    2014-01-01

    Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology. PMID:24623762

  14. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy.

    PubMed

    Lieberman, Andrew P; Yu, Zhigang; Murray, Sue; Peralta, Raechel; Low, Audrey; Guo, Shuling; Yu, Xing Xian; Cortes, Constanza J; Bennett, C Frank; Monia, Brett P; La Spada, Albert R; Hung, Gene

    2014-05-01

    Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients. PMID:24746732

  15. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes.

    PubMed

    Mei, Yuan; Monteiro, Patricia; Zhou, Yang; Kim, Jin-Ah; Gao, Xian; Fu, Zhanyan; Feng, Guoping

    2016-02-25

    Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain. PMID:26886798

  16. Early environmental therapy rescues brain development in a mouse model of Down syndrome.

    PubMed

    Begenisic, Tatjana; Sansevero, Gabriele; Baroncelli, Laura; Cioni, Giovanni; Sale, Alessandro

    2015-10-01

    Down syndrome (DS), the most common genetic disorder associated with intellectual disabilities, is an untreatable condition characterized by a number of developmental defects and permanent deficits in the adulthood. Ts65Dn mice, the major animal model for DS, display severe cognitive and synaptic plasticity defects closely resembling the human phenotype. Here, we employed a multidisciplinary approach to investigate, for the first time in developing Ts65Dn mice, the effects elicited by early environmental enrichment (EE) on brain maturation and function. We report that exposure to EE resulted in a robust increase in maternal care levels displayed by Ts65Dn mothers and led to a normalization of declarative memory abilities and hippocampal plasticity in trisomic offspring. The positive effects of EE on Ts65Dn phenotype were not limited to the cognitive domain, but also included a rescue of visual system maturation. The beneficial EE effects were accompanied by increased BDNF and correction of over-expression of the GABA vesicular transporter vGAT. These findings highlight the beneficial impact of early environmental stimuli and their potential for application in the treatment of major functional deficits in children with DS. PMID:26244989

  17. Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.

    PubMed

    Hong, Suk-Hyun; Dvorak-Ewell, Melita; Stevens, Hazel Y; Barish, Grant D; Castro, Glenda L; Nofsinger, Russell; Frangos, John A; Shoback, Dolores; Evans, Ronald M

    2013-11-19

    Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression. PMID:24191050

  18. Rescue of a primary myelofibrosis model by retinoid-antagonist therapy

    PubMed Central

    Hong, Suk-Hyun; Dvorak-Ewell, Melita; Stevens, Hazel Y.; Barish, Grant D.; Castro, Glenda L.; Nofsinger, Russell; Frangos, John A.; Shoback, Dolores; Evans, Ronald M.

    2013-01-01

    Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRTmRID) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRTmRID mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT–retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRTmRID mice results in up-regulation of TGF-β and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression. PMID:24191050

  19. CD40 Activation Rescues Antiviral CD8+ T Cells from PD-1-Mediated Exhaustion

    PubMed Central

    Isogawa, Masanori; Chung, Josan; Murata, Yasuhiro; Kakimi, Kazuhiro; Chisari, Francis V.

    2013-01-01

    The intrahepatic immune environment is normally biased towards tolerance. Nonetheless, effective antiviral immune responses can be induced against hepatotropic pathogens. To examine the immunological basis of this paradox we studied the ability of hepatocellularly expressed hepatitis B virus (HBV) to activate immunologically naïve HBV-specific CD8+ T cell receptor (TCR) transgenic T cells after adoptive transfer to HBV transgenic mice. Intrahepatic priming triggered vigorous in situ T cell proliferation but failed to induce interferon gamma production or cytolytic effector function. In contrast, the same T cells differentiated into cytolytic effector T cells in HBV transgenic mice if Programmed Death 1 (PD-1) expression was genetically ablated, suggesting that intrahepatic antigen presentation per se triggers negative regulatory signals that prevent the functional differentiation of naïve CD8+ T cells. Surprisingly, coadministration of an agonistic anti-CD40 antibody (αCD40) inhibited PD-1 induction and restored T cell effector function, thereby inhibiting viral gene expression and causing a necroinflammatory liver disease. Importantly, the depletion of myeloid dendritic cells (mDCs) strongly diminished the αCD40 mediated functional differentiation of HBV-specific CD8+ T cells, suggesting that activation of mDCs was responsible for the functional differentiation of HBV-specific CD8+ T cells in αCD40 treated animals. These results demonstrate that antigen-specific, PD-1-mediated CD8+ T cell exhaustion can be rescued by CD40-mediated mDC-activation. PMID:23853599

  20. Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model.

    PubMed

    Hüttenrauch, M; Brauß, A; Kurdakova, A; Borgers, H; Klinker, F; Liebetanz, D; Salinas-Riester, G; Wiltfang, J; Klafki, H W; Wirths, O

    2016-01-01

    The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia. PMID:27138799

  1. Rescue Shuttle Flight Re-Entry: Controlling Astronaut Thermal Exposure

    NASA Technical Reports Server (NTRS)

    Gillis, David B.; Hamilton, Douglas; Ilcus, Stana; Stepaniak, Phil; Polk, J. D.; Son, Chang; Bue, Grant

    2008-01-01

    A rescue mission for the STS-125 Hubble Telescope Repair Mission requires reentry from space with 11 crew members aboard, exceeding past cabin thermal load experience and risking crew thermal stress potentially causing cognitive performance and physiological decrements. The space shuttle crew cabin air revitalization system (ARS) was designed to support a nominal crew complement of 4 to 7 crew and 10 persons in emergencies, all in a shirt-sleeve environment. Subsequent to the addition of full pressure suits with individual cooling units, the ARS cannot maintain a stable temperature in the crew cabin during reentry thermal loads. Bulk cabin thermal models, used for rescue mission planning and analysis of crew cabin air, were unable to accurately represent crew workstation values of air flow, carbon dioxide, and heat content for the middeck. Crew temperature models suggested significantly elevated core temperatures. Planning for an STS-400 potential rescue of seven stranded crew utilized computational fluid dynamics (CFD) models to demonstrate inhomogeneous cabin thermal properties and improve analysis compared to bulk models. In the absence of monitoring of crew temperature, heart rate, metabolic rate and incomplete engineering data on the performance of the integrated cooling garment/cooling unit (ICG/CU) at cabin temperatures above 75 degrees F, related systems & models were reevaluated and tests conducted with humans in the loop. Changes to the cabin ventilation, ICU placement, crew reentry suit-donning procedures, Orbiter Program wave-off policy and post-landing power down and crew extraction were adopted. A second CFD and core temperature model incorporated the proposed changes and confirmed satisfactory cabin temperature, improved air distribution, and estimated core temperatures within safe limits. CONCLUSIONS: These changes in equipment, in-flight and post-landing procedures, and policy were implemented for the STS-400 rescue shuttle & will be implemented in

  2. Development of Space Shuttle Rescue and Recovery Operations

    NASA Technical Reports Server (NTRS)

    Chandler, Michael

    2011-01-01

    As the first Space Shuttle launch was still in our future, many from NASA, the Department of Defense (DoD) and NASA contractors were busy planning for not only a nominal launch and return, but contingency operations at the launch pad and landing sites. Prior to the first launch, detailed coordination, planning and simulations were conducted at all three locations and internal rescue procedures were taught at Kennedy Space Center (KSC). Later in the Program, the Transoceanic Abort Landing (TAL) sites were added in Europe and Africa. For the 51L mission a new TAL site was brought on line in Morocco. However, upon launch, the Shuttle Program experienced it's first lost. During the following months a complete review of all contingency operations (launch and landing) was completed. Many enhancements were made based on the reviews following. A Mode VIII water rescue was developed for NASA by the DoD before the STS-26 launch. Different concepts were explored and being debated by NASA. Training of the contingency forces was required before final decisions were made forcing the teaching of two different sets of procedures. To assist with training, a video was developed for the fire/crash/rescue personnel. This accompanied the detailed extraction procedures that were developed by a combination of KSC and DoD firemen. Training for the fire/crash/rescue personnel at Vandenberg AFB was also being planned before the accident happen. The fire/crash/rescue mockup that was being built at Chanute AFB was diverted to Edwards AFB. Educational Objectives: With the emphasis on Commercial Crew Programs for Space flight it is important that all involved understand what is required to prepare for contingencies. Cost effective means of being prepared for contingencies are needed. Questions: 1. When should planning for nominal and contingency operations begin? 2. What type of training aids are needed for contingency operations? 3. Who were the major contributors to Shuttle contingency

  3. 46 CFR 160.156-11 - Fabrication of prototype rescue boats and fast rescue boats for approval.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... accordance with the procedures for independent laboratory inspection in 46 CFR part 159, subpart 159.007 and... 46 CFR 159.005-11. (2) The independent laboratory must make such inspections as are necessary to... inspecting— (i) Fiber Reinforced Plastic (FRP) Construction. (A) FRP components of each prototype rescue...

  4. 46 CFR 160.156-11 - Fabrication of prototype rescue boats and fast rescue boats for approval.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... accordance with the procedures for independent laboratory inspection in 46 CFR part 159, subpart 159.007 and... 46 CFR 159.005-11. (2) The independent laboratory must make such inspections as are necessary to... inspecting— (i) Fiber Reinforced Plastic (FRP) Construction. (A) FRP components of each prototype rescue...

  5. 46 CFR 160.156-11 - Fabrication of prototype rescue boats and fast rescue boats for approval.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... accordance with the procedures for independent laboratory inspection in 46 CFR part 159, subpart 159.007 and... 46 CFR 159.005-11. (2) The independent laboratory must make such inspections as are necessary to... inspecting— (i) Fiber Reinforced Plastic (FRP) Construction. (A) FRP components of each prototype rescue...

  6. 14 CFR 139.319 - Aircraft rescue and firefighting: Operational requirements.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Aircraft rescue and firefighting... AND OPERATIONS CERTIFICATION OF AIRPORTS Operations § 139.319 Aircraft rescue and firefighting: Operational requirements. (a) Rescue and firefighting capability. Except as provided in paragraph (c) of...

  7. 14 CFR 139.319 - Aircraft rescue and firefighting: Operational requirements.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Aircraft rescue and firefighting... AND OPERATIONS CERTIFICATION OF AIRPORTS Operations § 139.319 Aircraft rescue and firefighting: Operational requirements. (a) Rescue and firefighting capability. Except as provided in paragraph (c) of...

  8. 14 CFR 139.317 - Aircraft rescue and firefighting: Equipment and agents.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Aircraft rescue and firefighting: Equipment... OPERATIONS CERTIFICATION OF AIRPORTS Operations § 139.317 Aircraft rescue and firefighting: Equipment and agents. Unless otherwise authorized by the Administrator, the following rescue and firefighting...

  9. 14 CFR 139.317 - Aircraft rescue and firefighting: Equipment and agents.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 3 2010-01-01 2010-01-01 false Aircraft rescue and firefighting: Equipment... OPERATIONS CERTIFICATION OF AIRPORTS Operations § 139.317 Aircraft rescue and firefighting: Equipment and agents. Unless otherwise authorized by the Administrator, the following rescue and firefighting...

  10. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  11. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  12. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  13. 46 CFR 12.10-9 - Endorsement for proficiency in fast rescue boats.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Endorsement for proficiency in fast rescue boats. 12.10... SEAMEN REQUIREMENTS FOR RATING ENDORSEMENTS Lifeboatman § 12.10-9 Endorsement for proficiency in fast rescue boats. (a) Each person engaged or employed as a lifeboatman proficient in fast rescue boats...

  14. 77 FR 64360 - Proposed Extension of Existing Information Collection; Mine Rescue Teams for Underground Metal...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-19

    ... Safety and Health Administration Proposed Extension of Existing Information Collection; Mine Rescue Teams...) to publish regulations which provide that mine rescue teams be available for rescue and recovery work... arrangements for such teams are to be borne by the operator of each such mine. II. Desired Focus of...

  15. 15 CFR 270.202 - Coordination with search and rescue efforts.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 1 2014-01-01 2014-01-01 false Coordination with search and rescue... SAFETY TEAMS NATIONAL CONSTRUCTION SAFETY TEAMS Investigations § 270.202 Coordination with search and rescue efforts. NIST will coordinate its investigation with any search and rescue or search and...

  16. 15 CFR 270.202 - Coordination with search and rescue efforts.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 1 2012-01-01 2012-01-01 false Coordination with search and rescue... SAFETY TEAMS NATIONAL CONSTRUCTION SAFETY TEAMS Investigations § 270.202 Coordination with search and rescue efforts. NIST will coordinate its investigation with any search and rescue or search and...

  17. 15 CFR 270.202 - Coordination with search and rescue efforts.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 1 2011-01-01 2011-01-01 false Coordination with search and rescue... SAFETY TEAMS NATIONAL CONSTRUCTION SAFETY TEAMS Investigations § 270.202 Coordination with search and rescue efforts. NIST will coordinate its investigation with any search and rescue or search and...

  18. 15 CFR 270.202 - Coordination with search and rescue efforts.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 1 2013-01-01 2013-01-01 false Coordination with search and rescue... SAFETY TEAMS NATIONAL CONSTRUCTION SAFETY TEAMS Investigations § 270.202 Coordination with search and rescue efforts. NIST will coordinate its investigation with any search and rescue or search and...

  19. 30 CFR 49.4 - Alternative mine rescue capability for special mining conditions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Alternative mine rescue capability for special mining conditions. 49.4 Section 49.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  20. 30 CFR 49.3 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Alternative mine rescue capability for small and remote mines. 49.3 Section 49.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  1. 30 CFR 49.3 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Alternative mine rescue capability for small and remote mines. 49.3 Section 49.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  2. 30 CFR 49.4 - Alternative mine rescue capability for special mining conditions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Alternative mine rescue capability for special mining conditions. 49.4 Section 49.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  3. 30 CFR 49.4 - Alternative mine rescue capability for special mining conditions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Alternative mine rescue capability for special mining conditions. 49.4 Section 49.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.4 Alternative mine rescue capability...

  4. 30 CFR 49.3 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Alternative mine rescue capability for small and remote mines. 49.3 Section 49.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.3 Alternative mine rescue capability...

  5. 30 CFR 49.4 - Alternative mine rescue capability for special mining conditions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Alternative mine rescue capability for special mining conditions. 49.4 Section 49.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  6. 30 CFR 49.3 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Alternative mine rescue capability for small and remote mines. 49.3 Section 49.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.3 Alternative mine rescue capability for small and remote mines. (a) If an underground...

  7. 30 CFR 49.4 - Alternative mine rescue capability for special mining conditions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Alternative mine rescue capability for special mining conditions. 49.4 Section 49.4 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.4 Alternative mine rescue capability for special mining conditions. (a) If an...

  8. 30 CFR 49.3 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Alternative mine rescue capability for small and remote mines. 49.3 Section 49.3 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal...

  9. 46 CFR 199.160 - Rescue boat embarkation, launching and recovery arrangements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 7 2010-10-01 2010-10-01 false Rescue boat embarkation, launching and recovery... Vessels § 199.160 Rescue boat embarkation, launching and recovery arrangements. (a) Each rescue boat must be capable of being launched with the vessel making headway of 5 knots in calm water. A painter...

  10. 46 CFR 199.160 - Rescue boat embarkation, launching and recovery arrangements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 7 2014-10-01 2014-10-01 false Rescue boat embarkation, launching and recovery... Vessels § 199.160 Rescue boat embarkation, launching and recovery arrangements. (a) Each rescue boat must be capable of being launched with the vessel making headway of 5 knots in calm water. A painter...

  11. 46 CFR 199.160 - Rescue boat embarkation, launching and recovery arrangements.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 7 2012-10-01 2012-10-01 false Rescue boat embarkation, launching and recovery... Vessels § 199.160 Rescue boat embarkation, launching and recovery arrangements. (a) Each rescue boat must be capable of being launched with the vessel making headway of 5 knots in calm water. A painter...

  12. 46 CFR 199.160 - Rescue boat embarkation, launching and recovery arrangements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 7 2013-10-01 2013-10-01 false Rescue boat embarkation, launching and recovery... Vessels § 199.160 Rescue boat embarkation, launching and recovery arrangements. (a) Each rescue boat must be capable of being launched with the vessel making headway of 5 knots in calm water. A painter...

  13. 46 CFR 199.160 - Rescue boat embarkation, launching and recovery arrangements.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 7 2011-10-01 2011-10-01 false Rescue boat embarkation, launching and recovery... Vessels § 199.160 Rescue boat embarkation, launching and recovery arrangements. (a) Each rescue boat must be capable of being launched with the vessel making headway of 5 knots in calm water. A painter...

  14. 77 FR 2017 - Safety Zone; Ice Rescue Exercise; Green Bay, Dyckesville, WI

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-13

    ... multiple agencies. The Captain of the Port Sector Lake has determined that this ice rescue exercise will... Port, Sector Lake Michigan, will be in the area of the ice rescue exercise at all times. (4) People or... SECURITY Coast Guard 33 CFR PART 165 RIN 1625-AA00 Safety Zone; Ice Rescue Exercise; Green Bay,...

  15. 30 CFR 49.13 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Alternative mine rescue capability for small and remote mines. 49.13 Section 49.13 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal...

  16. 30 CFR 49.13 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Alternative mine rescue capability for small and remote mines. 49.13 Section 49.13 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal...

  17. 30 CFR 49.13 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Alternative mine rescue capability for small and remote mines. 49.13 Section 49.13 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal...

  18. 30 CFR 49.7 - Physical requirements for mine rescue team.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Physical requirements for mine rescue team. 49.7 Section 49.7 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines §...

  19. 30 CFR Appendix to Subpart B of... - Optional Form for Certifying Mine Rescue Teams

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Optional Form for Certifying Mine Rescue Teams Appendix to Subpart B of Part 49 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines Pt....

  20. 30 CFR 49.7 - Physical requirements for mine rescue team.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Physical requirements for mine rescue team. 49.7 Section 49.7 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS § 49.7 Physical requirements for mine rescue team. (a) Each...

  1. 30 CFR Appendix to Subpart B - Optional Form for Certifying Mine Rescue Teams

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Optional Form for Certifying Mine Rescue Teams Appendix to Subpart B Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal Mines Pt. 49, Subpt. B,...

  2. 30 CFR 49.13 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Alternative mine rescue capability for small and remote mines. 49.13 Section 49.13 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal...

  3. 30 CFR 49.7 - Physical requirements for mine rescue team.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Physical requirements for mine rescue team. 49.7 Section 49.7 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Metal and Nonmetal Mines §...

  4. 30 CFR 49.13 - Alternative mine rescue capability for small and remote mines.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Alternative mine rescue capability for small and remote mines. 49.13 Section 49.13 Mineral Resources MINE SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR EDUCATION AND TRAINING MINE RESCUE TEAMS Mine Rescue Teams for Underground Coal...

  5. The ghosts of selection past reduces the probability of plastic rescue but increases the likelihood of evolutionary rescue to novel stressors in experimental populations of wild yeast.

    PubMed

    Samani, Pedram; Bell, Graham

    2016-03-01

    Persistence by adaptation is called evolutionary rescue. Evolutionary rescue is more likely in populations that have been previously exposed to lower doses of the same stressor. Environmental fluctuations might also reduce the possibility of rescue, but little is known about the effect of evolutionary history on the likelihood of rescue. In this study, we hypothesised that the ubiquitous operation of generalised stress responses in many organisms increases the likelihood of rescue after exposure to other stressors. We tested this hypothesis with experimental populations that had been exposed to long-term starvation and were then selected on different, unrelated stressors. We found that prior adaptation to starvation imposes contrary effects on the plastic and evolutionary responses of populations to subsequent stressors. When first exposed to new stressors, such populations become extinct more often. If they survive the initial exposure to the new stressors, however, they are more likely to undergo evolutionary rescue. PMID:26777785

  6. Constitutive Nuclear Expression of Dentin Matrix Protein 1 Fails to Rescue the Dmp1-null Phenotype*

    PubMed Central

    Lin, Shuxian; Zhang, Qi; Cao, Zhengguo; Lu, Yongbo; Zhang, Hua; Yan, Kevin; Liu, Ying; McKee, Marc D.; Qin, Chunlin; Chen, Zhi; Feng, Jian Q.

    2014-01-01

    Dentin matrix protein 1 (DMP1) plays multiple roles in bone, tooth, phosphate homeostasis, kidney, salivary gland, reproductive cycles, and the development of cancer. In vitro studies have indicated two different biological mechanisms: 1) as a matrix protein, DMP1 interacts with αvβ3 integrin and activates MAP kinase signaling; and 2) DMP1 serves as a transcription co-factor. In vivo studies have demonstrated its key role in osteocytes. This study attempted to determine whether DMP1 functions as a transcription co-factor and regulates osteoblast functions. For gene expression comparisons using adenovirus constructs, we targeted the expression of DMP1 either to the nucleus only by replacing the endogenous signal peptide with a nuclear localization signal (NLS) sequence (referred to as NLSDMP1) or to the extracellular matrix as the WT type (referred to as SPDMP1) in MC3T3 osteoblasts. High levels of DMP1 in either form greatly increased osteogenic gene expression in an identical manner. However, the targeted NLSDMP1 transgene driven by a 3.6-kb rat Col 1α1 promoter in the nucleus of osteoblasts and osteocytes failed to rescue the phenotyope of Dmp1-null mice, whereas the SPDMP1 transgene rescued the rickets defect. These studies support the notion that DMP1 functions as an extracellular matrix protein, rather than as a transcription co-factor in vivo. We also show that DMP1 continues its expression in osteoblasts during postnatal development and that the deletion of Dmp1 leads to an increase in osteoblast proliferation. However, poor mineralization in the metaphysis indicates a critical role for DMP1 in both osteoblasts and osteocytes. PMID:24917674

  7. Beta tubulin isoforms are not interchangeable for rescuing impaired radial migration due to Tubb3 knockdown.

    PubMed

    Saillour, Yoann; Broix, Loïc; Bruel-Jungerman, Elodie; Lebrun, Nicolas; Muraca, Giuseppe; Rucci, Julien; Poirier, Karine; Belvindrah, Richard; Francis, Fiona; Chelly, Jamel

    2014-03-15

    Over the last years, the critical role of cytoskeletal proteins in cortical development including neuronal migration as well as in neuronal morphology has been well established. Inputs from genetic studies were provided through the identification of several mutated genes encoding either proteins associated with microtubules (DCX, LIS1, KIF2A, KIF5C, DYNC1H1) or tubulin subunits (TUBA1A, TUBB2B, TUBB5 and TUBG1), in malformations of cortical development (MCD). We also reported the identification of missense mutations in TUBB3, the postmitotic neuronal specific tubulin, in six different families presenting either polymicrogyria or gyral disorganization in combination with cerebellar and basal ganglial abnormalities. Here, we investigate further the association between TUBB3 mutations and MCDs by analyzing the consequences of Tubb3 knockdown on cortical development in mice. Using the in utero-electroporation approach, we demonstrate that Tubb3 knockdown leads to delayed bipolar morphology and radial migration with evidence, suggesting that the neuronal arrest is a transient phenomenon overcome after birth. Silenced blocked cells display a round-shape and decreased number of processes and a delay in the acquisition of the bipolar morphology. Also, more Tbr2 positive cells are observed, although less cells express the proliferation marker Ki67, suggesting that Tubb3 inactivation might have an indirect effect on intermediate progenitor proliferation. Furthermore, we show by rescue experiments the non-interchangeability of other beta-tubulins which are unable to rescue the phenotype. Our study highlights the critical and specific role of Tubb3 on the stereotyped morphological changes and polarization processes that are required for initiating radial migration to the cortical plate. PMID:24179174

  8. Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment.

    PubMed

    Langlois, Chantale; Jorquera, Rossana; Orejuela, Diana; Bergeron, Anne; Finegold, Milton J; Rhead, William J; Tanguay, Robert M

    2008-03-01

    Hereditary tyrosinemia type 1 (HT1) is a recessive disease caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) that catalyzes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. In mice models of HT1, FAH deficiency causes death within the first 24h after birth. Administration of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC) prevents neonatal death in HT1 mice, ameliorates the HT1 phenotype but does not prevent development of hepatocellular carcinoma later on. FAA has been shown to deplete cells of glutathione by forming adducts. We tested whether a combination of a cell membrane permeable derivative of glutathione, glutathione monoethylester (GSH-MEE) and vitamin C could provide an alternative effective treatment for HT1. GSH-MEE (10 mmol/kg/j)/vitamin C (0.5 mmol/kg/j) treatment was given orally to pregnant/nursing female mice. While FAH-/- pups died in absence of treatment, all FAH-/- pups survived the critical first 24h of life when the mothers were on the GSH-MEE/vitamin C treatment and showed normal growth until postnatal day 10 (P10). However, after P10, pups showed failure to thrive, lethargy and died around P17. Thus, GSH-MEE/vitamin C supplementation could rescue the mice model of HT1 from neonatal death but it did not prevent the appearance of a HT1 phenotype in the second week after birth. PMID:18023223

  9. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer

    PubMed Central

    Bortolussi, Giulia; Zentilin, Lorena; Baj, Gabriele; Giraudi, Pablo; Bellarosa, Cristina; Giacca, Mauro; Tiribelli, Claudio; Muro, Andrés F.

    2012-01-01

    Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination.—Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A. F. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. PMID:22094718

  10. Evolutionary rescue: linking theory for conservation and medicine.

    PubMed

    Alexander, Helen K; Martin, Guillaume; Martin, Oliver Y; Bonhoeffer, Sebastian

    2014-12-01

    Evolutionary responses that rescue populations from extinction when drastic environmental changes occur can be friend or foe. The field of conservation biology is concerned with the survival of species in deteriorating global habitats. In medicine, in contrast, infected patients are treated with chemotherapeutic interventions, but drug resistance can compromise eradication of pathogens. These contrasting biological systems and goals have created two quite separate research communities, despite addressing the same central question of whether populations will decline to extinction or be rescued through evolution. We argue that closer integration of the two fields, especially of theoretical understanding, would yield new insights and accelerate progress on these applied problems. Here, we overview and link mathematical modelling approaches in these fields, suggest specific areas with potential for fruitful exchange, and discuss common ideas and issues for empirical testing and prediction. PMID:25558278

  11. Muskmelon embryo rescue techniques using in vitro embryo culture.

    PubMed

    Nuñez-Palenius, Hector Gordon; Ramírez-Malagón, Rafael; Ochoa-Alejo, Neftalí

    2011-01-01

    Among the major cucurbit vegetables, melon (Cucumis melo) has one of the greatest polymorphic fruit types and botanical varieties. Some melon fruits have excellent aroma, variety of flesh colors, deeper flavor, and more juice compared to other cucurbits. Despite numerous available melon cultivars, some of them are exceedingly susceptible to several diseases. The genetic background carrying the genes for tolerance and/or resistance for those diseases is found in wild melon landraces. Unfortunately, the commercial melon varieties are not able to produce viable hybrids when crossed with their wild melon counterparts. Plant tissue culture techniques are needed to surpass those genetic barriers. In vitro melon embryo rescue has played a main role to obtain viable hybrids originated from commercial versus wild melon crosses. In this chapter, an efficient and simple embryo rescue melon protocol is thoroughly described. PMID:21207265

  12. Simulation of extra-vehicular activity (EVA) self-rescue

    NASA Technical Reports Server (NTRS)

    Brody, Adam R.; Jacoby, Rick; Ellis, Stephen R.

    1991-01-01

    Self-rescue during EVA is examined in terms of the use of a hand-held thruster that is similar to the hand-held maneuvering units HHMU developed for earlier programs. The problem of assessing velocity-increment requirements is addressed by means of examples of simulation technologies for studying EVA. The technologies evaluated include virtual reality systems such as the Virtual Interactive Environment Workstation (VIEW) and the Space Operations Simulator, and standard approaches like the air-bearing floor and the space shuttle. The VIEW is employed for a study of five trained NASA subjects that conduct a simulated return to a spacecraft with an HMMU under variable conditions. The study demonstrates the efficacy of VIEW for obtaining fuel-consumption values, and separation velocity is identified as the most significant determinant of the fuel and time requirements for a self-rescue operation.

  13. Road traffic crashes managed by Rescue 1122 in Lahore, Pakistan.

    PubMed

    Tahir, Navid; Naseer, Rizwan; Khan, Samina Mohsin; Macassa, Gloria; Hashmi, Waseem; Durrani, Mohsin

    2012-01-01

    The objective of this retrospective study was to describe demographic characteristics, injury patterns and causes of road traffic crashes (RTCs) managed by Rescue 1122 in Lahore, Pakistan during the period 2005-2010. In total 123,268 RTCs were reported and responded by Rescue 1122 ambulance service during the study period. Of the 132,504 victims of RTCs, there were 67% male and 33% female subjects, and the maximum share (65%) was reported among people aged 16-35 years. Motorcyclists were involved in 45% of crashes, with over-speeding (40%) found to be the major reason of these collisions. Similarly, minor injuries (65%) and fractures (25%) were the most reported outcome of these crashes. It is concluded that data from ambulance services, if appropriately collected, can provide valuable epidemiological information to monitor RTCs in developing countries. However, in Pakistan, the collection of data as well as the registration process needs further improvement. PMID:22047006

  14. Evolutionary rescue: linking theory for conservation and medicine

    PubMed Central

    Alexander, Helen K; Martin, Guillaume; Martin, Oliver Y; Bonhoeffer, Sebastian

    2014-01-01

    Evolutionary responses that rescue populations from extinction when drastic environmental changes occur can be friend or foe. The field of conservation biology is concerned with the survival of species in deteriorating global habitats. In medicine, in contrast, infected patients are treated with chemotherapeutic interventions, but drug resistance can compromise eradication of pathogens. These contrasting biological systems and goals have created two quite separate research communities, despite addressing the same central question of whether populations will decline to extinction or be rescued through evolution. We argue that closer integration of the two fields, especially of theoretical understanding, would yield new insights and accelerate progress on these applied problems. Here, we overview and link mathematical modelling approaches in these fields, suggest specific areas with potential for fruitful exchange, and discuss common ideas and issues for empirical testing and prediction. PMID:25558278

  15. US Search and Rescue Mission Control Center functions

    NASA Technical Reports Server (NTRS)

    1977-01-01

    A satellite aided Search and Rescue (SAR) Mission concept consisting of a local coverage bent pipe system, and a global coverage system is described. The SAR instrument is to consist of a Canadian repeater and a French processor for which Canada and France, respectively are to evaluate health and trends. Performance evaluations of each system were provided. The United States and Canada will each have a Search and Rescue Mission Control Center (MCC) and their functions were also examined. A summary of the interface requirements necessary to perform each function was included as well as the information requirements between the USMCC and each of its interfaces. Physical requirements such as location, manning etc. of the USMCC were discussed.

  16. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

    PubMed

    Ongali, Brice; Nicolakakis, Nektaria; Tong, Xin-Kang; Aboulkassim, Tahar; Papadopoulos, Panayiota; Rosa-Neto, Pedro; Lecrux, Clotilde; Imboden, Hans; Hamel, Edith

    2014-08-01

    Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-β (Aβ) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aβ pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aβ species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors. PMID:24807206

  17. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.

    PubMed

    Wang, I-Fang; Guo, Bo-Shen; Liu, Yu-Chih; Wu, Cheng-Chun; Yang, Chun-Hung; Tsai, Kuen-Jer; Shen, Che-Kun James

    2012-09-11

    TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies. PMID:22932872

  18. Cardiomyocyte ultrastructural damage in β-thalassaemic mice

    PubMed Central

    Sanyear, Chanita; Butthep, Punnee; Nithipongvanich, Ramaneeya; Sirankapracha, Pornpan; Winichagoon, Pranee; Fucharoen, Suthat; Svasti, Saovaros

    2013-01-01

    β-thalassaemia is a hereditary anaemia resulting from the absence or reduction in β-globin chain production. Heart complications related to iron overload are the most serious cause of death in these patients. In this report cardiac pathology of β-thalassaemic mice was evaluated by light and electron microscopy. The study was carried out in thalassaemic mice carrying human β-thalassaemia mutation, IVSII-654 (654), transgenic mice carrying human βE-globin transgene insertion (E4), thalassaemic mice with human βE-globin transgene insertion (654/E4) and homozygous thalassaemic mice rescued by the human βE-globin transgene (R), which is generated by cross-breeding between the 654 and E4 mice. Histology showed iron deposition in cardiac myocytes of 654 and R mice, but the ultrastructural damage was observed only in the R mice when compared with the wild type, 654, E4 and 654/E4 mice. Histopathological changes in the cardiomyocytes of the R mice included mitochondrial swelling, loss of myofilaments and the presence of lipofuscin, related to the increased level of tissue iron content. The progressive ultrastructural pathology in R mice cardiomyocytes is consistent with the ultrastructural pathology previously studied in patients with thalassaemia. Thus, this R thalassaemic mouse model is suitable for in vivo pathophysiological study of thalassaemic heart. PMID:24020406

  19. Rescue Surgery 19 Years after Composite Root and Hemiarch Replacement

    PubMed Central

    Seeburger, Joerg; Etz, Christian D.; Sauer, Matthias; Lehmkuhl, Lukas; Misfeld, Martin; Mohr, Friedrich W.

    2013-01-01

    A 59-year-old male patient with Marfan's syndrome was referred to our clinic due to acute chest pain. His medical history contains complex surgery for type A aortic dissection 19 years ago including composite root replacement using a mechanical aortic valve. Immediate computed tomography indicated perforation at the distal ascending aortic anastomosis plus complete avulsion of both coronary ostia. The patient underwent successful rescue surgery with ascending aortic and arch replacement using a modified Cabrol technique. PMID:23662240

  20. Real Time GPS Positioning and Data Transmission For Rescue Services

    NASA Astrophysics Data System (ADS)

    Cefalo, R.; Degrassi, F.; Manzoni, G.; Moro, A.; Martinolli, S.; Pagurut, R.; Piemonte, A.; Sluga, T.

    Real time differential and interferential kinematic GPS positioning are under test for accurate rescue services by using DARC radio data transmission for RTCM messages from a reference station to the users and by SMS via GSM or GLOBALSTAR from the users to a control centre. EGNOS is under test too. The results of several experi- ments are shown. Problems, advantages and possible improvements with map on line availability and updating are discussed.

  1. ROBOTICS: Rescue Droids Stumble in an Urban Jungle.

    PubMed

    Sincell, M

    2000-08-11

    AUSTIN, TEXAS--Here at the 17th Annual National Conference on Artificial Intelligence, four teams of engineers fielded mechanical contestants in the first annual urban ruin search-and-rescue competition--a simulated catastrophe created to test intelligent lifesaving robots that may one day lead rescuers to people trapped in the precarious rubble of collapsed buildings. The competition indicated that the technology still has a way to go. PMID:17839147

  2. Science guides search and rescue after the 2006 Philippine landslide.

    PubMed

    Lagmay, Alfredo Mahar A; Tengonciang, Arlene Mae P; Rodolfo, Raymond S; Soria, Janneli Lea A; Baliatan, Eden G; Paguican, Engielle R; Ong, John Burtkenley T; Lapus, Mark R; Fernandez, Dan Ferdinand D; Quimba, Zareth P; Uichanco, Christopher L

    2008-09-01

    A rockslide-debris avalanche destroyed the remote village of Guinsaugon in Southern Leyte, Philippines, on 17 February 2006. Although search and rescue procedures were implemented immediately, the scale of the landslide and a lack of information about its nature resulted in unfocused and imprecise efforts in the early days of the operation. Technical support was only introduced five days after the event, provided by a team of volunteer geologists, geophysicists, and meteorologists. By the time search and rescue operations were transferred to specific target sites, however, the chances of finding survivors trapped under the rubble had diminished. In such critical situations, speed, accuracy, and the maximum appropriation of resources are crucial. We emphasise here the need for a systematic and technically informed approach to search and rescue missions in large-scale landslide disaster contexts, and the formulation of better disaster management policies in general. Standard procedures must be developed and enforced to improve how civil authorities respond to natural calamities. PMID:18958912

  3. Efficient transgenesis mediated by pigmentation rescue in zebrafish.

    PubMed

    Harrold, Itrat; Carbonneau, Seth; Moore, Bethany M; Nguyen, Gina; Anderson, Nicole M; Saini, Amandeep S; Kanki, John P; Jette, Cicely A; Feng, Hui

    2016-01-01

    The zebrafish represents a revolutionary tool in large-scale genetic and small-molecule screens for gene and drug discovery. Transgenic zebrafish are often utilized in these screens. Many transgenic fish lines are maintained in the heterozygous state due to the lethality associated with homozygosity; thus, their progeny must be sorted to ensure a population expressing the transgene of interest for use in screens. Sorting transgenic embryos under a fluorescence microscope is very labor-intensive and demands fine-tuned motor skills. Here we report an efficient transgenic method of utilizing pigmentation rescue of nacre mutant fish for accurate naked-eye identification of both mosaic founders and stable transgenic zebrafish. This was accomplished by co-injecting two constructs with the I-SceI meganuclease enzyme into pigmentless nacre embryos: I-SceI-mitfa:mitfa-I-SceI to rescue the pigmentation and I-SceI-zpromoter:gene-of-interest-I-SceI to express the gene of interest under a zebrafish promoter (zpromoter). Pigmentation rescue reliably predicted transgene integration. Compared with other transgenic techniques, our approach significantly increases the overall percentage of founders and facilitates accurate naked-eye identification of stable transgenic fish, greatly reducing laborious fluorescence microscope sorting and PCR genotyping. Thus, this approach is ideal for generating transgenic fish for large-scale screens. PMID:26757807

  4. Indirect evolutionary rescue: prey adapts, predator avoids extinction

    PubMed Central

    Yamamichi, Masato; Miner, Brooks E

    2015-01-01

    Recent studies have increasingly recognized evolutionary rescue (adaptive evolution that prevents extinction following environmental change) as an important process in evolutionary biology and conservation science. Researchers have concentrated on single species living in isolation, but populations in nature exist within communities of interacting species, so evolutionary rescue should also be investigated in a multispecies context. We argue that the persistence or extinction of a focal species can be determined solely by evolutionary change in an interacting species. We demonstrate that prey adaptive evolution can prevent predator extinction in two-species predator–prey models, and we derive the conditions under which this indirect evolutionary interaction is essential to prevent extinction following environmental change. A nonevolving predator can be rescued from extinction by adaptive evolution of its prey due to a trade-off for the prey between defense against predation and population growth rate. As prey typically have larger populations and shorter generations than their predators, prey evolution can be rapid and have profound effects on predator population dynamics. We suggest that this process, which we term ‘indirect evolutionary rescue’, has the potential to be critically important to the ecological and evolutionary responses of populations and communities to dramatic environmental change. PMID:26366196

  5. Group Task Force on Satellite Rescue and Repair

    NASA Technical Reports Server (NTRS)

    1992-01-01

    The Group Task Force was chartered by the Administrator of NASA to recommend 'a policy outlining the criteria, the design standards, and the pricing model to guide NASA in assessing the responsibilities for government and nongovernment Satellite Rescue and Repair Missions.' Criteria for accepting such missions, risks, and benefits to all sectors of our economy involved in satellite services, adequacy of planning and training, and the impact on NASA's primary mission were reviewed. The Group began by asking a more fundamental question; is satellite rescue and repair a logical element of NASA's mission? Factors considered were: (1) the probability of rescue or repair opportunities arising; (2) the economic justification for such attempts; (3) the benefits to NASA, both from such ad hoc learning experiences in space operations and the impact on the public perception of NASA; (4) the effect of such unanticipated missions on NASA's scheduled activities; (5) any potential effect on NASA's technical capability to work in space; and (6) any potential effect on U.S. economic competitiveness.

  6. Of rescue and responsibility: learning to live with limits.

    PubMed

    Morreim, E H

    1994-10-01

    Universal access to health care is still a dream rather than a reality in the United States. This is partly because a rule of rescue, by impelling us to help people in need, urges us to ignore the limits of our health care policies wherever those limits would adversely affect a given individual. As the rule of rescue undermines whatever limits we set on health care entitlements, it can thwart the cost containment so essential to expanding access. Rather than accept unlimited expense, we have thus far declined to universalize health care. The situation is exacerbated by an economic insulation shielding patients and physicians from the costs of care, prompting both to regard health care as free, an unlimited right. To reverse this costly entitlement mentality and place reasonable limits on rescue, patients must exercise greater personal responsibility for the costs of their care by directly experiencing some of the economic consequences of their health care decisions. Several mechanisms are available to accomplish this goal without posing economic barriers to needed care or penalizing people for becoming ill. PMID:7815001

  7. Vulture rescue and rehabilitation in South Africa: an urban perspective.

    PubMed

    Naidoo, V; Wolter, K; Espie, I; Kotze, A

    2011-03-01

    South Africa is home to 9 vulture species, of which 7 are endangered. While the cause of the population declines remains largely speculative, a vast amount of effort has been dedicated towards the protection of populations by ensuring sustainable and safe food sources for the various colonies. Limited focus was placed in the past on efforts related to the rescue and/or rehabilitation (R&R) of injured birds and the release of these birds back into the wild. This paper provides an overview of the causes, the impact and success of 3 organisations involved in R&R efforts of vultures in the Magaliesberg mountain range and surrounding areas over a period of 10 years. Study material included 162 Cape griffon (CGV) and 38 African white-backed (AWBV) vultures. Datasets include the number, sex and age of birds received, the reason the vultures were brought in for R&R, surgical interventions performed and outcomes of rescue efforts. The CGV dominated the rehabilitation attempts. Results further show that a large number of apparently healthy birds were presented for veterinary treatment. The R&R data clearly indicate that the major cause of injuries was birds colliding with overhead pylons, as a high number of soft tissue and skeletal injuries were observed. The study also shows that successful releases of rescued birds are possible. It is concluded that urbanisation has had a major negative impact on vultures around the Magaliesberg mountain range. PMID:21826834

  8. Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia.

    PubMed

    Clinkenbeard, Erica L; Cass, Taryn A; Ni, Pu; Hum, Julia M; Bellido, Teresita; Allen, Matthew R; White, Kenneth E

    2016-06-01

    The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2.3-cre(+) and Fgf23(Δ/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p < 0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p < 0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(Δ/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(Δ/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p < 0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23

  9. Space safety and rescue 1979-1981: Worldwide disaster response, rescue and safety employing space-borne systems

    NASA Technical Reports Server (NTRS)

    Brown, J. W. (Editor)

    1983-01-01

    Selected papers from the 1979, 1980, and 1981 IAA symposia on space safety and rescue and on worldwide disaster response, safety, and rescue employing spaceborne systems are presented. Available papers published elsewhere and those presented at the 1976, 1977, and 1978 symposia are presented in abstract form. Subjects discussed include man-made space debris, nuclear-waste disposal in space, space-station safety design, psychological training, the introduction of female crewmembers, analysis of the November 23, 1980 earthquake as a design basis for satellite emergency communication, disaster warning using the GOES satellite, and satellite communications for disaster relief operations. Three reviews of the application of space technology to emergency and disaster relief and prevention, given at other symposia in 1981, are presented in an appendix. No individual items are abstracted in this volume

  10. Individually Ventilated Cages Impose Cold Stress on Laboratory Mice: A Source of Systemic Experimental Variability

    PubMed Central

    David, John M; Knowles, Scott; Lamkin, Donald M; Stout, David B

    2013-01-01

    Individual ventilated cages (IVC) are increasing in popularity. Although mice avoid IVC in preference testing, they show no aversion when provided additional nesting material or the cage is not ventilated. Given the high ventilation rate in IVC, we developed 3 hypotheses: that mice housed in IVC experience more cold stress than do mice housed in static cages; that IVC-induced cold stress affects the results of experiments using mice; and that, when provided shelters, mice behaviorally thermoregulate and thereby rescue the cold-stress effects of IVC. To test these hypotheses, we housed mice in IVC, IVC with shelters, and static cages maintained at 20 to 21 °C. We quantified the cold stress of each housing system on mice by assessing nonshivering thermogenesis and brown adipose vacuolation. To test housing effects in a common, murine model of human disease, we implanted mice with subcutaneous epidermoid carcinoma cells and quantified tumor growth, tumor metabolism, and adrenal weight. Mice housed in IVC had histologic signs of cold stress and significantly higher nonshivering thermogenesis, smaller subcutaneous tumors, lower tumor metabolism, and larger adrenal weights than did mice in static cages. Shelters rescued IVC-induced nonshivering thermogenesis, adrenal enlargement, and phenotype-dependent cold-mediated histologic changes in brown adipose tissue and tumor size. IVC impose chronic cold stress on mice, alter experimental results, and are a source of systemic confounders throughout rodent-dependent research. Allowing mice to exhibit behavioral thermoregulation through seeking shelter markedly rescues the experiment-altering effects of housing-imposed cold stress, improves physiologic uniformity, and increases experimental reproducibility across housing systems. PMID:24351762

  11. A ground moving target emergency tracking method for catastrophe rescue

    NASA Astrophysics Data System (ADS)

    Zhou, X.; Li, D.; Li, G.

    2014-11-01

    In recent years, great disasters happen now and then. Disaster management test the emergency operation ability of the government and society all over the world. Immediately after the occurrence of a great disaster (e.g., earthquake), a massive nationwide rescue and relief operation need to be kicked off instantly. In order to improve the organizations efficiency of the emergency rescue, the organizers need to take charge of the information of the rescuer teams, including the real time location, the equipment with the team, the technical skills of the rescuers, and so on. One of the key factors for the success of emergency operations is the real time location of the rescuers dynamically. Real time tracking methods are used to track the professional rescuer teams now. But volunteers' participation play more and more important roles in great disasters. However, real time tracking of the volunteers will cause many problems, e.g., privacy leakage, expensive data consumption, etc. These problems may reduce the enthusiasm of volunteers' participation for catastrophe rescue. In fact, the great disaster is just small probability event, it is not necessary to track the volunteers (even rescuer teams) every time every day. In order to solve this problem, a ground moving target emergency tracking method for catastrophe rescue is presented in this paper. In this method, the handheld devices using GPS technology to provide the location of the users, e.g., smart phone, is used as the positioning equipment; an emergency tracking information database including the ID of the ground moving target (including the rescuer teams and volunteers), the communication number of the handheld devices with the moving target, and the usually living region, etc., is built in advance by registration; when catastrophe happens, the ground moving targets that living close to the disaster area will be filtered by the usually living region; then the activation short message will be sent to the selected

  12. Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

    PubMed Central

    Parkinson, Elizabeth I.; Bair, Joseph S.; Nakamura, Bradley A.; Lee, Hyang Y.; Kuttab, Hani I.; Southgate, Emma H.; Lezmi, Stéphane; Lau, Gee W.; Hergenrother, Paul J.

    2015-01-01

    Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections. PMID:25907309

  13. Rescue of peripheral and CNS axon defects in mice lacking NMNAT2.

    PubMed

    Gilley, Jonathan; Adalbert, Robert; Yu, Gang; Coleman, Michael P

    2013-08-14

    NMNAT2 is an NAD(+)-synthesizing enzyme with an essential axon maintenance role in primary culture neurons. We have generated an Nmnat2 gene trap mouse to examine the role of NMNAT2 in vivo. Homozygotes die perinatally with a severe peripheral nerve/axon defect and truncated axons in the optic nerve and other CNS regions. The cause appears to be limited axon extension, rather than dying-back degeneration of existing axons, which was previously proposed for the NMNAT2-deficient Blad mutant mouse. Neurite outgrowth in both PNS and CNS neuronal cultures consistently stalls at 1-2 mm, similar to the length of truncated axons in the embryos. Crucially, this suggests an essential role for NMNAT2 during axon growth. In addition, we show that the Wallerian degeneration slow protein (Wld(S)), a more stable, aberrant NMNAT that can substitute the axon maintenance function of NMNAT2 in primary cultures, can also correct developmental defects associated with NMNAT2 deficiency. This is dose-dependent, with extension of life span to at least 3 months by homozygous levels of Wld(S) the most obvious manifestation. Finally, we propose that endogenous mechanisms also compensate for otherwise limiting levels of NMNAT2. This could explain our finding that conditional silencing of a single Nmnat2 allele triggers substantial degeneration of established neurites, whereas similar, or greater, reduction of NMNAT2 in constitutively depleted neurons is compatible with normal axon growth and survival. A requirement for NMNAT2 for both axon growth and maintenance suggests that reduced levels could impair axon regeneration as well as axon survival in aging and disease. PMID:23946398

  14. Three types of rescue can avert extinction in a changing environment.

    PubMed

    Hufbauer, Ruth A; Szűcs, Marianna; Kasyon, Emily; Youngberg, Courtney; Koontz, Michael J; Richards, Christopher; Tuff, Ty; Melbourne, Brett A

    2015-08-18

    Setting aside high-quality large areas of habitat to protect threatened populations is becoming increasingly difficult as humans fragment and degrade the environment. Biologists and managers therefore must determine the best way to shepherd small populations through the dual challenges of reductions in both the number of individuals and genetic variability. By bringing in additional individuals, threatened populations can be increased in size (demographic rescue) or provided with variation to facilitate adaptation and reduce inbreeding (genetic rescue). The relative strengths of demographic and genetic rescue for reducing extinction and increasing growth of threatened populations are untested, and which type of rescue is effective may vary with population size. Using the flour beetle (Tribolium castaneum) in a microcosm experiment, we disentangled the genetic and demographic components of rescue, and compared them with adaptation from standing genetic variation (evolutionary rescue in the strictest sense) using 244 experimental populations founded at either a smaller (50 individuals) or larger (150 individuals) size. Both types of rescue reduced extinction, and those effects were additive. Over the course of six generations, genetic rescue increased population sizes and intrinsic fitness substantially. Both large and small populations showed evidence of being able to adapt from standing genetic variation. Our results support the practice of genetic rescue in facilitating adaptation and reducing inbreeding depression, and suggest that demographic rescue alone may suffice in larger populations even if only moderately inbred individuals are available for addition. PMID:26240320

  15. Three types of rescue can avert extinction in a changing environment

    PubMed Central

    Hufbauer, Ruth A.; Szűcs, Marianna; Kasyon, Emily; Youngberg, Courtney; Koontz, Michael J.; Richards, Christopher; Tuff, Ty; Melbourne, Brett A.

    2015-01-01

    Setting aside high-quality large areas of habitat to protect threatened populations is becoming increasingly difficult as humans fragment and degrade the environment. Biologists and managers therefore must determine the best way to shepherd small populations through the dual challenges of reductions in both the number of individuals and genetic variability. By bringing in additional individuals, threatened populations can be increased in size (demographic rescue) or provided with variation to facilitate adaptation and reduce inbreeding (genetic rescue). The relative strengths of demographic and genetic rescue for reducing extinction and increasing growth of threatened populations are untested, and which type of rescue is effective may vary with population size. Using the flour beetle (Tribolium castaneum) in a microcosm experiment, we disentangled the genetic and demographic components of rescue, and compared them with adaptation from standing genetic variation (evolutionary rescue in the strictest sense) using 244 experimental populations founded at either a smaller (50 individuals) or larger (150 individuals) size. Both types of rescue reduced extinction, and those effects were additive. Over the course of six generations, genetic rescue increased population sizes and intrinsic fitness substantially. Both large and small populations showed evidence of being able to adapt from standing genetic variation. Our results support the practice of genetic rescue in facilitating adaptation and reducing inbreeding depression, and suggest that demographic rescue alone may suffice in larger populations even if only moderately inbred individuals are available for addition. PMID:26240320

  16. Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants.

    PubMed

    Wang, Bei; Long, Jason E; Flandin, Pierre; Pla, Ramon; Waclaw, Ronald R; Campbell, Kenneth; Rubenstein, John L R

    2013-05-01

    Mice lacking the Dlx1 and Dlx2 homeobox genes (Dlx1/2 mutants) have severe deficits in subpallial differentiation, including overexpression of the Gsx1 and Gsx2 homeobox genes. To investigate whether Gsx overexpression contributes to the Dlx1/2 mutant phenotypes, we made compound loss-of-function mutants. Eliminating Gsx2 function from the Dlx1/2 mutants rescued the increased expression of Ascl1 and Hes5 (Notch signaling mediators) and Olig2 (oligodendrogenesis mediator). In addition, Dlx1/2;Gsx2 mutants, like Dlx1/2;Ascl1 mutants, exacerbated the Gsx2 and Dlx1/2 patterning and differentiation phenotypes, particularly in the lateral ganglionic eminence (LGE) caudal ganglionic eminence (CGE), and septum, including loss of GAD1 expression. On the other hand, eliminating Gsx1 function from the Dlx1/2 mutants (Dlx1/2;Gsx1 mutants) did not severely exacerbate their phenotype; on the contrary, it resulted in a partial rescue of medial ganglionic eminence (MGE) properties, including interneuron migration to the cortex. Thus, despite their redundant properties, Gsx1 and -2 have distinct interactions with Dlx1 and -2. Gsx2 interaction is strongest in the LGE, CGE, and septum, whereas the Gsx1 interaction is strongest in the MGE. From these studies, and earlier studies, we present a model of the transcriptional network that regulates early steps of subcortical development. PMID:23042297

  17. Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse.

    PubMed

    Dallérac, Glenn; Perronnet, Caroline; Chagneau, Carine; Leblanc-Veyrac, Pascale; Samson-Desvignes, Nathalie; Peltekian, Elise; Danos, Olivier; Garcia, Luis; Laroche, Serge; Billard, Jean-Marie; Vaillend, Cyrille

    2011-09-01

    Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a protein that fulfills important functions in both muscle and brain. The mdx mouse model of DMD, which also lacks dystrophin, shows a marked reduction in γ-aminobutyric acid type A (GABA(A))-receptor clustering in central inhibitory synapses and enhanced long-term potentiation (LTP) at CA3-CA1 synapses of the hippocampus. We have recently shown that U7 small nuclear RNAs modified to encode antisense sequences and expressed from recombinant adeno-associated viral (rAAV) vectors are able to induce skipping of the mutated exon 23 and to rescue expression of a functional dystrophin-like product both in the muscle and nervous tissue in vivo. In the brain, this rescue was accompanied by restoration of both the size and number of hippocampal GABA(A)-receptor clustering. Here, we report that 25.2±8% of re-expression two months after intrahippocampal injection of rAAV reverses the abnormally enhanced LTP phenotype at CA3-CA1 synapses of mdx mice. These results suggests that dystrophin expression indirectly influences synaptic plasticity through modulation of GABA(A)-receptor clustering and that re-expression of the otherwise deficient protein in the adult can significantly alleviate alteration of neural functions in DMD. PMID:21624465

  18. Trisomic hemopoietic stem cells of fetal origin restore hemopoiesis in lethally irradiated mice

    SciTech Connect

    Herbst, E.W.; Pluznik, D.H.; Gropp, A.; Uthgenannt, H.

    1981-03-13

    Autosomal trisomy in the mouse is invariably associated with fetal or early postnatal death. Hemopoietic stem cells from fetuses trisomic for chromosome 12 or 19 can be rescued by transplantation into lethally irradiated mice. These trisomic cells restore hemopoiesis, including lymphopoiesis, in the irradiated mice and establish a permanent and almost complete engraftment. There is no evidence that hemopoietic cells with trisomy 12 or 19 are cytogenetically unstable.

  19. Prolactin Rescues Immature B-Cells from Apoptosis Induced by B-Cell Receptor Cross-Linking

    PubMed Central

    Flores-Fernández, Rocio; Blanco-Favela, Francisco; Fuentes-Pananá, Ezequiel M.; Chávez-Sánchez, Luis; Gorocica-Rosete, Patricia; Pizaña-Venegas, Alberto; Chávez-Rueda, Adriana Karina

    2016-01-01

    Prolactin has an immunomodulatory effect and has been associated with B-cell-triggered autoimmune diseases, such as systemic lupus erythematosus (SLE). In mice that develop SLE, the PRL receptor is expressed in early bone marrow B-cells, and increased levels of PRL hasten disease manifestations, which are correlated with a reduction in the absolute number of immature B-cells. The aim of this work was to determine the effect of PRL in an in vitro system of B-cell tolerance using WEHI-231 cells and immature B-cells from lupus prone MRL/lpr mice. WEHI-231 cells express the long isoform of the PRL receptor, and PRL rescued the cells from cell death by decreasing the apoptosis induced by the cross-linking of the B-cell antigen receptor (BCR) as measured by Annexin V and active caspase-3. This decrease in apoptosis may have been due to the PRL and receptor interaction, which increased the relative expression of antiapoptotic Bcl-xL and decreased the relative expression of proapoptotic Bad. In immature B-cells from MRL/lpr mice, PRL increased the viability and decreased the apoptosis induced by the cross-linking of BCR, which may favor the maturation of self-reactive B-cells and contribute to the onset of disease. PMID:27314053

  20. Riluzole rescues glutamate alterations, cognitive deficits, and tau pathology associated with P301L tau expression.

    PubMed

    Hunsberger, Holly C; Weitzner, Daniel S; Rudy, Carolyn C; Hickman, James E; Libell, Eric M; Speer, Rebecca R; Gerhardt, Greg A; Reed, Miranda N

    2015-10-01

    Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease (AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 (CA3), and cornu ammonis 1 (CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. PMID:26146790

  1. Tactical mobile robots for urban search and rescue

    NASA Astrophysics Data System (ADS)

    Blitch, John; Sidki, Nahid; Durkin, Tim

    2000-07-01

    Few disasters can inspire more compassion for victims and families than those involving structural collapse. Video clips of children's bodies pulled from earthquake stricken cities and bombing sties tend to invoke tremendous grief and sorrow because of the totally unpredictable nature of the crisis and lack of even the slightest degree of negligence (such as with those who choose to ignore storm warnings). Heartbreaking stories of people buried alive for days provide a visceral and horrific perspective of some of greatest fears ever to be imagined by human beings. Current trends toward urban sprawl and increasing human discord dictates that structural collapse disasters will continue to present themselves at an alarming rate. The proliferation of domestic terrorism, HAZMAT and biological contaminants further complicates the matter further and presents a daunting problem set for Urban Search and Rescue (USAR) organizations around the world. This paper amplifies the case for robot assisted search and rescue that was first presented during the KNOBSAR project initiated at the Colorado School of Mines in 1995. It anticipates increasing technical development in mobile robot technologies and promotes their use for a wide variety of humanitarian assistance missions. Focus is placed on development of advanced robotic systems that are employed in a complementary tool-like fashion as opposed to traditional robotic approaches that portend to replace humans in hazardous tasks. Operational challenges for USAR are presented first, followed by a brief history of mobiles robot development. The paper then presents conformal robotics as a new design paradigm with emphasis on variable geometry and volumes. A section on robot perception follows with an initial attempt to characterize sensing in a volumetric manner. Collaborative rescue is then briefly discussed with an emphasis on marsupial operations and linked mobility. The paper concludes with an emphasis on Human Robot Interface

  2. Designing Allosteric Control into Enzymes by Chemical Rescue of Structure

    SciTech Connect

    Deckert, Katelyn; Budiardjo, S. Jimmy; Brunner, Luke C.; Lovell, Scott; Karanicolas, John

    2012-08-07

    Ligand-dependent activity has been engineered into enzymes for purposes ranging from controlling cell morphology to reprogramming cellular signaling pathways. Where these successes have typically fused a naturally allosteric domain to the enzyme of interest, here we instead demonstrate an approach for designing a de novo allosteric effector site directly into the catalytic domain of an enzyme. This approach is distinct from traditional chemical rescue of enzymes in that it relies on disruption and restoration of structure, rather than active site chemistry, as a means to achieve modulate function. We present two examples, W33G in a {beta}-glycosidase enzyme ({beta}-gly) and W492G in a {beta}-glucuronidase enzyme ({beta}-gluc), in which we engineer indole-dependent activity into enzymes by removing a buried tryptophan side chain that serves as a buttress for the active site architecture. In both cases, we observe a loss of function, and in both cases we find that the subsequent addition of indole can be used to restore activity. Through a detailed analysis of {beta}-gly W33G kinetics, we demonstrate that this rescued enzyme is fully functionally equivalent to the corresponding wild-type enzyme. We then present the apo and indole-bound crystal structures of {beta}-gly W33G, which together establish the structural basis for enzyme inactivation and rescue. Finally, we use this designed switch to modulate {beta}-glycosidase activity in living cells using indole. Disruption and recovery of protein structure may represent a general technique for introducing allosteric control into enzymes, and thus may serve as a starting point for building a variety of bioswitches and sensors.

  3. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

    PubMed Central

    Polito, Vinicia A; Li, Hongmei; Martini-Stoica, Heidi; Wang, Baiping; Yang, Li; Xu, Yin; Swartzlander, Daniel B; Palmieri, Michela; di Ronza, Alberto; Lee, Virginia M-Y; Sardiello, Marco; Ballabio, Andrea; Zheng, Hui

    2014-01-01

    Accumulating evidence implicates impairment of the autophagy-lysosome pathway in Alzheimer's disease (AD). Recently discovered, transcription factor EB (TFEB) is a molecule shown to play central roles in cellular degradative processes. Here we investigate the role of TFEB in AD mouse models. In this study, we demonstrate that TFEB effectively reduces neurofibrillary tangle pathology and rescues behavioral and synaptic deficits and neurodegeneration in the rTg4510 mouse model of tauopathy with no detectable adverse effects when expressed in wild-type mice. TFEB specifically targets hyperphosphorylated and misfolded Tau species present in both soluble and aggregated fractions while leaving normal Tau intact. We provide in vitro evidence that this effect requires lysosomal activity and we identify phosphatase and tensin homolog (PTEN) as a direct target of TFEB that is required for TFEB-dependent aberrant Tau clearance. The specificity and efficacy of TFEB in mediating the clearance of toxic Tau species makes it an attractive therapeutic target for treating diseases of tauopathy including AD. PMID:25069841

  4. TGF-β Inhibition Rescues Hematopoietic Stem Cell Defects and Bone Marrow Failure in Fanconi Anemia.

    PubMed

    Zhang, Haojian; Kozono, David E; O'Connor, Kevin W; Vidal-Cardenas, Sofia; Rousseau, Alix; Hamilton, Abigail; Moreau, Lisa; Gaudiano, Emily F; Greenberger, Joel; Bagby, Grover; Soulier, Jean; Grompe, Markus; Parmar, Kalindi; D'Andrea, Alan D

    2016-05-01

    Fanconi anemia (FA) is an inherited DNA repair disorder characterized by progressive bone marrow failure (BMF) from hematopoietic stem and progenitor cell (HSPC) attrition. A greater understanding of the pathogenesis of BMF could improve the therapeutic options for FA patients. Using a genome-wide shRNA screen in human FA fibroblasts, we identify transforming growth factor-β (TGF-β) pathway-mediated growth suppression as a cause of BMF in FA. Blocking the TGF-β pathway improves the survival of FA cells and rescues the proliferative and functional defects of HSPCs derived from FA mice and FA patients. Inhibition of TGF-β signaling in FA HSPCs results in elevated homologous recombination (HR) repair with a concomitant decrease in non-homologous end-joining (NHEJ), accounting for the improvement in cellular growth. Together, our results suggest that elevated TGF-β signaling contributes to BMF in FA by impairing HSPC function and may be a potential therapeutic target for the treatment of FA. PMID:27053300

  5. Mast cells rescue implantation defects caused by c-kit deficiency

    PubMed Central

    Woidacki, K; Popovic, M; Metz, M; Schumacher, A; Linzke, N; Teles, A; Poirier, F; Fest, S; Jensen, F; Rabinovich, G A; Maurer, M; Zenclussen, A C

    2013-01-01

    Various physiologically relevant processes are regulated by the interaction of the receptor tyrosine kinase (c-Kit) and its ligand stem cell factor (SCF), with SCF known to be the most important growth factor for mast cells (MCs). In spite of their traditional role in allergic disorders and innate immunity, MCs have lately emerged as versatile modulators of a variety of physiologic and pathologic processes. Here we show that MCs are critical for pregnancy success. Uterine MCs presented a unique phenotype, accumulated during receptivity and expanded upon pregnancy establishment. KitW-sh/W-sh mice, whose MC deficiency is based on restricted c-Kit gene expression, exhibited severely impaired implantation, which could be completely rescued by systemic or local transfer of wild-type bone marrow-derived MCs. Transferred wild-type MCs favored normal implantation, induced optimal spiral artery remodeling and promoted the expression of MC proteases, transforming growth factor-β and connective tissue growth factor. MCs contributed to trophoblast survival, placentation and fetal growth through secretion of the glycan-binding protein galectin-1. Our data unveil unrecognized roles for MCs at the fetomaternal interface with critical implications in reproductive medicine. PMID:23328669

  6. MDM2 inhibition rescues neurogenic and cognitive deficits in a mouse model of fragile X syndrome.

    PubMed

    Li, Yue; Stockton, Michael E; Bhuiyan, Ismat; Eisinger, Brian E; Gao, Yu; Miller, Jessica L; Bhattacharyya, Anita; Zhao, Xinyu

    2016-04-27

    Fragile X syndrome, the most common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein (FMRP). However, the mechanism remains unclear, and effective treatment is lacking. We show that loss of FMRP leads to activation of adult mouse neural stem cells (NSCs) and a subsequent reduction in the production of neurons. We identified the ubiquitin ligase mouse double minute 2 homolog (MDM2) as a target of FMRP. FMRP regulates Mdm2 mRNA stability, and loss of FMRP resulted in elevated MDM2 mRNA and protein. Further, we found that increased MDM2 expression led to reduced P53 expression in adult mouse NSCs, leading to alterations in NSC proliferation and differentiation. Treatment with Nutlin-3, a small molecule undergoing clinical trials for treating cancer, specifically inhibited the interaction of MDM2 with P53, and rescued neurogenic and cognitive deficits in FMRP-deficient mice. Our data reveal a potential regulatory role for FMRP in the balance between adult NSC activation and quiescence, and identify a potential new treatment for fragile X syndrome. PMID:27122614

  7. Bioenergetic Impairment in Animal and Cellular Models of Alzheimer's Disease: PARP-1 Inhibition Rescues Metabolic Dysfunctions.

    PubMed

    Martire, Sara; Fuso, Andrea; Mosca, Luciana; Forte, Elena; Correani, Virginia; Fontana, Mario; Scarpa, Sigfrido; Maras, Bruno; d'Erme, Maria

    2016-08-10

    Amyloid-beta peptide accumulation in the brain is one of the main hallmarks of Alzheimer's disease. The amyloid aggregation process is associated with the generation of free radical species responsible for mitochondrial impairment and DNA damage that in turn activates poly(ADP-ribose)polymerase 1 (PARP-1). PARP-1 catalyzes the poly(ADP-ribosylation), a post-translational modification of proteins, cleaving the substrate NAD+ and transferring the ADP-ribose moieties to the enzyme itself or to an acceptor protein to form branched polymers of ADP-ribose. In this paper, we demonstrate that a mitochondrial dysfunction occurs in Alzheimer's transgenic mice TgCRND8, in SH-SY5Y treated with amyloid-beta and in 7PA2 cells. Moreover, PARP-1 activation contributes to the functional energetic decline affecting cytochrome oxidase IV protein levels, oxygen consumption rates, and membrane potential, resulting in cellular bioenergetic deficit. We also observed, for the first time, an increase of pyruvate kinase 2 expression, suggesting a modulation of the glycolytic pathway by PARP-1. PARP-1 inhibitors are able to restore both mitochondrial impairment and pyruvate kinase 2 expression. The overall data here presented indicate a pivotal role for this enzyme in the bioenergetic network of neuronal cells and open new perspectives for investigating molecular mechanisms underlying energy charge decline in Alzheimer's disease. In this scenario, PARP-1 inhibitors might represent a novel therapeutic intervention to rescue cellular energetic metabolism. PMID:27567805

  8. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits.

    PubMed

    Zhou, Bing; Yu, Panpan; Lin, Mei-Yao; Sun, Tao; Chen, Yanmin; Sheng, Zu-Hang

    2016-07-01

    Although neuronal regeneration is a highly energy-demanding process, axonal mitochondrial transport progressively declines with maturation. Mature neurons typically fail to regenerate after injury, thus raising a fundamental question as to whether mitochondrial transport is necessary to meet enhanced metabolic requirements during regeneration. Here, we reveal that reduced mitochondrial motility and energy deficits in injured axons are intrinsic mechanisms controlling regrowth in mature neurons. Axotomy induces acute mitochondrial depolarization and ATP depletion in injured axons. Thus, mature neuron-associated increases in mitochondria-anchoring protein syntaphilin (SNPH) and decreases in mitochondrial transport cause local energy deficits. Strikingly, enhancing mitochondrial transport via genetic manipulation facilitates regenerative capacity by replenishing healthy mitochondria in injured axons, thereby rescuing energy deficits. An in vivo sciatic nerve crush study further shows that enhanced mitochondrial transport in snph knockout mice accelerates axon regeneration. Understanding deficits in mitochondrial trafficking and energy supply in injured axons of mature neurons benefits development of new strategies to stimulate axon regeneration. PMID:27268498

  9. Microglial Contact Prevents Excess Depolarization and Rescues Neurons from Excitotoxicity123

    PubMed Central

    Kato, Go; Wake, Hiroaki; Akiyoshi, Ryohei; Miyamoto, Akiko; Eto, Kei; Ishikawa, Tatsuya; Moorhouse, Andrew J.

    2016-01-01

    Abstract Microglia survey and directly contact neurons in both healthy and damaged brain, but the mechanisms and functional consequences of these contacts are not yet fully elucidated. Combining two-photon imaging and patch clamping, we have developed an acute experimental model for studying the role of microglia in CNS excitotoxicity induced by neuronal hyperactivity. Our model allows us to simultaneously examine the effects of repetitive supramaximal stimulation on axonal morphology, neuronal membrane potential, and microglial migration, using cortical brain slices from Iba-1 eGFP mice. We demonstrate that microglia exert an acute and highly localized neuroprotective action under conditions of neuronal hyperactivity. Evoking repetitive action potentials in individual layer 2/3 pyramidal neurons elicited swelling of axons, but not dendrites, which was accompanied by a large, sustained depolarization of soma membrane potential. Microglial processes migrated to these swollen axons in a mechanism involving both ATP and glutamate release via volume-activated anion channels. This migration was followed by intensive microglial wrapping of affected axons and, in some cases, the removal of axonal debris that induced a rapid soma membrane repolarization back to resting potentials. When the microglial migration was pharmacologically blocked, the activity-induced depolarization continued until cell death ensued, demonstrating that the microglia–axon contact served to prevent pathological depolarization of the soma and maintain neuronal viability. This is a novel aspect of microglia surveillance: detecting, wrapping, and rescuing neuronal soma from damage due to excessive activity. PMID:27390772

  10. Insulin-producing cells from embryonic stem cells rescues hyperglycemia via intra-spleen migration

    PubMed Central

    Ren, Meng; Shang, Changzhen; Zhong, Xiaomei; Guo, Ruomi; Lao, Guojuan; Wang, Xiaoyi; Cheng, Hua; Min, Jun; Yan, Li; Shen, Jun

    2014-01-01

    Implantation of embryonic stem cells (ESC)-derived insulin-producing cells has been extensively investigated for treatment of diabetes in animal models. However, the in vivo behavior and migration of transplanted cells in diabetic models remains unclear. Here we investigated the location and migration of insulin-producing cells labeled with superparamagnetic iron oxide (SPIO) using a dynamic MRI tracking method. SPIO labeled cells showed hypointense signal under the kidney subcapsules of diabetic mice on MRI, and faded gradually over the visiting time. However, new hypointense signal appeared in the spleen 1 week after transplantation, and became obvious with the time prolongation. Further histological examination proved the immigrated cells were insulin and C-peptide positive cells which were evenly distributed throughout the spleen. These intra-spleen insulin-producing cells maintained their protective effects against hyperglycemia in vivo, and these effects were reversed upon spleen removal. Transplantation of insulin-producing cells through spleen acquired an earlier blood glucose control as compared with that through kidney subcapsules. In summary, our data demonstrate that insulin-producing cells transplanted through kidney subcapsules were not located in situ but migrated into spleen, and rescues hyperglycemia in diabetic models. MRI may provide a novel tracking method for preclinical cell transplantation therapy of diabetes continuously and non-invasively. PMID:25533571

  11. A partial structural and functional rescue of a retinitis pigmentosa model with compacted DNA nanoparticles.

    PubMed

    Cai, Xue; Nash, Zack; Conley, Shannon M; Fliesler, Steven J; Cooper, Mark J; Naash, Muna I

    2009-01-01

    Previously we have shown that compacted DNA nanoparticles can drive high levels of transgene expression after subretinal injection in the mouse eye. Here we delivered compacted DNA nanoparticles containing a therapeutic gene to the retinas of a mouse model of retinitis pigmentosa. Nanoparticles containing the wild-type retinal degeneration slow (Rds) gene were injected into the subretinal space of rds(+/-) mice on postnatal day 5. Gene expression was sustained for up to four months at levels up to four times higher than in controls injected with saline or naked DNA. The nanoparticles were taken up into virtually all photoreceptors and mediated significant structural and biochemical rescue of the disease without histological or functional evidence of toxicity. Electroretinogram recordings showed that nanoparticle-mediated gene transfer restored cone function to a near-normal level in contrast to transfer of naked plasmid DNA. Rod function was also improved. These findings demonstrate that compacted DNA nanoparticles represent a viable option for development of gene-based interventions for ocular diseases and obviate major barriers commonly encountered with non-viral based therapies. PMID:19390689

  12. Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging.

    PubMed

    Gerstein, Hilary; Lindstrom, Mary J; Burger, Corinna

    2013-08-01

    Homer1c has been shown to play a role in learning and memory. Overexpression of Homer1c in the hippocampus can improve memory in normal rats and can also rescue spatial learning deficits in Homer1 knockout mice. In a previous study, we found that Homer1c mRNA is upregulated after a spatial learning paradigm in aged rats that successfully learn the task, when compared to aged rats that are learning-impaired (AI). This study was designed to validate the role of Homer1c in successful cognitive aging. In this article, we report that gene delivery of Homer1c into the hippocampus of aged learning-impaired rats significantly improves individual performance on an object location memory task. The learning ability of these rats on the Morris Water Maze was also superior to that of AI control rats. In summary, using 2 independent spatial memory tasks, we demonstrate that Homer1c is sufficient to improve the spatial learning deficits in a rodent model of cognitive aging. These results point to Homer1c as a potential therapeutic target for improving age-related cognitive impairment. PMID:23523268

  13. Insulin-producing cells from embryonic stem cells rescues hyperglycemia via intra-spleen migration.

    PubMed

    Ren, Meng; Shang, Changzhen; Zhong, Xiaomei; Guo, Ruomi; Lao, Guojuan; Wang, Xiaoyi; Cheng, Hua; Min, Jun; Yan, Li; Shen, Jun

    2014-01-01

    Implantation of embryonic stem cells (ESC)-derived insulin-producing cells has been extensively investigated for treatment of diabetes in animal models. However, the in vivo behavior and migration of transplanted cells in diabetic models remains unclear. Here we investigated the location and migration of insulin-producing cells labeled with superparamagnetic iron oxide (SPIO) using a dynamic MRI tracking method. SPIO labeled cells showed hypointense signal under the kidney subcapsules of diabetic mice on MRI, and faded gradually over the visiting time. However, new hypointense signal appeared in the spleen 1 week after transplantation, and became obvious with the time prolongation. Further histological examination proved the immigrated cells were insulin and C-peptide positive cells which were evenly distributed throughout the spleen. These intra-spleen insulin-producing cells maintained their protective effects against hyperglycemia in vivo, and these effects were reversed upon spleen removal. Transplantation of insulin-producing cells through spleen acquired an earlier blood glucose control as compared with that through kidney subcapsules. In summary, our data demonstrate that insulin-producing cells transplanted through kidney subcapsules were not located in situ but migrated into spleen, and rescues hyperglycemia in diabetic models. MRI may provide a novel tracking method for preclinical cell transplantation therapy of diabetes continuously and non-invasively. PMID:25533571

  14. Functionalists and zombis: Sorcery as spandrel and social rescue.

    PubMed

    Littlewood, Roland

    2009-12-01

    At one level, anthropologists remain functionalists in that they generally see acts and institutions as contributing to a greater social whole only through which they make sense. Thus, sorcery accusations have been traditionally interpreted in terms of maintaining social harmony and cohesion. In the case of Haitian zombification, the zombi seems a locally misidentified victim who is frequently mentally ill. As a hapless non-agent, the zombi cannot initiate the sorcery accusations, so how do we understand the recognition and rescue of the zombi, either in terms of social function or social action? PMID:27269907

  15. Shuttle remote manipulator system safety and rescue support capabilities

    NASA Technical Reports Server (NTRS)

    Brown, J. W.; Whitehead, G. D.

    1977-01-01

    The Remote Manipulator System (RMS) incorporates a manipulator arm with a payload-handling end effector, an arm positioning mechanism and a control system. The RMS is designed to capture and deploy free-flying payloads up to 4.6 m in diameter and 18.3 m long, weighing 14,515 kg. This paper describes the RMS with attention given to the arm, the supporting subsystems, and safety design features (displays and controls, the mechanical subsystem and operations). Man-in-the-loop simulations for the assurance of RMS and crew safety are described and the use of the RMS for EVA rescue support is considered in detail.

  16. Launch-Off-Need Shuttle Hubble Rescue Mission: Medical Issues

    NASA Technical Reports Server (NTRS)

    Hamilton, Douglas; Gillis, David; Ilcus, Linda; Perchonok, Michele; Polk, James; Brandt, Keith; Powers, Edward; Stepaniak, Phillip

    2008-01-01

    The Space Shuttle Hubble repair mission (STS-125) is unique in that a rescue mission (STS-400) has to be ready to launch before STS-125 life support runs out should the vehicle become stranded. The shuttle uses electrical power derived from fuel cells that use cryogenic oxygen and hydrogen (CRYO) to run all subsystems including the Environmental Control System. If the STS-125 crew cannot return to Earth due to failure of a critical subsystem, they must power down all nonessential systems and wait to be rescued by STS-400. This power down will cause the cabin temperature to be 60 F or less and freeze the rest of the vehicle, preventing it from attempting a reentry. After an emergency has been declared, STS-125 must wait at least 7 days to power down since that is the earliest that STS-400 can be launched. Problem The delayed power down of STS-125 causes CYRO to be consumed at high rates and limits the survival time after STS-400 launches to 10 days or less. CRYO will run out sooner every day that the STS-400 launch is delayed (weather at launch, technical issues etc.). To preserve CRYO and lithium hydroxide (LiOH - carbon dioxide removal) the crew will perform no exercise to reduce their metabolic rates, yet each deconditioned STS-125 crewmember must perform an EVA to rescue himself. The cabin may be cold for 10 days, which may cause shivering, increasing the metabolic rate of the STS-125 crew. Solution To preserve LiOH, the STS-125 manifest includes nutrition bars with low carbohydrate content to maintain crew respiratory quotient (RQ) below 0.85 as opposed to the usual shuttle galley food which is rich in carbohydrates and keeps the RQ at approximately 0.95. To keep the crew more comfortable in the cold vehicle warm clothing also has been included. However, with no exercise and limited diet, the deconditioned STS-125 crew returning on STS-400 may not be able to egress the vehicle autonomously requiring a supplemented crash-and-rescue capability.

  17. Impacted and Fractured Biliary Basket: A Second Basket Rescue Technique.

    PubMed

    Benatta, Mohammed Amine; Desjeux, Ariane; Barthet, Marc; Grimaud, Jean Charles; Gasmi, Mohamed

    2016-01-01

    A 59-year-old woman was treated with ERCP, ES, and biliary plastic stent, for large and multiple common bile duct stones. During a second ERCP basket extraction was impacted with a round entrapped stone. The basket handle was cut off; a metal sheath of extraendoscopic lithotriptor was advanced over the basket. The mechanical lithotripsy was complicated with basket traction wires fracturing, without breakage of the stone. A rescue standard basket was pushed until it caught the basket/stone complex. Using this method disengagement of the whole fractured basket/stone complex was achieved without need of surgery. It is the third case reported in the English literature. PMID:27293442

  18. ECMO for Cardiac Rescue after Accidental Intravenous Mepivacaine Application

    PubMed Central

    Froehle, Michael; Haas, Nikolaus A.; Kirchner, Guenther; Kececioglu, Deniz; Sandica, Eugen

    2012-01-01

    Mepivacaine is a potent local anaesthetic and used for infiltration and regional anaesthesia in adults and pediatric patients. Intoxications with mepivacaine affect mainly the CNS and the cardiovascular system. We present a case of accidental intravenous mepivacaine application and intoxication of an infant resulting in seizure, broad complex bradyarrhythmia, arterial hypotension and finally cardiac arrest. The patient could be rescued by prolonged resuscitations and a rapid initiation of ECMO and survived without neurological damage. The management strategies of this rare complication including promising other treatment options with lipid emulsions are discussed. PMID:22966472

  19. Impacted and Fractured Biliary Basket: A Second Basket Rescue Technique

    PubMed Central

    Benatta, Mohammed Amine; Desjeux, Ariane; Barthet, Marc; Grimaud, Jean Charles; Gasmi, Mohamed

    2016-01-01

    A 59-year-old woman was treated with ERCP, ES, and biliary plastic stent, for large and multiple common bile duct stones. During a second ERCP basket extraction was impacted with a round entrapped stone. The basket handle was cut off; a metal sheath of extraendoscopic lithotriptor was advanced over the basket. The mechanical lithotripsy was complicated with basket traction wires fracturing, without breakage of the stone. A rescue standard basket was pushed until it caught the basket/stone complex. Using this method disengagement of the whole fractured basket/stone complex was achieved without need of surgery. It is the third case reported in the English literature. PMID:27293442

  20. Power sources for search and rescue 406 MHz beacons

    NASA Astrophysics Data System (ADS)

    Attia, Alan I.; Perrone, David E.

    The results of a study directed at the selection of a commercially available, safe, low cost, light weight and long storage life battery for search and rescue (Sarsat) 406 MHz emergency beacons are presented. In the course of this work, five electrochemical systems (lithium-manganese dioxide, lithium-carbon monofluoride, lithium-silver vanadium oxide, alkaline cells, and cadmium-mercuric oxide) were selected for limited experimental studies to determine their suitability for this application. Two safe, commercially available batteries (lithium-manganese dioxide and lithium-carbon monofluoride) which meet the near term requirements and several alternatives for the long term were identified.

  1. Search and rescue satellite-aided tracking system

    NASA Technical Reports Server (NTRS)

    Trudell, B.; Gutwein, J. M.; Vollmers, R.; Wammer, D.

    1980-01-01

    The objective of Sarsat is to demonstrate that satellites can greatly facilitate the monitoring, detection, and location of distress incidents alerted by Emergency Locator Transmitters (ELTs) and Emergency Position Indicating Radio Beacons (EPIRBs) carried on commercial, military, and general aviation aircraft and some marine vessels. The detection and location will be accomplished by relaying, via satellite, ELT/EPIRB distress information to ground stations, which will complete the data processing and forward alert and position location data to rescue coordination services. This paper presents a Sarsat system description and a summary of Coast Guard and USAF objectives for the initial demonstration and evaluation tests of Sarsat.

  2. Power sources for search and rescue 406 MHz beacons

    NASA Technical Reports Server (NTRS)

    Attia, Alan I.; Perrone, David E.

    1987-01-01

    The results of a study directed at the selection of a commercially available, safe, low cost, light weight and long storage life battery for search and rescue (Sarsat) 406 MHz emergency beacons are presented. In the course of this work, five electrochemical systems (lithium-manganese dioxide, lithium-carbon monofluoride, lithium-silver vanadium oxide, alkaline cells, and cadmium-mercuric oxide) were selected for limited experimental studies to determine their suitability for this application. Two safe, commercially available batteries (lithium-manganese dioxide and lithium-carbon monofluoride) which meet the near term requirements and several alternatives for the long term were identified.

  3. Anti-Transforming Growth Factor ß Antibody Treatment Rescues Bone Loss and Prevents Breast Cancer Metastasis to Bone

    PubMed Central

    Biswas, Swati; Nyman, Jeffry S.; Alvarez, JoAnn; Chakrabarti, Anwesa; Ayres, Austin; Sterling, Julie; Edwards, James; Rana, Tapasi; Johnson, Rachelle; Perrien, Daniel S.; Lonning, Scott; Shyr, Yu; Matrisian, Lynn M.; Mundy, Gregory R.

    2011-01-01

    Breast cancer often metastasizes to bone causing osteolytic bone resorption which releases active TGFβ. Because TGFβ favors progression of breast cancer metastasis to bone, we hypothesized that treatment using anti-TGFβ antibody may reduce tumor burden and rescue tumor-associated bone loss in metastatic breast cancer. In this study we have tested the efficacy of an anti-TGFβ antibody 1D11 preventing breast cancer bone metastasis. We have used two preclinical breast cancer bone metastasis models, in which either human breast cancer cells or murine mammary tumor cells were injected in host mice via left cardiac ventricle. Using several in vivo, in vitro and ex vivo assays, we have demonstrated that anti-TGFβ antibody treatment have significantly reduced tumor burden in the bone along with a statistically significant threefold reduction in osteolytic lesion number and tenfold reduction in osteolytic lesion area. A decrease in osteoclast numbers (p = 0.027) in vivo and osteoclastogenesis ex vivo were also observed. Most importantly, in tumor-bearing mice, anti-TGFβ treatment resulted in a twofold increase in bone volume (p<0.01). In addition, treatment with anti-TGFβ antibody increased the mineral-to-collagen ratio in vivo, a reflection of improved tissue level properties. Moreover, anti-TGFβ antibody directly increased mineralized matrix formation in calverial osteoblast (p = 0.005), suggesting a direct beneficial role of anti-TGFβ antibody treatment on osteoblasts. Data presented here demonstrate that anti-TGFβ treatment may offer a novel therapeutic option for tumor-induced bone disease and has the dual potential for simultaneously decreasing tumor burden and rescue bone loss in breast cancer to bone metastases. This approach of intervention has the potential to reduce skeletal related events (SREs) in breast cancer survivors. PMID:22096521

  4. TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.

    PubMed

    Binukumar, B K; Zheng, Ya-Li; Shukla, Varsha; Amin, Niranjana D; Grant, Philip; Pant, Harish C

    2014-01-01

    Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy. PMID:24326517

  5. A Review of Mine Rescue Ensembles for Underground Coal Mining in the United States

    PubMed Central

    Kilinc, F. Selcen; Monaghan, William D.; Powell, Jeffrey B.

    2016-01-01

    The mining industry is among the top ten industries nationwide with high occupational injury and fatality rates, and mine rescue response may be considered one of the most hazardous activities in mining operations. In the aftermath of an underground mine fire, explosion or water inundation, specially equipped and trained teams have been sent underground to fight fires, rescue entrapped miners, test atmospheric conditions, investigate the causes of the disaster, or recover the dead. Special personal protective ensembles are used by the team members to improve the protection of rescuers against the hazards of mine rescue and recovery. Personal protective ensembles used by mine rescue teams consist of helmet, cap lamp, hood, gloves, protective clothing, boots, kneepads, facemask, breathing apparatus, belt, and suspenders. While improved technology such as wireless warning and communication systems, lifeline pulleys, and lighted vests have been developed for mine rescuers over the last 100 years, recent research in this area of personal protective ensembles has been minimal due to the trending of reduced exposure of rescue workers. In recent years, the exposure of mine rescue teams to hazardous situations has been changing. However, it is vital that members of the teams have the capability and proper protection to immediately respond to a wide range of hazardous situations. Currently, there are no minimum requirements, best practice documents, or nationally recognized consensus standards for protective clothing used by mine rescue teams in the United States (U.S.). The following review provides a summary of potential issues that can be addressed by rescue teams and industry to improve potential exposures to rescue team members should a disaster situation occur. However, the continued trending in the mining industry toward non-exposure to potential hazards for rescue workers should continue to be the primary goal. To assist in continuing this trend, the mining industry

  6. Differential rescue of the renal and hepatic disease in an autosomal recessive polycystic kidney disease mouse mutant. A new model to study the liver lesion.

    PubMed Central

    Yoder, B. K.; Richards, W. G.; Sommardahl, C.; Sweeney, W. E.; Michaud, E. J.; Wilkinson, J. E.; Avner, E. D.; Woychik, R. P.

    1997-01-01

    Autosomal recessive polycystic kidney disease (ARPKD) is characterized by biliary and renal lesions that produce significant morbidity and mortality. The biliary ductual ectasia and hepatic portal fibrosis associated with ARPKD have not been well studied even though such lesions markedly affect the clinical course of patients after renal replacement therapy such as dialysis or transplantation. Here we describe the generation of a new mouse model to study the hepatic lesions associated with polycystic kidney disease. This model was generated by differentially rescuing the renal pathology in the orpk mutant mouse that displays a hepatorenal pathology that is similar to that seen in human patients with ARPKD. This was accomplished by expressing, as a transgene in the mutant animals, the cloned wild-type version of the gene associated with the mutant locus in this line of mice. Although renal function in the rescue animals is normal, the liver still exhibits biliary and ductular hyperplasia along with varying degrees of hepatic portal fibrosis that is indistinguishable from that in the mutant animals. Most important, the rescue animals survive significantly longer than mutants and will permit a more detailed analysis of the clinical and cellular pathophysiology of the hepatic defect associated with this disease. Images Figure 1 Figure 3 Figure 5 PMID:9176412

  7. Establishment of a Rescue System for Canine Distemper Virus

    PubMed Central

    Gassen, Uta; Collins, Fergal M.; Duprex, W. Paul; Rima, Bert K.

    2000-01-01

    Canine distemper virus (CDV) has been rescued from a full-length cDNA clone. Besides Measles virus (MV) and Rinderpest virus, a third morbillivirus is now available for genetic analysis using reverse genetics. A plasmid p(+)CDV was constructed by sequential cloning using the Onderstepoort vaccine strain large-plaque-forming variant. The presence of a T7 promoter allowed transcription of full-length antigenomic RNA by a T7 RNA polymerase, which was provided by a host range mutant of vaccinia virus (MVA-T7). Plasmids expressing the nucleocapsid protein, the phosphoprotein, and the viral RNA-dependent RNA polymerase, also under control of a T7 promoter, have been generated. Infection of HeLa cells with MVA-T7 and subsequent transfection of p(+)CDV plus the helper plasmids led to syncytium formation and release of infectious recombinant (r) CDV. Comparison of the rescued virus with the parental virus revealed no major differences in the progression of infection or in the shape and size of syncytia. A genetic tag, consisting of two nucleotide changes within the coding region of the L protein, has been identified in the rCDV genome. Expression by rCDV of all the major viral structural proteins has been demonstrated by immunofluorescence. PMID:11044118

  8. Space rescue system definition (system performance analysis and trades)

    NASA Astrophysics Data System (ADS)

    Housten, Sam; Elsner, Tim; Redler, Ken; Svendsen, Hal; Wenzel, Sheri

    This paper addresses key technical issues involved in the system definition of the Assured Crew Return Vehicle (ACRV). The perspective on these issues is that of a prospective ACRV contractor, performing system analysis and trade studies. The objective of these analyses and trade studies is to develop the recovery vehicle system concept and top level requirements. The starting point for this work is the definition of the set of design missions for the ACRV. This set of missions encompasses three classes of contingency/emergency (crew illness/injury, space station catastrophe/failure, transportation element catastrophe/failure). The need is to provide a system to return Space Station crew to Earth quickly (less than 24 hours) in response to randomly occurring contingency events over an extended period of time (30 years of planned Space Station life). The main topics addressed and characterized in this paper include the following: Key Recovery (Rescue) Site Access Considerations; Rescue Site Locations and Distribution; Vehicle Cross Range vs Site Access; On-orbit Loiter Capability and Vehicle Design; and Water vs. Land Recovery.

  9. GIS plays key role in NYC Rescue and Relief Operation

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    New York City, Sept. 17—The posters of missing loved ones are pasted onto New York City walls and street signs six days after 2 hijacked commercial airlines destroyed the World Trade Center in lower Manhattan on September 11. Several miles uptown from “ground zero,” heightened security hovers around the city's Office of Emergency Management rescue and relief command center, an around-the-clock operation. Police, firefighters, military, officials with the Federal Emergency Management Agency, communications technicians, and a beehive of others work in controlled chaos in this cavernous, convention center-sized hall, lined with computers and adorned with several American flags.After the original command center at 7 World Trade Center collapsed to rubble as an after-effect of the plane strikes, city officials scrambled to recreate it. Alan Leidner, director of New York's citywide geographic information systems (GIS), and who is with the Department of Information Technology and Telecommunications, knew that maps would be an integral component of the rescue and relief efforts. Maps provide emergency workers and others with accurate and detailed scientific data in the form of visual aids upon which they can make informed decisions.

  10. Chloroquine rescues A549 cells from paraquat-induced death.

    PubMed

    Xu, Lingjie; Wang, Zhong

    2016-04-01

    Paraquat (PQ) is a widely used herbicide associated with a high mortality rate, yet, there are no effective treatments for PQ poisoning. PQ may damage alveolar type II cells leading to moderate to severe acute respiratory distress syndrome (ARDS). The present study was undertaken to show that PQ causes alveolar type II (A549) cell death and to evaluate whether chloroquine (CQ) can protect A549 cells against PQ-induced cell death. The results showed that high concentrations of PQ resulted in toxicity, as indicated by a decrease in cell viability. More importantly, for the first time, CQ was found to improve cell viability of PQ treated A549 cells. Moreover, our data demonstrated that CQ increased lysosome-associated membrane protein-1, lysosome-associated membrane protein-2 and light chain-3 expressions, suggesting that the mechanism by which CQ rescues PQ-induced cytotoxicity may be through protection of the lysosomal membrane or up-regulation of autophagy. In conclusion, our study indicates that CQ may be used as a potential drug to rescue PQ-induced ARDS. PMID:26154125

  11. Etv2 rescues Flk1 mutant embryoid bodies

    PubMed Central

    Rasmussen, Tara L.; Martin, Cindy M.; Walter, Camille A.; Shi, Xiaozhong; Perlingeiro, Rita; Koyano-Nakagawa, Naoko; Garry, Daniel J.

    2013-01-01

    Independent mouse knockouts of Etv2 and Flk1 are embryonic lethal and lack hematopoietic and endothelial lineages. We previously reported that Flk1 activates Etv2 in the initiation of hematopoiesis and vasculogenesis. However, Flk1 and its ligand VEGF are expressed throughout development, from E7.0 to adulthood, whereas Etv2 is expressed only transiently during embryogenesis. These observations suggest a complex regulatory interaction between Flk1 and Etv2. To further examine the Flk1 and Etv2 regulatory interaction, we transduced Etv2 and Flk1 mutant ES cells with viral integrants that inducibly overexpress Flk1 or Etv2. We demonstrated that forced expression of Etv2 rescued the hematopoietic and endothelial potential of differentiating Flk1 and Etv2 mutant cells. We further discovered that forced expression of Flk1 can rescue that of the Flk1, but not Etv2 mutant cells. Therefore, we conclude that the requirement for Flk1 can be bypassed by expressing Etv2, supporting the notion that disruption of Etv2 expression is responsible for the early phenotypes of the Etv2 and Flk1 mutant embryos. PMID:23606617

  12. Genetic rescue and inbreeding depression in Mexican wolves.

    PubMed

    Fredrickson, Richard J; Siminski, Peter; Woolf, Melissa; Hedrick, Philip W

    2007-09-22

    Although inbreeding can reduce individual fitness and contribute to population extinction, gene flow between inbred but unrelated populations may overcome these effects. Among extant Mexican wolves (Canis lupus baileyi), inbreeding had reduced genetic diversity and potentially lowered fitness, and as a result, three unrelated captive wolf lineages were merged beginning in 1995. We examined the effect of inbreeding and the merging of the founding lineages on three fitness traits in the captive population and on litter size in the reintroduced population. We found little evidence of inbreeding depression among captive wolves of the founding lineages, but large fitness increases, genetic rescue, for all traits examined among F1 offspring of the founding lineages. In addition, we observed strong inbreeding depression among wolves descended from F1 wolves. These results suggest a high load of deleterious alleles in the McBride lineage, the largest of the founding lineages. In the wild, reintroduced population, there were large fitness differences between McBride wolves and wolves with ancestry from two or more lineages, again indicating a genetic rescue. The low litter and pack sizes observed in the wild population are consistent with this genetic load, but it appears that there is still potential to establish vigorous wild populations. PMID:17609180

  13. Biobotic insect swarm based sensor networks for search and rescue

    NASA Astrophysics Data System (ADS)

    Bozkurt, Alper; Lobaton, Edgar; Sichitiu, Mihail; Hedrick, Tyson; Latif, Tahmid; Dirafzoon, Alireza; Whitmire, Eric; Verderber, Alexander; Marin, Juan; Xiong, Hong

    2014-06-01

    The potential benefits of distributed robotics systems in applications requiring situational awareness, such as search-and-rescue in emergency situations, are indisputable. The efficiency of such systems requires robotic agents capable of coping with uncertain and dynamic environmental conditions. For example, after an earthquake, a tremendous effort is spent for days to reach to surviving victims where robotic swarms or other distributed robotic systems might play a great role in achieving this faster. However, current technology falls short of offering centimeter scale mobile agents that can function effectively under such conditions. Insects, the inspiration of many robotic swarms, exhibit an unmatched ability to navigate through such environments while successfully maintaining control and stability. We have benefitted from recent developments in neural engineering and neuromuscular stimulation research to fuse the locomotory advantages of insects with the latest developments in wireless networking technologies to enable biobotic insect agents to function as search-and-rescue agents. Our research efforts towards this goal include development of biobot electronic backpack technologies, establishment of biobot tracking testbeds to evaluate locomotion control efficiency, investigation of biobotic control strategies with Gromphadorhina portentosa cockroaches and Manduca sexta moths, establishment of a localization and communication infrastructure, modeling and controlling collective motion by learning deterministic and stochastic motion models, topological motion modeling based on these models, and the development of a swarm robotic platform to be used as a testbed for our algorithms.

  14. Mountain Search and Rescue with Remotely Piloted Aircraft Systems

    NASA Astrophysics Data System (ADS)

    Silvagni, Mario; Tonoli, Andrea; Zenerino, Enrico; Chiaberge, Marcello

    2016-04-01

    Remotely Piloted Aircraft Systems (RPAS) also known as Unmanned Aerial Systems (UAS) are nowadays becoming more and more popular in several applications. Even though a complete regulation is not yet available all over the world, researches, tests and some real case applications are wide spreading. These technologies can bring many benefits also to the mountain operations especially in emergencies and harsh environmental conditions, such as Search and Rescue (SAR) and avalanche rescue missions. In fact, during last decade, the number of people practicing winter sports in backcountry environment is increased and one of the greatest hazards for recreationists and professionals are avalanches. Often these accidents have severe consequences leading, mostly, to asphyxia-related death, which is confirmed by the hard drop of survival probability after ten minutes from the burying. Therefore, it is essential to minimize the time of burial. Modern avalanche beacon (ARTVA) interface guides the rescuer during the search phase reducing its time. Even if modern avalanche beacons are valid and reliable, the seeking range influences the rescue time. Furthermore, the environment and morphologic conditions of avalanches usually complicates the rescues. The recursive methodology of this kind of searching offers the opportunity to use automatic device like drones (RPAS). These systems allow performing all the required tasks autonomously, with high accuracy and without exposing the rescuers to additional risks due to secondary avalanches. The availability of highly integrated electronics and subsystems specifically meant for the applications, better batteries, miniaturized payload and, in general, affordable prices, has led to the availability of small RPAS with very good performances that can give interesting application opportunities in unconventional environments. The present work is one of the outcome from the experience made by the authors in RPAS fields and in Mechatronics

  15. Early Social Enrichment Rescues Adult Behavioral and Brain Abnormalities in a Mouse Model of Fragile X Syndrome

    PubMed Central

    Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

    2015-01-01

    Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases. PMID:25348604

  16. An mGlu5-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia.

    PubMed

    Balu, Darrick T; Li, Yan; Takagi, Shunsuke; Presti, Kendall Taylor; Ramikie, Teniel S; Rook, Jerri M; Jones, Carrie K; Lindsley, Craig W; Conn, P Jeffrey; Bolshakov, Vadim Y; Coyle, Joseph T

    2016-07-01

    There is substantial evidence that NMDA receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia (SCZ). A recent large-scale genome-wide association study identified serine racemase (SR), the enzyme that produces the NMDAR co-agonist D-serine, as a risk gene for SCZ. Serine racemase knockout (SR-/-) mice, which lack D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in SCZ. Metabotropic glutamate receptor 5 (mGlu5)-positive allosteric modulators (PAMs) are currently being developed to treat cognitive dysfunction. We used in vitro electrophysiology to determine whether the mGlu5 PAM VU0409551 directly enhances NMDAR function in hippocampal slices from adult male SR-/- mice. We administered VU0409551 systemically for 5 days to adult male wild-type C57BL/6 animals to determine the optimal dose to test in SR-/- mice. We used western blot analyses and trace-fear conditioning to determine whether 5 days of VU0409551 treatment could reverse the neuroplasticity and learning deficits, respectively, in SR-/- mice. We show that VU0409551 enhances NMDAR function and rescues long-term potentiation in hippocampal slices obtained from SR-/- mice. Systemic treatment with VU0409551 (10 and 30 mg/kg) to wild-type mice causes a dose-dependent increase in the Akt/GS3Kα/β signaling pathway, which is reduced in SR-/- mice and in SCZ. Furthermore, the administration of VU0409551 to SR-/- mice reverses their deficits in several neuroplasticity signaling pathways and improves their contextual fear memory. These results support positive allosteric modulation of mGlu5, particularly with VU0409551, as a viable mechanism to reverse the deficits in NMDAR function, synaptic plasticity, and memory that are known to be impaired in SCZ. PMID:26741285

  17. Resistance Training for Rescue Divers in the Sport Scuba Diving Industry.

    ERIC Educational Resources Information Center

    Mier, Constance M.; Kegeles, Sharon

    2002-01-01

    Asserts that the need for certified rescue divers increases as the diving industry grows. Rescue divers must be physically prepared to perform several dives in one day and to carry equipment on and off the boat. Physical recovery is also important, as they must be alert at all times to potential emergency situations. This require high levels of…

  18. 30 CFR 57.4330 - Surface firefighting, evacuation, and rescue procedures.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Surface firefighting, evacuation, and rescue... NONMETAL MINES Fire Prevention and Control Firefighting Procedures/alarms/drills § 57.4330 Surface firefighting, evacuation, and rescue procedures. (a) Mine operators shall establish emergency...

  19. 14 CFR 139.315 - Aircraft rescue and firefighting: Index determination.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 3 2011-01-01 2011-01-01 false Aircraft rescue and firefighting: Index... CERTIFICATION OF AIRPORTS Operations § 139.315 Aircraft rescue and firefighting: Index determination. (a) An... alternate compliance must be described in the ACM and must include: (1) Pre-arranged firefighting...

  20. 30 CFR 57.4330 - Surface firefighting, evacuation, and rescue procedures.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Surface firefighting, evacuation, and rescue... NONMETAL MINES Fire Prevention and Control Firefighting Procedures/alarms/drills § 57.4330 Surface firefighting, evacuation, and rescue procedures. (a) Mine operators shall establish emergency...