Examination of the interaction of different lighting conditions and chronic mild stress in animal model.

PubMed

Muller, A; Gal, N; Betlehem, J; Fuller, N; Acs, P; Kovacs, G L; Fusz, K; Jozsa, R; Olah, A

2015-09-01

We examined the effects of different shift work schedules and chronic mild stress (CMS) on mood using animal model. The most common international shift work schedules in nursing were applied by three groups of Wistar-rats and a control group with normal light-dark cycle. One subgroup from each group was subjected to CMS. Levels of anxiety and emotional life were evaluated in light-dark box. Differences between the groups according to independent and dependent variables were examined with one- and two-way analysis of variance, with a significance level defined at p < 0.05. Interaction of lighting regimen and CMS was proved to be significant according to time spent in the light compartment and the average number of changes between the light and dark compartments. Results of our examination confirm that the changes of lighting conditions evocate anxiety more prominently than CMS. No significant differences were found between the results of the low rotating group and the control group, supposing that this schedule is the least harmful to health. Our results on the association between the use of lighting regimens and the level of CMS provide evidence that the fast rotating shift work schedule puts the heaviest load on the organism of animals.

Antidepressant like effects of hydrolysable tannins of Terminalia catappa leaf extract via modulation of hippocampal plasticity and regulation of monoamine neurotransmitters subjected to chronic mild stress (CMS).

PubMed

Chandrasekhar, Y; Ramya, E M; Navya, K; Phani Kumar, G; Anilakumar, K R

2017-02-01

Terminalia catappa L. belonging to Combretaceae family is a folk medicine, known for its multiple pharmacological properties, but the neuro-modulatory effect of TC against chronic mild stress was seldom explored. The present study was designed to elucidate potential antidepressant-like effect of Terminalia cattapa (leaf) hydro-alcoholic extract (TC) by using CMS model for a period of 7 weeks. Identification of hydrolysable tannins was done by using LC-MS. After the CMS exposure, mice groups were administered with imipramine (IMP, 10mg/kg, i.p.) and TC (25, 50 and 100mg/kg of TC, p.o.). Behavioural paradigms used for the study included forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT). After behavioural tests, monoamine neurotransmitter, cortisol, AchE, oxidative stress levels and mRNA expression studies relevant to depression were assessed. TC supplementation significantly reversed CMS induced immobility time in FST and other behavioural paradigms. Moreover, TC administration significantly restored CMS induced changes in concentrations of hippocampal neurotransmitters (5-HT, DA and NE) as well as levels of acetyl cholinesterase, cortisol, monoamine oxidases (MAO-A, MAO-B), BDNF, CREB, and p-CREB. It suggests that TC supplementation could supress stress induced depression by regulating monoamine neurotransmitters, CREB, BDNF, cortisol, AchE level as well as by amelioration of oxidative stress. Hence TC can be used as a complementary medicine against depression-like disorder. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Susceptibility of a potential animal model for pathological anxiety to chronic mild stress.

PubMed

Salomons, Amber R; Kortleve, Tessa; Reinders, Niels R; Kirchhoff, Susanne; Arndt, Saskia S; Ohl, Frauke

2010-06-19

When anxiety-related behaviour in animals appears to lack adaptive value, it might be defined as pathological. Adaptive behaviour can be assessed for example by changes in behavioural responses over time, i.e. habituation. Thus, non-adaptive anxiety would be reflected by a lack of habituation. Recently, we found that 129P3/J mice are characterised by non-adaptive avoidance behaviour after repeated test exposure. The present study was aimed at investigating the sensitivity of the behavioural profile of these animals to exposure to a chronic mild stress (CMS) paradigm followed by repeated exposure to the modified hole board test. If the behavioural profile of 129P3/J mice mirrors pathological anxiety, their behavioural habituation under repeated test exposure conditions should be affected by CMS treatment. The results confirm the profound lack of habituation with respect to anxiety-related behaviour in both control and CMS treated mice. Additionally, CMS treated animals revealed a lower exploratory behaviour, reduced locomotor activity and increased arousal-related behaviour over time when compared to control individuals, proving an extension of their impaired habituation behaviour. Although no effects of CMS treatment on plasma corticosterone levels were found, higher immediate early gene expression in the bed nucleus of the stria terminalis and the ventrolateral periaqueductal grey in CMS treated mice indicated that 129P3/J mice are susceptible to the negative effects of CMS treatment at both the behavioural and the functional level. These results support the hypothesis that 129P3/J mice might be an interesting model for pathological anxiety. Copyright 2010 Elsevier B.V. All rights reserved.

Disturbed diurnal rhythm of three classical phase markers in the chronic mild stress rat model of depression.

PubMed

Christiansen, S L; Højgaard, K; Wiborg, O; Bouzinova, E V

2016-09-01

Disturbances of circadian rhythms have been suggested to be a causal factor in the development of major depressive disorder. However, the mechanisms underlying the association between circadian rhythm abnormalities and mood disorders are still unknown. In the current study the association between diurnal pattern of key phase markers (melatonin, corticosterone, and core body temperature) and anhedonic-like behavior was investigated using the highly validated rat chronic mild stress (CMS) model of depression. Phase marker measurements were done after 3.5 weeks of CMS in 48 control rats and 48 anhedonic-like rats at 6 time points within 24h. The results showed that anhedonic-like behavior associates with changes in all three phase markers: an increased dark phase melatonin secretion, an additional peak in corticosterone level in the beginning of the light phase, and hypothermia in the dark phase. The result adds to the validity of the CMS model in general and in particular to be adequate as a model for studying the chronobiology of depressive disorder. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

Differential proteomic analysis of the anti-depressive effects of oleamide in a rat chronic mild stress model of depression.

PubMed

Ge, Lin; Zhu, Ming-Ming; Yang, Jing-Yu; Wang, Fang; Zhang, Rong; Zhang, Jing-Hai; Shen, Jing; Tian, Hui-Fang; Wu, Chun-Fu

2015-04-01

Depression is a complex psychiatric disorder, and its etiology and pathophysiology are not completely understood. Depression involves changes in many biogenic amine, neuropeptide, and oxidative systems, as well as alterations in neuroendocrine function and immune-inflammatory pathways. Oleamide is a fatty amide which exhibits pharmacological effects leading to hypnosis, sedation, and anti-anxiety effects. In the present study, the chronic mild stress (CMS) model was used to investigate the antidepressant-like activity of oleamide. Rats were exposed to 10weeks of CMS or control conditions and were then subsequently treated with 2weeks of daily oleamide (5mg/kg, i.p.), fluoxetine (10mg/kg, i.p.), or vehicle. Protein extracts from the hippocampus were then collected, and hippocampal maps were generated by way of two-dimensional gel electrophoresis (2-DE). Altered proteins induced by CMS and oleamide were identified through mass spectrometry and database searches. Compared to the control group, the CMS rats exhibited significantly less body weight gain and decreased sucrose consumption. Treatment with oleamide caused a reversal of the CMS-induced deficit in sucrose consumption. In the proteomic analysis, 12 protein spots were selected and identified. CMS increased the levels of adenylate kinase isoenzyme 1 (AK1), nucleoside diphosphate kinase B (NDKB), histidine triad nucleotide-binding protein 1 (HINT1), acyl-protein thioesterase 2 (APT-2), and glutathione S-transferase A4 (GSTA4). Compared to the CMS samples, seven spots changed significantly following treatment with oleamide, including GSTA4, glutathione S-transferase A6 (GSTA6), GTP-binding nuclear protein Ran (Ran-GTP), ATP synthase subunit d, transgelin-3, small ubiquitin-related modifier 2 (SUMO2), and eukaryotic translation initiation factor 5A-1 (eIF5A1). Of these seven proteins, the level of eIF5A1 was up-regulated, whereas the remaining proteins were down-regulated. In conclusion, oleamide has antidepressant-like properties in the CMS rat model. The identification of proteins altered by CMS and oleamide treatment provides support for targeting these proteins in the development of novel therapies for depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T.

PubMed

Hemanth Kumar, B S; Mishra, Sushanta Kumar; Rana, Poonam; Singh, Sadhana; Khushu, Subash

2012-06-15

Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy ((1)H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. (1)H MRS was performed in both control and CMS rats (n=10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA+NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using (1)H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression. Copyright © 2012 Elsevier B.V. All rights reserved.

Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress.

PubMed

Song, Li; Che, Wang; Min-Wei, Wang; Murakami, Yukihisa; Matsumoto, Kinzo

2006-02-01

Increasing evidences indicate the concurrence and interrelationship of depression and cognitive impairments. The present study was undertaken to investigate the effects of two depressive animal models, learned helplessness (LH) and chronic mild stress (CMS), on the cognitive functions of mice in the Morris water maze task. Our results demonstrated that both LH and CMS significantly decreased the cognitive performance of stressed mice in the water maze task. The escaping latency to the platform was prolonged and the probe test percentage in the platform quadrant was reduced. These two models also increased the plasma corticosterone concentration and decreased the brain derived neurotrophic factor (BDNF) and cAMP-response element-biding protein (CREB) messenger ribonucleic acid (mRNA) levels in hippocampus, which might cause the spatial cognition deficits. Repeated treatment with antidepressant drugs, imipramine (Imi) and fluoxetine (Flu), significantly reduced the plasma corticosterone concentration and enhanced the BDNF and CREB levels. Furthermore, antidepressant treated animals showed an ameliorated cognitive performance compared with the vehicle treated stressed animals. These data suggest that both LH and CMS impair the spatial cognitive function and repeated treatment with antidepressant drugs decreases the prevalence of cognitive impairments induced by these two animal models. Those might in part be attributed to the reduced plasma corticosterone and enhanced hippocampal BDNF and CREB expressions. This study provided a better understanding of molecular mechanisms underlying interactions of depression and cognitive impairments, although animal models used in this study can mimic only some aspects of depression or cognition of human.

Day and night: diurnal phase influences the response to chronic mild stress

PubMed Central

Aslani, Shilan; Harb, Mazen R.; Costa, Patricio S.; Almeida, Osborne F. X.; Sousa, Nuno; Palha, Joana A.

2014-01-01

Chronic mild stress (CMS) protocols are widely used to create animal models of depression. Despite this, the inconsistencies in the reported effects may be indicative of crucial differences in methodology. Here, we considered the time of the diurnal cycle in which stressors are applied as a possible relevant temporal variable underlying the association between stress and behavior. Most laboratories test behavior during the light phase of the diurnal cycle, which corresponds to the animal's resting period. Here, rats stressed either in their resting (light phase) or active (dark phase) periods were behaviorally characterized in the light phase. When exposure to CMS occurred during the light phase of the day cycle, rats displayed signs of depressive and anxiety-related behaviors. This phenotype was not observed when CMS was applied during the dark (active) period. Interestingly, although no differences in spatial and reference memory were detected (Morris water maze) in animals in either stress period, those stressed in the light phase showed marked impairments in the probe test. These animals also showed significant dendritic atrophy in the hippocampal dentate granule neurons, with a decrease in the number of spines. Taken together, the observations reported demonstrate that the time in which stress is applied has differential effects on behavioral and neurostructural phenotypes. PMID:24672446

Effects of chronic mild stress on the development of drug dependence in rats.

PubMed

Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Litwa, Ewa; Willner, Paul

2014-09-01

There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

Antidepressant effects of ginseng total saponins in the forced swimming test and chronic mild stress models of depression.

PubMed

Dang, Haixia; Chen, Ying; Liu, Xinmin; Wang, Qiong; Wang, Liwei; Jia, William; Wang, Yuqing

2009-11-13

Ginseng total saponins (GTS) are the major active components of Panax ginseng C.A. Meyer, which has been used as a popular tonic herb for 2000 years in Far East countries. In the present study, two classic animal models: the forced swimming test (FST) and the chronic mild stress (CMS) model were used to evaluate the antidepressant-like activities of GTS. It was observed that GTS at doses of 50 and 100 mg/kg significantly reduced the immobility time in the FST in mice after 7-day treatment. GTS also reversed the reduction in the sucrose preference index, decrease in locomotor activity as well as prolongation of latency of feeding in the novelty environment displayed by CMS rats. In addition, HPLC-ECD and immunohistochemical staining analysis indicated that the CMS-induced decrease in monoamine neurotransmitter concentration and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were almost completely reversed by GTS. In conclusion, GTS exerts antidepressant-like effects in two highly specific and predictive animal models of depression. The activity of GTS in antidepression may be mediated partly through enhancing the monoamine neurotransmitter concentration and BDNF expression in the hippocampus.

Compressive Deformation Behavior of Closed-Cell Micro-Pore Magnesium Composite Foam.

PubMed

Wang, Jing; Wang, Nannan; Liu, Xin; Ding, Jian; Xia, Xingchuan; Chen, Xueguang; Zhao, Weimin

2018-05-04

The closed-cell micro-pore magnesium composite foam with hollow ceramic microspheres (CMs) was fabricated by a modified melt foaming method. The effect of CMs on the compressive deformation behavior of CM-containing magnesium composite foam was investigated. Optical microscopy and scanning electron microscopy were used for observation of the microstructure. Finite element modeling of the magnesium composite foam was established to predict localized stress, fracture of CMs, and the compressive deformation behavior of the foam. The results showed that CMs and pores directly affected the compressive deformation behavior of the magnesium composite foam by sharing a part of load applied on the foam. Meanwhile, the presence of Mg₂Si phase influenced the mechanical properties of the foam by acting as the crack source during the compression process.

Compressive Deformation Behavior of Closed-Cell Micro-Pore Magnesium Composite Foam

PubMed Central

Wang, Jing; Wang, Nannan; Liu, Xin; Ding, Jian; Xia, Xingchuan; Chen, Xueguang; Zhao, Weimin

2018-01-01

The closed-cell micro-pore magnesium composite foam with hollow ceramic microspheres (CMs) was fabricated by a modified melt foaming method. The effect of CMs on the compressive deformation behavior of CM-containing magnesium composite foam was investigated. Optical microscopy and scanning electron microscopy were used for observation of the microstructure. Finite element modeling of the magnesium composite foam was established to predict localized stress, fracture of CMs, and the compressive deformation behavior of the foam. The results showed that CMs and pores directly affected the compressive deformation behavior of the magnesium composite foam by sharing a part of load applied on the foam. Meanwhile, the presence of Mg2Si phase influenced the mechanical properties of the foam by acting as the crack source during the compression process. PMID:29734700

Chronic mild stress in submissive mice: Marked polydipsia and social avoidance without hedonic deficit in the sucrose preference test.

PubMed

Gross, Moshe; Pinhasov, Albert

2016-02-01

In the Chronic Mild Stress (CMS) protocol, rodents are exposed to unpredictable stressors to induce anxiety-like behavior and hedonic deficit in the Sucrose Preference test (SPT). Since CMS-induced anxiety- and anhedonic-like behavior may depend upon individual vulnerability to stress, we hypothesized that selectively bred Submissive (Sub) mice would exhibit heightened anxiety- and anhedonic-like behavior, in response to CMS exposure. We anticipated that the testing of Sub mice alongside their Wt counterparts in a battery of behavioral assays would identify parameters most sensitive to CMS effects. To test these assumptions, Sub mice and their outbred Sabra (Wt) counterparts underwent a five-week CMS-SPT regimen. CMS exposure led to reduced preference for sucrose (sucrose-sweetened water as percent of total intake) among both mouse strains (p<0.01 Wt; p<0.05 Sub). However, this effect was attributed to CMS-induced polydipsia, indicated by mice's increased water consumption, (p<0.01 Wt and Sub), without changes in sucrose intake. Furthermore, CMS-exposed Sub mice, but not Wt, demonstrated impaired social exploration in the Three Chamber test (p<0.05) and anxiety-like effects in the Elevated Plus Maze (p<0.05). Moreover, in a separate experiment, social isolation alone was sufficient to induce polydipsia in Sub mice, without affecting Wt mice's drinking behavior. The present findings suggest that the EPM and Three Chamber tests may be valuable complementary measures of CMS effects, alongside the Sucrose Preference test, and introduce the Sub mouse strain for use in study of susceptibility to stress. Copyright © 2015 Elsevier B.V. All rights reserved.

Gender differences in CMS and the effects of antidepressant venlafaxine in rats.

PubMed

Xing, Yanli; He, Jie; Hou, Jian; Lin, Fei; Tian, Jingwei; Kurihara, Hiroshi

2013-11-01

Gender differences in susceptibility to chronic mild stress (CMS) and effects of venlafaxine in rats have been investigated in the current study. Male and female SD rats were exposed to CMS or CMS plus chronic venlafaxine administration (10mg/kg, 21days) in order to study depressive behavior in rats. Rats were tested in open field test and sucrose preference test to figure out gender differences in behavior. Then serum corticosterone and the expression of FKBP5 in hippocampus of rats were detected to explore the possible mechanism. The results showed that the CMS impact on behavioral parameters and corticosterone levels and response to venlafaxine were gender dependent. Female rats appeared more vulnerable in the dysregulation of HPA axis to CMS. Venlafaxine treatment normalized depressive-like behavior in both gender. However, venlafaxine treated male rats exhibited better improved explore behavior and anhedonia. FKBP5 might be involved in the explanation of gender differences in CMS and venlafaxine treatment. Male and female rats respond differently to chronic stress and venlafaxine continuous treatment. This results have guiding meaning in design of trials related to stress induced depression. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effect of strawberry (Fragaria x ananasa) as antidepresant activity on mice induced by stress

NASA Astrophysics Data System (ADS)

Hazar, Siti; Fitri, Lulu L.

2015-09-01

Depression is a physiological disorder on the brain and may induce the reduction levels of monoamine neurotransmitters, serotonin and the increased levels of stress hormone, corticosterone. The use of antidepressant drugs causing side effect, therefore natural agents are used as alternative therapy. The objectives of this study are to determine the effect of strawberries in the murine experiments in increasing serotonin level as well as decreasing in the immobility time of mice on Forced Swimming Task (FST). Forty-eight male outbreed of 4 weeks old mice strain Swiss Webster with average body weight of 18-22 grams were divided into six groups of eight mice, as follows: (1) non-stressed, (2) Chronic Mild Stressed (CMS), (3) strawberry extract (with dose of 464.1 mg/kg) and CMS, (4) strawberry extract (with dose of 928.2 mg/kg) and CMS, (5) fisetin (with a dose of 10 mg/kg) and CMS, and (6) amitriptyline (an antidepressant, with a dose of 3.25 mg/kg) and CMS as a comparison group. Chronic Mild Stress (CMS) method were used as induction of stress consisted of seven different stressors and assigned randomly for 35 days. Provision of treatment was made during the 14 days preparations on day 22 to day 35. At the end of treatments, all mice were assigned on FST test for immobility time measurements. Next, all mice were decapitated and the brains were isolated. Serotonin levels were measured using High Performance Liquid Chromatography (HPLC) with UV-visible light detector. The results showed that the immobility time of group mice which were given by the strawberries (928.2 mg/kg) and fisetin had shorter duration than the positive control group. Furthermore, the level of serotonin in the test group increased compared to CMS group. Corticosterone levels of treatment mice were increased significantly compared to non-stressed mice. Therefore, it can be concluded that strawberries are able to improve depressive symptoms by decreasing immobility time and increasing levels of serotonin compared with CMS group.

Chronic Mild Stress Assay Leading to Early Onset and Propagation of Alzheimer's Disease Phenotype in Mouse Models.

PubMed

Cuadrado-Tejedor, Mar; García-Osta, Ana

2016-01-01

A comprehensive chronic mild stress (CMS) procedure is presented, which consists in the application of unpredictable mild stressors to animal models in a random order for several weeks. This assay can be applied to Alzheimer's disease (AD) mouse models, leading to accelerated onset and increased severity of AD phenotypes and signs, including memory deficits and the accumulation of amyloid-β and phospho-tau. These assays open the way towards advanced studies on the influence of sustained mild stress, stress responses and pathways on the onset and propagation of Alzheimer's disease.

Sex-dependent influence of chronic mild stress (CMS) on voluntary alcohol consumption; study of neurobiological consequences.

PubMed

Marco, Eva M; Ballesta, Javier Antonio; Irala, Carlos; Hernández, María-Donina; Serrano, María Elisa; Mela, Virginia; López-Gallardo, Meritxell; Viveros, María-Paz

2017-01-01

Alcohol use disorder and depression are highly comorbid, and both conditions exhibit important sexual dimorphisms. Here, we aimed to investigate voluntary alcohol consumption after 6weeks of chronic mild stress (CMS) in Wistar rats - employed as an animal model of depression. Male and female rats were investigated, and changes in several molecular markers were analysed in frontal cortex (FCx) and hippocampal formation (HF). CMS induced depressive-like responses in the forced swimming test - increased immobility time - in male and female animals, without affecting anhedonia (sucrose preference test) nor motor activity (holeboard); body weight gain and food intake were diminished only among CMS males. Voluntary alcohol consumption was evaluated in a two-bottle choice paradigm (ethanol 20% versus tap water) for 4 consecutive days; females exhibited a higher preference for alcohol compared to male animals. In particular, alcohol consumption was significantly higher among CMS females compared to CMS male animals. Remarkably, similar changes in both male and female animals exposed to CMS were observed regarding the expression levels of NCAM-140KDa (decrease), GFAP and CB1R expression (increase) within the FCx as well as for HF PSD-95 levels (increase). However, contrasting effects in males and females were reported in relation to synaptophysin (SYN) protein levels within the FCx, HF CB1R expression (a decrease among male animals but an increase in females); while the opposite pattern was observed for NCAM-140KDa protein levels in the HF. A decrease in CB2R expression was only observed in the HF of CMS-females. The present study suggests that male and female animals might be differentially affected by CMS regarding later voluntary alcohol consumption. In this initial approach, cortical SYN, and NCAM-140KDa, CB1R and CB2R expression within the HF have arisen as potential candidates to explain such sex differences in behaviour. However, the depression-alcoholism relationship still deserves further investigation. Copyright © 2016. Published by Elsevier Inc.

Isolation stress and chronic mild stress induced immobility in the defensive burying behavior and a transient increased ethanol intake in Wistar rats.

PubMed

Vázquez-León, Priscila; Martínez-Mota, Lucía; Quevedo-Corona, Lucía; Miranda-Páez, Abraham

2017-09-01

Stress can be experienced with or without adverse effects, of which anxiety and depression are two of the most important due to the frequent comorbidity with alcohol abuse in humans. Historically, stress has been considered a cause of drug use, particularly alcohol abuse due to its anxiolytic effects. In the present work we exposed male Wistar rats to two different stress conditions: single housing (social isolation, SI), and chronic mild stress (CMS). We compared both stressed groups to group-housed rats and rats without CMS (GH) to allow the determination of a clear behavioral response profile related to their respective endocrine stress response and alcohol intake pattern. We found that SI and CMS, to a greater extent, induced short-lasting increased sucrose consumption, a transient increase in serum corticosterone level, high latency/immobility, and low burying behavior in the defensive burying behavior (DBB) test, and a transient increase in alcohol intake. Thus, the main conclusion was that stress caused by both SI and CMS induced immobility in the DBB test and, subsequently, induced a transient increased voluntary ethanol intake in Wistar rats with a free-choice home-cage drinking paradigm. Copyright © 2017 Elsevier Inc. All rights reserved.

Rose oil (from Rosa × damascena Mill.) vapor attenuates depression-induced oxidative toxicity in rat brain.

PubMed

Nazıroğlu, Mustafa; Kozlu, Süleyman; Yorgancıgil, Emre; Uğuz, Abdülhadi Cihangir; Karakuş, Kadir

2013-01-01

Oxidative stress is a critical route of damage in various physiological stress-induced disorders, including depression. Rose oil may be a useful treatment for depression because it contains flavonoids which include free radical antioxidant compounds such as rutin and quercetin. We investigated the effects of absolute rose oil (from Rosa × damascena Mill.) and experimental depression on lipid peroxidation and antioxidant levels in the cerebral cortex of rats. Thirty-two male rats were randomly divided into four groups. The first group was used as control, while depression was induced in the second group using chronic mild stress (CMS). Oral (1.5 ml/kg) and vapor (0.15 ml/kg) rose oil were given for 28 days to CMS depression-induced rats, constituting the third and fourth groups, respectively. The sucrose preference test was used weekly to identify depression-like phenotypes during the experiment. At the end of the experiment, cerebral cortex samples were taken from all groups. The lipid peroxidation levels in the cerebral cortex in the CMS group were higher than in control whereas their levels were decreased by rose oil vapor exposure. The vitamin A, vitamin E, vitamin C and β-carotene concentrations in the cerebral cortex were lower in the CMS group than in the control group whereas their concentrations were higher in the rose oil vapor plus CMS group. The CMS-induced antioxidant vitamin changes were not modulated by oral treatment. Glutathione peroxidase activity and reduced glutathione did not change statistically in the four groups following CMS or either treatment. In conclusion, experimental depression is associated with elevated oxidative stress while treatment with rose oil vapor induced protective effects on oxidative stress in depression.

Protective effects of chronic mild stress during adolescence in the low-novelty responder rat.

PubMed

Rana, Samir; Nam, Hyungwoo; Glover, Matthew E; Akil, Huda; Watson, Stanley J; Clinton, Sarah M; Kerman, Ilan A

2016-01-01

Stress-elicited behavioral and physiologic responses vary widely across individuals and depend on a combination of environmental and genetic factors. Adolescence is an important developmental period when neural circuits that guide emotional behavior and stress reactivity are still maturing. A critical question is whether stress exposure elicits contrasting effects when it occurs during adolescence versus adulthood. We previously found that Sprague-Dawley rats selectively bred for low-behavioral response to novelty (bred Low Responders; bLRs) are particularly sensitive to chronic unpredictable mild stress (CMS) exposure in adulthood, which exacerbates their typically high levels of spontaneous depressive- and anxiety-like behavior. Given developmental processes known to occur during adolescence, we sought to determine whether the impact of CMS on bLR rats is equivalent when they are exposed to it during adolescence as compared with adulthood. Young bLR rats were either exposed to CMS or control condition from postnatal days 35-60. As adults, we found that CMS-exposed bLRs maintained high levels of sucrose preference and exhibited increased social exploration along with decreased immobility on the forced swim test compared with bLR controls. These data indicate a protective effect of CMS exposure during adolescence in bLR rats.

Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1.

PubMed

Garcia-Garcia, Alvaro L; Elizalde, Natalia; Matrov, Denis; Harro, Jaanus; Wojcik, Sonja M; Venzala, Elisabet; Ramírez, Maria J; Del Rio, Joaquin; Tordera, Rosa M

2009-08-01

Many studies link depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/gamma-aminobutyric acid (GABA) cycle may account for this imbalance. Evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affect the glutamate/GABA cycle and induce helpless behavior. We studied decreased VGLUT1 as a potential factor enhancing a depressive-like phenotype in an animal model. Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the VGLUT1+/- and wildtype. The regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle, and behavior by both genotype and chronic mild stress (CMS) were studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was studied. VGLUT1+/- mice showed increased neuronal synthesis of glutamate; decreased cortical and hippocampal GABA, VGLUT1, and excitatory amino acid transporter 1 (EAAT1) as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, the vesicular GABA transporter (VGAT), and glutamic acid decarboxylase 65 (GAD65) in both areas and led to upregulation of EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety, and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown. These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress.

Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus

PubMed Central

Jiang, Bo; Xiong, Zhe; Yang, Jun; Wang, Wei; Wang, Yue; Hu, Zhuang-Li; Wang, Fang; Chen, Jian-Guo

2012-01-01

BACKGROUND AND PURPOSE Ginsenoside Rg1 (Rg1) is one of the major bioactive ingredients of Panax ginseng with little toxicity and has been shown to have neuroprotective effects. In this study, we investigated the antidepressant-like effect of Rg1 in models of depression in mice. EXPERIMENTAL APPROACH The effects of Rg1 were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Rg1 was also investigated in the chronic mild stress (CMS) mouse model of depression with imipramine as the positive control. Changes in hippocampal neurogenesis and spine density, the brain-derived neurotrophic factor (BDNF) signalling pathway, and serum corticosterone level after chronic stress and Rg1 treatment were then investigated. The tryptophan hydroxylase inhibitor and the tyrosine kinase B inhibitor were also used to explore the antidepressive mechanisms of Rg1. KEY RESULTS Ginsenoside Rg1 exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. It was also effective in the CMS model of depression. Furthermore, Rg1 up-regulated the BDNF signalling pathway in the hippocampus and down-regulated serum corticosterone level during the CMS procedure. In addition, Rg1 was able to reverse the decrease in dendritic spine density and hippocampal neurogenesis caused by CMS. However, Rg1 had no discernable effect on the monoaminergic system. CONCLUSIONS AND IMPLICATIONS Our results provide the first evidence that Rg1 has antidepressant activity via activation of the BDNF signalling pathway and up-regulation of hippocampal neurogenesis. PMID:22335772

Ogura-CMS in Chinese cabbage (Brassica rapa ssp. pekinensis) causes delayed expression of many nuclear genes.

PubMed

Dong, Xiangshu; Kim, Wan Kyu; Lim, Yong-Pyo; Kim, Yeon-Ki; Hur, Yoonkang

2013-02-01

We investigated the mechanism regulating cytoplasmic male sterility (CMS) in Brassica rapa ssp. pekinensis using floral bud transcriptome analyses of Ogura-CMS Chinese cabbage and its maintainer line in B. rapa 300-K oligomeric probe (Br300K) microarrays. Ogura-CMS Chinese cabbage produced few and infertile pollen grains on indehiscent anthers. Compared to the maintainer line, CMS plants had shorter filaments and plant growth, and delayed flowering and pollen development. In microarray analysis, 4646 genes showed different expression, depending on floral bud size, between Ogura-CMS and its maintainer line. We found 108 and 62 genes specifically expressed in Ogura-CMS and its maintainer line, respectively. Ogura-CMS line-specific genes included stress-related, redox-related, and B. rapa novel genes. In the maintainer line, genes related to pollen coat and germination were specifically expressed in floral buds longer than 3mm, suggesting insufficient expression of these genes in Ogura-CMS is directly related to dysfunctional pollen. In addition, many nuclear genes associated with auxin response, ATP synthesis, pollen development and stress response had delayed expression in Ogura-CMS plants compared to the maintainer line, which is consistent with the delay in growth and development of Ogura-CMS plants. Delayed expression may reduce pollen grain production and/or cause sterility, implying that mitochondrial, retrograde signaling delays nuclear gene expression. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Diffusion MRI and MR spectroscopy reveal microstructural and metabolic brain alterations in chronic mild stress exposed rats: A CMS recovery study.

PubMed

Khan, Ahmad Raza; Hansen, Brian; Wiborg, Ove; Kroenke, Christopher D; Jespersen, Sune Nørhøj

2018-02-15

Chronic mild stress (CMS) induced depression elicits several debilitating symptoms and causes a significant economic burden on society. High variability in the symptomatology of depression poses substantial impediment to accurate diagnosis and therapy outcome. CMS exposure induces significant metabolic and microstructural alterations in the hippocampus (HP), prefrontal cortex (PFC), caudate-putamen (CP) and amygdala (AM), however, recovery from these maladaptive changes are limited and this may provide negative effects on the therapeutic treatment and management of depression. The present study utilized anhedonic rats from the unpredictable CMS model of depression to study metabolic recovery in the ventral hippocampus (vHP) and microstructural recovery in the HP, AM, CP, and PFC. The study employed 1 H MR spectroscopy ( 1 H MRS) and in-vivo diffusion MRI (d-MRI) at the age of week 18 (week 1 post CMS exposure) week 20 (week 3 post CMS) and week 25 (week 8 post CMS exposure) in the anhedonic group, and at the age of week 18 and week 22 in the control group. The d-MRI data have provided an array of diffusion tensor metrics (FA, MD, AD, and RD), and fast kurtosis metrics (MKT, W L and W T ). CMS exposure induced a significant metabolic alteration in vHP, and significant microstructural alterations were observed in the HP, AM, and PFC in comparison to the age match control and within the anhedonic group. A significantly high level of N-acetylaspartate (NAA) was observed in vHP at the age of week 18 in comparison to age match control and week 20 and week 25 of the anhedonic group. HP and AM showed significant microstructural alterations up to the age of week 22 in the anhedonic group. PFC showed significant microstructural alterations only at the age of week 18, however, most of the metrics showed significantly higher value at the age of week 20 in the anhedonic group. The significantly increased NAA concentration may indicate impaired catabolism due to astrogliosis or oxidative stress. The significantly increased W L in the AM and HP may indicate hypertrophy of AM and reduced volume of HP. Such metabolic and microstructural alterations could be useful in disease diagnosis and follow-up treatment intervention in depression and similar disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of supplementation with fish oil and n-3 PUFAs enriched egg yolk phospholipids on anhedonic-like response and body weight in the rat chronic mild stress model of depression.

PubMed

Rutkowska, M; Trocha, M; Szandruk, M; Słupski, W; Rymaszewska, J

2013-08-01

Polyunsaturated fatty acids play an important role in the human organism. They guarantee a normal function of nervous cells, influence neurotransmission, and build some elements of cellular membranes. Several reports indicate an association between a deficiency of polyunsaturated fatty acids and depression. The aim of this study was to examine the effects of diet supplemented with fish oil, which is rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) and n-3 PUFAs enriched phospholipids ("super lecithin") obtained from designed eggs on anhedonic-like response and body weight in the rat chronic mild stress (CMS) model of depression. The results showed that neither fish oil nor n-3 PUFAs enriched egg yolk phospholipids supplementation reversed disturbances caused by CMS, such as anhedonic-like state or reduction of body weight gain.

ω-3 and folic acid act against depressive-like behavior and oxidative damage in the brain of rats subjected to early- or late-life stress.

PubMed

Réus, Gislaine Z; Maciel, Amanda L; Abelaira, Helena M; de Moura, Airam B; de Souza, Thays G; Dos Santos, Thais R; Darabas, Ana Caroline; Parzianello, Murilo; Matos, Danyela; Abatti, Mariane; Vieira, Ana Carolina; Fucillini, Vanessa; Michels, Monique; Dal-Pizzol, Felipe; Quevedo, João

2018-03-30

To investigate the antidepressant and antioxidant effects of omega-3, folic acid and n-acetylcysteine (NAC) in rats which were subjected to early or late life stress. Early stress was induced through maternal deprivation (MD), while late life stress was induced using the chronic mild stress (CMS) protocol. Young rats which were subjected to MD and the adult rats which were subjected to CMS were treated with omega-3 fatty acids (0.72 g/kg), NAC (20 mg/kg) or folic acid (50 mg/kg) once/day, for a period of 20 days. Then, the animals' immobility times were evaluated using the forced swimming test. Oxidative stress parameters were evaluated in the brain. Depressive-like behavior induced by CMS was prevented by NAC and folic acid, and depressive-like behavior induced by MD was prevented by NAC, folic acid and omega-3. NAC, folic acid and omega-3 were able to exert antioxidant effects in the brain of rats subjected to CMS or MD. These preventive treatments decreased the levels of protein carbonylation and lipid peroxidation, and also decreased the concentrations of nitrite/nitrate and reduced the activity of myeloperoxidase activity in the rat brain which was induced by CMS or MD. NAC, folic acid and omega-3 increased superoxide dismutase and catalase activities in the rat brain subjected to early or late life stress. NAC, omega-3 and folic acid may present interesting lines of treatment based on their antioxidant properties, which cause an inhibition of behavioral and brain changes that occur from stressful life events. Copyright © 2018 Elsevier Inc. All rights reserved.

Dehydroepiandrosterone increases the number and dendrite maturation of doublecortin cells in the dentate gyrus of middle age male Wistar rats exposed to chronic mild stress.

PubMed

Herrera-Pérez, J J; Martínez-Mota, L; Jiménez-Rubio, G; Ortiz-López, L; Cabrera-Muñoz, E A; Galindo-Sevilla, N; Zambrano, E; Hernández-Luis, F; Ramírez-Rodríguez, G B; Flores-Ramos, M

2017-03-15

Aging increases the vulnerability to stress and risk of developing depression. These changes have been related to a reduction of dehydroepiandrosterone (DHEA) levels, an adrenal steroid with anti-stress effects. Also, adult hippocampal neurogenesis decreases during aging and its alteration or impaired is related to the development of depression. Besides, it has been hypothesized that DHEA increases the formation of new neurons. However, it is unknown whether treatment with DHEA in aging may stimulate the dendrite maturation of newborn neurons and reversing depressive-like signs evoked by chronic stress exposure. Here aged male rats (14 months old) were subjected to a scheme of chronic mild stress (CMS) during six weeks, received a treatment with DHEA from the third week of CMS. Changes in body weight and sucrose preference (SP) were measured once a week. DHEA levels were measured in serum, identification of doublecortin-(DCX)-, BrdU- and BrdU/NeuN-labeled cells was done in the dentate gyrus of the hippocampus. CMS produced a gradual reduction in the body weight, but no changes in the SP were observed. Treatment enhanced levels of DHEA, but lack of recovery on body weight of stressed rats. Aging reduced the number of DCX-, BrdU- and BrdU/NeuN- cells but DHEA just significantly increased the number of DCX-cells in rats under CMS and controls, reaching levels of young non-stressed rats (used here as a reference of an optimal status of health). In rats under CMS, DHEA facilitated dendritic maturation of immature new neurons. Our results reveal that DHEA improves neural plasticity even in conditions of CMS in middle age rats. Thus, this hormone reverted the decrement of DCX-cells caused during normal aging. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of myocardial ischemia during intense mental stress using flight simulation in airline pilots with coronary artery disease to that produced with conventional mental and treadmill exercise stress testing.

PubMed

Doorey, Andrew; Denenberg, Barry; Sagar, Vidya; Hanna, Tracy; Newman, Jack; Stone, Peter H

2011-09-01

Mental stress increases cardiovascular morbidity and mortality. Although laboratory mental stress often causes less myocardial ischemia than exercise stress (ES), it is unclear whether mental stress is intrinsically different or differences are due to less hemodynamic stress with mental stress. We sought to evaluate the hemodynamic and ischemic response to intense realistic mental stress created by modern flight simulators and compare this response to that of exercise treadmill testing and conventional laboratory mental stress (CMS) testing in pilots with coronary disease. Sixteen airline pilots with angiographically documented coronary disease and documented myocardial ischemia during ES were studied using maximal treadmill ES, CMS, and aviation mental stress (AMS) testing. AMS testing was done in a sophisticated simulator using multiple system failures as stressors. Treadmill ES testing resulted in the highest heart rate, but AMS caused a higher blood pressure response than CMS. Maximal rate-pressure product was not significantly different between ES and AMS (25,646 vs 23,347, p = 0.08), although these were higher than CMS (16,336, p <0.0001). Despite similar hemodynamic stress induced by ES and AMS, AMS resulted in significantly less ST-segment depression and nuclear ischemia than ES. Differences in induction of ischemia by mental stress compared to ES do not appear to be due to the creation of less hemodynamic stress. In conclusion, even with equivalent hemodynamic stress, intense realistic mental stress induced by flight simulators results in significantly less myocardial ischemia than ES as measured by ST-segment depression and nuclear ischemia. Copyright © 2011 Elsevier Inc. All rights reserved.

Young-Adult Male Rats' Vulnerability to Chronic Mild Stress Is Reflected by Anxious-Like instead of Depressive-Like Behaviors.

PubMed

José Jaime, Herrera-Pérez; Venus, Benítez-Coronel; Graciela, Jiménez-Rubio; Tania, Hernández-Hernández Olivia; Lucía, Martínez-Mota

2016-01-01

In a previous study, we found that chronic mild stress (CMS) paradigm did not induce anhedonia in young-adult male rats but it reduced their body weight gain. These contrasting results encouraged us to explore other indicators of animal's vulnerability to stress such as anxious-like behaviors, since stress is an etiologic factor also for anxiety. Thus, in this study, we evaluated the vulnerability of these animals to CMS using behavioral tests of depression or anxiety and measuring serum corticosterone. Male Wistar rats were exposed to four weeks of CMS; the animals' body weight and sucrose preference (indicator of anhedonia) were assessed after three weeks, and, after the fourth week, some animals were evaluated in a behavioral battery (elevated plus maze, defensive burying behavior, and forced swimming tests); meanwhile, others were used to measure serum corticosterone. We found that CMS (1) did not affect sucrose preference, immobility behavior in the forced swimming test, or serum corticosterone; (2) decreased body weight gain; and (3) increased the rat's entries into closed arms of the plus maze and the cumulative burying behavior. These data indicate that young male rats' vulnerability to CMS is reflected as poor body weight gain and anxious-like instead of depressive-like behaviors.

Young-Adult Male Rats' Vulnerability to Chronic Mild Stress Is Reflected by Anxious-Like instead of Depressive-Like Behaviors

PubMed Central

José Jaime, Herrera-Pérez; Venus, Benítez-Coronel; Graciela, Jiménez-Rubio; Tania, Hernández-Hernández Olivia

2016-01-01

In a previous study, we found that chronic mild stress (CMS) paradigm did not induce anhedonia in young-adult male rats but it reduced their body weight gain. These contrasting results encouraged us to explore other indicators of animal's vulnerability to stress such as anxious-like behaviors, since stress is an etiologic factor also for anxiety. Thus, in this study, we evaluated the vulnerability of these animals to CMS using behavioral tests of depression or anxiety and measuring serum corticosterone. Male Wistar rats were exposed to four weeks of CMS; the animals' body weight and sucrose preference (indicator of anhedonia) were assessed after three weeks, and, after the fourth week, some animals were evaluated in a behavioral battery (elevated plus maze, defensive burying behavior, and forced swimming tests); meanwhile, others were used to measure serum corticosterone. We found that CMS (1) did not affect sucrose preference, immobility behavior in the forced swimming test, or serum corticosterone; (2) decreased body weight gain; and (3) increased the rat's entries into closed arms of the plus maze and the cumulative burying behavior. These data indicate that young male rats' vulnerability to CMS is reflected as poor body weight gain and anxious-like instead of depressive-like behaviors. PMID:27433469

The effect of chronic mild stress on tumor-bearing rats' behavior and its mechanism.

PubMed

Xiu, Li-Juan; Lin, Hui-Ming; Wei, Pin-Kang

2010-03-31

Much evidence has demonstrated that stress and tumor interact, but the mechanisms are poorly understood. The purpose of this study is to discuss the effect of unpredictable chronic mild stress (CMS) upon the behavior of Walker 256 tumor-bearing rats and its mechanism. Observe the effects of CMS on the sucrose consumption, activities, body weight and levels of serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats, and on the levels of Bcl-2 and the phosphor-ERK1/2 in their hippocampus. CMS can reduce the average sucrose consumption, behavioral scores, body weight gain, expression of Bcl-2 and p-ERK1/2 protein in hippocampus, and increase serums TNF-alpha and IL-6 of both tumor-bearing rats and non-tumor-bearing rats. The stressed tumor-bearing rats had less sucrose consumption, body weight gain and lower behavioral scores, but higher level of serum TNF-alpha than stressed non-tumor-bearing rats. A negative correlation was found between the levels of serum TNF-alpha and sucrose consumption, while a positive correlation between the expression of Bcl-2 protein in hippocampus proper and sucrose consumption. CMS can reduce the protein levels of Bcl-2 and p-ERK1/2 in the rats' hippocampus, which contributes to the changes in the rats' behavior caused by CMS. Tumor-bearing rats are prone to behave depressively after the exposure to CMS. Our findings have suggested that the tumor, by increasing the inflammatory reaction, can be taken as a stressor, affecting the hippocampus and consequently causing depression by decreasing the expression of Bcl-2 and p-ERK1/2 in hippocampus. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Effects of chronic mild stress on rats selectively bred for behavior related to bipolar disorder and depression.

PubMed

Murray, Ryan; Boss-Williams, Katherine A; Weiss, Jay M

2013-07-02

To test the possibility that chronic mild stress (CMS) might be unreliable in producing its often-intended outcome (i.e., decreased preference for sucrose, hypothesized to represent depression-relevant anhedonia) because it is typically applied to "normal" rats, a CMS procedure was applied to rats that may possess genetic susceptibility to affective disorders, having had been selectively-bred to show behavior indicative of such disorders. These rat lines were: Hyperactive (HYPER) rats, which show characteristics of bipolar disorder, Swim-test Susceptible (SUS) and Swim-test Resistant (RES) rats, being susceptible or resistant to effects of stress in the swim test, Swim High-active (SwHi) and Swim Low-active (SwLo) rats, which innately show high or low activity in the swim test. These selectively-bred lines were compared to normal, non-selectively bred (NS) rats. During CMS, HYPER rats, both females and males, as well as RES and SwHi rats, showed reduced consumption of a palatable 2% sucrose solution, and reduced preference for sucrose (vs. water) in comparison to non-stressed rats (no CMS) of the same lines. In contrast, CMS produced no decrease in sucrose consumption or in preference for sucrose in normal NS rats, and actually a caused a slight increase in sucrose consumption and preference in male NS rats. Other measures that indicate depression - food intake and motor activity in the home cage - were also assessed. SwLo and SwHi showed greater sensitivity to having their home-cage ambulatory activity reduced by CMS than did NS rats, but no other such differences relative to NS rats were seen for these other measures; thus, changes in sucrose intake or preference could not be explained by a change in caloric intake. These results suggest that the genetic attributes of animals can influence the outcome of CMS, and that the application of CMS to normal, non-selected rats may account, at least in part, for the unreliability of CMS in decreasing consumption of palatable substances and decreasing preference for such substances. Copyright © 2013. Published by Elsevier Inc.

Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice.

PubMed

Cheng, Jie; Dong, Shuqi; Yi, Litao; Geng, Di; Liu, Qing

2018-06-01

Magnolol, the main constituent of Magnolia officinalis, has been shown to produce antidepressant-like effect in rodents. Growing evidence shows that neuroinflammation, oxidative stress and neuroendocrine contribute to the pathogenesis of major depression. Here, the aim of this present study was to determine whether magnolol affected these systems in mice exposed to chronic mild stress (CMS). The ameliorative effect of magnolol on depressive-like symptoms was investigated through behavioral tests, including the classical sucrose preference and forced swimming tests. The behavioral evaluation showed that magnolol reversed the depressive-like deficits both in sucrose preference test and forced swimming test. The elevation of prefrontal cortex pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was decreased by magnolol. Consistently, the microglia activation by CMS was also alleviated by magnolol. In addition, the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CMS was attenuated by magnolol. Moreover, the increased lipid peroxidation such as malonaldehyde (MDA) and decreased antioxidant defense enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) induced by CMS were also reversed by magnolol. These findings suggest that administration of magnolol could alleviate depressive-like behaviors in CMS mice that are mediated by suppressing neuroinflammation and oxidative stress in the prefrontal cortex. Copyright © 2018 Elsevier B.V. All rights reserved.

Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice.

PubMed

Gutknecht, Lise; Popp, Sandy; Waider, Jonas; Sommerlandt, Frank M J; Göppner, Corinna; Post, Antonia; Reif, Andreas; van den Hove, Daniel; Strekalova, Tatyana; Schmitt, Angelika; Colaςo, Maria B N; Sommer, Claudia; Palme, Rupert; Lesch, Klaus-Peter

2015-07-01

While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.

Treadmill exercise alleviates chronic mild stress-induced depression in rats.

PubMed

Lee, Taeck-Hyun; Kim, Kijeong; Shin, Mal-Soon; Kim, Chang-Ju; Lim, Baek-Vin

2015-12-01

Depression is a major cause of disability and one of the most common public health problems. In the present study, antidepressive effect of treadmill exercise on chronic mild stress (CMS)-induced depression in rats was investigated. For this, sucrose intake test, immunohistochemistry for 5-bromo-2'-deoxyuridine, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining, and Western blot analysis for brain-derived neurotrophic factor, cyclic adenosine monophosphate response element binding protein, and endothelial nitric oxide synthase were conducted. Following adaptation to the animal vivarium and two baseline fluid intake tests, the animals were divided into four groups: the control group, the CMS-induced depression group, the CMS-induced depression and exercise group, and the CMS-induced depression and fluoxetine-treated group. The animals in the CMS groups were exposed to the CMS conditions for 8 weeks and those in the control group were exposed to the control conditions for 8 weeks. After 4 weeks of CMS, the rats in the CMS-induced depression and exercise group were made to run on a motorized treadmill for 30 min once a day for 4 weeks. In the present results, treadmill exercise alleviated CMS-induced depressive symptoms. Treadmill exercise restored sucrose consumption, increased cell proliferation, and decreased apoptotic cell death. The present results suggest the possibility that exercise may improve symptoms of depression.

Effect of tribulus terrestris saponins on behavior and neuroendocrine in chronic mild stress depression rats.

PubMed

Wang, Zhe; Zhang, Dongdong; Hui, Shan; Zhang, Yingjin; Hu, Suiyu

2013-04-01

To observe the effect of tribulus terrestris saponins (TTS) on behavior and neuroendocrine of chronic mild stress (CMS) depression rats. Thirty male Sprague-Dawley rats were randomly allocated to six groups: vehicle group, CMS group, CMS + fluoxetine group and CMS + TTS of low-dosage (0.375 g/kg), medium-dosage (0.75 g/kg) and high-dosage (2.25 g/kg) groups. All rats except the vehicle group singly housed and exposed an unpredicted sequence of mild stressors. The behavior of rats was detected by open-field test (OFT) and sucrose preference test (SPT). The concentration of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) in serum of the rats were detected by radioimmunoassay. The concentration of cortisol (CORT) in serum was detected by enzyme immunoassay. CMS procedure not only significantly decreased the scores of crossing, rears and grooming in OFT and the sucrose preference in SPT (all P < 0.01), but also markedly increased serum CRH and CORT levels (both P < 0.05). Treatment with TTS (0.75 and 2.25 g/kg) could significantly prevent all of these abnormalities induced by CMS (P < 0.05, P < 0.01). CMS can affect rat behavior and neuroendocrine and cause depression. TTS has the antagonism on CMS and produce antidepressive effects.

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice.

PubMed

Zhang, Qi; Guo, Fei; Fu, Zhi-wen; Zhang, Bing; Huang, Cheng-gang; Li, Yang

2016-02-01

N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg(-1)·d(-1)) or a positive-control drug, fluoxetine (10 mg·kg(-1)·d(-1)) for 3 weeks. Behavioral assessments were carried out every week. In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltage-dependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

Demyelinating evidences in CMS rat model of depression: a DTI study at 7 T.

PubMed

Hemanth Kumar, B S; Mishra, S K; Trivedi, R; Singh, S; Rana, P; Khushu, S

2014-09-05

Depression is among the most debilitating diseases worldwide. Long-term exposure to stressors plays a major role in development of human depression. Chronic mild stress (CMS) seems to be a valid animal model for depression. Diffusion tensor imaging (DTI) is capable of inferring microstructural abnormalities of the white matter and has shown to serve as non-invasive marker of specific pathology. We developed a CMS rat model of depression and validated with behavioral experiments. We measured the diffusion indices (mean diffusivity (MD), fractional anisotropy (FA), axial (λ∥) and radial (λ⊥) diffusivity) to investigate the changes in CMS rat brain during depression onset. Diffusion indices have shown to be useful to discriminate myelin damage from axon loss. DTI was performed in both control and CMS rats (n=10, in each group) and maps of FA, MD, λ∥ and λ⊥ diffusivity values were generated using in-house built software. The diffusion indices were calculated by region of interest (ROI) analysis in different brain regions like the frontal cortex, hippocampus, hypothalamus, cingulum, thalamus, caudate putamen, corpus callosum, cerebral peduncle and sensory motor cortex. The results showed signs of demyelination, reflected by increased MD, decreased FA and increased λ⊥. The results also suggest a possible role of edema or inflammation concerning the brain morphology in CMS rats. The overall finding using DTI suggests there might be a major role of loss of myelin sheath, which leads to disrupted connectivity between the limbic area and the prefrontal cortex during the onset of depression. Our findings indicate that interpretation of these indices may provide crucial information about the type and severity of mood disorders. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1.

PubMed

Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

2014-11-01

The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.

Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1

PubMed Central

Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

2015-01-01

The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA’s but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression. PMID:24946016

Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors.

PubMed

Lisowski, Pawel; Juszczak, Grzegorz R; Goscik, Joanna; Wieczorek, Marek; Zwierzchowski, Lech; Swiergiel, Artur H

2011-01-01

There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses. Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.

Hyperoside protects against chronic mild stress-induced learning and memory deficits.

PubMed

Gong, Yeli; Yang, Youhua; Chen, Xiaoqing; Yang, Min; Huang, Dan; Yang, Rong; Zhou, Lianying; Li, Changlei; Xiong, Qiuju; Xiong, Zhe

2017-07-01

Hyperoside (quercetin-3-O-b-d-galactosidepyranose) is a plant-derived flavonoid mainly found in fruits, fruit juices (most notably flavanols, flavanones, and anthocyanins) and Chinese traditional medicines. It has been applied to relieve pain and improve cardiovascular functions in clinic. However, the effects of hyperoside on cognitive impairment induced by chronic stress and the underlying molecular mechanisms remain unclear. In the current study, we used chronic mild stress (CMS) rats to investigate the effects of hyperoside on learning and memory and further explore the possible mechanisms. Our results demonstrated that hyperoside reduced the escape latency and the swimming distance of CMS rats in Morris water maze test and reversed depressive symptoms in forced swim test (FST) and sucrose preference test. In addition, hyperoside increased the expression of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS rats without influencing the corticosterone (CORT) level in blood plasma. Furthermore, K252a, an inhibitor of the BDNF receptor TrkB, prevented the protective effects of hyperoside on learning and memory in CMS rats. Taken together, these results indicate that hyperoside reverses the cognitive impairment induced by CMS, which is associated with the regulation of BDNF signaling pathway. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

CMS results in the Combined Computing Readiness Challenge CCRC'08

NASA Astrophysics Data System (ADS)

Bonacorsi, D.; Bauerdick, L.; CMS Collaboration

2009-12-01

During February and May 2008, CMS participated to the Combined Computing Readiness Challenge (CCRC'08) together with all other LHC experiments. The purpose of this worldwide exercise was to check the readiness of the Computing infrastructure for LHC data taking. Another set of major CMS tests called Computing, Software and Analysis challenge (CSA'08) - as well as CMS cosmic runs - were also running at the same time: CCRC augmented the load on computing with additional tests to validate and stress-test all CMS computing workflows at full data taking scale, also extending this to the global WLCG community. CMS exercised most aspects of the CMS computing model, with very comprehensive tests. During May 2008, CMS moved more than 3.6 Petabytes among more than 300 links in the complex Grid topology. CMS demonstrated that is able to safely move data out of CERN to the Tier-1 sites, sustaining more than 600 MB/s as a daily average for more than seven days in a row, with enough headroom and with hourly peaks of up to 1.7 GB/s. CMS ran hundreds of simultaneous jobs at each Tier-1 site, re-reconstructing and skimming hundreds of millions of events. After re-reconstruction the fresh AOD (Analysis Object Data) has to be synchronized between Tier-1 centers: CMS demonstrated that the required inter-Tier-1 transfers are achievable within a few days. CMS also showed that skimmed analysis data sets can be transferred to Tier-2 sites for analysis at sufficient rate, regionally as well as inter-regionally, achieving all goals in about 90% of >200 links. Simultaneously, CMS also ran a large Tier-2 analysis exercise, where realistic analysis jobs were submitted to a large set of Tier-2 sites by a large number of people to produce a chaotic workload across the systems, and with more than 400 analysis users in May. Taken all together, CMS routinely achieved submissions of 100k jobs/day, with peaks up to 200k jobs/day. The achieved results in CCRC'08 - focussing on the distributed workflows - are presented and discussed.

Chronic mild stress increases alcohol intake in mice with low dopamine D2 receptor levels.

PubMed

Delis, Foteini; Thanos, Panayotis K; Rombola, Christina; Rosko, Lauren; Grandy, David; Wang, Gene-Jack; Volkow, Nora D

2013-02-01

Alcohol use disorders emerge from a complex interaction between environmental and genetic factors. Stress and dopamine D2 receptor levels (DRD2) have been shown to play a central role in alcoholism. To better understand the interactions between DRD2 and stress in ethanol intake behavior, we subjected Drd2 wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice to 4 weeks of chronic mild stress (CMS) and to an ethanol two-bottle choice during CMS weeks 2-4. Prior to and at the end of the experiment, the animals were tested in the forced swim and open field tests. We measured ethanol intake and preference, immobility in the force swim test, and activity in the open field. We show that under no CMS, Drd2+/- and Drd2-/- mice had lower ethanol intake and preference compared with Drd2+/+. Exposure to CMS decreased ethanol intake and preference in Drd2+/+ and increased them in Drd2+/- and Drd2-/- mice. At baseline, Drd2+/- and Drd2-/- mice had significantly lower activity in the open field than Drd2+/+, whereas no genotype differences were observed in the forced swim test. Exposure to CMS increased immobility during the forced swim test in Drd2+/- mice, but not in Drd2+/+ or Drd2-/- mice, and ethanol intake reversed this behavior. No changes were observed in open field test measures. These findings suggest that in the presence of a stressful environment, low DRD2 levels are associated with increased ethanol intake and preference and that under this condition, increased ethanol consumption could be used as a strategy to alleviate negative mood. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Short- and long-term effects of stress during adolescence on emotionality and HPA function of animals exposed to alcohol prenatally

PubMed Central

Raineki, Charlis; Chew, Leanne; Mok, Perry; Ellis, Linda; Weinberg, Joanne

2016-01-01

Prenatal alcohol exposure (PAE) is associated with extremely high rates of psychopathologies, which may be mediated by the hypothalamic-pituitary-adrenal (HPA) dysregulation observed in exposed individuals. Of relevance, PAE carries an increased risk of exposure to stressful environments throughout life. Importantly, stressful experiences during adolescence increase vulnerability to psychopathologies. However, little is known about how adolescent stressful experiences in the context of PAE-induced HPA dysregulation may further alter the developmental trajectory and potentially contribute to the disproportionally high rate of psychopathologies observed in this population. Here we investigate the short-and long-term effects of adolescent chronic mild stress (CMS) on the emergence of anxiety-/depressive-like behaviors (open-field and forced swim test - FST) and on HPA activity (corticosterone and type 1 CRH receptor – CRHR1) in PAE male and female rats. Under non-CMS conditions, open field results indicate that PAE induced inappropriate behavior (increased time in center) in males and females, with increased activity in female adolescents, but anxiety-like behavior in adult PAE females. Conversely, FST results indicate that PAE induced depressive-like behavior in adolescent males. Exposure to CMS resulted in increased activity in adolescent males and anxiety-like behaviors in adult females. Moreover, PAE and/or CMS altered corticosterone and CRHR1 expression in the mPFC and amygdala. Together, these results suggest that PAE and adolescent CMS induce dynamic neurobehavioral alterations that manifest differently depending on the age and sex of the animal. These results highlight the importance of using both sexes as well as an ontogenetic approach when investigating the effects of environmental adversity. PMID:27567117

Chronic Mild Stress Alters Kynurenine Pathways Changing the Glutamate Neurotransmission in Frontal Cortex of Rats.

PubMed

Martín-Hernández, David; Tendilla-Beltrán, Hiram; Madrigal, José L M; García-Bueno, Borja; Leza, Juan C; Caso, Javier R

2018-05-03

Immune stimulation might be involved in the pathophysiology of major depressive disorder (MDD). This stimulation induces indoleamine 2,3-dioxygenase (IDO), an enzyme that reduces the tryptophan bioavailability to synthesize serotonin. IDO products, kynurenine metabolites, exert neurotoxic/neuroprotective actions through glutamate receptors. Thus, we study elements of these pathways linked to kynurenine metabolite activity examining whether antidepressants (ADs) can modulate them. Male Wistar rats were exposed to chronic mild stress (CMS), and some of them were treated with ADs. The expression of elements of the IDO pathway, including kynurenine metabolites, and their possible modulation by ADs was studied in the frontal cortex (FC). CMS increased IDO expression in FC compared to control group, and ADs restored the IDO expression levels to control values. CMS-induced IDO expression led to increased levels of the excitotoxic quinolinic acid (QUINA) compared to control, and ADs prevented the rise in such levels. Neither CMS nor ADs changed significantly the antiexcitotoxic kynurenic acid (KYNA) levels. The QUINA/KYNA ratio, calculated as excitotoxicity risk indicator, increased after CMS and ADs prevented this increase. CMS lowered excitatory amino acid transporter (EAAT)-1 and EAAT-4 expression, and some ADs restored their expression levels. Furthermore, CMS decreased N-methyl-D-aspartate receptor (NMDAR)-2A and 2B protein expression, and ADs mitigated this decrease. Our research examines the link between CMS-induced pro-inflammatory cytokines and the kynurenine pathway; it shows that CMS alters the kynurenine pathway in rat FC. Importantly, it also reveals the ability of classic ADs to prevent potentially harmful situations related to the brain scenario caused by CMS.

Engineered myocardium model to study the roles of HIF-1α and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress.

PubMed

Acun, Aylin; Zorlutuna, Pinar

2017-08-01

Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1α (HIF-1α), with its novel alternative regulator, HIF-1α antisense RNA1 (HIF1A-AS1), in these interactions were investigated. We encapsulated CMs in photo-crosslinkable, biomimetic hydrogels with or without ECs, then exposed to oxidative stress followed by normoxia. With precisely controlled microenvironment provided by the model tissues, cell-cell interactions were restricted to be solely through the secreted factors. CM survival after oxidative stress was significantly improved, in the presence of ECs, when cells were in the model tissues that were functionalized with cell attachment motifs. Importantly, the cardioprotective effect of ECs was reduced when HIF-1α expression was knocked down suggesting that HIF-1α is involved in cardioprotection from oxidative damage, provided through secreted factors conferred by the ECs. Using model tissues, we showed that cell survival increased with increased cell-cell communication and enhanced cell-matrix interactions. In addition, whole genome transcriptome analysis showed, for the first time to our knowledge, a possible role for HIF1A-AS1 in oxidative regulation of HIF-1α. We showed that although HIF1A-AS1 knockdown helps CM survival, its effect is overridden by CM-EC bidirectional interactions as we showed that the conditioned media taken from the CM-EC co-cultures improved CM survival, regardless of HIF1A-AS1 expression. Cardiovascular diseases, most of which are associated with oxidative stress, is the most common cause of death worldwide. Thus, understanding the molecular events as well as the role of intercellular communication under oxidative stress is upmost importance in its prevention. In this study we used 3D engineered tissue models to investigate the role of HIF-1α and its regulation in EC-mediated cardioprotection. We showed that EC-mediated protection is only possible when there is a bidirectional crosstalk between ECs and CMs even without physical cell-cell contact. In addition, this protective effect is at least partially related to cell-ECM interactions and HIF-1α, which is regulated by HIF1A-AS1 under oxidative stress. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Repeated asenapine treatment does not participate in the mild stress induced FosB/ΔFosB expression in the rat hypothalamic paraventricular nucleus neurons.

PubMed

Kiss, Alexander; Majercikova, Zuzana

2017-02-01

Effect of repeated asenapine (ASE) treatment on FosB/ΔFosB expression was studied in the hypothalamic paraventricular nucleus (PVN) of male rats exposed to chronic mild stress (CMS) for 21days. Our intention was to find out whether repeated ASE treatment for 14days may: 1) induce FosB/ΔFosB expression in the PVN; 2) activate selected PVN neuronal phenotypes, synthesizing oxytocin (OXY), vasopressin (AVP), corticoliberin (CRH) or tyrosine hydroxylase (TH); and 3) interfere with the impact of CMS. Control, ASE, CMS, and CMS+ASE treated groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. From the 7th day of CMS, rats received ASE (0.3mg/kg) or saline (300μl/rat) subcutaneously, twice a day for 14days. They were sacrificed on the day 22nd (16-18h after last treatments). FosB/ΔFosB was visualized with avidin biotin peroxidase complex and OXY, AVP, CRH or TH antibodies by fluorescent dyes. Saline and ASE did not promote FosB/ΔFosB expression in the PVN. CMS and CMS+ASE elicited FosB/ΔFosB-expression in the PVN, whereas, ASE did not augment or attenuate FosB/ΔFosB induction elicited by CMS. FosB/ΔFosB-CRH occurred after CMS and CMS+ASE treatments in the PVN middle sector, while FosB/ΔFosB-AVP and FosB/ΔFosB-OXY after CMS and CMS+ASE treatments in the PVN posterior sector. FosB/ΔFosB-TH colocalization was rare. Larger FosB/ΔFosB profiles, running above the PVN, did not show any colocalizations. The study provides an anatomical/functional knowledge about an unaccented nature of prolonged ASE treatment at the level of PVN and excludes its positive or negative interplay with CMS effect. Data indicate that long-lasting ASE treatment might not act as a stressor acting at the PVN level. Copyright © 2016 Elsevier Ltd. All rights reserved.

Temperature Calculations in the Coastal Modeling System

DTIC Science & Technology

2017-04-01

tide) and river discharge at model boundaries, wave radiation stress, and wind forcing over a model computational domain. Physical processes calculated...calculated in the CMS using the following meteorological parameters: solar radiation, cloud cover, air temperature, wind speed, and surface water temperature...during a clear (i.e., cloudless) sky (Wm-2); CLDC is the cloud cover fraction (0-1.0); SWR is the surface reflection coefficient; and SHDf is the

Evolution of permeability and Biot coefficient at high mean stresses in high porosity sandstone

DOE PAGES

Ingraham, Mathew D.; Bauer, Stephen J.; Issen, Kathleen A.; ...

2017-05-01

A series of constant mean stress (CMS) and constant shear stress (CSS) tests were performed to investigate the evolution of permeability and Biot coefficient at high mean stresses in a high porosity reservoir analog (Castlegate sandstone). Permeability decreases as expected with increasing mean stress, from about 20 Darcy at the beginning of the tests to between 1.5 and 0.3 Darcy at the end of the tests (mean stresses up to 275 MPa). The application of shear stress causes permeability to drop below that of a hydrostatic test at the same mean stress. Results show a nearly constant rate decrease inmore » the Biot coefficient as the mean stress increases during hydrostatic loading, and as the shear stress increases during CMS loading. In conclusion, CSS tests show a stabilization of the Biot coefficient after the application of shear stress.« less

Evolution of permeability and Biot coefficient at high mean stresses in high porosity sandstone

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

Ingraham, Mathew D.; Bauer, Stephen J.; Issen, Kathleen A.

A series of constant mean stress (CMS) and constant shear stress (CSS) tests were performed to investigate the evolution of permeability and Biot coefficient at high mean stresses in a high porosity reservoir analog (Castlegate sandstone). Permeability decreases as expected with increasing mean stress, from about 20 Darcy at the beginning of the tests to between 1.5 and 0.3 Darcy at the end of the tests (mean stresses up to 275 MPa). The application of shear stress causes permeability to drop below that of a hydrostatic test at the same mean stress. Results show a nearly constant rate decrease inmore » the Biot coefficient as the mean stress increases during hydrostatic loading, and as the shear stress increases during CMS loading. In conclusion, CSS tests show a stabilization of the Biot coefficient after the application of shear stress.« less

Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression

NASA Astrophysics Data System (ADS)

Zhao, Jing; Jung, Yang-Hee; Jang, Choon-Gon; Chun, Kwang-Hoon; Kwon, Sung Won; Lee, Jeongmi

2015-03-01

Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.

The protective effects of social bonding on behavioral and pituitary-adrenal axis reactivity to chronic mild stress in prairie voles.

PubMed

McNeal, Neal; Appleton, Katherine M; Johnson, Alan Kim; Scotti, Melissa-Ann L; Wardwell, Joshua; Murphy, Rachel; Bishop, Christina; Knecht, Alison; Grippo, Angela J

2017-03-01

Positive social interactions may protect against stress. This study investigated the beneficial effects of pairing with a social partner on behaviors and neuroendocrine function in response to chronic mild stress (CMS) in 13 prairie vole pairs. Following 5 days of social bonding, male and female prairie voles were exposed to 10 days of CMS (mild, unpredictable stressors of varying durations, for instance, strobe light, white noise, and damp bedding), housed with either the social partner (paired group) or individually (isolated group). Active and passive behavioral responses to the forced swim test (FST) and tail-suspension test (TST), and plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone, were measured in all prairie voles following the CMS period. Both female and male prairie voles housed with a social partner displayed lower durations of passive behavioral responses (immobility, a maladaptive behavioral response) in the FST (mean ± SEM; females: 17.3 ± 5.4 s; males: 9.3 ± 4.6 s) and TST (females: 56.8 ± 16.4 s; males: 40.2 ± 11.3 s), versus both sexes housed individually (females, FST: 98.6 ± 12.9 s; females, TST: 155.1 ± 19.3 s; males, FST: 92.4 ± 14.1 s; males, TST: 158.9 ± 22.0 s). Female (but not male) prairie voles displayed attenuated plasma stress hormones when housed with a male partner (ACTH: 945 ± 24.7 pg/ml; corticosterone: 624 ± 139.5 ng/ml), versus females housed individually (ACTH: 1100 ± 23.2 pg/ml; corticosterone: 1064 ± 121.7 ng/ml). These results may inform understanding of the benefits of social interactions on stress resilience. Lay Summary: Social stress can lead to depression. The study of social bonding and stress using an animal model will inform understanding of the protective effects of social bonds. This study showed that social bonding in a rodent model can protect against behavioral responses to stress, and may also be protective against the elevation of stress hormones. This study provides evidence that bonding and social support are valuable for protecting against stress in humans.

Eff ect of a single asenapine treatment on Fos expression in the brain catecholamine-synthesizing neurons: impact of a chronic mild stress preconditioning.

PubMed

Osacka, J; Horvathova, L; Majercikova, Z; Kiss, Alexander

2017-04-25

Fos protein expression in catecholamine-synthesizing neurons of the substantia nigra (SN) pars compacta (SNC, A8), pars reticulata (SNR, A9), and pars lateralis (SNL), the ventral tegmental area (VTA, A10), the locus coeruleus (LC, A6) and subcoeruleus (sLC), the ventrolateral pons (PON-A5), the nucleus of the solitary tract (NTS-A2), the area postrema (AP), and the ventrolateral medulla (VLM-A1) was quantitatively evaluated aft er a single administration of asenapine (ASE) (designated for schizophrenia treatment) in male Wistar rats preconditioned with a chronic unpredictable variable mild stress (CMS) for 21 days. Th e aim of the present study was to reveal whether a single ASE treatment may 1) activate Fos expression in the brain areas selected; 2) activate tyrosine hydroxylase (TH)-synthesizing cells displaying Fos presence; and 3) be modulated by CMS preconditioning. Control (CON), ASE, CMS, and CMS+ASE groups were used. CMS included restraint, social isolation, crowding, swimming, and cold. Th e ASE and CMS+ASE groups received a single dose of ASE (0.3 mg/kg, s.c.) and CON and CMS saline (300 μl/rat, s.c.). The animals were sacrificed 90 min aft er the treatments. Fos protein and TH-labeled immunoreactive perikarya were analyzed on double labeled histological sections and enumerated on captured pictures using combined light and fluorescence microscope illumination. Saline or CMS alone did not promote Fos expression in any of the structures investigated. ASE alone or in combination with CMS elicited Fos expression in two parts of the SN (SNC, SNR) and the VTA. Aside from some cells in the central gray tegmental nuclei adjacent to LC, where a small number of Fos profiles occurred, none or negligible Fos occurrence was detected in the other structures investigated including the LC and sLC, PON-A5, NTS-A2, AP, and VLM-A1. CMS preconditioning did not infl uence the level of Fos induction in the SN and VTA elicited by ASE administration. Similarly, the ratio between the amount of free Fos and Fos colocalized with TH was not aff ected by stress preconditioning in the SNC, SNR, and the VTA. Th e present study provides an anatomical/functional knowledge about the nature of the acute ASE treatment on the catecholamine-synthesizing neurons activity in certain brain structures and their missing interplay with the CMS preconditioning.

Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice.

PubMed

Couch, Yvonne; Trofimov, Alexander; Markova, Natalyia; Nikolenko, Vladimir; Steinbusch, Harry W; Chekhonin, Vladimir; Schroeter, Careen; Lesch, Klaus-Peter; Anthony, Daniel C; Strekalova, Tatyana

2016-05-16

Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.

A multilayer model for inferring dry deposition using standard meteorological measurements

NASA Astrophysics Data System (ADS)

Meyers, Tilden P.; Finkelstein, Peter; Clarke, John; Ellestad, Thomas G.; Sims, Pamela F.

1998-09-01

In this paper, we describe the latest version of the dry deposition inferential model, which is used to estimate the deposition velocities (Vd) for SO2, O3, HNO3, and particles with diameters less than 2 μm. The dry deposition networks operated by the National Oceanic and Atmospheric Administration (NOAA) and the Environmental Protection Agency (EPA) use this model to estimate dry deposition on a weekly basis. This model uses a multilayer approach, discretizing the vegetated canopy into 20 layers. The use of canopy radiative transfer and simple wind profile models allows for estimates of stomatal (rs) and leaf boundary layer (rb) resistances to be determined at each layer in the plant canopy for both sunlit and shaded leaves. The effect of temperature, water stress, and vapor pressure deficits on the stomatal resistance (rs) have been included. Comparisons of modeled deposition velocities are made with extensive direct measurements performed at three different locations with different crops. The field experiment is discussed in some detail. Overall, modeled O3 deposition velocities are in good agreement with measured values with the average mean bias for all surfaces of the order of 0.01 cm/s or less. For SO2, mean biases range from -0.05 for corn to 0.15 cm/s for soybeans, while for HNO3, they range from 0.09 for corn to 0.47 cm/s for pasture.

Stress alters asenapine-induced Fos expression in the Meynert's nucleus: response of adjacent hypocretin and melanin-concentrating hormone neurons in rat.

PubMed

Majercikova, Z; Kiss, A

2016-01-01

Asenapine (ASE), an atypical antipsychotic drug used in the treatment of schizophrenia, induces Fos expression in forebrain. Effect of ASE on activity of basal nucleus of Meynert (NBM) cells, a part of the striatal-cortical circuits, was studied. We were also interested to reveal whether a chronic unpredictable variable mild stress (CMS) preconditioning might affect the ASE impact. Rats were divided into as follows: controls-vehicle, controls-ASE, stressed-vehicle and stressed-ASE groups. CMS included restrain, social isolation, crowding, swimming and cold applied for 21 days. On the 22nd day, rats were subcutaneously injected with ASE (0.3 mg/kg) or vehicle (saline 300 μl/rat), 90 min prior euthanizing. After transcardial fixation, brains were cut into 30 μm thick coronal sections. Fos protein presence, as indicator of cell activity, was detected by ABC immunohistochemistry. Hypocretin (Hcrt) and melanin-concentrating hormone (MCH) containing cells were visualized with fluorescent dyes. ASE induced significant increase in Fos expression in NBM in both controls and CMS preconditioned rats in comparison with the related vehicle-treated controls. CMS preconditioning, however, significantly lowered the Fos response to ASE in NBM. From Hrct and MCH cells, only Hcrt ones displayed Fos presence in response to ASE. This study demonstrates for the first time that ASE may target a special group of cells occupying NBM, which effect can be modulated by CMS preconditioning. This finding extends a view that ASE impact may extend beyond the classical forebrain target areas common for the action of all antipsychotics and might be helpful in the identification of sites and side effects of its therapeutic actions.

Effects of chronic mild stress on behavioral and neurobiological parameters - Role of glucocorticoid.

PubMed

Chen, Jiao; Wang, Zhen-zhen; Zuo, Wei; Zhang, Shuai; Chu, Shi-feng; Chen, Nai-hong

2016-02-01

Major depression is thought to originate from maladaptation to adverse events, particularly when impairments occur in mood-related brain regions. Hypothalamus-pituitary-adrenal (HPA) axis is one of the major systems involved in physiological stress response. HPA axis dysfunction and high glucocorticoid concentrations play an important role in the pathogenesis of depression. In addition, astrocytic disability and dysfunction of neurotrophin brain-derived neurotrophin factor (BDNF) greatly influence the development of depression and anxiety disorders. Therefore, we investigated whether depressive-like and anxiety-like behaviors manifest in the absence of glucocorticoid production and circulation in adrenalectomized (ADX) rats after chronic mild stress (CMS) exposure and its potential molecular mechanisms. The results demonstrate that glucocorticoid-controlled rats showed anxiety-like behaviors but not depression-like behaviors after CMS. Molecular and cellular changes included the decreased BDNF in the hippocampus, astrocytic dysfunction with connexin43 (cx43) decreasing and abnormality in gap junction in prefrontal cortex (PFC). Interestingly, we did not find any changes in glucocorticoid receptor (GR) or its chaperone protein FK506 binding protein 51 (FKBP5) expression in the hippocampus or PFC in ADX rats subjected to CMS. In conclusion, the production and circulation of glucocorticoids are one of the contributing factors in the development of depression-like behaviors in response to CMS. In contrast, the effects of CMS on anxiety-like behaviors are independent of the presence of circulating glucocorticoids. Meanwhile, stress decreased GR expression and enhanced FKBP5 expression via higher glucocorticoid exposure. Gap junction dysfunction and changes in BDNF may be associated with anxiety-like behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Pool Formation in Boulder-Bed Streams: Implications From 1-D and 2-D Numerical Modeling

NASA Astrophysics Data System (ADS)

Harrison, L. R.; Keller, E. A.

2003-12-01

In mountain rivers of Southern California, boulder-large roughness elements strongly influence flow hydraulics and pool formation and maintenance. In these systems, boulders appear to control the stream morphology by converging flow and producing deep pools during channel forming discharges. Our research goal is to develop quantitative relationships between boulder roughness elements, temporal patterns of scour and fill, and geomorphic processes that are important in producing pool habitat. The longitudinal distribution of shear stress, unit stream power and velocity were estimated along a 48 m reach on Rattlesnake Creek, using the HEC-RAS v 3.0 and River 2-D numerical models. The reach has an average slope of 0.02 and consists of a pool-riffle sequence with a large boulder constriction directly above the pool. Model runs were performed for a range of stream discharges to test if scour and fill thresholds for pool and riffle environments could be identified. Results from the HEC-RAS simulations identified that thresholds in shear stress, unit stream power and mean velocity occur above a discharge of 5.0 cms. Results from the one-dimensional analysis suggest that the reversal in competency is likely due to changes in cross-sectional width at varying flows. River 2-D predictions indicated that strong transverse velocity gradients were present through the pool at higher modeled discharges. At a flow of 0.5 cms (roughly 1/10th bankfull discharge), velocities are estimated at 0.6 m/s and 1.3 m/s for the pool and riffle, respectively. During discharges of 5.15 cms (approximate bankfull discharge), the maximum velocity in the pool center increased to nearly 3.0 m/s, while the maximum velocity over the riffle is estimated at approximately 2.5 cms. These results are consistent with those predicted by HEC-RAS, though the reversal appears to be limited to a narrow jet that occurs through the pool head and pool center. Model predictions suggest that the velocity reversal is produced by a boulder-bedrock constriction that rapidly decreases the channel width above the pool by roughly 25 percent. The width constriction creates highly turbulent flow capable of scouring bed material through the pool. The high velocity core that is produced through the pool center appears to be enhanced by the formation of a large eddy directly below the boulder. Values of unit stream power and shear stress indicate that the pool exit is an area of deposition of bed material due to a decrease in tractive force. The presence of a strong transverse velocity gradient suggests that only a portion of the flow is responsible for scouring bed material. After we eliminate the dead water zone, the lowest five percent of the velocity range, patterns of effective width between pools and riffles begin to emerge. The ratio of flow width between adjacent pools and riffles is one measure of flow convergence. At a discharge of 0.5 cms, the ratio of effective width between pools and riffles is roughly 1:1, implying that there is uniform flow with little flow convergence. At a discharge of 5.15 cms the width ratio between the pool and riffle is about 1:3, demonstrating the strong convergent flow patterns at the pool head. The observed effective width relationship suggests that when considering restoration designs, boulders should be placed in areas that replicate natural convergence and divergence patterns in order to maximize pool area and depth.

Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast Kv7.1 Recycling

PubMed Central

Piccini, Ilaria; Fehrmann, Edda; Frank, Stefan; Müller, Frank U.; Greber, Boris; Seebohm, Guiscard

2017-01-01

The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the Kv7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid Kv7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1-deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of Kv7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, Kv7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes-like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by Kv7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast Kv7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening. PMID:28959214

Adrenergic Stress Protection of Human iPS Cell-Derived Cardiomyocytes by Fast Kv7.1 Recycling.

PubMed

Piccini, Ilaria; Fehrmann, Edda; Frank, Stefan; Müller, Frank U; Greber, Boris; Seebohm, Guiscard

2017-01-01

The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the K v 7.1 channel encoded by KCNQ1 . Current knowledge, however, does not sufficiently explain the full extent of rapid K v 7.1 activation and may hence be incomplete. Using inducible genetic KCNQ1 complementation in KCNQ1 -deficient human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we here reinvestigate the functional role of K v 7.1 in adapting human CMs to adrenergic stress. Under baseline conditions, K v 7.1 was barely detectable at the plasma membrane of hiPSC-CMs, yet it fully protected these from adrenergic stress-induced beat-to-beat variability of repolarization and torsade des pointes -like arrhythmia. Furthermore, isoprenaline treatment increased field potential durations specifically in KCNQ1-deficient CMs to cause these adverse macroscopic effects. Mechanistically, we find that the protective action by K v 7.1 resides in a rapid translocation of channel proteins from intracellular stores to the plasma membrane, induced by adrenergic signaling. Gene silencing experiments targeting RAB GTPases, mediators of intracellular vesicle trafficking, showed that fast K v 7.1 recycling under acute stress conditions is RAB4A-dependent.Our data reveal a key mechanism underlying the rapid adaptation of human cardiomyocytes to adrenergic stress. These findings moreover aid to the understanding of disease pathology in long QT syndrome and bear important implications for safety pharmacological screening.

Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression.

PubMed

Lu, Yanxia; Ho, Cyrus S; Liu, Xin; Chua, Anna N; Wang, Wei; McIntyre, Roger S; Ho, Roger C

2017-01-01

This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS) which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9), CMS+fluoxetine (n = 9) and the control (n = 6) groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively (p<0.05). There was a trend of reduction of IL-6 and TNF-α concentration. This study revealed the potential therapeutic effects of fluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.

Synergistic effect of estradiol and fluoxetine in young adult and middle-aged female rats in two models of experimental depression.

PubMed

Récamier-Carballo, Soledad; Estrada-Camarena, Erika; Reyes, Rebeca; Fernández-Guasti, Alonso

2012-08-01

The antidepressant effect of estrogens combined with antidepressants is controversial: some preclinical data showed that estrogens facilitate the effect of antidepressants in the forced swimming test (FST) in young adult rats, while others failed to find such effect in middle-aged rats in the chronic mild stress (CMS) model. In clinics similar differences were reported and may be due to the compounds, the depression model or type of depression, the experimental design, and the age of the subjects or the women's menopause stage. The objective of this study was to analyze the antidepressant-like effect of the combination of 17β-estradiol (E(2)) and fluoxetine (FLX) in young adults (2-4 months) and middle-aged (12-14 months) ovariectomized (OVX) rats in two experimental models: FST and CMS. E(2) (5 and 10 μg/rat) and FLX (2.5 and 10 mg/kg) per se dose-dependently reduced immobility in both age groups and, in young adults both compounds increased swimming, whereas in middle-aged rats they increased swimming and climbing. Analysis of the antidepressant-like effect of the combination of suboptimal doses of FLX (1.25 mg/kg) and E(2) (2.5 μg/rat) showed a decrease in immobility and an increase in swimming in both age groups. In the CMS, chronic E(2) (2.5 μg/rat) with FLX (1.25 mg/kg) augmented relative sucrose intake, but middle-aged rats responded 2 weeks earlier than young adults. These results show that the antidepressant-like effect of the combination of E(2) and FLX in young adult and middle-aged female rats is evidenced in the two animal models of depression: FST and CMS. Copyright © 2012 Elsevier B.V. All rights reserved.

Pollen developmental defects in ZD-CMS rice line explored by cytological, molecular and proteomic approaches.

PubMed

Yan, Junjie; Tian, Han; Wang, Shuzhen; Shao, Jinzhen; Zheng, Yinzhen; Zhang, Hongyuan; Guo, Lin; Ding, Yi

2014-08-28

Cytoplasmic male sterility (CMS) is a widely observed phenomenon, which is especially useful in hybrid seed production. Meixiang A (MxA) is a new rice CMS line derived from a pollen-free sterile line named Yunnan ZidaoA (ZD-CMS). In this study, a homologous WA352 gene with variation in two nucleotides was identified in MxA. Cytological analysis revealed that MxA was aborted in the early uninucleate stage. The protein expression profiles of MxA and its maintainer line MeixiangB (MxB) were systematically compared using iTRAQ-based quantitative proteomics technology using young florets at the early uninucleate stage. A total of 688 proteins were quantified in both rice lines, and 45 of these proteins were found to be differentially expressed. Bioinformatics analysis indicated a large number of the proteins involved in carbohydrate metabolism or the stress response were downregulated in MxA, suggesting that these metabolic processes had been hindered during pollen development in MxA. The ROS (reactive oxygen species) level was increased in the mitochondrion of MxA, and further ultrastructural analysis showed the mitochondria with disrupted cristae in the rice CMS line MxA. These findings substantially contribute to our knowledge of pollen developmental defects in ZD-CMS rice line. MeixiangA (MxA) is a new type of rice CMS line, which is derived from pollen-free sterile line Yunnan ZidaoA. In this study, the cytological, molecular and proteomic approaches were used to study the characteristics of this new CMS line. Cytological study indicates the CMS line is aborted at the early uninucleate stage. A potential sterile gene ZD352 is identified in MxA, the protein product of which is mainly accumulated at the MMC/Meiotic stage. iTRAQ based proteomic analysis is performed to study the relevant proteins involved in the CMS occurance, 45 proteins are found to be significant differentially expressed and these proteins are involved in many cellular processes such as carbohydrate metabolism, stress response, protein synthesis. To our knowledge, this is the first report using the iTRAQ-labeled quantitative proteomic to study the protein expression variation during the abortion processes between a CMS line and its maintainer line. These results provide new insights on the CMS mechanisms of ZD-CMS rice line. Copyright © 2014 Elsevier B.V. All rights reserved.

Particle Tracking Model (PTM) with Coastal Modeling System (CMS)

DTIC Science & Technology

2015-11-04

Coastal Inlets Research Program Particle Tracking Model (PTM) with Coastal Modeling System ( CMS ) The Particle Tracking Model (PTM) is a Lagrangian...currents and waves. The Coastal Inlets Research Program (CIRP) supports the PTM with the Coastal Modeling System ( CMS ), which provides coupled wave...and current forcing for PTM simulations. CMS -PTM is implemented in the Surface-water Modeling System, a GUI environment for input development

A Population WB-PBPK Model of Colistin and its Prodrug CMS in Pigs: Focus on the Renal Distribution and Excretion.

PubMed

Viel, Alexis; Henri, Jérôme; Bouchène, Salim; Laroche, Julian; Rolland, Jean-Guy; Manceau, Jacqueline; Laurentie, Michel; Couet, William; Grégoire, Nicolas

2018-03-12

The objective was the development of a whole-body physiologically-based pharmacokinetic (WB-PBPK) model for colistin, and its prodrug colistimethate sodium (CMS), in pigs to explore their tissue distribution, especially in kidneys. Plasma and tissue concentrations of CMS and colistin were measured after systemic administrations of different dosing regimens of CMS in pigs. The WB-PBPK model was developed based on these data according to a non-linear mixed effect approach and using NONMEM software. A detailed sub-model was implemented for kidneys to handle the complex disposition of CMS and colistin within this organ. The WB-PBPK model well captured the kinetic profiles of CMS and colistin in plasma. In kidneys, an accumulation and slow elimination of colistin were observed and well described by the model. Kidneys seemed to have a major role in the elimination processes, through tubular secretion of CMS and intracellular degradation of colistin. Lastly, to illustrate the usefulness of the PBPK model, an estimation of the withdrawal periods after veterinary use of CMS in pigs was made. The WB-PBPK model gives an insight into the renal distribution and elimination of CMS and colistin in pigs; it may be further developed to explore the colistin induced-nephrotoxicity in humans.

Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine.

PubMed

Ellis, Bradley W; Acun, Aylin; Can, U Isik; Zorlutuna, Pinar

2017-03-01

The heart wall tissue, or the myocardium, is one of the main targets in cardiovascular disease prevention and treatment. Animal models have not been sufficient in mimicking the human myocardium as evident by the very low clinical translation rates of cardiovascular drugs. Additionally, current in vitro models of the human myocardium possess several shortcomings such as lack of physiologically relevant co-culture of myocardial cells, lack of a 3D biomimetic environment, and the use of non-human cells. In this study, we address these shortcomings through the design and manufacture of a myocardium-on-chip (MOC) using 3D cell-laden hydrogel constructs and human induced pluripotent stem cell (hiPSC) derived myocardial cells. The MOC utilizes 3D spatially controlled co-culture of hiPSC derived cardiomyocytes (iCMs) and hiPSC derived endothelial cells (iECs) integrated among iCMs as well as in capillary-like side channels, to better mimic the microvasculature seen in native myocardium. We first fully characterized iCMs using immunostaining, genetic, and electrochemical analysis and iECs through immunostaining and alignment analysis to ensure their functionality, and then seeded these cells sequentially into the MOC device. We showed that iECs could be cultured within the microfluidic device without losing their phenotypic lineage commitment, and align with the flow upon physiological level shear stresses. We were able to incorporate iCMs within the device in a spatially controlled manner with the help of photocrosslinkable polymers. The iCMs were shown to be viable and functional within the device up to 7 days, and were integrated with the iECs. The iCMs and iECs in this study were derived from the same hiPSC cell line, essentially mimicking the myocardium of an individual human patient. Such devices are essential for personalized medicine studies where the individual drug response of patients with different genetic backgrounds can be tested in a physiologically relevant manner.

Human iPSC-derived myocardium-on-chip with capillary-like flow for personalized medicine

PubMed Central

Ellis, Bradley W.; Acun, Aylin; Can, U. Isik; Zorlutuna, Pinar

2017-01-01

The heart wall tissue, or the myocardium, is one of the main targets in cardiovascular disease prevention and treatment. Animal models have not been sufficient in mimicking the human myocardium as evident by the very low clinical translation rates of cardiovascular drugs. Additionally, current in vitro models of the human myocardium possess several shortcomings such as lack of physiologically relevant co-culture of myocardial cells, lack of a 3D biomimetic environment, and the use of non-human cells. In this study, we address these shortcomings through the design and manufacture of a myocardium-on-chip (MOC) using 3D cell-laden hydrogel constructs and human induced pluripotent stem cell (hiPSC) derived myocardial cells. The MOC utilizes 3D spatially controlled co-culture of hiPSC derived cardiomyocytes (iCMs) and hiPSC derived endothelial cells (iECs) integrated among iCMs as well as in capillary-like side channels, to better mimic the microvasculature seen in native myocardium. We first fully characterized iCMs using immunostaining, genetic, and electrochemical analysis and iECs through immunostaining and alignment analysis to ensure their functionality, and then seeded these cells sequentially into the MOC device. We showed that iECs could be cultured within the microfluidic device without losing their phenotypic lineage commitment, and align with the flow upon physiological level shear stresses. We were able to incorporate iCMs within the device in a spatially controlled manner with the help of photocrosslinkable polymers. The iCMs were shown to be viable and functional within the device up to 7 days, and were integrated with the iECs. The iCMs and iECs in this study were derived from the same hiPSC cell line, essentially mimicking the myocardium of an individual human patient. Such devices are essential for personalized medicine studies where the individual drug response of patients with different genetic backgrounds can be tested in a physiologically relevant manner. PMID:28396709

Male aromatase-knockout mice exhibit normal levels of activity, anxiety and "depressive-like" symptomatology.

PubMed

Dalla, C; Antoniou, K; Papadopoulou-Daifoti, Z; Balthazart, J; Bakker, J

2005-09-08

It is well known that estradiol derived from neural aromatization of testosterone plays a crucial role in the development of the male brain and the display of sexual behaviors in adulthood. It was recently found that male aromatase knockout mice (ArKO) deficient in estradiol due to a mutation in the aromatase gene have general deficits in coital behavior and are sexually less motivated. We wondered whether these behavioral deficits of ArKO males could be related to changes in activity, exploration, anxiety and "depressive-like" symptomatology. ArKO and wild type (WT) males were subjected to open field (OF), elevated plus maze (EPM), and forced swim tests (FST), after being exposed or not to chronic mild stress (CMS). CMS was used to evaluate the impact of chronic stressful procedures and to unveil possible differences between genotypes. There was no effect of genotype on OF, EPM and FST behavioral parameters. WT and ArKO mice exposed to CMS or not exhibited the same behavioral profile during these three types of tests. However, all CMS-exposed mice (ArKO and WT) spent less time in the center of the EPM. Additionally, floating duration measured in the FST increased between two tests in both WT and ArKO mice, though that increase was less prominent in mice previously subjected to CMS than in controls. Therefore, both ArKO and WT males displayed the same behavior and had the same response to CMS however CMS exposure slightly modified the behavior displayed by mice of both genotypes in the FST and EPM paradigms. These results show that ArKO males display normal levels of activity, exploration, anxiety and "depressive-like" symptomatology and thus their deficits in sexual behavior are specific in nature and do not result indirectly from other behavioral changes.

Therapeutic effects of 10-HzPulsed wave lasers in rat depression model: A comparison between near-infrared and red wavelengths.

PubMed

Salehpour, Farzad; Rasta, Seyed Hossein; Mohaddes, Gisou; Sadigh-Eteghad, Saeed; Salarirad, Sima

2016-09-01

The application of transcranial low-level light/laser therapy (tLLLT) in the range of red to near-infrared (NIR) spectrum for psychological disorders is a new area that is attracting growing interest in recent years. The photomodulation effects of NIR and red coherent lights on the activity of cytochrome c oxidase in neuronal cells of brain have been recently introduced. This study, therefore, sought to compare the therapeutic effects of 10-Hz pulsed wave NIR (810 nm) laser with red (630 nm) laser using the same delivered energy density and Citalopram in rat chronic mild stress (CMS) model of depression and anxiety. CMS procedures (for 4 weeks) were used to induce stress. GaAlAs diode laser with red and NIR wavelengths on 10-Hz pulsed wave (50% duty cycle) were used to perform tLLLT treatment for three weeks. An energy density of about 1.2 J/cm-(2) per each session was delivered through a light spot with a diameter of 3-mm to the prefrontal cortex for both wavelengths. Citalopram (10 mg/kg, Intraperitoneal) was administered for twenty-one consecutive days to the drug group. The findings of the present study showed an increase in swimming and decrease in immobility time, for both NIR laser and Citalopram groups compared to the stress group in forced swimming test. Anxiety-like behaviors showed insignificant decrease in all treatment groups in elevated plus maze test. The induction of stress significantly increased serum cortisol levels and treatments with both red laser and Citalopram decreased it. Hyperglycemia induced by CMS returned to normal levels in all treatment groups. The assessment of body weight also showed a significant increase in NIR laser group compared to the stress group by the end of the experiment. This study showed that non-invasive tLLLT using 10-Hz pulsed NIR laser light was as effective as Citalopram and more effective than red laser in the treatment of depressive-like behaviors and may help improve tLLLT as an alternative non-pharmacological treatments of psychological disorders such as depression. Lasers Surg. Med. 48:695-705, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Altered Connexin 43 and Connexin 45 protein expression in the heart as a function of social and environmental stress in the prairie vole.

PubMed

Grippo, Angela J; Moffitt, Julia A; Henry, Matthew K; Firkins, Rachel; Senkler, Jonathan; McNeal, Neal; Wardwell, Joshua; Scotti, Melissa-Ann L; Dotson, Ashley; Schultz, Rachel

2015-01-01

Exposure to social and environmental stressors may influence behavior as well as autonomic and cardiovascular regulation, potentially leading to depressive disorders and cardiac dysfunction including elevated sympathetic drive, reduced parasympathetic function, and ventricular arrhythmias. The cellular mechanisms that underlie these interactions are not well understood. One mechanism may involve alterations in the expression of Connexin43 (Cx43) and Connexin45 (Cx45), gap junction proteins in the heart that play an important role in ensuring efficient cell-to-cell coupling and the maintenance of cardiac rhythmicity. The present study investigated the hypothesis that long-term social isolation, combined with mild environmental stressors, would produce both depressive behaviors and altered Cx43 and Cx45 expression in the left ventricle of prairie voles - a socially monogamous rodent model. Adult, female prairie voles were exposed to either social isolation (n = 22) or control (paired, n = 23) conditions (4 weeks), alone or in combination with chronic mild stress (CMS) (1 week). Social isolation, versus paired control conditions, produced significantly (p < 0.05) increased depressive behaviors in a 5-min forced swim test, and CMS exacerbated (p < 0.05) these behaviors. Social isolation (alone) reduced (p < 0.05) total Cx43 expression in the left ventricle; whereas CMS (but not isolation) increased (p < 0.05) total Cx45 expression and reduced (p < 0.05) the Cx43/Cx45 ratio, measured via Western blot analysis. The present findings provide insight into potential cellular mechanisms underlying altered cardiac rhythmicity associated with social and environmental stress in the prairie vole.

Storage element performance optimization for CMS analysis jobs

NASA Astrophysics Data System (ADS)

Behrmann, G.; Dahlblom, J.; Guldmyr, J.; Happonen, K.; Lindén, T.

2012-12-01

Tier-2 computing sites in the Worldwide Large Hadron Collider Computing Grid (WLCG) host CPU-resources (Compute Element, CE) and storage resources (Storage Element, SE). The vast amount of data that needs to processed from the Large Hadron Collider (LHC) experiments requires good and efficient use of the available resources. Having a good CPU efficiency for the end users analysis jobs requires that the performance of the storage system is able to scale with I/O requests from hundreds or even thousands of simultaneous jobs. In this presentation we report on the work on improving the SE performance at the Helsinki Institute of Physics (HIP) Tier-2 used for the Compact Muon Experiment (CMS) at the LHC. Statistics from CMS grid jobs are collected and stored in the CMS Dashboard for further analysis, which allows for easy performance monitoring by the sites and by the CMS collaboration. As part of the monitoring framework CMS uses the JobRobot which sends every four hours 100 analysis jobs to each site. CMS also uses the HammerCloud tool for site monitoring and stress testing and it has replaced the JobRobot. The performance of the analysis workflow submitted with JobRobot or HammerCloud can be used to track the performance due to site configuration changes, since the analysis workflow is kept the same for all sites and for months in time. The CPU efficiency of the JobRobot jobs at HIP was increased approximately by 50 % to more than 90 %, by tuning the SE and by improvements in the CMSSW and dCache software. The performance of the CMS analysis jobs improved significantly too. Similar work has been done on other CMS Tier-sites, since on average the CPU efficiency for CMSSW jobs has increased during 2011. Better monitoring of the SE allows faster detection of problems, so that the performance level can be kept high. The next storage upgrade at HIP consists of SAS disk enclosures which can be stress tested on demand with HammerCloud workflows, to make sure that the I/O-performance is good.

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

PubMed

Shen, Ji-Duo; Wei, Yu; Li, Yu-Jie; Qiao, Jing-Yi; Li, Yu-Cheng

2017-08-01

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Effect of vitamin E on reversibility of renal function following discontinuation of colistin in rats: Histological and biochemical investigations.

PubMed

Ghlissi, Zohra; Hakim, Ahmed; Mnif, Hela; Kallel, Rim; Zeghal, Khaled; Boudawara, Tahiya; Sahnoun, Zouheir

2018-01-01

This study was carried out to evaluate spontaneous renal regeneration after stopping colistin methanesulfonate (CMS), which induces tubular damage, and the curative effect of Vitamin E (vit E) in rats. Animals were given the following: sterile saline (n = 6), 300,000 IU/kg/ day of CMS (n = 24), or 450,000 IU/kg/day of CMS (n = 24) for seven days. Each CMS group was subdivided into four subgroups (n = 6) and sacrificed as follows: (i) 12 h after stopping CMS, (ii) two weeks after stopping CMS, (iii) two weeks after stopping treatment with vit E, and (iv) two weeks after stopping treatment with olive oil. Subsequently, plasma creatinine (pCr), urine N-acetyl-b-D-glucosaminidase (NAG), renal tissue level of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione reductase (GSH), and renal histology were tested. CMS-induced tubular damage increased the NAG and MDA levels and decreased the SOD and GSH activities. After two weeks of stopping CMS, there was no significant renal recovery. However, treatment with vit E improved tubular regeneration and reduced the biochemical impairments. Two weeks might not be long enough for significant spontaneous renal regeneration. Improvement of renal parameters by vit E could be explained by the reduction of oxidative stress damage.

The impact of chronic mild stress on long-term depressive behavior in rats which have survived sepsis.

PubMed

Steckert, Amanda V; Dominguini, Diogo; Michels, Monique; Abelaira, Helena M; Tomaz, Débora B; Sonai, Beatriz; de Moura, Airam B; Matos, Danyela; da Silva, Júlia B I; Réus, Gislaine Z; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe

2017-11-01

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Recognition of psychiatric disorders with a religious content by members of the clergy of different denominations in the Netherlands].

PubMed

Noort, A; Braam, A W; van Gool, A R; Verhagen, P J; Beekman, A T F

2012-01-01

Clergy members (CMS) frequently provide support and counselling for people with psychological and psychiatric disorders. There is evidence in the literature that CMS consider themselves to be inadequately trained to recognise psychiatric disorders. To investigate to what extent CMS are able to recognise psychiatric symptoms. CMS were recruited in the south-west of the Netherlands among various denominations (Roman Catholic, strict (orthodox) Protestant, moderate Protestant and Evangelical; n = 143) by means of a regional sampling method. The participating CMS (n = 143) and a control group consisting of mental health care professionals MPHS; n = 73) evaluated four vignettes of psychiatric problems with a religious content: two were about a psychiatric disorder (a psychotic state and a psychotic depression/melancholic state), and two concerned non-psychiatric states (a spiritual/religious experience and a mourning reaction with a religious dilemma). For each vignette the respondents scored the suitability of psychiatric medication, the desirability of mental health care, the severity of the disorder and whether there was a religious or spiritual aetiology. Some CMS were able to recognise psychiatric problems almost as well as the MHPS, but among the CMS the degree of recognition varied according to the denomination. Recognition was relatively poor among Evangelical CMS, but was best among the strict Protestant CMS. Evangelical pastors and strict Protestant CMS tended to interpret the non-psychiatric states as pathological. The findings of this study emphasise the need for collaboration between MHPS and CMS and stress the importance of consultation.

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

PubMed Central

Nguyen, Tri-Hung; Lieu, Linh Thuy; Nguyen, Gary; Bischof, Robert J.; Meeusen, Els N.; Li, Jian; Nation, Roger L.

2016-01-01

ABSTRACT Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research. PMID:27821445

The antidepressant-like effects of pioglitazone in a chronic mild stress mouse model are associated with PPARγ-mediated alteration of microglial activation phenotypes.

PubMed

Zhao, Qiuying; Wu, Xiaohui; Yan, Shuo; Xie, Xiaofang; Fan, Yonghua; Zhang, Jinqiang; Peng, Cheng; You, Zili

2016-10-04

Discoveries that microglia-mediated neuroinflammation is involved in the pathological process of depression provided a new strategy for novel antidepressant therapy. Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor regulating inflammation and microglial polarization and, therefore, a potential target for resolving depressive disorders. Our hypothesis was that antidepressant effects could be achieved through anti-inflammatory and neuroprotective activities by PPARγ-dependent microglia-modulating agents. Chronic mild stress (CMS) treatment was performed on C57BL/6 mice for 6 weeks. After 3 weeks with the CMS procedure, depressive-like behaviors were evaluated by sucrose preference (SP), tail suspension test (TST), forced swimming test (FST), and locomotor activity. Pioglitazone was administered intragastrically once per day for 3 weeks at different doses. Neuroinflammatory cytokines were determined by real time-PCR (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot. The activated microglial state was confirmed by immunohistochemistry. N9 microglial cells were subjected to lipopolysaccharide, pioglitazone, and GW9662 to discuss the phenotype of activated microglia by RT-PCR, ELISA, and western blot. It was demonstrated that the PPARγ agonist pioglitazone (2.5 mg/kg) ameliorated depression-like behaviors in CMS-treated mice, as indicated by body weight (BW), the SP test, the FST, and the TST. The amelioration of the depression was blocked by the PPARγ antagonist GW9662. The expression of M1 markers (IL-1β, IL-6, TNFα, iNOS, and CCL2) increased, and the gene expression of M2 markers (Ym1, Arg1, IL-4, IL-10, and TGFβ) decreased in the hippocampus of the stress-treated mice. Pioglitazone significantly inhibited the increased numbers and morphological alterations of microglia in the hippocampus, reduced the elevated expression of microglial M1 markers, and increased the downgraded expression of microglial M2 markers in C57BL/6 mice exposed to CMS. In an in vitro experiment, pioglitazone reversed the imbalance of M1 and M2 inflammatory cytokines, which is correlated with the inhibition of nuclear factor kB activation and is expressed in LPS-stimulated N9 microglial cells. We showed that pioglitazone administration induce the neuroprotective phenotype of microglia and ameliorate depression-like behaviors in CMS-treated C57BL/6 mice. These data suggested that the microglia-modulating agent pioglitazone present a beneficial choice for depression.

Flow variation and substrate type affect dislodgement of the freshwater polychaete, Manayunkia speciosa

USGS Publications Warehouse

Malakauskas, David M.; Wilson, Sarah J.; Wilzbach, Margaret A.; Som, Nicholas A.

2013-01-01

We quantified microscale flow forces and their ability to entrain the freshwater polychaete, Manayunkia speciosa, the intermediate host for 2 myxozoan parasites (Ceratomyxa shasta and Parvicapsula minibicornis) that cause substantial mortalities in salmonid fishes in the Pacific Northwest. In a laboratory flume, we measured the shear stress associated with 2 mean flow velocities and 3 substrates and quantified associated dislodgement of polychaetes, evaluated survivorship of dislodged polychaetes, and observed behavioral responses of the polychaetes in response to increased flow. We used a generalized linear mixed model to estimate the probability of polychaete dislodgement for treatment combinations of velocity (mean flow velocity  =  55 cm/s with a shear velocity  =  3 cm/s, mean flow velocity  =  140 cm/s with a shear velocity  =  5 cm/s) and substrate type (depositional sediments and analogs of rock faces and the filamentous alga, Cladophora). Few polychaetes were dislodged at shear velocities <3 cm/s on any substrate. Above this level of shear, probability of dislodgement was strongly affected by both substrate type and velocity. After accounting for substrate, odds of dislodgement were 8× greater at the higher flow. After accounting for velocity, probability of dislodgement was greatest from fine sediments, intermediate from rock faces, and negligible from Cladophora. Survivorship of dislodged polychaetes was high. Polychaetes exhibited a variety of behaviors for avoiding increases in flow, including extrusion of mucus, burrowing into sediments, and movement to lower-flow microhabitats. Our findings suggest that polychaete populations probably exhibit high resilience to flow-mediated disturbances.

Coastal Modeling System

DTIC Science & Technology

2015-11-04

Coastal Inlets Research Program Coastal Modeling System The work unit develops the Coastal Modeling System ( CMS ) and conducts basic research to...further understanding of sediment transport under mixed oceanic and atmospheric forcing. The CMS is a suite of coupled two-dimensional numerical...models for simulations of waves, hydrodynamics, salinity and sediment transport, and morphology change. The CMS was identified by the USACE Hydraulics

Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice.

PubMed

Wu, Shuhui; Gao, Qiang; Zhao, Pei; Gao, Yuan; Xi, Yanjie; Wang, Xiaoting; Liang, Ying; Shi, Haishui; Ma, Yuxia

2016-03-15

Increasing evidence suggests that depression is accompanied by dysregulation of neuroimmune system. Sulforaphane (SFN) is a natural compound with antioxidative, anti-inflammatory and neuroprotective activities. The present study aims to investigate the effects of SFN on depressive- and anxiety-like behaviors as well as potential neuroimmune mechanisms in mice. Repeated SFN administration (10mg/kg, i.p.) significantly decreased the immobility time in the forced swimming test (FST), tail suspension test (TST), and latency time to feeding in the novelty suppressed feeding test (NSF), and increased the time in the central zone in the open field test (OPT). Using the chronic mild stress (CMS) paradigm, we confirmed that repeated SFN (10mg/kg, i.p.) administration significantly increased sucrose preference in the sucrose preference test (SPT), and immobility time in the FST and TST of mice subjected to CMS. Also, SFN treatment significantly reversed anxiety-like behaviors (assessed by the OPT and NSF) of chronically stressed mice. Finally, ELISA analysis showed that SFN administration blocked the increase in the serum levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in chronically stressed mice. In summary, these findings demonstrated that SFN has antidepressant- and anxiolytic-like activities in stressed mice model of depression, which likely occurs by inhibiting the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory response to stress. These data support further exploration for developing SFN as a novel agent to treat depression and anxiety disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

Coastal Modeling System: Mathematical Formulations and Numerical Methods

DTIC Science & Technology

2014-03-01

sediment transport , and morphology change. The CMS was designed and developed for coastal inlets and navigation applications, including channel...numerical methods of hydrodynamic, salinity and sediment transport , and morphology change model CMS-Flow. The CMS- Flow uses the Finite Volume...and the influence of coastal structures. The implicit hydrodynamic model is coupled to a nonequilibrium transport model of multiple-sized total

Modeling of flow-induced shear stress applied on 3D cellular scaffolds: Implications for vascular tissue engineering.

PubMed

Lesman, Ayelet; Blinder, Yaron; Levenberg, Shulamit

2010-02-15

Novel tissue-culture bioreactors employ flow-induced shear stress as a means of mechanical stimulation of cells. We developed a computational fluid dynamics model of the complex three-dimensional (3D) microstructure of a porous scaffold incubated in a direct perfusion bioreactor. Our model was designed to predict high shear-stress values within the physiological range of those naturally sensed by vascular cells (1-10 dyne/cm(2)), and will thereby provide suitable conditions for vascular tissue-engineering experiments. The model also accounts for cellular growth, which was designed as an added cell layer grown on all scaffold walls. Five model variants were designed, with geometric differences corresponding to cell-layer thicknesses of 0, 50, 75, 100, and 125 microm. Four inlet velocities (0.5, 1, 1.5, and 2 cm/s) were applied to each model. Wall shear-stress distribution and overall pressure drop calculations were then used to characterize the relation between flow rate, shear stress, cell-layer thickness, and pressure drop. The simulations showed that cellular growth within 3D scaffolds exposes cells to elevated shear stress, with considerably increasing average values in correlation to cell growth and inflow velocity. Our results provide in-depth analysis of the microdynamic environment of cells cultured within 3D environments, and thus provide advanced control over tissue development in vitro. 2009 Wiley Periodicals, Inc.

Anti-aging effects of vitamin C on human pluripotent stem cell-derived cardiomyocytes.

PubMed

Kim, Yoon Young; Ku, Seung-Yup; Huh, Yul; Liu, Hung-Ching; Kim, Seok Hyun; Choi, Young Min; Moon, Shin Yong

2013-10-01

Human pluripotent stem cells (hPSCs) have arisen as a source of cells for biomedical research due to their developmental potential. Stem cells possess the promise of providing clinicians with novel treatments for disease as well as allowing researchers to generate human-specific cellular metabolism models. Aging is a natural process of living organisms, yet aging in human heart cells is difficult to study due to the ethical considerations regarding human experimentation as well as a current lack of alternative experimental models. hPSC-derived cardiomyocytes (CMs) bear a resemblance to human cardiac cells and thus hPSC-derived CMs are considered to be a viable alternative model to study human heart cell aging. In this study, we used hPSC-derived CMs as an in vitro aging model. We generated cardiomyocytes from hPSCs and demonstrated the process of aging in both human embryonic stem cell (hESC)- and induced pluripotent stem cell (hiPSC)-derived CMs. Aging in hESC-derived CMs correlated with reduced membrane potential in mitochondria, the accumulation of lipofuscin, a slower beating pattern, and the downregulation of human telomerase RNA (hTR) and cell cycle regulating genes. Interestingly, the expression of hTR in hiPSC-derived CMs was not significantly downregulated, unlike in hESC-derived CMs. In order to delay aging, vitamin C was added to the cultured CMs. When cells were treated with 100 μM of vitamin C for 48 h, anti-aging effects, specifically on the expression of telomere-related genes and their functionality in aging cells, were observed. Taken together, these results suggest that hPSC-derived CMs can be used as a unique human cardiomyocyte aging model in vitro and that vitamin C shows anti-aging effects in this model.

Two non-allelic nuclear genes restore fertility in a gametophytic pattern and enhance abiotic stress tolerance in the hybrid rice plant.

PubMed

Huang, Wenchao; Hu, Jun; Yu, Changchun; Huang, Qi; Wan, Lei; Wang, Lili; Qin, Xiaojian; Ji, Yanxiao; Zhu, Renshan; Li, Shaoqing; Zhu, Yingguo

2012-03-01

In indica rice, the HongLian (HL)-type combination of cytoplasmic male sterility (CMS) and fertility restoration (Rf) is widely used for the production of commercial hybrid seeds in China, Laos, Vietnam and other Southeast Asian countries. Generally, any member of the gametophytic fertility restoration system, 50% of the pollen in hybrid F(1) plants displays recovered sterility. In this study, however, a HL-type hybrid variety named HongLian You6 had approximately 75% normal (viable) pollen rather than the expected 50%. To resolve this discrepancy, several fertility segregation populations, including F(2) and BC(1)F(1) derived from the HL-CMS line Yuetai A crossed with the restorer line 9311, were constructed and subjected to genetic analysis. A gametophytic restoration model was discovered to involve two non-allelic nuclear restorer genes, Rf5 and Rf6. The Rf5 had been previously identified using a positional clone strategy. The Rf6 gene represents a new restorer gene locus, which was mapped to the short arm of chromosome 8. The hybrid F(1) plants containing one restorer gene, either Rf5 or Rf6, displayed 50% normal pollen grains with I(2)-KI solution; however, those with both Rf5 and Rf6 displayed 75% normal pollens. We also established that the hybrid F(1) plants including both non-allelic restorer genes exhibited an increased stable seed setting when subjected to stress versus the F(1) plants with only one restorer gene. Finally, we discuss the breeding scheme for the plant gametophytic CMS/Rf system.

Impact of in Vitro Gastrointestinal Digestion and Transepithelial Transport on Antioxidant and ACE-Inhibitory Activities of Brewer's Spent Yeast Autolysate.

PubMed

Vieira, Elsa F; das Neves, José; Vitorino, Rui; Dias da Silva, Diana; Carmo, Helena; Ferreira, Isabel M P L V O

2016-10-05

Brewer's spent yeast (BSY) autolysates may have potential applications as food ingredients or nutraceuticals due to their antioxidant and ACE-inhibitory activities. The impact of simulated gastrointestinal (GI) digestion, the interaction with intracellular sources of oxidative stress, the intestinal cell permeability of BSY peptides, and the antioxidant and ACE-inhibitory activities of BSY permeates were assayed. Gastrointestinal digestion of BSY autolysates enhanced antioxidant and ACE-inhibitory activities as measured in vitro. No cytotoxic effects were observed on Caco-2 cells after exposure to the digested BSY autolysates within a concentration range of 0.5 to 3.0 mg of peptides/mL. A protective role to induced oxidative stress was observed. The transepithelial transport assays indicate high apparent permeability coefficient (P app ) values for BSY peptides across Caco-2/HT29-MTX cell monolayer (14.5-26.1 × 10 -6 cm/s) and for Caco-2 cell monolayer model (12.4-20.8 × 10 -6 cm/s), while the antioxidant and ACE-inhibitory activities found in flux material from the basolateral side suggest transepithelial absorption of bioactive compounds.

IK1-enhanced human-induced pluripotent stem cell-derived cardiomyocytes: an improved cardiomyocyte model to investigate inherited arrhythmia syndromes

PubMed Central

Vaidyanathan, Ravi; Markandeya, Yogananda S.; Kamp, Timothy J.; Makielski, Jonathan C.; January, Craig T.

2016-01-01

Currently available induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) do not ideally model cellular mechanisms of human arrhythmic disease due to lack of a mature action potential (AP) phenotype. In this study, we create and characterize iPS-CMs with an electrically mature AP induced by potassium inward rectifier (IK1) enhancement. The advantages of IK1-enhanced iPS-CMs include the absence of spontaneous beating, stable resting membrane potentials at approximately −80 mV and capability for electrical pacing. Compared with unenhanced, IK1-enhanced iPS-CMs calcium transient amplitudes were larger (P < 0.05) with a typical staircase pattern. IK1-enhanced iPS-CMs demonstrated a twofold increase in cell size and membrane capacitance and increased DNA synthesis compared with control iPS-CMs (P < 0.05). Furthermore, IK1-enhanced iPS-CMs expressing the F97C-CAV3 long QT9 mutation compared with wild-type CAV3 demonstrated an increase in AP duration and late sodium current. IK1-enhanced iPS-CMs represent a more mature cardiomyocyte model to study arrhythmia mechanisms. PMID:27059077

CMS-Wave

DTIC Science & Technology

2015-10-30

Coastal Inlets Research Program CMS -Wave CMS -Wave is a two-dimensional spectral wind-wave generation and transformation model that employs a forward...marching, finite-difference method to solve the wave action conservation equation. Capabilities of CMS -Wave include wave shoaling, refraction... CMS -Wave can be used in either on a half- or full-plane mode, with primary waves propagating from the seaward boundary toward shore. It can

The effect of mechanical stress on electric resistance of nanographite-epoxy composites

NASA Astrophysics Data System (ADS)

Vovchenko, L.; Lazarenko, A.; Matzui, L.; Zhuravkov, A.

2012-03-01

The in-plane electric resistance Ra of composite materials (CMs) thermoexfoliated graphite(TEG)-epoxy resin(ED) under compression along compacting C-axis has been investigated by four-probe method. TEG content was 5-75 wt%. It was shown that specimens prepared by cold pressing are denser and reveal lower values of electric resistivity in comparison with specimens prepared by pouring. It was found that compression of the specimens leads to plastic deformation of specimens (εpl) and essential irreversible decrease of electric resistance during the first cycle of loading (up to 50 MPa), especially for the poured specimens with low density. Within the proposed model the contact resistance Rk between graphite particles in CM has been evaluated and it was shown that it increased with the decrease in TEG content in CM and depends on compacting method of CMs and the dispersity of graphite filler.

Comparative Gene Expression Analyses Reveal Distinct Molecular Signatures between Differentially Reprogrammed Cardiomyocytes.

PubMed

Zhou, Yang; Wang, Li; Liu, Ziqing; Alimohamadi, Sahar; Yin, Chaoying; Liu, Jiandong; Qian, Li

2017-09-26

Cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) or directly reprogrammed from non-myocytes (induced cardiomyocytes [iCMs]) are promising sources for heart regeneration or disease modeling. However, the similarities and differences between iPSC-CMs and iCMs are still unknown. Here, we performed transcriptome analyses of beating iPSC-CMs and iCMs generated from cardiac fibroblasts (CFs) of the same origin. Although both iPSC-CMs and iCMs establish CM-like molecular features globally, iPSC-CMs exhibit a relatively hyperdynamic epigenetic status, whereas iCMs exhibit a maturation status that more closely resembles that of adult CMs. Based on gene expression of metabolic enzymes, iPSC-CMs primarily employ glycolysis, whereas iCMs utilize fatty acid oxidation as the main pathway. Importantly, iPSC-CMs and iCMs exhibit different cell-cycle status, alteration of which influenced their maturation. Therefore, our study provides a foundation for understanding the pros and cons of different reprogramming approaches. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

How Patronage Politics Undermines Parental Participation and Accountability: Community-Managed Schools in Honduras and Guatemala

ERIC Educational Resources Information Center

Altschuler, Daniel

2013-01-01

This article shows how patronage politics affects a popular international education model: community-managed schools (CMS). Focusing on Honduras's CMS initiative, PROHECO (Programa Hondureno de Educacion Comunitaria), I demonstrate how patronage can undermine CMS accountability. Whereas supporters argue that CMS increases accountability, partisan…

A Non-Equilibrium Sediment Transport Model for Coastal Inlets and Navigation Channels

DTIC Science & Technology

2011-01-01

exchange of water , sediment, and nutrients between estuaries and the ocean. Because of the multiple interacting forces (waves, wind, tide, river...in parallel using OpenMP. The CMS takes advantage of the Surface- water Modeling System (SMS) interface for grid generation and model setup, as well...as for plotting and post- processing (Zundel, 2000). The circulation model in the CMS (called CMS-Flow) computes the unsteady water level and

Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells.

PubMed

Mossine, Valeri V; Chance, Deborah L; Waters, James K; Mawhinney, Thomas P

2018-05-21

Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects in the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, a hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here on testing paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistimethate (CMS)/colistin and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, toxins, and their combinations were evaluated by simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and the Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100-150 μM) and prompted a significant increase in the oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested the cell proliferation at clinically achievable (< 1 mM) concentrations, as well, with CMS displaying a surprisingly high cytotoxicity (ED 50 = 180 μM) in BEAS-2B. The dose-response curves were probed by the median-effect analysis which established a synergistically enhanced cytotoxicity of the PYO/CMS combination in all three airway cell lines; a particularly strong effect was observed in the BEAS-2B cells, with the combination index (CI) = 0.27 at ED 50 PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM N -acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS/PYO doses. These findings suggest further evaluations of CMS safety are needed, along with a search for means to moderate the potentially cytotoxic interactions. Copyright © 2018 Mossine et al.

DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis.

PubMed

Hua, Yao; Huang, Xin-Yan; Zhou, Li; Zhou, Qi-Gang; Hu, Yao; Luo, Chun-Xia; Li, Fei; Zhu, Dong-Ya

2008-10-01

Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. Our recent study shows that endogenous nitric oxide (NO) contributes to chronic mild stress (CMS)-induced depression by suppressing hippocampal neurogenesis. The aim of this study was to investigate the effects of exogenous NO in CMS-induced depression in young adult mice. In normal mice, administration of a pure NO donor (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate; 0.4 mg/kg, i.p., for 7 days) produced an antidepressant-like effect and significantly increased hippocampal neurogenesis. The mice exposed to CMS exhibited behavioral changes typical of depression and impaired neurogenesis in the hippocampus. Treatment with DETA/NONOate (0.4 mg/kg, i.p., for 7 days) reversed CMS-induced behavioral despair and hippocampal neurogenesis impairment. We treated mice with a telomerase inhibitor 3'-azido-deoxythymidine (AZT; 100 mg/kg, i.p., for 14 days) to disrupt neurogenesis. From day 4 to day 11 of AZT treatment, mice were injected with DETA/NONOate (0.4 mg/kg, i.p., for 7 days). Disrupting hippocampal neurogenesis blocked the antidepressant effect of DETA/NONOate. Our findings suggest that exogenous NO benefits chronic stress-induced depression by stimulating hippocampal neurogenesis and may represent a novel approach for the treatment of depressive disorders.

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy.

PubMed

Cho, Gun-Sik; Lee, Dong I; Tampakakis, Emmanouil; Murphy, Sean; Andersen, Peter; Uosaki, Hideki; Chelko, Stephen; Chakir, Khalid; Hong, Ingie; Seo, Kinya; Chen, Huei-Sheng Vincent; Chen, Xiongwen; Basso, Cristina; Houser, Steven R; Tomaselli, Gordon F; O'Rourke, Brian; Judge, Daniel P; Kass, David A; Kwon, Chulan

2017-01-10

Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC-CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of transplantation into rats. The similarity was further supported by single-cell RNA-sequencing analysis. Moreover, this in vivo maturation allowed patient-derived PSC-CMs to reveal the disease phenotype of arrhythmogenic right ventricular cardiomyopathy, which manifests predominantly in adults. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy

PubMed Central

Cho, Gun-Sik; Lee, Dong I.; Tampakakis, Emmanouil; Murphy, Sean; Andersen, Peter; Uosaki, Hideki; Chelko, Stephen; Chakir, Khalid; Hong, Ingie; Seo, Kinya; Vincent Chen, Huei-Sheng; Chen, Xiongwen; Basso, Cristina; Houser, Steven R.; Tomaselli, Gordon F.; O’Rourke, Brian; Judge, Daniel P.; Kass, David A.; Kwon, Chulan

2016-01-01

SUMMARY Pluripotent stem cells (PSCs) offer unprecedented opportunities for disease modeling and personalized medicine. However, PSC-derived cells exhibit fetal-like characteristics and remain immature in a dish. This has emerged as a major obstacle for their application for late-onset diseases. We previously showed that there is a neonatal arrest of long-term cultured PSC-derived cardiomyocytes (PSC-CMs). Here, we demonstrate that PSC-CMs mature into adult CMs when transplanted into neonatal hearts. PSC-CMs became similar to adult CMs in morphology, structure, and function within a month of the transplantation into rats. The similarity was further supported by single-cell RNA-sequencing analysis. Moreover, this in vivo maturation allowed patient-derived PSC-CMs to reveal the disease phenotype of arrhythmogenic right ventricular cardiomyopathy, which predominantly manifests in adults. This study lays a foundation for understanding human CM maturation and pathogenesis and can be instrumental in PSC-based modeling of adult heart diseases. PMID:28076798

A comparison between antidepressant effects of transcranial near-infrared laser and citalopram in a rat model of depression

NASA Astrophysics Data System (ADS)

Salehpour, Farzad; Rasta, Seyed Hossein; Mohaddes, Gisou; Sadigh-Eteghad, Saeed; Salarirad, Sima

2017-02-01

Depression is a common psychiatric disorder that its prevalence has been reported to be 16% among adults. In recent years, transcranial near-infrared laser therapy (NILT) has gained considerable attention as a novel non-pharmaceutical method for depression. The present study was designed to compare the efficacy of two different treatment strategies in a rat model of depression. Forty male Wistar rats (180-200 g) divided into 4 groups: control, depressive, depressive-NILT, and depressive-Citalopram. All animals excepted control group was exposed to chronic mild stress (CMS) for 4 weeks. Rats in laser group received 10-Hz pulsed NILT (810 nm, energy density 1.2 J/cm2 per session) transcranially for a total of 12 sessions over a three-week period. Citalopram (10 mg/kg, Intraperitoneal) was administered for 21 consecutive days. Depressive-like behavior was tested in the forced swimming test (FST) model. Serum cortisol levels were also determined. The results of FST showed an increase in swimming and decrease in immobility period, for both NILT and Citalopram groups compared to the stress group. There was also no significant difference between the experimental groups in climbing behavior. The induction of CMS significantly increased serum cortisol levels and treatments with NILT and Citalopram decreased it. Our findings showed that NILT will be more beneficial to improve the depressive-like behaviors in the rat. Our data also showed that transcranial NILT was as effective as Citalopram in the treatment of depression. Therefore, these pieces of evidence may help improve NILT as an alternative non-pharmaceutical method for depression therapy.

Model-free quantification of dynamic PET data using nonparametric deconvolution

PubMed Central

Zanderigo, Francesca; Parsey, Ramin V; Todd Ogden, R

2015-01-01

Dynamic positron emission tomography (PET) data are usually quantified using compartment models (CMs) or derived graphical approaches. Often, however, CMs either do not properly describe the tracer kinetics, or are not identifiable, leading to nonphysiologic estimates of the tracer binding. The PET data are modeled as the convolution of the metabolite-corrected input function and the tracer impulse response function (IRF) in the tissue. Using nonparametric deconvolution methods, it is possible to obtain model-free estimates of the IRF, from which functionals related to tracer volume of distribution and binding may be computed, but this approach has rarely been applied in PET. Here, we apply nonparametric deconvolution using singular value decomposition to simulated and test–retest clinical PET data with four reversible tracers well characterized by CMs ([11C]CUMI-101, [11C]DASB, [11C]PE2I, and [11C]WAY-100635), and systematically compare reproducibility, reliability, and identifiability of various IRF-derived functionals with that of traditional CMs outcomes. Results show that nonparametric deconvolution, completely free of any model assumptions, allows for estimates of tracer volume of distribution and binding that are very close to the estimates obtained with CMs and, in some cases, show better test–retest performance than CMs outcomes. PMID:25873427

Comparison of the performance of the CMS Hierarchical Condition Category (CMS-HCC) risk adjuster with the Charlson and Elixhauser comorbidity measures in predicting mortality.

PubMed

Li, Pengxiang; Kim, Michelle M; Doshi, Jalpa A

2010-08-20

The Centers for Medicare and Medicaid Services (CMS) has implemented the CMS-Hierarchical Condition Category (CMS-HCC) model to risk adjust Medicare capitation payments. This study intends to assess the performance of the CMS-HCC risk adjustment method and to compare it to the Charlson and Elixhauser comorbidity measures in predicting in-hospital and six-month mortality in Medicare beneficiaries. The study used the 2005-2006 Chronic Condition Data Warehouse (CCW) 5% Medicare files. The primary study sample included all community-dwelling fee-for-service Medicare beneficiaries with a hospital admission between January 1st, 2006 and June 30th, 2006. Additionally, four disease-specific samples consisting of subgroups of patients with principal diagnoses of congestive heart failure (CHF), stroke, diabetes mellitus (DM), and acute myocardial infarction (AMI) were also selected. Four analytic files were generated for each sample by extracting inpatient and/or outpatient claims for each patient. Logistic regressions were used to compare the methods. Model performance was assessed using the c-statistic, the Akaike's information criterion (AIC), the Bayesian information criterion (BIC) and their 95% confidence intervals estimated using bootstrapping. The CMS-HCC had statistically significant higher c-statistic and lower AIC and BIC values than the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality across all samples in analytic files that included claims from the index hospitalization. Exclusion of claims for the index hospitalization generally led to drops in model performance across all methods with the highest drops for the CMS-HCC method. However, the CMS-HCC still performed as well or better than the other two methods. The CMS-HCC method demonstrated better performance relative to the Charlson and Elixhauser methods in predicting in-hospital and six-month mortality. The CMS-HCC model is preferred over the Charlson and Elixhauser methods if information about the patient's diagnoses prior to the index hospitalization is available and used to code the risk adjusters. However, caution should be exercised in studies evaluating inpatient processes of care and where data on pre-index admission diagnoses are unavailable.

Automatic identification of bullet signatures based on consecutive matching striae (CMS) criteria.

PubMed

Chu, Wei; Thompson, Robert M; Song, John; Vorburger, Theodore V

2013-09-10

The consecutive matching striae (CMS) numeric criteria for firearm and toolmark identifications have been widely accepted by forensic examiners, although there have been questions concerning its observer subjectivity and limited statistical support. In this paper, based on signal processing and extraction, a model for the automatic and objective counting of CMS is proposed. The position and shape information of the striae on the bullet land is represented by a feature profile, which is used for determining the CMS number automatically. Rapid counting of CMS number provides a basis for ballistics correlations with large databases and further statistical and probability analysis. Experimental results in this report using bullets fired from ten consecutively manufactured barrels support this developed model. Published by Elsevier Ireland Ltd.

Human pluripotent stem cell-derived cardiomyocytes for heart regeneration, drug discovery and disease modeling: from the genetic, epigenetic, and tissue modeling perspectives.

PubMed

Chow, Maggie; Boheler, Kenneth R; Li, Ronald A

2013-08-14

Heart diseases remain a major cause of mortality and morbidity worldwide. However, terminally differentiated human adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate. Directed differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into CMs has enabled clinicians and researchers to pursue the novel therapeutic paradigm of cell-based cardiac regeneration. In addition to tissue engineering and transplantation studies, the need for functional CMs has also prompted researchers to explore molecular pathways and develop strategies to improve the quality, purity and quantity of hESC-derived and iPSC-derived CMs. In this review, we describe various approaches in directed CM differentiation and driven maturation, and discuss potential limitations associated with hESCs and iPSCs, with an emphasis on the role of epigenetic regulation and chromatin remodeling, in the context of the potential and challenges of using hESC-CMs and iPSC-CMs for drug discovery and toxicity screening, disease modeling, and clinical applications.

CMS Nonpayment Policy, Quality Improvement, and Hospital-Acquired Conditions: An Integrative Review.

PubMed

Bae, Sung-Heui

This integrative review synthesized evidence on the consequences of the Centers for Medicare & Medicaid Services (CMS) nonpayment policy on quality improvement initiatives and hospital-acquired conditions. Fourteen articles were included. This review presents strong evidence that the CMS policy has spurred quality improvement initiatives; however, the relationships between the CMS policy and hospital-acquired conditions are inconclusive. In future research, a comprehensive model of implementation of the CMS nonpayment policy would help us understand the effectiveness of this policy.

Applying the Technology Acceptance Model (TAM) to Explore the Effects of a Course Management System (CMS)-Assisted EFL Writing Instruction

ERIC Educational Resources Information Center

Tsai, Yea-Ru

2015-01-01

This study illustrates a teaching model that utilizes a Blackboard (Bb) course management system (CMS) to support English writing instruction. It was implemented in a blended English research paper (RP) writing course, with specific learning resources and activities offered inside and outside the Bb CMS. A quasi-experimental study in which the…

Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

PubMed

Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

2011-03-23

Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

Exploiting analytics techniques in CMS computing monitoring

NASA Astrophysics Data System (ADS)

Bonacorsi, D.; Kuznetsov, V.; Magini, N.; Repečka, A.; Vaandering, E.

2017-10-01

The CMS experiment has collected an enormous volume of metadata about its computing operations in its monitoring systems, describing its experience in operating all of the CMS workflows on all of the Worldwide LHC Computing Grid Tiers. Data mining efforts into all these information have rarely been done, but are of crucial importance for a better understanding of how CMS did successful operations, and to reach an adequate and adaptive modelling of the CMS operations, in order to allow detailed optimizations and eventually a prediction of system behaviours. These data are now streamed into the CERN Hadoop data cluster for further analysis. Specific sets of information (e.g. data on how many replicas of datasets CMS wrote on disks at WLCG Tiers, data on which datasets were primarily requested for analysis, etc) were collected on Hadoop and processed with MapReduce applications profiting of the parallelization on the Hadoop cluster. We present the implementation of new monitoring applications on Hadoop, and discuss the new possibilities in CMS computing monitoring introduced with the ability to quickly process big data sets from mulltiple sources, looking forward to a predictive modeling of the system.

First Experiences with CMS Data Storage on the GEMSS System at the INFN-CNAF Tier-1

NASA Astrophysics Data System (ADS)

Andreotti, D.; Bonacorsi, D.; Cavalli, A.; Pra, S. Dal; Dell'Agnello, L.; Forti, Alberto; Grandi, C.; Gregori, D.; Gioi, L. Li; Martelli, B.; Prosperini, A.; Ricci, P. P.; Ronchieri, Elisabetta; Sapunenko, V.; Sartirana, A.; Vagnoni, V.; Zappi, Riccardo

A brand new Mass Storage System solution called "Grid-Enabled Mass Storage System" (GEMSS) -based on the Storage Resource Manager (StoRM) developed by INFN, on the General Parallel File System by IBM and on the Tivoli Storage Manager by IBM -has been tested and deployed at the INFNCNAF Tier-1 Computing Centre in Italy. After a successful stress test phase, the solution is now being used in production for the data custodiality of the CMS experiment at CNAF. All data previously recorded on the CASTOR system have been transferred to GEMSS. As final validation of the GEMSS system, some of the computing tests done in the context of the WLCG "Scale Test for the Experiment Program" (STEP'09) challenge were repeated in September-October 2009 and compared with the results previously obtained with CASTOR in June 2009. In this paper, the GEMSS system basics, the stress test activity and the deployment phase -as well as the reliability and performance of the system -are overviewed. The experiences in the use of GEMSS at CNAF in preparing for the first months of data taking of the CMS experiment at the Large Hadron Collider are also presented.

CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia

PubMed Central

Di Pasquale, E; Lodola, F; Miragoli, M; Denegri, M; Avelino-Cruz, J E; Buonocore, M; Nakahama, H; Portararo, P; Bloise, R; Napolitano, C; Condorelli, G; Priori, S G

2013-01-01

Induced pluripotent stem cells (iPSC) offer a unique opportunity for developmental studies, disease modeling and regenerative medicine approaches in humans. The aim of our study was to create an in vitro ‘patient-specific cell-based system' that could facilitate the screening of new therapeutic molecules for the treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited form of fatal arrhythmia. Here, we report the development of a cardiac model of CPVT through the generation of iPSC from a CPVT patient carrying a heterozygous mutation in the cardiac ryanodine receptor gene (RyR2) and their subsequent differentiation into cardiomyocytes (CMs). Whole-cell patch-clamp and intracellular electrical recordings of spontaneously beating cells revealed the presence of delayed afterdepolarizations (DADs) in CPVT-CMs, both in resting conditions and after β-adrenergic stimulation, resembling the cardiac phenotype of the patients. Furthermore, treatment with KN-93 (2-[N-(2-hydroxyethyl)]-N-(4methoxybenzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine), an antiarrhythmic drug that inhibits Ca2+/calmodulin-dependent serine–threonine protein kinase II (CaMKII), drastically reduced the presence of DADs in CVPT-CMs, rescuing the arrhythmic phenotype induced by catecholaminergic stress. In addition, intracellular calcium transient measurements on 3D beating clusters by fast resolution optical mapping showed that CPVT clusters developed multiple calcium transients, whereas in the wild-type clusters, only single initiations were detected. Such instability is aggravated in the presence of isoproterenol and is attenuated by KN-93. As seen in our RyR2 knock-in CPVT mice, the antiarrhythmic effect of KN-93 is confirmed in these human iPSC-derived cardiac cells, supporting the role of this in vitro system for drug screening and optimization of clinical treatment strategies. PMID:24113177

Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and "depressed" mice exposed to chronic mild stress.

PubMed

Franceschelli, A; Sens, J; Herchick, S; Thelen, C; Pitychoutis, P M

2015-04-02

During the past decade, one of the most striking discoveries in the treatment of major depression was the clinical finding that a single infusion of a sub-anesthetic dose of the N-methyl-d-aspartate receptor antagonist ketamine produces a rapid (i.e. within a few hours) and long-lasting (i.e. up to two weeks) antidepressant effect in both treatment-resistant depressed patients and in animal models of depression. Notably, converging clinical and preclinical evidence support that responsiveness to antidepressant drugs is sex-differentiated. Strikingly, research regarding the antidepressant-like effects of ketamine has focused almost exclusively on the male sex. Herein we report that female C57BL/6J stress-naïve mice are more sensitive to the rapid and the sustained antidepressant-like effects of ketamine in the forced swim test (FST). In particular, female mice responded to lower doses of ketamine (i.e. 3mg/kg at 30 min and 5mg/kg at 24h post-injection), doses that were not effective in their male counterparts. Moreover, tissue levels of the excitatory amino acids glutamate and aspartate, as well as serotonergic activity, were affected in a sex-dependent manner in the prefrontal cortex and the hippocampus, at the same time-points. Most importantly, a single injection of ketamine (10mg/kg) induced sex-dependent behavioral effects in mice subjected to the chronic mild stress (CMS) model of depression. Intriguingly, female mice were more reactive to the earlier effects of ketamine, as assessed in the open field and the FST (at 30 min and 24h post-treatment, respectively) but the antidepressant potential of the drug proved to be longer lasting in males, as assessed in the splash test and the FST (days 5 and 7 post-treatment, respectively). Taken together, present data revealed that ketamine treatment induces sex-dependent rapid and sustained neurochemical and behavioral antidepressant-like effects in stress-naïve and CMS-exposed C57BL/6J mice. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

The Status of the Cms Experiment

NASA Astrophysics Data System (ADS)

Green, Dan

The CMS experiment was completely assembled in the fall of 2008 after a decade of design, construction and installation. During the last two years, cosmic ray data were taken on a regular basis. These data have enabled CMS to align the detector components, both spatially and temporally. Initial use of muons has also established the relative alignment of the CMS tracking and muon systems. In addition, the CMS calorimetry has been crosschecked with test beam data, thus providing an initial energy calibration of CMS calorimetry to about 5%. The CMS magnet has been powered and field mapped. The trigger and data acquisition systems have been installed and run at full speed. The tiered data analysis system has been exercised at full design bandwidth for Tier0, Tier1 and Tier2 sites. Monte Carlo simulation of the CMS detector has been constructed at a detailed geometric level and has been tuned to test beam and other production data to provide a realistic model of the CMS detector prior to first collisions.

Matrigel Mattress: A Method for the Generation of Single Contracting Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

PubMed

Feaster, Tromondae K; Cadar, Adrian G; Wang, Lili; Williams, Charles H; Chun, Young Wook; Hempel, Jonathan E; Bloodworth, Nathaniel; Merryman, W David; Lim, Chee Chew; Wu, Joseph C; Knollmann, Björn C; Hong, Charles C

2015-12-04

The lack of measurable single-cell contractility of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) currently limits the utility of hiPSC-CMs for evaluating contractile performance for both basic research and drug discovery. To develop a culture method that rapidly generates contracting single hiPSC-CMs and allows quantification of cell shortening with standard equipment used for studying adult CMs. Single hiPSC-CMs were cultured for 5 to 7 days on a 0.4- to 0.8-mm thick mattress of undiluted Matrigel (mattress hiPSC-CMs) and compared with hiPSC-CMs maintained on a control substrate (<0.1-mm thick 1:60 diluted Matrigel, control hiPSC-CMs). Compared with control hiPSC-CMs, mattress hiPSC-CMs had more rod-shape morphology and significantly increased sarcomere length. Contractile parameters of mattress hiPSC-CMs measured with video-based edge detection were comparable with those of freshly isolated adult rabbit ventricular CMs. Morphological and contractile properties of mattress hiPSC-CMs were consistent across cryopreserved hiPSC-CMs generated independently at another institution. Unlike control hiPSC-CMs, mattress hiPSC-CMs display robust contractile responses to positive inotropic agents, such as myofilament calcium sensitizers. Mattress hiPSC-CMs exhibit molecular changes that include increased expression of the maturation marker cardiac troponin I and significantly increased action potential upstroke velocity because of a 2-fold increase in sodium current (INa). The Matrigel mattress method enables the rapid generation of robustly contracting hiPSC-CMs and enhances maturation. This new method allows quantification of contractile performance at the single-cell level, which should be valuable to disease modeling, drug discovery, and preclinical cardiotoxicity testing. © 2015 American Heart Association, Inc.

Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy.

PubMed

Lin, Bo; Li, Yang; Han, Lu; Kaplan, Aaron D; Ao, Ying; Kalra, Spandan; Bett, Glenna C L; Rasmusson, Randall L; Denning, Chris; Yang, Lei

2015-05-01

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca(2+), mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca(2+) level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients. © 2015. Published by The Company of Biologists Ltd.

Evolution of wave and tide over vegetation region in nearshore waters

NASA Astrophysics Data System (ADS)

Zhang, Mingliang; Zhang, Hongxing; Zhao, Kaibin; Tang, Jun; Qin, Huifa

2017-08-01

Coastal wetlands are an important ecosystem in nearshore regions, where complex flow characteristics occur because of the interactions among tides, waves, and plants, especially in the discontinuous flow of the intertidal zone. In order to simulate the wave and wave-induced current in coastal waters, in this study, an explicit depth-averaged hydrodynamic (HD) model has been dynamically coupled with a wave spectral model (CMS-Wave) by sharing the tide and wave data. The hydrodynamic model is based on the finite volume method; the intercell flux is computed using the Harten-Lax-van Leer (HLL) approximate Riemann solver for computing the dry-to-wet interface; the drag force of vegetation is modeled as the sink terms in the momentum equations. An empirical wave energy dissipation term with plant effect has been derived from the wave action balance equation to account for the resistance induced by aquatic vegetation in the CMS-Wave model. The results of the coupling model have been verified using the measured data for the case with wave-tide-vegetation interactions. The results show that the wave height decreases significantly along the wave propagation direction in the presence of vegetation. In the rip channel system, the oblique waves drive a meandering longshore current; it moves from left to right past the cusps with oscillations. In the vegetated region, the wave height is greatly attenuated due to the presence of vegetation, and the radiation stresses are noticeably changed as compared to the region without vegetation. Further, vegetation can affect the spatial distribution of mean velocity in a rip channel system. In the co-exiting environment of tides, waves, and vegetation, the locations of wave breaking and wave-induced radiation stress also vary with the water level of flooding or ebb tide in wetland water, which can also affect the development and evolution of wave-induced current.

Genetic control of invasive plants species using selfish genetic elements

PubMed Central

Hodgins, Kathryn A; Rieseberg, Loren; Otto, Sarah P

2009-01-01

Invasive plants cause substantial environmental damage and economic loss. Here, we explore the possibility that a selfish genetic element found in plants called cytoplasmic male sterility (CMS) could be exploited for weed control. CMS is caused by mutations in the mitochondrial genome that sterilize male reproductive organs. We developed an analytical model and a spatial simulation to assess the use of CMS alleles to manage weed populations. Specifically, we examined how fertility, selfing, pollen limitation and dispersal influenced extinction rate and time until extinction in populations where CMS arises. We found that the introduction of a CMS allele can cause rapid population extinction, but only under a restricted set of conditions. Both models suggest that the CMS strategy will be appropriate for species where pollen limitation is negligible, inbreeding depression is high and the fertility advantage of females over hermaphrodites is substantial. In general, spatial structure did not have a strong influence on the simulation outcome, although low pollen dispersal and intermediate levels of seed dispersal tended to reduce population extinction rates. Given these results, the introduction of CMS alleles into a population of invasive plants probably represents an effective control method for only a select number of species. PMID:25567898

Exploiting Analytics Techniques in CMS Computing Monitoring

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

Bonacorsi, D.; Kuznetsov, V.; Magini, N.

The CMS experiment has collected an enormous volume of metadata about its computing operations in its monitoring systems, describing its experience in operating all of the CMS workflows on all of the Worldwide LHC Computing Grid Tiers. Data mining efforts into all these information have rarely been done, but are of crucial importance for a better understanding of how CMS did successful operations, and to reach an adequate and adaptive modelling of the CMS operations, in order to allow detailed optimizations and eventually a prediction of system behaviours. These data are now streamed into the CERN Hadoop data cluster formore » further analysis. Specific sets of information (e.g. data on how many replicas of datasets CMS wrote on disks at WLCG Tiers, data on which datasets were primarily requested for analysis, etc) were collected on Hadoop and processed with MapReduce applications profiting of the parallelization on the Hadoop cluster. We present the implementation of new monitoring applications on Hadoop, and discuss the new possibilities in CMS computing monitoring introduced with the ability to quickly process big data sets from mulltiple sources, looking forward to a predictive modeling of the system.« less

Risk factors for cardiomyopathy syndrome (CMS) in Norwegian salmon farming.

PubMed

Bang Jensen, Britt; Brun, Edgar; Fineid, Birgitte; Larssen, Rolf Bjerke; Kristoffersen, Anja B

2013-12-12

Cardiomyopathy syndrome (CMS) has been an economically important disease in Norwegian aquaculture since the 1990s. In this study, data on monthly production characteristics and case registrations were combined in a cohort study and supplemented with a questionnaire-based case-control survey on management factors in order to identify risk factors for CMS. The cohort study included cases and controls from 2005 to 2012. From this dataset differences between all cases and controls were analyzed by a mixed effect multivariate logistic regression. From this we found that the probability of CMS increased with increasing time in the sea, infection pressure, and cohort size, and that cohorts which had previously been diagnosed with heart and skeletal muscle inflammation or which were in farms with a history of CMS in previous cohorts had double the odds of developing CMS. The model was then used to calculate the predicted value for each cohort from which additional data were obtained via the questionnaire-based survey and used as offset for calculating the probability of CMS in a semi-univariate analysis of additional risk factors. Finally, the model was used to calculate the probability of developing CMS in 100 different scenarios in which the cohorts were subject to increasingly worse conditions with regards to the risk factors from the dataset. We believe that this exercise is a good way of communicating the findings to farmers, so they can make informed decisions when trying to avoid CMS in their fish cohorts.

Potential Regional Sediment Management (RSM) Projects in the Haleiwa Region, Oahu, Hawaii

DTIC Science & Technology

2014-05-01

relic stream channels on wave -induced flow patterns. Wave breaking and energy dissipation over the reefs result in return currents (from nearshore to...long), (c) a stub breakwater (80 ft long), and (d) a wave absorber (140 ft long). The non-federal sponsor for the harbor is the State of Hawaii...Coastal Inlets Research Program (CIRP) Coastal Modeling System (CMS) numerical models CMS- Wave and CMS- Flow (Sanchez et al. 2011) were implemented to

Characterizing observed circulation patterns within a bay using HF radar and numerical model simulations

NASA Astrophysics Data System (ADS)

O'Donncha, Fearghal; Hartnett, Michael; Nash, Stephen; Ren, Lei; Ragnoli, Emanuele

2015-02-01

In this study, High Frequency Radar (HFR), observations in conjunction with numerical model simulations investigate surface flow dynamics in a tidally-active, wind-driven bay; Galway Bay situated on the West coast of Ireland. Comparisons against ADCP sensor data permit an independent assessment of HFR and model performance, respectively. Results show root-mean-square (rms) differences in the range 10 - 12cm/s while model rms equalled 12 - 14cm/s. Subsequent analysis focus on a detailed comparison of HFR and model output. Harmonic analysis decompose both sets of surface currents based on distinct flow process, enabling a correlation analysis between the resultant output and dominant forcing parameters. Comparisons of barotropic model simulations and HFR tidal signal demonstrate consistently high agreement, particularly of the dominant M2 tidal signal. Analysis of residual flows demonstrate considerably poorer agreement, with the model failing to replicate complex flows. A number of hypotheses explaining this discrepancy are discussed, namely: discrepancies between regional-scale, coastal-ocean models and globally-influenced bay-scale dynamics; model uncertainties arising from highly-variable wind-driven flows across alarge body of water forced by point measurements of wind vectors; and the high dependence of model simulations on empirical wind-stress coefficients. The research demonstrates that an advanced, widely-used hydro-environmental model does not accurately reproduce aspects of surface flow processes, particularly with regards wind forcing. Considering the significance of surface boundary conditions in both coastal and open ocean dynamics, the viability of using a systematic analysis of results to improve model predictions is discussed.

78 FR 29139 - Medicare Program; Bundled Payments for Care Improvement Model 1 Open Period

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-17

... initiative. DATES: Model 1 of the Bundled Payments for Care Improvement Deadline: Interested organizations... initiative. For additional information on this initiative go to the CMS Center for Medicare and Medicaid Innovation Web site at http://innovation.cms.gov/initiatives/BPCI-Model-1/index.html . SUPPLEMENTARY...

HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia.

PubMed

Saito, Yukihiro; Nakamura, Kazufumi; Yoshida, Masashi; Sugiyama, Hiroki; Takano, Makoto; Nagase, Satoshi; Morita, Hiroshi; Kusano, Kengo F; Ito, Hiroshi

2018-05-30

A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4-overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC-CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate-supplemented conditions. Cardiac balls containing 5 × 10 3 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker.

Challenging data and workload management in CMS Computing with network-aware systems

NASA Astrophysics Data System (ADS)

D, Bonacorsi; T, Wildish

2014-06-01

After a successful first run at the LHC, and during the Long Shutdown (LS1) of the accelerator, the workload and data management sectors of the CMS Computing Model are entering into an operational review phase in order to concretely assess area of possible improvements and paths to exploit new promising technology trends. In particular, since the preparation activities for the LHC start, the Networks have constantly been of paramount importance for the execution of CMS workflows, exceeding the original expectations - as from the MONARC model - in terms of performance, stability and reliability. The low-latency transfers of PetaBytes of CMS data among dozens of WLCG Tiers worldwide using the PhEDEx dataset replication system is an example of the importance of reliable Networks. Another example is the exploitation of WAN data access over data federations in CMS. A new emerging area of work is the exploitation of Intelligent Network Services, including also bandwidth on demand concepts. In this paper, we will review the work done in CMS on this, and the next steps.

Collision models in quantum optics

NASA Astrophysics Data System (ADS)

Ciccarello, Francesco

2017-12-01

Quantum collision models (CMs) provide advantageous case studies for investigating major issues in open quantum systems theory, and especially quantum non-Markovianity. After reviewing their general definition and distinctive features, we illustrate the emergence of a CM in a familiar quantum optics scenario. This task is carried out by highlighting the close connection between the well-known input-output formalism and CMs. Within this quantum optics framework, usual assumptions in the CMs' literature - such as considering a bath of noninteracting yet initially correlated ancillas - have a clear physical origin.

Patient-Specific Human Induced Pluripotent Stem Cell Model Assessed with Electrical Pacing Validates S107 as a Potential Therapeutic Agent for Catecholaminergic Polymorphic Ventricular Tachycardia

PubMed Central

Sasaki, Kenichi; Makiyama, Takeru; Yoshida, Yoshinori; Wuriyanghai, Yimin; Kamakura, Tsukasa; Nishiuchi, Suguru; Hayano, Mamoru; Harita, Takeshi; Yamamoto, Yuta; Kohjitani, Hirohiko; Hirose, Sayako; Chen, Jiarong; Kawamura, Mihoko; Ohno, Seiko; Itoh, Hideki; Takeuchi, Ayako; Matsuoka, Satoshi; Miura, Masaru; Sumitomo, Naokata; Horie, Minoru; Yamanaka, Shinya; Kimura, Takeshi

2016-01-01

Introduction Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. However, it is not invariably successful to recapitulate the disease phenotype because of the immaturity of hiPSC-derived cardiomyocytes (hiPSC-CMs). The purpose of this study was to establish and analyze iPSC-based model of catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by adrenergically mediated lethal arrhythmias, more precisely using electrical pacing that could promote the development of new pharmacotherapies. Method and Results We generated hiPSCs from a 37-year-old CPVT patient and differentiated them into cardiomyocytes. Under spontaneous beating conditions, no significant difference was found in the timing irregularity of spontaneous Ca2+ transients between control- and CPVT-hiPSC-CMs. Using Ca2+ imaging at 1 Hz electrical field stimulation, isoproterenol induced an abnormal diastolic Ca2+ increase more frequently in CPVT- than in control-hiPSC-CMs (control 12% vs. CPVT 43%, p<0.05). Action potential recordings of spontaneous beating hiPSC-CMs revealed no significant difference in the frequency of delayed afterdepolarizations (DADs) between control and CPVT cells. After isoproterenol application with pacing at 1 Hz, 87.5% of CPVT-hiPSC-CMs developed DADs, compared to 30% of control-hiPSC-CMs (p<0.05). Pre-incubation with 10 μM S107, which stabilizes the closed state of the ryanodine receptor 2, significantly decreased the percentage of CPVT-hiPSC-CMs presenting DADs to 25% (p<0.05). Conclusions We recapitulated the electrophysiological features of CPVT-derived hiPSC-CMs using electrical pacing. The development of DADs in the presence of isoproterenol was significantly suppressed by S107. Our model provides a promising platform to study disease mechanisms and screen drugs. PMID:27764147

Impact of repeated asenapine treatment on FosB/ΔFosB expression in neurons of the rat central nucleus of the amygdala: colocalization with corticoliberine (CRH) and effect of an unpredictable mild stress preconditioning.

PubMed

Majercikova, Z; Kiss, A

2015-04-01

FosB/ΔFosB expression in the central amygdalar nucleus (CeA) in response to repeated asenapine (ASE) treatment (an atypical antipsychotic used for the treatment of schizophrenia) was studied in normal rats and rats preconditioned with chronic unpredictable variable mild stress (CMS). The goal of this study was to reveal whether repeated ASE treatment for 14 days may: 1) induce FosB/ΔFosB expression in the amygdala, 2) activate CRH-synthesizing neurons in the CeA, and 3) interfere with 21 days lasting concomitant CMS preconditioning. Four groups of animals were studied: controls and ASE-, CMS-, and CMS+ASE-treated ones. CMS consisted of the restrain, social isolation, crowding, swimming, and cold and lasted 21 days. The ASE and CMS+ASE groups were from the 7th day of the experiment treated with ASE (0.3 mg/kg, subcutaneously - s.c.) twice a day, i.e. together for 14 days. Controls and CMS groups were treated with saline (300 µl/rat, s.c.) twice a day for 14 days. All the animals were sacrificed on the 22nd day, i.e. 16-18 hours after the last treatments. Single FosB/ΔFosB, FosB/ΔFosB colocalizations with CRH, and CRH immunolabeled perikarya were investigated in the CeA using a combined light and fluorescent immunohistochemistry. The distribution aspect of the black FosB/ΔFosB profiles was homogeneous over the whole CeA and no significant differences in the number of FosB/ΔFosB profiles between the individual groups of the rats really occurred. The level of colocalization pattern of FosB/ΔFosB in CRH perikarya was also very similar between the individual groups and in each case it reached approximately 10% of double-labeling. No differences were also seen in the number of CRH immunolabeled perikarya. The density of CRH nerve projections within the CeA was very alike in the individual groups of animals investigated. The study provides a new anatomical/functional finding about the lack of the stimulatory effect of the repeated ASE treatment on the expression of FosB/ΔFosB, FosB/ΔFosB/CRH colocalizations, and CRH immunolabeled perikarya number in the CeA. In addition, CMS preconditioning itself neither stimulated nor inhibited FosB/ΔFosB expression, nor altered the impact of ASE on the activity of CRH neurons in the CeA.

A model of determining a fair market value for teaching residents: who profits?

PubMed

Cullen, Edward J; Lawless, Stephen T; Hertzog, James H; Penfil, Scott; Bradford, Kathleen K; Nadkarni, Vinay M; Corddry, David H; Costarino, Andrew T

2003-07-01

Centers for Medicare & Medicaid Services (CMS) Health Resources and Services Administration Children's Hospitals Graduate Medical Education (GME) Payment Program now supports freestanding children's teaching hospitals. To analyze the fair market value impact of GME payment on resident teaching efforts in our pediatric intensive care unit (PICU). Cost-accounting model, developed from a 1-year retrospective, descriptive, single-institution, longitudinal study, applied to physician teachers, residents, and CMS. Sixteen-bed PICU in a freestanding, university-affiliated children's teaching hospital. Pediatric critical care physicians, second-year residents. Cost of physician opportunity time; CMS investment return; the teaching physicians' investment return; residents' investment return; service balance between CMS and teaching service investment margins; economic balance points; fair market value. GME payments to our hospital increased 4.8-fold from 577 886 dollars to 2 772 606 dollars during a 1-year period. Critical care physicians' teaching opportunity cost rose from 250 097 dollars to 262 215 dollars to provide 1523 educational hours (6853 relative value units). Residents' net financial value for service provided to the PICU rose from 245 964 dollars to 317 299 dollars. There is an uneven return on investment in resident education for CMS, critical care physicians, and residents. Economic balance points are achievable for the present educational efforts of the CMS, critical care physicians, and residents if the present direct medical education payment increases from 29.38% to 36%. The current CMS Health Resources and Services Administration Children's Hospitals GME Payment Program produces uneven investment returns for CMS, critical care physicians, and residents. We propose a cost-accounting model, based on perceived production capability measured in relative value units and available GME funds, that would allow a clinical service to balance and obtain a fair market value for the resident education efforts of CMS, physician teachers, and residents.

Waves at Navigation Structures

DTIC Science & Technology

2014-10-27

upgrades the Coastal Modeling System’s (CMS) wave model CMS-Wave, a phase-averaged spectral wave model, and BOUSS-2D, a Boussinesq -type nonlinear wave...nearshore wave processes in practical applications. These capabilities facilitate optimization of innovative infrastructure for navigation systems to...navigation systems . The advanced models develop probabilistic engineering design estimates for rehabilitation of coastal structures to evaluate the

Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes

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

Lee, Sujeong, E-mail: crystalee@gmail.com; Lee, Hyang-Ae, E-mail: hyangaelee@gmail.com; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799

2016-04-01

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effectsmore » of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD{sub 90}) and 50% (APD{sub 50}) repolarization, reduced the maximum upstroke velocity (dV/dt{sub max}) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including I{sub Kr}, I{sub Ks}, I{sub Na}, and I{sub Ca}. Among them, I{sub Kr} and I{sub Na} showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K{sup +} channels. - Highlights: • Nefazodone prolonged APD and decreased upstroke velocity of APs in hiPSC-CMs. • Nefazodone inhibited cardiac ion channels, especially I{sub Kr} and I{sub Na}, in hiPSC-CMs. • Nefazodone-induced AP changes are mainly the result of I{sub Kr} and I{sub Na} inhibition. • hiPSC-CMs are sensitive model to validate nefazodone-induced cardiotoxicity. • hiPSC-CMs provide an integrated approach for evaluating mechanism of drug actions.« less

The CMS Tier0 goes cloud and grid for LHC Run 2

DOE PAGES

Hufnagel, Dirk

2015-12-23

In 2015, CMS will embark on a new era of collecting LHC collisions at unprecedented rates and complexity. This will put a tremendous stress on our computing systems. Prompt Processing of the raw data by the Tier-0 infrastructure will no longer be constrained to CERN alone due to the significantly increased resource requirements. In LHC Run 2, we will need to operate it as a distributed system utilizing both the CERN Cloud-based Agile Infrastructure and a significant fraction of the CMS Tier-1 Grid resources. In another big change for LHC Run 2, we will process all data using the multi-threadedmore » framework to deal with the increased event complexity and to ensure efficient use of the resources. Furthermore, this contribution will cover the evolution of the Tier-0 infrastructure and present scale testing results and experiences from the first data taking in 2015.« less

The CMS TierO goes Cloud and Grid for LHC Run 2

NASA Astrophysics Data System (ADS)

Hufnagel, Dirk

2015-12-01

In 2015, CMS will embark on a new era of collecting LHC collisions at unprecedented rates and complexity. This will put a tremendous stress on our computing systems. Prompt Processing of the raw data by the Tier-0 infrastructure will no longer be constrained to CERN alone due to the significantly increased resource requirements. In LHC Run 2, we will need to operate it as a distributed system utilizing both the CERN Cloud-based Agile Infrastructure and a significant fraction of the CMS Tier-1 Grid resources. In another big change for LHC Run 2, we will process all data using the multi-threaded framework to deal with the increased event complexity and to ensure efficient use of the resources. This contribution will cover the evolution of the Tier-0 infrastructure and present scale testing results and experiences from the first data taking in 2015.

A Planning and Assessment Model for Developing Effective CMS Support

ERIC Educational Resources Information Center

Johnson, Douglas F.

2004-01-01

At the University of Florida, in Spring 2003, more than 32,000 individuals enrolled in courses using the centrally-supported Course Management System (CMS). Because less than 1 full time equivalent (FTE) was allocated to support the CMS, this created problems for both users and support providers. In the face of rapid growth, support resources for…

Large scale commissioning and operational experience with tier-2 to tier-2 data transfer links in CMS

NASA Astrophysics Data System (ADS)

Letts, J.; Magini, N.

2011-12-01

Tier-2 to Tier-2 data transfers have been identified as a necessary extension of the CMS computing model. The Debugging Data Transfers (DDT) Task Force in CMS was charged with commissioning Tier-2 to Tier-2 PhEDEx transfer links beginning in late 2009, originally to serve the needs of physics analysis groups for the transfer of their results between the storage elements of the Tier-2 sites associated with the groups. PhEDEx is the data transfer middleware of the CMS experiment. For analysis jobs using CRAB, the CMS Remote Analysis Builder, the challenges of remote stage out of job output at the end of the analysis jobs led to the introduction of a local fallback stage out, and will eventually require the asynchronous transfer of user data over essentially all of the Tier-2 to Tier-2 network using the same PhEDEx infrastructure. In addition, direct file sharing of physics and Monte Carlo simulated data between Tier-2 sites can relieve the operational load of the Tier-1 sites in the original CMS Computing Model, and already represents an important component of CMS PhEDEx data transfer volume. The experience, challenges and methods used to debug and commission the thousands of data transfers links between CMS Tier-2 sites world-wide are explained and summarized. The resulting operational experience with Tier-2 to Tier-2 transfers is also presented.

CMS Physics Technical Design Report, Volume II: Physics Performance

NASA Astrophysics Data System (ADS)

CMS Collaboration

2007-06-01

CMS is a general purpose experiment, designed to study the physics of pp collisions at 14 TeV at the Large Hadron Collider (LHC). It currently involves more than 2000 physicists from more than 150 institutes and 37 countries. The LHC will provide extraordinary opportunities for particle physics based on its unprecedented collision energy and luminosity when it begins operation in 2007. The principal aim of this report is to present the strategy of CMS to explore the rich physics programme offered by the LHC. This volume demonstrates the physics capability of the CMS experiment. The prime goals of CMS are to explore physics at the TeV scale and to study the mechanism of electroweak symmetry breaking—through the discovery of the Higgs particle or otherwise. To carry out this task, CMS must be prepared to search for new particles, such as the Higgs boson or supersymmetric partners of the Standard Model particles, from the start-up of the LHC since new physics at the TeV scale may manifest itself with modest data samples of the order of a few fb -1 or less. The analysis tools that have been developed are applied to study in great detail and with all the methodology of performing an analysis on CMS data specific benchmark processes upon which to gauge the performance of CMS. These processes cover several Higgs boson decay channels, the production and decay of new particles such as Z' and supersymmetric particles, B s production and processes in heavy ion collisions. The simulation of these benchmark processes includes subtle effects such as possible detector miscalibration and misalignment. Besides these benchmark processes, the physics reach of CMS is studied for a large number of signatures arising in the Standard Model and also in theories beyond the Standard Model for integrated luminosities ranging from 1 fb -1 to 30 fb -1 . The Standard Model processes include QCD, B -physics, diffraction, detailed studies of the top quark properties, and electroweak physics topics such as the W and Z 0 boson properties. The production and decay of the Higgs particle is studied for many observable decays, and the precision with which the Higgs boson properties can be derived is determined. About ten different supersymmetry benchmark points are analysed using full simulation. The CMS discovery reach is evaluated in the SUSY parameter space covering a large variety of decay signatures. Furthermore, the discovery reach for a plethora of alternative models for new physics is explored, notably extra dimensions, new vector boson high mass states, little Higgs models, technicolour and others. Methods to discriminate between models have been investigated. This report is organized as follows. Chapter 1, the Introduction, describes the context of this document. Chapters 2 6 describe examples of full analyses, with photons, electrons, muons, jets, missing E T , B-mesons and τ's, and for quarkonia in heavy ion collisions. Chapters 7 15 describe the physics reach for Standard Model processes, Higgs discovery and searches for new physics beyond the Standard Model.

[Effect of Kaixinsan on monoamine oxidase activity].

PubMed

Wang, Shi; Dong, Xian-Zhe; Tan, Xiao; Wang, Yu-Ning; Liu, Ping

2016-05-01

To observe the effect of antidepressant medicine prescription, Kaixinsan (KXS) on monoamine oxidase (MAO) activity, and explore the mechanism of KXS in elevating the levels of monoamine neurotransmitter from the perspective of metabolism, in vitro enzyme reaction system and C6 neuroglial cells, the effect of KXS at different concentrations on MAO-A and MAO-B activity was observed. In animal studies, the effect of KXS at different concentrations on MAO-A and MAO-B activities of brain mitochondrialin normal rats and solitary chronic unpredictable moderate stress (CMS) model rats after intragastric administration for 1, 2, 3 weeks. Results showed that 10 g•L⁻¹ KXS could significantly reduce the activity of MAO-A and MAO-B in enzyme reaction system; and in C6 cells, KXS within 0.625-10 g•L⁻¹ concentration range had no significant effect on the activity of MAO-A, but had obvious inhibitory effect on the activity of MAO-B in a dose dependent manner. KXS had no significant effect on the activity of MAO-A and MAO-B in brains of normal rats after action for 1, 2, 3 weeks. After 2 and 3 weeks treatment with 338 mg•kg⁻¹ dose KXS, MAO-A activity in the brain of CMS rats was decreased as compared with the model group (P<0.05), while KXS had no significant effect on MAO-B activity after 1, 2, 3 weeks of treatment. The results indicated that KXS had certain effect on in vitro MAO-A and MAO-B activity, had no effect on brain MAO-A and MAO-B activity in vivo in normal rats, and had certain inhibitory effect on MAO-A activity in brains of CMS rats. Copyright© by the Chinese Pharmaceutical Association.

Bringing the CMS distributed computing system into scalable operations

NASA Astrophysics Data System (ADS)

Belforte, S.; Fanfani, A.; Fisk, I.; Flix, J.; Hernández, J. M.; Kress, T.; Letts, J.; Magini, N.; Miccio, V.; Sciabà, A.

2010-04-01

Establishing efficient and scalable operations of the CMS distributed computing system critically relies on the proper integration, commissioning and scale testing of the data and workload management tools, the various computing workflows and the underlying computing infrastructure, located at more than 50 computing centres worldwide and interconnected by the Worldwide LHC Computing Grid. Computing challenges periodically undertaken by CMS in the past years with increasing scale and complexity have revealed the need for a sustained effort on computing integration and commissioning activities. The Processing and Data Access (PADA) Task Force was established at the beginning of 2008 within the CMS Computing Program with the mandate of validating the infrastructure for organized processing and user analysis including the sites and the workload and data management tools, validating the distributed production system by performing functionality, reliability and scale tests, helping sites to commission, configure and optimize the networking and storage through scale testing data transfers and data processing, and improving the efficiency of accessing data across the CMS computing system from global transfers to local access. This contribution reports on the tools and procedures developed by CMS for computing commissioning and scale testing as well as the improvements accomplished towards efficient, reliable and scalable computing operations. The activities include the development and operation of load generators for job submission and data transfers with the aim of stressing the experiment and Grid data management and workload management systems, site commissioning procedures and tools to monitor and improve site availability and reliability, as well as activities targeted to the commissioning of the distributed production, user analysis and monitoring systems.

Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts

PubMed Central

Chong, James J.H.; Yang, Xiulan; Don, Creighton W.; Minami, Elina; Liu, Yen-Wen; Weyers, Jill J; Mahoney, William M.; Van Biber, Benjamin; Cook, Savannah M.; Palpant, Nathan J; Gantz, Jay; Fugate, James A.; Muskheli, Veronica; Gough, G. Michael; Vogel, Keith W.; Astley, Cliff A.; Hotchkiss, Charlotte E.; Baldessari, Audrey; Pabon, Lil; Reinecke, Hans; Gill, Edward A.; Nelson, Veronica; Kiem, Hans-Peter; Laflamme, Michael A.; Murry, Charles E.

2014-01-01

Pluripotent stem cells provide a potential solution to current epidemic rates of heart failure 1 by providing human cardiomyocytes to support heart regeneration 2. Studies of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in small animal models have shown favorable effects of this treatment 3–7. It remains unknown, however, whether clinical scale hESC-CMs transplantation is feasible, safe or can provide large-scale myocardial regeneration. Here we show that hESC-CMs can be produced at a clinical scale (>1 billion cells/batch) and cryopreserved with good viability. Using a non-human primate (NHP) model of myocardial ischemia-reperfusion, we show that that cryopreservation and intra-myocardial delivery of 1 billion hESC-CMs generates significant remuscularization of the infarcted heart. The hESC-CMs showed progressive but incomplete maturation over a three-month period. Grafts were perfused by host vasculature, and electromechanical junctions between graft and host myocytes were present within 2 weeks of engraftment. Importantly, grafts showed regular calcium transients that were synchronized to the host electrocardiogram, indicating electromechanical coupling. In contrast to small animal models 7, non-fatal ventricular arrhythmias were observed in hESC-CM engrafted primates. Thus, hESC-CMs can remuscularize substantial amounts of the infarcted monkey heart. Comparable remuscularization of a human heart should be possible, but potential arrhythmic complications need to be overcome. PMID:24776797

CMS Analysis School Model

NASA Astrophysics Data System (ADS)

Malik, S.; Shipsey, I.; Cavanaugh, R.; Bloom, K.; Chan, Kai-Feng; D'Hondt, J.; Klima, B.; Narain, M.; Palla, F.; Rolandi, G.; Schörner-Sadenius, T.

2014-06-01

To impart hands-on training in physics analysis, CMS experiment initiated the concept of CMS Data Analysis School (CMSDAS). It was born over three years ago at the LPC (LHC Physics Centre), Fermilab and is based on earlier workshops held at the LPC and CLEO Experiment. As CMS transitioned from construction to the data taking mode, the nature of earlier training also evolved to include more of analysis tools, software tutorials and physics analysis. This effort epitomized as CMSDAS has proven to be a key for the new and young physicists to jump start and contribute to the physics goals of CMS by looking for new physics with the collision data. With over 400 physicists trained in six CMSDAS around the globe, CMS is trying to engage the collaboration in its discovery potential and maximize physics output. As a bigger goal, CMS is striving to nurture and increase engagement of the myriad talents, in the development of physics, service, upgrade, education of those new to CMS and the career development of younger members. An extension of the concept to the dedicated software and hardware schools is also planned, keeping in mind the ensuing upgrade phase.

Altered calcium handling and increased contraction force in human embryonic stem cell derived cardiomyocytes following short term dexamethasone exposure

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

Kosmidis, Georgios; Bellin, Milena; Ribeiro, Marcelo C.

One limitation in using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) for disease modeling and cardiac safety pharmacology is their immature functional phenotype compared with adult cardiomyocytes. Here, we report that treatment of human embryonic stem cell derived cardiomyocytes (hESC-CMs) with dexamethasone, a synthetic glucocorticoid, activated glucocorticoid signaling which in turn improved their calcium handling properties and contractility. L-type calcium current and action potential properties were not affected by dexamethasone but significantly faster calcium decay, increased forces of contraction and sarcomeric lengths, were observed in hESC-CMs after dexamethasone exposure. Activating the glucocorticoid pathway can thus contribute to mediating hPSC-CMs maturation.more » - Highlights: • Dexamethasone accelerates Ca{sup 2+} transient decay in hESC-CMs. • Dexamethasone enhances SERCA and NCX function in hESC-CMs. • Dexamethasone increases force of contraction and sarcomere length in hESC-CMs. • Dexamethasone does not alter I{sub Ca,L} and action potential characteristics in hESC-CMs.« less

Modelling and simulating a crisis management system: an organisational perspective

NASA Astrophysics Data System (ADS)

Chaawa, Mohamed; Thabet, Inès; Hanachi, Chihab; Ben Said, Lamjed

2017-04-01

Crises are complex situations due to the dynamism of the environment, its unpredictability and the complexity of the interactions among several different and autonomous involved organisations. In such a context, establishing an organisational view as well as structuring organisations' communications and their functioning is a crucial requirement. In this article, we propose a multi-agent organisational model (OM) to abstract, simulate and analyse a crisis management system (CMS). The objective is to evaluate the CMS from an organisational view, to assess its strength as well as its weakness and to provide deciders with some recommendations for a more flexible and reactive CMS. The proposed OM is illustrated through a real case study: a snowstorm in a Tunisian region. More precisely, we made the following contribution: firstly, we provide an environmental model that identifies the concepts involved in the crisis. Then, we define a role model that copes with the involved actors. In addition, we specify the organisational structure and the interaction model that rule communications and structure actors' functioning. Those models, built following the GAIA methodology, abstract the CMS from an organisational perspective. Finally, we implemented a customisable multi-agent simulator based on the Janus platform to analyse, through several performed simulations, the organisational model.

Beneficial effects of exercise and its molecular mechanisms on depression in rats

PubMed Central

Zheng, Hang; Liu, Yanyou; Li, Wei; Yang, Bo; Chen, Dengbang; Wang, Xiaojia; Jiang, Zhou; Wang, Hongxing; Wang, Zhengrong; Cornelisson, G.; Halberg, F.

2008-01-01

Exercise showed the beneficial effects on mental health in depressed sufferers, whereas, its underlying mechanisms remained unresolved. This study utilized the chronic unpredictable stress (CNS) animal model of depression to evaluate the effects of exercise on depressive behaviors and spatial performance in rats. Furthermore, we tested the hypothesis that the capacity of exercise to reverse the harmful effects of CNS was relative to the hypothalamo–pituitary–adrenal (HPA) system and brain-derived neurotrophic factor (BDNF) in the hippocampus. Animal groups were exposed to CNS for 4 weeks with and without access to voluntary wheel running. Stressed rats consumed significantly less of a 1% sucrose solution during CNS and exhibited a significant decrease in open field behavior. On the other hand, they showed impaired spatial performance in Morris water maze test 2 weeks after the end of CNS. Further, CNS significantly decreased hippocampal BDNF mRNA levels. However, voluntary exercise improved or even reversed these harmful behavioral effects in stressed rats. Furthermore, exercise counteracted a decrease in hippocampal BDNF mRNA caused by CNS. In addition, we also found that CMS alone increased circulating corticosterone (CORT) significantly and decreased hippocampal glucocorticoid receptor (GR) mRNA. At the same time, exercise alone increased CORT moderately and did not affect hippocampal GR mRNA levels. While, when both CNS and exercise were combined, exercise reduced the increase of CORT and the decrease of GR caused by CMS. The results demonstrated that: (1) exercise reversed the harmful effects of CNS on mood and spatial performance in rats and (2) the behavioral changes induced by exercise and/or CNS might be associated with hippocampal BDNF levels, and in addition, the HPA system might play different roles in the two different processes. PMID:16290283

Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT transporters and glycolytic enzymes.

PubMed

Garcia, Nahuel A; Moncayo-Arlandi, Javier; Sepulveda, Pilar; Diez-Juan, Antonio

2016-03-01

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship, which is essential for maintaining the metabolic requirements of the heart. Little is known about the mechanisms that regulate nutrient flow from ECs to associated CMs, especially in situations of acute stress when local active processes are required to regulate endothelial transport. We examined whether CM-derived exosomes can modulate glucose transport and metabolism in ECs. In conditions of glucose deprivation, CMs increase the synthesis and secretion of exosomes. These exosomes are loaded with functional glucose transporters and glycolytic enzymes, which are internalized by ECs, leading to increased glucose uptake, glycolytic activity, and pyruvate production in recipient cells. These findings establish CM-derived exosomes as key components of the cardio-endothelial communication system which, through intercellular protein complementation, would allow a rapid response from ECs to increase glucose transport and a putative uptake of metabolic fuels from blood to CMs. This CM-EC protein complementation process might have implications for metabolic regulation in health and disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Webinar on PTM with CMS

DTIC Science & Technology

2013-12-04

Coral Reef Dredging Project SAV Migrating Fish Coral Reef Dredging Project SAV Migrating Fish... Coral Reef Dredging Project SAV Migrating Fish Coral Reef Dredging Project Coastal and Hydraulics Laboratory 22 Dredging Materials and...Introduction to CMS Coastal and Hydraulics Laboratory Integrated waves , current, and sediment transport model in the Surface-water Modeling

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

PubMed Central

Judge, Luke M.; Perez-Bermejo, Juan A.; Truong, Annie; Ribeiro, Alexandre J.S.; Yoo, Jennie C.; Jensen, Christina L.; Mandegar, Mohammad A.; Huebsch, Nathaniel; Kaake, Robyn M.; So, Po-Lin; Srivastava, Deepak; Krogan, Nevan J.

2017-01-01

Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of-function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity. PMID:28724793

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress.

PubMed

Judge, Luke M; Perez-Bermejo, Juan A; Truong, Annie; Ribeiro, Alexandre Js; Yoo, Jennie C; Jensen, Christina L; Mandegar, Mohammad A; Huebsch, Nathaniel; Kaake, Robyn M; So, Po-Lin; Srivastava, Deepak; Pruitt, Beth L; Krogan, Nevan J; Conklin, Bruce R

2017-07-20

Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype. To model BAG3 cardiomyopathy in a human system, we generated an isogenic series of human induced pluripotent stem cells (iPSCs) with loss-of-function mutations in BAG3. Heterozygous BAG3 mutations reduced protein expression, disrupted myofibril structure, and compromised contractile function in iPSC-derived cardiomyocytes (iPS-CMs). BAG3-deficient iPS-CMs were particularly sensitive to further myofibril disruption and contractile dysfunction upon exposure to proteasome inhibitors known to cause cardiotoxicity. We performed affinity tagging of the endogenous BAG3 protein and mass spectrometry proteomics to further define the cardioprotective chaperone complex that BAG3 coordinates in the human heart. Our results establish a model for evaluating protein quality control pathways in human cardiomyocytes and their potential as therapeutic targets and susceptibility factors for cardiac drug toxicity.

Toward Personalized Medicine: Using Cardiomyocytes Differentiated From Urine-Derived Pluripotent Stem Cells to Recapitulate Electrophysiological Characteristics of Type 2 Long QT Syndrome.

PubMed

Jouni, Mariam; Si-Tayeb, Karim; Es-Salah-Lamoureux, Zeineb; Latypova, Xenia; Champon, Benoite; Caillaud, Amandine; Rungoat, Anais; Charpentier, Flavien; Loussouarn, Gildas; Baró, Isabelle; Zibara, Kazem; Lemarchand, Patricia; Gaborit, Nathalie

2015-09-01

Human genetically inherited cardiac diseases have been studied mainly in heterologous systems or animal models, independent of patients' genetic backgrounds. Because sources of human cardiomyocytes (CMs) are extremely limited, the use of urine samples to generate induced pluripotent stem cell-derived CMs would be a noninvasive method to identify cardiac dysfunctions that lead to pathologies within patients' specific genetic backgrounds. The objective was to validate the use of CMs differentiated from urine-derived human induced pluripotent stem (UhiPS) cells as a new cellular model for studying patients' specific arrhythmia mechanisms. Cells obtained from urine samples of a patient with long QT syndrome who harbored the HERG A561P gene mutation and his asymptomatic noncarrier mother were reprogrammed using the episomal-based method. UhiPS cells were then differentiated into CMs using the matrix sandwich method.UhiPS-CMs showed proper expression of atrial and ventricular myofilament proteins and ion channels. They were electrically functional, with nodal-, atrial- and ventricular-like action potentials recorded using high-throughput optical and patch-clamp techniques. Comparison of HERG expression from the patient's UhiPS-CMs to the mother's UhiPS-CMs showed that the mutation led to a trafficking defect that resulted in reduced delayed rectifier K(+) current (IKr). This phenotype gave rise to action potential prolongation and arrhythmias. UhiPS cells from patients carrying ion channel mutations can be used as novel tools to differentiate functional CMs that recapitulate cardiac arrhythmia phenotypes. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

PubMed Central

W. S. Yapa, Shalini; Li, Jian; Porter, Christopher J. H.; Nation, Roger L.

2013-01-01

Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. PMID:23917323

Cellular Manufacturing System with Dynamic Lot Size Material Handling

NASA Astrophysics Data System (ADS)

Khannan, M. S. A.; Maruf, A.; Wangsaputra, R.; Sutrisno, S.; Wibawa, T.

2016-02-01

Material Handling take as important role in Cellular Manufacturing System (CMS) design. In several study at CMS design material handling was assumed per pieces or with constant lot size. In real industrial practice, lot size may change during rolling period to cope with demand changes. This study develops CMS Model with Dynamic Lot Size Material Handling. Integer Linear Programming is used to solve the problem. Objective function of this model is minimizing total expected cost consisting machinery depreciation cost, operating costs, inter-cell material handling cost, intra-cell material handling cost, machine relocation costs, setup costs, and production planning cost. This model determines optimum cell formation and optimum lot size. Numerical examples are elaborated in the paper to ilustrate the characterictic of the model.

CMS-G from Beta vulgaris ssp. maritima is maintained in natural populations despite containing an atypical cytochrome c oxidase.

PubMed

Meyer, Etienne H; Lehmann, Caroline; Boivin, Stéphane; Brings, Lea; De Cauwer, Isabelle; Bock, Ralph; Kühn, Kristina; Touzet, Pascal

2018-02-23

While mitochondrial mutants of the respiratory machinery are rare and often lethal, cytoplasmic male sterility (CMS), a mitochondrially inherited trait that results in pollen abortion, is frequently encountered in wild populations. It generates a breeding system called gynodioecy. In Beta vulgaris ssp. maritima , a gynodioecious species, we found CMS-G to be widespread across the distribution range of the species. Despite the sequencing of the mitochondrial genome of CMS-G, the mitochondrial sterilizing factor causing CMS-G is still unknown. By characterizing biochemically CMS-G, we found that the expression of several mitochondrial proteins is altered in CMS-G plants. In particular, Cox1, a core subunit of the cytochrome c oxidase (complex IV), is larger but can still assemble into complex IV. However, the CMS-G-specific complex IV was only detected as a stabilized dimer. We did not observe any alteration of the affinity of complex IV for cytochrome c ; however, in CMS-G, complex IV capacity is reduced. Our results show that CMS-G is maintained in many natural populations despite being associated with an atypical complex IV. We suggest that the modified complex IV could incur the associated cost predicted by theoretical models to maintain gynodioecy in wild populations. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

On the penetration of a hot diapir through a strongly temperature-dependent viscosity medium

NASA Technical Reports Server (NTRS)

Daly, S. F.; Raefsky, A.

1985-01-01

The ascent of a hot spherical body through a fluid with a strongly temperature-dependent viscosity has been studied using an axisymmetric finite element method. Numerical solutions range over Peclet numbers of 0.1 - 1000 from constant viscosity up to viscosity variations of 100,000. Both rigid and stress-free boundary conditions were applied at the surface of the sphere. The dependence of drag on viscosity variation was shown to have no dependence on the stress boundary condition except for a Stokes flow scaling factor. A Nusselt number parameterization based on the stress-free constant viscosity functional dependence on the Peclet number scaled by a parameter depending on the viscosity structure fits both stress-free and rigid boundary condition data above viscosity variations of 100. The temperature scale height was determined as a function of sphere radius. For the simple physical model studied in this paper pre-heating is required to reduce the ambient viscosity of the country rock to less than 10 to the 22nd sq cm/s in order for a 10 km diapir to penetrate a distance of several radii.

Quality inspection of anisotropic scintillating lead tungstate (PbWO 4) crystals through measurement of interferometric fringe pattern parameters

NASA Astrophysics Data System (ADS)

Cocozzella, N.; Lebeau, M.; Majni, G.; Paone, N.; Rinaldi, D.

2001-08-01

Scintillating crystals are widely used as detectors in radiographic systems, computerized axial tomography devices and in calorimeters employed in high-energy physics. This paper results from a project motivated by the development of the CMS calorimeter at CERN, which will make use of a large number of scintillating crystals. In order to prevent crystals from breaking because of internal residual stress, a quality control system based on optic inspection of interference fringe patterns was developed. The principle of measurement procedures was theoretically modelled, and then a dedicated polariscope was designed and built, in order to observe the crystals under induced stresses or to evaluate the residual internal stresses. The results are innovative and open a new perspective for scintillating crystals quality control: the photoelastic constant normal to the optic axis of the lead tungstate crystals (PbWO 4) was measured, and the inspection procedure developed is applicable to mass production, not only to optimize the crystal processing, but also to establish a quality inspection procedure.

Chronic mild stress facilitates melanoma tumor growth in mouse lines selected for high and low stress-induced analgesia.

PubMed

Ragan, Agnieszka R; Lesniak, Anna; Bochynska-Czyz, Marta; Kosson, Anna; Szymanska, Hanna; Pysniak, Kazimiera; Gajewska, Marta; Lipkowski, Andrzej W; Sacharczuk, Mariusz

2013-09-01

Both chronic stress conditions and hyperergic reaction to environmental stress are known to enhance cancer susceptibility. We described two mouse lines that displayed high (HA) and low (LA) swim stress-induced analgesia (SSIA) to investigate the relationship between inherited differences in sensitivity to stress and proneness to an increased growth rate of subcutaneously inoculated melanoma. These lines display several genetic and physiological differences, among which distinct sensitivity to mutagens and susceptibility to cancer are especially noticeable. High analgesic mice display high proneness both to stress and a rapid local spread of B16F0 melanoma. However, stress-resistant LA mice do not develop melanoma tumors after inoculation, or if so, tumors regress spontaneously. We found that the chronic mild stress (CMS) procedure leads to enhanced interlinear differences in melanoma susceptibility. Tumors developed faster in stress conditions in both lines. However, LA mice still displayed a tendency for spontaneous regression, and 50% of LA mice did not develop a tumor, even under stressed conditions. Moreover, we showed that chronic stress, but not tumor progression, induces depressive behavior, which may be an important clue in cancer therapy. Our results clearly indicate how the interaction between genetic susceptibility to stress and environmental stress determine the risk and progression of melanoma. To our knowledge, HA/LA mouse lines are the first animal models of distinct melanoma progression mediated by inherited differences in stress reactivity.

Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys.

PubMed

Marchand, Sandrine; Bouchene, Salim; de Monte, Michèle; Guilleminault, Laurent; Montharu, Jérôme; Cabrera, Maria; Grégoire, Nicolas; Gobin, Patrice; Diot, Patrice; Couet, William; Vecellio, Laurent

2015-10-01

The objective of this study was to compare two different nebulizers: Eflow rapid® and Pari LC star® by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC® star than with Eflow Rapid® nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star® than the Eflow rapid® system. A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star® than with the Eflow Rapid® system.

Cardiometabolic Syndrome in People With Spinal Cord Injury/Disease: Guideline-Derived and Nonguideline Risk Components in a Pooled Sample.

PubMed

Nash, Mark S; Tractenberg, Rochelle E; Mendez, Armando J; David, Maya; Ljungberg, Inger H; Tinsley, Emily A; Burns-Drecq, Patricia A; Betancourt, Luisa F; Groah, Suzanne L

2016-10-01

To assess cardiometabolic syndrome (CMS) risk definitions in spinal cord injury/disease (SCI/D). Cross-sectional analysis of a pooled sample. Two SCI/D academic medical and rehabilitation centers. Baseline data from subjects in 7 clinical studies were pooled; not all variables were collected in all studies; therefore, participant numbers varied from 119 to 389. The pooled sample included men (79%) and women (21%) with SCI/D >1 year at spinal cord levels spanning C3-T2 (American Spinal Injury Association Impairment Scale [AIS] grades A-D). Not applicable. We computed the prevalence of CMS using the American Heart Association/National Heart, Lung, and Blood Institute guideline (CMS diagnosis as sum of risks ≥3 method) for the following risk components: overweight/obesity, insulin resistance, hypertension, and dyslipidemia. We compared this prevalence with the risk calculated from 2 routinely used nonguideline CMS risk assessments: (1) key cut scores identifying insulin resistance derived from the homeostatic model 2 (HOMA2) method or quantitative insulin sensitivity check index (QUICKI), and (2) a cardioendocrine risk ratio based on an inflammation (C-reactive protein [CRP])-adjusted total cholesterol/high-density lipoprotein cholesterol ratio. After adjustment for multiple comparisons, injury level and AIS grade were unrelated to CMS or risk factors. Of the participants, 13% and 32.1% had CMS when using the sum of risks or HOMA2/QUICKI model, respectively. Overweight/obesity and (pre)hypertension were highly prevalent (83% and 62.1%, respectively), with risk for overweight/obesity being significantly associated with CMS diagnosis (sum of risks, χ(2)=10.105; adjusted P=.008). Insulin resistance was significantly associated with CMS when using the HOMA2/QUICKI model (χ(2)2=21.23, adjusted P<.001). Of the subjects, 76.4% were at moderate to high risk from elevated CRP, which was significantly associated with CMS determination (both methods; sum of risks, χ(2)2=10.198; adjusted P=.048 and HOMA2/QUICKI, χ(2)2=10.532; adjusted P=.04). As expected, guideline-derived CMS risk factors were prevalent in individuals with SCI/D. Overweight/obesity, hypertension, and elevated CRP were common in SCI/D and, because they may compound risks associated with CMS, should be considered population-specific risk determinants. Heightened surveillance for risk, and adoption of healthy living recommendations specifically directed toward weight reduction, hypertension management, and inflammation control, should be incorporated as a priority for disease prevention and management. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Stimulatory effect of desipramine on lung metastases of adenocarcinoma MADB 106 in stress highly-sensitive and stress non-reactive rats.

PubMed

Grygier, Beata; Kubera, Marta; Wrona, Danuta; Roman, Adam; Basta-Kaim, Agnieszka; Gruca, Piotr; Papp, Mariusz; Rogoz, Zofia; Leskiewicz, Monika; Budziszewska, Boguslawa; Regulska, Magdalena; Korzeniak, Barbara; Curzytek, Katarzyna; Glombik, Katarzyna; Slusarczyk, Joanna; Maes, Michael; Lason, Wladyslaw

2018-01-03

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8 + and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats. Copyright © 2017. Published by Elsevier Inc.

Hydrodynamic Modeling for Channel and Shoreline Stabilization at Rhodes Point, Smith Island, MD

DTIC Science & Technology

2016-11-01

shorelines. Both Alternatives included the same revetment structure for protecting the south shoreline. The Coastal Modeling System (CMS, including CMS...ER D C/ CH L TR -1 6- 17 Coastal Inlets Research Program Hydrodynamic Modeling for Channel and Shoreline Stabilization at Rhodes Point...acwc.sdp.sirsi.net/client/default. Coastal Inlets Research Program ERDC/CHL TR-16-17 November 2016 Hydrodynamic Modeling for Channel and Shoreline

Protective role of Nrf2 against mechanical-stretch-induced apoptosis in mouse fibroblasts: a potential therapeutic target of mechanical-trauma-induced stress urinary incontinence.

PubMed

Li, Qiannan; Li, Bingshu; Liu, Cheng; Wang, Linlin; Tang, Jianming; Hong, Li

2018-01-10

We investigated the protective effect and underlying molecular mechanism of nuclear factor-E2-related factor 2 (Nrf2) against mechanical-stretch-induced apoptosis in mouse fibroblasts. Normal cells, Nrf2 silencing cells, and Nrf2 overexpressing cells were respectively divided into two groups-nonintervention and cyclic mechanical strain (CMS)-subjected to CMS of 5333 μ (1.0 Hz for 4 h), six groups in total (control, CMS, shNfe212, shNfe212 + CMS, LV-shNfe212, and LV-shNfe212 + CMS). After treatment, cell apoptosis; cell-cycle distribution; expressions of Nrf2, Bax, Bcl-2, Cyt-C, caspase-3, caspase-9, cleaved-caspase-3, and cleaved-caspase-9; mitochondrial membrane potential (ΔΨm); reactive oxygen species (ROS); and malondialdehyde (MDA) levels were measured. Thirty virgin female C57BL/6 mice were divided into two groups: control (without intervention) and vaginal distension (VD) groups, which underwent VD for 1 h with an 8-mm dilator (0.3 ml saline). Leak-point pressure (LPP) was tested on day 7 after VD; Nrf2 expression, apoptosis, and MDA levels were then measured in urethra and anterior vaginal wall. Mechanical stretch decreased Nrf2 messenger RNA (mRNA) and protein expressions. Overexpression of Nrf2 alleviated mechanical-stretch-induced cell apoptosis; S-phase arrest of cell cycle; up-regulation of Bax, cytochrome C (Cyt-C), ROS, MDA, ratio of cleaved-caspase-3/caspase-3 and cleaved-caspase-9/caspase-9; and exacerbated the decrease of Bcl2 and ΔΨm in L929 cells. On the contrary, silencing of Nrf2 showed opposite effects. Besides, VD reduced LPP levels and Nrf2 expression and increased cell apoptosis and MDA generation in the urethra and anterior vaginal wall. Nrf2 exhibits a protective role against mechanical-stretch -induced apoptosis on mouse fibroblasts, which might indicate a potential therapeutic target of mechanical-trauma-induced stress urinary incontinence (SUI).

The effects of music on the cardiovascular system and cardiovascular health.

PubMed

Trappe, Hans-Joachim

2010-12-01

Music may not only improve quality of life but may also effect changes in heart rate and heart rate variability. It has been shown that cerebral flow was significantly lower when listening to 'Va pensiero' from Verdi's 'Nabucco' (70.4±3.3 cm/s) compared with 'Libiam nei lieti calici' from Verdi's 'La Traviata' (70.2±3.1 cm/s) (p<0.02) or Bach's Cantata No. 169 'Gott soll allein mein Herze haben' (70.9±2.9 cm/s) (p<0.02). There was no significant difference in cerebral flow during rest (67.6±3.3 cm/s) or when listening to Beethoven's Ninth Symphony (69.4±3.1 cm/s). It was reported that relaxing music significantly decreases the level of anxiety of patients in a preoperative setting (State-Trait Anxiety Inventory (STAI)-X-1 score 34)-to a greater extent even than orally administered midazolam (STAI-X-1 score 36) (p<0.001). In addition the score was better after surgery in the music group (STAI-X-1 score 30) compared with the midazolam group (STAI-X-1 score 34) (p<0.001). Higher effectiveness and absence of apparent adverse effects make relaxing, preoperative music a useful alternative to midazolam for premedication. In addition, there is sufficient practical evidence of stress reduction suggesting that a proposed regimen of listening to music while resting in bed after open-heart surgery is important in clinical use. After 30 min of bed rest, there was a significant difference in cortisol levels between the music (484.4 mmol/l) and the non-music group (618.8 mmol/l) (p<0.02). Vocal and orchestral music produce significantly better correlations between cardiovascular or respiratory signals compared with music with a more uniform emphasis (p<0.05). The greatest benefit on health is visible with classical music and meditation music, whereas heavy metal music or techno are not only ineffective but possibly dangerous and can lead to stress and/or life-threatening arrhythmias. The music of many composers most effectively improves quality of life, will increase health and probably prolong life, particularly music by Bach, Mozart or Italian composers.

CMS Analysis School Model

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

Malik, S.; Shipsey, I.; Cavanaugh, R.

To impart hands-on training in physics analysis, CMS experiment initiated the concept of CMS Data Analysis School (CMSDAS). It was born over three years ago at the LPC (LHC Physics Centre), Fermilab and is based on earlier workshops held at the LPC and CLEO Experiment. As CMS transitioned from construction to the data taking mode, the nature of earlier training also evolved to include more of analysis tools, software tutorials and physics analysis. This effort epitomized as CMSDAS has proven to be a key for the new and young physicists to jump start and contribute to the physics goals ofmore » CMS by looking for new physics with the collision data. With over 400 physicists trained in six CMSDAS around the globe, CMS is trying to engage the collaboration in its discovery potential and maximize physics output. As a bigger goal, CMS is striving to nurture and increase engagement of the myriad talents, in the development of physics, service, upgrade, education of those new to CMS and the career development of younger members. An extension of the concept to the dedicated software and hardware schools is also planned, keeping in mind the ensuing upgrade phase.« less

Evolution of CMS workload management towards multicore job support

NASA Astrophysics Data System (ADS)

Pérez-Calero Yzquierdo, A.; Hernández, J. M.; Khan, F. A.; Letts, J.; Majewski, K.; Rodrigues, A. M.; McCrea, A.; Vaandering, E.

2015-12-01

The successful exploitation of multicore processor architectures is a key element of the LHC distributed computing system in the coming era of the LHC Run 2. High-pileup complex-collision events represent a challenge for the traditional sequential programming in terms of memory and processing time budget. The CMS data production and processing framework is introducing the parallel execution of the reconstruction and simulation algorithms to overcome these limitations. CMS plans to execute multicore jobs while still supporting singlecore processing for other tasks difficult to parallelize, such as user analysis. The CMS strategy for job management thus aims at integrating single and multicore job scheduling across the Grid. This is accomplished by employing multicore pilots with internal dynamic partitioning of the allocated resources, capable of running payloads of various core counts simultaneously. An extensive test programme has been conducted to enable multicore scheduling with the various local batch systems available at CMS sites, with the focus on the Tier-0 and Tier-1s, responsible during 2015 of the prompt data reconstruction. Scale tests have been run to analyse the performance of this scheduling strategy and ensure an efficient use of the distributed resources. This paper presents the evolution of the CMS job management and resource provisioning systems in order to support this hybrid scheduling model, as well as its deployment and performance tests, which will enable CMS to transition to a multicore production model for the second LHC run.

Evolution of CMS Workload Management Towards Multicore Job Support

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

Perez-Calero Yzquierdo, A.; Hernández, J. M.; Khan, F. A.

The successful exploitation of multicore processor architectures is a key element of the LHC distributed computing system in the coming era of the LHC Run 2. High-pileup complex-collision events represent a challenge for the traditional sequential programming in terms of memory and processing time budget. The CMS data production and processing framework is introducing the parallel execution of the reconstruction and simulation algorithms to overcome these limitations. CMS plans to execute multicore jobs while still supporting singlecore processing for other tasks difficult to parallelize, such as user analysis. The CMS strategy for job management thus aims at integrating single andmore » multicore job scheduling across the Grid. This is accomplished by employing multicore pilots with internal dynamic partitioning of the allocated resources, capable of running payloads of various core counts simultaneously. An extensive test programme has been conducted to enable multicore scheduling with the various local batch systems available at CMS sites, with the focus on the Tier-0 and Tier-1s, responsible during 2015 of the prompt data reconstruction. Scale tests have been run to analyse the performance of this scheduling strategy and ensure an efficient use of the distributed resources. This paper presents the evolution of the CMS job management and resource provisioning systems in order to support this hybrid scheduling model, as well as its deployment and performance tests, which will enable CMS to transition to a multicore production model for the second LHC run.« less

Waves at Navigation Structures

DTIC Science & Technology

2015-10-30

upgrades the Coastal Modeling System (CMS) wave models CMS-Wave, a phase- averaged spectral wave model, and BOUSS-2D, a Boussinesq type nonlinear wave...developing WaveNet and TideNet, two Web-based tool systems for wind and wave data access and processing, which provide critical data for USACE project...practical applications, resulting in optimization of navigation system to improve safety, reliability and operations with innovative infrastructures

WLCG scale testing during CMS data challenges

NASA Astrophysics Data System (ADS)

Gutsche, O.; Hajdu, C.

2008-07-01

The CMS computing model to process and analyze LHC collision data follows a data-location driven approach and is using the WLCG infrastructure to provide access to GRID resources. As a preparation for data taking, CMS tests its computing model during dedicated data challenges. An important part of the challenges is the test of the user analysis which poses a special challenge for the infrastructure with its random distributed access patterns. The CMS Remote Analysis Builder (CRAB) handles all interactions with the WLCG infrastructure transparently for the user. During the 2006 challenge, CMS set its goal to test the infrastructure at a scale of 50,000 user jobs per day using CRAB. Both direct submissions by individual users and automated submissions by robots were used to achieve this goal. A report will be given about the outcome of the user analysis part of the challenge using both the EGEE and OSG parts of the WLCG. In particular, the difference in submission between both GRID middlewares (resource broker vs. direct submission) will be discussed. In the end, an outlook for the 2007 data challenge is given.

Enantioselectively controlled release of chiral drug (metoprolol) using chiral mesoporous silica materials

NASA Astrophysics Data System (ADS)

Guo, Zhen; Du, Yu; Liu, Xianbin; Ng, Siu-Choon; Chen, Yuan; Yang, Yanhui

2010-04-01

Chiral porous materials have attracted burgeoning attention on account of their potential applications in many areas, such as enantioseparation, chiral catalysis, chemical sensors and drug delivery. In this report, chiral mesoporous silica (CMS) materials with various pore sizes and structures were prepared using conventional achiral templates (other than chiral surfactant) and a chiral cobalt complex as co-template. The synthesized CMS materials were characterized by x-ray diffraction, nitrogen physisorption, scanning electron microscope and transmission electron microscope. These CMS materials, as carriers, were demonstrated to be able to control the enantioselective release of a representative chiral drug (metoprolol). The release kinetics, as modeled by the power law equation, suggested that the release profiles of metoprolol were remarkably dependent on the pore diameter and pore structure of CMS materials. More importantly, R- and S-enantiomers of metoprolol exhibited different release kinetics on CMS compared to the corresponding achiral mesoporous silica (ACMS), attributable to the existence of local chirality on the pore wall surface of CMS materials. The chirality of CMS materials on a molecular level was further substantiated by vibrational circular dichroism measurements.

Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model.

PubMed

Ghlissi, Zohra; Hakim, Ahmed; Sila, Assaad; Mnif, Hela; Zeghal, Khaled; Rebai, Tarek; Bougatef, Ali; Sahnoun, Zouheir

2014-05-01

We evaluated the effect of astaxanthin (ASX) and vitamin E (vit E) on colistin methanesulfonate (CMS) induced-nephrotoxicity in rats. Animals were treated with sterile saline, 300000 or 450 000 IU/kg/day of CMS, CMS + ASX (20 mg/kg), CMS + vit E (100 mg/kg), or CMS + 1 ml/kg olive oil (OO) for 7 days. The plasma/urine creatinine (Cr) level, urine γ-glutamyl-transferase (GGT) level, and renal tissue activities in malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reductase (GSH), as well as renal histology were performed. CMS induced a tubular damage, increased the GGT and MDA levels, and decreased the activities of SOD, CAT, GPx and GSH. Co-treatment with ASX or vit E restored all biochemical parameters cited above and improved the histopathological damage. Nephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ASX or vit E seems to be related to their antioxidant properties. Copyright © 2014 Elsevier B.V. All rights reserved.

Human induced pluripotent stem cell-derived cardiomyocytes as an in vitro model for coxsackievirus B3-induced myocarditis and antiviral drug screening platform.

PubMed

Sharma, Arun; Marceau, Caleb; Hamaguchi, Ryoko; Burridge, Paul W; Rajarajan, Kuppusamy; Churko, Jared M; Wu, Haodi; Sallam, Karim I; Matsa, Elena; Sturzu, Anthony C; Che, Yonglu; Ebert, Antje; Diecke, Sebastian; Liang, Ping; Red-Horse, Kristy; Carette, Jan E; Wu, Sean M; Wu, Joseph C

2014-08-29

Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. A major causative agent for viral myocarditis is the B3 strain of coxsackievirus, a positive-sense RNA enterovirus. However, human cardiac tissues are difficult to procure in sufficient enough quantities for studying the mechanisms of cardiac-specific viral infection. This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. hiPSC-CMs were infected with a luciferase-expressing coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs for alterations in cellular morphology and calcium handling. Viral proliferation in hiPSC-CMs was quantified using bioluminescence imaging. Antiviral compounds including interferonβ1, ribavirin, pyrrolidine dithiocarbamate, and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with reported drug effects in previous studies. Mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways after interferonβ1 treatment. This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to predict antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that can screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion. © 2014 American Heart Association, Inc.

Comparing 2 methods of assessing 30-day readmissions: what is the impact on hospital profiling in the veterans health administration?

PubMed

Mull, Hillary J; Chen, Qi; O'Brien, William J; Shwartz, Michael; Borzecki, Ann M; Hanchate, Amresh; Rosen, Amy K

2013-07-01

The Centers for Medicare and Medicaid Services' (CMS) all-cause readmission measure and the 3M Health Information System Division Potentially Preventable Readmissions (PPR) measure are both used for public reporting. These 2 methods have not been directly compared in terms of how they identify high-performing and low-performing hospitals. To examine how consistently the CMS and PPR methods identify performance outliers, and explore how the PPR preventability component impacts hospital readmission rates, public reporting on CMS' Hospital Compare website, and pay-for-performance under CMS' Hospital Readmission Reduction Program for 3 conditions (acute myocardial infarction, heart failure, and pneumonia). We applied the CMS all-cause model and the PPR software to VA administrative data to calculate 30-day observed FY08-10 VA hospital readmission rates and hospital profiles. We then tested the effect of preventability on hospital readmission rates and outlier identification for reporting and pay-for-performance by replacing the dependent variable in the CMS all-cause model (Yes/No readmission) with the dichotomous PPR outcome (Yes/No preventable readmission). The CMS and PPR methods had moderate correlations in readmission rates for each condition. After controlling for all methodological differences but preventability, correlations increased to >90%. The assessment of preventability yielded different outlier results for public reporting in 7% of hospitals; for 30% of hospitals there would be an impact on Hospital Readmission Reduction Program reimbursement rates. Despite uncertainty over which readmission measure is superior in evaluating hospital performance, we confirmed that there are differences in CMS-generated and PPR-generated hospital profiles for reporting and pay-for-performance, because of methodological differences and the PPR's preventability component.

Harmonisation of Global Land-Use Scenarios for the Period 1500-2100 for IPCC-AR5

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

Hurtt, George; Chini, Louise Parsons; Frolking, Steve

2009-06-01

In preparation for the fifth Intergovernmental Panel on Climate Change climate change assessment (IPCC-AR5), the international community is developing new advanced computer models (CMs) to address the combined effects of human activities (e.g. land-use and fossil fuel emissions) on the carbon-climate system. In addition, four Representative Concentration Pathway (RCP) scenarios of the future (2005-2100) are being developed by four Integrated Assessment Modeling teams (IAMs) to be used as input to the CMs for future climate projections. The diversity of requirements and approaches among CMs and IAMs for tracking land-use changes (past, present, and future), presents major challenges for treating land-usemore » comprehensively and consistently between these communities. As part of an international working group, we have been working to meet these challenges by developing a "harmonized" set of land-use change scenarios that smoothly connects gridded historical reconstructions of land-use with future projections, in a format required by CMs. This approach to harmonizing the treatment of land-use between two key modeling communities, CMs and IAMs, represents a major advance that will facilitate more consistent and fuller treatments of land-use/land-use change effects including both CO2 emissions and corresponding land-surface changes.« less

Maturation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) in 3D collagen matrix: Effects of niche cell supplementation and mechanical stimulation.

PubMed

Zhang, W; Kong, C W; Tong, M H; Chooi, W H; Huang, N; Li, R A; Chan, B P

2017-02-01

Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) are regarded as a promising source for regenerative medicine, drug testing and disease modeling. Nevertheless, cardiomyocytes are immature in terms of their contractile structure, metabolism and electrophysiological properties. Here, we fabricate cardiac muscle strips by encapsulating hESC-CMs in collagen-based biomaterials. Supplementation of niche cells at 3% to the number of hESC-CMs enhance the maturation of the hESC-CMs in 3D tissue matrix. The benefits of adding mesenchymal stem cells (MSCs) are comparable to that of adding fibroblasts. These two cell types demonstrate similar effects in promoting the compaction and cell spreading, as well as expression of maturation markers at both gene and protein levels. Mechanical loading, particularly cyclic stretch, produces engineered cardiac tissues with higher maturity in terms of twitch force, elastic modulus, sarcomere length and molecular signature, when comparing to static stretch or non-stretched controls. The current study demonstrates that the application of niche cells and mechanical stretch both stimulate the maturation of hESC-CMs in 3D architecture. Our results therefore suggest that this 3D model can be used for in vitro cardiac maturation study. Cardiomyocytes derived from human embryonic stem cells (hESC-CMs) are regarded as being a promising source of cells for regenerative medicine, drug testing and disease modeling. Nevertheless, cardiomyocytes are immature in terms of their contractile structure, metabolism and electrophysiological properties. In the current study, we have fabricated cardiac muscle strips by encapsulating hESC-CMs in collagen-based biomaterials and demonstrated that supplementation of mesenchymal niche cells as well as provision of mechanical loading particularly stretching have significantly promoted the maturation of the cardiomyocytes and hence improved the mechanical functional characteristics of the tissue strips. Specifically, with 3% niche cells including both fibroblasts and mesenchymal stem cells, a more mature hESC-CMs derived cardiac strip was resulted, in terms of compaction and spreading of cells, and upregulation of molecular signature in both gene and protein expression of maturation. Mechanical loading, particularly cyclic stretch, produces engineered cardiac tissues with higher maturity in terms of molecular signature markers and functional parameters including twitch force, elastic modulus and sarcomere length, when comparing with static stretch or non-stretched controls. The current study demonstrates that the application of niche cells and mechanical stretch both stimulate the maturation of hESC-CMs in 3D architecture, resulting in more mature cardiac strips. Our results contribute to bioengineering of functional heart tissue strips for drug screening and disease modeling. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Carboxymethyl starch mucoadhesive microspheres as gastroretentive dosage form.

PubMed

Lemieux, Marc; Gosselin, Patrick; Mateescu, Mircea Alexandru

2015-12-30

Carboxymethyl starch microspheres (CMS-MS) were produced from carboxymethyl starch powder (CMS-P) with a degree of substitution (DS) from 0.1 to 1.5 in order to investigate the influence of DS on physicochemical, drug release and mucoadhesion properties as well as interactions with gastrointestinal tract (GIT) epithelial barrier models. Placebo and furosemide loaded CMS-MS were obtained by emulsion-crosslinking with sodium trimetaphosphate (STMP). DS had an impact on increasing equilibrium water uptake and modulating drug release properties of the CMS-MS according to the surrounding pH. The transepithelial electrical resistance (TEER) of NCI-N87 gastric cell monolayers was not influenced in presence of CMS-MS, whereas that of Caco-2 intestinal cell monolayers decreased with increasing DS but recovered initial values at about 15h post-treatment. CMS-MS with increasing DS also enhanced furosemide permeability across both NCI-N87 and Caco-2 monolayers at pH gradients from 3.0 to 7.4. Mucoadhesion of CMS-MS on gastric mucosa (acidic condition) increased with the DS up to 55% for a DS of 1.0 but decreased on neutral intestinal mucosa to less than 10% with DS of 0.1. The drug release, permeability enhancement and mucoadhesive properties of the CMS-MS suggest CMS-MS with DS between 0.6 and 1.0 as suitable excipient for gastroretentive oral delivery dosage forms. Copyright © 2015 Elsevier B.V. All rights reserved.

Cognitive Models for Integrating Testing and Instruction, Phase II. Methodology Program.

ERIC Educational Resources Information Center

Quellmalz, Edys S.; Shaha, Steven

The potential of a cognitive model task analysis scheme (CMS) that specifies features of test problems shown by research to affect performance is explored. CMS describes the general skill area and the generic task or problem type. It elaborates features of the problem situation and required responses found by research to influence performance.…

Macrohabitat models of occurrence for the threatened Cheat Mountain salamander, Plethodon nettingi

Treesearch

Lester O. Dillard; Kevin R. Russell; W. Mark Ford

2008-01-01

The federally threatened Cheat Mountain salamander (Plethodon nettingi; hereafter CMS) is known to occur at approximately 70 small, scattered sites in the Allegheny Mountains of eastern West Virginia. We used a comparative modeling approach to explain the landscape-level distribution and habitat relationships of CMS in relation to a suite of biotic...

Opening the Black Box of Clinical Collaboration in Integrated Care Models for Frail, Elderly Patients

ERIC Educational Resources Information Center

de Stampa, Matthieu; Vedel, Isabelle; Bergman, Howard; Novella, Jean-Luc; Lechowski, Laurent; Ankri, Joel; Lapointe, Liette

2013-01-01

Purpose: The purpose of the study was to understand better the clinical collaboration process among primary care physicians (PCPs), case managers (CMs), and geriatricians in integrated models of care. Methods: We conducted a qualitative study with semistructured interviews. A purposive sample of 35 PCPs, 7 CMs, and 4 geriatricians was selected in…

High-Content Electrophysiological Analysis of Human Pluripotent Stem Cell-Derived Cardiomyocytes (hPSC-CMs).

PubMed

Kong, Chi-Wing; Geng, Lin; Li, Ronald A

2018-01-01

Considerable interest has been raised to develop human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as a model for drug discovery and cardiotoxicity screening. High-content electrophysiological analysis of currents generated by transmembrane cell surface ion channels has been pursued to complement such emerging applications. Here we describe practical procedures and considerations for accomplishing successful assays of hPSC-CMs using an automated planar patch-clamp system.

China's Rural Cooperative Medical Scheme: a type of health insurance or a type of health cooperative?

PubMed

Wang, Fang; Liang, Yuan

2017-03-01

The Cooperative Medical Scheme (CMS) was popular in rural China in the 1960s and 1970s, having garnered praise from the World Bank and World Health Organization as an unprecedented example of a successful health care model in a low-income developing country. However, the CMS almost collapsed in the 1980s. Based on its historical origins and main activities, we think the CMS functioned as a health cooperative rather than a health insurance scheme. Perhaps, however, the importance to the CMS of cooperation between institutions has been overestimated. Overlooked, yet equally important, has been the cooperation between health workers and farmers to target health-related risk factors associated with agricultural work and ways of life. The 'cooperative' character of the CMS includes two aspects: cooperative institutions and cooperative behaviour. Although the CMS collapsed in China, similar schemes are flourishing elsewhere in the world. In the future, in-depth analysis of these schemes is required.

Congenital Myasthenic Syndromes or Inherited Disorders of Neuromuscular Transmission: Recent Discoveries and Open Questions

PubMed Central

Nicole, Sophie; Azuma, Yoshiteru; Bauché, Stéphanie; Eymard, Bruno; Lochmüller, Hanns; Slater, Clarke

2017-01-01

Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models. Frontier forms between CMS and congenital myopathy, which have been genetically and clinically identified, underline the poorly understood interplay between the synaptic and extrasynaptic molecules in the neuromuscular system. In addition, precise electrophysiological and histopathological investigations of individuals with CMS suggest an important role of NMJ plasticity in the response to CMS pathogenesis. While efficient drug-based treatments are already available to improve neuromuscular transmission for most forms of CMS, others, as well as neurological and muscular comorbidities, remain resistant. Taken together, the available pathological data point to physiological issues which remain to be understood in order to achieve precision medicine with efficient therapeutics for all individuals suffering from CMS. PMID:29125502

The Role of Computational Modeling and Simulation in the Total Product Life Cycle of Peripheral Vascular Devices

PubMed Central

Morrison, Tina M.; Dreher, Maureen L.; Nagaraja, Srinidhi; Angelone, Leonardo M.; Kainz, Wolfgang

2018-01-01

The total product life cycle (TPLC) of medical devices has been defined by four stages: discovery and ideation, regulatory decision, product launch, and postmarket monitoring. Manufacturers of medical devices intended for use in the peripheral vasculature, such as stents, inferior vena cava (IVC) filters, and stent-grafts, mainly use computational modeling and simulation (CM&S) to aid device development and design optimization, supplement bench testing for regulatory decisions, and assess postmarket changes or failures. For example, computational solid mechanics and fluid dynamics enable the investigation of design limitations in the ideation stage. To supplement bench data in regulatory submissions, manufactures can evaluate the effects of anatomical characteristics and expected in vivo loading environment on device performance. Manufacturers might also harness CM&S to aid root-cause analyses that are necessary when failures occur postmarket, when the device is exposed to broad clinical use. Once identified, CM&S tools can then be used for redesign to address the failure mode and re-establish the performance profile with the appropriate models. The Center for Devices and Radiological Health (CDRH) wants to advance the use of CM&S for medical devices and supports the development of virtual physiological patients, clinical trial simulations, and personalized medicine. Thus, the purpose of this paper is to describe specific examples of how CM&S is currently used to support regulatory submissions at different phases of the TPLC and to present some of the stakeholder-led initiatives for advancing CM&S for regulatory decision-making. PMID:29479395

The Role of Computational Modeling and Simulation in the Total Product Life Cycle of Peripheral Vascular Devices.

PubMed

Morrison, Tina M; Dreher, Maureen L; Nagaraja, Srinidhi; Angelone, Leonardo M; Kainz, Wolfgang

2017-01-01

The total product life cycle (TPLC) of medical devices has been defined by four stages: discovery and ideation, regulatory decision, product launch, and postmarket monitoring. Manufacturers of medical devices intended for use in the peripheral vasculature, such as stents, inferior vena cava (IVC) filters, and stent-grafts, mainly use computational modeling and simulation (CM&S) to aid device development and design optimization, supplement bench testing for regulatory decisions, and assess postmarket changes or failures. For example, computational solid mechanics and fluid dynamics enable the investigation of design limitations in the ideation stage. To supplement bench data in regulatory submissions, manufactures can evaluate the effects of anatomical characteristics and expected in vivo loading environment on device performance. Manufacturers might also harness CM&S to aid root-cause analyses that are necessary when failures occur postmarket, when the device is exposed to broad clinical use. Once identified, CM&S tools can then be used for redesign to address the failure mode and re-establish the performance profile with the appropriate models. The Center for Devices and Radiological Health (CDRH) wants to advance the use of CM&S for medical devices and supports the development of virtual physiological patients, clinical trial simulations, and personalized medicine. Thus, the purpose of this paper is to describe specific examples of how CM&S is currently used to support regulatory submissions at different phases of the TPLC and to present some of the stakeholder-led initiatives for advancing CM&S for regulatory decision-making.

Underreporting of nursing home utilization on the CMS-2728 in older incident dialysis patients and implications for assessing mortality risk.

PubMed

Bowling, C Barrett; Zhang, Rebecca; Franch, Harold; Huang, Yijian; Mirk, Anna; McClellan, William M; Johnson, Theodore M; Kutner, Nancy G

2015-03-21

The usage of nursing home (NH) services is a marker of frailty among older adults. Although the Centers for Medicare & Medicaid Services (CMS) revised the Medical Evidence Report Form CMS-2728 in 2005 to include data collection on NH institutionalization, the validity of this item has not been reported. There were 27,913 patients ≥ 75 years of age with incident end-stage renal disease (ESRD) in 2006, which constituted our analysis cohort. We determined the accuracy of the CMS-2728 using a matched cohort that included the CMS Minimum Data Set (MDS) 2.0, often employed as a "gold standard" metric for identifying patients receiving NH care. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the CMS-2728 NH item. Next, we compared characteristics and mortality risk by CMS-2728 and MDS NH status agreement. The sensitivity, specificity, PPV and NPV of the CMS-2728 for NH status were 33%, 97%, 80% and 79%, respectively. Compared to those without the MDS or CMS-2728 NH indicator (No MDS/No 2728), multivariable adjusted hazard ratios (95% confidence interval) for mortality associated with NH status were 1.55 (1.46 - 1.64) for MDS/2728, 1.48 (1.42 - 1.54) for MDS/No 2728, and 1.38 (1.25 - 1.52) for No MDS/2728. NH utilization was more strongly associated with mortality than other CMS-2728 items in the model. The CMS-2728 underestimated NH utilization among older adults with incident ESRD. The potential for misclassification may have important ramifications for assessing prognosis, developing advanced care plans and providing coordinated care.

A Bayesian approach for calibrating probability judgments

NASA Astrophysics Data System (ADS)

Firmino, Paulo Renato A.; Santana, Nielson A.

2012-10-01

Eliciting experts' opinions has been one of the main alternatives for addressing paucity of data. In the vanguard of this area is the development of calibration models (CMs). CMs are models dedicated to overcome miscalibration, i.e. judgment biases reflecting deficient strategies of reasoning adopted by the expert when inferring about an unknown. One of the main challenges of CMs is to determine how and when to intervene against miscalibration, in order to enhance the tradeoff between costs (time spent with calibration processes) and accuracy of the resulting models. The current paper dedicates special attention to this issue by presenting a dynamic Bayesian framework for monitoring, diagnosing, and handling miscalibration patterns. The framework is based on Beta-, Uniform, or Triangular-Bernoulli models and classes of judgmental calibration theories. Issues regarding the usefulness of the proposed framework are discussed and illustrated via simulation studies.

Comparative analysis of mitochondrial genomes between the hau cytoplasmic male sterility (CMS) line and its iso-nuclear maintainer line in Brassica juncea to reveal the origin of the CMS-associated gene orf288.

PubMed

Heng, Shuangping; Wei, Chao; Jing, Bing; Wan, Zhengjie; Wen, Jing; Yi, Bin; Ma, Chaozhi; Tu, Jinxing; Fu, Tingdong; Shen, Jinxiong

2014-04-30

Cytoplasmic male sterility (CMS) is not only important for exploiting heterosis in crop plants, but also as a model for investigating nuclear-cytoplasmic interaction. CMS may be caused by mutations, rearrangement or recombination in the mitochondrial genome. Understanding the mitochondrial genome is often the first and key step in unraveling the molecular and genetic basis of CMS in plants. Comparative analysis of the mitochondrial genome of the hau CMS line and its maintainer line in B. juneca (Brassica juncea) may help show the origin of the CMS-associated gene orf288. Through next-generation sequencing, the B. juncea hau CMS mitochondrial genome was assembled into a single, circular-mapping molecule that is 247,903 bp in size and 45.08% in GC content. In addition to the CMS associated gene orf288, the genome contains 35 protein-encoding genes, 3 rRNAs, 25 tRNA genes and 29 ORFs of unknown function. The mitochondrial genome sizes of the maintainer line and another normal type line "J163-4" are both 219,863 bp and with GC content at 45.23%. The maintainer line has 36 genes with protein products, 3 rRNAs, 22 tRNA genes and 31 unidentified ORFs. Comparative analysis the mitochondrial genomes of the hau CMS line and its maintainer line allowed us to develop specific markers to separate the two lines at the seedling stage. We also confirmed that different mitotypes coexist substoichiometrically in hau CMS lines and its maintainer lines in B. juncea. The number of repeats larger than 100 bp in the hau CMS line (16 repeats) are nearly twice of those found in the maintainer line (9 repeats). Phylogenetic analysis of the CMS-associated gene orf288 and four other homologous sequences in Brassicaceae show that orf288 was clearly different from orf263 in Brassica tournefortii despite of strong similarity. The hau CMS mitochondrial genome was highly rearranged when compared with its iso-nuclear maintainer line mitochondrial genome. This study may be useful for studying the mechanism of natural CMS in B. juncea, performing comparative analysis on sequenced mitochondrial genomes in Brassicas, and uncovering the origin of the hau CMS mitotype and structural and evolutionary differences between different mitotypes.

Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients.

PubMed

Boisson, Matthieu; Jacobs, Matthieu; Grégoire, Nicolas; Gobin, Patrice; Marchand, Sandrine; Couet, William; Mimoz, Olivier

2014-12-01

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Comparison of Intrapulmonary and Systemic Pharmacokinetics of Colistin Methanesulfonate (CMS) and Colistin after Aerosol Delivery and Intravenous Administration of CMS in Critically Ill Patients

PubMed Central

Boisson, Matthieu; Jacobs, Matthieu; Grégoire, Nicolas; Gobin, Patrice; Marchand, Sandrine; Mimoz, Olivier

2014-01-01

Colistin is an old antibiotic that has recently gained a considerable renewal of interest for the treatment of pulmonary infections due to multidrug-resistant Gram-negative bacteria. Nebulization seems to be a promising form of administration, but colistin is administered as an inactive prodrug, colistin methanesulfonate (CMS); however, differences between the intrapulmonary concentrations of the active moiety as a function of the route of administration in critically ill patients have not been precisely documented. In this study, CMS and colistin concentrations were measured on two separate occasions within the plasma and epithelial lining fluid (ELF) of critically ill patients (n = 12) who had received 2 million international units (MIU) of CMS by aerosol delivery and then intravenous administration. The pharmacokinetic analysis was conducted using a population approach and completed by pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations. The ELF colistin concentrations varied considerably (9.53 to 1,137 mg/liter), but they were much higher than those in plasma (0.15 to 0.73 mg/liter) after aerosol delivery but not after intravenous administration of CMS. Following CMS aerosol delivery, typically, 9% of the CMS dose reached the ELF, and only 1.4% was presystemically converted into colistin. PK-PD analysis concluded that there was much higher antimicrobial efficacy after CMS aerosol delivery than after intravenous administration. These new data seem to support the use of aerosol delivery of CMS for the treatment of pulmonary infections in critical care patients. PMID:25267660

Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model

PubMed Central

Shiba, Yuji; Filice, Dominic; Fernandes, Sarah; Minami, Elina; Dupras, Sarah K.; Van Biber, Benjamin; Trinh, Peter; Hirota, Yusuke; Gold, Joseph D.; Viswanathan, Mohan; Laflamme, Michael A.

2014-01-01

Background Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were recently shown to be capable of electromechanical integration following their direct injection into intact or recently injured guinea pig hearts, and hESC-CM transplantation in recently injured hearts correlated with improvements in contractile function and a reduction in the incidence of arrhythmias. The present study was aimed at determining the ability of hESC-CMs to integrate and modulate electrical stability following transplantation in a chronic model of cardiac injury. Methods & Results At 28 days following cardiac cryoinjury, guinea pigs underwent intra-cardiac injection of hESC-CMs, non-cardiac hESC-derivatives (non-CMs) or vehicle. Histology confirmed partial remuscularization of the infarct zone in hESC-CM recipients, while non-CM recipients showed heterogeneous xenografts. The three experimental groups showed no significant difference in the left ventricular dimensions or fractional shortening by echocardiography or in the incidence of spontaneous arrhythmias by telemetric monitoring. While recipients of hESC-CMs and vehicle showed a similar incidence of arrhythmias induced by programmed electrical stimulation at 4-weeks post-transplantation, non-CM recipients proved to be highly inducible, with a ~3-fold greater incidence of induced arrhythmias. In parallel studies, we investigated the ability of hESC-CMs to couple with host myocardium in chronically injured hearts by the intravital imaging of hESC-CM grafts that stably expressed a fluorescent reporter of graft activation, the genetically-encoded calcium sensor GCaMP3. In this work, we found that only ~38% (5 of 13) of recipients of GCaMP3+ hESC-CMs showed fluorescent transients that were coupled to the host electrocardiogram. Conclusions hESC-CMs engraft in chronically injured hearts without increasing the incidence of arrhythmias, but their electromechanical integration is more limited than was previously reported following their transplantation in a subacute injury model. Moreover, non-CM grafts may promote arrhythmias under certain conditions, a finding that underscores the need for input preparations of high cardiac purity. PMID:24516260

Implementation of NASTRAN on the IBM/370 CMS operating system

NASA Technical Reports Server (NTRS)

Britten, S. S.; Schumacker, B.

1980-01-01

The NASA Structural Analysis (NASTRAN) computer program is operational on the IBM 360/370 series computers. While execution of NASTRAN has been described and implemented under the virtual storage operating systems of the IBM 370 models, the IBM 370/168 computer can also operate in a time-sharing mode under the virtual machine operating system using the Conversational Monitor System (CMS) subset. The changes required to make NASTRAN operational under the CMS operating system are described.

A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat.

PubMed

Bouchene, Salim; Marchand, Sandrine; Couet, William; Friberg, Lena E; Gobin, Patrice; Lamarche, Isabelle; Grégoire, Nicolas; Björkman, Sven; Karlsson, Mats O

2018-04-17

Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K p . Colistin and its prodrug, colistin methanesulfonate (CMS) K p priors were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting in vivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a non-linear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K p were estimated using in silico K p priors (I) or K p were estimated using experimental K p priors (II) or K p were fixed to the experimental values (III). The WB-PBPK model best described colistun and CMS plasma concentration-time profiles in scenario II. Colistin predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigating the impact of disease state on colistin disposition. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

PubMed Central

Wang, Peng; Li, Hui; Barde, Swapnali; Zhang, Ming-Dong; Sun, Jing; Wang, Tong; Zhang, Pan; Luo, Hanjiang; Wang, Yongjun; Yang, Yutao; Wang, Chuanyue; Svenningsson, Per; Theodorsson, Elvar; Hökfelt, Tomas G. M.; Xu, Zhi-Qing David

2016-01-01

The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects. PMID:27457954

PhenoWorld: a new paradigm to screen rodent behavior

PubMed Central

Castelhano-Carlos, M; Costa, P S; Russig, H; Sousa, N

2014-01-01

Modeling depression in animals has inherent complexities that are augmented by intrinsic difficulties to measure the characteristic features of the disorder. Herein, we describe the PhenoWorld (PhW), a new setting in which groups of six rats lived in an ethological enriched environment, and have their feeding, locomotor activity, sleeping and social behavior automatically monitored. A battery of emotional and cognitive tests was used to characterize the behavioral phenotype of animals living in the PhW and in standard conditions (in groups of six and two rats), after exposure to an unpredictable chronic mild stress paradigm (uCMS) and antidepressants. Data reveal that animals living in the PhW displayed similar, but more striking, behavioral differences when exposed to uCMS, such as increased behavioral despair shown in the forced swimming test, resting/sleep behavior disturbances and reduced social interactions. Moreover, several PhW-cage behaviors, such as spontaneous will to go for food or exercise in running wheels, proved to be sensitive indicators of depressive-like behavior. In summary, this new ethological enriched paradigm adds significant discriminative power to screen depressive-like behavior, in particularly rodent's hedonic behavior. PMID:26126181

Passage Key Inlet, Florida; CMS Modeling and Borrow Site Impact Analysis

DTIC Science & Technology

2016-06-01

Impact Analysis by Kelly R. Legault and Sirisha Rayaprolu PURPOSE: This Coastal and Hydraulics Engineering Technical Note (CHETN) describes the...use of a nested Coastal Modeling System (CMS) model for Passage Key Inlet, which is one of the connections between the Gulf of Mexico and Tampa Bay...driven sediment transport at Passage Key Inlet. This analysis resulted in issuing a new Florida Department of Environmental Protection (FDEP) permit to

Simulation of strong ground motion parameters of the 1 June 2013 Gulf of Suez earthquake, Egypt

NASA Astrophysics Data System (ADS)

Toni, Mostafa

2017-06-01

This article aims to simulate the ground motion parameters of the moderate magnitude (ML 5.1) June 1, 2013 Gulf of Suez earthquake, which represents the largest instrumental earthquake to be recorded in the middle part of the Gulf of Suez up to now. This event was felt in all cities located on both sides of the Gulf of Suez, with minor damage to property near the epicenter; however, no casualties were observed. The stochastic technique with the site-dependent spectral model is used to simulate the strong ground motion parameters of this earthquake in the cities located at the western side of the Gulf of Suez and north Red Sea namely: Suez, Ain Sokhna, Zafarana, Ras Gharib, and Hurghada. The presence of many tourist resorts and the increase in land use planning in the considered cities represent the motivation of the current study. The simulated parameters comprise the Peak Ground Acceleration (PGA), Peak Ground Velocity (PGV), and Peak Ground Displacement (PGD), in addition to Pseudo Spectral Acceleration (PSA). The model developed for ground motion simulation is validated by using the recordings of three accelerographs installed around the epicenter of the investigated earthquake. Depending on the site effect that has been determined in the investigated areas by using geotechnical data (e.g., shear wave velocities and microtremor recordings), the investigated areas are classified into two zones (A and B). Zone A is characterized by higher site amplification than Zone B. The ground motion parameters are simulated at each zone in the considered areas. The results reveal that the highest values of PGA, PGV, and PGD are observed at Ras Gharib city (epicentral distance ∼ 11 km) as 67 cm/s2, 2.53 cm/s, and 0.45 cm respectively for Zone A, and as 26.5 cm/s2, 1.0 cm/s, and 0.2 cm respectively for Zone B, while the lowest values of PGA, PGV, and PGD are observed at Suez city (epicentral distance ∼ 190 km) as 3.0 cm/s2, 0.2 cm/s, and 0.05 cm/s respectively for Zone A, and as 1.3 cm/s2, 0.1 cm/s, and 0.024 cm respectively for Zone B. Also the highest PSA values are observed in Ras Gharib city as 200 cm/s2 and 78 cm/s2 for Zone A and Zone B respectively, while the lowest PSA values are observed in Suez city as 7 cm/s2 and 3 cm/s2 for Zone A and Zone B respectively. These results show a good agreement with the earthquake magnitude, epicentral distances, and site characterizations as well.

Human cardiomyocyte generation from pluripotent stem cells: A state-of-art.

PubMed

Talkhabi, Mahmood; Aghdami, Nasser; Baharvand, Hossein

2016-01-15

The human heart is considered a non-regenerative organ. Worldwide, cardiovascular diseases continue to be the leading cause of death. Despite advances in cardiac treatment, myocardial repair remains severely limited by the lack of an appropriate source of viable cardiomyocytes (CMs) to replace damaged tissue. Human pluripotent stem cells (hPSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can efficiently be differentiated into functional CMs necessary for cell replacement therapy and other potential applications. The number of protocols that derive CMs from hPSCs has increased exponentially over the past decade following observation of the first human beating CMs. A number of highly efficient, chemical based protocols have been developed to generate human CMs (hCMs) in small-scale and large-scale suspension systems. To reduce the heterogeneity of hPSC-derived CMs, the differentiation protocols were modulated to exclusively generate atrial-, ventricular-, and nodal-like CM subtypes. Recently, remarkable advances have been achieved in hCM generation including chemical-based cardiac differentiation, cardiac subtype specification, large-scale suspension culture differentiation, and development of chemically defined culture conditions. These hCMs could be useful particularly in the context of in vitro disease modeling, pharmaceutical screening and in cellular replacement therapies once the safety issues are overcome. Herein we review recent progress in the in vitro generation of CMs and cardiac subtypes from hPSCs and discuss their potential applications and current limitations. Copyright © 2015 Elsevier Inc. All rights reserved.

A simulation framework for the CMS Track Trigger electronics

NASA Astrophysics Data System (ADS)

Amstutz, C.; Magazzù, G.; Weber, M.; Palla, F.

2015-03-01

A simulation framework has been developed to test and characterize algorithms, architectures and hardware implementations of the vastly complex CMS Track Trigger for the high luminosity upgrade of the CMS experiment at the Large Hadron Collider in Geneva. High-level SystemC models of all system components have been developed to simulate a portion of the track trigger. The simulation of the system components together with input data from physics simulations allows evaluating figures of merit, like delays or bandwidths, under realistic conditions. The use of SystemC for high-level modelling allows co-simulation with models developed in Hardware Description Languages, e.g. VHDL or Verilog. Therefore, the simulation framework can also be used as a test bench for digital modules developed for the final system.

Pharmacokinetics of Chinese medicines: strategies and perspectives.

PubMed

Yan, Ru; Yang, Ying; Chen, Yijia

2018-01-01

The modernization and internationalization of Chinese medicines (CMs) are hampered by increasing concerns on the safety and the efficacy. Pharmacokinetic (PK) study is indispensable to establish concentration-activity/toxicity relationship and facilitate target identification and new drug discovery from CMs. To cope with tremendous challenges rooted from chemical complexity of CMs, the classic PK strategies have evolved rapidly from PK study focusing on marker/main drug components to PK-PD correlation study adopting metabolomics approaches to characterize associations between disposition of global drug-related components and host metabolic network shifts. However, the majority of PK studies of CMs have adopted the approaches tailored for western medicines and focused on the systemic exposures of drug-related components, most of which were found to be too low to account for the holistic benefits of CMs. With an area under concentration-time curve- or activity-weighted approach, integral PK attempts to understand the PK-PD relevance with the integrated PK profile of multiple co-existing structural analogs (prototyes/metabolites). Cellular PK-PD complements traditional PK-PD when drug targets localize inside the cells, instead of at the surface of cell membrane or extracellular space. Considering the validated clinical benefits of CMs, reverse pharmacology-based reverse PK strategy was proposed to facilitate target identification and new drug discovery. Recently, gut microbiota have demonstrated multifaceted roles in drug efficacy/toxicity. In traditional oral intake, the presystemic interactions of CMs with gut microbiota seem inevitable, which can contribute to the holistic benefits of CMs through biotransforming CMs components, acting as the peripheral target, and regulating host drug disposition. Hence, we propose a global PK-PD approach which includes the presystemic interaction of CMs with gut microbiota and combines omics with physiologically based pharmacokinetic modeling to offer a comprehensive understanding of the PK-PD relationship of CMs. Moreover, validated clinical benefits of CMs and poor translational potential of animal PK data urge more research efforts in human PK study.

Human adipose tissue from normal and tumoral breast regulates the behavior of mammary epithelial cells.

PubMed

Pistone Creydt, Virginia; Fletcher, Sabrina Johanna; Giudice, Jimena; Bruzzone, Ariana; Chasseing, Norma Alejandra; Gonzalez, Eduardo Gustavo; Sacca, Paula Alejandra; Calvo, Juan Carlos

2013-02-01

Stromal-epithelial interactions mediate both breast development and breast cancer progression. In the present work, we evaluated the effects of conditioned media (CMs) of human adipose tissue explants from normal (hATN) and tumor (hATT) breast on proliferation, adhesion, migration and metalloproteases activity on tumor (MCF-7 and IBH-7) and non-tumor (MCF-10A) human breast epithelial cell lines. Human adipose tissues were obtained from patients and the conditioned medium from hATN and hATT collected after 24 h of incubation. MCF-10A, MCF-7 and IBH-7 cells were grown and incubated with CMs and proliferation and adhesion, as well as migration ability and metalloprotease activity, of epithelial cells after exposing cell cultures to hATN- or hATT-CMs were quantified. The statistical significance between different experimental conditions was evaluated by one-way ANOVA. Tukey's post hoc tests were performed. Tumor and non-tumor breast epithelial cells significantly increased their proliferation activity after 24 h of treatment with hATT-CMs compared to control-CMs. Furthermore, cellular adhesion of these two tumor cell lines was significantly lower with hATT-CMs than with hATN-CMs. Therefore, hATT-CMs seem to induce significantly lower expression or less activity of the components involved in cellular adhesion than hATN-CMs. In addition, hATT-CMs induced pro-MMP-9 and MMP-9 activity and increased the migration of MCF-7 and IBH-7 cells compared to hATN-CMs. We conclude that the microenvironment of the tumor interacts in a dynamic way with the mutated epithelium. This evidence leads to the possibility to modify the tumor behavior/phenotype through the regulation or modification of its microenvironment. We developed a model in which we obtained CMs from adipose tissue explants completely, either from normal or tumor breast. In this way, we studied the contribution of soluble factors independently of the possible effects of direct cell contact.

Cell type-specific in vivo expression of genes encoding signalling molecules in the brain in response to chronic mild stress and chronic treatment with fluoxetine.

PubMed

Dong, Lu; Li, Baoman; Verkhratsky, Alexei; Peng, Liang

2015-08-01

Previously, we reported that chronic treatment with fluoxetine increased gene expression of 5-hydroxytryptamine receptor 2B (5-HT2BR), cytosolic phospholipase 2α (cPLA2α), glutamate receptor, ionotropic kainate 2 (GluK2) and adenosine deaminase acting on RNA 2 (ADAR2), in cultured astrocytes and astrocytes freshly isolated from transgenic mice tagged with an astrocyte-specific marker. In contrast, neurones isolated from transgenic mice tagged with a neurone-specific marker and exposed to fluoxetine showed an increase in gene expression of glutamate receptor, ionotropic kainate 4 (GluK4) and 5-hydroxytryptamine receptor 2C (5-HT2CR). In a mouse model of anhedonia, the downregulation of 5-HT2BR, cPLA2α, ADAR2 and GluK4 but not GluK2 and 5-HT2CR was detected. To investigate the effects of chronic mild stress (CMS) and/or fluoxetine treatment on gene expression of 5-HT2BR, 5-HT2CR, cPLA2α, ADAR2, GluK2 and GluK4 specifically in astrocytes and neurones. Transgenic mice tagged with either astrocyte- or neurone-specific markers were exposed to the CMS. Real-time PCR was applied to determine expression of messenger RNA (mRNA). We found that (i) mRNAs of the 5-HT2BR and cPLA2α in astrocytes and GluK4 in neurones were significantly reduced in mice that became anhedonic; the mRNA levels were restored by fluoxetine treatment; (ii) ADAR2 in astrocytes was decreased by the CMS but showed no response to fluoxetine in anhedonic animals; (iii) neither GluK2 expression in astrocytes nor 5-HT2CR expression in neurones were affected in anhedonic animals, although expression of 5-HT2CR mRNA was upregulated by fluoxetine. Our results indicate that the effects of chronic treatment with fluoxetine are not only dependent on the cell type studied but also on the development of anhedonia. This suggests that fluoxetine may affect major depression (MD) patients and healthy people in a different manner.

Mechanical signaling coordinates the embryonic heartbeat.

PubMed

Chiou, Kevin K; Rocks, Jason W; Chen, Christina Yingxian; Cho, Sangkyun; Merkus, Koen E; Rajaratnam, Anjali; Robison, Patrick; Tewari, Manorama; Vogel, Kenneth; Majkut, Stephanie F; Prosser, Benjamin L; Discher, Dennis E; Liu, Andrea J

2016-08-09

In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, β-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats.

Are computational models of any use to psychiatry?

PubMed

Huys, Quentin J M; Moutoussis, Michael; Williams, Jonathan

2011-08-01

Mathematically rigorous descriptions of key hypotheses and theories are becoming more common in neuroscience and are beginning to be applied to psychiatry. In this article two fictional characters, Dr. Strong and Mr. Micawber, debate the use of such computational models (CMs) in psychiatry. We present four fundamental challenges to the use of CMs in psychiatry: (a) the applicability of mathematical approaches to core concepts in psychiatry such as subjective experiences, conflict and suffering; (b) whether psychiatry is mature enough to allow informative modelling; (c) whether theoretical techniques are powerful enough to approach psychiatric problems; and (d) the issue of communicating clinical concepts to theoreticians and vice versa. We argue that CMs have yet to influence psychiatric practice, but that they help psychiatric research in two fundamental ways: (a) to build better theories integrating psychiatry with neuroscience; and (b) to enforce explicit, global and efficient testing of hypotheses through more powerful analytical methods. CMs allow the complexity of a hypothesis to be rigorously weighed against the complexity of the data. The paper concludes with a discussion of the path ahead. It points to stumbling blocks, like the poor communication between theoretical and medical communities. But it also identifies areas in which the contributions of CMs will likely be pivotal, like an understanding of social influences in psychiatry, and of the co-morbidity structure of psychiatric diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

Comparative genomics of Clavibacter michiganensis subspecies, pathogens of important agricultural crops.

PubMed

Tambong, James T

2017-01-01

Subspecies of Clavibacter michiganensis are important phytobacterial pathogens causing devastating diseases in several agricultural crops. The genome organizations of these pathogens are poorly understood. Here, the complete genomes of 5 subspecies (C. michiganensis subsp. michiganensis, Cmi; C. michiganensis subsp. sepedonicus, Cms; C. michiganensis subsp. nebraskensis, Cmn; C. michiganensis subsp. insidiosus, Cmi and C. michiganensis subsp. capsici, Cmc) were analyzed. This study assessed the taxonomic position of the subspecies based on 16S rRNA and genome-based DNA homology and concludes that there is ample evidence to elevate some of the subspecies to species-level. Comparative genomics analysis indicated distinct genomic features evident on the DNA structural atlases and annotation features. Based on orthologous gene analysis, about 2300 CDSs are shared across all the subspecies; and Cms showed the highest number of subspecies-specific CDS, most of which are mobile elements suggesting that Cms could be more prone to translocation of foreign genes. Cms and Cmi had the highest number of pseudogenes, an indication of potential degenerating genomes. The stress response factors that may be involved in cold/heat shock, detoxification, oxidative stress, osmoregulation, and carbon utilization are outlined. For example, the wco-cluster encoding for extracellular polysaccharide II is highly conserved while the sucrose-6-phosphate hydrolase that catalyzes the hydrolysis of sucrose-6-phosphate yielding glucose-6-phosphate and fructose is highly divergent. A unique second form of the enzyme is only present in Cmn NCPPB 2581. Also, twenty-eight plasmid-borne CDSs in the other subspecies were found to have homologues in the chromosomal genome of Cmn which is known not to carry plasmids. These CDSs include pathogenesis-related factors such as Endocellulases E1 and Beta-glucosidase. The results presented here provide an insight of the functional organization of the genomes of five core C. michiganensis subspecies, enabling a better understanding of these phytobacteria.

Comparative genomics of Clavibacter michiganensis subspecies, pathogens of important agricultural crops

PubMed Central

2017-01-01

Subspecies of Clavibacter michiganensis are important phytobacterial pathogens causing devastating diseases in several agricultural crops. The genome organizations of these pathogens are poorly understood. Here, the complete genomes of 5 subspecies (C. michiganensis subsp. michiganensis, Cmi; C. michiganensis subsp. sepedonicus, Cms; C. michiganensis subsp. nebraskensis, Cmn; C. michiganensis subsp. insidiosus, Cmi and C. michiganensis subsp. capsici, Cmc) were analyzed. This study assessed the taxonomic position of the subspecies based on 16S rRNA and genome-based DNA homology and concludes that there is ample evidence to elevate some of the subspecies to species-level. Comparative genomics analysis indicated distinct genomic features evident on the DNA structural atlases and annotation features. Based on orthologous gene analysis, about 2300 CDSs are shared across all the subspecies; and Cms showed the highest number of subspecies-specific CDS, most of which are mobile elements suggesting that Cms could be more prone to translocation of foreign genes. Cms and Cmi had the highest number of pseudogenes, an indication of potential degenerating genomes. The stress response factors that may be involved in cold/heat shock, detoxification, oxidative stress, osmoregulation, and carbon utilization are outlined. For example, the wco-cluster encoding for extracellular polysaccharide II is highly conserved while the sucrose-6-phosphate hydrolase that catalyzes the hydrolysis of sucrose-6-phosphate yielding glucose-6-phosphate and fructose is highly divergent. A unique second form of the enzyme is only present in Cmn NCPPB 2581. Also, twenty-eight plasmid-borne CDSs in the other subspecies were found to have homologues in the chromosomal genome of Cmn which is known not to carry plasmids. These CDSs include pathogenesis-related factors such as Endocellulases E1 and Beta-glucosidase. The results presented here provide an insight of the functional organization of the genomes of five core C. michiganensis subspecies, enabling a better understanding of these phytobacteria. PMID:28319117

The dynamics of subtidal poleward flows over a narrow continental shelf, Palos Verdes, CA

USGS Publications Warehouse

Noble, M.A.; Ryan, H.F.; Wiberg, P.L.

2002-01-01

The Palos Verdes peninsula is a short, very narrow (< 3 km) shelf in southern California that is bracketed by two large embayments. In May 1992, arrays of up to 4 moorings and 2 benthic tripods were deployed in a yearlong study of the circulation processes over this shelf and the adjacent slope. Wind stress, coastal sea level, atmospheric pressure and wave records were obtained from offshore sites and from coastal stations surrounding Palos Verdes. Bottom stress calculated for the mid-shelf sites using a boundary-layer model and data from the above instruments indicated the bottom drag coefficient over this shelf is about 0.003 Currents flow toward the northwest along the shelf and upper slope. Speeds are generally around 20-30 cm/s. There was no obvious seasonal structure in the flow. The first EOF for subtidal alongshelf current accounted for nearly 70% of the variance at sites on the shelf and upper slope. The dominant fluctuations had periods between 5 and 20 days, periods longer than seen in the regional wind stress field. Coastal sea level and the alongshore gradient in sea level had a similar concentration of energy in the 5-20 day frequency band. About 30% of the alongshelf flow was coherent with the alongshelf pressure gradient; currents flowed down the pressure gradient with minimal phase lag. Winds accounted for only 15-20% of the variance in subtidal currents, but the measured effect of wind stress was large. A 1 dyne/cm2 wind stress was associated with a 20-30 cm/s alongshore current. Both the regional wind stress and the alongshelf pressure gradients had spatial scales much larger than found on this small shelf. Subtidal flows forced by these regional fields were set up in the adjacent, much broader basins. The currents amplified as they moved onto the narrow shelf between the basins. Hence, local wind-driven currents had anomalously large amplitudes. The momentum equations for alongshelf wind or pressure gradients did not balance because some of the measured terms were associated with regional fields, others with local process. Our observations suggest that it is more difficult to determine which measured fields reflect the local processes in regions with rapidly changing topography. ?? 2002 Elsevier Science Ltd. All rights reserved.

Differentiation and characterization of rhesus monkey atrial and ventricular cardiomyocytes from induced pluripotent stem cells.

PubMed

Zhang, Xiaoqian; Cao, Henghua; Bai, Shuyun; Huo, Weibang; Ma, Yue

2017-04-01

The combination of non-human primate animals and their induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) provides not only transplantation models for cell-based therapy of heart diseases, but also opportunities for heart-related drug research on both cellular and animal levels. However, the subtypes and electrophysiology properties of non-human primate iPSC-CMs hadn't been detailed characterized. In this study, we generated rhesus monkey induced pluripotent stem cells (riPSCs), and efficiently differentiated them into ventricular or atrial cardiomyocytes by modulating retinoic acid (RA) pathways. Our results revealed that the electrophysiological characteristics and response to canonical drugs of riPSC-CMs were similar with those of human pluripotent stem cell derived CMs. Therefore, rhesus monkeys and their iPSC-CMs provide a powerful and practicable system for heart related biomedical research. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Impact of Reimbursement Cuts on the Sustainability and Accessibility of Dopamine Transporter Imaging.

PubMed

Covington, Matthew F; McMillan, Natalie A; Kuo, Phillip H

2016-09-01

Dopamine transporter single-photon emission computed tomography imaging utilizing iodine-123 ioflupane is accurate for differentiation of Parkinson disease from essential tremor. This study evaluates how reimbursement for I-123 ioflupane imaging changed between 2011 (year of FDA approval) and 2014 (year after loss of pass-through status for hospital-based outpatient imaging from CMS). I-123 ioflupane reimbursement data for our institution's hospital-based imaging were compared between two periods: (1) July 2011 to October 2012, and (2) 2014. For each time period separately and in combination, averages and ranges of reimbursement for private insurance and CMS were analyzed and compared. A model to ensure recouping of radiopharmaceutical costs was developed. Review yielded 247 studies from July 2011 to October 2012 and 94 studies from 2014. Average reimbursement per study fell from $2,469 (US dollars) in 2011 to 2012 to $1,657 in 2014. CMS reduced average reimbursement by $1,148 in 2014 because of loss of radiopharmaceutical pass-through status. Average reimbursements from CMS versus private payors markedly differed in 2011 to 2012 at $2,266 versus $2,861, respectively, and in 2014 at $1,118 versus $3,470, respectively. Between 2011 to 2012 and 2014, the CMS percentage increased from 54% to 78%. Assuming that I-123 ioflupane cost $2,000, our model based on 2014 data predicts a practice with greater than 60% CMS patients would no longer recover radiopharmaceutical costs. Reimbursement levels, payor mix, scanner location, and radiopharmaceutical costs are all critical, variable factors for modeling the financial viability of I-123 ioflupane imaging and, by extrapolation, future radiopharmaceuticals. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Regional CMS Modeling: Southwest Florida Gulf Coast

DTIC Science & Technology

2016-05-01

by Kelly R. Legault and Tanya M. Beck PURPOSE: This Coastal and Hydraulics Engineering technical note (CHETN) describes a regional application of...the U.S. Army Corps of Engineers (USACE) Engineer Research and Development Center (ERDC) Coastal Modeling System (CMS). This application spans three...Active federal projects include the Pinellas County Shore Protection Project (SPP), Tampa Harbor Deeping Project, Manatee County SPP at Anna Maria

Purification of Cardiomyocytes from Differentiating Pluripotent Stem Cells using Molecular Beacons Targeting Cardiomyocyte-Specific mRNA

PubMed Central

Kim, Sangsung; Park, Hun-Jun; Byun, Jaemin; Cho, Kyu-Won; Saafir, Talib; Song, Ming-Ke; Yu, Shan Ping; Wagner, Mary; Bao, Gang; Yoon, Young-Sup

2013-01-01

Background While methods for generating cardiomyocytes (CMs) from pluripotent stem cells (PSCs) have been reported, current methods produce heterogeneous mixtures of CMs and non-CM cells. Here, we report an entirely novel system in which PSC-derived CMs are purified by CM-specific molecular beacons (MBs). MBs are nano-scale probes that emit a fluorescence signal when hybridized to target mRNAs. Method and Results Five MBs targeting mRNAs of either cardiac troponin T or myosin heavy chain 6/7 were generated. Among five MBs, a MB targeting myosin heavy chain 6/7 mRNA (MHC1-MB) identified up to 99% of HL-1 CMs, a mouse CM cell line, but < 3% of four non-CM cell types in flow cytometry analysis, indicating that MHC1-MB is specific for identifying CMs. We delivered MHC1-MB into cardiomyogenically differentiated PSCs through nucleofection. The detection rate of CMs was similar to the percentages of cardiac troponin T (TNNT2) or cardiac troponin I (TNNI3)-positive CMs, supporting the specificity of MBs. Finally, MHC1-MB-positive cells were FACS-sorted from mouse and human PSC differentiating cultures and ~97% cells expressed TNNT2- or TNNI3 determined by flow cytometry. These MB-based sorted cells maintained their CM characteristics verified by spontaneous beating, electrophysiologic studies, and expression of cardiac proteins. When transplanted in a myocardial infarction model, MB-based purified CMs improved cardiac function and demonstrated significant engraftment for 4 weeks without forming tumors. Conclusions We developed a novel CM selection system that allows production of highly purified CMs. These purified CMs and this system can be valuable for cell therapy and drug discovery. PMID:23995537

Searching for confining hidden valleys at LHCb, ATLAS, and CMS

NASA Astrophysics Data System (ADS)

Pierce, Aaron; Shakya, Bibhushan; Tsai, Yuhsin; Zhao, Yue

2018-05-01

We explore strategies for probing hidden valley scenarios exhibiting confinement. Such scenarios lead to a moderate multiplicity of light hidden hadrons for generic showering and hadronization similar to QCD. Their decays are typically soft and displaced, making them challenging to probe with traditional LHC searches. We show that the low trigger requirements and excellent track and vertex reconstruction at LHCb provide a favorable environment to search for such signals. We propose novel search strategies in both muonic and hadronic channels. We also study existing ATLAS and CMS searches and compare them with our proposals at LHCb. We find that the reach at LHCb is generically better in the parameter space we consider here, even with optimistic background estimations for ATLAS and CMS searches. We discuss potential modifications at ATLAS and CMS that might make these experiments competitive with the LHCb reach. Our proposed searches can be applied to general hidden valley models as well as exotic Higgs boson decays, such as in twin Higgs models.

Human induced pluripotent stem cell‐derived versus adult cardiomyocytes: an in silico electrophysiological study on effects of ionic current block

PubMed Central

Paci, M; Hyttinen, J; Rodriguez, B

2015-01-01

Background and Purpose Two new technologies are likely to revolutionize cardiac safety and drug development: in vitro experiments on human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) and in silico human adult ventricular cardiomyocyte (hAdultV‐CM) models. Their combination was recently proposed as a potential replacement for the present hERG‐based QT study for pharmacological safety assessments. Here, we systematically compared in silico the effects of selective ionic current block on hiPSC‐CM and hAdultV‐CM action potentials (APs), to identify similarities/differences and to illustrate the potential of computational models as supportive tools for evaluating new in vitro technologies. Experimental Approach In silico AP models of ventricular‐like and atrial‐like hiPSC‐CMs and hAdultV‐CM were used to simulate the main effects of four degrees of block of the main cardiac transmembrane currents. Key Results Qualitatively, hiPSC‐CM and hAdultV‐CM APs showed similar responses to current block, consistent with results from experiments. However, quantitatively, hiPSC‐CMs were more sensitive to block of (i) L‐type Ca2+ currents due to the overexpression of the Na+/Ca2+ exchanger (leading to shorter APs) and (ii) the inward rectifier K+ current due to reduced repolarization reserve (inducing diastolic potential depolarization and repolarization failure). Conclusions and Implications In silico hiPSC‐CMs and hAdultV‐CMs exhibit a similar response to selective current blocks. However, overall hiPSC‐CMs show greater sensitivity to block, which may facilitate in vitro identification of drug‐induced effects. Extrapolation of drug effects from hiPSC‐CM to hAdultV‐CM and pro‐arrhythmic risk assessment can be facilitated by in silico predictions using biophysically‐based computational models. PMID:26276951

Are Evidence-based Practices Associated With Effective Prevention of Hospital-acquired Pressure Ulcers in US Academic Medical Centers?

PubMed

Padula, William V; Gibbons, Robert D; Valuck, Robert J; Makic, Mary B F; Mishra, Manish K; Pronovost, Peter J; Meltzer, David O

2016-05-01

In 2008, the Centers for Medicare and Medicaid Services (CMS) established nonpayment policies resulting from costliness of hospital-acquired pressure ulcers (HAPUs) to hospitals. This prompted hospitals to adopt quality improvement (QI) interventions that increase use of evidence-based practices (EBPs) for HAPU prevention. To evaluate the longitudinal impact of CMS policy and QI adoption on HAPU rates. We characterized longitudinal adoption of 25 QI interventions that support EBPs through hospital leadership, staff, information technology, and performance and improvement. Quarterly counts of HAPU incidence and inpatient characteristics were collected from 55 University HealthSystem Consortium hospitals between 2007 and 2012. Mixed-effects regression models tested the longitudinal association of CMS policy, HAPU coding, and QI on HAPU rates. The models assumed level-2 random intercepts and random effects for CMS policy and EBP implementation to account for between-hospital variability in HAPU incidence. Controlling for all 25 QI interventions, specific updates to EBPs for HAPU prevention had a significant, though modest reduction on HAPU rates (-1.86 cases/quarter; P=0.002) and the effect of CMS nonpayment policy on HAPU prevention was much greater (-11.32 cases/quarter; P<0.001). HAPU rates were significantly lower after changes in CMS reimbursement. Reductions are associated with hospital-wide implementation of EBPs for HAPU prevention. Given that administrative data were used, it remains unknown whether these improvements were due to changes in coding or improved quality of care.

Are Evidence-based Practices Associated with Effective Prevention of Hospital-acquired Pressure Ulcers in U.S. Academic Medical Centers?

PubMed Central

Padula, William V.; Gibbons, Robert D.; Valuck, Robert J.; Makic, Mary Beth F.; Mishra, Manish K.; Pronovost, Peter J.; Meltzer, David O.

2016-01-01

Background In 2008, the Centers for Medicare and Medicaid Services (CMS) established nonpayment policies resulting from costliness of hospital-acquired pressure ulcers (HAPUs) to hospitals. This prompted hospitals to adopt quality improvement (QI) interventions that increase use of evidence-based practices (EBPs) for HAPU prevention. Objective To evaluate the longitudinal impact of CMS policy and QI adoption on HAPU rates. Methods We characterized longitudinal adoption of 25 QI interventions that support EBPs through hospital leadership, staff, information technology, and performance and improvement. Quarterly counts of HAPU incidence and inpatient characteristics were collected from 55 UHC hospitals between 2007–2012. Mixed-effects regression models tested the longitudinal association of CMS policy, HAPU coding and QI on HAPU rates. The models assumed level-2 random-intercepts and random effects for CMS policy and EBP implementation to account for between-hospital variability in HAPU incidence. Results Controlling for all 25 QI interventions, specific updates to EBPs for HAPU prevention had a significant, though modest reduction on HAPU rates (−1.86 cases/quarter; p=0.002) and the effect of CMS nonpayment policy on HAPU prevention was much greater (−11.32 cases/quarter; p<0.001). Conclusions HAPU rates were significantly lower following changes in CMS reimbursement. Reductions are associated with hospital-wide implementation of EBPs for HAPU prevention. Given that administrative data were used, it remains unknown whether these improvements were due to changes in coding or improved quality of care. PMID:27078824

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

PubMed

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

2015-03-01

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

Comparative transcript profiling of alloplasmic male-sterile lines revealed altered gene expression related to pollen development in rice (Oryza sativa L.).

PubMed

Hu, Jihong; Chen, Guanglong; Zhang, Hongyuan; Qian, Qian; Ding, Yi

2016-08-05

Cytoplasmic male sterility (CMS) is an ideal model for investigating the mitochondrial-nuclear interaction and down-regulated genes in CMS lines which might be the candidate genes for pollen development in rice. In this study, a set of rice alloplasmic sporophytic CMS lines was obtained by successive backcrossing of Meixiang B, with three different cytoplasmic types: D62A (D type), ZS97A (WA type) and XQZ-A (DA type). Using microarray, the anther transcript profiles of the three indica rice CMS lines revealed 622 differentially expressed genes (DEGs) in each of the three CMS lines compared with the maintainer line Meixiang B. GO and MapMan analysis indicated that these DEGs were mainly involved in lipid metabolism and cell wall organization. Compared with the gene expression of sporophytic and gametophytic CMS lines, 303 DEGs were identified and 56 of them were down-regulated in all the CMS lines of rice. These down-regulated DEGs in the CMS lines were found to be involved in tapetum or cell wall formation and their suppressed expression might be related to male sterility. Weighted gene co-expression network analysis (WGCNA) revealed that two modules were significantly associated with male sterility and many hub genes that were differentially expressed in the CMS lines. A large set of putative genes involved in anther development was identified in the present study. The results will give some information for the nuclear gene regulation by different cytoplasmic genotypes and provide a rich resource for further functional research on the pollen development in rice.

RNA Editing Responses to Oxidative Stress between a Wild Abortive Type Male-Sterile Line and Its Maintainer Line

PubMed Central

Xiong, Jie; Tao, Tao; Luo, Zhi; Yan, Shuaigang; Liu, Yi; Yu, Xinqiao; Liu, Guolan; Xia, Hui; Luo, Lijun

2017-01-01

RNA editing of mitochondrial gene transcripts plays a central role during plant development and evolutionary adaptation. RNA editing has previously been reported to differ between the rice cytoplasmic male sterile (CMS) line and its maintainer line, which has been suggested as a cause for their different performances under environmental stress. To specifically test this hypothesis, a wild abortive (WA) CMS line (Huhan-1A) and its maintainer line (Huhan-1B) were utilized to investigate performances in response to oxidative stress, as well as RNA editing efficiencies on transcripts of six selected mitochondrial genes. Compared to the maintainer line, Huhan-1A represented both lower plant height and total antioxidant capacity, possessed higher total soluble protein and chlorophyll contents, accumulated less H2O2 content on the 3rd day after treatment (DAT), and exhibited higher survival ratio after re-watering. Furthermore, a total of 90 editing sites were detected on transcripts of six mitochondrial genes (atp9, nad2, nad7, nad9, ccmB, and ccmC) in both Huhan-1A and Huhan-1B on the 0, 1st, and 3rd DAT. Forty-eight sites were furthermore determined as stress-responsive sites (SRS). Generally, in response to oxidative stress, SRS in Huhan-1A increased the resulting editing efficiencies, while SRS in Huhan-1B decreased the resulting editing efficiencies. In addition, 33 and 22 sites at ccmB and ccmC were differentially edited between Huhan-1A and Huhan-1B, respectively, on the 0, 1st, and 3rd DAT. Editing efficiencies of ccmB and ccmC were generally lower in Huhan-1A (ccmB, 37.3–47.8%; ccmC, 41.2–52.3%) than those in Huhan-1B (ccmB, 82.6–86.5%; ccmC, 81.0–82.9%). Deficiencies of RNA editing in Huhan-1A at ccmB and ccmC could lead to the loss of transmembrane domains in their protein structures. Consequently, differences in RNA editing at ccmB and ccmC between the WA-CMS line and its maintainer line partially explained their different performances under stress. Moreover, we detected differences in expressions of pentatricopeptide repeat (PPR) genes between both lines, as well as significant correlations with RNA editing. Our study indicated potential associations of RNA editing and PPR genes in rice tolerance to abiotic stresses. However, the underlying molecular mechanisms of stress-adaptation, which are attributed to RNA editing on transcripts of mitochondrial genes, require further investigation. PMID:29234339

Qualification and calibration tests of detector modules for the CMS Pixel Phase 1 upgrade

NASA Astrophysics Data System (ADS)

Zhu, D.; Backhaus, M.; Berger, P.; Meinhard, M.; Starodumov, A.; Tavolaro, V.

2018-01-01

In high energy particle physics, accelerator- and detector-upgrades always go hand in hand. The instantaneous luminosity of the Large Hadron Collider will increase to up to L = 2×1034cm-2s-1 during Run 2 until 2023. In order to cope with such luminosities, the pixel detector of the CMS experiment has been replaced early 2017. The so-called CMS Pixel phase 1 upgrade detector consists of 1184 modules with new design. An important production step is the module qualification and calibration, ensuring their proper functionality within the detector. This paper summarizes the qualification and calibration tests and results of modules used in the innermost two detector layers with focus on methods using module-internal calibration signals. Extended characterizations on pixel level such as electronic noise and bump bond connectivity, optimization of operational parameters, sensor quality and thermal stress resistance were performed using a customized setup with controlled environment. It could be shown that the selected modules have on average 0.55‰ ± 0.01‰ defective pixels and that all performance parameters stay within their specifications.

Geomorphic Identification and Verification of Recent Sedimentation Patterns in the Woonasquatucket River, North Providence, Rhode Island

DTIC Science & Technology

2007-03-01

8 The Centre Cotton Manufacturing Company (1812).................................................................. 9...112 Data collection...sedimentation surface) derived from the CF:CS 210Pb model. Data are not available for vibracores CMS- SD-4210 and CMS-SD-4213 in 1938 and 1958 and

Verification and Validation of the Coastal Modeling System. Report 2: CMS-Wave

DTIC Science & Technology

2011-12-01

Figure 44. Offshore bathymetry showing NDBC and CDIP buoy locations. ........................................ 70 Figure 45. CMS-Wave modeling domain...the four measurement stations. During the same time intervals, offshore wave information was available from a Coastal Data Information Program ( CDIP ...were conducted with a grid of 236 × 398 cells with variable cell spacing of 30 to 200 m (see Figure 28). Directional wave spectra from CDIP 036 served

Bundled payment and enhanced recovery after surgery.

PubMed

Huang, Jeffrey

2015-01-01

Medicare's fee-for-service (FFS) payment model may contribute to unsustainable spending growth. Payers are turning to alternative payment methods. The leading alternative payment model to the FFS problem is bundled payment. The Centers for Medicare & Medicaid Services (CMS) is taking another step to improve healthcare quality at lower cost. The CMS's Center for Medicare and Medicaid Innovation developed four models of bundled payments and 48 discrete clinical condition episodes. Many surgical care procedures are included in the 48 different clinical condition episodes.

Noninvasive Detection and Imaging of Molecular Markers in Live Cardiomyocytes Derived from Human Embryonic Stem Cells

PubMed Central

Pascut, Flavius C.; Goh, Huey T.; Welch, Nathan; Buttery, Lee D.; Denning, Chris; Notingher, Ioan

2011-01-01

Raman microspectroscopy (RMS) was used to detect and image molecular markers specific to cardiomyocytes (CMs) derived from human embryonic stem cells (hESCs). This technique is noninvasive and thus can be used to discriminate individual live CMs within highly heterogeneous cell populations. Principal component analysis (PCA) of the Raman spectra was used to build a classification model for identification of individual CMs. Retrospective immunostaining imaging was used as the gold standard for phenotypic identification of each cell. We were able to discriminate CMs from other phenotypes with >97% specificity and >96% sensitivity, as calculated with the use of cross-validation algorithms (target 100% specificity). A comparison between Raman spectral images corresponding to selected Raman bands identified by the PCA model and immunostaining of the same cells allowed assignment of the Raman spectral markers. We conclude that glycogen is responsible for the discrimination of CMs, whereas myofibril proteins have a lesser contribution. This study demonstrates the potential of RMS for allowing the noninvasive phenotypic identification of hESC progeny. With further development, such label-free optical techniques may enable the separation of high-purity cell populations with mature phenotypes, and provide repeated measurements to monitor time-dependent molecular changes in live hESCs during differentiation in vitro. PMID:21190678

Selfish evolution of cytonuclear hybrid incompatibility in Mimulus

PubMed Central

Finseth, Findley R.; Barr, Camille M.; Fishman, Lila

2016-01-01

Intraspecific coevolution between selfish elements and suppressors may promote interspecific hybrid incompatibility, but evidence of this process is rare. Here, we use genomic data to test alternative models for the evolution of cytonuclear hybrid male sterility in Mimulus. In hybrids between Iron Mountain (IM) Mimulus guttatus × Mimulus nasutus, two tightly linked M. guttatus alleles (Rf1/Rf2) each restore male fertility by suppressing a local mitochondrial male-sterility gene (IM-CMS). Unlike neutral models for the evolution of hybrid incompatibility loci, selfish evolution predicts that the Rf alleles experienced strong selection in the presence of IM-CMS. Using whole-genome sequences, we compared patterns of population-genetic variation in Rf at IM to a neighbouring population that lacks IM-CMS. Consistent with local selection in the presence of IM-CMS, the Rf region shows elevated FST, high local linkage disequilibrium and a distinct haplotype structure at IM, but not at Cone Peak (CP), suggesting a recent sweep in the presence of IM-CMS. In both populations, Rf2 exhibited lower polymorphism than other regions, but the low-diversity outliers were different between CP and IM. Our results confirm theoretical predictions of ubiquitous cytonuclear conflict in plants and provide a population-genetic mechanism for the evolution of a common form of hybrid incompatibility. PMID:27629037

Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening.

PubMed

Sharma, Arun; Wu, Joseph C; Wu, Sean M

2013-12-24

Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well.

Comparison of the accuracy of maxillary position between conventional model surgery and virtual surgical planning.

PubMed

Ritto, F G; Schmitt, A R M; Pimentel, T; Canellas, J V; Medeiros, P J

2018-02-01

The aim of this study was to determine whether virtual surgical planning (VSP) is an accurate method for positioning the maxilla when compared to conventional articulator model surgery (CMS), through the superimposition of computed tomography (CT) images. This retrospective study included the records of 30 adult patients submitted to bimaxillary orthognathic surgery. Two groups were created according to the treatment planning performed: CMS and VSP. The treatment planning protocol was the same for all patients. Pre- and postoperative CT images were superimposed and the linear distances between upper jaw reference points were measured. Measurements were then compared to the treatment planning, and the difference in accuracy between CMS and VSP was determined using the t-test for independent samples. The success criterion adopted was a mean linear difference of <2mm. The mean linear difference between planned and obtained movements for CMS was 1.27±1.05mm, and for VSP was 1.20±1.08mm. With CMS, 80% of overlapping reference points had a difference of <2mm, while for VSP this value was 83.6%. There was no statistically significant difference between the two techniques regarding accuracy (P>0.05). Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Selfish evolution of cytonuclear hybrid incompatibility in Mimulus.

PubMed

Case, Andrea L; Finseth, Findley R; Barr, Camille M; Fishman, Lila

2016-09-14

Intraspecific coevolution between selfish elements and suppressors may promote interspecific hybrid incompatibility, but evidence of this process is rare. Here, we use genomic data to test alternative models for the evolution of cytonuclear hybrid male sterility in Mimulus In hybrids between Iron Mountain (IM) Mimulus guttatus × Mimulus nasutus, two tightly linked M. guttatus alleles (Rf1/Rf2) each restore male fertility by suppressing a local mitochondrial male-sterility gene (IM-CMS). Unlike neutral models for the evolution of hybrid incompatibility loci, selfish evolution predicts that the Rf alleles experienced strong selection in the presence of IM-CMS. Using whole-genome sequences, we compared patterns of population-genetic variation in Rf at IM to a neighbouring population that lacks IM-CMS. Consistent with local selection in the presence of IM-CMS, the Rf region shows elevated FST, high local linkage disequilibrium and a distinct haplotype structure at IM, but not at Cone Peak (CP), suggesting a recent sweep in the presence of IM-CMS. In both populations, Rf2 exhibited lower polymorphism than other regions, but the low-diversity outliers were different between CP and IM. Our results confirm theoretical predictions of ubiquitous cytonuclear conflict in plants and provide a population-genetic mechanism for the evolution of a common form of hybrid incompatibility. © 2016 The Author(s).

Patient-Specific Induced Pluripotent Stem Cell as a Model for Familial Dilated Cardiomyopathy

PubMed Central

Sun, Ning; Yazawa, Masayuki; Liu, Jianwei; Han, Leng; Sanchez-Freire, Veronica; Abilez, Oscar J.; Navarrete, Enrique G.; Hu, Shijun; Wang, Li; Lee, Andrew; Pavlovic, Aleksandra; Lin, Shin; Chen, Rui; Hajjar, Roger J.; Snyder, Michael P.; Dolmetsch, Ricardo E.; Butte, Manish J.; Ashley, Euan A.; Longaker, Michael T.; Robbins, Robert C.; Wu, Joseph C.

2013-01-01

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy, characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific models, investigating underlying mechanisms, and optimizing therapy. Here we generated cardiomyocytes (CMs) from iPSCs derived from patients of a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to the control healthy individuals in the same family cohort, DCM iPSC-CMs exhibited altered Ca2+ handling, decreased contractility, and abnormal sarcomeric α-actinin distribution. When stimulated with β-adrenergic agonist, DCM iPSC-CMs showed characteristics of failure such as reduced beating rates, compromised contraction, and significantly more cells with abnormal sarcomeric α-actinin distribution. β-adrenergic blocker treatment and over-expression of sarcoplasmic reticulum Ca2+ ATPase (Serca2a) improved DCM iPSC-CMs function. Our study demonstrated that human DCM iPSC-CMs recapitulated to some extent the disease phenotypes morphologically and functionally, and thus can serve as a useful platform for exploring molecular and cellular mechanisms and optimizing treatment of this particular disease. PMID:22517884

Mechanical signaling coordinates the embryonic heartbeat

PubMed Central

Chiou, Kevin K.; Rocks, Jason W.; Chen, Christina Yingxian; Cho, Sangkyun; Merkus, Koen E.; Rajaratnam, Anjali; Robison, Patrick; Tewari, Manorama; Vogel, Kenneth; Majkut, Stephanie F.; Prosser, Benjamin L.; Discher, Dennis E.; Liu, Andrea J.

2016-01-01

In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, β-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts—consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats. PMID:27457951

Risk factors for covered metallic stent migration in patients with distal malignant biliary obstruction due to pancreatic cancer.

PubMed

Nakai, Yousuke; Isayama, Hiroyuki; Kogure, Hirofumi; Hamada, Tsuyoshi; Togawa, Osamu; Ito, Yukiko; Matsubara, Saburo; Arizumi, Toshihiko; Yagioka, Hiroshi; Mizuno, Suguru; Sasaki, Takashi; Yamamoto, Natsuyo; Hirano, Kenji; Tada, Minoru; Koike, Kazuhiko

2014-09-01

Covered metallic stents (CMSs) were developed to overcome tumor ingrowth in uncovered metallic stents (UMSs) for malignant biliary obstruction, but superiority of CMSs over UMSs is still controversial due to the high migration rate in CMS. Therefore, we conducted this retrospective analysis to clarify risk factors for stent migration, including mechanical properties of CMSs. Patients with unresectable pancreatic cancer, receiving CMS for distal malignant biliary obstruction in five tertiary care centers, were retrospectively studied. Univariate and multivariate analyses to identify prognostic factors for early (< 6 months) stent migration were performed using a proportional hazards model with death or stent occlusion without stent migration as a competing risk. Two mechanical properties were included in the analysis: axial force, the recovery force that leads to a CMS straightening, and radial force (RF), the expansion force against the stricture. Among 290 patients who received CMS placement for distal malignant biliary obstruction, stent migration rate was 15.2%. CMS migrated early (< 6 months) in 10.0% and distally in 11.7%, respectively. In the multivariate analysis, significant risk factors for early stent migration were chemotherapy (subdistribution hazard ratios [SHR] 4.46, P = 0.01), CMS with low RF (SHR 2.23, P = 0.03), and duodenal invasion (SHR 2.25, P = 0.02). CMS with low RF, chemotherapy, and duodenal invasion were associated with CMS migration from our study. © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

RooStatsCms: A tool for analysis modelling, combination and statistical studies

NASA Astrophysics Data System (ADS)

Piparo, D.; Schott, G.; Quast, G.

2010-04-01

RooStatsCms is an object oriented statistical framework based on the RooFit technology. Its scope is to allow the modelling, statistical analysis and combination of multiple search channels for new phenomena in High Energy Physics. It provides a variety of methods described in literature implemented as classes, whose design is oriented to the execution of multiple CPU intensive jobs on batch systems or on the Grid.

Bundled Payments in Total Joint Replacement: Keeping Our Care Affordable and High in Quality.

PubMed

McLawhorn, Alexander S; Buller, Leonard T

2017-09-01

The purpose of this review was to evaluate the literature regarding bundle payment reimbursement models for total joint arthroplasty (TJA). From an economic standpoint, TJA are cost-effective, but they represent a substantial expense to the Centers for Medicare & Medicaid Services (CMS). Historically, fee-for-service payment models resulted in highly variable cost and quality. CMS introduced Bundled Payments for Care Improvement (BPCI) in 2012 and subsequently the Comprehensive Care for Joint Replacement (CJR) reimbursement model in 2016 to improve the value of TJA from the perspectives of both CMS and patients, by improving quality via cost control. Early results of bundled payments are promising, but preserving access to care for patients with high comorbidity burdens and those requiring more complex care is a lingering concern. Hospitals, regardless of current participation in bundled payments, should develop care pathways for TJA to maximize efficiency and patient safety.

Transcriptome dynamics of human pluripotent stem cell-derived contracting cardiomyocytes using an embryoid body model with fetal bovine serum.

PubMed

Jung, Kwang Bo; Son, Ye Seul; Lee, Hana; Jung, Cho-Rok; Kim, Janghwan; Son, Mi-Young

2017-07-25

Cardiomyocyte (CM) differentiation techniques for generating adult-like mature CMs remain imperfect, and the plausible underlying mechanisms remain unclear; however, there are a number of current protocols available. Here, to explore the mechanisms controlling cardiac differentiation, we analyzed the genome-wide transcription dynamics occurring during the differentiation of human pluripotent stem cells (hPSCs) into CMs using embryoid body (EB) formation. We optimized and updated the protocol to efficiently generate contracting CMs from hPSCs by adding fetal bovine serum (FBS) as a medium supplement, which could have a significant impact on the efficiency of cardiac differentiation. To identify genes, biological processes, and pathways involved in the cardiac differentiation of hPSCs, integrative and comparative analyses of the transcriptome profiles of differentiated CMs from hPSCs and of control CMs of the adult human heart (CM-AHH) were performed using gene ontology, functional annotation clustering, and pathway analyses. Several genes commonly regulated in the differentiated CMs and CM-AHH were enriched in pathways related to cell cycle and nucleotide metabolism. Strikingly, we found that current differentiation protocols did not promote sufficient expression of genes involved in oxidative phosphorylation to differentiate CMs from hPSCs compared to the expression levels in CM-AHH. Therefore, to obtain mature CMs similar to CM-AHH, these deficient pathways in CM differentiation, such as energy-related pathways, must be augmented prior to use for in vitro and in vivo applications. This approach opens up new avenues for facilitating the utilization of hPSC-derived CMs in biomedical research, drug evaluation, and clinical applications for patients with cardiac failure.

Medicare capitation model, functional status, and multiple comorbidities: model accuracy

PubMed Central

Noyes, Katia; Liu, Hangsheng; Temkin-Greener, Helena

2012-01-01

Objective This study examined financial implications of CMS-Hierarchical Condition Categories (HCC) risk-adjustment model on Medicare payments for individuals with comorbid chronic conditions. Study Design The study used 1992-2000 data from the Medicare Current Beneficiary Survey and corresponding Medicare claims. The pairs of comorbidities were formed based on the prior evidence about possible synergy between these conditions and activities of daily living (ADL) deficiencies and included heart disease and cancer, lung disease and cancer, stroke and hypertension, stroke and arthritis, congestive heart failure (CHF) and osteoporosis, diabetes and coronary artery disease, CHF and dementia. Methods For each beneficiary, we calculated the actual Medicare cost ratio as the ratio of the individual’s annualized costs to the mean annual Medicare cost of all people in the study. The actual Medicare cost ratios, by ADLs, were compared to the HCC ratios under the CMS-HCC payment model. Using multivariate regression models, we tested whether having the identified pairs of comorbidities affects the accuracy of CMS-HCC model predictions. Results The CMS-HCC model underpredicted Medicare capitation payments for patients with hypertension, lung disease, congestive heart failure and dementia. The difference between the actual costs and predicted payments was partially explained by beneficiary functional status and less than optimal adjustment for these chronic conditions. Conclusions Information about beneficiary functional status should be incorporated in reimbursement models since underpaying providers for caring for population with multiple comorbidities may provide severe disincentives for managed care plans to enroll such individuals and to appropriately manage their complex and costly conditions. PMID:18837646

Generation of functional cardiomyocytes from rat embryonic and induced pluripotent stem cells using feeder-free expansion and differentiation in suspension culture.

PubMed

Dahlmann, Julia; Awad, George; Dolny, Carsten; Weinert, Sönke; Richter, Karin; Fischer, Klaus-Dieter; Munsch, Thomas; Leßmann, Volkmar; Volleth, Marianne; Zenker, Martin; Chen, Yaoyao; Merkl, Claudia; Schnieke, Angelika; Baraki, Hassina; Kutschka, Ingo; Kensah, George

2018-01-01

The possibility to generate cardiomyocytes from pluripotent stem cells in vitro has enormous significance for basic research, disease modeling, drug development and heart repair. The concept of heart muscle reconstruction has been studied and optimized in the rat model using rat primary cardiovascular cells or xenogeneic pluripotent stem cell derived-cardiomyocytes for years. However, the lack of rat pluripotent stem cells (rPSCs) and their cardiovascular derivatives prevented the establishment of an authentic clinically relevant syngeneic or allogeneic rat heart regeneration model. In this study, we comparatively explored the potential of recently available rat embryonic stem cells (rESCs) and induced pluripotent stem cells (riPSCs) as a source for cardiomyocytes (CMs). We developed feeder cell-free culture conditions facilitating the expansion of undifferentiated rPSCs and initiated cardiac differentiation by embryoid body (EB)-formation in agarose microwell arrays, which substituted the robust but labor-intensive hanging drop (HD) method. Ascorbic acid was identified as an efficient enhancer of cardiac differentiation in both rPSC types by significantly increasing the number of beating EBs (3.6 ± 1.6-fold for rESCs and 17.6 ± 3.2-fold for riPSCs). These optimizations resulted in a differentiation efficiency of up to 20% cTnTpos rPSC-derived CMs. CMs showed spontaneous contractions, expressed cardiac markers and had typical morphological features. Electrophysiology of riPSC-CMs revealed different cardiac subtypes and physiological responses to cardio-active drugs. In conclusion, we describe rPSCs as a robust source of CMs, which is a prerequisite for detailed preclinical studies of myocardial reconstruction in a physiologically and immunologically relevant small animal model.

Oxytocin and cardioprotection in diabetes and obesity.

PubMed

Jankowski, Marek; Broderick, Tom L; Gutkowska, Jolanta

2016-06-07

Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs.

Tailoring Mathematical Models to Stem-Cell Derived Cardiomyocyte Lines Can Improve Predictions of Drug-Induced Changes to Their Electrophysiology.

PubMed

Lei, Chon Lok; Wang, Ken; Clerx, Michael; Johnstone, Ross H; Hortigon-Vinagre, Maria P; Zamora, Victor; Allan, Andrew; Smith, Godfrey L; Gavaghan, David J; Mirams, Gary R; Polonchuk, Liudmila

2017-01-01

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, provide mechanistic insights, and translate these findings to adult cardiomyocyte (CM) electrophysiology. However, different cell lines display different expression of ion channels, pumps and receptors, and show differences in electrophysiology. In this exploratory study, we use a mathematical model based on iPSC-CMs from Cellular Dynamic International (CDI, iCell), and compare its predictions to novel experimental recordings made with the Axiogenesis Cor.4U line. We show that tailoring this model to the specific cell line, even using limited data and a relatively simple approach, leads to improved predictions of baseline behavior and response to drugs. This demonstrates the need and the feasibility to tailor models to individual cell lines, although a more refined approach will be needed to characterize individual currents, address differences in ion current kinetics, and further improve these results.

The Development of Chorus Motivation Scale (CMS) for Prospective Music Teacher

ERIC Educational Resources Information Center

Ozgul, Ilhan; Yigit, Nalan

2017-01-01

The purpose of this study was to develop a Chorus Motivation Scale (CMS) that is tested in terms of reliability and construct validity by determining the student perceptions of effective motivation strategies in Chorus training in Turkish Music Teacher Training Model. In order to develop a Chorus Motivation Scale, Questionnaire-Effective…

Downscaling Global Emissions and Its Implications Derived from Climate Model Experiments

PubMed Central

Abe, Manabu; Kinoshita, Tsuguki; Hasegawa, Tomoko; Kawase, Hiroaki; Kushida, Kazuhide; Masui, Toshihiko; Oka, Kazutaka; Shiogama, Hideo; Takahashi, Kiyoshi; Tatebe, Hiroaki; Yoshikawa, Minoru

2017-01-01

In climate change research, future scenarios of greenhouse gas and air pollutant emissions generated by integrated assessment models (IAMs) are used in climate models (CMs) and earth system models to analyze future interactions and feedback between human activities and climate. However, the spatial resolutions of IAMs and CMs differ. IAMs usually disaggregate the world into 10–30 aggregated regions, whereas CMs require a grid-based spatial resolution. Therefore, downscaling emissions data from IAMs into a finer scale is necessary to input the emissions into CMs. In this study, we examined whether differences in downscaling methods significantly affect climate variables such as temperature and precipitation. We tested two downscaling methods using the same regionally aggregated sulfur emissions scenario obtained from the Asian-Pacific Integrated Model/Computable General Equilibrium (AIM/CGE) model. The downscaled emissions were fed into the Model for Interdisciplinary Research on Climate (MIROC). One of the methods assumed a strong convergence of national emissions intensity (e.g., emissions per gross domestic product), while the other was based on inertia (i.e., the base-year remained unchanged). The emissions intensities in the downscaled spatial emissions generated from the two methods markedly differed, whereas the emissions densities (emissions per area) were similar. We investigated whether the climate change projections of temperature and precipitation would significantly differ between the two methods by applying a field significance test, and found little evidence of a significant difference between the two methods. Moreover, there was no clear evidence of a difference between the climate simulations based on these two downscaling methods. PMID:28076446

Pleiotropy of cardiometabolic syndrome with obesity-related anthropometric traits determined using empirically derived kinships from the Busselton Health Study.

PubMed

Cadby, Gemma; Melton, Phillip E; McCarthy, Nina S; Almeida, Marcio; Williams-Blangero, Sarah; Curran, Joanne E; VandeBerg, John L; Hui, Jennie; Beilby, John; Musk, A W; James, Alan L; Hung, Joseph; Blangero, John; Moses, Eric K

2018-01-01

Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h 2 ) and genetic correlations (r g ) between 15 anthropometric and 9 CMS traits. Anthropometric traits were adjusted by body mass index (BMI) to determine whether the observed genetic correlation was independent of obesity. After adjustment for multiple testing, all CMS and anthropometric traits were significantly heritable (h 2 range 0.18-0.57). We identified 50 significant genetic correlations (r g range: - 0.37 to 0.75) between CMS and anthropometric traits. Five genetic correlations remained significant after adjustment for BMI [high density lipoprotein cholesterol (HDL-C) and waist-hip ratio; triglycerides and waist-hip ratio; triglycerides and waist-height ratio; non-HDL-C and waist-height ratio; insulin and iliac skinfold thickness]. This study provides evidence for the presence of potentially pleiotropic genes that affect both anthropometric and CMS traits, independently of obesity.

Patch-Clamp Recording from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Improving Action Potential Characteristics through Dynamic Clamp

PubMed Central

Veerman, Christiaan C.; Zegers, Jan G.; Mengarelli, Isabella; Bezzina, Connie R.

2017-01-01

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for studying inherited cardiac arrhythmias and developing drug therapies to treat such arrhythmias. Unfortunately, until now, action potential (AP) measurements in hiPSC-CMs have been hampered by the virtual absence of the inward rectifier potassium current (IK1) in hiPSC-CMs, resulting in spontaneous activity and altered function of various depolarising and repolarising membrane currents. We assessed whether AP measurements in “ventricular-like” and “atrial-like” hiPSC-CMs could be improved through a simple, highly reproducible dynamic clamp approach to provide these cells with a substantial IK1 (computed in real time according to the actual membrane potential and injected through the patch-clamp pipette). APs were measured at 1 Hz using perforated patch-clamp methodology, both in control cells and in cells treated with all-trans retinoic acid (RA) during the differentiation process to increase the number of cells with atrial-like APs. RA-treated hiPSC-CMs displayed shorter APs than control hiPSC-CMs and this phenotype became more prominent upon addition of synthetic IK1 through dynamic clamp. Furthermore, the variability of several AP parameters decreased upon IK1 injection. Computer simulations with models of ventricular-like and atrial-like hiPSC-CMs demonstrated the importance of selecting an appropriate synthetic IK1. In conclusion, the dynamic clamp-based approach of IK1 injection has broad applicability for detailed AP measurements in hiPSC-CMs. PMID:28867785

Combinatorial Polymer Matrices Enhance In Vitro Maturation of Human Induced Pluripotent Cell Cell-Derived Cardiomyocytes

PubMed Central

Chun, Young Wook; Balikov, Daniel A.; Feaster, Tromondae K.; Williams, Charles H.; Sheng, Calvin C.; Lee, Jung-Bok; Boire, Timothy C.; Neely, M. Diana; Bellan, Leon M.; Ess, Kevin C.; Bowman, Aaron B.; Sung, Hak-Joon; Hong, Charles C.

2015-01-01

Cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs) hold great promise for modeling human heart diseases. However, iPSC-CMs studied to date resemble immature embryonic myocytes and therefore do not adequately recapitulate native adult cardiomyocyte phenotypes. Since extracellular matrix plays an essential role in heart development and maturation in vivo, we sought to develop a synthetic culture matrix that could enhance functional maturation of iPSC-CMs in vitro. In this study, we employed a library of combinatorial polymers comprising of three functional subunits - poly-ε-caprolacton (PCL), polyethylene glycol (PEG), and carboxylated PCL (cPCL) - as synthetic substrates for culturing human iPSC-CMs. Of these, iPSC-CMs cultured on 4%PEG-96%PCL (each % indicates the corresponding molar ratio) exhibit the greatest contractility and mitochondrial function. These functional enhancements are associated with increased expression of cardiac myosin light chain-2v, cardiac troponin I and integrin alpha-7. Importantly, iPSC-CMs cultured on 4%PEG-95%PCL demonstrate troponin I (TnI) isoform switch from the fetal slow skeletal TnI (ssTnI) to the postnatal cardiac TnI (cTnI), the first report of such transition in vitro. Finally, culturing iPSC-CMs on 4%PEG-96%PCL also significantly increased expression of genes encoding intermediate filaments known to transduce integrin-mediated mechanical signals to the myofilaments. In summary, our study demonstrates that synthetic culture matrices engineered from combinatorial polymers can be utilized to promote in vitro maturation of human iPSC-CMs through the engagement of critical matrix-integrin interactions. PMID:26204225

A Standardized Chinese Herbal Decoction, Kai-Xin-San, Restores Decreased Levels of Neurotransmitters and Neurotrophic Factors in the Brain of Chronic Stress-Induced Depressive Rats

PubMed Central

Zhu, Kevin Yue; Mao, Qing-Qiu; Ip, Siu-Po; Choi, Roy Chi-Yan; Dong, Tina Ting-Xia; Lau, David Tai-Wai; Tsim, Karl Wah-Keung

2012-01-01

Kai-xin-san (KXS), a Chinese herbal decoction being prescribed by Sun Simiao in Beiji Qianjin Yaofang about 1400 years ago, contains Ginseng Radix et Rhizoma, Polygalae Radix, Acori tatarinowii Rhizoma, and Poria. KXS has been used to treat stress-related psychiatric disease with the symptoms of depression and forgetfulness in ancient China until today. However, the mechanism of its antidepression action is still unknown. Here, the chronic mild-stress-(CMS-) induced depressive rats were applied in exploring the action mechanisms of KXS treatment. Daily intragastric administration of KXS for four weeks significantly alleviated the CMS-induced depressive symptoms displayed by enhanced sucrose consumption. In addition, the expressions of those molecular bio-markers relating to depression in rat brains were altered by the treatment of KXS. These KXS-regulated brain biomarkers included: (i) the levels of dopamine, norepinephrine, and serotonin (ii) the transcript levels of proteins relating to neurotransmitter metabolism; (iii) the transcript levels of neurotrophic factors and their receptors. The results suggested that the anti-depressant-like action of KXS might be mediated by an increase of neurotransmitters and expression of neurotrophic factors and its corresponding receptors in the brain. Thus, KXS could serve as alternative medicine, or health food supplement, for patients suffering from depression. PMID:22973399

Searches for Kaluza-Klein graviton excitations and microscopic black holes with the aid of the CMS detector at the LHC

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

Savina, M. V., E-mail: savina@cern.ch

2015-06-15

A survey of the results of the Compact Muon Solenoid (CMS) experiment that concern searches for massive Kaluza-Klein graviton excitations and microscopic black holes, quantum black holes, and string balls within models of low-energy multidimensional gravity is presented on behalf of the CMS Collaboration. The analysis in question is performed on the basis of a complete sample of data accumulated for proton-proton collisions at the c.m. energies of 7 and 8 TeV at the Large Hadron Collider (LHC) over the period spanning 2010 and 2012.

Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria.

PubMed

Plachouras, D; Karvanen, M; Friberg, L E; Papadomichelakis, E; Antoniadou, A; Tsangaris, I; Karaiskos, I; Poulakou, G; Kontopidou, F; Armaganidis, A; Cars, O; Giamarellou, H

2009-08-01

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Tissue and Animal Models of Sudden Cardiac Death

PubMed Central

Sallam, Karim; Li, Yingxin; Sager, Philip T.; Houser, Steven R.; Wu, Joseph C.

2015-01-01

Sudden Cardiac Death (SCD) is a common cause of death in patients with structural heart disease, genetic mutations or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with SCD. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell derived Cardiomyocytes (iPSC-CMs) resemble, but are not identical, to adult human cardiomyocytes, and provide a new platform for studying arrhythmic disorders leading to SCD. A variety of platforms exist to phenotype cellular models including conventional and automated patch clamp, multi-electrode array, and computational modeling. iPSC-CMs have been used to study Long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy and other hereditary cardiac disorders. Although iPSC-CMs are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of SCD. PMID:26044252

Investigating Gender and Racial/Ethnic Invariance in Use of a Course Management System in Higher Education

ERIC Educational Resources Information Center

Li, Yi; Wang, Qiu; Campbell, John

2015-01-01

This study focused on learning equity in colleges and universities where teaching and learning depends heavily on computer technologies. The study used the Structural Equation Modeling (SEM) to investigate gender and racial/ethnic heterogeneity in the use of a computer based course management system (CMS). Two latent variables (CMS usage and…

Theory of compressive modeling and simulation

NASA Astrophysics Data System (ADS)

Szu, Harold; Cha, Jae; Espinola, Richard L.; Krapels, Keith

2013-05-01

Modeling and Simulation (M&S) has been evolving along two general directions: (i) data-rich approach suffering the curse of dimensionality and (ii) equation-rich approach suffering computing power and turnaround time. We suggest a third approach. We call it (iii) compressive M&S (CM&S); because the basic Minimum Free-Helmholtz Energy (MFE) facilitating CM&S can reproduce and generalize Candes, Romberg, Tao & Donoho (CRT&D) Compressive Sensing (CS) paradigm as a linear Lagrange Constraint Neural network (LCNN) algorithm. CM&S based MFE can generalize LCNN to 2nd order as Nonlinear augmented LCNN. For example, during the sunset, we can avoid a reddish bias of sunlight illumination due to a long-range Rayleigh scattering over the horizon. With CM&S we can take instead of day camera, a night vision camera. We decomposed long wave infrared (LWIR) band with filter into 2 vector components (8~10μm and 10~12μm) and used LCNN to find pixel by pixel the map of Emissive-Equivalent Planck Radiation Sources (EPRS). Then, we up-shifted consistently, according to de-mixed sources map, to the sub-micron RGB color image. Moreover, the night vision imaging can also be down-shifted at Passive Millimeter Wave (PMMW) imaging, suffering less blur owing to dusty smokes scattering and enjoying apparent smoothness of surface reflectivity of man-made objects under the Rayleigh resolution. One loses three orders of magnitudes in the spatial Rayleigh resolution; but gains two orders of magnitude in the reflectivity, and gains another two orders in the propagation without obscuring smog . Since CM&S can generate missing data and hard to get dynamic transients, CM&S can reduce unnecessary measurements and their associated cost and computing in the sense of super-saving CS: measuring one & getting one's neighborhood free .

Differences in Contractile Function of Myofibrils within Human Embryonic Stem Cell-Derived Cardiomyocytes vs. Adult Ventricular Myofibrils Are Related to Distinct Sarcomeric Protein Isoforms

PubMed Central

Iorga, Bogdan; Schwanke, Kristin; Weber, Natalie; Wendland, Meike; Greten, Stephan; Piep, Birgit; dos Remedios, Cristobal G.; Martin, Ulrich; Zweigerdt, Robert; Kraft, Theresia; Brenner, Bernhard

2018-01-01

Characterizing the contractile function of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is key for advancing their utility for cellular disease models, promoting cell based heart repair, or developing novel pharmacological interventions targeting cardiac diseases. The aim of the present study was to understand whether steady-state and kinetic force parameters of β-myosin heavy chain (βMyHC) isoform-expressing myofibrils within human embryonic stem cell-derived cardiomyocytes (hESC-CMs) differentiated in vitro resemble those of human ventricular myofibrils (hvMFs) isolated from adult donor hearts. Contractile parameters were determined using the same micromechanical method and experimental conditions for both types of myofibrils. We identified isoforms and phosphorylation of main sarcomeric proteins involved in the modulation of force generation of both, chemically demembranated hESC-CMs (d-hESC-CMs) and hvMFs. Our results indicate that at saturating Ca2+ concentration, both human-derived contractile systems developed forces with similar rate constants (0.66 and 0.68 s−1), reaching maximum isometric force that was significantly smaller for d-hESC-CMs (42 kPa) than for hvMFs (94 kPa). At submaximal Ca2+-activation, where intact cardiomyocytes normally operate, contractile parameters of d-hESC-CMs and hvMFs exhibited differences. Ca2+ sensitivity of force was higher for d-hESC-CMs (pCa50 = 6.04) than for hvMFs (pCa50 = 5.80). At half-maximum activation, the rate constant for force redevelopment was significantly faster for d-hESC-CMs (0.51 s−1) than for hvMFs (0.28 s−1). During myofibril relaxation, kinetics of the slow force decay phase were significantly faster for d-hESC-CMs (0.26 s−1) than for hvMFs (0.21 s−1), while kinetics of the fast force decay were similar and ~20x faster. Protein analysis revealed that hESC-CMs had essentially no cardiac troponin-I, and partially non-ventricular isoforms of some other sarcomeric proteins, explaining the functional discrepancies. The sarcomeric protein isoform pattern of hESC-CMs had features of human cardiomyocytes at an early developmental stage. The study indicates that morphological and ultrastructural maturation of βMyHC isoform-expressing hESC-CMs is not necessarily accompanied by ventricular-like expression of all sarcomeric proteins. Our data suggest that hPSC-CMs could provide useful tools for investigating inherited cardiac diseases affecting contractile function during early developmental stages. PMID:29403388

Morphological and genetic characterization of a new cytoplasmic male sterility system (oxa CMS) in stem mustard (Brassica juncea).

PubMed

Heng, Shuangping; Liu, Sansan; Xia, Chunxiu; Tang, HongYu; Xie, Fei; Fu, Tingdong; Wan, Zhengjie

2018-01-01

KEY MESSAGE: oxa CMS is a new cytoplasmic male sterility type in Brassica juncea. oxa CMS is a cytoplasmic male sterility (CMS) line that has been widely used in the production and cultivation of stem mustard in the southwestern China. In this study, different CMS-type specific mitochondrial markers were used to confirm that oxa CMS is distinct from the pol CMS, ogu CMS, nap CMS, hau CMS, tour CMS, Moricandia arvensis CMS, orf220-type CMS, etc., that have been previously reported in Brassica crops. Pollen grains of the oxa CMS line are sterile with a self-fertility rate of almost 0% and the sterility strain rate and sterility degree of oxa CMS is 100% due to a specific flower structure and flowering habit. Scanning electron microscopy revealed that most pollen grains in mature anthers of the oxa CMS line are empty, flat and deflated. Semi-thin section further showed that the abortive stage of anther development in oxa CMS is initiated at the late uninucleate stage. Abnormally vacuolated microspores caused male sterility in the oxa CMS line. This cytological study combined with marker-assisted selection showed that oxa CMS is a novel CMS type in stem mustard (Brassica juncea). Interestingly, the abortive stage of oxa CMS is later than those in other CMS types reported in Brassica crops, and there is no negative effect on the oxa CMS line growth period. This study demonstrated that this novel oxa CMS has a unique flower structure with sterile pollen grains at the late uninucleate stage. Our results may help to uncover the mechanism of oxa CMS in Brassica juncea.

tkLayout: a design tool for innovative silicon tracking detectors

NASA Astrophysics Data System (ADS)

Bianchi, G.

2014-03-01

A new CMS tracker is scheduled to become operational for the LHC Phase 2 upgrade in the early 2020's. tkLayout is a software package developed to create 3d models for the design of the CMS tracker and to evaluate its fundamental performance figures. The new tracker will have to cope with much higher luminosity conditions, resulting in increased track density, harsher radiation exposure and, especially, much higher data acquisition bandwidth, such that equipping the tracker with triggering capabilities is envisaged. The design of an innovative detector involves deciding on an architecture offering the best trade-off among many figures of merit, such as tracking resolution, power dissipation, bandwidth, cost and so on. Quantitatively evaluating these figures of merit as early as possible in the design phase is of capital importance and it is best done with the aid of software models. tkLayout is a flexible modeling tool: new performance estimates and support for different detector geometries can be quickly added, thanks to its modular structure. Besides, the software executes very quickly (about two minutes), so that many possible architectural variations can be rapidly modeled and compared, to help in the choice of a viable detector layout and then to optimize it. A tracker geometry is generated from simple configuration files, defining the module types, layout and materials. Support structures are automatically added and services routed to provide a realistic tracker description. The tracker geometries thus generated can be exported to the standard CMS simulation framework (CMSSW) for full Monte Carlo studies. tkLayout has proven essential in giving guidance to CMS in studying different detector layouts and exploring the feasibility of innovative solutions for tracking detectors, in terms of design, performance and projected costs. This tool has been one of the keys to making important design decisions for over five years now and has also enabled project engineers and simulation experts to focus their efforts on other important or specific issues. Even if tkLayout was designed for the CMS tracker upgrade project, its flexibility makes it experiment-agnostic, so that it could be easily adapted to model other tracking detectors. The technology behind tkLayout is presented, as well as some of the results obtained in the context of the CMS silicon tracker design studies.

Dendritic Core-Multishell Nanocarriers in Murine Models of Healthy and Atopic Skin.

PubMed

Radbruch, Moritz; Pischon, Hannah; Ostrowski, Anja; Volz, Pierre; Brodwolf, Robert; Neumann, Falko; Unbehauen, Michael; Kleuser, Burkhard; Haag, Rainer; Ma, Nan; Alexiev, Ulrike; Mundhenk, Lars; Gruber, Achim D

2017-12-01

Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e.g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment.Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection.Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis.Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.

Beam-dynamic effects at the CMS BRIL van der Meer scans

NASA Astrophysics Data System (ADS)

Babaev, A.

2018-03-01

The CMS Beam Radiation Instrumentation and Luminosity Project (BRIL) is responsible for the simulation and measurement of luminosity, beam conditions and radiation fields in the CMS experiment. The project is engaged in operating and developing new detectors (luminometers), adequate for the experimental conditions associated with high values of instantaneous luminosity delivered by the CERN LHC . BRIL operates several detectors based on different physical principles and technologies. Precise and accurate measurements of the delivered luminosity is of paramount importance for the CMS physics program. The absolute calibration of luminosity is achieved by the van der Meer method, which is carried out under specially tailored conditions. This paper presents models used to simulate of beam-dynamic effects arising due to the electromagnetic interaction of colliding bunches. These effects include beam-beam deflection and dynamic-β effect. Both effects are important to luminosity measurements and influence calibration constants at the level of 1-2%. The simulations are carried out based on 2016 CMS van der Meer scan data for proton-proton collisions at a center-of-mass energy of 13 TeV.

Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing.

PubMed

Hönzke, Stefan; Gerecke, Christian; Elpelt, Anja; Zhang, Nan; Unbehauen, Michael; Kral, Vivian; Fleige, Emanuel; Paulus, Florian; Haag, Rainer; Schäfer-Korting, Monika; Kleuser, Burkhard; Hedtrich, Sarah

2016-11-28

Drug loaded dendritic core-multishell (CMS) nanocarriers are of especial interest for the treatment of skin diseases, owing to their striking dermal delivery efficiencies following topical applications. CMS nanocarriers are composed of a polyglycerol core, connected by amide-bonds to an inner alkyl shell and an outer methoxy poly(ethylene glycol) shell. Since topically applied nanocarriers are subjected to biodegradation, the application of conventional amide-based CMS nanocarriers (10-A-18-350) has been limited by the potential production of toxic polyglycerol amines. To circumvent this issue, three tailored ester-based CMS nanocarriers (10-E-12-350, 10-E-15-350, 10-E-18-350) of varying inner alkyl chain length were synthesized and comprehensively characterized in terms of particle size, drug loading, biodegradation and dermal drug delivery efficiency. Dexamethasone (DXM), a potent drug widely used for the treatment of inflammatory skin diseases, was chosen as a therapeutically relevant test compound for the present study. Ester- and amide-based CMS nanocarriers delivered DXM more efficiently into human skin than a commercially available DXM cream. Subsequent in vitro and in vivo toxicity studies identified CMS (10-E-15-350) as the most biocompatible carrier system. The anti-inflammatory potency of DXM-loaded CMS (10-E-15-350) nanocarriers was assessed in TNFα supplemented skin models, where a significant reduction of the pro-inflammatory cytokine IL-8 was seen, with markedly greater efficacy than commercial DXM cream. In summary, we report the rational design and characterization of tailored, biodegradable, ester-based CMS nanocarriers, and their subsequent stepwise screening for biocompatibility, dermal delivery efficiency and therapeutic efficacy in a top-down approach yielding the best carrier system for topical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid Electrical Stimulation Increased Cardiac Apoptosis Through Disturbance of Calcium Homeostasis and Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

PubMed

Geng, Le; Wang, Zidun; Cui, Chang; Zhu, Yue; Shi, Jiaojiao; Wang, Jiaxian; Chen, Minglong

2018-06-15

Heart failure induced by tachycardia, the most common arrhythmia, is frequently observed in clinical practice. This study was designed to investigate the underlying mechanisms. Rapid electrical stimulation (RES) at a frequency of 3 Hz was applied on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for 7 days, with 8 h/day and 24 h/day set to represent short-term and long-term tachycardia, respectively. Age-matched hiPSC-CMs without electrical stimulation or with slow electrical stimulation (1 Hz) were set as no electrical stimulation (NES) control or low-frequency electrical stimulation (LES) control. Following stimulation, JC-1 staining flow cytometry analysis was performed to examine mitochondrial conditions. Apoptosis in hiPSC-CMs was evaluated using Hoechst staining and Annexin V/propidium iodide (AV/PI) staining flow cytometry analysis. Calcium transients and L-type calcium currents were recorded to evaluate calcium homeostasis. Western blotting and qPCR were performed to evaluate the protein and mRNA expression levels of apoptosis-related genes and calcium homeostasis-regulated genes. Compared to the controls, hiPSC-CMs following RES presented mitochondrial dysfunction and an increased apoptotic percentage. Amplitudes of calcium transients and L-type calcium currents were significantly decreased in hiPSC-CMs with RES. Molecular analysis demonstrated upregulated expression of Caspase3 and increased Bax/Bcl-2 ratio. Genes related to calcium re-sequence were downregulated, while phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII) was significantly upregulated following RES. There was no significant difference between the NES control and LES control groups in these aspects. Inhibition of CaMKII with 1 µM KN93 partly reversed these adverse effects of RES. RES on hiPSC-CMs disturbed calcium homeostasis, which led to mitochondrial stress, promoted cell apoptosis and caused electrophysiological remodeling in a time-dependent manner. CaMKII played a central role in the damages induced by RES, pharmacological inhibition of CaMKII activity partly reversed the adverse effects of RES on both structural and electrophysiological properties of cells. © 2018 The Author(s). Published by S. Karger AG, Basel.

Proteomic analysis reveals strong mitochondrial involvement in cytoplasmic male sterility of pepper (Capsicum annuum L.).

PubMed

Guo, Jinju; Wang, Peng; Cheng, Qing; Sun, Limin; Wang, Hongyu; Wang, Yutong; Kao, Lina; Li, Yanan; Qiu, Tuoyu; Yang, Wencai; Shen, Huolin

2017-09-25

Although cytoplasmic male sterility (CMS) is widely used for developing pepper hybrids, its molecular mechanism remains unclear. In this study, we used a high-throughput proteomics method called label-free to compare protein abundance across a pepper CMS line (A-line) and its isogenic maintainer line (B-line). Data are available via ProteomeXchange with identifier PXD006104. Approximately 324 differentially abundant protein species were identified and quantified; among which, 47 were up-accumulated and 140 were down-accumulated in the A-line; additionally, 75 and 62 protein species were specifically accumulated in the A-line and B-line, respectively. Protein species involved in pollen exine formation, pyruvate metabolic processes, the tricarboxylic acid cycle, the mitochondrial electron transport chain, and oxidative stress response were observed to be differentially accumulated between A-line and B-line, suggesting their potential roles in the regulation of pepper pollen abortion. Based on our data, we proposed a potential regulatory network for pepper CMS that unifies these processes. Artificial emasculation is a major obstacle in pepper hybrid breeding for its high labor cost and poor seed purity. While the use of cytoplasmic male sterility (CMS) in hybrid system is seriously frustrated because a long time is needed to cultivate male sterility line and its isogenic restore line. Transgenic technology is an effective and rapid method to obtain male sterility lines and its widely application has very important significance in speeding up breeding process in pepper. Although numerous studies have been conducted to select the genes related to male sterility, the molecular mechanism of cytoplasmic male sterility in pepper remains unknown. In this study, we used the high-throughput proteomic method called "label-free", coupled with liquid chromatography-quadrupole mass spectrometry (LC-MS/MS), to perform a novel comparison of expression profiles in a CMS pepper line and its maintainer line. Based on our results, we proposed a potential regulated protein network involved in pollen development as a novel mechanism of pepper CMS. Copyright © 2017. Published by Elsevier B.V.

Intelligent systems and advanced user interfaces for design, operation, and maintenance of command management systems

NASA Technical Reports Server (NTRS)

Potter, William J.; Mitchell, Christine M.

1993-01-01

Historically, command management systems (CMS) have been large and expensive spacecraft-specific software systems that were costly to build, operate, and maintain. Current and emerging hardware, software, and user interface technologies may offer an opportunity to facilitate the initial formulation and design of a spacecraft-specific CMS as well as to develop a more generic CMS system. New technologies, in addition to a core CMS common to a range of spacecraft, may facilitate the training and enhance the efficiency of CMS operations. Current mission operations center (MOC) hardware and software include Unix workstations, the C/C++ programming languages, and an X window interface. This configuration provides the power and flexibility to support sophisticated and intelligent user interfaces that exploit state-of-the-art technologies in human-machine interaction, artificial intelligence, and software engineering. One of the goals of this research is to explore the extent to which technologies developed in the research laboratory can be productively applied in a complex system such as spacecraft command management. Initial examination of some of these issues in CMS design and operation suggests that application of technologies such as intelligent planning, case-based reasoning, human-machine systems design and analysis tools (e.g., operator and designer models), and human-computer interaction tools (e.g., graphics, visualization, and animation) may provide significant savings in the design, operation, and maintenance of the CMS for a specific spacecraft as well as continuity for CMS design and development across spacecraft. The first six months of this research saw a broad investigation by Georgia Tech researchers into the function, design, and operation of current and planned command management systems at Goddard Space Flight Center. As the first step, the researchers attempted to understand the current and anticipated horizons of command management systems at Goddard. Preliminary results are given on CMS commonalities and causes of low re-use, and methods are proposed to facilitate increased re-use.

Impact of calcium-sensitive dyes on the beating properties and pharmacological responses of human iPS-derived cardiomyocytes using the calcium transient assay.

PubMed

Kopljar, Ivan; Hermans, An N; Teisman, Ard; Gallacher, David J; Lu, Hua Rong

Calcium-based screening of hiPS-CMs is a useful preclinical safety evaluation platform with the ability to generate robust signals that facilitates high-throughput screening and data analysis. However, due to the potential inherent toxicities, it is important to understand potential effects of different calcium-sensitive dyes on the hiPS-CMs model. We compared three calcium-sensitive fluorescence dyes (Cal520, ACTOne and Calcium 5) for their impact on the variability, the beating properties and the pharmacological responses of hiPS-CMs using the Hamamatsu FDSS/μCell imaging platform. Direct effects of three dyes on the electrophysiological properties of hiPS-CMs were evaluated with the multi-electrode array (MEA) Axion Maestro platform. We propose a specific experimental protocol for each dye which gives the most optimal assay conditions to minimize variability and possible adverse effects. We showed that Cal520 had the smallest effect on hiPS-CMs together with the longest-lasting stable amplitude signal (up to 4 h). Although all dyes had a (minor) acute effect on hiPS-CMs, in the form of reduced beat rate and prolonged field potential duration, the selection of the dye did not influence the pharmacological response of four cardioactive drugs (dofetilide, moxifloxacin, nimodipine and isoprenaline). In conclusion, we have documented that different calcium sensitive dyes have only minor direct (acute) effects on hiPS-CMs with Cal520 showing the least effects and the longest lasting signal amplitude. Importantly, drug-induced pharmacological responses in hiPS-CMs were comparable between the three dyes. These findings should help further improve the robustness of the hiPS-CMs-based calcium transient assay as a predictive, preclinical cardiac safety evaluation tool. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of BEM for ceramic composites

NASA Technical Reports Server (NTRS)

Henry, D. P.; Banerjee, P. K.; Dargush, G. F.; Hopkins, D. A.; Goldberg, R. K.

1993-01-01

BEST-CMS (boundary element solution technology - composite modeling system) is an advanced engineering system for the micro-analysis of fiber composite structures. BEST-CMS is based upon the boundary element program BEST3D which was developed for NASA by Pratt and Whitney Aircraft and the State University of New York at Buffalo under contract NAS3-23697. BEST-CMS presently has the capabilities for elastostatic analysis, steady-state and transient heat transfer analysis, steady-state and transient concurrent thermoelastic analysis, and elastoplastic and creep analysis. The fibers are assumed to be perfectly bonded to the composite matrix, or in the case of static or steady-state analysis, the fibers may be assumed to have spring connections, thermal resistance, and/or frictional sliding between the fibers and the composite matrix. The primary objective of this user's manual is to provide an overview of all BEST-CMS capabilities, along with detailed descriptions of the input data requirements. In the next chapter, a brief review of the theoretical background is presented for each analysis category. Then, chapter three discusses the key aspects of the numerical implementation, while chapter four provides a tutorial for the beginning BEST-CMS user. The heart of the manual, however, is in chapter five, where a complete description of all data input items is provided. Within this chapter, the individual entries are grouped on a functional basis for a more coherent presentation. Chapter six includes sample problems and should be of considerable assistance to the novice. Chapter seven includes capsules of a number of fiber-composite analysis problems that have been solved using BEST-CMS. This chapter is primarily descriptive in nature and is intended merely to illustrate the level of analysis that is possible within the present BEST-CMS system. Chapter eight contains a detail description of the BEST-CMS Neutral File which is helpful in writing an interface between BEST-CMS and any graphic post-processor program. Finally, all pertinent references are listed in chapter nine.

Testing the 2-TeV resonance with trileptons

DOE PAGES

Das, Arindam; Nagata, Natsumi; Okada, Nobuchika

2016-03-09

The CMS collaboration has reported a 2.8 excess in the search of the SU(2) R gauge bosons decaying through right-handed neutrinos into the two electron plus two jets (more » $eejj$) final states. This can be explained if the SU(2) Rcharged gauge bosons W$$±\\atop{R}$$ have a mass of around 2TeV and a right-handed neutrino with a mass of O(1)TeV mainly decays to electron. Indeed, recent results in several other experiments, especially that from the ATLAS diboson resonance search, also indicate signatures of such a 2TeV gauge boson. However, a lack of the same-sign electron events in the CMS $eejj$ search challenges the interpretation of the right-handed neutrino as a Majorana fermion. Taking this situation into account, in this paper, we consider a possibility of explaining the CMS eejj excess based on the SU(2) L ⓍSU(2) RⓍ U(1) B-L gauge theory with pseudo-Dirac neutrinos. We fi nd that both the CMS excess events and the ATLAS diboson anomaly can actually be explained in this framework without conflicting with the current experimental bounds. This setup in general allows sizable left-right mixing in both the charged gauge boson and neutrino sectors, which enables us to probe this model through the trilepton plus missing energy search at the LHC. It turns out that the number of events in this channel predicted in our model is in good agreement with that observed by the CMS collaboration. We also discuss prospects for testing this model at the LHC Run-II experiments.« less

Yield performance and stability of CMS-based triticale hybrids.

PubMed

Mühleisen, Jonathan; Piepho, Hans-Peter; Maurer, Hans Peter; Reif, Jochen Christoph

2015-02-01

CMS-based triticale hybrids showed only marginal midparent heterosis for grain yield and lower dynamic yield stability compared to inbred lines. Hybrids of triticale (×Triticosecale Wittmack) are expected to possess outstanding yield performance and increased dynamic yield stability. The objectives of the present study were to (1) examine the optimum choice of the biometrical model to compare yield stability of hybrids versus lines, (2) investigate whether hybrids exhibit a more pronounced grain yield performance and yield stability, and (3) study optimal strategies to predict yield stability of hybrids. Thirteen female and seven male parental lines and their 91 factorial hybrids as well as 30 commercial lines were evaluated for grain yield in up to 20 environments. Hybrids were produced using a cytoplasmic male sterility (CMS)-inducing cytoplasm that originated from Triticumtimopheevii Zhuk. We found that the choice of the biometrical model can cause contrasting results and concluded that a group-by-environment interaction term should be added to the model when estimating stability variance of hybrids and lines. midparent heterosis for grain yield was on average 3 % with a range from -15.0 to 11.5 %. No hybrid outperformed the best inbred line. Hybrids had, on average, lower dynamic yield stability compared to the inbred lines. Grain yield performance of hybrids could be predicted based on midparent values and general combining ability (GCA)-predicted values. In contrast, stability variance of hybrids could be predicted only based on GCA-predicted values. We speculated that negative effects of the used CMS cytoplasm might be the reason for the low performance and yield stability of the hybrids. For this purpose a detailed study on the reasons for the drawback of the currently existing CMS system in triticale is urgently required comprising also the search of potentially alternative hybridization systems.

Upgrades for the CMS simulation

DOE PAGES

Lange, D. J.; Hildreth, M.; Ivantchenko, V. N.; ...

2015-05-22

Over the past several years, the CMS experiment has made significant changes to its detector simulation application. The geometry has been generalized to include modifications being made to the CMS detector for 2015 operations, as well as model improvements to the simulation geometry of the current CMS detector and the implementation of a number of approved and possible future detector configurations. These include both completely new tracker and calorimetry systems. We have completed the transition to Geant4 version 10, we have made significant progress in reducing the CPU resources required to run our Geant4 simulation. These have been achieved throughmore » both technical improvements and through numerical techniques. Substantial speed improvements have been achieved without changing the physics validation benchmarks that the experiment uses to validate our simulation application for use in production. As a result, we will discuss the methods that we implemented and the corresponding demonstrated performance improvements deployed for our 2015 simulation application.« less

Site-level habitat models for the endemic, threatened Cheat Mountain salamander (Plethodon nettingi): the importance of geophysical and biotic attributes for predicting occurrence

Treesearch

Lester O. Dillard; Kevin R. Russell; W. Mark Ford

2008-01-01

The federally threatened Cheat Mountain salamander (Plethodon nettingi; hereafter CMS) is known to occur in approximately 70 small, scattered populations in the Allegheny Mountains of eastern West Virginia, USA. Current conservation and management efforts on federal, state, and private lands involving CMS largely rely on small scale, largely...

Human-Induced Pluripotent Stem Cell Technology and Cardiomyocyte Generation: Progress and Clinical Applications.

PubMed

Di Baldassarre, Angela; Cimetta, Elisa; Bollini, Sveva; Gaggi, Giulia; Ghinassi, Barbara

2018-05-25

Human-induced pluripotent stem cells (hiPSCs) are reprogrammed cells that have hallmarks similar to embryonic stem cells including the capacity of self-renewal and differentiation into cardiac myocytes. The improvements in reprogramming and differentiating methods achieved in the past 10 years widened the use of hiPSCs, especially in cardiac research. hiPSC-derived cardiac myocytes (CMs) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models and useful tools for drug discovery and toxicology testing. In addition, hiPSCs can be used as sources of cells for cardiac regeneration in animal models. Here, we review the advances in the genetic and epigenetic control of cardiomyogenesis that underlies the significant improvement of the induced reprogramming of somatic cells to CMs; the methods used to improve scalability of throughput assays for functional screening and drug testing in vitro; the phenotypic characteristics of hiPSCs-derived CMs and their ability to rescue injured CMs through paracrine effects; we also cover the novel approaches in tissue engineering for hiPSC-derived cardiac tissue generation, and finally, their immunological features and the potential use in biomedical applications.

The Impact of Hospital Size on CMS Hospital Profiling.

PubMed

Sosunov, Eugene A; Egorova, Natalia N; Lin, Hung-Mo; McCardle, Ken; Sharma, Vansh; Gelijns, Annetine C; Moskowitz, Alan J

2016-04-01

The Centers for Medicare & Medicaid Services (CMS) profile hospitals using a set of 30-day risk-standardized mortality and readmission rates as a basis for public reporting. These measures are affected by hospital patient volume, raising concerns about uniformity of standards applied to providers with different volumes. To quantitatively determine whether CMS uniformly profile hospitals that have equal performance levels but different volumes. Retrospective analysis of patient-level and hospital-level data using hierarchical logistic regression models with hospital random effects. Simulation of samples including a subset of hospitals with different volumes but equal poor performance (hospital effects=+3 SD in random-effect logistic model). A total of 1,085,568 Medicare fee-for-service patients undergoing 1,494,993 heart failure admissions in 4930 hospitals between July 1, 2005 and June 30, 2008. CMS methodology was used to determine the rank and proportion (by volume) of hospitals reported to perform "Worse than US National Rate." Percent of hospitals performing "Worse than US National Rate" was ∼40 times higher in the largest (fifth quintile by volume) compared with the smallest hospitals (first quintile). A similar gradient was seen in a cohort of 100 hospitals with simulated equal poor performance (0%, 0%, 5%, 20%, and 85% in quintiles 1 to 5) effectively leaving 78% of poor performers undetected. Our results illustrate the disparity of impact that the current CMS method of hospital profiling has on hospitals with higher volumes, translating into lower thresholds for detection and reporting of poor performance.

Choice of Tuning Parameters on 3D IC Engine Simulations Using G-Equation

DOE PAGES

Liu, Jinlong; Szybist, James; Dumitrescu, Cosmin

2018-04-03

3D CFD spark-ignition IC engine simulations are extremely complex for the regular user. Truly-predictive CFD simulations for the turbulent flame combustion that solve fully coupled transport/chemistry equations may require large computational capabilities unavailable to regular CFD users. A solution is to use a simpler phenomenological model such as the G-equation that decouples transport/chemistry result. Such simulation can still provide acceptable and faster results at the expense of predictive capabilities. While the G-equation is well understood within the experienced modeling community, the goal of this paper is to document some of them for a novice or less experienced CFD user whomore » may not be aware that phenomenological models of turbulent flame combustion usually require heavy tuning and calibration from the user to mimic experimental observations. This study used ANSYS® Forte, Version 17.2, and the built-in G-equation model, to investigate two tuning constants that influence flame propagation in 3D CFD SI engine simulations: the stretch factor coefficient, Cms and the flame development coefficient, Cm2. After identifying several Cm2-Cms pairs that matched experimental data at one operating conditions, simulation results showed that engine models that used different Cm2-Cms sets predicted similar combustion performance, when the spark timing, engine load, and engine speed were changed from the operating condition used to validate the CFD simulation. A dramatic shift was observed when engine speed was doubled, which suggested that the flame stretch coefficient, Cms, had a much larger influence at higher engine speeds compared to the flame development coefficient, Cm2. Therefore, the Cm2-Cms sets that predicted a higher turbulent flame under higher in-cylinder pressure and temperature increased the peak pressure and efficiency. This suggest that the choice of the Cm2-Cms will affect the G-equation-based simulation accuracy when engine speed increases from the one used to validate the model. As a result, for the less-experienced CFD user and in the absence of enough experimental data that would help retune the tuning parameters at various operating conditions, the purpose of a good G-equation-based 3D engine simulation is to guide and/or complement experimental investigations, not the other way around. Only a truly-predictive simulation that fully couples the turbulence/chemistry equations can help reduce the amount of experimental work.« less

Choice of Tuning Parameters on 3D IC Engine Simulations Using G-Equation

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

Liu, Jinlong; Szybist, James; Dumitrescu, Cosmin

3D CFD spark-ignition IC engine simulations are extremely complex for the regular user. Truly-predictive CFD simulations for the turbulent flame combustion that solve fully coupled transport/chemistry equations may require large computational capabilities unavailable to regular CFD users. A solution is to use a simpler phenomenological model such as the G-equation that decouples transport/chemistry result. Such simulation can still provide acceptable and faster results at the expense of predictive capabilities. While the G-equation is well understood within the experienced modeling community, the goal of this paper is to document some of them for a novice or less experienced CFD user whomore » may not be aware that phenomenological models of turbulent flame combustion usually require heavy tuning and calibration from the user to mimic experimental observations. This study used ANSYS® Forte, Version 17.2, and the built-in G-equation model, to investigate two tuning constants that influence flame propagation in 3D CFD SI engine simulations: the stretch factor coefficient, Cms and the flame development coefficient, Cm2. After identifying several Cm2-Cms pairs that matched experimental data at one operating conditions, simulation results showed that engine models that used different Cm2-Cms sets predicted similar combustion performance, when the spark timing, engine load, and engine speed were changed from the operating condition used to validate the CFD simulation. A dramatic shift was observed when engine speed was doubled, which suggested that the flame stretch coefficient, Cms, had a much larger influence at higher engine speeds compared to the flame development coefficient, Cm2. Therefore, the Cm2-Cms sets that predicted a higher turbulent flame under higher in-cylinder pressure and temperature increased the peak pressure and efficiency. This suggest that the choice of the Cm2-Cms will affect the G-equation-based simulation accuracy when engine speed increases from the one used to validate the model. As a result, for the less-experienced CFD user and in the absence of enough experimental data that would help retune the tuning parameters at various operating conditions, the purpose of a good G-equation-based 3D engine simulation is to guide and/or complement experimental investigations, not the other way around. Only a truly-predictive simulation that fully couples the turbulence/chemistry equations can help reduce the amount of experimental work.« less

Detection of the Diversity of Cytoplasmic Male Sterility Sources in Broccoli (Brassica Oleracea var. Italica) Using Mitochondrial Markers.

PubMed

Shu, Jinshuai; Liu, Yumei; Li, Zhansheng; Zhang, Lili; Fang, Zhiyuan; Yang, Limei; Zhuang, Mu; Zhang, Yangyong; Lv, Honghao

2016-01-01

Broccoli (Brassica oleracea var. italica) is an important commercial vegetable crop. As part of an efficient pollination system, cytoplasmic male sterility (CMS) has been widely used for broccoli hybrid production. Identifying the original sources of CMS in broccoli accessions has become an important part of broccoli breeding. In this study, the diversity of the CMS sources of 39 broccoli accessions, including 19 CMS lines and 20 hybrids, were analyzed using mitochondrial markers. All CMS accessions contained the ogu orf138-related DNA fragment and the key genes of nap CMS, pol CMS, and tour CMS were not detected. The 39 CMS accessions were divided into five groups using six orf138-related and two simple sequence repeat markers. We observed that ogu CMS R3 constituted 79.49% of the CMS sources. CMS6 and CMS26 were differentiated from the other accessions using a specific primer. CMS32 was distinguished from the other accessions based on a 78-nucleotide deletion at the same locus as the orf138-related sequence. When the coefficient was about 0.90, five CMS accessions (13CMS6, 13CMS23, 13CMS24, 13CMS37, and 13CMS39) exhibiting abnormal floral organs with poor seed setting were grouped together. The polymerase chain reaction amplification profiles for these five accessions differed from those of the other accessions. We identified eight useful molecular markers that can be used to detect CMS types during broccoli breeding. Our data also provide important information relevant to future studies on the possible origins and molecular mechanisms of CMS in broccoli.

Detection of the Diversity of Cytoplasmic Male Sterility Sources in Broccoli (Brassica Oleracea var. Italica) Using Mitochondrial Markers

PubMed Central

Shu, Jinshuai; Liu, Yumei; Li, Zhansheng; Zhang, Lili; Fang, Zhiyuan; Yang, Limei; Zhuang, Mu; Zhang, Yangyong; Lv, Honghao

2016-01-01

Broccoli (Brassica oleracea var. italica) is an important commercial vegetable crop. As part of an efficient pollination system, cytoplasmic male sterility (CMS) has been widely used for broccoli hybrid production. Identifying the original sources of CMS in broccoli accessions has become an important part of broccoli breeding. In this study, the diversity of the CMS sources of 39 broccoli accessions, including 19 CMS lines and 20 hybrids, were analyzed using mitochondrial markers. All CMS accessions contained the ogu orf138-related DNA fragment and the key genes of nap CMS, pol CMS, and tour CMS were not detected. The 39 CMS accessions were divided into five groups using six orf138-related and two simple sequence repeat markers. We observed that ogu CMS R3 constituted 79.49% of the CMS sources. CMS6 and CMS26 were differentiated from the other accessions using a specific primer. CMS32 was distinguished from the other accessions based on a 78-nucleotide deletion at the same locus as the orf138-related sequence. When the coefficient was about 0.90, five CMS accessions (13CMS6, 13CMS23, 13CMS24, 13CMS37, and 13CMS39) exhibiting abnormal floral organs with poor seed setting were grouped together. The polymerase chain reaction amplification profiles for these five accessions differed from those of the other accessions. We identified eight useful molecular markers that can be used to detect CMS types during broccoli breeding. Our data also provide important information relevant to future studies on the possible origins and molecular mechanisms of CMS in broccoli. PMID:27446156

Integration of end-user Cloud storage for CMS analysis

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

Riahi, Hassen; Aimar, Alberto; Ayllon, Alejandro Alvarez

End-user Cloud storage is increasing rapidly in popularity in research communities thanks to the collaboration capabilities it offers, namely synchronisation and sharing. CERN IT has implemented a model of such storage named, CERNBox, integrated with the CERN AuthN and AuthZ services. To exploit the use of the end-user Cloud storage for the distributed data analysis activity, the CMS experiment has started the integration of CERNBox as a Grid resource. This will allow CMS users to make use of their own storage in the Cloud for their analysis activities as well as to benefit from synchronisation and sharing capabilities to achievemore » results faster and more effectively. It will provide an integration model of Cloud storages in the Grid, which is implemented and commissioned over the world’s largest computing Grid infrastructure, Worldwide LHC Computing Grid (WLCG). In this paper, we present the integration strategy and infrastructure changes needed in order to transparently integrate end-user Cloud storage with the CMS distributed computing model. We describe the new challenges faced in data management between Grid and Cloud and how they were addressed, along with details of the support for Cloud storage recently introduced into the WLCG data movement middleware, FTS3. Finally, the commissioning experience of CERNBox for the distributed data analysis activity is also presented.« less

Integration of end-user Cloud storage for CMS analysis

DOE PAGES

Riahi, Hassen; Aimar, Alberto; Ayllon, Alejandro Alvarez; ...

2017-05-19

End-user Cloud storage is increasing rapidly in popularity in research communities thanks to the collaboration capabilities it offers, namely synchronisation and sharing. CERN IT has implemented a model of such storage named, CERNBox, integrated with the CERN AuthN and AuthZ services. To exploit the use of the end-user Cloud storage for the distributed data analysis activity, the CMS experiment has started the integration of CERNBox as a Grid resource. This will allow CMS users to make use of their own storage in the Cloud for their analysis activities as well as to benefit from synchronisation and sharing capabilities to achievemore » results faster and more effectively. It will provide an integration model of Cloud storages in the Grid, which is implemented and commissioned over the world’s largest computing Grid infrastructure, Worldwide LHC Computing Grid (WLCG). In this paper, we present the integration strategy and infrastructure changes needed in order to transparently integrate end-user Cloud storage with the CMS distributed computing model. We describe the new challenges faced in data management between Grid and Cloud and how they were addressed, along with details of the support for Cloud storage recently introduced into the WLCG data movement middleware, FTS3. Finally, the commissioning experience of CERNBox for the distributed data analysis activity is also presented.« less

Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease.

PubMed

Chou, Shih-Jie; Yu, Wen-Chung; Chang, Yuh-Lih; Chen, Wen-Yeh; Chang, Wei-Chao; Chien, Yueh; Yen, Jiin-Cherng; Liu, Yung-Yang; Chen, Shih-Jen; Wang, Chien-Ying; Chen, Yu-Han; Niu, Dau-Ming; Lin, Shing-Jong; Chen, Jaw-Wen; Chiou, Shih-Hwa; Leu, Hsin-Bang

2017-04-01

Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease. Copyright © 2017 Elsevier B.V. All rights reserved.

The ShakeOut earthquake source and ground motion simulations

USGS Publications Warehouse

Graves, R.W.; Houston, Douglas B.; Hudnut, K.W.

2011-01-01

The ShakeOut Scenario is premised upon the detailed description of a hypothetical Mw 7.8 earthquake on the southern San Andreas Fault and the associated simulated ground motions. The main features of the scenario, such as its endpoints, magnitude, and gross slip distribution, were defined through expert opinion and incorporated information from many previous studies. Slip at smaller length scales, rupture speed, and rise time were constrained using empirical relationships and experience gained from previous strong-motion modeling. Using this rupture description and a 3-D model of the crust, broadband ground motions were computed over a large region of Southern California. The largest simulated peak ground acceleration (PGA) and peak ground velocity (PGV) generally range from 0.5 to 1.0 g and 100 to 250 cm/s, respectively, with the waveforms exhibiting strong directivity and basin effects. Use of a slip-predictable model results in a high static stress drop event and produces ground motions somewhat higher than median level predictions from NGA ground motion prediction equations (GMPEs).

Constraints on models of scalar and vector leptoquarks decaying to a quark and a neutrino at $$\\sqrt{s}=$$ 13 TeV

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

Sirunyan, Albert M; et al.

The results of a previous search by the CMS Collaboration for squarks and gluinos are reinterpreted to constrain models of leptoquark (LQ) production. The search considers jets in association with a transverse momentum imbalance, using themore » $$M_\\mathrm{T2}$$ variable. The analysis uses proton-proton collision data at $$\\sqrt{s}=$$ 13 TeV, recorded with the CMS detector at the LHC in 2016 and corresponding to an integrated luminosity of 35.9 fb$$^{-1}$$. Leptoquark pair production is considered with LQ decays to a neutrino and a top, bottom, or light quark. This reinterpretation considers higher mass values than the original CMS search to constrain both scalar and vector LQs. Limits on the cross section for LQ pair production are derived at the 95% confidence level depending on the LQ decay mode. A vector LQ decaying with a 50% branching fraction to t$$\

Neural network based glucose - insulin metabolism models for children with Type 1 diabetes.

PubMed

Mougiakakou, Stavroula G; Prountzou, Aikaterini; Iliopoulou, Dimitra; Nikita, Konstantina S; Vazeou, Andriani; Bartsocas, Christos S

2006-01-01

In this paper two models for the simulation of glucose-insulin metabolism of children with Type 1 diabetes are presented. The models are based on the combined use of Compartmental Models (CMs) and artificial Neural Networks (NNs). Data from children with Type 1 diabetes, stored in a database, have been used as input to the models. The data are taken from four children with Type 1 diabetes and contain information about glucose levels taken from continuous glucose monitoring system, insulin intake and food intake, along with corresponding time. The influences of taken insulin on plasma insulin concentration, as well as the effect of food intake on glucose input into the blood from the gut, are estimated from the CMs. The outputs of CMs, along with previous glucose measurements, are fed to a NN, which provides short-term prediction of glucose values. For comparative reasons two different NN architectures have been tested: a Feed-Forward NN (FFNN) trained with the back-propagation algorithm with adaptive learning rate and momentum, and a Recurrent NN (RNN), trained with the Real Time Recurrent Learning (RTRL) algorithm. The results indicate that the best prediction performance can be achieved by the use of RNN.

Examining deterrence of adult sex crimes: A semi-parametric intervention time series approach.

PubMed

Park, Jin-Hong; Bandyopadhyay, Dipankar; Letourneau, Elizabeth

2014-01-01

Motivated by recent developments on dimension reduction (DR) techniques for time series data, the association of a general deterrent effect towards South Carolina (SC)'s registration and notification (SORN) policy for preventing sex crimes was examined. Using adult sex crime arrestee data from 1990 to 2005, the the idea of Central Mean Subspace (CMS) is extended to intervention time series analysis (CMS-ITS) to model the sequential intervention effects of 1995 (the year SC's SORN policy was initially implemented) and 1999 (the year the policy was revised to include online notification) on the time series spectrum. The CMS-ITS model estimation was achieved via kernel smoothing techniques, and compared to interrupted auto-regressive integrated time series (ARIMA) models. Simulation studies and application to the real data underscores our model's ability towards achieving parsimony, and to detect intervention effects not earlier determined via traditional ARIMA models. From a public health perspective, findings from this study draw attention to the potential general deterrent effects of SC's SORN policy. These findings are considered in light of the overall body of research on sex crime arrestee registration and notification policies, which remain controversial.

Occupational Health and Safety of Finnish Dairy Farmers Using Automatic Milking Systems.

PubMed

Karttunen, Janne P; Rautiainen, Risto H; Lunner-Kolstrup, Christina

2016-01-01

Conventional pipeline and parlor milking expose dairy farmers and workers to adverse health outcomes. In recent years, automatic milking systems (AMS) have gained much popularity in Finland, but the changes in working conditions when changing to AMS are not well known. The aim of this study was to investigate the occupational health and safety risks in using AMS, compared to conventional milking systems (CMS). An anonymous online survey was sent to each Finnish dairy farm with an AMS in 2014. Only those dairy farmers with prior work experience in CMS were included in the final analysis consisting of frequency distributions and descriptive statistics. We received 228 usable responses (131 male and 97 female; 25.2% response rate). The majority of the participants found that AMS had brought flexibility to the organization of farm work, and it had increased leisure time, quality of life, productivity of dairy work, and the attractiveness of dairy farming among the younger generation. In addition, AMS reduced the perceived physical strain on the musculoskeletal system as well as the risk of occupational injuries and diseases, compared to CMS. However, working in close proximity to the cattle, particularly training of heifers to use the AMS, was regarded as a high-risk work task. In addition, the daily cleaning of the AMS and manual handling of rejected milk were regarded as physically demanding. The majority of the participants stated that mental stress caused by the monotonous, repetitive, paced, and hurried work had declined after changing to AMS. However, many indicated increased mental stress because of the demanding management of the AMS. Nightly alarms caused by the AMS, lack of adequately skilled hired labor or farm relief workers, and the 24/7 standby for the AMS were issues that also caused mental stress. Based on this study, AMS may have significant potential in the prevention of adverse health outcomes in milking of dairy cows. In addition, AMS may improve the productivity of dairy work and sustainability of dairy production. However, certain characteristics of the AMS require further attention with regard to occupational health and safety risks.

Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes

PubMed Central

Bizy, Alexandra; Guerrero-Serna, Guadalupe; Hu, Bin; Ponce-Balbuena, Daniela; Willis, B. Cicero; Zarzoso, Manuel; Ramirez, Rafael J.; Sener, Michelle F.; Mundada, Lakshmi V.; Klos, Matthew; Devaney, Eric J.; Vikstrom, Karen L.; Herron, Todd J.; Jalife, José

2014-01-01

Applications of human induced pluripotent stemcell derived-cardiac myocytes (hiPSC-CMs) would be strengthened by the ability to generate specific cardiac myocyte (CM) lineages. However, purification of lineage-specific hiPSC-CMs is limited by the lack of cell marking techniques. Here, we have developed an iPSC-CM marking system using recombinant adenoviral reporter constructs with atrial- or ventricular-specific myosin light chain-2 (MLC-2) promoters. MLC-2a and MLC-2v selected hiPSC-CMs were purified by fluorescence-activated cell sorting and their biochemical and electrophysiological phenotypes analyzed. We demonstrate that the phenotype of both populations remained stable in culture and they expressed the expected sarcomeric proteins, gap junction proteins and chamber-specific transcription factors. Compared to MLC-2a cells, MLC-2v selected CMs had larger action potential amplitudes and durations. In addition, by immunofluorescence, we showed that MLC-2 isoform expression can be used to enrich hiPSC-CM consistent with early atrial and ventricularmyocyte lineages. However, only the ventricular myosin light chain-2 promoter was able to purify a highly homogeneous population of iPSC-CMs. Using this approach, it is now possible to develop ventricular-specific disease models using iPSC-CMs while atrial-specific iPSC-CM cultures may require additional chamber-specific markers. PMID:24095945

Using Amazon's Elastic Compute Cloud to dynamically scale CMS computational resources

NASA Astrophysics Data System (ADS)

Evans, D.; Fisk, I.; Holzman, B.; Melo, A.; Metson, S.; Pordes, R.; Sheldon, P.; Tiradani, A.

2011-12-01

Large international scientific collaborations such as the Compact Muon Solenoid (CMS) experiment at the Large Hadron Collider have traditionally addressed their data reduction and analysis needs by building and maintaining dedicated computational infrastructure. Emerging cloud computing services such as Amazon's Elastic Compute Cloud (EC2) offer short-term CPU and storage resources with costs based on usage. These services allow experiments to purchase computing resources as needed, without significant prior planning and without long term investments in facilities and their management. We have demonstrated that services such as EC2 can successfully be integrated into the production-computing model of CMS, and find that they work very well as worker nodes. The cost-structure and transient nature of EC2 services makes them inappropriate for some CMS production services and functions. We also found that the resources are not truely "on-demand" as limits and caps on usage are imposed. Our trial workflows allow us to make a cost comparison between EC2 resources and dedicated CMS resources at a University, and conclude that it is most cost effective to purchase dedicated resources for the "base-line" needs of experiments such as CMS. However, if the ability to use cloud computing resources is built into an experiment's software framework before demand requires their use, cloud computing resources make sense for bursting during times when spikes in usage are required.

Myosin light chain 2-based selection of human iPSC-derived early ventricular cardiac myocytes.

PubMed

Bizy, Alexandra; Guerrero-Serna, Guadalupe; Hu, Bin; Ponce-Balbuena, Daniela; Willis, B Cicero; Zarzoso, Manuel; Ramirez, Rafael J; Sener, Michelle F; Mundada, Lakshmi V; Klos, Matthew; Devaney, Eric J; Vikstrom, Karen L; Herron, Todd J; Jalife, José

2013-11-01

Applications of human induced pluripotent stem cell derived-cardiac myocytes (hiPSC-CMs) would be strengthened by the ability to generate specific cardiac myocyte (CM) lineages. However, purification of lineage-specific hiPSC-CMs is limited by the lack of cell marking techniques. Here, we have developed an iPSC-CM marking system using recombinant adenoviral reporter constructs with atrial- or ventricular-specific myosin light chain-2 (MLC-2) promoters. MLC-2a and MLC-2v selected hiPSC-CMs were purified by fluorescence-activated cell sorting and their biochemical and electrophysiological phenotypes analyzed. We demonstrate that the phenotype of both populations remained stable in culture and they expressed the expected sarcomeric proteins, gap junction proteins and chamber-specific transcription factors. Compared to MLC-2a cells, MLC-2v selected CMs had larger action potential amplitudes and durations. In addition, by immunofluorescence, we showed that MLC-2 isoform expression can be used to enrich hiPSC-CM consistent with early atrial and ventricular myocyte lineages. However, only the ventricular myosin light chain-2 promoter was able to purify a highly homogeneous population of iPSC-CMs. Using this approach, it is now possible to develop ventricular-specific disease models using iPSC-CMs while atrial-specific iPSC-CM cultures may require additional chamber-specific markers. © 2013.

Experience in Grid Site Testing for ATLAS, CMS and LHCb with HammerCloud

NASA Astrophysics Data System (ADS)

Elmsheuser, Johannes; Medrano Llamas, Ramón; Legger, Federica; Sciabà, Andrea; Sciacca, Gianfranco; Úbeda García, Mario; van der Ster, Daniel

2012-12-01

Frequent validation and stress testing of the network, storage and CPU resources of a grid site is essential to achieve high performance and reliability. HammerCloud was previously introduced with the goals of enabling VO- and site-administrators to run such tests in an automated or on-demand manner. The ATLAS, CMS and LHCb experiments have all developed VO plugins for the service and have successfully integrated it into their grid operations infrastructures. This work will present the experience in running HammerCloud at full scale for more than 3 years and present solutions to the scalability issues faced by the service. First, we will show the particular challenges faced when integrating with CMS and LHCb offline computing, including customized dashboards to show site validation reports for the VOs and a new API to tightly integrate with the LHCbDIRAC Resource Status System. Next, a study of the automatic site exclusion component used by ATLAS will be presented along with results for tuning the exclusion policies. A study of the historical test results for ATLAS, CMS and LHCb will be presented, including comparisons between the experiments’ grid availabilities and a search for site-based or temporal failure correlations. Finally, we will look to future plans that will allow users to gain new insights into the test results; these include developments to allow increased testing concurrency, increased scale in the number of metrics recorded per test job (up to hundreds), and increased scale in the historical job information (up to many millions of jobs per VO).

Integration and validation testing for PhEDEx, DBS and DAS with the PhEDEx LifeCycle agent

NASA Astrophysics Data System (ADS)

Boeser, C.; Chwalek, T.; Giffels, M.; Kuznetsov, V.; Wildish, T.

2014-06-01

The ever-increasing amount of data handled by the CMS dataflow and workflow management tools poses new challenges for cross-validation among different systems within CMS experiment at LHC. To approach this problem we developed an integration test suite based on the LifeCycle agent, a tool originally conceived for stress-testing new releases of PhEDEx, the CMS data-placement tool. The LifeCycle agent provides a framework for customising the test workflow in arbitrary ways, and can scale to levels of activity well beyond those seen in normal running. This means we can run realistic performance tests at scales not likely to be seen by the experiment for some years, or with custom topologies to examine particular situations that may cause concern some time in the future. The LifeCycle agent has recently been enhanced to become a general purpose integration and validation testing tool for major CMS services. It allows cross-system integration tests of all three components to be performed in controlled environments, without interfering with production services. In this paper we discuss the design and implementation of the LifeCycle agent. We describe how it is used for small-scale debugging and validation tests, and how we extend that to large-scale tests of whole groups of sub-systems. We show how the LifeCycle agent can emulate the action of operators, physicists, or software agents external to the system under test, and how it can be scaled to large and complex systems.

45 CFR 150.203 - Circumstances requiring CMS enforcement.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Circumstances requiring CMS enforcement. 150.203... CARE ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement Processes for... requiring CMS enforcement. CMS enforces HIPAA requirements to the extent warranted (as determined by CMS) in...

Explore the high-density QCD medium via particle correlations in pPb collisions at CMS

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

Li, Wei, E-mail: wl33@rice.edu

2015-01-15

The observation of a long-range, near-side two-particle correlation (“ridge”) in very high multiplicity proton–proton and proton–lead collisions has opened up new opportunity of studying novel QCD phenomena in small collision systems. In 2013, high luminosity pPb data were collected by the CMS experiment at the LHC. New results of two- and multi-particle correlations in pPb collisions from CMS are presented over a wide event multiplicity and transverse momentum range. A direct comparison of pPb and PbPb systems is provided. Physics implications, especially in the context of color glass condensate and hydrodynamics models are also discussed.

Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses.

PubMed

Marchand, Sandrine; Lamarche, Isabelle; Gobin, Patrice; Couet, William

2010-08-01

The aim of this study was to evaluate the effect of colistin methanesulphonate (CMS) dose on CMS and colistin pharmacokinetics in rats. Three rats per group received an intravenous bolus of CMS at a dose of 5, 15, 30, 60 or 120 mg/kg. Arterial blood samples were drawn at 0, 5, 15, 30, 60, 90, 120, 150 and 180 min. CMS and colistin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of CMS and colistin were calculated by non-compartmental analysis. Linear relationships were observed between CMS and colistin AUCs to infinity and CMS doses, as well as between CMS and colistin C(max) and CMS doses. CMS and colistin pharmacokinetics were linear for a range of colistin concentrations covering the range of values encountered and recommended in patients even during treatment with higher doses.

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy.

PubMed

Bauché, Stéphanie; Vellieux, Geoffroy; Sternberg, Damien; Fontenille, Marie-Joséphine; De Bruyckere, Elodie; Davoine, Claire-Sophie; Brochier, Guy; Messéant, Julien; Wolf, Lucie; Fardeau, Michel; Lacène, Emmanuelle; Romero, Norma; Koenig, Jeanine; Fournier, Emmanuel; Hantaï, Daniel; Streichenberger, Nathalie; Manel, Veronique; Lacour, Arnaud; Nadaj-Pakleza, Aleksandra; Sukno, Sylvie; Bouhour, Françoise; Laforêt, Pascal; Fontaine, Bertrand; Strochlic, Laure; Eymard, Bruno; Chevessier, Frédéric; Stojkovic, Tanya; Nicole, Sophie

2017-08-01

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients' muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a "tubular aggregates myopathy with synaptopathy".

CARDIOMYOPATHY AND WORSENED ISCHEMIC HEART FAILURE IN SM22-α CRE-MEDIATED NEUROPILIN-1 NULL MICE: DYSREGULATION OF PGC1α AND MITOCHONDRIAL HOMEOSTASIS

PubMed Central

Wang, Ying; Cao, Ying; Yamada, Satsuki; Thirunavukkarasu, Mahesh; Nin, Veronica; Joshi, Mandip; Rishi, Muhammed T.; Bhattacharya, Santanu; Camacho-Pereira, Juliana; Sharma, Anil K.; Shameer, Khader; Kocher, Jean-Pierre A.; Sanchez, Juan A; Wang, Enfeng; Hoeppner, Luke H.; Dutta, Shamit K.; Leof1, Edward B.; Shah, Vijay; Claffey, Kevin P.; Chini, Eduardo; Simons, Michael; Terzic, Andre; Maulik, Nilanjana; Mukhopadhyay, Debabrata

2015-01-01

Objective Neuropilin-1 (NRP-1) is a multi-domain membrane receptor involved in angiogenesis and development of neuronal circuits, however, the role of NRP-1 in cardiovascular pathophysiology remains elusive. Approach and Results In this study, we first observed that deletion of NRP-1 induced peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) in cardiomyocytes (CMs) and vascular smooth muscle cells (VSMCs), which was accompanied by dysregulated cardiac mitochondrial accumulation and induction of cardiac hypertrophy- and stress-related markers. To investigate the role of NRP-1 in vivo, we generated mice lacking Nrp-1 in CMs and VSMCs (SM22-α-Nrp-1 KO), which exhibited decreased survival rates, developed cardiomyopathy and aggravated ischemia-induced heart failure. Mechanistically, we found that NRP-1 specifically controls PGC1α and PPARγ in CMs through crosstalk with Notch1 and Smad2 signaling pathways respectively. Moreover, SM22-α-Nrp-1 KO mice exhibited impaired physical activities and altered metabolite levels in serum, liver, and adipose tissues, as demonstrated by global metabolic profiling analysis. Conclusions Our findings provide new insights into the cardio-protective role of NRP-1 and its influence on global metabolism. PMID:25882068

CMS reimbursement reform and the incidence of hospital-acquired pulmonary embolism or deep vein thrombosis.

PubMed

Gidwani, Risha; Bhattacharya, Jay

2015-05-01

In October 2008, the Centers for Medicare & Medicaid Services (CMS) stopped reimbursing hospitals for the marginal cost of treating certain preventable hospital-acquired conditions. This study evaluates whether CMS's refusal to pay for hospital-acquired pulmonary embolism (PE) or deep vein thrombosis (DVT) resulted in a lower incidence of these conditions. We employ difference-in-differences modeling using 2007-2009 data from the Nationwide Inpatient Sample, an all-payer database of inpatient discharges in the U.S. Discharges between 1 January 2007 and 30 September 2008 were considered "before payment reform;" discharges between 1 October 2008 and 31 December 2009 were considered "after payment reform." Hierarchical regression models were fit to account for clustering of observations within hospitals. The "before payment reform" and "after payment reform" incidences of PE or DVT among 65-69-year-old Medicare recipients were compared with three different control groups of: a) 60-64-year-old non-Medicare patients; b) 65-69-year-old non-Medicare patients; and c) 65-69-year-old privately insured patients. Hospital reimbursements for the control groups were not affected by payment reform. CMS payment reform for hospital-based reimbursement of patients with hip and knee replacement surgeries. The outcome was the incidence proportion of hip and knee replacement surgery admissions that developed pulmonary embolism or deep vein thrombosis. At baseline, pulmonary embolism or deep vein thrombosis were present in 0.81% of all hip or knee replacement surgeries for Medicare patients aged 65-69 years old. CMS payment reform resulted in a 35% lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis in these patients (p = 0.015). Results were robust to sensitivity analyses. CMS's refusal to pay for hospital-acquired conditions resulted in a lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis after hip or knee replacement surgery. Payment reform had the desired direction of effect.

A genetic algorithm for a bi-objective mathematical model for dynamic virtual cell formation problem

NASA Astrophysics Data System (ADS)

Moradgholi, Mostafa; Paydar, Mohammad Mahdi; Mahdavi, Iraj; Jouzdani, Javid

2016-09-01

Nowadays, with the increasing pressure of the competitive business environment and demand for diverse products, manufacturers are force to seek for solutions that reduce production costs and rise product quality. Cellular manufacturing system (CMS), as a means to this end, has been a point of attraction to both researchers and practitioners. Limitations of cell formation problem (CFP), as one of important topics in CMS, have led to the introduction of virtual CMS (VCMS). This research addresses a bi-objective dynamic virtual cell formation problem (DVCFP) with the objective of finding the optimal formation of cells, considering the material handling costs, fixed machine installation costs and variable production costs of machines and workforce. Furthermore, we consider different skills on different machines in workforce assignment in a multi-period planning horizon. The bi-objective model is transformed to a single-objective fuzzy goal programming model and to show its performance; numerical examples are solved using the LINGO software. In addition, genetic algorithm (GA) is customized to tackle large-scale instances of the problems to show the performance of the solution method.

Further Developments of BEM for Micro and Macromechanical Analyses of Composites: Boundary Element Software Technology-Composite User's Manual

NASA Technical Reports Server (NTRS)

Banerjee, P. K.; Henry, D. P.; Hopkins, D. A.; Goldberg, R. K.

1997-01-01

BEST-CMS (Boundary Element Solution Technology - Composite Modeling System) is an advanced engineering system for the micro-analysis of fiber composite structures. BEST-CMS is based upon the boundary element program BEST3D which was developed for NASA by Pratt and Whitney Aircraft and the State University of New York at Buffalo under contract NAS3-23697. BEST-CMS presently has the capabilities for elastostatic analysis, steady-state and transient heat transfer analysis, steady-state and transient concurrent thermoelastic analysis and elastoplastic and creep analysis. The fibers are assumed to be perfectly bonded to the composite matrix, or in the case of static or steady-state analysis, the fibers may be assumed to have spring connections, thermal resistance, and/or frictional sliding between the fibers and the composite matrix. The primary objective of this User's Manual is to provide an overview of all BEST-CMS capabilities, along with detailed descriptions of the input data requirements. A brief review of the theoretical background is presented for each analysis category. Then, Chapter 3 discusses the key aspects of the numerical implementation, while Chapter 4 provides a tutorial for the beginning BEST-CMS user. The heart of the manual, however, is in Chapter 5, where a complete description of all data input items is provided. Within this chapter, the individual entries are grouped on a functional basis for a more coherent presentation. Chapter 6 includes sample problems and should be of considerable assistance to the novice. Chapter 7 includes capsules of a number of fiber-composite analysis problems that have been solved using BEST-CMS. This chapter is primarily descriptive in nature and is intended merely to illustrate the level of analysis that is possible within the present BEST-CMS system. Chapter 8 contains a detailed description of the BEST-CMS Neutral File which is helpful in writing an interface between BEST- CMS and any graphic post-processor program. Finally, all pertinent references are listed in Chapter 9.

Drug Screening Using a Library of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals Disease Specific Patterns of Cardiotoxicity

PubMed Central

Liang, Ping; Lan, Feng; Lee, Andrew S.; Gong, Tingyu; Sanchez-Freire, Veronica; Wang, Yongming; Diecke, Sebastian; Sallam, Karim; Knowles, Joshua W.; Wang, Paul J.; Nguyen, Patricia K.; Bers, Donald M.; Robbins, Robert C.; Wu, Joseph C.

2013-01-01

Background Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with pre-existing heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds. Methods and Results Action potential duration (APD) and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome (LQT), familial hypertrophic cardiomyopathy (HCM), and familial dilated cardiomyopathy (DCM). Disease phenotypes were verified in LQT, HCM, and DCM iPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene (hERG) expressing human embryonic kidney (HEK293) cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in HEK293 cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by APD and quantification of drug-induced arrhythmias such as early after depolarizations (EADs) and delayed after depolarizations (DADs). Conclusions We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, LQT, HCM, and DCM patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than standard hERG test or healthy control hiPSC-CM/hESC-CM screening assays. PMID:23519760

The Impact of Disability and Social Determinants of Health on Condition-Specific Readmissions beyond Medicare Risk Adjustments: A Cohort Study.

PubMed

Meddings, Jennifer; Reichert, Heidi; Smith, Shawna N; Iwashyna, Theodore J; Langa, Kenneth M; Hofer, Timothy P; McMahon, Laurence F

2017-01-01

Readmission rates after pneumonia, heart failure, and acute myocardial infarction hospitalizations are risk-adjusted for age, gender, and medical comorbidities and used to penalize hospitals. To assess the impact of disability and social determinants of health on condition-specific readmissions beyond current risk adjustment. Retrospective cohort study of Medicare patients using 1) linked Health and Retirement Study-Medicare claims data (HRS-CMS) and 2) Healthcare Cost and Utilization Project State Inpatient Databases (Florida, Washington) linked with ZIP Code-level measures from the Census American Community Survey (ACS-HCUP). Multilevel logistic regression models assessed the impact of disability and selected social determinants of health on readmission beyond current risk adjustment. Outcomes measured were readmissions ≤30 days after hospitalizations for pneumonia, heart failure, or acute myocardial infarction. HRS-CMS models included disability measures (activities of daily living [ADL] limitations, cognitive impairment, nursing home residence, home healthcare use) and social determinants of health (spouse, children, wealth, Medicaid, race). ACS-HCUP model measures were ZIP Code-percentage of residents ≥65 years of age with ADL difficulty, spouse, income, Medicaid, and patient-level and hospital-level race. For pneumonia, ≥3 ADL difficulties (OR 1.61, CI 1.079-2.391) and prior home healthcare needs (OR 1.68, CI 1.204-2.355) increased readmission in HRS-CMS models (N = 1631); ADL difficulties (OR 1.20, CI 1.063-1.352) and 'other' race (OR 1.14, CI 1.001-1.301) increased readmission in ACS-HCUP models (N = 27,297). For heart failure, children (OR 0.66, CI 0.437-0.984) and wealth (OR 0.53, CI 0.349-0.787) lowered readmission in HRS-CMS models (N = 2068), while black (OR 1.17, CI 1.056-1.292) and 'other' race (OR 1.14, CI 1.036-1.260) increased readmission in ACS-HCUP models (N = 37,612). For acute myocardial infarction, nursing home status (OR 4.04, CI 1.212-13.440) increased readmission in HRS-CMS models (N = 833); 'other' patient-level race (OR 1.18, CI 1.012-1.385) and hospital-level race (OR 1.06, CI 1.001-1.125) increased readmission in ACS-HCUP models (N = 17,496). Disability and social determinants of health influence readmission risk when added to the current Medicare risk adjustment models, but the effect varies by condition.

Impact of carbonaceous materials in soil on the transport of soil-bound PAHs during rainfall-runoff events.

PubMed

Luo, Xiaolin; Zheng, Yi; Wu, Bin; Lin, Zhongrong; Han, Feng; Zhang, Wei; Wang, Xuejun

2013-11-01

Polycyclic Aromatic Hydrocarbons (PAHs) transported from contaminated soils by surface runoff pose significant risk for aquatic ecosystems. Based on a rainfall-runoff simulation experiment, this study investigated the impact of carbonaceous materials (CMs) in soil, identified by organic petrology analysis, on the transport of soil-bound PAHs under rainfall conditions. The hypothesis that composition of soil organic matter significantly impacts the enrichment and transport of PAHs was proved. CMs in soil, varying significantly in content, mobility and adsorption capacity, act differently on the transport of PAHs. Anthropogenic CMs like black carbon (BC) largely control the transport, as PAHs may be preferentially attached to them. Eventually, this study led to a rethink of the traditional enrichment theory. An important implication is that CMs in soil have to be explicitly considered to appropriately model the nonpoint source pollution of PAHs (possibly other hydrophobic chemicals as well) and assess its environmental risk. Copyright © 2013 Elsevier Ltd. All rights reserved.

Event Display for the Visualization of CMS Events

NASA Astrophysics Data System (ADS)

Bauerdick, L. A. T.; Eulisse, G.; Jones, C. D.; Kovalskyi, D.; McCauley, T.; Mrak Tadel, A.; Muelmenstaedt, J.; Osborne, I.; Tadel, M.; Tu, Y.; Yagil, A.

2011-12-01

During the last year the CMS experiment engaged in consolidation of its existing event display programs. The core of the new system is based on the Fireworks event display program which was by-design directly integrated with the CMS Event Data Model (EDM) and the light version of the software framework (FWLite). The Event Visualization Environment (EVE) of the ROOT framework is used to manage a consistent set of 3D and 2D views, selection, user-feedback and user-interaction with the graphics windows; several EVE components were developed by CMS in collaboration with the ROOT project. In event display operation simple plugins are registered into the system to perform conversion from EDM collections into their visual representations which are then managed by the application. Full event navigation and filtering as well as collection-level filtering is supported. The same data-extraction principle can also be applied when Fireworks will eventually operate as a service within the full software framework.

Use of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) to Monitor Compound Effects on Cardiac Myocyte Signaling Pathways.

PubMed

Guo, Liang; Eldridge, Sandy; Furniss, Mike; Mussio, Jodie; Davis, Myrtle

2015-09-01

There is a need to develop mechanism-based assays to better inform risk of cardiotoxicity. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are rapidly gaining acceptance as a biologically relevant in vitro model for use in drug discovery and cardiotoxicity screens. Utilization of hiPSC-CMs for mechanistic investigations would benefit from confirmation of the expression and activity of cellular pathways that are known to regulate cardiac myocyte viability and function. This unit describes an approach to demonstrate the presence and function of signaling pathways in hiPSC-CMs and the effects of treatments on these pathways. We present a workflow that employs protocols to demonstrate protein expression and functional integrity of signaling pathway(s) of interest and to characterize biological consequences of signaling modulation. These protocols utilize a unique combination of structural, functional, and biochemical endpoints to interrogate compound effects on cardiomyocytes. Copyright © 2015 John Wiley & Sons, Inc.

JSH-23 prevents depressive-like behaviors in mice subjected to chronic mild stress: Effects on inflammation and antioxidant defense in the hippocampus.

PubMed

Wang, Qi; Dong, Xiaomei; Li, Nannan; Wang, Yan; Guan, Xiaofeng; Lin, Yiwei; Kang, Jiguang; Zhang, Xia; Zhang, Yuchen; Li, Xiaobai; Xu, Tianchao

2018-06-01

Nuclear factor-kappa B (NF-κB), which is reported to play an important role in the pathogenesis of depression, also has a central role in the genesis and progression of inflammation. Here, we have targeted the nuclear translocation of NF-κB using 4-methyl-N1-(3-phenyl-propyl)-benzene-1,2-diamine (JSH-23) to elucidate its role in depression. We investigated the antidepressant-like effects of JSH-23 in the chronic mild stress (CMS) mouse model, which is a valid, reasonably reliable, and useful model of depression. The antidepressant-like effects of JSH-23 were evaluated using the sucrose preference test (SPT) and the forced swimming test (FST). We also assessed inflammatory markers [interleukin (IL)-6 and tumor necrosis factor-α (TNF-α)] and components of antioxidant defense [superoxide dismutase (SOD) and nuclear factor erythroid-2-related factor 2 (Nrf 2)] in the hippocampus. Fluoxetine, a classical antidepressant, was used in this study as a positive control. Administration of JSH-23 significantly prevented the decreased sucrose preference in the SPT and prevented the increased immobility time in the FST caused by CMS, but had no effect on locomotor activity. Expression of NF-κB p65 protein in the hippocampus was decreased, and elevated levels of IL-6 and TNF-α were reduced, after JSH-23 administration. In addition to its anti-inflammatory effect, JSH-23 treatment increased the expression of SOD and Nrf 2 in the hippocampus, suggesting that it strengthens antioxidant defense. The current study demonstrated that inhibiting the NF-κB signaling cascade using JSH-23 prevented depressive-like behaviors by decreasing inflammation and improving antioxidant defense in the hippocampus. We concluded that NF-κB activation plays an important role in the pathophysiology of depression and that targeting NF-κB signaling may provide a novel and effective therapy for depression. Additional preclinical studies and clinical trials are, however, needed to further elucidate the effects of this therapeutic strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

The profitability of automatic milking on Dutch dairy farms.

PubMed

Bijl, R; Kooistra, S R; Hogeveen, H

2007-01-01

Several studies have reported on the profitability of automatic milking based on different simulation models, but a data-based study using actual farm data has been lacking. The objective of this study was to analyze the profitability of dairy farms having an automatic milking system (AMS) compared with farms using a conventional milking system (CMS) based on real accounting data. In total, 62 farms (31 using an AMS and 31 using a CMS) were analyzed for the year 2003 in a case control study. Differences between the years 2002 and 2003 also were analyzed by comparing a subgroup of 16 farms with an AMS and 16 farms with a CMS. Matching was based on the time of investment in a milking system (same year), the total milk production per year, and intensity of land use (kg/ha). Results from 2003 showed that the farms with an AMS used, on average, 29% less labor than farms with a CMS. In contrast, farms using a CMS grew faster (37,132 kg of milk quota and 5 dairy cows) than farms with an AMS (-3,756 kg milk quota and 0.5 dairy cows) between 2002 and 2003. Dairy farmers with a CMS had larger (euro7,899) revenues than those with an AMS. However, no difference in the margin on dairy production was detected, partly because of numerically greater (euro6,822) variable costs on CMS farms. Dairy farms were compared financially based on the amount of money that was available for rent, depreciation, interest, labor, and profit (RDILP). The CMS farms had more money (euro15,566) available for RDILP than the AMS farms. This difference was caused by larger fixed costs (excluding labor) for the AMS farms, larger contractor costs (euro6,422), and larger costs for gas, water, and electricity (euro1,549). Differences in costs for contractors and for gas, water, and electricity were statistically significant. When expressed per full-time employee, AMS farms had greater revenues, margins, and gross margins per full-time employee than did CMS farms. This resulted in a substantially greater (but not statistically significant) RDILP per full-time employee (euro12,953) for AMS farms compared with CMS farms. Depreciation and interest costs for automatic milking were not available but were calculated based on several assumptions. Assuming larger purchase costs and a shorter depreciation time for AMS than for CMS, costs for depreciation and interest were larger for AMS farms than for CMS farms. Larger fixed costs should be compensated for by the amount of labor that has become available after introducing the milking robot. Therefore, farm managers should decide whether the extra time acquired by automatic milking balances against the extra costs associated with an AMS.

Importance of weak minerals on earthquake mechanics

NASA Astrophysics Data System (ADS)

Kaneki, S.; Hirono, T.

2017-12-01

The role of weak minerals such as smectite and talc on earthquake mechanics is one of the important issues, and has been debated for recent several decades. Traditionally weak minerals in fault have been reported to weaken fault strength causing from its low frictional resistance. Furthermore, velocity-strengthening behavior of such weak mineral (talc) is considered to responsible for fault creep (aseismic slip) in the San Andreas fault. In contrast, recent studies reported that large amount of weak smectite in the Japan Trench could facilitate gigantic seismic slip during the 2011 Tohoku-oki earthquake. To investigate the role of weak minerals on rupture propagation process and magnitude of slip, we focus on the frictional properties of carbonaceous materials (CMs), which is the representative weak materials widely distributed in and around the convergent boundaries. Field observation and geochemical analyses revealed that graphitized CMs-layer is distributed along the slip surface of a fossil plate-subduction fault. Laboratory friction experiments demonstrated that pure quartz, bulk mixtures with bituminous coal (1 wt.%), and quartz with layered coal samples exhibited almost similar frictional properties (initial, yield, and dynamic friction). However, mixtures of quartz (99 wt.%) and layered graphite (1 wt.%) showed significantly lower initial and yield friction coefficient (0.31 and 0.50, respectively). Furthermore, the stress ratio S, defined as (yield stress-initial stress)/(initial stress-dynamic stress), increased in layered graphite samples (1.97) compared to quartz samples (0.14). Similar trend was observed in smectite-rich fault gouge. By referring the reported results of dynamic rupture propagation simulation using S ratio of 1.4 (typical value for the Japan Trench) and 2.0 (this study), we confirmed that higher S ratio results in smaller slip distance by approximately 20 %. On the basis of these results, we could conclude that weak minerals have lower initial/yield strength and higher S ratio, and thus restrain magnitude of slip during earthquake.

An intermittent rocking platform for integrated expansion and differentiation of human pluripotent stem cells to cardiomyocytes in suspended microcarrier cultures.

PubMed

Ting, Sherwin; Chen, Allen; Reuveny, Shaul; Oh, Steve

2014-09-01

The development of novel platforms for large scale production of human embryonic stem cells (hESC) derived cardiomyocytes (CM) becomes more crucial as the demand for CMs in preclinical trials, high throughput cardio toxicity assays and future regenerative therapeutics rises. To this end, we have designed a microcarrier (MC) suspension agitated platform that integrates pluripotent hESC expansion followed by CM differentiation in a continuous, homogenous process. Hydrodynamic shear stresses applied during the hESC expansion and CM differentiation steps drastically reduced the capability of the cells to differentiate into CMs. Applying vigorous stirring during pluripotent hESC expansion on Cytodex 1 MC in spinner cultures resulted in low CM yields in the following differentiation step (cardiac troponin-T (cTnT): 22.83±2.56%; myosin heavy chain (MHC): 19.30±5.31%). Whereas the lower shear experienced in side to side rocker (wave type) platform resulted in higher CM yields (cTNT: 47.50±7.35%; MHC: 42.85±2.64%). The efficiency of CM differentiation is also affected by the hydrodynamic shear stress applied during the first 3days of the differentiation stage. Even low shear applied continuously by side to side rocker agitation resulted in very low CM differentiation efficiency (cTnT<5%; MHC<2%). Simply by applying intermittent agitation during these 3days followed by continuous agitation for the subsequent 9days, CM differentiation efficiency can be substantially increased (cTNT: 65.73±10.73%; MHC: 59.73±9.17%). These yields are 38.3% and 39.3% higher (for cTnT and MHC respectively) than static culture control. During the hESC expansion phase, cells grew on continuously agitated rocker platform as pluripotent cell/MC aggregates (166±88×10(5)μm(2)) achieving a cell concentration of 3.74±0.55×10(6)cells/mL (18.89±2.82 fold expansion) in 7days. These aggregates were further differentiated into CMs using a WNT modulation differentiation protocol for the subsequent 12days on a rocking platform with an intermittent agitation regime during the first 3days. Collectively, the integrated MC rocker platform produced 190.5±58.8×10(6) CMs per run (31.75±9.74 CM/hESC seeded). The robustness of the system was demonstrated by using 2 cells lines, hESC (HES-3) and human induced pluripotent stem cell (hiPSC) IMR-90. The CM/MC aggregates formed extensive sarcomeres that exhibited cross-striations confirming cardiac ontogeny. Functionality of the CMs was demonstrated by monitoring the effect of inotropic drug, Isoproterenol on beating frequency. In conclusion, we have developed a simple robust and scalable platform that integrates both hESC expansion and CM differentiation in one unit process which is capable of meeting the need for large amounts of CMs. Copyright © 2014. Published by Elsevier B.V.

Prolonged swimming performance of northern squawfish

USGS Publications Warehouse

Mesa, Matthew G.; Olson, Todd M.

1993-01-01

We determined the prolonged swimming performance of two size-classes of northern squawfish Ptychocheilus oregonensis at 12 and 18°C. The percentage of fish fatigued was positively related to water velocity and best described by an exponential model. At 12°C, the velocity at which 50% of the fish fatigued (FV50) was estimated to be 2.91 fork lengths per second (FL/s; 100 cm/s) for medium-sized fish (30–39 cm) and 2.45 FL/s (104 cm/s) for large fish (40–49 cm). At 18°C, estimated FV50 was 3.12 FL/s (107 cm/s) for medium fish and 2.65 FL/s (112 cm/s) for large fish. Rate of change in percent fatigue was affected by fish size and water temperature. Large fish fatigued at a higher rate than medium-sized fish; all fish fatigued faster at 12 than at 18°C. The mean times to fatigue at velocities of 102–115 cm/s ranged from 14 to 28 min and were not affected by fish size or water temperature. Our results indicate that water velocities from 100 to 130 cm/s may exclude or reduce predation by northern squawfish around juvenile salmonid bypass outfalls at Columbia River dams, at least during certain times of the year. We recommend that construction or modification of juvenile salmonid bypass facilities place the outfall in an area of high water velocity and distant from eddies, submerged cover, and littoral areas.

Direct Cardiac Reprogramming as a Novel Therapeutic Strategy for Treatment of Myocardial Infarction.

PubMed

Ma, Hong; Wang, Li; Liu, Jiandong; Qian, Li

2017-01-01

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds great promise as a novel therapy for the treatment of heart failure, a common and morbid disease that is usually caused by irreversible loss of functional cardiomyocytes (CMs). Recently, we and others showed that in a murine model of acute myocardial infarction, delivery of three transcription factors, Gata4, Mef2c, and Tbx5 converted endogenous cardiac fibroblasts into functional iCMs. These iCMs integrated electrically and mechanically with surrounding myocardium, resulting in a reduction in scar size and an improvement in heart function. Our findings suggest that iCM reprogramming may be a means of regenerating functional CMs in vivo for patients with heart disease. However, because relatively little is known about the factors that regulate iCM reprogramming, the applicability of iCM reprogramming is currently limited to the experimental settings in which it has been attempted. Specific hurdles include the relatively low conversion rate of iCMs and the need for reprogramming to occur in the context of acute injury. Therefore, before this treatment can become a viable therapy for human heart disease, the optimal condition for efficient iCM generation must be determined. Here, we provide a detailed protocol for both in vitro and in vivo iCM generation that has been optimized so far in our lab. We hope that this protocol will lay a foundation for future further improvement of iCM generation and provide a platform for mechanistic studies.

Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

PubMed Central

Kuppusamy, Kavitha T.; Jones, Daniel C.; Sperber, Henrik; Madan, Anup; Fischer, Karin A.; Rodriguez, Marita L.; Pabon, Lil; Zhu, Wei-Zhong; Tulloch, Nathaniel L.; Yang, Xiulan; Sniadecki, Nathan J.; Laflamme, Michael A.; Murry, Charles E.; Ruohola-Baker, Hannele

2015-01-01

In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain- and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7–driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research. PMID:25964336

Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Bradycardiac Effects Caused by Co-Administration of Sofosbuvir and Amiodarone.

PubMed

Yu, Yankun; Liu, Feng; He, Liuming; Ramakrishna, Seeram; Zheng, Monica; Bu, Lei; Xu, Ying

2018-05-30

Co-administration of sofosbuvir, an anti-hepatitis C virus medication, and antiarrhythmic amiodarone causes symptomatic severe bradycardia in patients and animal models. However, in a few in vitro studies, the combination of sofosbuvir and amiodarone resulted in tachycardiac effects in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This discrepancy may be attributable to the use of immature hiPSC-CMs in the in vitro studies. To address this, we evaluated the ability of our in-house hiPSC-CMs to assess the interactions between sofosbuvir and amiodarone in vitro. We performed whole-cell patch recordings on hiPSC-CMs to examine the cardiac effect of sofosbuvir and amiodarone, alone or in combination. We found that sofosbuvir and amiodarone caused bradycardiac effects (the beating rate decreased to 75% of the vehicle control, P < 0.001) on our hiPSC-CMs when applied in combination, but they had no significant effect when applied alone. Furthermore, the bradycardiac effect was membrane potential dependent: it increased with depolarization. This raised the possibility that the bradycardiac effects in vivo may originate in nodal cells, which have a more depolarized resting membrane potential compared with ventricular cells. The bradycardiac effects of sofosbuvir plus amiodarone in vitro are consistent with the clinical phenotype and suggest that our hiPSC-CMs may serve as a useful tool in assessing cardiac safety during drug discovery and development process.

77 FR 31618 - Medicaid Program; Announcement of Requirements and Registration for CMS Provider Screening...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-29

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Medicare & Medicaid Services (CMS) [CMS-2382-N... Challenge AGENCY: Centers for Medicare & Medicaid Services (CMS), HHS. ACTION: Notice. SUMMARY: The Centers for Medicare & Medicaid Services (CMS), is announcing the launch of the ``CMS Provider Screening...

Measurement of the W charge asymmetry in production with jets using 5 inverse-femtobarns of data measured at center of mass energy = 7TeV with CMS

NASA Astrophysics Data System (ADS)

Lawson, Philip Daniel

A measurement of the electron charge asymmetry in p+p→W production in association with jets at sqrt{s}=7 TeV is presented. The dataset corresponds to an integrated luminosity of L=5fb-1 recorded by the CMS detector in proton-proton collisions at the LHC. The sample represents a large increase in statistical precision with respect to previous CMS results and describes a first study of charge asymmetry measured in p+p→W+1 jet events. Full comparisons to previous results and theoretical predictions are provided and recommendations for extending the analysis to produce valuable input for future PDF models are made.

Bundle Payment Program Initiative: Roles of a Nurse Navigator and Home Health Professionals.

PubMed

Peiritsch, Heather

2017-06-01

With the passage of the Affordable Care Act, The Centers for Medicare and Medicaid (CMS) introduced a new value-based payment model, the Bundle Payment Care Initiative. The CMS Innovation (Innovation Center) authorized hospitals to participate in a pilot to test innovative payment and service delivery models that have a potential to reduce Medicare expenditures while maintaining or improving the quality of care for beneficiaries. A hospital-based home care agency, Abington Jefferson Health Home Care Department, led the initiative for the development and implementation of the Bundled Payment Program. This was a creative and innovative method to improve care along the continuum while testing a value-based care model.

Psychometric properties of seven self-report measures of posttraumatic stress disorder in college students with mixed civilian trauma exposure.

PubMed

Adkins, Jennifer W; Weathers, Frank W; McDevitt-Murphy, Meghan; Daniels, Jennifer B

2008-12-01

In this study psychometric properties of seven self-report measures of posttraumatic stress disorder (PTSD) were compared. The seven scales evaluated were the Davidson Trauma Scale (DTS), the PTSD Checklist (PCL), the Posttraumatic Stress Diagnostic Scale (PDS), the Civilian Mississippi Scale (CMS), the Impact of Event Scale-Revised (IES-R), the Penn Inventory for Posttraumatic Stress Disorder (Penn), and the PK scale of the MMPI-2 (PK). Participants were 239 (79 male and 160 female) trauma-exposed undergraduates. All seven measures exhibited good test-retest reliability and internal consistency. The PDS, PCL and DTS demonstrated the best convergent validity; the IES-R, PDS, and PCL demonstrated the best discriminant validity; and the PDS, PCL, and IES-R demonstrated the best diagnostic utility. Overall, results most strongly support the use of the PDS and the PCL for the assessment of PTSD in this population.

The long journey to the Higgs boson and beyond at the LHC: Emphasis on CMS

NASA Astrophysics Data System (ADS)

Virdee, Tejinder Singh

2016-11-01

Since 2010 there has been a rich harvest of results on standard model physics by the ATLAS and CMS experiments operating on the Large Hadron Collider. In the summer of 2012, a spectacular discovery was made by these experiments of a new, heavy particle. All the subsequently analysed data point strongly to the properties of this particle as those expected for the Higgs boson associated with the Brout-Englert-Higgs mechanism postulated to explain the spontaneous symmetry breaking in the electroweak sector, thereby explaining how elementary particles acquire mass. This article focuses on the CMS experiment, the technological challenges encountered in its construction, describing some of the physics results obtained so far, including the discovery of the Higgs boson, and searches for the widely anticipated new physics beyond the standard model, and peer into the future involving the high-luminosity phase of the LHC. This article is complementary to the one by Peter Jenni4 that focuses on the ATLAS experiment.

Dynamic behavior of cellular materials and cellular structures: Experiments and modeling

NASA Astrophysics Data System (ADS)

Gao, Ziyang

Cellular solids, including cellular materials and cellular structures (CMS), have attracted people's great interests because of their low densities and novel physical, mechanical, thermal, electrical and acoustic properties. They offer potential for lightweight structures, energy absorption, thermal management, etc. Therefore, the studies of cellular solids have become one of the hottest research fields nowadays. From energy absorption point of view, any plastically deformed structures can be divided into two types (called type I and type II), and the basic cells of the CMS may take the configurations of these two types of structures. Accordingly, separated discussions are presented in this thesis. First, a modified 1-D model is proposed and numerically solved for a typical type II structure. Good agreement is achieved with the previous experimental data, hence is used to simulate the dynamic behavior of a type II chain. Resulted from different load speeds, interesting collapse modes are observed, and the parameters which govern the cell's post-collapse behavior are identified through a comprehensive non-dimensional analysis on general cellular chains. Secondly, the MHS specimens are chosen as an example of type I foam materials because of their good uniformity of the cell geometry. An extensive experimental study was carried out, where more attention was paid to their responses to dynamic loadings. Great enhancement of the stress-strain curve was observed in dynamic cases, and the energy absorption capacity is found to be several times higher than that of the commercial metal foams. Based on the experimental study, finite elemental simulations and theoretical modeling are also conducted, achieving good agreements and demonstrating the validities of those models. It is believed that the experimental, numerical and analytical results obtained in the present study will certainly deepen the understanding of the unsolved fundamental issues on the mechanical behavior of cellular solids and make substantial contributions to the theoretical advance of impact dynamics.

Novel MRI Contrast Agent from Magnetotactic Bacteria Enables In Vivo Tracking of iPSC-derived Cardiomyocytes.

PubMed

Mahmoudi, Morteza; Tachibana, Atsushi; Goldstone, Andrew B; Woo, Y Joseph; Chakraborty, Papia; Lee, Kayla R; Foote, Chandler S; Piecewicz, Stephanie; Barrozo, Joyce C; Wakeel, Abdul; Rice, Bradley W; Bell Iii, Caleb B; Yang, Phillip C

2016-06-06

Therapeutic delivery of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) represents a novel clinical approach to regenerate the injured myocardium. However, methods for robust and accurate in vivo monitoring of the iCMs are still lacking. Although superparamagnetic iron oxide nanoparticles (SPIOs) are recognized as a promising tool for in vivo tracking of stem cells using magnetic resonance imaging (MRI), their signal persists in the heart even weeks after the disappearance of the injected cells. This limitation highlights the inability of SPIOs to distinguish stem cell viability. In order to overcome this shortcoming, we demonstrate the use of a living contrast agent, magneto-endosymbionts (MEs) derived from magnetotactic bacteria for the labeling of iCMs. The ME-labeled iCMs were injected into the infarcted area of murine heart and probed by MRI and bioluminescence imaging (BLI). Our findings demonstrate that the MEs are robust and effective biological contrast agents to track iCMs in an in vivo murine model. We show that the MEs clear within one week of cell death whereas the SPIOs remain over 2 weeks after cell death. These findings will accelerate the clinical translation of in vivo MRI monitoring of transplanted stem cell at high spatial resolution and sensitivity.

A search for a heavy Majorana neutrino and a radiation damage simulation for the HF detector

NASA Astrophysics Data System (ADS)

Wetzel, James William

A search for heavy Majorana neutrinos is performed using an event signature defined by two same-sign muons accompanied by two jets. This search is an extension of previous searches, (L3, DELPHI, CMS, ATLAS), using 19.7 fb -1 of data from the 2012 Large Hadron Collider experimental run collected by the Compact Muon Solenoid experiment. A mass window of 40-500 GeV/ c2 is explored. No excess events above Standard Model backgrounds is observed, and limits are set on the mixing element squared, |VmuN|2, as a function of Majorana neutFnrino mass. The Hadronic Forward (HF) Detector's performance will degrade as a function of the number of particles delivered to the detector over time, a quantity referred to as integrated luminosity and measured in inverse femtobarns (fb-1). In order to better plan detector upgrades, the CMS Forward Calorimetry Task Force (FCAL) group and the CMS Hadronic Calorimeter (HCAL) group have requested that radiation damage be simulated and the subsequent performance of the HF subdetector be studied. The simulation was implemented into both the CMS FastSim and CMS FullSim simulation packages. Standard calorimetry performance metrics were computed and are reported. The HF detector can expect to perform well through the planned delivery of 3000 fb-1.

Strongly-sheared wind-forced currents in the nearshore regions of the central Southern California Bight

USGS Publications Warehouse

Noble, Marlene A.; Rosenberger, Kurt; Robertson, George L.

2015-01-01

Contrary to many previous reports, winds do drive currents along the shelf in the central portion of the Southern California Bight (SCB). Winds off Huntington Beach CA are the dominant forcing for currents over the nearshore region of the shelf (water depths less than 20 m). Winds control about 50–70% of the energy in nearshore alongshelf surface currents. The wind-driven current amplitudes are also anomalously high. For a relatively weak 1 dyne/cm2 wind stress, the alongshelf surface current amplitudes in this region can reach 80 cm/s or more. Mid-depth current amplitudes for the same wind stress are around 30–40 cm/s. These wind-driven surface current amplitudes are much larger than previously measured over other nearshore shelf regions, perhaps because this program is one of the few that measured currents within a meter of the surface. The near-bed cross-shelf currents over the nearshore region of the Huntington Beach shelf have an Ekman response to winds in that they upwell (downwell) for down (up) coast winds. This response disappears further offshore. Hence, there is upwelling in the SCB, but it does not occur across the entire shelf. Subthermocline water in the nearshore region that may contain nutrients and plankton move onshore when winds are southeastward, but subthermocline water over the shelf break is not transported to the beach. The currents over the outer shelf are not predominately controlled by winds, consistent with previous reports. Instead, they are mainly driven by cross-shelf pressure gradients that are independent of local wind stress.

Targeting the minimal supersymmetric standard model with the compact muon solenoid experiment

NASA Astrophysics Data System (ADS)

Bein, Samuel Louis

An interpretation of CMS searches for evidence of supersymmetry in the context of the minimal supersymmetric Standard Model (MSSM) is given. It is found that supersymmetric particles with color charge are excluded in the mass range below about 400 GeV, but neutral and weakly-charged sparticles remain non-excluded in all mass ranges. Discussion of the non-excluded regions of the model parameter space is given, including details on the strengths and weaknesses of existing searches, and recommendations for future analysis strategies. Advancements in the modeling of events arising from quantum chromodynamics and electroweak boson production, which are major backgrounds in searches for new physics at the LHC, are also presented. These methods have been implemented as components of CMS searches for supersymmetry in proton-proton collisions resulting in purely hadronic events (i.e., events with no identified leptons) at a center of momentum energy of 13 TeV. These searches, interpreted in the context of simplified models, exclude supersymmetric gluons (gluinos) up to masses of 1400 to 1600 GeV, depending on the model considered, and exclude scalar top quarks with masses up to about 800 GeV, assuming a massless lightest supersymmetric particle. A search for non-excluded supersymmetry models is also presented, which uses multivariate discriminants to isolate potential signal candidate events. The search achieves sensitivity to new physics models in background-dominated kinematic regions not typically considered by analyses, and rules out supersymmetry models that survived 7 and 8 TeV searches performed by CMS.

Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue.

PubMed

Zhang, Miao; D'Aniello, Cristina; Verkerk, Arie O; Wrobel, Eva; Frank, Stefan; Ward-van Oostwaard, Dorien; Piccini, Ilaria; Freund, Christian; Rao, Jyoti; Seebohm, Guiscard; Atsma, Douwe E; Schulze-Bahr, Eric; Mummery, Christine L; Greber, Boris; Bellin, Milena

2014-12-16

Jervell and Lange-Nielsen syndrome (JLNS) is one of the most severe life-threatening cardiac arrhythmias. Patients display delayed cardiac repolarization, associated high risk of sudden death due to ventricular tachycardia, and congenital bilateral deafness. In contrast to the autosomal dominant forms of long QT syndrome, JLNS is a recessive trait, resulting from homozygous (or compound heterozygous) mutations in KCNQ1 or KCNE1. These genes encode the α and β subunits, respectively, of the ion channel conducting the slow component of the delayed rectifier K(+) current, IKs. We used complementary approaches, reprogramming patient cells and genetic engineering, to generate human induced pluripotent stem cell (hiPSC) models of JLNS, covering splice site (c.478-2A>T) and missense (c.1781G>A) mutations, the two major classes of JLNS-causing defects in KCNQ1. Electrophysiological comparison of hiPSC-derived cardiomyocytes (CMs) from homozygous JLNS, heterozygous, and wild-type lines recapitulated the typical and severe features of JLNS, including pronounced action and field potential prolongation and severe reduction or absence of IKs. We show that this phenotype had distinct underlying molecular mechanisms in the two sets of cell lines: the previously unidentified c.478-2A>T mutation was amorphic and gave rise to a strictly recessive phenotype in JLNS-CMs, whereas the missense c.1781G>A lesion caused a gene dosage-dependent channel reduction at the cell membrane. Moreover, adrenergic stimulation caused action potential prolongation specifically in JLNS-CMs. Furthermore, sensitivity to proarrhythmic drugs was strongly enhanced in JLNS-CMs but could be pharmacologically corrected. Our data provide mechanistic insight into distinct classes of JLNS-causing mutations and demonstrate the potential of hiPSC-CMs in drug evaluation.

Screening drug-induced arrhythmia [corrected] using human induced pluripotent stem cell-derived cardiomyocytes and low-impedance microelectrode arrays.

PubMed

Navarrete, Enrique G; Liang, Ping; Lan, Feng; Sanchez-Freire, Verónica; Simmons, Chelsey; Gong, Tingyu; Sharma, Arun; Burridge, Paul W; Patlolla, Bhagat; Lee, Andrew S; Wu, Haodi; Beygui, Ramin E; Wu, Sean M; Robbins, Robert C; Bers, Donald M; Wu, Joseph C

2013-09-10

Drug-induced arrhythmia is one of the most common causes of drug development failure and withdrawal from market. This study tested whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with a low-impedance microelectrode array (MEA) system could improve on industry-standard preclinical cardiotoxicity screening methods, identify the effects of well-characterized drugs, and elucidate underlying risk factors for drug-induced arrhythmia. hiPSC-CMs may be advantageous over immortalized cell lines because they possess similar functional characteristics as primary human cardiomyocytes and can be generated in unlimited quantities. Pharmacological responses of beating embryoid bodies exposed to a comprehensive panel of drugs at 65 to 95 days postinduction were determined. Responses of hiPSC-CMs to drugs were qualitatively and quantitatively consistent with the reported drug effects in literature. Torsadogenic hERG blockers, such as sotalol and quinidine, produced statistically and physiologically significant effects, consistent with patch-clamp studies, on human embryonic stem cell-derived cardiomyocytes hESC-CMs. False-negative and false-positive hERG blockers were identified accurately. Consistent with published studies using animal models, early afterdepolarizations and ectopic beats were observed in 33% and 40% of embryoid bodies treated with sotalol and quinidine, respectively, compared with negligible early afterdepolarizations and ectopic beats in untreated controls. We found that drug-induced arrhythmias can be recapitulated in hiPSC-CMs and documented with low impedance MEA. Our data indicate that the MEA/hiPSC-CM assay is a sensitive, robust, and efficient platform for testing drug effectiveness and for arrhythmia screening. This system may hold great potential for reducing drug development costs and may provide significant advantages over current industry standard assays that use immortalized cell lines or animal models.

Phenomenological MSSM interpretation of CMS searches in pp collisions at $$ \\sqrt{s}=7 $$ and 8 TeV

DOE PAGES

Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; ...

2016-10-24

Searches for new physics by the CMS collaboration are interpreted in the framework of the phenomenological minimal supersymmetric standard model (pMSSM). The data samples used in this study were collected atmore » $$ \\sqrt{s}=7 $$ and 8 TeV and have integrated luminosities of 5.0 fb$$^{-1}$$ and 19.5 fb$$^{-1}$$, respectively. A global Bayesian analysis is performed, incorporating results from a broad range of CMS supersymmetry searches, as well as constraints from other experiments. Because the pMSSM incorporates several well-motivated assumptions that reduce the 120 parameters of the MSSM to just 19 parameters defined at the electroweak scale, it is possible to assess the results of the study in a relatively straightforward way. Approximately half of the model points in a potentially accessible subspace of the pMSSM are excluded, including all pMSSM model points with a gluino mass below 500 GeV, as well as models with a squark mass less than 300 GeV. Models with chargino and neutralino masses below 200 GeV are disfavored, but no mass range of model points can be ruled out based on the analyses considered. Lastly, the nonexcluded regions in the pMSSM parameter space are characterized in terms of physical processes and key observables, and implications for future searches are discussed.« less

Phenomenological MSSM interpretation of CMS searches in pp collisions at $$ \\sqrt{s}=7 $$ and 8 TeV

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

Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.

Searches for new physics by the CMS collaboration are interpreted in the framework of the phenomenological minimal supersymmetric standard model (pMSSM). The data samples used in this study were collected atmore » $$ \\sqrt{s}=7 $$ and 8 TeV and have integrated luminosities of 5.0 fb$$^{-1}$$ and 19.5 fb$$^{-1}$$, respectively. A global Bayesian analysis is performed, incorporating results from a broad range of CMS supersymmetry searches, as well as constraints from other experiments. Because the pMSSM incorporates several well-motivated assumptions that reduce the 120 parameters of the MSSM to just 19 parameters defined at the electroweak scale, it is possible to assess the results of the study in a relatively straightforward way. Approximately half of the model points in a potentially accessible subspace of the pMSSM are excluded, including all pMSSM model points with a gluino mass below 500 GeV, as well as models with a squark mass less than 300 GeV. Models with chargino and neutralino masses below 200 GeV are disfavored, but no mass range of model points can be ruled out based on the analyses considered. Lastly, the nonexcluded regions in the pMSSM parameter space are characterized in terms of physical processes and key observables, and implications for future searches are discussed.« less

Phenomenological MSSM interpretation of CMS searches in pp collisions at √{s}=7 and 8 TeV

NASA Astrophysics Data System (ADS)

Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; Adam, W.; Asilar, E.; Bergauer, T.; Brandstetter, J.; Brondolin, E.; Dragicevic, M.; Erö, J.; Flechl, M.; Friedl, M.; Frühwirth, R.; Ghete, V. M.; Hartl, C.; Hörmann, N.; Hrubec, J.; Jeitler, M.; König, A.; Krammer, M.; Krätschmer, I.; Liko, D.; Matsushita, T.; Mikulec, I.; Rabady, D.; Rad, N.; Rahbaran, B.; Rohringer, H.; Schieck, J.; Schöfbeck, R.; Strauss, J.; Treberer-Treberspurg, W.; Waltenberger, W.; Wulz, C.-E.; Mossolov, V.; Shumeiko, N.; Suarez Gonzalez, J.; Alderweireldt, S.; Cornelis, T.; de Wolf, E. A.; Janssen, X.; Knutsson, A.; Lauwers, J.; Luyckx, S.; van de Klundert, M.; van Haevermaet, H.; van Mechelen, P.; van Remortel, N.; van Spilbeeck, A.; Abu Zeid, S.; Blekman, F.; D'Hondt, J.; Daci, N.; de Bruyn, I.; Deroover, K.; Heracleous, N.; Keaveney, J.; Lowette, S.; Moortgat, S.; Moreels, L.; Olbrechts, A.; Python, Q.; Strom, D.; Tavernier, S.; van Doninck, W.; van Mulders, P.; van Onsem, G. P.; van Parijs, I.; Brun, H.; Caillol, C.; Clerbaux, B.; de Lentdecker, G.; Fasanella, G.; Favart, L.; Goldouzian, R.; Grebenyuk, A.; Karapostoli, G.; Lenzi, T.; Léonard, A.; Maerschalk, T.; Marinov, A.; Perniè, L.; Randle-Conde, A.; Seva, T.; Vander Velde, C.; Vanlaer, P.; Yonamine, R.; Zenoni, F.; Zhang, F.; Beernaert, K.; Benucci, L.; Cimmino, A.; Crucy, S.; Dobur, D.; Fagot, A.; Garcia, G.; Gul, M.; McCartin, J.; Ocampo Rios, A. A.; Poyraz, D.; Ryckbosch, D.; Salva, S.; Sigamani, M.; Tytgat, M.; van Driessche, W.; Yazgan, E.; Zaganidis, N.; Basegmez, S.; Beluffi, C.; Bondu, O.; Brochet, S.; Bruno, G.; Caudron, A.; Ceard, L.; de Visscher, S.; Delaere, C.; Delcourt, M.; Favart, D.; Forthomme, L.; Giammanco, A.; Jafari, A.; Jez, P.; Komm, M.; Lemaitre, V.; Mertens, A.; Musich, M.; Nuttens, C.; Perrini, L.; Piotrzkowski, K.; Quertenmont, L.; Selvaggi, M.; Vidal Marono, M.; Beliy, N.; Hammad, G. H.; Aldá Júnior, W. L.; Alves, F. L.; Alves, G. A.; Brito, L.; Correa Martins Junior, M.; Hamer, M.; Hensel, C.; Moraes, A.; Pol, M. E.; Rebello Teles, P.; Belchior Batista Das Chagas, E.; Carvalho, W.; Chinellato, J.; Custódio, A.; da Costa, E. M.; de Jesus Damiao, D.; de Oliveira Martins, C.; Fonseca de Souza, S.; Huertas Guativa, L. M.; Malbouisson, H.; Matos Figueiredo, D.; Mora Herrera, C.; Mundim, L.; Nogima, H.; Prado da Silva, W. L.; Santoro, A.; Sznajder, A.; Tonelli Manganote, E. J.; Vilela Pereira, A.; Ahuja, S.; Bernardes, C. A.; de Souza Santos, A.; Dogra, S.; Fernandez Perez Tomei, T. R.; Gregores, E. M.; Mercadante, P. G.; Moon, C. S.; Novaes, S. F.; Padula, Sandra S.; Romero Abad, D.; Ruiz Vargas, J. C.; Aleksandrov, A.; Hadjiiska, R.; Iaydjiev, P.; Rodozov, M.; Stoykova, S.; Sultanov, G.; Vutova, M.; Dimitrov, A.; Glushkov, I.; Litov, L.; Pavlov, B.; Petkov, P.; Fang, W.; Ahmad, M.; Bian, J. G.; Chen, G. M.; Chen, H. S.; Chen, M.; Cheng, T.; Du, R.; Jiang, C. H.; Leggat, D.; Plestina, R.; Romeo, F.; Shaheen, S. M.; Spiezia, A.; Tao, J.; Wang, C.; Wang, Z.; Zhang, H.; Asawatangtrakuldee, C.; Ban, Y.; Li, Q.; Liu, S.; Mao, Y.; Qian, S. J.; Wang, D.; Xu, Z.; Avila, C.; Cabrera, A.; Chaparro Sierra, L. F.; Florez, C.; Gomez, J. P.; Gomez Moreno, B.; Sanabria, J. C.; Godinovic, N.; Lelas, D.; Puljak, I.; Ribeiro Cipriano, P. M.; Antunovic, Z.; Kovac, M.; Brigljevic, V.; Kadija, K.; Luetic, J.; Micanovic, S.; Sudic, L.; Attikis, A.; Mavromanolakis, G.; Mousa, J.; Nicolaou, C.; Ptochos, F.; Razis, P. A.; Rykaczewski, H.; Finger, M.; Finger, M.; Elkafrawy, T.; Mahmoud, M. A.; Mohammed, Y.; Calpas, B.; Kadastik, M.; Murumaa, M.; Raidal, M.; Tiko, A.; Veelken, C.; Eerola, P.; Pekkanen, J.; Voutilainen, M.; Härkönen, J.; Karimäki, V.; Kinnunen, R.; Lampén, T.; Lassila-Perini, K.; Lehti, S.; Lindén, T.; Luukka, P.; Peltola, T.; Tuominiemi, J.; Tuovinen, E.; Wendland, L.; Talvitie, J.; Tuuva, T.; Besancon, M.; Couderc, F.; Dejardin, M.; Denegri, D.; Fabbro, B.; Faure, J. L.; Favaro, C.; Ferri, F.; Ganjour, S.; Givernaud, A.; Gras, P.; Hamel de Monchenault, G.; Jarry, P.; Locci, E.; Machet, M.; Malcles, J.; Rander, J.; Rosowsky, A.; Titov, M.; Zghiche, A.; Abdulsalam, A.; Antropov, I.; Baffioni, S.; Beaudette, F.; Busson, P.; Cadamuro, L.; Chapon, E.; Charlot, C.; Davignon, O.; Filipovic, N.; Granier de Cassagnac, R.; Jo, M.; Kraml, S.; Lisniak, S.; Miné, P.; Naranjo, I. N.; Nguyen, M.; Ochando, C.; Ortona, G.; Paganini, P.; Pigard, P.; Regnard, S.; Salerno, R.; Sirois, Y.; Strebler, T.; Yilmaz, Y.; Zabi, A.; Agram, J.-L.; Andrea, J.; Aubin, A.; Bloch, D.; Brom, J.-M.; Buttignol, M.; Chabert, E. C.; Chanon, N.; Collard, C.; Conte, E.; Coubez, X.; Fontaine, J.-C.; Gelé, D.; Goerlach, U.; Goetzmann, C.; Le Bihan, A.-C.; Merlin, J. A.; Skovpen, K.; van Hove, P.; Gadrat, S.; Beauceron, S.; Bernet, C.; Boudoul, G.; Bouvier, E.; Carrillo Montoya, C. A.; Chierici, R.; Contardo, D.; Courbon, B.; Depasse, P.; El Mamouni, H.; Fan, J.; Fay, J.; Gascon, S.; Gouzevitch, M.; Ille, B.; Lagarde, F.; Laktineh, I. B.; Lethuillier, M.; Mirabito, L.; Pequegnot, A. L.; Perries, S.; Popov, A.; Ruiz Alvarez, J. D.; Sabes, D.; Sordini, V.; Vander Donckt, M.; Verdier, P.; Viret, S.; Toriashvili, T.; Tsamalaidze, Z.; Autermann, C.; Beranek, S.; Feld, L.; Heister, A.; Kiesel, M. K.; Klein, K.; Lipinski, M.; Ostapchuk, A.; Preuten, M.; Raupach, F.; Schael, S.; Schulte, J. 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M.; Pistone, C.; Pooth, O.; Stahl, A.; Aldaya Martin, M.; Asin, I.; Bartosik, N.; Behnke, O.; Behrens, U.; Borras, K.; Burgmeier, A.; Campbell, A.; Contreras-Campana, C.; Costanza, F.; Diez Pardos, C.; Dolinska, G.; Dooling, S.; Dorland, T.; Eckerlin, G.; Eckstein, D.; Eichhorn, T.; Flucke, G.; Gallo, E.; Garay Garcia, J.; Geiser, A.; Gizhko, A.; Gunnellini, P.; Hauk, J.; Hempel, M.; Jung, H.; Kalogeropoulos, A.; Karacheban, O.; Kasemann, M.; Katsas, P.; Kieseler, J.; Kleinwort, C.; Korol, I.; Lange, W.; Leonard, J.; Lipka, K.; Lobanov, A.; Lohmann, W.; Mankel, R.; Melzer-Pellmann, I.-A.; Meyer, A. B.; Mittag, G.; Mnich, J.; Mussgiller, A.; Naumann-Emme, S.; Nayak, A.; Ntomari, E.; Perrey, H.; Pitzl, D.; Placakyte, R.; Raspereza, A.; Roland, B.; Sahin, M. Ö.; Saxena, P.; Schoerner-Sadenius, T.; Seitz, C.; Spannagel, S.; Stefaniuk, N.; Trippkewitz, K. D.; Walsh, R.; Wissing, C.; Blobel, V.; Centis Vignali, M.; Draeger, A. 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U.; Müller, T.; Müller, Th.; Plagge, M.; Quast, G.; Rabbertz, K.; Röcker, S.; Roscher, F.; Schröder, M.; Sieber, G.; Simonis, H. J.; Ulrich, R.; Wagner-Kuhr, J.; Wayand, S.; Weber, M.; Weiler, T.; Williamson, S.; Wöhrmann, C.; Wolf, R.; Anagnostou, G.; Daskalakis, G.; Geralis, T.; Giakoumopoulou, V. A.; Kyriakis, A.; Loukas, D.; Psallidas, A.; Topsis-Giotis, I.; Agapitos, A.; Kesisoglou, S.; Panagiotou, A.; Saoulidou, N.; Tziaferi, E.; Evangelou, I.; Flouris, G.; Foudas, C.; Kokkas, P.; Loukas, N.; Manthos, N.; Papadopoulos, I.; Paradas, E.; Strologas, J.; Bencze, G.; Hajdu, C.; Hidas, P.; Horvath, D.; Sikler, F.; Veszpremi, V.; Vesztergombi, G.; Zsigmond, A. J.; Beni, N.; Czellar, S.; Karancsi, J.; Molnar, J.; Szillasi, Z.; Bartók, M.; Makovec, A.; Raics, P.; Trocsanyi, Z. L.; Ujvari, B.; Choudhury, S.; Mal, P.; Mandal, K.; Sahoo, D. K.; Sahoo, N.; Swain, S. K.; Bansal, S.; Beri, S. B.; Bhatnagar, V.; Chawla, R.; Gupta, R.; Bhawandeep, U.; Kalsi, A. 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M.; Fahim, A.; Khakzad, M.; Mohammadi Najafabadi, M.; Naseri, M.; Paktinat Mehdiabadi, S.; Rezaei Hosseinabadi, F.; Safarzadeh, B.; Zeinali, M.; Felcini, M.; Grunewald, M.; Abbrescia, M.; Calabria, C.; Caputo, C.; Colaleo, A.; Creanza, D.; Cristella, L.; de Filippis, N.; de Palma, M.; Fiore, L.; Iaselli, G.; Maggi, G.; Maggi, M.; Miniello, G.; My, S.; Nuzzo, S.; Pompili, A.; Pugliese, G.; Radogna, R.; Ranieri, A.; Selvaggi, G.; Silvestris, L.; Venditti, R.; Abbiendi, G.; Battilana, C.; Bonacorsi, D.; Braibant-Giacomelli, S.; Brigliadori, L.; Campanini, R.; Capiluppi, P.; Castro, A.; Cavallo, F. R.; Chhibra, S. S.; Codispoti, G.; Cuffiani, M.; Dallavalle, G. M.; Fabbri, F.; Fanfani, A.; Fasanella, D.; Giacomelli, P.; Grandi, C.; Guiducci, L.; Marcellini, S.; Masetti, G.; Montanari, A.; Navarria, F. L.; Perrotta, A.; Rossi, A. M.; Rovelli, T.; Siroli, G. 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M.; Lanza, G.; Lista, L.; Meola, S.; Merola, M.; Paolucci, P.; Sciacca, C.; Thyssen, F.; Azzi, P.; Bacchetta, N.; Benato, L.; Bisello, D.; Boletti, A.; Branca, A.; Carlin, R.; Checchia, P.; Dall'Osso, M.; Dorigo, T.; Dosselli, U.; Gasparini, F.; Gasparini, U.; Gozzelino, A.; Kanishchev, K.; Lacaprara, S.; Margoni, M.; Meneguzzo, A. T.; Pazzini, J.; Pozzobon, N.; Ronchese, P.; Simonetto, F.; Torassa, E.; Tosi, M.; Ventura, S.; Zanetti, M.; Zotto, P.; Zucchetta, A.; Zumerle, G.; Braghieri, A.; Magnani, A.; Montagna, P.; Ratti, S. P.; Re, V.; Riccardi, C.; Salvini, P.; Vai, I.; Vitulo, P.; Alunni Solestizi, L.; Bilei, G. M.; Ciangottini, D.; Fanò, L.; Lariccia, P.; Mantovani, G.; Menichelli, M.; Saha, A.; Santocchia, A.; Androsov, K.; Azzurri, P.; Bagliesi, G.; Bernardini, J.; Boccali, T.; Castaldi, R.; Ciocci, M. A.; Dell'Orso, R.; Donato, S.; Fedi, G.; Foà, L.; Giassi, A.; Grippo, M. T.; Ligabue, F.; Lomtadze, T.; Martini, L.; Messineo, A.; Palla, F.; Rizzi, A.; Savoy-Navarro, A.; Spagnolo, P.; Tenchini, R.; Tonelli, G.; Venturi, A.; Verdini, P. G.; Barone, L.; Cavallari, F.; D'Imperio, G.; Del Re, D.; Diemoz, M.; Gelli, S.; Jorda, C.; Longo, E.; Margaroli, F.; Meridiani, P.; Organtini, G.; Paramatti, R.; Preiato, F.; Rahatlou, S.; Rovelli, C.; Santanastasio, F.; Amapane, N.; Arcidiacono, R.; Argiro, S.; Arneodo, M.; Bellan, R.; Biino, C.; Cartiglia, N.; Costa, M.; Covarelli, R.; Degano, A.; Demaria, N.; Finco, L.; Kiani, B.; Mariotti, C.; Maselli, S.; Migliore, E.; Monaco, V.; Monteil, E.; Obertino, M. M.; Pacher, L.; Pastrone, N.; Pelliccioni, M.; Pinna Angioni, G. L.; Ravera, F.; Romero, A.; Ruspa, M.; Sacchi, R.; Solano, A.; Staiano, A.; Belforte, S.; Candelise, V.; Casarsa, M.; Cossutti, F.; Della Ricca, G.; Gobbo, B.; La Licata, C.; Schizzi, A.; Zanetti, A.; Kropivnitskaya, A.; Nam, S. K.; Kim, D. H.; Kim, G. N.; Kim, M. S.; Kong, D. J.; Lee, S.; Lee, S. W.; Oh, Y. D.; Sakharov, A.; Sekmen, S.; Son, D. C.; Brochero Cifuentes, J. A.; Kim, H.; Kim, T. J.; Song, S.; Cho, S.; Choi, S.; Go, Y.; Gyun, D.; Hong, B.; Kim, H.; Kim, Y.; Lee, B.; Lee, K.; Lee, K. S.; Lee, S.; Lim, J.; Park, S. K.; Roh, Y.; Yoo, H. D.; Choi, M.; Kim, H.; Kim, J. H.; Lee, J. S. H.; Park, I. C.; Ryu, G.; Ryu, M. S.; Choi, Y.; Goh, J.; Kim, D.; Kwon, E.; Lee, J.; Yu, I.; Dudenas, V.; Juodagalvis, A.; Vaitkus, J.; Ahmed, I.; Ibrahim, Z. A.; Komaragiri, J. R.; Md Ali, M. A. B.; Mohamad Idris, F.; Wan Abdullah, W. A. T.; Yusli, M. N.; Zolkapli, Z.; Casimiro Linares, E.; Castilla-Valdez, H.; de La Cruz-Burelo, E.; Heredia-de La Cruz, I.; Hernandez-Almada, A.; Lopez-Fernandez, R.; Mejia Guisao, J.; Sanchez-Hernandez, A.; Carrillo Moreno, S.; Vazquez Valencia, F.; Pedraza, I.; Salazar Ibarguen, H. A.; Morelos Pineda, A.; Krofcheck, D.; Butler, P. H.; Ahmad, A.; Ahmad, M.; Hassan, Q.; Hoorani, H. R.; Khan, W. A.; Khurshid, T.; Shoaib, M.; Waqas, M.; Bialkowska, H.; Bluj, M.; Boimska, B.; Frueboes, T.; Górski, M.; Kazana, M.; Nawrocki, K.; Romanowska-Rybinska, K.; Szleper, M.; Traczyk, P.; Zalewski, P.; Brona, G.; Bunkowski, K.; Byszuk, A.; Doroba, K.; Kalinowski, A.; Konecki, M.; Krolikowski, J.; Misiura, M.; Olszewski, M.; Walczak, M.; Bargassa, P.; Beirão da Cruz E Silva, C.; di Francesco, A.; Faccioli, P.; Ferreira Parracho, P. G.; Gallinaro, M.; Hollar, J.; Leonardo, N.; Lloret Iglesias, L.; Nemallapudi, M. V.; Nguyen, F.; Rodrigues Antunes, J.; Seixas, J.; Toldaiev, O.; Vadruccio, D.; Varela, J.; Vischia, P.; Bunin, P.; Gavrilenko, M.; Golutvin, I.; Gorbunov, I.; Kamenev, A.; Karjavin, V.; Lanev, A.; Malakhov, A.; Matveev, V.; Moisenz, P.; Palichik, V.; Perelygin, V.; Savina, M.; Shmatov, S.; Shulha, S.; Skatchkov, N.; Smirnov, V.; Voytishin, N.; Zarubin, A.; Golovtsov, V.; Ivanov, Y.; Kim, V.; Kuznetsova, E.; Levchenko, P.; Murzin, V.; Oreshkin, V.; Smirnov, I.; Sulimov, V.; Uvarov, L.; Vavilov, S.; Vorobyev, A.; Andreev, Yu.; Dermenev, A.; Gninenko, S.; Golubev, N.; Karneyeu, A.; Kirsanov, M.; Krasnikov, N.; Pashenkov, A.; Tlisov, D.; Toropin, A.; Epshteyn, V.; Gavrilov, V.; Lychkovskaya, N.; Popov, V.; Pozdnyakov, I.; Safronov, G.; Spiridonov, A.; Vlasov, E.; Zhokin, A.; Chadeeva, M.; Danilov, M.; Markin, O.; Rusinov, V.; Tarkovskii, E.; Andreev, V.; Azarkin, M.; Dremin, I.; Kirakosyan, M.; Leonidov, A.; Mesyats, G.; Rusakov, S. V.; Baskakov, A.; Belyaev, A.; Boos, E.; Dubinin, M.; Dudko, L.; Ershov, A.; Gribushin, A.; Klyukhin, V.; Kodolova, O.; Lokhtin, I.; Miagkov, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.; Azhgirey, I.; Bayshev, I.; Bitioukov, S.; Kachanov, V.; Kalinin, A.; Konstantinov, D.; Krychkine, V.; Petrov, V.; Ryutin, R.; Sobol, A.; Tourtchanovitch, L.; Troshin, S.; Tyurin, N.; Uzunian, A.; Volkov, A.; Adzic, P.; Cirkovic, P.; Devetak, D.; Milosevic, J.; Rekovic, V.; Alcaraz Maestre, J.; Calvo, E.; Cerrada, M.; Chamizo Llatas, M.; Colino, N.; de La Cruz, B.; Delgado Peris, A.; Escalante Del Valle, A.; Fernandez Bedoya, C.; Fernández Ramos, J. P.; Flix, J.; Fouz, M. C.; Garcia-Abia, P.; Gonzalez Lopez, O.; Goy Lopez, S.; Hernandez, J. M.; Josa, M. I.; Navarro de Martino, E.; Pérez-Calero Yzquierdo, A.; Puerta Pelayo, J.; Quintario Olmeda, A.; Redondo, I.; Romero, L.; Soares, M. S.; de Trocóniz, J. 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M.; Bloch, P.; Bocci, A.; Bonato, A.; Botta, C.; Breuker, H.; Camporesi, T.; Castello, R.; Cepeda, M.; Cerminara, G.; D'Alfonso, M.; D'Enterria, D.; Dabrowski, A.; Daponte, V.; David, A.; de Gruttola, M.; de Guio, F.; de Roeck, A.; di Marco, E.; Dobson, M.; Dordevic, M.; Dorney, B.; Du Pree, T.; Duggan, D.; Dünser, M.; Dupont, N.; Elliott-Peisert, A.; Franzoni, G.; Fulcher, J.; Funk, W.; Gigi, D.; Gill, K.; Girone, M.; Glege, F.; Guida, R.; Gundacker, S.; Guthoff, M.; Hammer, J.; Harris, P.; Hegeman, J.; Innocente, V.; Janot, P.; Kirschenmann, H.; Knünz, V.; Kortelainen, M. J.; Kousouris, K.; Lecoq, P.; Lourenço, C.; Lucchini, M. T.; Magini, N.; Malgeri, L.; Mannelli, M.; Martelli, A.; Masetti, L.; Meijers, F.; Mersi, S.; Meschi, E.; Moortgat, F.; Morovic, S.; Mulders, M.; Neugebauer, H.; Orfanelli, S.; Orsini, L.; Pape, L.; Perez, E.; Peruzzi, M.; Petrilli, A.; Petrucciani, G.; Pfeiffer, A.; Pierini, M.; Piparo, D.; Racz, A.; Reis, T.; Rolandi, G.; Rovere, M.; Ruan, M.; Sakulin, H.; Sauvan, J. B.; Schäfer, C.; Schwick, C.; Seidel, M.; Sharma, A.; Silva, P.; Simon, M.; Sphicas, P.; Steggemann, J.; Stoye, M.; Takahashi, Y.; Treille, D.; Triossi, A.; Tsirou, A.; Veres, G. I.; Wardle, N.; Wöhri, H. K.; Zagozdzinska, A.; Zeuner, W. D.; Bertl, W.; Deiters, K.; Erdmann, W.; Horisberger, R.; Ingram, Q.; Kaestli, H. C.; Kotlinski, D.; Langenegger, U.; Rohe, T.; Bachmair, F.; Bäni, L.; Bianchini, L.; Casal, B.; Dissertori, G.; Dittmar, M.; Donegà, M.; Eller, P.; Grab, C.; Heidegger, C.; Hits, D.; Hoss, J.; Kasieczka, G.; Lecomte, P.; Lustermann, W.; Mangano, B.; Marionneau, M.; Martinez Ruiz Del Arbol, P.; Masciovecchio, M.; Meinhard, M. T.; Meister, D.; Micheli, F.; Musella, P.; Nessi-Tedaldi, F.; Pandolfi, F.; Pata, J.; Pauss, F.; Perrin, G.; Perrozzi, L.; Quittnat, M.; Rossini, M.; Schönenberger, M.; Starodumov, A.; Takahashi, M.; Tavolaro, V. R.; Theofilatos, K.; Wallny, R.; Aarrestad, T. K.; Amsler, C.; Caminada, L.; Canelli, M. F.; Chiochia, V.; de Cosa, A.; Galloni, C.; Hinzmann, A.; Hreus, T.; Kilminster, B.; Lange, C.; Ngadiuba, J.; Pinna, D.; Rauco, G.; Robmann, P.; Salerno, D.; Yang, Y.; Chen, K. H.; Doan, T. H.; Jain, Sh.; Khurana, R.; Konyushikhin, M.; Kuo, C. M.; Lin, W.; Lu, Y. J.; Pozdnyakov, A.; Yu, S. S.; Kumar, Arun; Chang, P.; Chang, Y. H.; Chang, Y. W.; Chao, Y.; Chen, K. 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M.; Paramesvaran, S.; Poll, A.; Sakuma, T.; Seif El Nasr-Storey, S.; Senkin, S.; Smith, D.; Smith, V. J.; Bell, K. W.; Belyaev, A.; Brew, C.; Brown, R. M.; Calligaris, L.; Cieri, D.; Cockerill, D. J. A.; Coughlan, J. A.; Harder, K.; Harper, S.; Olaiya, E.; Petyt, D.; Shepherd-Themistocleous, C. H.; Thea, A.; Tomalin, I. R.; Williams, T.; Worm, S. D.; Baber, M.; Bainbridge, R.; Buchmuller, O.; Bundock, A.; Burton, D.; Casasso, S.; Citron, M.; Colling, D.; Corpe, L.; Dauncey, P.; Davies, G.; de Wit, A.; Della Negra, M.; Dunne, P.; Elwood, A.; Futyan, D.; Hall, G.; Iles, G.; Lane, R.; Lucas, R.; Lyons, L.; Magnan, A.-M.; Malik, S.; Mastrolorenzo, L.; Nash, J.; Nikitenko, A.; Pela, J.; Penning, B.; Pesaresi, M.; Raymond, D. M.; Richards, A.; Rose, A.; Seez, C.; Tapper, A.; Uchida, K.; Vazquez Acosta, M.; Virdee, T.; Zenz, S. C.; Cole, J. E.; Hobson, P. R.; Khan, A.; Kyberd, P.; Leslie, D.; Reid, I. D.; Symonds, P.; Teodorescu, L.; Turner, M.; Borzou, A.; Call, K.; Dittmann, J.; Hatakeyama, K.; Liu, H.; Pastika, N.; Charaf, O.; Cooper, S. I.; Henderson, C.; Rumerio, P.; Arcaro, D.; Avetisyan, A.; Bose, T.; Gastler, D.; Rankin, D.; Richardson, C.; Rohlf, J.; Sulak, L.; Zou, D.; Alimena, J.; Benelli, G.; Berry, E.; Cutts, D.; Ferapontov, A.; Garabedian, A.; Hakala, J.; Heintz, U.; Jesus, O.; Laird, E.; Landsberg, G.; Mao, Z.; Narain, M.; Piperov, S.; Sagir, S.; Syarif, R.; Breedon, R.; Breto, G.; Calderon de La Barca Sanchez, M.; Chauhan, S.; Chertok, M.; Conway, J.; Conway, R.; Cox, P. T.; Erbacher, R.; Funk, G.; Gardner, M.; Gunion, J.; Ko, W.; Lander, R.; McLean, C.; Mulhearn, M.; Pellett, D.; Pilot, J.; Ricci-Tam, F.; Shalhout, S.; Smith, J.; Squires, M.; Stolp, D.; Tripathi, M.; Wilbur, S.; Yohay, R.; Cousins, R.; Everaerts, P.; Florent, A.; Hauser, J.; Ignatenko, M.; Saltzberg, D.; Takasugi, E.; Valuev, V.; Weber, M.; Burt, K.; Clare, R.; Ellison, J.; Gary, J. W.; Hanson, G.; Heilman, J.; Ivova Paneva, M.; Jandir, P.; Kennedy, E.; Lacroix, F.; Long, O. R.; Malberti, M.; Olmedo Negrete, M.; Shrinivas, A.; Wei, H.; Wimpenny, S.; Yates, B. R.; Branson, J. G.; Cerati, G. B.; Cittolin, S.; D'Agnolo, R. T.; Derdzinski, M.; Holzner, A.; Kelley, R.; Klein, D.; Letts, J.; MacNeill, I.; Olivito, D.; Padhi, S.; Pieri, M.; Sani, M.; Sharma, V.; Simon, S.; Tadel, M.; Vartak, A.; Wasserbaech, S.; Welke, C.; Würthwein, F.; Yagil, A.; Zevi Della Porta, G.; Bradmiller-Feld, J.; Campagnari, C.; Dishaw, A.; Dutta, V.; Flowers, K.; Franco Sevilla, M.; Geffert, P.; George, C.; Golf, F.; Gouskos, L.; Gran, J.; Incandela, J.; McColl, N.; Mullin, S. D.; Richman, J.; Stuart, D.; Suarez, I.; West, C.; Yoo, J.; Anderson, D.; Apresyan, A.; Bendavid, J.; Bornheim, A.; Bunn, J.; Chen, Y.; Duarte, J.; Mott, A.; Newman, H. B.; Pena, C.; Spiropulu, M.; Vlimant, J. R.; Xie, S.; Zhu, R. Y.; Andrews, M. B.; Azzolini, V.; Calamba, A.; Carlson, B.; Ferguson, T.; Paulini, M.; Russ, J.; Sun, M.; Vogel, H.; Vorobiev, I.; Cumalat, J. P.; Ford, W. T.; Gaz, A.; Jensen, F.; Johnson, A.; Krohn, M.; Mulholland, T.; Nauenberg, U.; Stenson, K.; Wagner, S. R.; Alexander, J.; Chatterjee, A.; Chaves, J.; Chu, J.; Dittmer, S.; Eggert, N.; Mirman, N.; Nicolas Kaufman, G.; Patterson, J. R.; Rinkevicius, A.; Ryd, A.; Skinnari, L.; Soffi, L.; Sun, W.; Tan, S. M.; Teo, W. D.; Thom, J.; Thompson, J.; Tucker, J.; Weng, Y.; Wittich, P.; Abdullin, S.; Albrow, M.; Apollinari, G.; Banerjee, S.; Bauerdick, L. A. T.; Beretvas, A.; Berryhill, J.; Bhat, P. C.; Bolla, G.; Burkett, K.; Butler, J. N.; Cheung, H. W. K.; Chlebana, F.; Cihangir, S.; Elvira, V. D.; Fisk, I.; Freeman, J.; Gottschalk, E.; Gray, L.; Green, D.; Grünendahl, S.; Gutsche, O.; Hanlon, J.; Hare, D.; Harris, R. M.; Hasegawa, S.; Hirschauer, J.; Hu, Z.; Jayatilaka, B.; Jindariani, S.; Johnson, M.; Joshi, U.; Klima, B.; Kreis, B.; Lammel, S.; Lewis, J.; Linacre, J.; Lincoln, D.; Lipton, R.; Liu, T.; Lopes de Sá, R.; Lykken, J.; Maeshima, K.; Marraffino, J. M.; Maruyama, S.; Mason, D.; McBride, P.; Merkel, P.; Mrenna, S.; Nahn, S.; Newman-Holmes, C.; O'Dell, V.; Pedro, K.; Prokofyev, O.; Rakness, G.; Sexton-Kennedy, E.; Soha, A.; Spalding, W. J.; Spiegel, L.; Stoynev, S.; Strobbe, N.; Taylor, L.; Tkaczyk, S.; Tran, N. V.; Uplegger, L.; Vaandering, E. W.; Vernieri, C.; Verzocchi, M.; Vidal, R.; Wang, M.; Weber, H. A.; Whitbeck, A.; Acosta, D.; Avery, P.; Bortignon, P.; Bourilkov, D.; Brinkerhoff, A.; Carnes, A.; Carver, M.; Curry, D.; Das, S.; Field, R. D.; Furic, I. K.; Konigsberg, J.; Korytov, A.; Kotov, K.; Ma, P.; Matchev, K.; Mei, H.; Milenovic, P.; Mitselmakher, G.; Rank, D.; Rossin, R.; Shchutska, L.; Snowball, M.; Sperka, D.; Terentyev, N.; Thomas, L.; Wang, J.; Wang, S.; Yelton, J.; Linn, S.; Markowitz, P.; Martinez, G.; Rodriguez, J. L.; Ackert, A.; Adams, J. R.; Adams, T.; Askew, A.; Bein, S.; Bochenek, J.; Diamond, B.; Haas, J.; Hagopian, S.; Hagopian, V.; Johnson, K. F.; Khatiwada, A.; Prosper, H.; Weinberg, M.; Baarmand, M. M.; Bhopatkar, V.; Colafranceschi, S.; Hohlmann, M.; Kalakhety, H.; Noonan, D.; Roy, T.; Yumiceva, F.; Adams, M. R.; Apanasevich, L.; Berry, D.; Betts, R. R.; Bucinskaite, I.; Cavanaugh, R.; Evdokimov, O.; Gauthier, L.; Gerber, C. E.; Hofman, D. J.; Kurt, P.; O'Brien, C.; Sandoval Gonzalez, I. D.; Turner, P.; Varelas, N.; Wu, Z.; Zakaria, M.; Zhang, J.; Bilki, B.; Clarida, W.; Dilsiz, K.; Durgut, S.; Gandrajula, R. P.; Haytmyradov, M.; Khristenko, V.; Merlo, J.-P.; Mermerkaya, H.; Mestvirishvili, A.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Snyder, C.; Tiras, E.; Wetzel, J.; Yi, K.; Anderson, I.; Barnett, B. A.; Blumenfeld, B.; Cocoros, A.; Eminizer, N.; Fehling, D.; Feng, L.; Gritsan, A. V.; Maksimovic, P.; Osherson, M.; Roskes, J.; Sarica, U.; Swartz, M.; Xiao, M.; Xin, Y.; You, C.; Baringer, P.; Bean, A.; Bruner, C.; Kenny, R. P.; Majumder, D.; Malek, M.; McBrayer, W.; Murray, M.; Sanders, S.; Stringer, R.; Wang, Q.; Ivanov, A.; Kaadze, K.; Khalil, S.; Makouski, M.; Maravin, Y.; Mohammadi, A.; Saini, L. K.; Skhirtladze, N.; Toda, S.; Lange, D.; Rebassoo, F.; Wright, D.; Anelli, C.; Baden, A.; Baron, O.; Belloni, A.; Calvert, B.; Eno, S. C.; Ferraioli, C.; Gomez, J. A.; Hadley, N. J.; Jabeen, S.; Kellogg, R. G.; Kolberg, T.; Kunkle, J.; Lu, Y.; Mignerey, A. C.; Shin, Y. H.; Skuja, A.; Tonjes, M. B.; Tonwar, S. C.; Apyan, A.; Barbieri, R.; Baty, A.; Bi, R.; Bierwagen, K.; Brandt, S.; Busza, W.; Cali, I. A.; Demiragli, Z.; Di Matteo, L.; Gomez Ceballos, G.; Goncharov, M.; Gulhan, D.; Iiyama, Y.; Innocenti, G. M.; Klute, M.; Kovalskyi, D.; Krajczar, K.; Lai, Y. S.; Lee, Y.-J.; Levin, A.; Luckey, P. D.; Marini, A. C.; McGinn, C.; Mironov, C.; Narayanan, S.; Niu, X.; Paus, C.; Roland, C.; Roland, G.; Salfeld-Nebgen, J.; Stephans, G. S. F.; Sumorok, K.; Tatar, K.; Varma, M.; Velicanu, D.; Veverka, J.; Wang, J.; Wang, T. W.; Wyslouch, B.; Yang, M.; Zhukova, V.; Benvenuti, A. C.; Dahmes, B.; Evans, A.; Finkel, A.; Gude, A.; Hansen, P.; Kalafut, S.; Kao, S. C.; Klapoetke, K.; Kubota, Y.; Lesko, Z.; Mans, J.; Nourbakhsh, S.; Ruckstuhl, N.; Rusack, R.; Tambe, N.; Turkewitz, J.; Acosta, J. G.; Oliveros, S.; Avdeeva, E.; Bartek, R.; Bloom, K.; Bose, S.; Claes, D. R.; Dominguez, A.; Fangmeier, C.; Gonzalez Suarez, R.; Kamalieddin, R.; Knowlton, D.; Kravchenko, I.; Meier, F.; Monroy, J.; Ratnikov, F.; Siado, J. E.; Snow, G. R.; Stieger, B.; Alyari, M.; Dolen, J.; George, J.; Godshalk, A.; Harrington, C.; Iashvili, I.; Kaisen, J.; Kharchilava, A.; Kumar, A.; Rappoccio, S.; Roozbahani, B.; Alverson, G.; Barberis, E.; Baumgartel, D.; Chasco, M.; Hortiangtham, A.; Massironi, A.; Morse, D. M.; Nash, D.; Orimoto, T.; Teixeira de Lima, R.; Trocino, D.; Wang, R.-J.; Wood, D.; Zhang, J.; Bhattacharya, S.; Hahn, K. A.; Kubik, A.; Low, J. F.; Mucia, N.; Odell, N.; Pollack, B.; Schmitt, M. H.; Sung, K.; Trovato, M.; Velasco, M.; Dev, N.; Hildreth, M.; Jessop, C.; Karmgard, D. J.; Kellams, N.; Lannon, K.; Marinelli, N.; Meng, F.; Mueller, C.; Musienko, Y.; Planer, M.; Reinsvold, A.; Ruchti, R.; Rupprecht, N.; Smith, G.; Taroni, S.; Valls, N.; Wayne, M.; Wolf, M.; Woodard, A.; Antonelli, L.; Brinson, J.; Bylsma, B.; Durkin, L. S.; Flowers, S.; Hart, A.; Hill, C.; Hughes, R.; Ji, W.; Ling, T. Y.; Liu, B.; Luo, W.; Puigh, D.; Rodenburg, M.; Winer, B. L.; Wulsin, H. W.; Driga, O.; Elmer, P.; Hardenbrook, J.; Hebda, P.; Koay, S. A.; Lujan, P.; Marlow, D.; Medvedeva, T.; Mooney, M.; Olsen, J.; Palmer, C.; Piroué, P.; Stickland, D.; Tully, C.; Zuranski, A.; Malik, S.; Barker, A.; Barnes, V. E.; Benedetti, D.; Bortoletto, D.; Gutay, L.; Jha, M. K.; Jones, M.; Jung, A. W.; Jung, K.; Miller, D. H.; Neumeister, N.; Radburn-Smith, B. C.; Shi, X.; Shipsey, I.; Silvers, D.; Sun, J.; Svyatkovskiy, A.; Wang, F.; Xie, W.; Xu, L.; Parashar, N.; Stupak, J.; Adair, A.; Akgun, B.; Chen, Z.; Ecklund, K. M.; Geurts, F. J. M.; Guilbaud, M.; Li, W.; Michlin, B.; Northup, M.; Padley, B. P.; Redjimi, R.; Roberts, J.; Rorie, J.; Tu, Z.; Zabel, J.; Betchart, B.; Bodek, A.; de Barbaro, P.; Demina, R.; Eshaq, Y.; Ferbel, T.; Galanti, M.; Garcia-Bellido, A.; Han, J.; Hindrichs, O.; Khukhunaishvili, A.; Lo, K. H.; Tan, P.; Verzetti, M.; Chou, J. P.; Contreras-Campana, E.; Ferencek, D.; Gershtein, Y.; Halkiadakis, E.; Heindl, M.; Hidas, D.; Hughes, E.; Kaplan, S.; Kunnawalkam Elayavalli, R.; Lath, A.; Nash, K.; Saka, H.; Salur, S.; Schnetzer, S.; Sheffield, D.; Somalwar, S.; Stone, R.; Thomas, S.; Thomassen, P.; Walker, M.; Foerster, M.; Riley, G.; Rose, K.; Spanier, S.; Thapa, K.; Bouhali, O.; Castaneda Hernandez, A.; Celik, A.; Dalchenko, M.; de Mattia, M.; Delgado, A.; Dildick, S.; Eusebi, R.; Gilmore, J.; Huang, T.; Kamon, T.; Krutelyov, V.; Mueller, R.; Osipenkov, I.; Pakhotin, Y.; Patel, R.; Perloff, A.; Rathjens, D.; Rose, A.; Safonov, A.; Tatarinov, A.; Ulmer, K. A.; Akchurin, N.; Cowden, C.; Damgov, J.; Dragoiu, C.; Dudero, P. R.; Faulkner, J.; Kunori, S.; Lamichhane, K.; Lee, S. W.; Libeiro, T.; Undleeb, S.; Volobouev, I.; Appelt, E.; Delannoy, A. G.; Greene, S.; Gurrola, A.; Janjam, R.; Johns, W.; Maguire, C.; Mao, Y.; Melo, A.; Ni, H.; Sheldon, P.; Tuo, S.; Velkovska, J.; Xu, Q.; Arenton, M. W.; Barria, P.; Cox, B.; Francis, B.; Goodell, J.; Hirosky, R.; Ledovskoy, A.; Li, H.; Neu, C.; Sinthuprasith, T.; Sun, X.; Wang, Y.; Wolfe, E.; Wood, J.; Xia, F.; Clarke, C.; Harr, R.; Karchin, P. E.; Kottachchi Kankanamge Don, C.; Lamichhane, P.; Sturdy, J.; Belknap, D. A.; Carlsmith, D.; Dasu, S.; Dodd, L.; Duric, S.; Gomber, B.; Grothe, M.; Herndon, M.; Hervé, A.; Klabbers, P.; Lanaro, A.; Levine, A.; Long, K.; Loveless, R.; Mohapatra, A.; Ojalvo, I.; Perry, T.; Pierro, G. A.; Polese, G.; Ruggles, T.; Sarangi, T.; Savin, A.; Sharma, A.; Smith, N.; Smith, W. H.; Taylor, D.; Verwilligen, P.; Woods, N.

2016-10-01

Searches for new physics by the CMS collaboration are interpreted in the framework of the phenomenological minimal supersymmetric standard model (pMSSM). The data samples used in this study were collected at √{s}=7 and 8 TeV and have integrated luminosities of 5.0 fb-1 and 19.5 fb-1, respectively. A global Bayesian analysis is performed, incorporating results from a broad range of CMS supersymmetry searches, as well as constraints from other experiments. Because the pMSSM incorporates several well-motivated assumptions that reduce the 120 parameters of the MSSM to just 19 parameters defined at the electroweak scale, it is possible to assess the results of the study in a relatively straightforward way. Approximately half of the model points in a potentially accessible subspace of the pMSSM are excluded, including all pMSSM model points with a gluino mass below 500 GeV, as well as models with a squark mass less than 300 GeV. Models with chargino and neutralino masses below 200 GeV are disfavored, but no mass range of model points can be ruled out based on the analyses considered. The nonexcluded regions in the pMSSM parameter space are characterized in terms of physical processes and key observables, and implications for future searches are discussed. [Figure not available: see fulltext.

Comparative analysis of the effects of electron and hole capture on the power characteristics of a semiconductor quantum-well laser

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

Sokolova, Z. N., E-mail: Zina.Sokolova@mail.ioffe.ru; Pikhtin, N. A.; Tarasov, I. S.

The operating characteristics of a semiconductor quantum-well laser calculated using three models are compared. These models are (i) a model not taking into account differences between the electron and hole parameters and using the electron parameters for both types of charge carriers; (ii) a model, which does not take into account differences between the electron and hole parameters and uses the hole parameters for both types of charge carriers; and (iii) a model taking into account the asymmetry between the electron and hole parameters. It is shown that, at the same velocity of electron and hole capture into an unoccupiedmore » quantum well, the laser characteristics, obtained using the three models, differ considerably. These differences are due to a difference between the filling of the electron and hole subbands in a quantum well. The electron subband is more occupied than the hole subband. As a result, at the same velocities of electron and hole capture into an empty quantum well, the effective electron-capture velocity is lower than the effective hole-capture velocity. Specifically, it is shown that for the laser structure studied the hole-capture velocity of 5 × 10{sup 5} cm/s into an empty quantum well and the corresponding electron-capture velocity of 3 × 10{sup 6} cm/s into an empty quantum well describe the rapid capture of these carriers, at which the light–current characteristic of the laser remains virtually linear up to high pump-current densities. However, an electron-capture velocity of 5 × 10{sup 5} cm/s and a corresponding hole-capture velocity of 8.4 × 10{sup 4} cm/s describe the slow capture of these carriers, causing significant sublinearity in the light–current characteristic.« less

Coronary Flow Velocity Reserve during Dobutamine Stress Echocardiography

PubMed Central

de Abreu, José Sebastião; Lima, José Wellington Oliveira; Diógenes, Tereza Cristina Pinheiro; Siqueira, Jordana Magalhães; Pimentel, Nayara Lima; Gomes, Pedro Sabino; de Abreu, Marília Esther Benevides; Paes, José Nogueira

2014-01-01

Background A coronary flow velocity reserve (CFVR) ≥ 2 is adequate to infer a favorable prognosis or the absence of significant coronary artery disease. Objective To identify parameters which are relevant to obtain CFVR (adequate or inadequate) in the left anterior descending coronary artery (LAD) during dobutamine stress echocardiography (DSE). Methods 100 patients referred for detection of myocardial ischemia by DSE were evaluated; they were instructed to discontinue the use of β-blockers 72 hours prior to the test. CFVR was calculated as a ratio of the diastolic peak velocity (cm/s) (DPV) on DSE (DPV-DSE) to baseline DPV at rest (DPV-Rest). In group I, CFVR was < 2 and, in group II, CFVR was ≥ 2. The Fisher's exact test and Student's t test were used for the statistical analyses. P values < 0.05 were considered statistically significant. Results At rest, the time (in seconds) to obtain Doppler in LAD in groups I and II was not different (53±31 vs. 45±32; p=0.23). During DSE, LAD was recorded in 92 patients. Group I patients were older (65.9±9.3 vs. 61.2±10.8 years; p=0.04), had lower ejection fraction (61±10 vs. 66±6%; p=0.005), higher DPV-Rest (36.81±08 vs. 25.63 ± 06cm/s; p<0.0001) and lower CFVR (1.67 ± 0.24 vs. 2.53 ± 0.57; p<0.0001), but no difference was observed regarding DPVDSE (61.40±16 vs. 64.23±16cm/s; p=0.42). β-blocker discontinuation was associated with a 4-fold higher chance of a CFVR < 2 (OR= 4; 95% CI [1.171-13.63], p=0.027). Conclusion DPV-Rest was the main parameter to determine an adequate CFVR. β-blocker discontinuation was significantly associated with inadequate CFVR. The high feasibility and the time to record the LAD corroborate the use of this methodology. PMID:24676368

Effects of Ocean Acidification and Flow on Oxygen and pH Conditions of Developing Squid (Doryteuthis pealeii) Egg Cases

NASA Astrophysics Data System (ADS)

Panyi, A.; Long, M. H.; Mooney, T. A.

2016-02-01

While young animals found future cohorts and populations, these early life stages are often particularly susceptible to conditions of the local environment in which they develop. The oxygen and pH of this critical developmental environment is likely impacted by the nearby physical conditions and the animals own respirations. Yet, in nearly all cases, this microenvironment is unknown, limiting our understanding of animal tolerances to current and future OA and hypoxic conditions. This study investigated the oxygen and pH environment adjacent to and within the egg cases of a keystone species, the longfin squid, Doryteuthis pealeii, under ambient and elevated CO2 (400 and 2200 ppm), and across differing water flow rates (0, 1, and 10 cm/s) using microprobes. Under both CO2 treatments, oxygen and pH in the egg case centers dropped dramatically across development to levels generally considered metabolically stressful even for adults. In the ambient CO2 trial, oxygen concentrations reached a minimum of 4.351 µmol/L, and pH reached a minimum of 7.36. In the elevated CO2 trial, oxygen concentrations reached a minimum of 9.910 µmol/L, and pH reached a minimum of 6.79. Flow appeared to alleviate these conditions, with highest O2 concentrations in the egg cases exposed to 10 cm/s flow in both CO2 trials, across all age classes measured. Surprisingly, all tested egg cases successfully hatched, demonstrating that developing D. pealeii embryos have a strong tolerance for low oxygen and pH, but there were more unsuccessful embryos counted in the 0 and 1 cm/s flow conditions. Further climate change could place young, keystone squid outside of their physiological limits, but water flow may play a key role in mitigating developmental stress to egg case bound embryos by increasing available oxygen.

42 CFR 493.1773 - Standard: Basic inspection requirements for all laboratories issued a CLIA certificate and CLIA...

Code of Federal Regulations, 2011 CFR

2011-10-01

... issued a certificate of accreditation, must permit CMS or a CMS agent to conduct validation and complaint inspections. (b) General requirements. As part of the inspection process, CMS or a CMS agent may require the... testing process (preanalytic, analytic, and postanalytic). (4) Permit CMS or a CMS agent access to all...

42 CFR 493.1773 - Standard: Basic inspection requirements for all laboratories issued a CLIA certificate and CLIA...

Code of Federal Regulations, 2012 CFR

2012-10-01

... issued a certificate of accreditation, must permit CMS or a CMS agent to conduct validation and complaint inspections. (b) General requirements. As part of the inspection process, CMS or a CMS agent may require the... testing process (preanalytic, analytic, and postanalytic). (4) Permit CMS or a CMS agent access to all...

42 CFR 493.1773 - Standard: Basic inspection requirements for all laboratories issued a CLIA certificate and CLIA...

Code of Federal Regulations, 2013 CFR

2013-10-01

... issued a certificate of accreditation, must permit CMS or a CMS agent to conduct validation and complaint inspections. (b) General requirements. As part of the inspection process, CMS or a CMS agent may require the... testing process (preanalytic, analytic, and postanalytic). (4) Permit CMS or a CMS agent access to all...

42 CFR 493.1773 - Standard: Basic inspection requirements for all laboratories issued a CLIA certificate and CLIA...

Code of Federal Regulations, 2014 CFR

2014-10-01

... issued a certificate of accreditation, must permit CMS or a CMS agent to conduct validation and complaint inspections. (b) General requirements. As part of the inspection process, CMS or a CMS agent may require the... testing process (preanalytic, analytic, and postanalytic). (4) Permit CMS or a CMS agent access to all...

42 CFR 493.1773 - Standard: Basic inspection requirements for all laboratories issued a CLIA certificate and CLIA...

Code of Federal Regulations, 2010 CFR

2010-10-01

... issued a certificate of accreditation, must permit CMS or a CMS agent to conduct validation and complaint inspections. (b) General requirements. As part of the inspection process, CMS or a CMS agent may require the... testing process (preanalytic, analytic, and postanalytic). (4) Permit CMS or a CMS agent access to all...

Search for new neutral gauge bosons with the CMS Experiment at the LHC

NASA Astrophysics Data System (ADS)

Lanyov, Alexander; Shmatov, Sergei; Zhizhin, Ilia

2018-04-01

A search for narrow resonances in dimuon invariant mass spectra has been performed using 13 fb-1 data obtained in 2016 from proton-proton collisions at √s = 13 TeV with the CMS experiment at the LHC. No evidence for physics beyond standard model is found. Limits on the production cross section and the masses of hypothetical particles that could appear in the scenarios of new physics have been set.

B physics and Quarkonia in CMS

NASA Astrophysics Data System (ADS)

Fiorendi, Sara

2017-12-01

The heavy-flavor sector offers the opportunity to perform indirect tests of beyond the Standard Model physics through precision measurements and of quantum chromodynamics (QCD) through particle production studies. A review of recent measurements on heavy flavors from the CMS experiment is presented. Results are based on data collected during LHC Run I and Run II and include measurements of heavy flavor production and properties, rare decays, CP violation, exotic and standard quarkonia. Warning, no authors found for 2017EPJWC.16407006.

MUSiC - Model-independent search for deviations from Standard Model predictions in CMS

NASA Astrophysics Data System (ADS)

Pieta, Holger

2010-02-01

We present an approach for a model independent search in CMS. Systematically scanning the data for deviations from the standard model Monte Carlo expectations, such an analysis can help to understand the detector and tune event generators. By minimizing the theoretical bias the analysis is furthermore sensitive to a wide range of models for new physics, including the uncounted number of models not-yet-thought-of. After sorting the events into classes defined by their particle content (leptons, photons, jets and missing transverse energy), a minimally prejudiced scan is performed on a number of distributions. Advanced statistical methods are used to determine the significance of the deviating regions, rigorously taking systematic uncertainties into account. A number of benchmark scenarios, including common models of new physics and possible detector effects, have been used to gauge the power of such a method. )

Intelligent Systems and Advanced User Interfaces for Design, Operation, and Maintenance of Command Management Systems

NASA Technical Reports Server (NTRS)

Mitchell, Christine M.

1998-01-01

Historically Command Management Systems (CMS) have been large, expensive, spacecraft-specific software systems that were costly to build, operate, and maintain. Current and emerging hardware, software, and user interface technologies may offer an opportunity to facilitate the initial formulation and design of a spacecraft-specific CMS as well as a to develop a more generic or a set of core components for CMS systems. Current MOC (mission operations center) hardware and software include Unix workstations, the C/C++ and Java programming languages, and X and Java window interfaces representations. This configuration provides the power and flexibility to support sophisticated systems and intelligent user interfaces that exploit state-of-the-art technologies in human-machine systems engineering, decision making, artificial intelligence, and software engineering. One of the goals of this research is to explore the extent to which technologies developed in the research laboratory can be productively applied in a complex system such as spacecraft command management. Initial examination of some of the issues in CMS design and operation suggests that application of technologies such as intelligent planning, case-based reasoning, design and analysis tools from a human-machine systems engineering point of view (e.g., operator and designer models) and human-computer interaction tools, (e.g., graphics, visualization, and animation), may provide significant savings in the design, operation, and maintenance of a spacecraft-specific CMS as well as continuity for CMS design and development across spacecraft with varying needs. The savings in this case is in software reuse at all stages of the software engineering process.

Multi-core processing and scheduling performance in CMS

NASA Astrophysics Data System (ADS)

Hernández, J. M.; Evans, D.; Foulkes, S.

2012-12-01

Commodity hardware is going many-core. We might soon not be able to satisfy the job memory needs per core in the current single-core processing model in High Energy Physics. In addition, an ever increasing number of independent and incoherent jobs running on the same physical hardware not sharing resources might significantly affect processing performance. It will be essential to effectively utilize the multi-core architecture. CMS has incorporated support for multi-core processing in the event processing framework and the workload management system. Multi-core processing jobs share common data in memory, such us the code libraries, detector geometry and conditions data, resulting in a much lower memory usage than standard single-core independent jobs. Exploiting this new processing model requires a new model in computing resource allocation, departing from the standard single-core allocation for a job. The experiment job management system needs to have control over a larger quantum of resource since multi-core aware jobs require the scheduling of multiples cores simultaneously. CMS is exploring the approach of using whole nodes as unit in the workload management system where all cores of a node are allocated to a multi-core job. Whole-node scheduling allows for optimization of the data/workflow management (e.g. I/O caching, local merging) but efficient utilization of all scheduled cores is challenging. Dedicated whole-node queues have been setup at all Tier-1 centers for exploring multi-core processing workflows in CMS. We present the evaluation of the performance scheduling and executing multi-core workflows in whole-node queues compared to the standard single-core processing workflows.

Search for third generation squarks in pp collisions at 13 TeV with CMS

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

Strobbe, Nadja C.

2016-11-14

Three searches for third generation squarks using proton-proton collision data at a center-of-mass energy of 13 TeV recorded by the CMS experiment at the LHC are presented. The data corre- spond to an integrated luminosity of 12.9 fb -1. The analyses define exclusive search regions and estimate contributions from standard model processes to these regions by using control samples in the data. No significant deviation from the standard model expectation is observed in the data. The results are interpreted in simplified SUSY models of direct and gluino-mediated top squark production. Depending on the model, top squark masses up to 910more » GeV and gluino masses up to 1780 GeV are excluded.« less

Search for a Heavy Neutrino and Right-Handed W of the Left-Right Symmetric Model with Cms Detector

NASA Astrophysics Data System (ADS)

Tlisov, Danila

2013-11-01

This work describes the first search for signals from the production of right-handed WR bosons and heavy neutrinos Nℓ (ℓ = e, μ), that arise naturally in the left-right symmetric extension to the Standard Model, with the CMS Experiment at the LHC using the 7 TeV pp collision data collected in 2010 and 2011 corresponding to an integrated luminosity of 240 pb-1. No excess over expectations from Standard Model processes is observed. For models with exact left-right symmetry (the same coupling in the left and right sectors) we exclude the region in the two-dimensional parameter space that extends to (MWR, MNℓ) = (1700 GeV, 600 GeV).

Diphoton searches (CMS)

NASA Astrophysics Data System (ADS)

Quittnat, Milena

2017-12-01

The search for high mass resonances decaying into two photons is well motivated by many physics scenarios beyond the standard model. This note summarizes the results of this search in proton-proton collision with a center-of-mass energy of √s = 13 TeV and an integrated luminosity of 3:3 fb-1 by the CMS experiment. It presents the interpretation of the results under spin-0 and spin-2 hypotheses with a relative width up to 5:6 × 10-2 in a mass region of 500 - 4500 GeV. The results of the √s = 13 TeV analysis are combined statistically with previous searches performed by the CMS collaboration, employing a center-of-mass energy of √s = 8 TeV and an integrated luminosity of 19:7 fb-1.

A conflict management scale for pharmacy.

PubMed

Austin, Zubin; Gregory, Paul A; Martin, Craig

2009-11-12

To develop and establish the validity and reliability of a conflict management scale specific to pharmacy practice and education. A multistage inventory-item development process was undertaken involving 93 pharmacists and using a previously described explanatory model for conflict in pharmacy practice. A 19-item inventory was developed, field tested, and validated. The conflict management scale (CMS) demonstrated an acceptable degree of reliability and validity for use in educational or practice settings to promote self-reflection and self-awareness regarding individuals' conflict management styles. The CMS provides a unique, pharmacy-specific method for individuals to determine and reflect upon their own conflict management styles. As part of an educational program to facilitate self-reflection and heighten self-awareness, the CMS may be a useful tool to promote discussions related to an important part of pharmacy practice.

Effects of intravenous bolus injection of nicorandil on renal artery flow velocity assessed by color Doppler ultrasound.

PubMed

Shimamoto, Yukiko; Kubo, Takashi; Tanabe, Kazumi; Emori, Hiroki; Katayama, Yosuke; Nishiguchi, Tsuyoshi; Taruya, Akira; Kameyama, Takeyoshi; Orii, Makoto; Yamano, Takashi; Kuroi, Akio; Yamaguchi, Tomoyuki; Takemoto, Kazushi; Matsuo, Yoshiki; Ino, Yasushi; Tanaka, Atsushi; Hozumi, Takeshi; Terada, Masaki; Akasaka, Takashi

2017-01-01

Previous animal studies have shown that a potassium channel opener, nicorandil, provokes vasodilation in renal microvasculature and increases renal blood flow. We conducted a clinical study that aimed to evaluate the effect of nicorandil on renal artery blood flow in comparison with nitroglycerin by using color Doppler ultrasound. The present study enrolled 40 patients with stable coronary artery disease who had no renal arterial stenosis and renal parenchymal disease. The patients received intravenous administration of nicorandil (n=20) or nitroglycerin (n=20). Before and after the administration, renal artery blood flow velocity was measured by color-guided pulsed-wave Doppler. The peak-systolic, end-diastolic, and mean renal artery blood flow velocities before the administration were not different between the nicorandil group and the nitroglycerin group. The peak-systolic (79±15cm/s to 99±21cm/s, p<0.001; and 78±19cm/s to 85±19cm/s, p=0.004), end-diastolic (22±5cm/s to 28±8cm/s, p<0.001; and 24±6cm/s to 26±6cm/s, p=0.005) and mean (41±6cm/s to 49±9cm/s, p<0.001; and 43±9cm/s to 45±9cm/s, p=0.009) renal artery flow velocities increased significantly in either group. The nominal changes in the peak-systolic (20±10cm/s vs. 7±8cm/s, p<0.001), end-diastolic (5±4cm/s vs. 2±3cm/s, p=0.001), and mean (8±5cm/s vs. 2±2cm/s, p<0.001) renal artery blood flow velocities were significantly greater in the nicorandil group compared with the nitroglycerin group. Intravenous nicorandil increased renal artery blood flow velocity in comparison with nitroglycerin. Nicorandil has a significant effect on renal hemodynamics. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Altered iPSC-derived neurons’ sodium channel properties in subjects with Monge's disease

PubMed Central

Zhao, Huiwen W.; Gu, Xiang Q.; Chailangkarn, Thanathom; Perkins, Guy; Callacondo, David; Appenzeller, Otto; Poulsen, Orit; Zhou, Dan; Muotri, Alysson R.; Haddad, Gabriel G.

2015-01-01

Monge's disease, also known as chronic mountain sickness (CMS), is a disease that potentially threatens more than 140 million highlanders during extended time living at a high altitude (over 2500m). The prevalence of CMS in Andeans is about 15-20%, suggesting that the majority of highlanders (non-CMS) are rather healthy at the high altitude; however, CMS subjects experience severe hypoxemia, erythrocytosis and many neurologic manifestations including migraine, headache, mental fatigue, confusion, and memory loss. The underlying mechanisms of CMS neuropathology are not well understood and no ideal treatment is available to prevent or cure CMS, except for phlebotomy. In the current study, we reprogrammed fibroblast cells from both CMS and non-CMS subjects’ skin biopsies into the induced pluripotent stem cells (iPSCs), then differentiated into neurons and compared their neuronal properties. We discovered that CMS neurons were much less excitable (higher rheobase) than non-CMS neurons. This decreased excitability was not caused by differences in passive neuronal properties, but instead by a significantly lowered Na+ channel current density and by a shift of the voltage-conductance curve in the depolarization direction. Our findings provide, for the first time, evidence of a neuronal abnormality in CMS subjects as compared to non-CMS subjects, hoping that such studies can pave the way to a better understanding of the neuropathology in CMS. PMID:25559931

Combining data from high-energy pp-reactions and neutrinoless double-beta decay: Limits on the mass of the right-handed boson

NASA Astrophysics Data System (ADS)

Civitarese, Osvaldo; Suhonen, Jouni; Zuber, Kai

2016-10-01

From the recently established lower-limits on the nonobservability of the neutrinoless double-beta decay of 76Ge (GERDA collaboration) and 136Xe (EXO-200 and KamLAND-Zen collaborations), combined with the ATLAS and CMS data, we extract limits for the left-right (LR) mixing angle, ζ, of the SU(2)L ×SU(2)R electroweak Hamiltonian. For the theoretical analysis, which is a model dependent, we have adopted a minimal extension of the Standard Model (SM) of Electroweak Interactions belonging to the SU(2)L ×SU(2)R representation. The nuclear-structure input of the analysis consists of a set of matrix elements and phase-space factors, and the experimental lower-limits for the half-lives. The other input are the ATLAS and CMS cross-section measurements of the pp-collisions into two-jets and two-leptons, performed at the large hadron collider (LHC). Our analysis yields the limit ζ < 10-3 for MR > 3TeV, by combining the model-dependent limits extracted from the double-beta-decay measurements and those extracted from the results of the CMS and ATLAS measurements.

Equilibrium relations and bipolar cognitive mapping for online analytical processing with applications in international relations and strategic decision support.

PubMed

Zhang, Wen-Ran

2003-01-01

Bipolar logic, bipolar sets, and equilibrium relations are proposed for bipolar cognitive mapping and visualization in online analytical processing (OLAP) and online analytical mining (OLAM). As cognitive models, cognitive maps (CMs) hold great potential for clustering and visualization. Due to the lack of a formal mathematical basis, however, CM-based OLAP and OLAM have not gained popularity. Compared with existing approaches, bipolar cognitive mapping has a number of advantages. First, bipolar CMs are formal logical models as well as cognitive models. Second, equilibrium relations (with polarized reflexivity, symmetry, and transitivity), as bipolar generalizations and fusions of equivalence relations, provide a theoretical basis for bipolar visualization and coordination. Third, an equilibrium relation or CM induces bipolar partitions that distinguish disjoint coalition subsets not involved in any conflict, disjoint coalition subsets involved in a conflict, disjoint conflict subsets, and disjoint harmony subsets. Finally, equilibrium energy analysis leads to harmony and stability measures for strategic decision and multiagent coordination. Thus, this work bridges a gap for CM-based clustering and visualization in OLAP and OLAM. Basic ideas are illustrated with example CMs in international relations.

Specialty Payment Model Opportunities and Assessment

PubMed Central

Mulcahy, Andrew W.; Chan, Chris; Hirshman, Samuel; Huckfeldt, Peter J.; Kofner, Aaron; Liu, Jodi L.; Lovejoy, Susan L.; Popescu, Ioana; Timbie, Justin W.; Hussey, Peter S.

2015-01-01

Abstract Gastroenterology and cardiology services are common and costly among Medicare beneficiaries. Episode-based payment, which aims to create incentives for high-quality, low-cost care, has been identified as a promising alternative payment model. This article describes research related to the design of episode-based payment models for ambulatory gastroenterology and cardiology services for possible testing by the Center for Medicare and Medicaid Innovation at the Centers for Medicare and Medicaid Services (CMS). The authors analyzed Medicare claims data to describe the frequency and characteristics of gastroenterology and cardiology index procedures, the practices that delivered index procedures, and the patients that received index procedures. The results of these analyses can help inform CMS decisions about the definition of episodes in an episode-based payment model; payment adjustments for service setting, multiple procedures, or other factors; and eligibility for the payment model. PMID:28083363

Forward and small-x QCD physics results from CMS experiment at LHC

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

Cerci, Deniz Sunar, E-mail: deniz.sunar.cerci@cern.ch

2016-03-25

The Compact Muon Solenoid (CMS) is one of the two large, multi-purpose experiments at the Large Hadron Collider (LHC) at CERN. During the Run I Phase a large pp collision dataset has been collected and the CMS collaboration has explored measurements that shed light on a new era. Forward and small-x quantum chromodynamics (QCD) physics measurements with CMS experiment covers a wide range of physics subjects. Some of highlights in terms of testing the very low-x QCD, underlying event and multiple interaction characteristics, photon-mediated processes, jets with large rapidity separation at high pseudo-rapidities and the inelastic proton-proton cross section dominatedmore » by diffractive interactions are presented. Results are compared to Monte Carlo (MC) models with different parameter tunes for the description of the underlying event and to perturbative QCD calculations. The prominent role of multi-parton interactions has been confirmed in the semihard sector but no clear deviation from the standard Dglap parton evolution due to Bfkl has been observed. An outlook to the prospects at 13 TeV is given.« less

Carbon Monitoring System Applications Framework: Lessons Learned from Stakeholder Engagement Activities

NASA Astrophysics Data System (ADS)

Sepulveda Carlo, E.; Escobar, V. M.; Delgado Arias, S.; Forgotson, C.

2017-12-01

The NASA Carbon Monitoring System initiated by U.S. Congress in 2010 is developing products that characterize and quantify carbon sources and sinks in the United States and the global tropics. In 2013, an applications effort was selected to engage potential end users and gather feedback about their data needs. For the past four years the CMS applications efforts has expanded and implemented a number of strategies to connect carbon scientists to decision-makers, contributing to the societal benefits of CMS data products. The applications efforts use crowd sourcing to collects feedback from stakeholders on challenges and lessons learned in the use of CMS data products. Some of the most common data needs from engaged organizations include above and below-ground biomass and fluxes in forestlands and wetlands, and greenhouse gas (GHG) emissions across all land use/cover and land use changes. Stakeholder organizations' needs for CMS data products support national GHG inventories following the Paris Agreement, carbon markets, and sub-national natural resources management and policies. The lessons learned report presents stakeholder specific applications, challenges, and successes from using CMS data products. To date, the most common uses of CMS products include: conservation efforts, emissions inventory, forestry and land cover applications, and carbon offset projects. The most common challenges include: the need for familiar and consistent products over time, budget constraints, and concern with uncertainty of modeled results. Recurrent recommendations from stakeholder indicate that CMS should provide high resolution (30m) and frequent data products updates (annually). The applications efforts have also helped identified success stories from different CMS projects, including the development of the GHG emissions inventory from Providence, RI, the improvement of the U.S. GHG Inventory though the use of satellite data, and the use of high resolution canopy cover maps for forestry, conservation, and ecosystem services applications in the tristate area of Maryland, Delaware and Pennsylvania. The presentation will discuss the applications framework methodology and strategy, as well as highlight some of the results and lessons learned from these applications efforts.

Fabrication of fibrillized collagen microspheres with the microstructure resembling an extracellular matrix.

PubMed

Matsuhashi, Aki; Nam, Kwangwoo; Kimura, Tsuyoshi; Kishida, Akio

2015-04-14

Microspheres using artificial or natural materials have been widely applied in the field of tissue engineering and drug delivery systems. Collagen is being widely used for microspheres because of its abundancy in the extracellular matrix (ECM), and its good biocompatibility. The purpose of this study is to establish the appropriate condition for preparing collagen microspheres (CMS) and fibrillized collagen microspheres (fCMS) using water-in-oil (W/O) emulsion. Collagen can be tailored to mimic the native cell environment possessing a similar microstructure to that of the ECM by conditioning the aqueous solution. We focused on the preparation of stable and injectable CMS and fCMS which is stable and would promote the healing response. Controlling the interfacial properties of hydrophilic-lipophilic balance (HLB), we obtained CMS and fCMS with various sizes and various morphologies. The microsphere prepared with wetting agents showed good microsphere formation, but too low or too high HLB value caused low yield and uncontrollable size distribution. The change in the surfactant amount and the rotor speed also affected the formation of the CMS and fCMS, where the low surfactant amount and fast rotor speed produced smaller CMS and fCMS. In the case of fCMS, the presence of NaCl made it possible to prepare stable fCMS without using any cross-linker due to fibrillogenesis and gelling of collagen molecules. The microstructure of fCMS was similar to that of the native tissue indicating that the fCMS would replicate its function in vivo.

Penetration, Completeness, and Representativeness of The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

PubMed

Jacobs, Jeffrey P; Shahian, David M; He, Xia; O'Brien, Sean M; Badhwar, Vinay; Cleveland, Joseph C; Furnary, Anthony P; Magee, Mitchell J; Kurlansky, Paul A; Rankin, J Scott; Welke, Karl F; Filardo, Giovanni; Dokholyan, Rachel S; Peterson, Eric D; Brennan, J Matthew; Han, Jane M; McDonald, Donna; Schmitz, DeLaine; Edwards, Fred H; Prager, Richard L; Grover, Frederick L

2016-01-01

The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) has been successfully linked to the Centers for Medicare and Medicaid (CMS) Medicare database, thereby facilitating comparative effectiveness research and providing information about long-term follow-up and cost. The present study uses this link to determine contemporary completeness, penetration, and representativeness of the STS ACSD. Using variables common to both STS and CMS databases, STS operations were linked to CMS data for all CMS coronary artery bypass graft (CABG) surgery hospitalizations discharged between 2000 and 2012, inclusive. For each CMS CABG hospitalization, it was determined whether a matching STS record existed. Center-level penetration (number of CMS sites with at least one matched STS participant divided by the total number of CMS CABG sites) increased from 45% in 2000 to 90% in 2012. In 2012, 973 of 1,081 CMS CABG sites (90%) were linked to an STS site. Patient-level penetration (number of CMS CABG hospitalizations done at STS sites divided by the total number of CMS CABG hospitalizations) increased from 51% in 2000 to 94% in 2012. In 2012, 71,634 of 76,072 CMS CABG hospitalizations (94%) occurred at an STS site. Completeness of case inclusion at STS sites (number of CMS CABG cases at STS sites linked to STS records divided by the total number of CMS CABG cases at STS sites) increased from 88% in 2000 to 98% in 2012. In 2012, 69,213 of 70,932 CMS CABG hospitalizations at STS sites (98%) were linked to an STS record. Linkage of STS and CMS databases demonstrates high and increasing penetration and completeness of the STS database. Linking STS and CMS data facilitates studying long-term outcomes and costs of cardiothoracic surgery. Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Understanding Climate Policy Data Needs. NASA Carbon Monitoring System Briefing: Characterizing Flux Uncertainty, Washington D.C., 11 January 2012

NASA Technical Reports Server (NTRS)

Brown, Molly E.; Macauley, Molly

2012-01-01

Climate policy in the United States is currently guided by public-private partnerships and actions at the local and state levels. This mitigation strategy is made up of programs that focus on energy efficiency, renewable energy, agricultural practices and implementation of technologies to reduce greenhouse gases. How will policy makers know if these strategies are working, particularly at the scales at which they are being implemented? The NASA Carbon Monitoring System (CMS) will provide information on carbon dioxide fluxes derived from observations of earth's land, ocean and atmosphere used in state of the art models describing their interactions. This new modeling system could be used to assess the impact of specific policy interventions on CO2 reductions, enabling an iterative, results-oriented policy process. In January of 2012, the CMS team held a meeting with carbon policy and decision makers in Washington DC to describe the developing modeling system to policy makers. The NASA CMS will develop pilot studies to provide information across a range of spatial scales, consider carbon storage in biomass, and improve measures of the atmospheric distribution of carbon dioxide. The pilot involves multiple institutions (four NASA centers as well as several universities) and over 20 scientists in its work. This pilot study will generate CO2 flux maps for two years using observational constraints in NASA's state-of -the-art models. Bottom-up surface flux estimates will be computed using data-constrained land and ocean models; comparison of the different techniques will provide some knowledge of uncertainty in these estimates. Ensembles of atmospheric carbon distributions will be computed using an atmospheric general circulation model (GEOS-5), with perturbations to the surface fluxes and to transport. Top-down flux estimates will be computed from observed atmospheric CO2 distributions (ACOS/GOSAT retrievals) alongside the forward-model fields, in conjunction with an inverse approach based on the CO2 model of GEOS ]Chem. The forward model ensembles will be used to build understanding of relationships among surface flux perturbations, transport uncertainty and atmospheric carbon concentration. This will help construct uncertainty estimates and information on the true spatial resolution of the top-down flux calculations. The relationship between the top-down and bottom-up flux distributions will be documented. Because the goal of NASA CMS is to be policy relevant, the scientists involved in the flux modeling pilot need to understand and be focused on the needs of the climate policy and decision making community. If policy makers are to use CMS products, they must be aware of the modeling effort and begin to design policies that can be evaluated with information. Improving estimates of carbon sequestered in forests, for example, will require information on the spatial variability of forest biomass that is far more explicit than is presently possible using only ground observations. Carbon mitigation policies being implemented by cities around the United States could be designed with the CMS data in mind, enabling sequential evaluation and subsequent improvements in incentives, structures and programs. The success of climate mitigation programs being implemented in the United States today will hang on the depth of the relationship between scientists and their policy and decision making counterparts. Ensuring that there is two-way communication between data providers and users is important for the success both of the policies and the scientific products meant to support them..

Specialty Payment Model Opportunities and Assessment: Gastroenterology and Cardiology Model Design Report.

PubMed

Mulcahy, Andrew W; Chan, Chris; Hirshman, Samuel; Huckfeldt, Peter J; Kofner, Aaron; Liu, Jodi L; Lovejoy, Susan L; Popescu, Ioana; Timbie, Justin W; Hussey, Peter S

2015-07-15

Gastroenterology and cardiology services are common and costly among Medicare beneficiaries. Episode-based payment, which aims to create incentives for high-quality, low-cost care, has been identified as a promising alternative payment model. This article describes research related to the design of episode-based payment models for ambulatory gastroenterology and cardiology services for possible testing by the Center for Medicare and Medicaid Innovation at the Centers for Medicare and Medicaid Services (CMS). The authors analyzed Medicare claims data to describe the frequency and characteristics of gastroenterology and cardiology index procedures, the practices that delivered index procedures, and the patients that received index procedures. The results of these analyses can help inform CMS decisions about the definition of episodes in an episode-based payment model; payment adjustments for service setting, multiple procedures, or other factors; and eligibility for the payment model.

78 FR 38986 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-28

... that information was collected under Part B. The QIMS Account Registration and the ESRD Application..., CMS-1728-94, CMS-10174, CMS-10305 and CMS-10488] Agency Information Collection Activities: Proposed... comment on CMS' intention to collect information from the public. Under the Paperwork Reduction Act of...

42 CFR 482.74 - Condition of participation: Notification to CMS.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 5 2010-10-01 2010-10-01 false Condition of participation: Notification to CMS... participation: Notification to CMS. (a) A transplant center must notify CMS immediately of any significant... conditions of participation. Instances in which CMS should receive information for follow up, as appropriate...

Perceptions, use and attitudes of pharmacy customers on complementary medicines and pharmacy practice.

PubMed

Braun, Lesley A; Tiralongo, Evelin; Wilkinson, Jenny M; Spitzer, Ondine; Bailey, Michael; Poole, Susan; Dooley, Michael

2010-07-20

Complementary medicines (CMs) are popular amongst Australians and community pharmacy is a major supplier of these products. This study explores pharmacy customer use, attitudes and perceptions of complementary medicines, and their expectations of pharmacists as they relate to these products. Pharmacy customers randomly selected from sixty large and small, metropolitan and rural pharmacies in three Australian states completed an anonymous, self administered questionnaire that had been pre-tested and validated. 1,121 customers participated (response rate 62%). 72% had used CMs within the previous 12 months, 61% used prescription medicines daily and 43% had used both concomitantly. Multivitamins, fish oils, vitamin C, glucosamine and probiotics were the five most popular CMs. 72% of people using CMs rated their products as 'very effective' or 'effective enough'. CMs were as frequently used by customers aged 60 years or older as younger customers (69% vs. 72%) although the pattern of use shifted with older age. Most customers (92%) thought pharmacists should provide safety information about CMs, 90% thought they should routinely check for interactions, 87% thought they should recommend effective CMs, 78% thought CMs should be recorded in customer's medication profile and 58% thought pharmacies stocking CMs should also employ a complementary medicine practitioner. Of those using CMs, 93% thought it important for pharmacists to be knowledgeable about CMs and 48% felt their pharmacist provides useful information about CMs. CMs are widely used by pharmacy customers of all ages who want pharmacists to be more involved in providing advice about these products.

Recombination Events Involving the atp9 Gene Are Associated with Male Sterility of CMS PET2 in Sunflower.

PubMed

Reddemann, Antje; Horn, Renate

2018-03-11

Cytoplasmic male sterility (CMS) systems represent ideal mutants to study the role of mitochondria in pollen development. In sunflower, CMS PET2 also has the potential to become an alternative CMS source for commercial sunflower hybrid breeding. CMS PET2 originates from an interspecific cross of H. petiolaris and H. annuus as CMS PET1, but results in a different CMS mechanism. Southern analyses revealed differences for atp6 , atp9 and cob between CMS PET2, CMS PET1 and the male-fertile line HA89. A second identical copy of atp6 was present on an additional CMS PET2-specific fragment. In addition, the atp9 gene was duplicated. However, this duplication was followed by an insertion of 271 bp of unknown origin in the 5' coding region of the atp9 gene in CMS PET2, which led to the creation of two unique open reading frames orf288 and orf231 . The first 53 bp of orf288 are identical to the 5' end of atp9 . Orf231 consists apart from the first 3 bp, being part of the 271-bp-insertion, of the last 228 bp of atp9 . These CMS PET2-specific orfs are co-transcribed. All 11 editing sites of the atp9 gene present in orf231 are fully edited. The anther-specific reduction of the co-transcript in fertility-restored hybrids supports the involvement in male-sterility based on CMS PET2.

CMS-2 Reverse Engineering and ENCORE/MODEL Integration

DTIC Science & Technology

1992-05-01

Automated extraction of design information from an existing software system written in CMS-2 can be used to document that system as-built, and that I The...extracted information is provided by a commer- dally available CASE tool. * Information describing software system design is automatically extracted...the displays in Figures 1, 2, and 3. T achiev ths GE 11 b iuo w as rjcs CM-2t Aa nsltr(M2da 1 n Joia Reverse EwngiernTcnlg 5RT [2GRE] . Two xampe fD

Deep phenotyping of human induced pluripotent stem cell-derived atrial and ventricular cardiomyocytes.

PubMed

Cyganek, Lukas; Tiburcy, Malte; Sekeres, Karolina; Gerstenberg, Kathleen; Bohnenberger, Hanibal; Lenz, Christof; Henze, Sarah; Stauske, Michael; Salinas, Gabriela; Zimmermann, Wolfram-Hubertus; Hasenfuss, Gerd; Guan, Kaomei

2018-06-21

Generation of homogeneous populations of subtype-specific cardiomyocytes (CMs) derived from human induced pluripotent stem cells (iPSCs) and their comprehensive phenotyping is crucial for a better understanding of the subtype-related disease mechanisms and as tools for the development of chamber-specific drugs. The goals of this study were to apply a simple and efficient method for differentiation of iPSCs into defined functional CM subtypes in feeder-free conditions and to obtain a comprehensive understanding of the molecular, cell biological, and functional properties of atrial and ventricular iPSC-CMs on both the single-cell and engineered heart muscle (EHM) level. By a stage-specific activation of retinoic acid signaling in monolayer-based and well-defined culture, we showed that cardiac progenitors can be directed towards a highly homogeneous population of atrial CMs. By combining the transcriptome and proteome profiling of the iPSC-CM subtypes with functional characterizations via optical action potential and calcium imaging, and with contractile analyses in EHM, we demonstrated that atrial and ventricular iPSC-CMs and -EHM highly correspond to the atrial and ventricular heart muscle, respectively. This study provides a comprehensive understanding of the molecular and functional identities characteristic of atrial and ventricular iPSC-CMs and -EHM and supports their suitability in disease modeling and chamber-specific drug screening.

From the CMS Computing Experience in the WLCG STEP'09 Challenge to the First Data Taking of the LHC Era

NASA Astrophysics Data System (ADS)

Bonacorsi, D.; Gutsche, O.

The Worldwide LHC Computing Grid (WLCG) project decided in March 2009 to perform scale tests of parts of its overall Grid infrastructure before the start of the LHC data taking. The "Scale Test for the Experiment Program" (STEP'09) was performed mainly in June 2009 -with more selected tests in September- October 2009 -and emphasized the simultaneous test of the computing systems of all 4 LHC experiments. CMS tested its Tier-0 tape writing and processing capabilities. The Tier-1 tape systems were stress tested using the complete range of Tier-1 work-flows: transfer from Tier-0 and custody of data on tape, processing and subsequent archival, redistribution of datasets amongst all Tier-1 sites as well as burst transfers of datasets to Tier-2 sites. The Tier-2 analysis capacity was tested using bulk analysis job submissions to backfill normal user activity. In this talk, we will report on the different performed tests and present their post-mortem analysis.

42 CFR 423.2063 - Applicability of laws, regulations and CMS Rulings.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Applicability of laws, regulations and CMS Rulings..., ALJ Hearings, MAC review, and Judicial Review § 423.2063 Applicability of laws, regulations and CMS... on ALJs and the MAC. (b) CMS Rulings are published under the authority of the CMS Administrator...

42 CFR 426.517 - CMS' statement regarding new evidence.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false CMS' statement regarding new evidence. 426.517... DETERMINATIONS Review of an NCD § 426.517 CMS' statement regarding new evidence. (a) CMS may review any new... experts; and (5) Presented during any hearing. (b) CMS may submit a statement regarding whether the new...

42 CFR 405.1063 - Applicability of laws, regulations and CMS Rulings.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Applicability of laws, regulations and CMS Rulings... Medicare Coverage Policies § 405.1063 Applicability of laws, regulations and CMS Rulings. (a) All laws and... the MAC. (b) CMS Rulings are published under the authority of the Administrator, CMS. Consistent with...

How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features.

PubMed

Lorenzoni, Paulo José; Scola, Rosana Herminia; Kay, Claudia Suemi Kamoi; Werneck, Lineu Cesar; Horvath, Rita; Lochmüller, Hanns

2018-06-01

Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases in which neuromuscular transmission is compromised. CMS resembling the Lambert-Eaton myasthenic syndrome (CMS-LEMS) are emerging as a rare group of distinct presynaptic CMS that share the same electrophysiological features. They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation. Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS. CMS-LEMS occurs due to deficits in acetylcholine vesicle release caused by dysfunction of different components in its pathway. To date, the genes that have been associated with CMS-LEMS are AGRN, SYT2, MUNC13-1, VAMP1, and LAMA5. Clinicians should keep in mind these newest subtypes of CMS-LEMS to achieve the correct diagnosis and therapy. We believe that CMS-LEMS must be included as an important diagnostic clue to genetic investigation in the diagnostic algorithms to CMS. We briefly review the main features of CMS-LEMS.

A search for long-lived particles that stop in the CMS detector and decay to muons

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

Alimena, Juliette

2016-05-01

A search for long-lived particles that are produced in proton-proton collisions at the CERN LHC, come to rest in the CMS detector, and decay to muons is presented. The decays of the stopped particles could be observed during the intervals between LHC beam crossings, at times that are well separated from any proton-proton collisions. The analysis uses 19.7 1/fb of 8 TeV data collected by CMS in 2012, during a search interval of 293 hours of trigger livetime. Massive, long-lived particles do not exist in the Standard Model, and so any sign of them would be an indication of newmore » physics. The results are interpreted with a model that predicts a long-lived particle that has a charge of twice the electron charge and that behaves like a lepton. Cross section limits are set for each long-lived particle mass as a function of lifetime, for lifetimes between 100 ns and 10 days. These are the first limits for long-lived stopped particles that decay to muons.« less

A novel photo-grafting of acrylamide onto carboxymethyl starch. 1. Utilization of CMS-g-PAAm in easy care finishing of cotton fabrics.

PubMed

El-Sheikh, Manal A

2016-11-05

The photosensitized grafting of vinyl monomers onto a range of polymeric substrates has been the subject of particular interest in the recent past. Carboxymethyl starch (CMS)-poly acrylamide (PAAm) graft copolymer (CMS-g-PAAm) with high graft yield was successfully prepared by grafting of acrylamide onto CMS using UV irradiation in the presence of the water soluble 4-(trimethyl ammoniummethyl) benzophenone chloride photoinitiator. CMS-g-PAAm with nitrogen content of 8.3% and grafting efficiency up to 98.9% was obtained using 100% AAm, a material: liquor ratio of 1:14 and 1% photinitiator at 30°C for 1h of UV irradiation. The synthesis of CMS-g-PAAm was confirmed by FTIR and Nitrogen content (%). Surface morphology of CMS and surface morphological changes of CMS after grafting with AAm were studied using SEM. Thermal properties of both CMS and CMS-g-PAAm were studied using TGA and DSC. To impart easy care finishing to cotton fabrics, aqueous formulations of: CMS-g-PAAm, dimethylol dihydroxy ethylene urea (DMDHEU), CMS-g-PAAm-DMDHEU mixture or methylolated CMS-g-PAAm were used. Cotton fabrics were padded in these formulations, squeezed to a wet pick up 100%, dried at 100°C for 5min, cured at 150°C for 5min, washed at 50°C for 10min and air-dried. CRA (crease recovery angle) of untreated fabrics and fabrics finished with a mixture of 2% CMS-g-PAAm and 10% DMDHEU or methylolated CMS-g-PAAm (10% formaldehyde) were: 136°, 190°, 288° respectively. Increasing the number of washing cycles up to five cycles results in an insignificant decrease in the CRA and a significant decrease in RF (releasable formaldehyde) of finished fabric samples. The morphologies of the finished and unfinished cotton fabrics were performed by SEM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Perceptions, use and attitudes of pharmacy customers on complementary medicines and pharmacy practice

PubMed Central

2010-01-01

Background Complementary medicines (CMs) are popular amongst Australians and community pharmacy is a major supplier of these products. This study explores pharmacy customer use, attitudes and perceptions of complementary medicines, and their expectations of pharmacists as they relate to these products. Methods Pharmacy customers randomly selected from sixty large and small, metropolitan and rural pharmacies in three Australian states completed an anonymous, self administered questionnaire that had been pre-tested and validated. Results 1,121 customers participated (response rate 62%). 72% had used CMs within the previous 12 months, 61% used prescription medicines daily and 43% had used both concomitantly. Multivitamins, fish oils, vitamin C, glucosamine and probiotics were the five most popular CMs. 72% of people using CMs rated their products as 'very effective' or 'effective enough'. CMs were as frequently used by customers aged 60 years or older as younger customers (69% vs. 72%) although the pattern of use shifted with older age. Most customers (92%) thought pharmacists should provide safety information about CMs, 90% thought they should routinely check for interactions, 87% thought they should recommend effective CMs, 78% thought CMs should be recorded in customer's medication profile and 58% thought pharmacies stocking CMs should also employ a complementary medicine practitioner. Of those using CMs, 93% thought it important for pharmacists to be knowledgeable about CMs and 48% felt their pharmacist provides useful information about CMs. Conclusions CMs are widely used by pharmacy customers of all ages who want pharmacists to be more involved in providing advice about these products. PMID:20646290

Recombination Events Involving the atp9 Gene Are Associated with Male Sterility of CMS PET2 in Sunflower

PubMed Central

Reddemann, Antje; Horn, Renate

2018-01-01

Cytoplasmic male sterility (CMS) systems represent ideal mutants to study the role of mitochondria in pollen development. In sunflower, CMS PET2 also has the potential to become an alternative CMS source for commercial sunflower hybrid breeding. CMS PET2 originates from an interspecific cross of H. petiolaris and H. annuus as CMS PET1, but results in a different CMS mechanism. Southern analyses revealed differences for atp6, atp9 and cob between CMS PET2, CMS PET1 and the male-fertile line HA89. A second identical copy of atp6 was present on an additional CMS PET2-specific fragment. In addition, the atp9 gene was duplicated. However, this duplication was followed by an insertion of 271 bp of unknown origin in the 5′ coding region of the atp9 gene in CMS PET2, which led to the creation of two unique open reading frames orf288 and orf231. The first 53 bp of orf288 are identical to the 5′ end of atp9. Orf231 consists apart from the first 3 bp, being part of the 271-bp-insertion, of the last 228 bp of atp9. These CMS PET2-specific orfs are co-transcribed. All 11 editing sites of the atp9 gene present in orf231 are fully edited. The anther-specific reduction of the co-transcript in fertility-restored hybrids supports the involvement in male-sterility based on CMS PET2. PMID:29534485

Elastic and Sorption Characteristics of an Epoxy Binder in a Composite During Its Moistening

NASA Astrophysics Data System (ADS)

Aniskevich, K.; Glaskova, T.; Jansons, J.

2005-07-01

Results of an experimental investigation into the elastic and sorption characteristics of a model composite material (CM) — epoxy resin filled with LiF crystals — during its moistening are presented. Properties of the binder in the CM with different filler contents ( v f = 0, 0.05, 0.11, 0.23, 0.28, 0.33, 0.38, and 0.46) were evaluated indirectly by using known micromechanical models of CMs. It was revealed that, for the CM in a conditionally initial state, the elastic modulus of the binder in it and the filler microstrain (change in the interplanar distance in the crystals, measured by the X-ray method) as functions of filler content had the same character. The elastic modulus of the binder in the CM with a low filler content was equal to that for the binder in a block; the elastic modulus of the binder in the CM decreased with increasing filler content. The maximum (corresponding to water saturation of the CM) stresses in the binder and the filler microstresses as functions of filler content were of the same character. Moreover, the absolute values of maximum stresses in the binder and of filler microstresses coincided for high and low contents of the filler. At v f = 0.2-0. 3, the filler microstrains exceeded the stresses in the binder. The effect of moisture on the epoxy binder in the CM with a high filler content was not entirely reversible: the elastic characteristics of the binder increased, the diffusivity decreased, and the ultimate water content increased after a moistening-drying cycle.

Explaining a CMS e e j j excess with R -parity violating supersymmetry and implications for neutrinoless double beta decay

NASA Astrophysics Data System (ADS)

Allanach, Ben; Biswas, Sanjoy; Mondal, Subhadeep; Mitra, Manimala

2015-01-01

A recent CMS search for the right-handed gauge boson WR reports an interesting deviation from the Standard Model. The search has been conducted in the e e j j channel and has shown a 2.8 σ excess around me e j j˜2 TeV . In this work, we explain the reported CMS excess with R -parity violating supersymmetry. We consider resonant selectron and sneutrino production, followed by the three body decays of the neutralino and chargino via an R -parity violating coupling. We fit the excess for slepton masses around 2 TeV. The scenario can further be tested in neutrinoless double beta decay (0 ν β β ) experiments. GERDA Phase-II will probe a significant portion of the good-fit parameter space.

A Conflict Management Scale for Pharmacy

PubMed Central

Gregory, Paul A.; Martin, Craig

2009-01-01

Objectives To develop and establish the validity and reliability of a conflict management scale specific to pharmacy practice and education. Methods A multistage inventory-item development process was undertaken involving 93 pharmacists and using a previously described explanatory model for conflict in pharmacy practice. A 19-item inventory was developed, field tested, and validated. Results The conflict management scale (CMS) demonstrated an acceptable degree of reliability and validity for use in educational or practice settings to promote self-reflection and self-awareness regarding individuals' conflict management styles. Conclusions The CMS provides a unique, pharmacy-specific method for individuals to determine and reflect upon their own conflict management styles. As part of an educational program to facilitate self-reflection and heighten self-awareness, the CMS may be a useful tool to promote discussions related to an important part of pharmacy practice. PMID:19960081

CMS event processing multi-core efficiency status

NASA Astrophysics Data System (ADS)

Jones, C. D.; CMS Collaboration

2017-10-01

In 2015, CMS was the first LHC experiment to begin using a multi-threaded framework for doing event processing. This new framework utilizes Intel’s Thread Building Block library to manage concurrency via a task based processing model. During the 2015 LHC run period, CMS only ran reconstruction jobs using multiple threads because only those jobs were sufficiently thread efficient. Recent work now allows simulation and digitization to be thread efficient. In addition, during 2015 the multi-threaded framework could run events in parallel but could only use one thread per event. Work done in 2016 now allows multiple threads to be used while processing one event. In this presentation we will show how these recent changes have improved CMS’s overall threading and memory efficiency and we will discuss work to be done to further increase those efficiencies.

Elastic Extension of a CMS Computing Centre Resources on External Clouds

NASA Astrophysics Data System (ADS)

Codispoti, G.; Di Maria, R.; Aiftimiei, C.; Bonacorsi, D.; Calligola, P.; Ciaschini, V.; Costantini, A.; Dal Pra, S.; DeGirolamo, D.; Grandi, C.; Michelotto, D.; Panella, M.; Peco, G.; Sapunenko, V.; Sgaravatto, M.; Taneja, S.; Zizzi, G.

2016-10-01

After the successful LHC data taking in Run-I and in view of the future runs, the LHC experiments are facing new challenges in the design and operation of the computing facilities. The computing infrastructure for Run-II is dimensioned to cope at most with the average amount of data recorded. The usage peaks, as already observed in Run-I, may however originate large backlogs, thus delaying the completion of the data reconstruction and ultimately the data availability for physics analysis. In order to cope with the production peaks, CMS - along the lines followed by other LHC experiments - is exploring the opportunity to access Cloud resources provided by external partners or commercial providers. Specific use cases have already been explored and successfully exploited during Long Shutdown 1 (LS1) and the first part of Run 2. In this work we present the proof of concept of the elastic extension of a CMS site, specifically the Bologna Tier-3, on an external OpenStack infrastructure. We focus on the “Cloud Bursting” of a CMS Grid site using a newly designed LSF configuration that allows the dynamic registration of new worker nodes to LSF. In this approach, the dynamically added worker nodes instantiated on the OpenStack infrastructure are transparently accessed by the LHC Grid tools and at the same time they serve as an extension of the farm for the local usage. The amount of resources allocated thus can be elastically modeled to cope up with the needs of CMS experiment and local users. Moreover, a direct access/integration of OpenStack resources to the CMS workload management system is explored. In this paper we present this approach, we report on the performances of the on-demand allocated resources, and we discuss the lessons learned and the next steps.

Effect of Wind Velocity on Flame Spread in Microgravity

NASA Technical Reports Server (NTRS)

Prasad, Kuldeep; Olson, Sandra L.; Nakamura, Yuji; Fujita, Osamu; Nishizawa, Katsuhiro; Ito, Kenichi; Kashiwagi, Takashi; Simons, Stephen N. (Technical Monitor)

2002-01-01

A three-dimensional, time-dependent model is developed describing ignition and subsequent transition to flame spread over a thermally thin cellulosic sheet heated by external radiation in a microgravity environment. A low Mach number approximation to the Navier Stokes equations with global reaction rate equations describing combustion in the gas phase and the condensed phase is numerically solved. The effects of a slow external wind (1-20 cm/s) on flame transition are studied in an atmosphere of 35% oxygen concentration. The ignition is initiated at the center part of the sample by generating a line-shape flame along the width of the sample. The calculated results are compared with data obtained in the 10s drop tower. Numerical results exhibit flame quenching at a wind speed of 1.0 cm/s, two localized flames propagating upstream along the sample edges at 1.5 cm/s, a single line-shape flame front at 5.0 cm/s, three flames structure observed at 10.0 cm/s (consisting of a single line-shape flame propagating upstream and two localized flames propagating downstream along sample edges) and followed by two line-shape flames (one propagating upstream and another propagating downstream) at 20.0 cm/s. These observations qualitatively compare with experimental data. Three-dimensional visualization of the observed flame complex, fuel concentration contours, oxygen and reaction rate isosurfaces, convective and diffusive mass flux are used to obtain a detailed understanding of the controlling mechanism, Physical arguments based on lateral diffusive flux of oxygen, fuel depletion, oxygen shadow of the flame and heat release rate are constructed to explain the various observed flame shapes.

Hybrid male sterility in Mimulus (Phrymaceae) is associated with a geographically restricted mitochondrial rearrangement.

PubMed

Case, Andrea L; Willis, John H

2008-05-01

Cytoplasmic male sterility (CMS) and nuclear fertility restoration (Rf) involves intergenomic coevolution. Although male-sterile phenotypes are rarely expressed in natural populations of angiosperms, CMS genes are thought to be common. The evolutionary dynamics of CMS/Rf systems are poorly understood, leaving gaps in our understanding of mechanisms and consequences of cytonuclear interactions. We characterized the molecular basis and geographic distribution of a CMS gene in Mimulus guttatus. We used outcrossing M. guttatus (with CMS and Rf) to self-fertilizing M. nasutus (lacking CMS and Rf) to generate hybrids segregating for CMS. Mitochondrial transcripts containing an essential gene (nad6) were perfectly associated with male sterility. The CMS mitotype was completely absent in M. nasutus, present in all genotypes collected from the original collection site, but in only two individuals from 34 other M. guttatus populations. This pattern suggests that the CMS likely originated at a single locality, spread to fixation within the population, but has not spread to other populations, indicating possible ecological or genetic constraints on dispersal of this CMS mitotype between populations. Extreme localization may be characteristic of CMS in hermaphroditic species, in contrast to geographically widespread mitotypes commonly found in gynodioecious species, and could directly contribute to hybrid incompatibilities in nature.

Angle-corrected imaging transcranial doppler sonography versus imaging and nonimaging transcranial doppler sonography in children with sickle cell disease.

PubMed

Krejza, J; Rudzinski, W; Pawlak, M A; Tomaszewski, M; Ichord, R; Kwiatkowski, J; Gor, D; Melhem, E R

2007-09-01

Nonimaging transcranial Doppler sonography (TCD) and imaging TCD (TCDI) are used for determination of the risk of stroke in children with sickle cell disease (SCD). The purpose was to compare angle-corrected, uncorrected TCDI, and TCD blood flow velocities in children with SCD. A total of 37 children (mean age, 7.8 +/- 3.0 years) without intracranial arterial narrowing determined with MR angiography, were studied with use of TCD and TCDI at the same session. Depth of insonation and TCDI mean velocities with and without correction for the angle of insonation in the terminal internal carotid artery (ICA) and middle (MCA), anterior (ACA), and posterior (PCA) cerebral arteries were compared with TCD velocities with use of a paired t test. Two arteries were not found on TCDI compared with 15 not found on TCD. Average angle of insonation in the MCA, ACA, ICA, and PCA was 31 degrees , 44 degrees , 25 degrees , and 29 degrees , respectively. TCDI and TCD mean depth of insonation for all arteries did not differ significantly; however, individual differences varied substantially. TCDI velocities were significantly lower than TCD velocities, respectively, for the right and left sides (mean +/- SD): MCA, 106 +/- 22 cm/s and 111 +/- 33 cm/s versus 130 +/- 19 cm/s and 134 +/- 26 cm/s; ICA, 90 +/- 14 cm/s and 98 +/- 27 cm/s versus 117 +/- 18 cm/s and 119 +/- 23 cm/s; ACA, 74 +/- 24 cm/s and 88 +/- 25 cm/s versus 105 +/- 23 cm/s and 105 +/- 31 cm/s; and PCA, 84 +/- 27 cm/s and 82 +/- 21 cm/s versus 95 +/- 23 cm/s and 94 +/- 20 cm/s. TCD and angle-corrected TCDI velocities were not statistically different except for higher angle-corrected TCDI values in the left ACA and right PCA. TCD velocities are significantly higher than TCDI velocities but are not different from the angle-corrected TCDI velocities. TCDI identifies the major intracranial arteries more effectively than TCD.

Social rank-associated stress vulnerability predisposes individuals to cocaine attraction.

PubMed

Yanovich, Chen; Kirby, Michael L; Michaelevski, Izhak; Yadid, Gal; Pinhasov, Albert

2018-01-29

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.

42 CFR 488.417 - Denial of payment for all new admissions.

Code of Federal Regulations, 2012 CFR

2012-10-01

... to CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State (for non-State operated NFs against which CMS is imposing no remedies); and (2) CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State...

42 CFR 488.417 - Denial of payment for all new admissions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... to CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State (for non-State operated NFs against which CMS is imposing no remedies); and (2) CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State...

42 CFR 488.417 - Denial of payment for all new admissions.

Code of Federal Regulations, 2014 CFR

2014-10-01

... to CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State (for non-State operated NFs against which CMS is imposing no remedies); and (2) CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State...

42 CFR 488.417 - Denial of payment for all new admissions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... to CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State (for non-State operated NFs against which CMS is imposing no remedies); and (2) CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State...

42 CFR 488.417 - Denial of payment for all new admissions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... to CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State (for non-State operated NFs against which CMS is imposing no remedies); and (2) CMS (for all facilities except non-State operated NFs against which CMS is imposing no remedies) or the State...

45 CFR 150.317 - Factors CMS uses to determine the amount of penalty.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Factors CMS uses to determine the amount of... RELATING TO HEALTH CARE ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement With Respect to Issuers and Non-Federal Governmental Plans-Civil Money Penalties § 150.317 Factors CMS...

40 CFR Table 1 to Subpart Qqqqq of... - Applicability of General Provisions to Subpart QQQQQ

Code of Federal Regulations, 2010 CFR

2010-07-01

.... § 63.8(e) CMS Performance Evaluation No Subpart QQQQQ does not require CMS performance evaluations... QQQQQ does not require performance tests or CMS performance evaluations. § 63.9(e) Notification of... CMS No Subpart QQQQQ does not require CMS performance evaluations. § 63.10(a), (b), (d)(1), (d)(4)-(5...

42 CFR 422.510 - Termination of contract by CMS.

Code of Federal Regulations, 2010 CFR

2010-10-01

... (CONTINUED) MEDICARE PROGRAM MEDICARE ADVANTAGE PROGRAM Application Procedures and Contracts for Medicare Advantage Organizations § 422.510 Termination of contract by CMS. (a) Termination by CMS. CMS may at any...

The diverse use of clouds by CMS

DOE PAGES

Andronis, Anastasios; Bauer, Daniela; Chaze, Olivier; ...

2015-12-23

The resources CMS is using are increasingly being offered as clouds. In Run 2 of the LHC the majority of CMS CERN resources, both in Meyrin and at the Wigner Computing Centre, will be presented as cloud resources on which CMS will have to build its own infrastructure. This infrastructure will need to run all of the CMS workflows including: Tier 0, production and user analysis. In addition, the CMS High Level Trigger will provide a compute resource comparable in scale to the total offered by the CMS Tier 1 sites, when it is not running as part of themore » trigger system. During these periods a cloud infrastructure will be overlaid on this resource, making it accessible for general CMS use. Finally, CMS is starting to utilise cloud resources being offered by individual institutes and is gaining experience to facilitate the use of opportunistically available cloud resources. Lastly, we present a snap shot of this infrastructure and its operation at the time of the CHEP2015 conference.« less

Multi-core processing and scheduling performance in CMS

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

Hernandez, J. M.; Evans, D.; Foulkes, S.

2012-01-01

Commodity hardware is going many-core. We might soon not be able to satisfy the job memory needs per core in the current single-core processing model in High Energy Physics. In addition, an ever increasing number of independent and incoherent jobs running on the same physical hardware not sharing resources might significantly affect processing performance. It will be essential to effectively utilize the multi-core architecture. CMS has incorporated support for multi-core processing in the event processing framework and the workload management system. Multi-core processing jobs share common data in memory, such us the code libraries, detector geometry and conditions data, resultingmore » in a much lower memory usage than standard single-core independent jobs. Exploiting this new processing model requires a new model in computing resource allocation, departing from the standard single-core allocation for a job. The experiment job management system needs to have control over a larger quantum of resource since multi-core aware jobs require the scheduling of multiples cores simultaneously. CMS is exploring the approach of using whole nodes as unit in the workload management system where all cores of a node are allocated to a multi-core job. Whole-node scheduling allows for optimization of the data/workflow management (e.g. I/O caching, local merging) but efficient utilization of all scheduled cores is challenging. Dedicated whole-node queues have been setup at all Tier-1 centers for exploring multi-core processing workflows in CMS. We present the evaluation of the performance scheduling and executing multi-core workflows in whole-node queues compared to the standard single-core processing workflows.« less

Inpatient Consults and Complications During Primary Total Joint Arthroplasty in a Bundled Care Model.

PubMed

Baumgartner, Billy T; Karas, Vasili; Kildow, Beau J; Cunningham, Daniel J; Klement, Mitchell R; Green, Cindy L; Attarian, David E; Seyler, Thorsten M

2018-04-01

The Centers for Medicare and Medicaid Services (CMS) are implementing changes in hospital reimbursement models for total joint arthroplasty (TJA), moving to value-based bundled payments from the fee-for-service model. The purpose of this study is to identify consults and complications during the perioperative period that increase financial burden. We combined CMS payment data for inpatient, professional, and postoperative with retrospective review of patients undergoing primary TJA and developed profiles of patients included in the Comprehensive Care for Joint Replacement bundle undergoing TJA. Statistical comparison of episode inpatient events and payments was conducted. Multiple regression analysis was adjusted for length of stay, disposition, and Charlson-Deyo comorbidity profile. Median total payment was $21,577.36, which exceeded the median bundle target payment of $20,625.00. Adjusted analyses showed that psychiatry consults (increase of $73,123.32; P < .001), internal medicine consults ($5789.38; P ≤ .001), pulmonary embolism ($35,273.68; P < .001), intensive care unit admission ($14,078.37; P < .001), and deep vein thrombosis ($9471.26; P = .019) resulted in increased payments using multivariate analysis adjusted for length of stay, Charlson-Deyo comorbidities, and discharge disposition. Patients with inpatient complications such as pulmonary embolism and/or deep vein thrombosis, intensive care unit admission, and medical/psychiatric consultation exceeded the CMS target. Although study results showed typical complication rates, acute inpatient consultation significantly increased utilization beyond the CMS target even when adjusted for length of stay, patient comorbidities, and discharge. Needed medical care should continue to be a priority for inpatients, and allowance for individual outliers should be considered in policy discussions. Copyright © 2017 Elsevier Inc. All rights reserved.

Complex aberrant splicing in the induced pluripotent stem cell-derived cardiomyocytes from a patient with long-QT syndrome carrying KCNQ1-A344Aspl mutation.

PubMed

Wuriyanghai, Yimin; Makiyama, Takeru; Sasaki, Kenichi; Kamakura, Tsukasa; Yamamoto, Yuta; Hayano, Mamoru; Harita, Takeshi; Nishiuchi, Suguru; Chen, Jiarong; Kohjitani, Hirohiko; Hirose, Sayako; Yokoi, Fumika; Gao, Jingshan; Chonabayashi, Kazuhisa; Watanabe, Ken; Ohno, Seiko; Yoshida, Yoshinori; Kimura, Takeshi; Horie, Minoru

2018-05-29

Long-QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1, which encodes the α-subunit of the slow delayed rectifier potassium current (I Ks ) channel. We previously reported that a synonymous mutation, c.1032G>A, p.A344Aspl in KCNQ1 is most commonly identified in the genotyped LQT1 Japanese patients, and the aberrant splicing was analyzed in the lymphocytes isolated from patients' blood samples. However, the mechanisms underlying the observed processes in human cardiomyocytes remains unclear. To establish and analyze patient-specific human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model carrying KCNQ1-A344Aspl. We generated hiPSCs from the peripheral blood mononuclear cells obtained from an LQT1 patient carrying KCNQ1-A344Aspl. Using the differentiated cardiomyocytes, we analyzed splicing variants and performed electrophysiological studies. We identified seven aberrant RNA variants in A344Aspl-hiPSC-CMs, more complex compared with those in the peripheral lymphocytes. Multi-electrode array analysis revealed that 1 μM isoproterenol significantly prolonged the duration of corrected field potential in A344Aspl-hiPSC-CMs, compared with that in the controls. Additionally, 100 nM E-4031, I Kr blocker, was shown to induce early afterdepolarization-like waveforms in A344Aspl-hiPSC-CMs. Action potential durations (APDs) did not significantly differ between the hiPSC-CM groups. After administrating 500 nM isoproterenol, APDs of A344Aspl-hiPSC-CMs were significantly longer than those of the controls. ML277 and phenylboronic acid, I Ks activators, ameliorated the APDs of hiPSC-CMs. We identified complex aberrant mRNA variants in the A344Aspl-hiPSC-CM model, and successfully recapitulated the clinical phenotypes of the patient with concealed LQT1. This model allows the investigation of the underlying mechanisms and development of novel therapies. Copyright © 2018. Published by Elsevier Inc.

Cardiotoxicity evaluation using human embryonic stem cells and induced pluripotent stem cell-derived cardiomyocytes.

PubMed

Zhao, Qi; Wang, Xijie; Wang, Shuyan; Song, Zheng; Wang, Jiaxian; Ma, Jing

2017-03-09

Cardiotoxicity remains an important concern in drug discovery. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have become an attractive platform to evaluate cardiotoxicity. However, the consistency between human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in prediction of cardiotoxicity has yet to be elucidated. Here we screened the toxicities of four representative drugs (E-4031, isoprenaline, quinidine, and haloperidol) using both hESC-CMs and hiPSC-CMs, combined with an impedance-based bioanalytical method. It showed that both hESC-CMs and hiPSC-CMs can recapitulate cardiotoxicity and identify the effects of well-characterized compounds. The combined platform of hPSC-CMs and an impedance-based bioanalytical method could improve preclinical cardiotoxicity screening, holding great potential for increasing drug development accuracy.

Dextrin-colistin conjugates as a model bioresponsive treatment for multidrug resistant bacterial infections.

PubMed

Ferguson, Elaine L; Azzopardi, Ernest; Roberts, Jessica L; Walsh, Timothy R; Thomas, David W

2014-12-01

Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, these studies developed and characterized a library of dextrin-colistin conjugates (dextrin molecular weight: 7500-48,000 g/mol) as a means of targeting the delivery of colistin. Optimum colistin release kinetics (following dextrin degradation by physiological concentrations of amylase (100 IU/L)) were observed in conjugates containing low molecular weight (∼7500 g/mol) dextrin with ∼1 mol % succinoylation (∼80% drug release within 48 h, compared to ∼33% from sodium colistin methanesulfonate (CMS, Colomycin)). These conjugates exhibited comparable antimicrobial activity to CMS in conventional MIC assays against a range of Gram-negative pathogens, but with significantly reduced in vitro toxicity toward kidney (IC₅₀ = CMS, 15.4 μg/mL; dextrin-colistin, 63.9 μg/mL) and macrophage (IC₅₀ = CMS, 111.3 μg/mL; dextrin-colistin, 303.9 μg/mL) cells. In vivo dose-escalation studies in rats demonstrated improved pharmacokinetics of the conjugates, with prolonged plasma levels of colistin (t₁/₂ 135-1271 min vs 53 min) and decreased toxicity, compared to colistin sulfate. These studies highlight the potential utility of "nanoantibiotic" polymer therapeutics to aid the safe, effective, and targeted delivery of colistin in the management of MDR infections.

Constant-Murley Score: systematic review and standardized evaluation in different shoulder pathologies.

PubMed

Vrotsou, Kalliopi; Ávila, Mónica; Machón, Mónica; Mateo-Abad, Maider; Pardo, Yolanda; Garin, Olatz; Zaror, Carlos; González, Nerea; Escobar, Antonio; Cuéllar, Ricardo

2018-05-10

The objective of this study was to evaluate the psychometric properties of the Constant-Murley Score (CMS) in various shoulder pathologies, based on a systematic review and expert standardized evaluations. A systematic review was performed in MEDLINE and EMBASE databases. Titles and abstracts were reviewed and finally the included articles were grouped according to patients' pathologies. Two expert evaluators independently assessed the CMS properties of reliability, validity, responsiveness to change, interpretability and burden score in each group, using the EMPRO (Evaluating Measures of Patient Reported Outcomes) tool. The CMS properties were assessed per attribute and overall for each considered group. Only the concept and measurement model was assessed globally. Five individual pathologies (i.e. subacromial, fractures, arthritis, instability and frozen shoulder) and two additional groups (i.e. various pathologies and healthy subjects) were considered. Overall EMPRO scores ranged from 58.6 for subacromial to 30.6 points for instability. Responsiveness to change was the only quality to obtain at least 50 points across all groups, but for frozen shoulder. Insufficient information was obtained in relation to the concept and measurement model and great variability was seen in the other evaluated attributes. The current evidence does not support the CMS as a gold standard in shoulder evaluation. Its use is advisable for subacromial pathology; but data are inconclusive for other shoulder conditions. Prospective studies exploring the psychometric properties of the scale, particularly for fractures, arthritis, instability and frozen shoulder are needed. Systematic review.

Disease management for chronically ill beneficiaries in traditional Medicare.

PubMed

Bott, David M; Kapp, Mary C; Johnson, Lorraine B; Magno, Linda M

2009-01-01

We summarize the Centers for Medicare and Medicaid Services' (CMS's) experience with disease management (DM) in fee-for-service Medicare. Since 1999, the CMS has conducted seven DM demonstrations involving some 300,000 beneficiaries in thirty-five programs. Programs include provider-based, third-party, and hybrid models. Reducing costs sufficient to cover program fees has proved particularly challenging. Final evaluations on twenty programs found three with evidence of quality improvement at or near budget-neutrality, net of fees. Interim monitoring covering at least twenty-one months on the remaining fifteen programs suggests that four are close to covering their fees. Characteristics of the traditional Medicare program present a challenge to these DM models.

42 CFR 426.415 - CMS' role in the LCD review.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false CMS' role in the LCD review. 426.415 Section 426... Review of an LCD § 426.415 CMS' role in the LCD review. CMS may provide to the ALJ, and all parties to the LCD review, information identifying the person who represents the contractor or CMS, if necessary...

A net-shaped multicellular formation facilitates the maturation of hPSC-derived cardiomyocytes through mechanical and electrophysiological stimuli

PubMed Central

Liu, Taoyan; Huang, Chengwu; Li, Hongxia; Wu, Fujian; Luo, Jianwen; Lu, Wenjing

2018-01-01

The use of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) is limited in drug discovery and cardiac disease mechanism studies due to cell immaturity. Although many approaches have been reported to improve the maturation of hiPSC-CMs, the elucidation of the process of maturation is crucial. We applied a small-molecule-based differentiation method to generate cardiomyocytes (CMs) with multiple aggregation forms. The motion analysis revealed significant physical differences in the differently shaped CMs, and the net-shaped CMs had larger motion amplitudes and faster velocities than the sheet-shaped CMs. The net-shaped CMs displayed accelerated maturation at the transcriptional level and were more similar to CMs with a prolonged culture time (30 days) than to sheet-d15. Ion channel genes and gap junction proteins were up-regulated in net-shaped CMs, indicating that robust contraction was coupled with enhanced ion channel and connexin expression. The net-shaped CMs also displayed improved myofibril ultrastructure under transmission electron microscopy. In conclusion, different multicellular hPSC-CM structures, such as the net-shaped pattern, are formed using the conditioned induction method, providing a useful tool to improve cardiac maturation. PMID:29661985

Human renal adipose tissue induces the invasion and progression of renal cell carcinoma.

PubMed

Campo-Verde-Arbocco, Fiorella; López-Laur, José D; Romeo, Leonardo R; Giorlando, Noelia; Bruna, Flavia A; Contador, David E; López-Fontana, Gastón; Santiano, Flavia E; Sasso, Corina V; Zyla, Leila E; López-Fontana, Constanza M; Calvo, Juan C; Carón, Rubén W; Creydt, Virginia Pistone

2017-11-07

We evaluated the effects of conditioned media (CMs) of human adipose tissue from renal cell carcinoma located near the tumor (hRATnT) or farther away from the tumor (hRATfT), on proliferation, adhesion and migration of tumor (786-O and ACHN) and non-tumor (HK-2) human renal epithelial cell lines. Human adipose tissues were obtained from patients with renal cell carcinoma (RCC) and CMs from hRATnT and hRATfT incubation. Proliferation, adhesion and migration were quantified in 786-O, ACHN and HK-2 cell lines incubated with hRATnT-, hRATfT- or control-CMs. We evaluated versican, adiponectin and leptin expression in CMs from hRATnT and hRATfT. We evaluated AdipoR1/2, ObR, pERK, pAkt y pPI3K expression on cell lines incubated with CMs. No differences in proliferation of cell lines was found after 24 h of treatment with CMs. All cell lines showed a significant decrease in cell adhesion and increase in cell migration after incubation with hRATnT-CMs vs. hRATfT- or control-CMs. hRATnT-CMs showed increased levels of versican and leptin, compared to hRATfT-CMs. AdipoR2 in 786-O and ACHN cells decreased significantly after incubation with hRATfT- and hRATnT-CMs vs. control-CMs. We observed a decrease in the expression of pAkt in HK-2, 786-O and ACHN incubated with hRATnT-CMs. This result could partially explain the observed changes in migration and cell adhesion. We conclude that hRATnT released factors, such as leptin and versican, could enhance the invasive potential of renal epithelial cell lines and could modulate the progression of the disease.

Down-regulation of Inwardly Rectifying K+ Currents in Astrocytes Derived from Patients with Monge's Disease.

PubMed

Wu, Wei; Yao, Hang; Zhao, Helen W; Wang, Juan; Haddad, Gabriel G

2018-03-15

Chronic mountain sickness (CMS) or Monge's disease is a disease in highlanders. These patients have a variety of neurologic symptoms such as migraine, mental fatigue, confusion, dizziness, loss of appetite, memory loss and neuronal degeneration. The cellular and molecular mechanisms underlying CMS neuropathology is not understood. In the previous study, we demonstrated that neurons derived from CMS patients' fibroblasts have a decreased expression and altered gating properties of voltage-gated sodium channel. In this study, we further characterize the electrophysiological properties of iPSC-derived astrocytes from CMS patients. We found that the current densities of the inwardly rectifying potassium (Kir) channels in CMS astrocytes (-5.7 ± 2.2 pA/pF at -140 mV) were significantly decreased as compared to non-CMS (-28.4 ± 3.4 pA/pF at -140 mV) and sea level subjects (-28.3 ± 5.3 pA/pF at -140 mV). We further demonstrated that the reduced Kir current densities in CMS astrocytes were caused by their decreased protein expression of Kir4.1 and Kir2.3 channels, while single channel properties (i.e., P o , conductance) of Kir channel in CMS astrocytes were not altered. In addition, we found no significant differences of outward potassium currents between CMS and non-CMS astrocytes. As compared to non-CMS and sea level subjects, the K + uptake ability in CMS astrocytes was significantly decreased. Taken together, our results suggest that down-regulation of Kir channels and the resulting decreased K + uptake ability in astrocytes could be one of the major molecular mechanisms underlying the neurologic manifestations in CMS patients. Published by Elsevier Ltd.

From Early Embryonic to Adult Stage: Comparative Study of Action Potentials of Native and Pluripotent Stem Cell-Derived Cardiomyocytes.

PubMed

Peinkofer, Gabriel; Burkert, Karsten; Urban, Katja; Krausgrill, Benjamin; Hescheler, Jürgen; Saric, Tomo; Halbach, Marcel

2016-10-01

Cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPS-CMs) are promising candidates for cell therapy, drug screening, and developmental studies. It is known that iPS-CMs possess immature electrophysiological properties, but an exact characterization of their developmental stage and subtype differentiation is hampered by a lack of knowledge of electrophysiological properties of native CMs from different developmental stages and origins within the heart. Thus, we sought to systematically investigate action potential (AP) properties of native murine CMs and to establish a database that allows classification of stem cell-derived CMs. Hearts from 129S2PasCrl mice were harvested at days 9-10, 12-14, and 16-18 postcoitum, as well as 1 day, 3-4 days, 1-2 weeks, 3-4 weeks, and 6 weeks postpartum. AP recordings in left and right atria and at apical, medial, and basal left and right ventricles were performed with sharp glass microelectrodes. Measurements revealed significant changes in AP morphology during pre- and postnatal murine development and significant differences between atria and ventricles, enabling a classification of developmental stage and subtype differentiation of stem cell-derived CMs based on their AP properties. For iPS-CMs derived from cell line TiB7.4, a typical ventricular phenotype was demonstrated at later developmental stages, while there were electrophysiological differences from atrial as well as ventricular native CMs at earlier stages. This finding supports that iPS-CMs can develop AP properties similar to native CMs, but points to differences in the maturation process between iPS-CMs and native CMs, which may be explained by dissimilar conditions during in vitro differentiation and in vivo development.

Pharmacokinetics of colistin methanesulfonate (CMS) in healthy Chinese subjects after single and multiple intravenous doses.

PubMed

Zhao, Miao; Wu, Xiao-Jie; Fan, Ya-Xin; Zhang, Ying-Yuan; Guo, Bei-Ning; Yu, Ji-Cheng; Cao, Guo-Ying; Chen, Yuan-Cheng; Wu, Ju-Fang; Shi, Yao-Guo; Li, Jian; Zhang, Jing

2018-05-01

The high prevalence of extensively drug-resistant Gram-negative pathogens has forced clinicians to use colistin as a last-line therapy. Knowledge on the pharmacokinetics of colistin methanesulfonate (CMS), an inactive prodrug, and colistin has increased substantially; however, the pharmacokinetics in the Chinese population is still unknown due to lack of a CMS product in China. This study aimed to evaluate the pharmacokinetics of a new CMS product developed in China in order to optimise dosing regimens. A total of 24 healthy subjects (12 female, 12 male) were enrolled in single- and multiple-dose pharmacokinetic (PK) studies. Concentrations of CMS and formed colistin in plasma and urine were measured, and PK analysis was conducted using a non-compartmental approach. Following a single CMS dose [2.36 mg colistin base activity (CBA) per kg, 1 h infusion], peak concentrations (C max ) of CMS and formed colistin were 18.0 mg/L and 0.661 mg/L, respectively. The estimated half-life (t 1/2 ) of CMS and colistin were 1.38 h and 4.49 h, respectively. Approximately 62.5% of the CMS dose was excreted via urine within 24 h after dosing, whilst only 1.28% was present in the form of colistin. Following multiple CMS doses, colistin reached steady-state within 24 h; there was no accumulation of CMS, but colistin accumulated slightly (R AUC  = 1.33). This study provides the first PK data in the Chinese population and is essential for designing CMS dosing regimens for use in Chinese hospitals. The urinary PK data strongly support the use of intravenous CMS for serious urinary tract infections. Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Differences in pharmacokinetics and pharmacodynamics of colistimethate sodium (CMS) and colistin between three different CMS dosage regimens in a critically ill patient infected by a multidrug-resistant Acinetobacter baumannii.

PubMed

Luque, Sònia; Grau, Santiago; Valle, Marta; Sorlí, Luisa; Horcajada, Juan Pablo; Segura, Concha; Alvarez-Lerma, Francisco

2013-08-01

Use of colistin has re-emerged for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, but information on its pharmacokinetics and pharmacodynamics is limited, especially in critically ill patients. Recent data from pharmacokinetic/pharmacodynamic (PK/PD) population studies have suggested that this population could benefit from administration of higher than standard doses of colistimethate sodium (CMS), but the relationship between administration of incremental doses of CMS and corresponding PK/PD parameters as well as its efficacy and toxicity have not yet been investigated in a clinical setting. The objective was to study the PK/PD differences of CMS and colistin between three different CMS dosage regimens in the same critically ill patient. A critically ill patient with nosocomial pneumonia caused by a MDR Acinetobacter baumannii received incremental doses of CMS. During administration of the different CMS dosage regimens, CMS and colistin plasma concentrations were determined and PK/PD indexes were calculated. With administration of the highest CMS dose once daily (720 mg every 24h), the peak plasma concentration of CMS and colistin increased to 40.51 mg/L and 1.81 mg/L, respectively, and the AUC0-24/MIC of colistin was 184.41. This dosage regimen was efficacious, and no nephrotoxicity or neurotoxicity was observed. In conclusion, a higher and extended-interval CMS dosage made it possible to increase the exposure of CMS and colistin in a critically ill patient infected by a MDR A. baumannii and allowed a clinical and microbiological optimal response to be achieved without evidence of toxicity. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Horizontal gene transfer of acetyltransferases, invertases and chorismate mutases from different bacteria to diverse recipients.

PubMed

Noon, Jason B; Baum, Thomas J

2016-04-12

Hoplolaimina plant-parasitic nematodes (PPN) are a lineage of animals with many documented cases of horizontal gene transfer (HGT). In a recent study, we reported on three likely HGT candidate genes in the soybean cyst nematode Heterodera glycines, all of which encode secreted candidate effectors with putative functions in the host plant. Hg-GLAND1 is a putative GCN5-related N-acetyltransferase (GNAT), Hg-GLAND13 is a putative invertase (INV), and Hg-GLAND16 is a putative chorismate mutase (CM), and blastp searches of the non-redundant database resulted in highest similarity to bacterial sequences. Here, we searched nematode and non-nematode sequence databases to identify all the nematodes possible that contain these three genes, and to formulate hypotheses about when they most likely appeared in the phylum Nematoda. We then performed phylogenetic analyses combined with model selection tests of alternative models of sequence evolution to determine whether these genes were horizontally acquired from bacteria. Mining of nematode sequence databases determined that GNATs appeared in Hoplolaimina PPN late in evolution, while both INVs and CMs appeared before the radiation of the Hoplolaimina suborder. Also, Hoplolaimina GNATs, INVs and CMs formed well-supported clusters with different rhizosphere bacteria in the phylogenetic trees, and the model selection tests greatly supported models of HGT over descent via common ancestry. Surprisingly, the phylogenetic trees also revealed additional, well-supported clusters of bacterial GNATs, INVs and CMs with diverse eukaryotes and archaea. There were at least eleven and eight well-supported clusters of GNATs and INVs, respectively, from different bacteria with diverse eukaryotes and archaea. Though less frequent, CMs from different bacteria formed supported clusters with multiple different eukaryotes. Moreover, almost all individual clusters containing bacteria and eukaryotes or archaea contained species that inhabit very similar niches. GNATs were horizontally acquired late in Hoplolaimina PPN evolution from bacteria most similar to the saprophytic and plant-pathogenic actinomycetes. INVs and CMs were horizontally acquired from bacteria most similar to rhizobacteria and Burkholderia soil bacteria, respectively, before the radiation of Hoplolaimina. Also, these three gene groups appear to have been frequent subjects of HGT from different bacteria to numerous, diverse lineages of eukaryotes and archaea, which suggests that these genes may confer important evolutionary advantages to many taxa. In the case of Hoplolaimina PPN, this advantage likely was an improved ability to parasitize plants.

An experimental overview of the seismic cycle

NASA Astrophysics Data System (ADS)

Spagnuolo, E.; Violay, M.; Passelegue, F. X.; Nielsen, S. B.; Di Toro, G.

2017-12-01

Earthquake nucleation is the last stage of the inter-seismic cycle where the fault surface evolves through the interplay of friction, healing, stress perturbations and strain events. Slip stability under rate-and state friction has been extensively discussed in terms of loading point velocity and equivalent fault stiffness, but fault evolution towards seismic runaway under complex loading histories (e.g. slow variations of tectonic stress, stress transfer from impulsive nearby seismic events) is not yet fully investigated. Nevertheless, the short term earthquake forecasting is based precisely on a relation between seismic productivity and loading history which remains up to date still largely unresolved. To this end we propose a novel experimental approach which avails of a closed loop control of the shear stress, a nominally infinite equivalent slip and transducers for continuous monitoring of acoustic emissions. This experimental simulation allows us to study the stress dependency and temporal evolution of spontaneous slip events occurring on a pre-existing fault subjected to different loading histories. The experimental fault has an initial roughness which mimic a population of randomly distributed asperities, which here are used as a proxy for patches which are either far or close to failure on an extended fault. Our observations suggest that the increase of shear stress may trigger either spontaneous slow slip (creep) or short-lived stick-slip bursts, eventually leading to a fast slip instability (seismic runaway) when slip rates are larger than a few cm/s. The event type and the slip rate are regulated at first order by the background shear stress whereas the ultimate strength of the entire fault is dominated by the number of asperities close to failure under a stress step. The extrapolation of these results to natural conditions might explain the plethora of events that often characterize seismic sequences. Nonetheless this experimental approach helps the definition of a scaling relation between the loading rate and cumulated slip which is relevant to the definition of a recurrence model for the seismic cycle.

Phenomenology of 2HDM with vectorlike quarks

NASA Astrophysics Data System (ADS)

Arhrib, A.; Benbrik, R.; King, S. J. D.; Manaut, B.; Moretti, S.; Un, C. S.

2018-05-01

In this paper, we examine the consistency of the Large Hadron Collider (LHC) data collected during Runs 1 and 2 by the ATLAS and CMS experiments with the predictions of a 2-Higgs doublet model embedding vectorlike quarks (VLQs) for p p →H , A production and H , A →γ γ decay mechanisms, respectively, of (nearly) degenerate C P -even (H ) and C P -odd (A ) Higgs bosons. We show that a scenario containing one single VLQ with electromagnetic charge 2 /3 can explain the above ATLAS and CMS data for masses in the region 350 GeV ≤mVLQ≤1.5 TeV or so, depending on tan β , and for several values of the mixing angle between the top quark (t ) and its VLQ counterpart (T ). We then perform a global fit onto the model by including all relevant experimental as well as theoretical constraints. The surviving samples of our analysis are discussed within 2 σ of the LHC measurements. Additionally, we also comment on the recent anomalous result reported by CMS using Run 2 data on the associated Standard Model Higgs boson production with top quark pairs p p →t t ¯ h with an observed significance of 3.3 σ . Other than these specific examples, we also present a phenomenological analysis of the main features of the model, including the most promising T decay channels.

Solving a mathematical model integrating unequal-area facilities layout and part scheduling in a cellular manufacturing system by a genetic algorithm.

PubMed

Ebrahimi, Ahmad; Kia, Reza; Komijan, Alireza Rashidi

2016-01-01

In this article, a novel integrated mixed-integer nonlinear programming model is presented for designing a cellular manufacturing system (CMS) considering machine layout and part scheduling problems simultaneously as interrelated decisions. The integrated CMS model is formulated to incorporate several design features including part due date, material handling time, operation sequence, processing time, an intra-cell layout of unequal-area facilities, and part scheduling. The objective function is to minimize makespan, tardiness penalties, and material handling costs of inter-cell and intra-cell movements. Two numerical examples are solved by the Lingo software to illustrate the results obtained by the incorporated features. In order to assess the effects and importance of integration of machine layout and part scheduling in designing a CMS, two approaches, sequentially and concurrent are investigated and the improvement resulted from a concurrent approach is revealed. Also, due to the NP-hardness of the integrated model, an efficient genetic algorithm is designed. As a consequence, computational results of this study indicate that the best solutions found by GA are better than the solutions found by B&B in much less time for both sequential and concurrent approaches. Moreover, the comparisons between the objective function values (OFVs) obtained by sequential and concurrent approaches demonstrate that the OFV improvement is averagely around 17 % by GA and 14 % by B&B.

Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells

PubMed Central

Lundy, Scott D.; Zhu, Wei-Zhong

2013-01-01

Despite preclinical studies demonstrating the functional benefit of transplanting human pluripotent stem cell-derived cardiomyocytes (PSC-CMs) into damaged myocardium, the ability of these immature cells to adopt a more adult-like cardiomyocyte (CM) phenotype remains uncertain. To address this issue, we tested the hypothesis that prolonged in vitro culture of human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived CMs would result in the maturation of their structural and contractile properties to a more adult-like phenotype. Compared to their early-stage counterparts (PSC-CMs after 20–40 days of in vitro differentiation and culture), late-stage hESC-CMs and hiPSC-CMs (80–120 days) showed dramatic differences in morphology, including increased cell size and anisotropy, greater myofibril density and alignment, sarcomeres visible by bright-field microscopy, and a 10-fold increase in the fraction of multinucleated CMs. Ultrastructural analysis confirmed improvements in the myofibrillar density, alignment, and morphology. We measured the contractile performance of late-stage hESC-CMs and hiPSC-CMs and noted a doubling in shortening magnitude with slowed contraction kinetics compared to the early-stage cells. We then examined changes in the calcium-handling properties of these matured CMs and found an increase in calcium release and reuptake rates with no change in the maximum amplitude. Finally, we performed electrophysiological assessments in hESC-CMs and found that late-stage myocytes have hyperpolarized maximum diastolic potentials, increased action potential amplitudes, and faster upstroke velocities. To correlate these functional changes with gene expression, we performed qPCR and found a robust induction of the key cardiac structural markers, including β-myosin heavy chain and connexin-43, in late-stage hESC-CMs and hiPSC-CMs. These findings suggest that PSC-CMs are capable of slowly maturing to more closely resemble the phenotype of adult CMs and may eventually possess the potential to regenerate the lost myocardium with robust de novo force-producing tissue. PMID:23461462

CMS Connect

NASA Astrophysics Data System (ADS)

Balcas, J.; Bockelman, B.; Gardner, R., Jr.; Hurtado Anampa, K.; Jayatilaka, B.; Aftab Khan, F.; Lannon, K.; Larson, K.; Letts, J.; Marra Da Silva, J.; Mascheroni, M.; Mason, D.; Perez-Calero Yzquierdo, A.; Tiradani, A.

2017-10-01

The CMS experiment collects and analyzes large amounts of data coming from high energy particle collisions produced by the Large Hadron Collider (LHC) at CERN. This involves a huge amount of real and simulated data processing that needs to be handled in batch-oriented platforms. The CMS Global Pool of computing resources provide +100K dedicated CPU cores and another 50K to 100K CPU cores from opportunistic resources for these kind of tasks and even though production and event processing analysis workflows are already managed by existing tools, there is still a lack of support to submit final stage condor-like analysis jobs familiar to Tier-3 or local Computing Facilities users into these distributed resources in an integrated (with other CMS services) and friendly way. CMS Connect is a set of computing tools and services designed to augment existing services in the CMS Physics community focusing on these kind of condor analysis jobs. It is based on the CI-Connect platform developed by the Open Science Grid and uses the CMS GlideInWMS infrastructure to transparently plug CMS global grid resources into a virtual pool accessed via a single submission machine. This paper describes the specific developments and deployment of CMS Connect beyond the CI-Connect platform in order to integrate the service with CMS specific needs, including specific Site submission, accounting of jobs and automated reporting to standard CMS monitoring resources in an effortless way to their users.

Phospholipase A2 activity-dependent and -independent fusogenic activity of Naja nigricollis CMS-9 on zwitterionic and anionic phospholipid vesicles.

PubMed

Chiou, Yi-Ling; Chen, Ying-Jung; Lin, Shinne-Ren; Chang, Long-Sen

2011-11-01

CMS-9, a phospholipase A(2) (PLA(2)) from Naja nigricollis venom, induced the death of human breast cancer MCF-7 cells accompanied with the formation of cell clumps without clear boundaries between cells. Annexin V-FITC staining indicated that abundant phosphatidylserine appeared on the outer membrane of MCF-7 cell clumps, implying the possibility that CMS-9 may promote membrane fusion via anionic phospholipids. To validate this proposition, fusogenic activity of CMS-9 on vesicles composed of zwitterionic phospholipid alone or a combination of zwitterionic and anionic phospholipids was examined. Although CMS-9-induced fusion of zwitterionic phospholipid vesicles depended on PLA(2) activity, CMS-9-induced fusion of vesicles containing anionic phospholipids could occur without the involvement of PLA(2) activity. Membrane-damaging activity of CMS-9 was associated with its fusogenicity. Moreover, CMS-9 induced differently membrane leakage and membrane fusion of vesicles with different compositions. Membrane fluidity and binding capability with phospholipid vesicles were not related to the fusogenicity of CMS-9. However, membrane-bound conformation and mode of CMS-9 depended on phospholipid compositions. Collectively, our data suggest that PLA(2) activity-dependent and -independent fusogenicity of CMS-9 are closely related to its membrane-bound modes and targeted membrane compositions. Copyright © 2011 Elsevier Ltd. All rights reserved.

42 CFR 411.382 - CMS's right to rescind advisory opinions.

Code of Federal Regulations, 2011 CFR

2011-10-01

... rescind advisory opinions. Any advice CMS gives in an opinion does not prejudice its right to reconsider... faith reliance upon CMS's advice under this part, provided— (a) The requestor presented to CMS a full...

42 CFR 411.382 - CMS's right to rescind advisory opinions.

Code of Federal Regulations, 2010 CFR

2010-10-01

... rescind advisory opinions. Any advice CMS gives in an opinion does not prejudice its right to reconsider... faith reliance upon CMS's advice under this part, provided— (a) The requestor presented to CMS a full...

Microgravity collisions of dust aggregates as an analogue to early planetesimal formation

NASA Astrophysics Data System (ADS)

Whizin, Akbar; Blum, Jürgen; Colwell, Joshua

2014-11-01

During the early stages of planet formation the dusty progenitors of planetesimals collided with each other continuously to form the seeds of planets. These collisions could result in growth or disruption depending on the individual impact velocities. Based on input from solar nebula models a laboratory-based microgravity dust collision experiment was developed for a drop tower at the Technische Universität Braunschweig, Germany. We collided 1.0 - 1.6 mm SiO2 dust aggregates with clusters of these aggregates at a range of velocities and mass ratios to determine the thresholds between bouncing, sticking, and fragmentation. Presented here are the results of 264 microgravity collisions occurring at velocities of 1 - 160 cm/s with target-impactor mass ratios of 5:1 to 400:1. We also present the coefficient of restitutions for low-velocity collisions and we find the specific collision energy of fragmentation Q* for aggregates of this size. We find sticking occurs at mass ratios larger than 40:1, but only for low velocities ≤ 3 cm/s, clear boundaries exist for bouncing up to 30 cm/s, and fragmentation at ~50 cm/s and up, with total disruption occurring above 1 m/s.

Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro.

PubMed

Qian, Li; Berry, Emily C; Fu, Ji-dong; Ieda, Masaki; Srivastava, Deepak

2013-06-01

Cardiac fibroblasts can be reprogrammed to cardiomyocyte-like cells by the introduction of three transcription factors: Gata4, Mef2c and Tbx5 (collectively referred to here as GMT). Resident cardiac fibroblasts can be converted in vivo into induced cardiomyocyte-like cells (iCMs) that closely resemble endogenous cardiomyocytes and electrically integrate with the host myocardium. In contrast, in vitro reprogramming yields many partially reprogrammed iCMs, with a few that reprogram fully into contracting myocytes (~3 out of 10,000 GMT-transduced cells). iCMs can be observed as early as 3 d after viral infection, and they continue to mature over 2 months before beating is observed. Despite the success of multiple groups, the inefficiency of in vitro reprogramming has made it challenging for others. However, given the advantages of in vitro iCMs for performing mechanistic studies and, if refined, for testing drugs or small molecules for personalized medicine and modeling cardiac disease in a dish, it is important to standardize the protocol to improve reproducibility and enhance the technology further. Here we describe a detailed step-by-step protocol for in vitro cardiac reprogramming using retroviruses encoding GMT.

Contribution of Chromosomes 1HchS and 6HchS to Fertility Restoration in the Wheat msH1 CMS System under Different Environmental Conditions

PubMed Central

Castillo, Almudena; Rodríguez-Suárez, Cristina; Martín, Azahara C.; Pistón, Fernando

2015-01-01

Exploiting hybrid wheat heterosis has been long pursued to increase crop yield, stability and uniformity. Cytoplasmic male sterility (CMS) systems based in the nuclear-cytoplasmic incompatible interactions are a classic way for hybrid seed production, but to date, no definitive system is available in wheat. The msH1 CMS system results from the incompatibility between the nuclear genome of wheat and the cytoplasmic genome of the wild barley Hordeum chilense. Fertility restoration of the CMS phenotype was first associated with the disomic addition of the short arm of chromosome 6H from H. chilense. In further studies it was observed that chromosome arm 1HchS was also implicated, and the combination of genes in both chromosome arms restored fertility more efficiently. In this work we aim to dissect the effect of each chromosome in fertility restoration when combined in different genomic backgrounds and under different environmental conditions. We propose a model to explain how restoration behaves in the msH1 system and generate valuable information necessary to develop an efficient system for hybrid wheat production. PMID:26192191

Production of muons from heavy-flavour hadron decays in p–Pb collisions at s NN = 5.02   TeV

DOE PAGES

Acharya, S.; Adamová, D.; Aggarwal, M. M.; ...

2017-03-28

The production of muons from heavy-flavour hadron decays in p–Pb collisions at √ sNN = 5.02 TeV was studied for 2< p T <16 GeV/c with the ALICE detector at the CERN LHC. The measurement was performed at forward (p-going direction) and backward (Pb-going direction) rapidity, in the ranges of rapidity in the centre-of-mass system (cms) 2.03 cms <3.53 and –4.46cms <–2.96, respectively. The production cross sections and nuclear modification factors are presented as a function of transverse momentum (p T). At forward rapidity, the nuclear modification factor is compatible with unity while at backward rapidity, in the interval 2.5more » < p T < 3.5 GeV/c, it is above unity by more than 2σ. The ratio of the forward-to-backward production cross sections is also measured in the overlapping interval 2.96<|y cms| < 3.53 and is smaller than unity by 3.7σ in 2.5< p T <3.5 GeV/c. The data are described by model calculations including cold nuclear matter effects.« less

Contribution of Chromosomes 1HchS and 6HchS to Fertility Restoration in the Wheat msH1 CMS System under Different Environmental Conditions.

PubMed

Castillo, Almudena; Rodríguez-Suárez, Cristina; Martín, Azahara C; Pistón, Fernando

2015-01-01

Exploiting hybrid wheat heterosis has been long pursued to increase crop yield, stability and uniformity. Cytoplasmic male sterility (CMS) systems based in the nuclear-cytoplasmic incompatible interactions are a classic way for hybrid seed production, but to date, no definitive system is available in wheat. The msH1 CMS system results from the incompatibility between the nuclear genome of wheat and the cytoplasmic genome of the wild barley Hordeum chilense. Fertility restoration of the CMS phenotype was first associated with the disomic addition of the short arm of chromosome 6H from H. chilense. In further studies it was observed that chromosome arm 1HchS was also implicated, and the combination of genes in both chromosome arms restored fertility more efficiently. In this work we aim to dissect the effect of each chromosome in fertility restoration when combined in different genomic backgrounds and under different environmental conditions. We propose a model to explain how restoration behaves in the msH1 system and generate valuable information necessary to develop an efficient system for hybrid wheat production.

42 CFR § 512.210 - Included and excluded services.

Code of Federal Regulations, 2010 CFR

2017-10-01

... SERVICES (CONTINUED) HEALTH CARE INFRASTRUCTURE AND MODEL PROGRAMS EPISODE PAYMENT MODEL Scope of Episodes...) Certain PBPM payments under models tested under section 1115A of the Act that CMS determines to be... PBPM model payments funded from the Innovation Center appropriation. (c) Updating the exclusion lists...

Induced Pluripotent Stem Cell–Derived Cardiomyocytes Provide In Vivo Biological Pacemaker Function

PubMed Central

Chauveau, Samuel; Anyukhovsky, Evgeny P.; Ben-Ari, Meital; Naor, Shulamit; Jiang, Ya-Ping; Danilo, Peter; Rahim, Tania; Burke, Stephanie; Qiu, Xiaoliang; Potapova, Irina A.; Doronin, Sergey V.; Brink, Peter R.; Binah, Ofer

2017-01-01

Background— Although multiple approaches have been used to create biological pacemakers in animal models, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) have not been investigated for this purpose. We now report pacemaker function of iPSC-CMs in a canine model. Methods and Results— Embryoid bodies were derived from human keratinocytes, their action potential characteristics determined, and their gene expression profiles and markers of differentiation identified. Atrioventricular blocked dogs were immunosuppressed, instrumented with VVI pacemakers, and injected subepicardially into the anterobasal left ventricle with 40 to 75 rhythmically contracting embryoid bodies (totaling 1.3–2×106 cells). ECG and 24-hour Holter monitoring were performed biweekly. After 4 to 13 weeks, epinephrine (1 μg kg−1 min−1) was infused, and the heart removed for histological or electrophysiological study. iPSC-CMs largely lost the markers of pluripotency, became positive for cardiac-specific markers. and manifested If-dependent automaticity. Epicardial pacing of the injection site identified matching beats arising from that site by week 1 after implantation. By week 4, 20% of beats were electronically paced, 60% to 80% of beats were matching, and mean and maximal biological pacemaker rates were 45 and 75 beats per minute. Maximum night and day rates of matching beats were 53±6.9 and 69±10.4 beats per minute, respectively, at 4 weeks. Epinephrine increased rate of matching beats from 35±4.3 to 65±4.0 beats per minute. Incubation of embryoid bodies with the vital dye, Dil, revealed the persistence of injected cells at the site of administration. Conclusions— iPSC-CMs can integrate into host myocardium and create a biological pacemaker. Although this is a promising development, rate and rhythm of the iPSC-CMs pacemakers remain to be optimized. PMID:28500172

Correlation between human ether‐a‐go‐go‐related gene channel inhibition and action potential prolongation

PubMed Central

Saxena, P; Hortigon‐Vinagre, M P; Beyl, S; Baburin, I; Andranovits, S; Iqbal, S M; Costa, A; IJzerman, A P; Kügler, P; Timin, E

2017-01-01

Background and Purpose Human ether‐a‐go‐go‐related gene (hERG; Kv11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro‐arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs). The interference from accompanying block of Cav1.2 and Nav1.5 channels was investigated along with an in silico AP model. Experimental Approach Drug‐induced changes in APD were assessed in hiPSC‐CMs using voltage‐sensitive dyes. The IC50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D150) required to prolong the APD at 90% (APD90) repolarization by 50%. Key Results The D150 in hiPSC‐CMs was linearly correlated with IC50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Cav1.2 and/or Nav1.5 in a channel state‐dependent manner. Adding Cav1.2 and Nav1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. Conclusions and Implications Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC‐CMs. The compounds that do not correlate have additional effects including concomitant block of Cav1.2 and/or Nav1.5 channels. In silico simulations of hiPSC‐CMs APs confirm the principle of the multiple ion channel effects. PMID:28681507

CMS users data management service integration and first experiences with its NoSQL data storage

NASA Astrophysics Data System (ADS)

Riahi, H.; Spiga, D.; Boccali, T.; Ciangottini, D.; Cinquilli, M.; Hernàndez, J. M.; Konstantinov, P.; Mascheroni, M.; Santocchia, A.

2014-06-01

The distributed data analysis workflow in CMS assumes that jobs run in a different location to where their results are finally stored. Typically the user outputs must be transferred from one site to another by a dedicated CMS service, AsyncStageOut. This new service is originally developed to address the inefficiency in using the CMS computing resources when transferring the analysis job outputs, synchronously, once they are produced in the job execution node to the remote site. The AsyncStageOut is designed as a thin application relying only on the NoSQL database (CouchDB) as input and data storage. It has progressed from a limited prototype to a highly adaptable service which manages and monitors the whole user files steps, namely file transfer and publication. The AsyncStageOut is integrated with the Common CMS/Atlas Analysis Framework. It foresees the management of nearly nearly 200k users' files per day of close to 1000 individual users per month with minimal delays, and providing a real time monitoring and reports to users and service operators, while being highly available. The associated data volume represents a new set of challenges in the areas of database scalability and service performance and efficiency. In this paper, we present an overview of the AsyncStageOut model and the integration strategy with the Common Analysis Framework. The motivations for using the NoSQL technology are also presented, as well as data design and the techniques used for efficient indexing and monitoring of the data. We describe deployment model for the high availability and scalability of the service. We also discuss the hardware requirements and the results achieved as they were determined by testing with actual data and realistic loads during the commissioning and the initial production phase with the Common Analysis Framework.

Opportunistic Resource Usage in CMS

NASA Astrophysics Data System (ADS)

Kreuzer, Peter; Hufnagel, Dirk; Dykstra, D.; Gutsche, O.; Tadel, M.; Sfiligoi, I.; Letts, J.; Wuerthwein, F.; McCrea, A.; Bockelman, B.; Fajardo, E.; Linares, L.; Wagner, R.; Konstantinov, P.; Blumenfeld, B.; Bradley, D.; Cms Collaboration

2014-06-01

CMS is using a tiered setup of dedicated computing resources provided by sites distributed over the world and organized in WLCG. These sites pledge resources to CMS and are preparing them especially for CMS to run the experiment's applications. But there are more resources available opportunistically both on the GRID and in local university and research clusters which can be used for CMS applications. We will present CMS' strategy to use opportunistic resources and prepare them dynamically to run CMS applications. CMS is able to run its applications on resources that can be reached through the GRID, through EC2 compliant cloud interfaces. Even resources that can be used through ssh login nodes can be harnessed. All of these usage modes are integrated transparently into the GlideIn WMS submission infrastructure, which is the basis of CMS' opportunistic resource usage strategy. Technologies like Parrot to mount the software distribution via CVMFS and xrootd for access to data and simulation samples via the WAN are used and will be described. We will summarize the experience with opportunistic resource usage and give an outlook for the restart of LHC data taking in 2015.

Study design and implementation for population pharmacokinetics of Chinese medicine: An expert consensus.

PubMed

Jiang, Jun-jie; Zhang, Wen; Xie, Yan-ming; Wang, Jian-nong; He, Fu-yuan; Xiong, Xin

2016-02-01

Although many population pharmacokinetics (PPK) researches have been conducted on chemical drugs, few have been in the field of Chinese medicine (CM). Each ingredient in CMs possesses different pharmacokinetic characteristics, therefore, it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations. To develop an expert consensus on study design and implementation for PPK of CM, in August 2013, 6 experts in the field of PPK, CMs pharmacology, and statistics discussed problems on the PPK research protocol of CMs, and a consensus was reached. The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected. The compositions with definite therapeutic effects were selected as indices, and specific time points and sample sizes were designed according to standard PPK design methods. Target components were tested through various chromatography methods. Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs (which assists in reasonable adjustments on clinical dosage). This consensus specifies the study design and implementation process of PPK. It provides guidance for the following: post-marketing clinical studies, in vivo investigations related to the metabolism in different populations, and development and clinical adjustment of dosages of CMs.

CMS changes in reimbursement for HAIs: setting a research agenda.

PubMed

Stone, Patricia W; Glied, Sherry A; McNair, Peter D; Matthes, Nikolas; Cohen, Bevin; Landers, Timothy F; Larson, Elaine L

2010-05-01

The Centers for Medicare and Medicaid Services (CMS) promulgated regulations commencing October 1, 2008, which deny payment for selected conditions occurring during the hospital stay and are not present on admission. Three of the 10 hospital-acquired conditions covered by the new CMS policy involve healthcare-associated infections, which are a common, expensive, and often preventable cause of inpatient morbidity and mortality. To outline a research agenda on the impact of CMS's payment policy on the healthcare system and the prevention of healthcare-associated infections. An invitational day-long conference was convened in April 2009. Including the planning committee and speakers there were 41 conference participants who were national experts and senior researchers. Building upon a behavioral model and organizational theory and management research a conceptual framework was applied to organize the wide range of issues that arose. A broad array of research topics was identified. Thirty-two research agenda items were organized in the areas of incentives, environmental factors, organizational factors, clinical outcomes, staff outcomes, and financial outcomes. Methodological challenges are also discussed. This policy is a first significant step to move output-based inpatient funding to outcome-based funding, and this agenda is applicable to all hospital-acquired conditions. Studies beginning soon will have the best hope of capturing data for the years preceding the policy change, a key element in non-experimental research. The CMS payment policy offers an excellent opportunity to understand and influence the use of financial incentives for improving patient safety.

NoSQL technologies for the CMS Conditions Database

NASA Astrophysics Data System (ADS)

Sipos, Roland

2015-12-01

With the restart of the LHC in 2015, the growth of the CMS Conditions dataset will continue, therefore the need of consistent and highly available access to the Conditions makes a great cause to revisit different aspects of the current data storage solutions. We present a study of alternative data storage backends for the Conditions Databases, by evaluating some of the most popular NoSQL databases to support a key-value representation of the CMS Conditions. The definition of the database infrastructure is based on the need of storing the conditions as BLOBs. Because of this, each condition can reach the size that may require special treatment (splitting) in these NoSQL databases. As big binary objects may be problematic in several database systems, and also to give an accurate baseline, a testing framework extension was implemented to measure the characteristics of the handling of arbitrary binary data in these databases. Based on the evaluation, prototypes of a document store, using a column-oriented and plain key-value store, are deployed. An adaption layer to access the backends in the CMS Offline software was developed to provide transparent support for these NoSQL databases in the CMS context. Additional data modelling approaches and considerations in the software layer, deployment and automatization of the databases are also covered in the research. In this paper we present the results of the evaluation as well as a performance comparison of the prototypes studied.

The utility of rat jejunal permeability for biopharmaceutics classification system.

PubMed

Zakeri-Milani, Parvin; Valizadeh, Hadi; Tajerzadeh, Hosnieh; Islambulchilar, Ziba

2009-12-01

The biopharmaceutical classification system has been developed to provide a scientific approach for classifying drug compounds based on their dose/solubility ratio and human intestinal permeability. Therefore in this study a new classification is presented, which is based on a correlation between rat and human intestinal permeability values. In situ technique in rat jejunum was used to determine the effective intestinal permeability of tested drugs. Then three dimensionless parameters--dose number, absorption number, and dissolution number (D(o), A(n), and D(n))--were calculated for each drug. Four classes of drugs were defined, that is, class I, D(0) < 0.5, P(eff(rat)) > 5.09 x 10(-5) cm/s; class II, D(o) > 1, P(eff(rat)) > 5.09 x 10( -5) cm/s; class III, D(0) < 0.5, P(eff(rat)) < 4.2 x 10(-5) cm/s; and class IV, D(o) > 1, P(eff(rat)) < 4.2 x 10(-5) cm/s. A region of borderline drugs (0.5 < D(o) < 1, 4.2 x 10(-5) < P(eff(rat)) < 5.09 x 10(-5) cm/s) was also defined. According to obtained results and proposed classification for drugs, it is concluded that drugs could be categorized correctly based on dose number and their intestinal permeability values in rat model using single-pass intestinal perfusion technique. This classification enables us to remark defined characteristics for intestinal absorption of all four classes using suitable cutoff points for both dose number and rat effective intestinal permeability values.

Pluripotent stem cells for cardiac regeneration: Overview of recent advances & emerging trends

PubMed Central

Pawani, Harsha; Bhartiya, Deepa

2013-01-01

Cell based regenerative therapy has emerged as one of the most promising options of treatment for patients suffering from heart failure. Various adult stem cells types have undergone extensive clinical trials with limited success which is believed to be more of a cytokine effect rather than cell therapy. Pluripotent human embryonic stem cells (hESCs) have emerged as an attractive candidate stem cell source for obtaining cardiomyocytes (CMs) because of their tremendous capacity for expansion and unquestioned potential to differentiate into CMs. Studies carried out in animal models indicate that ES-derived CMs can partially remuscularize infarcted hearts and improve contractile function; however, the effect was not sustained over long follow up periods due to their limited capacity of cell division in vivo. Thus, the concept of transplanting multipotent cardiovascular progenitors derived from ES cells has emerged since the progenitors retain robust proliferative ability and multipotent nature enabling repopulation of other myocardial elements also in addition to CMs. Transplantation of CMs (progenitors) seeded in biodegradable scaffold and gel based engineered constructs has met with modest success due to issues like cell penetration, nutrient and oxygen availability and inflammation triggered during scaffold degradation inversely affecting the seeded cells. Recently cell sheet based tissue engineering involving culturing cells on ‘intelligent’ polymers has been evolved. Generation of a 3-D pulsatile myocardial tissue has been achieved. However, these advances have to be looked at with cautious optimism as many challenges need to be overcome before using these in clinical practice. PMID:23563370

Electrophysiological Analysis of human Pluripotent Stem Cell-derived Cardiomyocytes (hPSC-CMs) Using Multi-electrode Arrays (MEAs).

PubMed

Sala, Luca; Ward-van Oostwaard, Dorien; Tertoolen, Leon G J; Mummery, Christine L; Bellin, Milena

2017-05-12

Cardiomyocytes can now be derived with high efficiency from both human embryonic and human induced-Pluripotent Stem Cells (hPSC). hPSC-derived cardiomyocytes (hPSC-CMs) are increasingly recognized as having great value for modeling cardiovascular diseases in humans, especially arrhythmia syndromes. They have also demonstrated relevance as in vitro systems for predicting drug responses, which makes them potentially useful for drug-screening and discovery, safety pharmacology and perhaps eventually for personalized medicine. This would be facilitated by deriving hPSC-CMs from patients or susceptible individuals as hiPSCs. For all applications, however, precise measurement and analysis of hPSC-CM electrical properties are essential for identifying changes due to cardiac ion channel mutations and/or drugs that target ion channels and can cause sudden cardiac death. Compared with manual patch-clamp, multi-electrode array (MEA) devices offer the advantage of allowing medium- to high-throughput recordings. This protocol describes how to dissociate 2D cell cultures of hPSC-CMs to small aggregates and single cells and plate them on MEAs to record their spontaneous electrical activity as field potential. Methods for analyzing the recorded data to extract specific parameters, such as the QT and the RR intervals, are also described here. Changes in these parameters would be expected in hPSC-CMs carrying mutations responsible for cardiac arrhythmias and following addition of specific drugs, allowing detection of those that carry a cardiotoxic risk.

Validation of an immortalized human (hBMEC) in vitro blood-brain barrier model.

PubMed

Eigenmann, Daniela Elisabeth; Jähne, Evelyn Andrea; Smieško, Martin; Hamburger, Matthias; Oufir, Mouhssin

2016-03-01

We recently established and optimized an immortalized human in vitro blood-brain barrier (BBB) model based on the hBMEC cell line. In the present work, we validated this mono-culture 24-well model with a representative series of drug substances which are known to cross or not to cross the BBB. For each individual compound, a quantitative UHPLC-MS/MS method in Ringer HEPES buffer was developed and validated according to current regulatory guidelines, with respect to selectivity, precision, and reliability. Various biological and analytical challenges were met during method validation, highlighting the importance of careful method development. The positive controls antipyrine, caffeine, diazepam, and propranolol showed mean endothelial permeability coefficients (P e) in the range of 17-70 × 10(-6) cm/s, indicating moderate to high BBB permeability when compared to the barrier integrity marker sodium fluorescein (mean P e 3-5 × 10(-6) cm/s). The negative controls atenolol, cimetidine, and vinblastine showed mean P e values < 10 × 10(-6) cm/s, suggesting low permeability. In silico calculations were in agreement with in vitro data. With the exception of quinidine (P-glycoprotein inhibitor and substrate), BBB permeability of all control compounds was correctly predicted by this new, easy, and fast to set up human in vitro BBB model. Addition of retinoic acid and puromycin did not increase transendothelial electrical resistance (TEER) values of the BBB model.

Signal Study of the Pair Production of Z’ Bosons Decaying to Dark Matter and Boosted Jets at CMS

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

Silverio, Diana Leon; Jayatilaka, Bo; Cremonesi, Matteo

2017-01-01

This study aims to develop a search for Dark Matter (DM) in a signature of missing transverse energy and jets in the CMS detector at the Large Hadron Collider at CERN. We study the generation of a simplified model for the pair production of spin-1 Z’ bosons, with one of them decaying into a pair of DM particles. The signal events are generated via MadGraph, in the LHE (Les Houches Event) file format, and their kinematics are studied.

Numerical investigation of perforated polymer microcantilever sensor for contractile behavior of cardiomyocytes

NASA Astrophysics Data System (ADS)

Khoa Nguyen, Trieu; Lee, Dong-Weon; Lee, Bong-Kee

2017-06-01

In this study, a numerical investigation of microcantilever sensors for detecting the contractile behavior of cardiomyocytes (CMs) was performed. Recently, a novel surface-patterned perforated SU-8 microcantilever sensor has been developed for the preliminary screening of cardiac toxicity. From the contractile motion of the CMs cultured on the microcantilever surface, a macroscopic bending of the microcantilever was obtained, which is considered to reflect a physiological change. As a continuation of the previous research, a novel numerical method based on a surface traction model was proposed and verified to further understand the bending behavior of the microcantilevers. Effects of various factors, including surface traction magnitude, focal area of CMs, and stiffness of microcantilever, on the bending displacement were investigated. From static and transient analyses, the focal area was found to be the most crucial factor. In addition, the current result can provide a design guideline for various micromechanical devices based on the same principle.

Fast emulation of track reconstruction in the CMS simulation

NASA Astrophysics Data System (ADS)

Komm, Matthias; CMS Collaboration

2017-10-01

Simulated samples of various physics processes are a key ingredient within analyses to unlock the physics behind LHC collision data. Samples with more and more statistics are required to keep up with the increasing amounts of recorded data. During sample generation, significant computing time is spent on the reconstruction of charged particle tracks from energy deposits which additionally scales with the pileup conditions. In CMS, the FastSimulation package is developed for providing a fast alternative to the standard simulation and reconstruction workflow. It employs various techniques to emulate track reconstruction effects in particle collision events. Several analysis groups in CMS are utilizing the package, in particular those requiring many samples to scan the parameter space of physics models (e.g. SUSY) or for the purpose of estimating systematic uncertainties. The strategies for and recent developments in this emulation are presented, including a novel, flexible implementation of tracking emulation while retaining a sufficient, tuneable accuracy.

42 CFR 405.1012 - When CMS or its contractors may be a party to a hearing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false When CMS or its contractors may be a party to a... Hearings § 405.1012 When CMS or its contractors may be a party to a hearing. (a) CMS and/or one or more of... unrepresented beneficiary. (b) CMS and/or the contractor(s) advises the ALJ, appellant, and all other parties...

Development of Cytoplasmic Male Sterile IR24 and IR64 Using CW-CMS/Rf17 System.

PubMed

Toriyama, Kinya; Kazama, Tomohiko

2016-12-01

A wild-abortive-type (WA) cytoplasmic male sterility (CMS) has been almost exclusively used for breeding three-line hybrid rice. Many indica cultivars are known to carry restorer genes for WA-CMS lines and cannot be used as maintainer lines. Especially elite indica cultivars IR24 and IR64 are known to be restorer lines for WA-CMS lines, and are used as male parents for hybrid seed production. If we develop CMS IR24 and CMS IR64, the combination of F1 pairs in hybrid rice breeding programs will be greatly broadened. For production of CMS lines and restorer lines of IR24 and IR64, we employed Chinese wild rice (CW)-type CMS/Restorer of fertility 17 (Rf17) system, in which fertility is restored by a single nuclear gene, Rf17. Successive backcrossing and marker-assisted selection of Rf17 succeeded to produce completely male sterile CMS lines and fully restored restorer lines of IR24 and IR64. CW-cytoplasm did not affect agronomic characteristics. Since IR64 is one of the most popular mega-varieties and used for breeding of many modern varieties, the CW-CMS line of IR64 will be useful for hybrid rice breeding.

Multibody model reduction by component mode synthesis and component cost analysis

NASA Technical Reports Server (NTRS)

Spanos, J. T.; Mingori, D. L.

1990-01-01

The classical assumed-modes method is widely used in modeling the dynamics of flexible multibody systems. According to the method, the elastic deformation of each component in the system is expanded in a series of spatial and temporal functions known as modes and modal coordinates, respectively. This paper focuses on the selection of component modes used in the assumed-modes expansion. A two-stage component modal reduction method is proposed combining Component Mode Synthesis (CMS) with Component Cost Analysis (CCA). First, each component model is truncated such that the contribution of the high frequency subsystem to the static response is preserved. Second, a new CMS procedure is employed to assemble the system model and CCA is used to further truncate component modes in accordance with their contribution to a quadratic cost function of the system output. The proposed method is demonstrated with a simple example of a flexible two-body system.

MUSiC - A Generic Search for Deviations from Monte Carlo Predictions in CMS

NASA Astrophysics Data System (ADS)

Hof, Carsten

2009-05-01

We present a model independent analysis approach, systematically scanning the data for deviations from the Standard Model Monte Carlo expectation. Such an analysis can contribute to the understanding of the CMS detector and the tuning of the event generators. Furthermore, due to the minimal theoretical bias this approach is sensitive to a variety of models of new physics, including those not yet thought of. Events are classified into event classes according to their particle content (muons, electrons, photons, jets and missing transverse energy). A broad scan of various distributions is performed, identifying significant deviations from the Monte Carlo simulation. We outline the importance of systematic uncertainties, which are taken into account rigorously within the algorithm. Possible detector effects and generator issues, as well as models involving supersymmetry and new heavy gauge bosons have been used as an input to the search algorithm.

42 CFR § 512.905 - Termination of the CR incentive payment model.

Code of Federal Regulations, 2010 CFR

2017-10-01

... 42 Public Health 5 2017-10-01 2017-10-01 false Termination of the CR incentive payment model. Â... HEALTH AND HUMAN SERVICES (CONTINUED) HEALTH CARE INFRASTRUCTURE AND MODEL PROGRAMS EPISODE PAYMENT MODEL Model Termination § 512.905 Termination of the CR incentive payment model. CMS may terminate the CR...

42 CFR 414.68 - Imaging accreditation.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Computed tomography. (iii) Nuclear medicine. (iv) Positron emission tomography. CMS-approved accreditation... if CMS takes an adverse action based on accreditation findings. (vi) Notify CMS, in writing... organization must permit its surveyors to serve as witnesses if CMS takes an adverse action based on...

42 CFR 414.68 - Imaging accreditation.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Computed tomography. (iii) Nuclear medicine. (iv) Positron emission tomography. CMS-approved accreditation... if CMS takes an adverse action based on accreditation findings. (vi) Notify CMS, in writing... organization must permit its surveyors to serve as witnesses if CMS takes an adverse action based on...

42 CFR 414.68 - Imaging accreditation.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Computed tomography. (iii) Nuclear medicine. (iv) Positron emission tomography. CMS-approved accreditation... if CMS takes an adverse action based on accreditation findings. (vi) Notify CMS, in writing... organization must permit its surveyors to serve as witnesses if CMS takes an adverse action based on...

42 CFR § 512.730 - Compliance enforcement for FFS-CR participants.

Code of Federal Regulations, 2010 CFR

2017-10-01

... HEALTH AND HUMAN SERVICES (CONTINUED) HEALTH CARE INFRASTRUCTURE AND MODEL PROGRAMS EPISODE PAYMENT MODEL CR Incentive Payment Model for EPM and Medicare Fee-for-Service Participants Provisions for Ffs-Cr... through monitoring by HHS (including CMS and OIG) of the CR incentive payment model, including but not...

Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior.

PubMed

Mandel, Yael; Weissman, Amir; Schick, Revital; Barad, Lili; Novak, Atara; Meiry, Gideon; Goldberg, Stanislav; Lorber, Avraham; Rosen, Michael R; Itskovitz-Eldor, Joseph; Binah, Ofer

2012-02-21

The sinoatrial node is the main impulse-generating tissue in the heart. Atrioventricular conduction block and arrhythmias caused by sinoatrial node dysfunction are clinically important and generally treated with electronic pacemakers. Although an excellent solution, electronic pacemakers incorporate limitations that have stimulated research on biological pacing. To assess the suitability of potential biological pacemakers, we tested the hypothesis that the spontaneous electric activity of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) exhibit beat rate variability and power-law behavior comparable to those of human sinoatrial node. We recorded extracellular electrograms from hESC-CMs and iPSC-CMs under stable conditions for up to 15 days. The beat rate time series of the spontaneous activity were examined in terms of their power spectral density and additional methods derived from nonlinear dynamics. The major findings were that the mean beat rate of hESC-CMs and iPSC-CMs was stable throughout the 15-day follow-up period and was similar in both cell types, that hESC-CMs and iPSC-CMs exhibited intrinsic beat rate variability and fractal behavior, and that isoproterenol increased and carbamylcholine decreased the beating rate in both hESC-CMs and iPSC-CMs. This is the first study demonstrating that hESC-CMs and iPSC-CMs exhibit beat rate variability and power-law behavior as in humans, thus supporting the potential capability of these cell sources to serve as biological pacemakers. Our ability to generate sinoatrial-compatible spontaneous cardiomyocytes from the patient's own hair (via keratinocyte-derived iPSCs), thus eliminating the critical need for immunosuppression, renders these myocytes an attractive cell source as biological pacemakers.

Crisis Management Systems: A Case Study for Aspect-Oriented Modeling

NASA Astrophysics Data System (ADS)

Kienzle, Jörg; Guelfi, Nicolas; Mustafiz, Sadaf

The intent of this document is to define a common case study for the aspect-oriented modeling research community. The domain of the case study is crisis management systems, i.e., systems that help in identifying, assessing, and handling a crisis situation by orchestrating the communication between all parties involved in handling the crisis, by allocating and managing resources, and by providing access to relevant crisis-related information to authorized users. This document contains informal requirements of crisis management systems (CMSs) in general, a feature model for a CMS product line, use case models for a car crash CMS (CCCMS), a domain model for the CCCMS, an informal physical architecture description of the CCCMS, as well as some design models of a possible object-oriented implementation of parts of the CCCMS backend. AOM researchers who want to demonstrate the power of their AOM approach or technique can hence apply the approach at the most appropriate level of abstraction.

Human renal adipose tissue induces the invasion and progression of renal cell carcinoma

PubMed Central

Campo-Verde-Arbocco, Fiorella; López-Laur, José D.; Romeo, Leonardo R.; Giorlando, Noelia; Bruna, Flavia A.; Contador, David E.; López-Fontana, Gastón; Santiano, Flavia E.; Sasso, Corina V.; Zyla, Leila E.; López-Fontana, Constanza M.; Calvo, Juan C.; Carón, Rubén W.; Creydt, Virginia Pistone

2017-01-01

We evaluated the effects of conditioned media (CMs) of human adipose tissue from renal cell carcinoma located near the tumor (hRATnT) or farther away from the tumor (hRATfT), on proliferation, adhesion and migration of tumor (786-O and ACHN) and non-tumor (HK-2) human renal epithelial cell lines. Human adipose tissues were obtained from patients with renal cell carcinoma (RCC) and CMs from hRATnT and hRATfT incubation. Proliferation, adhesion and migration were quantified in 786-O, ACHN and HK-2 cell lines incubated with hRATnT-, hRATfT- or control-CMs. We evaluated versican, adiponectin and leptin expression in CMs from hRATnT and hRATfT. We evaluated AdipoR1/2, ObR, pERK, pAkt y pPI3K expression on cell lines incubated with CMs. No differences in proliferation of cell lines was found after 24 h of treatment with CMs. All cell lines showed a significant decrease in cell adhesion and increase in cell migration after incubation with hRATnT-CMs vs. hRATfT- or control-CMs. hRATnT-CMs showed increased levels of versican and leptin, compared to hRATfT-CMs. AdipoR2 in 786-O and ACHN cells decreased significantly after incubation with hRATfT- and hRATnT-CMs vs. control-CMs. We observed a decrease in the expression of pAkt in HK-2, 786-O and ACHN incubated with hRATnT-CMs. This result could partially explain the observed changes in migration and cell adhesion. We conclude that hRATnT released factors, such as leptin and versican, could enhance the invasive potential of renal epithelial cell lines and could modulate the progression of the disease. PMID:29212223

Mitochondrial nad2 gene is co-transcripted with CMS-associated orfB gene in cytoplasmic male-sterile stem mustard (Brassica juncea).

PubMed

Yang, Jing-Hua; Zhang, Ming-Fang; Yu, Jing-Quan

2009-02-01

The transcriptional patterns of mitochondrial respiratory related genes were investigated in cytoplasmic male-sterile and fertile maintainer lines of stem mustard, Brassica juncea. There were numerous differences in nad2 (subunit 2 of NADH dehydrogenase) between stem mustard CMS and its maintainer line. One novel open reading frame, hereafter named orfB gene, was located at the downstream of mitochondrial nad2 gene in the CMS. The novel orfB gene had high similarity with YMF19 family protein, orfB in Raphanus sativus, Helianthus annuus, Nicotiana tabacum and Beta vulgaris, orfB-CMS in Daucus carota, atp8 gene in Arabidopsis thaliana, 5' flanking of orf224 in B. napus (nap CMS) and 5' flanking of orf220 gene in CMS Brassica juncea. Three copies probed by specific fragment (amplified by primers of nad2F and nad2R from CMS) were found in the CMS line following Southern blotting digested with HindIII, but only a single copy in its maintainer line. Meanwhile, two transcripts were shown in the CMS line following Northern blotting while only one transcript was detected in the maintainer line, which were probed by specific fragment (amplified by primers of nad2F and nad2R from CMS). Meanwhile, the expression of nad2 gene was reduced in CMS bud compared to that in its maintainer line. We thus suggested that nad2 gene may be co-transcripted with CMS-associated orfB gene in the CMS. In addition, the specific fragment that was amplified by primers of nad2F and nad2R just spanned partial sequences of nad2 gene and orfB gene. Such alterations in the nad2 gene would impact the activity of NADH dehydrogenase, and subsequently signaling, inducing the expression of nuclear genes involved in male sterility in this type of cytoplasmic male sterility.

Composite quantum collision models

NASA Astrophysics Data System (ADS)

Lorenzo, Salvatore; Ciccarello, Francesco; Palma, G. Massimo

2017-09-01

A collision model (CM) is a framework to describe open quantum dynamics. In its memoryless version, it models the reservoir R as consisting of a large collection of elementary ancillas: the dynamics of the open system S results from successive collisions of S with the ancillas of R . Here, we present a general formulation of memoryless composite CMs, where S is partitioned into the very open system under study S coupled to one or more auxiliary systems {Si} . Their composite dynamics occurs through internal S -{Si} collisions interspersed with external ones involving {Si} and the reservoir R . We show that important known instances of quantum non-Markovian dynamics of S —such as the emission of an atom into a reservoir featuring a Lorentzian, or multi-Lorentzian, spectral density or a qubit subject to random telegraph noise—can be mapped on to such memoryless composite CMs.

Risk factors for acute kidney injury in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics: a retrospective cohort study

PubMed Central

2013-01-01

Introduction Use of colistin methanesulfonate (CMS) was abandoned in the 1970s because of excessive nephrotoxicity, but it has been reintroduced as a last-resort treatment for extensively drug-resistant infections caused by gram-negative bacteria (Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumonia). We conducted a retrospective cohort study to evaluate risk factors for new-onset acute kidney injury (AKI) in critically ill patients receiving high intravenous doses of colistin methanesulfonate and/or other nephrotoxic antibiotics. Methods The cohort consisted of 279 adults admitted to two general ICUs in teaching hospitals between 1 April 2009 and 30 June 2011 with 1) no evidence on admission of acute or chronic kidney disease; and 2) treatment for more than seven days with CMS and/or other nephrotoxic antimicrobials (NAs, that is, aminoglycosides, glycopeptides). Logistic regression analysis was used to identify risk factors associated with this outcome. Results The 279 cases that met the inclusion criteria included 147 patients treated with CMS, alone (n = 90) or with NAs (n = 57), and 132 treated with NAs alone. The 111 (40%) who developed AKI were significantly older and had significantly higher Simplified Acute Physiology Score II (SAPS II) scores than those who did not develop AKI, but rates of hypertension, diabetes mellitus and congestive heart failure were similar in the two groups. The final logistic regression model showed that in the 147 patients who received CMS alone or with NAs, onset of AKI during the ICU stay was associated with septic shock and with SAPS II scores ≥43. Similar results were obtained in the 222 patients treated with CMS alone or NAs alone. Conclusions In severely ill ICU patients without pre-existing renal disease who receive CMS high-dose for more than seven days, CMS therapy does not appear to be a risk factor for this outcome. Instead, the development of AKI was strongly correlated with the presence of septic shock and with the severity of the patients as reflected by the SAPS II score. PMID:23945197

Carbohydrate fatty acid monosulphate esters are safe and effective adjuvants for humoral responses.

PubMed

Hilgers, Luuk A Th; Platenburg, Peter Paul L I; Bajramovic, Jeffrey; Veth, Jennifer; Sauerwein, Robert; Roeffen, Will; Pohl, Marie; van Amerongen, Geert; Stittelaar, Koert J; van den Bosch, Johannes F

2017-05-31

Carbohydrate fatty acid sulphate esters (CFASEs) formulated in a squalane-in-water emulsion are effective adjuvants for humoral responses to a wide range of antigens in various animal species but rise in body temperature and local reactions albeit mild or minimal hampers application in humans. In rabbits, body temperature increased 1°C one day after intramuscular (IM) injection, which returned to normal during the next day. The effect increased with increasing dose of CFASE but not with the number of injections (up to 5). Antigen enhanced the rise in body temperature after booster immunization (P<0.01) but not after priming. Synthetic CFASEs are mixtures of derivatives containing no sulphate, one or multiple sulphate groups and the monosulphate derivatives (CMS) were isolated, incorporated in a squalane in-water emulsion and investigated. In contrast to CFASE, CMS adjuvant did not generate rise in body temperature or local reactions in rabbits immunized with a purified, recombinant malaria chimeric antigen R0.10C. In comparison to alum, CMS adjuvant revealed approximately 30-fold higher antibody titres after the first and >100-fold after the second immunization. In ferrets immunized with 7.5μg of inactivated influenza virus A/H7N9, CMS adjuvant gave 100-fold increase in HAI antibody titres after the first and 25-fold after the second immunisation, which were 10-20-fold higher than with the MF59-like AddaVax adjuvant. In both models, a single immunisation with CMS adjuvant revealed similar or higher titres than two immunisations with either benchmark, without detectable systemic and local adverse effects. Despite striking chemical similarities with monophospholipid A (MPL), CMS adjuvant did not activate human TLR4 expressed on HEK cells. We concluded that the synthetic CMS adjuvant is a promising candidate for poor immunogens and single-shot vaccines and that rise in body temperature, local reactions or activation of TLR4 is not a pre-requisite for high adjuvanticity. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Responding to GPs' information resource needs: implementation and evaluation of a complementary medicines information resource in Queensland general practice

PubMed Central

2011-01-01

Background Australian General Practitioners (GPs) are in the forefront of primary health care and in an excellent position to communicate with their patients and educate them about Complementary Medicines (CMs) use. However previous studies have demonstrated that GPs lack the knowledge required about CMs to effectively communicate with patients about their CMs use and they perceive a need for information resources on CMs to use in their clinical practice. This study aimed to develop, implement, and evaluate a CMs information resource in Queensland (Qld) general practice. Methods The results of the needs assessment survey of Qld general practitioners (GPs) informed the development of a CMs information resource which was then put through an implementation and evaluation cycle in Qld general practice. The CMs information resource was a set of evidence-based herbal medicine fact sheets. This resource was utilised by 100 Qld GPs in their clinical practice for four weeks and was then evaluated. The evaluation assessed GPs' (1) utilisation of the resource (2) perceived quality, usefulness and satisfaction with the resource and (3) perceived impact of the resource on their knowledge, attitudes, and practice of CMs. Results Ninety two out of the 100 GPs completed the four week evaluation of the fact sheets and returned the post-intervention survey. The herbal medicine fact sheets produced by this study were well accepted and utilised by Qld GPs. The majority of GPs perceived that the fact sheets were a useful resource for their clinical practice. The fact sheets improved GPs' attitudes towards CMs, increased their knowledge of those herbal medicines and improved their communication with their patients about those specific herbs. Eighty-six percent of GPs agreed that if they had adequate resources on CMs, like the herbal medicine fact sheets, then they would communicate more to their patients about their use of CMs. Conclusion Further educational interventions on CMs need to be provided to GPs to increase their knowledge of CMs and to improve their communication with patients about their CMs use. PMID:21933434

Turbulence intensity in a region of interest 2cm distal to the carotid bifurcation in a family of seven anthropomorphic flow phantoms

NASA Astrophysics Data System (ADS)

Powell, Janet L.; Poepping, Tamie L.

2011-03-01

An in vitro flow system has been used to assess the flow disturbances downstream of the stenosis in a family of seven carotid bifurcation phantoms modelling varying plaque build-up both axially symmetrically (concentrically) and asymmetrically (eccentrically). Radio frequency data were collected for 10 s at each of over 1000 sites within each model, and a sliding 1024-point FFT is applied to the data to extract the Doppler spectrum every 12 ms. From this, the ensemble average over 10 cardiac cycles of the spectral mean velocity, and the root mean square over these same 10 cardiac cycles - the turbulence intensity (TI), can be obtained as a function of an ensemble averaged cardiac cycle at each spatial point in all phantoms. TI was investigated by looking at the average over a 25 mm2 square region of interest in the ICA centered 2 cm distal to the apex of the bifurcation. TI in the region of interest increased with stenosis severity; at 23ms following peak systole, the time point when TI was maximal for the majority of models, this ranged from 2.4+/-0.1 cm/s in the non-diseased model to 6.6+/-0.3, 16.0+/-1.4 and 26.1+/-1.3 cm/s in the 30, 50 and 70% concentrically stenosed (by NASCET criteria) models, respectively. Similarly, TI was 8.3+/-0.7, 19.9+/-1.1, and 26.2+/-1.2 cm/s in the 30, 50 and 70% eccentrically stenosed models, respectively. Differences in TI between models, both in increasing stenosis severity and between eccentricities, were statistically different except between the 70% concentric and eccentric models.

Understanding flavour at the LHC

ScienceCinema

Nir, Yosef

2018-05-22

Huge progress in flavour physics has been achieved by the two B-factories and the Tevatron experiments. This progress has, however, deepened the new physics flavour puzzle: If there is new physics at the TeV scale, why aren't flavour changing neutral current processes enhanced by orders of magnitude compared to the standard model predictions? The forthcoming ATLAS and CMS experiments can potentially solve this puzzle. Perhaps even more surprisingly, these experiments can potentially lead to progress in understanding the standard model flavour puzzle: Why is there smallness and hierarchy in the flavour parameters? Thus, a rich and informative flavour program is awaiting us not only in the flavour-dedicated LHCb experiment, but also in the high-pT ATLAS and CMS experiments.

Coloron-assisted leptoquarks at the LHC

DOE PAGES

Bai, Yang; Berger, Joshua

2015-06-30

Recent searches for a first-generation leptoquark by the CMS collaboration have shown around 2.5σ deviations from Standard Model predictions in both the eejj and eνjj channels. Furthermore, the eejj invariant mass distribution has another 2.8σ excess from the CMS right-handed W plus heavy neutrino search. We point out that additional leptoquark production from a heavy coloron decay can provide a good explanation for all three excesses. The coloron has a mass around 2.1 TeV and the leptoquark mass can vary from 550 GeV to 650 GeV. A key prediction of this model is an edge in the total m Tmore » distribution of eνjj events at around 2.1 TeV.« less

Search for dijet resonances in 7 TeV pp collisions at CMS.

PubMed

Khachatryan, V; Sirunyan, A M; Tumasyan, A; Adam, W; Bergauer, T; Dragicevic, M; Erö, J; Fabjan, C; Friedl, M; Frühwirth, R; Ghete, V M; Hammer, J; Hänsel, S; Hartl, C; Hoch, M; Hörmann, N; Hrubec, J; Jeitler, M; Kasieczka, G; Kiesenhofer, W; Krammer, M; Liko, D; Mikulec, I; Pernicka, M; Rohringer, H; Schöfbeck, R; Strauss, J; Taurok, A; Teischinger, F; Waltenberger, W; Walzel, G; Widl, E; Wulz, C-E; Mossolov, V; Shumeiko, N; Suarez Gonzalez, J; Benucci, L; Ceard, L; De Wolf, E A; Janssen, X; Maes, T; Mucibello, L; Ochesanu, S; Roland, B; Rougny, R; Selvaggi, M; Van Haevermaet, H; Van Mechelen, P; Van Remortel, N; Adler, V; Beauceron, S; Blyweert, S; D'Hondt, J; Devroede, O; Kalogeropoulos, A; Maes, J; Maes, M; Tavernier, S; Van Doninck, W; Van Mulders, P; Villella, I; Chabert, E C; Charaf, O; Clerbaux, B; De Lentdecker, G; Dero, V; Gay, A P R; Hammad, G H; Hreus, T; Marage, P E; Thomas, L; Vander Velde, C; Vanlaer, P; Wickens, J; Costantini, S; Grunewald, M; Klein, B; Marinov, A; Ryckbosch, D; Thyssen, F; Tytgat, M; Vanelderen, L; Verwilligen, P; Walsh, S; Zaganidis, N; Basegmez, S; Bruno, G; Caudron, J; De Favereau De Jeneret, J; Delaere, C; Demin, P; Favart, D; Giammanco, A; Grégoire, G; Hollar, J; Lemaitre, V; Militaru, O; Ovyn, S; Pagano, D; Pin, A; Piotrzkowski, K; Quertenmont, L; Schul, N; Beliy, N; Caebergs, T; Daubie, E; Alves, G A; De Jesus Damiao, D; Pol, M E; Souza, M H G; Carvalho, W; Da Costa, E M; De Oliveira Martins, C; Fonseca De Souza, S; Mundim, L; Nogima, H; Oguri, V; Otalora Goicochea, J M; Prado Da Silva, W L; Santoro, A; Silva Do Amaral, S M; Sznajder, A; Torres Da Silva De Araujo, F; Dias, F A; Dias, M A F; Fernandez Perez Tomei, T R; Gregores, E M; Marinho, F; Novaes, S F; Padula, Sandra S; Darmenov, N; Dimitrov, L; Genchev, V; Iaydjiev, P; Piperov, S; Rodozov, M; Stoykova, S; Sultanov, G; Tcholakov, V; Trayanov, R; Vankov, I; Dyulendarova, M; Hadjiiska, R; Kozhuharov, V; Litov, L; Marinova, E; Mateev, M; Pavlov, B; Petkov, P; Bian, J G; Chen, G M; Chen, H S; Jiang, C H; Liang, D; Liang, S; Wang, J; Wang, J; Wang, X; Wang, Z; Yang, M; Zang, J; Zhang, Z; Ban, Y; Guo, S; Hu, Z; Li, W; Mao, Y; Qian, S J; Teng, H; Zhu, B; Cabrera, A; Gomez Moreno, B; Ocampo Rios, A A; Osorio Oliveros, A F; Sanabria, J C; Godinovic, N; Lelas, D; Lelas, K; Plestina, R; Polic, D; Puljak, I; Antunovic, Z; Dzelalija, M; Brigljevic, V; Duric, S; Kadija, K; Morovic, S; Attikis, A; Fereos, R; Galanti, M; Mousa, J; Nicolaou, C; Ptochos, F; Razis, P A; Rykaczewski, H; Abdel-Basit, A; Assran, Y; Mahmoud, M A; Hektor, A; Kadastik, M; Kannike, K; Müntel, M; Raidal, M; Rebane, L; Azzolini, V; Eerola, P; Czellar, S; Härkönen, J; Heikkinen, A; Karimäki, V; Kinnunen, R; Klem, J; Kortelainen, M J; Lampén, T; Lassila-Perini, K; Lehti, S; Lindén, T; Luukka, P; Mäenpää, T; Tuominen, E; Tuominiemi, J; Tuovinen, E; Ungaro, D; Wendland, L; Banzuzi, K; Korpela, A; Tuuva, T; Sillou, D; Besancon, M; Dejardin, M; Denegri, D; Fabbro, B; Faure, J L; Ferri, F; Ganjour, S; Gentit, F X; Givernaud, A; 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Klein, K; Merz, J; Mohr, N; Ostapchuk, A; Perieanu, A; Raupach, F; Sammet, J; Schael, S; Sprenger, D; Weber, H; Weber, M; Wittmer, B; Ata, M; Bender, W; Erdmann, M; Frangenheim, J; Hebbeker, T; Hinzmann, A; Hoepfner, K; Hof, C; Klimkovich, T; Klingebiel, D; Kreuzer, P; Lanske, D; Magass, C; Masetti, G; Merschmeyer, M; Meyer, A; Papacz, P; Pieta, H; Reithler, H; Schmitz, S A; Sonnenschein, L; Steggemann, J; Teyssier, D; Bontenackels, M; Davids, M; Duda, M; Flügge, G; Geenen, H; Giffels, M; Haj Ahmad, W; Heydhausen, D; Kress, T; Kuessel, Y; Linn, A; Nowack, A; Perchalla, L; Pooth, O; Rennefeld, J; Sauerland, P; Stahl, A; Thomas, M; Tornier, D; Zoeller, M H; Aldaya Martin, M; Behrenhoff, W; Behrens, U; Bergholz, M; Borras, K; Campbell, A; Castro, E; Dammann, D; Eckerlin, G; Flossdorf, A; Flucke, G; Geiser, A; Glushkov, I; Hauk, J; Jung, H; Kasemann, M; Katkov, I; Katsas, P; Kleinwort, C; Kluge, H; Knutsson, A; Krücker, D; Kuznetsova, E; Lange, W; Lohmann, W; Mankel, R; Marienfeld, M; Melzer-Pellmann, I-A; Meyer, A B; Mnich, J; Mussgiller, A; Olzem, J; Parenti, A; Raspereza, A; Raval, A; Schmidt, R; Schoerner-Sadenius, T; Sen, N; Stein, M; Tomaszewska, J; Volyanskyy, D; Walsh, R; Wissing, C; Autermann, C; Bobrovskyi, S; Draeger, J; Eckstein, D; Enderle, H; Gebbert, U; Kaschube, K; Kaussen, G; Klanner, R; Mura, B; Naumann-Emme, S; Nowak, F; Pietsch, N; Sander, C; Schettler, H; Schleper, P; Schröder, M; Schum, T; Schwandt, J; Srivastava, A K; Stadie, H; Steinbrück, G; Thomsen, J; Wolf, R; Bauer, J; Buege, V; Cakir, A; Chwalek, T; Daeuwel, D; De Boer, W; Dierlamm, A; Dirkes, G; Feindt, M; Gruschke, J; Hackstein, C; Hartmann, F; Heinrich, M; Held, H; Hoffmann, K H; Honc, S; Kuhr, T; Martschei, D; Mueller, S; Müller, Th; Neuland, M B; Niegel, M; Oberst, O; Oehler, A; Ott, J; Peiffer, T; Piparo, D; Quast, G; Rabbertz, K; Ratnikov, F; Renz, M; Sabellek, A; Saout, C; Scheurer, A; Schieferdecker, P; Schilling, F-P; Schott, G; Simonis, H J; Stober, F M; Troendle, D; Wagner-Kuhr, J; Zeise, M; Zhukov, V; Ziebarth, E B; Daskalakis, G; Geralis, T; Kesisoglou, S; Kyriakis, A; Loukas, D; Manolakos, I; Markou, A; Markou, C; Mavrommatis, C; Petrakou, E; Gouskos, L; Mertzimekis, T; Panagiotou, A; Evangelou, I; Kokkas, P; Manthos, N; Papadopoulos, I; Patras, V; Triantis, F A; Aranyi, A; Bencze, G; Boldizsar, L; Debreczeni, G; Hajdu, C; Horvath, D; Kapusi, A; Krajczar, K; Sikler, F; Vesztergombi, G; Beni, N; Molnar, J; Palinkas, J; Szillasi, Z; Veszpremi, V; Raics, P; Trocsanyi, Z L; Ujvari, B; Bansal, S; Beri, S B; Bhatnagar, V; Jindal, M; Kaur, M; Kohli, J M; Mehta, M Z; Nishu, N; Saini, L K; Sharma, A; Sharma, R; Singh, A P; Singh, J B; Singh, S P; Ahuja, S; Bhattacharya, S; Chauhan, S; Choudhary, B C; Gupta, P; Jain, S; Jain, S; Kumar, A; Shivpuri, R K; Choudhury, R K; Dutta, D; Kailas, S; Kataria, S K; Mohanty, A K; Pant, L M; Shukla, P; Suggisetti, P; Aziz, T; Guchait, M; Gurtu, A; Maity, M; Majumder, D; Majumder, G; Mazumdar, K; Mohanty, G B; Saha, A; Sudhakar, K; Wickramage, N; Banerjee, S; 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Onel, Y; Ozok, F; Sen, S; Wetzel, J; Yetkin, T; Yi, K; Barnett, B A; Blumenfeld, B; Bonato, A; Eskew, C; Fehling, D; Giurgiu, G; Gritsan, A V; Guo, Z J; Hu, G; Maksimovic, P; Rappoccio, S; Swartz, M; Tran, N V; Whitbeck, A; Baringer, P; Bean, A; Benelli, G; Grachov, O; Murray, M; Noonan, D; Radicci, V; Sanders, S; Wood, J S; Zhukova, V; Bandurin, D; Bolton, T; Chakaberia, I; Ivanov, A; Makouski, M; Maravin, Y; Shrestha, S; Svintradze, I; Wan, Z; Gronberg, J; Lange, D; Wright, D; Baden, A; Boutemeur, M; Eno, S C; Ferencek, D; Gomez, J A; Hadley, N J; Kellogg, R G; Kirn, M; Lu, Y; Mignerey, A C; Rossato, K; Rumerio, P; Santanastasio, F; Skuja, A; Temple, J; Tonjes, M B; Tonwar, S C; Twedt, E; Alver, B; Bauer, G; Bendavid, J; Busza, W; Butz, E; Cali, I A; Chan, M; Dutta, V; Everaerts, P; Gomez Ceballos, G; Goncharov, M; Hahn, K A; Harris, P; Kim, Y; Klute, M; Lee, Y-J; Li, W; Loizides, C; Luckey, P D; Ma, T; Nahn, S; Paus, C; Roland, C; Roland, G; Rudolph, M; Stephans, G S F; Sumorok, K; Sung, K; Wenger, E A; Wyslouch, B; Xie, S; Yang, M; Yilmaz, Y; Yoon, A S; Zanetti, M; Cole, P; Cooper, S I; Cushman, P; Dahmes, B; De Benedetti, A; Dudero, P R; Franzoni, G; Haupt, J; Klapoetke, K; Kubota, Y; Mans, J; Rekovic, V; Rusack, R; Sasseville, M; Singovsky, A; Cremaldi, L M; Godang, R; Kroeger, R; Perera, L; Rahmat, R; Sanders, D A; Summers, D; Bloom, K; Bose, S; Butt, J; Claes, D R; Dominguez, A; Eads, M; Keller, J; Kelly, T; Kravchenko, I; Lazo-Flores, J; Lundstedt, C; Malbouisson, H; Malik, S; Snow, G R; Baur, U; Godshalk, A; Iashvili, I; Kharchilava, A; Kumar, A; Smith, K; Zennamo, J; Alverson, G; Barberis, E; Baumgartel, D; Boeriu, O; Chasco, M; Kaadze, K; Reucroft, S; Swain, J; Wood, D; Zhang, J; Anastassov, A; Kubik, A; Odell, N; Ofierzynski, R A; Pollack, B; Pozdnyakov, A; Schmitt, M; Stoynev, S; Velasco, M; Won, S; Antonelli, L; Berry, D; Hildreth, M; Jessop, C; Karmgard, D J; Kolb, J; Kolberg, T; Lannon, K; Luo, W; Lynch, S; Marinelli, N; Morse, D M; Pearson, T; Ruchti, R; Slaunwhite, J; Valls, N; Warchol, J; Wayne, M; Ziegler, J; Bylsma, B; Durkin, L S; Gu, J; Hill, C; Killewald, P; Ling, T Y; Rodenburg, M; Williams, G; Adam, N; Berry, E; Elmer, P; Gerbaudo, D; Halyo, V; Hebda, P; Hunt, A; Jones, J; Laird, E; Lopes Pegna, D; Marlow, D; Medvedeva, T; Mooney, M; Olsen, J; Piroué, P; Saka, H; Stickland, D; Tully, C; Werner, J S; Zuranski, A; Acosta, J G; Huang, X T; Lopez, A; Mendez, H; Oliveros, S; Ramirez Vargas, J E; Zatserklyaniy, A; Alagoz, E; Barnes, V E; Bolla, G; Borrello, L; Bortoletto, D; Everett, A; Garfinkel, A F; Gecse, Z; Gutay, L; Jones, M; Koybasi, O; Laasanen, A T; Leonardo, N; Liu, C; Maroussov, V; Meier, M; Merkel, P; Miller, D H; Neumeister, N; Potamianos, K; Shipsey, I; Silvers, D; Svyatkovskiy, A; Yoo, H D; Zablocki, J; Zheng, Y; Jindal, P; Parashar, N; Boulahouache, C; Cuplov, V; Ecklund, K M; Geurts, F J M; Liu, J H; Morales, J; Padley, B P; Redjimi, R; Roberts, J; Zabel, J; Betchart, B; Bodek, A; Chung, Y S; de Barbaro, P; Demina, R; Eshaq, Y; Flacher, H; Garcia-Bellido, A; Goldenzweig, P; Gotra, Y; Han, J; Harel, A; Miner, D C; Orbaker, D; Petrillo, G; Vishnevskiy, D; Zielinski, M; Bhatti, A; Demortier, L; Goulianos, K; Lungu, G; Mesropian, C; Yan, M; Atramentov, O; Barker, A; Duggan, D; Gershtein, Y; Gray, R; Halkiadakis, E; Hidas, D; Hits, D; Lath, A; Panwalkar, S; Patel, R; Richards, A; Rose, K; Schnetzer, S; Somalwar, S; Stone, R; Thomas, S; Cerizza, G; Hollingsworth, M; Spanier, S; Yang, Z C; York, A; Asaadi, J; Eusebi, R; Gilmore, J; Gurrola, A; Kamon, T; Khotilovich, V; Montalvo, R; Nguyen, C N; Pivarski, J; Safonov, A; Sengupta, S; Tatarinov, A; Toback, D; Weinberger, M; Akchurin, N; Bardak, C; Damgov, J; Jeong, C; Kovitanggoon, K; Lee, S W; Mane, P; Roh, Y; Sill, A; Volobouev, I; Wigmans, R; Yazgan, E; Appelt, E; Brownson, E; Engh, D; Florez, C; Gabella, W; Johns, W; Kurt, P; Maguire, C; Melo, A; Sheldon, P; Velkovska, J; Arenton, M W; Balazs, M; Boutle, S; Buehler, M; Conetti, S; Cox, B; Francis, B; Hirosky, R; Ledovskoy, A; Lin, C; Neu, C; Patel, T; Yohay, R; Gollapinni, S; Harr, R; Karchin, P E; Loggins, V; Mattson, M; Milstène, C; Sakharov, A; Anderson, M; Bachtis, M; Bellinger, J N; Carlsmith, D; Dasu, S; Efron, J; Gray, L; Grogg, K S; Grothe, M; Hall-Wilton, R; Herndon, M; Klabbers, P; Klukas, J; Lanaro, A; Lazaridis, C; Leonard, J; Liu, J; Lomidze, D; Loveless, R; Mohapatra, A; Parker, W; Reeder, D; Ross, I; Savin, A; Smith, W H; Swanson, J; Weinberg, M

2010-11-19

A search for narrow resonances in the dijet mass spectrum is performed using data corresponding to an integrated luminosity of 2.9 pb⁻¹ collected by the CMS experiment at the Large Hadron Collider. Upper limits at the 95% confidence level are presented on the product of the resonance cross section, branching fraction into dijets, and acceptance, separately for decays into quark-quark, quark-gluon, or gluon-gluon pairs. The data exclude new particles predicted in the following models at the 95% confidence level: string resonances, with mass less than 2.50 TeV, excited quarks, with mass less than 1.58 TeV, and axigluons, colorons, and E6 diquarks, in specific mass intervals. This extends previously published limits on these models.

Midwifery education today.

PubMed

Carr, Katherine Camacho; Brucker, Mary C

2002-12-01

Today, there are more than 7000 CNMs and CMs in the United States, who attend approximately 9% of American births annually in hospitals, birth centers, and homes. Midwives work in a variety of practice models, including group practices with physicians, HMOs, private practices, rural and urban community health centers, and large managed care organizations. CNMs and CMs also serve as administrators, policy makers, and consultants in international maternal and child health. Midwifery education has come a long way since 1931, when the first education program started. The dedication of CNMs to our clients and the midwifery model of care, as well as these midwifery educational innovations, will continue to support the profession's goals of offering humane, holistic, and safe health care to women and their families.

A component modes projection and assembly model reduction methodology for articulated, multi-flexible body structures

NASA Technical Reports Server (NTRS)

Lee, Allan Y.; Tsuha, Walter S.

1993-01-01

A two-stage model reduction methodology, combining the classical Component Mode Synthesis (CMS) method and the newly developed Enhanced Projection and Assembly (EP&A) method, is proposed in this research. The first stage of this methodology, called the COmponent Modes Projection and Assembly model REduction (COMPARE) method, involves the generation of CMS mode sets, such as the MacNeal-Rubin mode sets. These mode sets are then used to reduce the order of each component model in the Rayleigh-Ritz sense. The resultant component models are then combined to generate reduced-order system models at various system configurations. A composite mode set which retains important system modes at all system configurations is then selected from these reduced-order system models. In the second stage, the EP&A model reduction method is employed to reduce further the order of the system model generated in the first stage. The effectiveness of the COMPARE methodology has been successfully demonstrated on a high-order, finite-element model of the cruise-configured Galileo spacecraft.

The elution of colistimethate sodium from polymethylmethacrylate and calcium phosphate cement beads.

PubMed

Waterman, Paige; Barber, Melissa; Weintrob, Amy C; VanBrakle, Regina; Howard, Robin; Kozar, Michael P; Andersen, Romney; Wortmann, Glenn

2012-06-01

Gram-negative bacilli resistance to all antibiotics, except for colistimethate sodium (CMS), is an emerging healthcare concern. Incorporating CMS into orthopedic cement to treat bone and soft-tissue infections due to these bacteria is attractive, but the data regarding the elution of CMS from cement are conflicting. The in vitro analysis of the elution of CMS from polymethylmethacrylate (PMMA) and calcium phosphate (CP) cement beads is reported. PMMA and CP beads containing CMS were incubated in phosphate-buffered saline and the eluate sampled at sequential time points. The inhibition of the growth of a strain of Acinetobacter baumannii complex by the eluate was measured by disk diffusion and microbroth dilution assays, and the presence of CMS in the eluate was measured by mass spectroscopy. Bacterial growth was inhibited by the eluate from both PMMA and CP beads. Mass spectroscopy demonstrated greater elution of CMS from CP beads than PMMA beads. The dose of CMS in PMMA beads was limited by failure of bead integrity. CMS elutes from both CP and PMMA beads in amounts sufficient to inhibit bacterial growth in vitro. The clinical implications of these findings require further study.

Opportunistic Resource Usage in CMS

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

Kreuzer, Peter; Hufnagel, Dirk; Dykstra, D.

2014-01-01

CMS is using a tiered setup of dedicated computing resources provided by sites distributed over the world and organized in WLCG. These sites pledge resources to CMS and are preparing them especially for CMS to run the experiment's applications. But there are more resources available opportunistically both on the GRID and in local university and research clusters which can be used for CMS applications. We will present CMS' strategy to use opportunistic resources and prepare them dynamically to run CMS applications. CMS is able to run its applications on resources that can be reached through the GRID, through EC2 compliantmore » cloud interfaces. Even resources that can be used through ssh login nodes can be harnessed. All of these usage modes are integrated transparently into the GlideIn WMS submission infrastructure, which is the basis of CMS' opportunistic resource usage strategy. Technologies like Parrot to mount the software distribution via CVMFS and xrootd for access to data and simulation samples via the WAN are used and will be described. We will summarize the experience with opportunistic resource usage and give an outlook for the restart of LHC data taking in 2015.« less

42 CFR 423.890 - Appeals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... sponsor or by CMS before notice of the reconsidered determination is made. (6) Decision of the informal written reconsideration. CMS informs the sponsor of the decision orally or through electronic mail. CMS sends a written decision to the sponsor on the sponsor's request. (7) Effect of CMS informal written...

45 CFR 150.221 - Transition to State enforcement.

Code of Federal Regulations, 2010 CFR

2010-10-01

... ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement Processes for... State enforcement. (a) If CMS determines that a State for which it has assumed enforcement authority has... appropriate to return enforcement authority to the State, CMS will enter into discussions with State officials...

45 CFR 150.213 - Form and content of notice.

Code of Federal Regulations, 2010 CFR

2010-10-01

... CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement Processes for Determining... consequence of a State's failure to substantially enforce HIPAA requirements is that CMS enforces them. (d... information that the State wishes CMS to consider in making the preliminary determination described in § 150...

45 CFR 150.321 - Determining the amount of penalty-aggravating circumstances.

Code of Federal Regulations, 2010 CFR

2010-10-01

... RELATING TO HEALTH CARE ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement..., if there are substantial or several aggravating circumstances, CMS sets the aggregate amount of the.... CMS considers the following circumstances to be aggravating circumstances: (a) The frequency of...

45 CFR 150.343 - Notice of proposed penalty.

Code of Federal Regulations, 2010 CFR

2010-10-01

... CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement With Respect to Issuers and Non-Federal Governmental Plans-Civil Money Penalties § 150.343 Notice of proposed penalty. If CMS... penalty. The notice includes the following: (a) A description of the HIPAA requirements that CMS has...

Commissioning the CERN IT Agile Infrastructure with experiment workloads

NASA Astrophysics Data System (ADS)

Medrano Llamas, Ramón; Harald Barreiro Megino, Fernando; Kucharczyk, Katarzyna; Kamil Denis, Marek; Cinquilli, Mattia

2014-06-01

In order to ease the management of their infrastructure, most of the WLCG sites are adopting cloud based strategies. In the case of CERN, the Tier 0 of the WLCG, is completely restructuring the resource and configuration management of their computing center under the codename Agile Infrastructure. Its goal is to manage 15,000 Virtual Machines by means of an OpenStack middleware in order to unify all the resources in CERN's two datacenters: the one placed in Meyrin and the new on in Wigner, Hungary. During the commissioning of this infrastructure, CERN IT is offering an attractive amount of computing resources to the experiments (800 cores for ATLAS and CMS) through a private cloud interface. ATLAS and CMS have joined forces to exploit them by running stress tests and simulation workloads since November 2012. This work will describe the experience of the first deployments of the current experiment workloads on the CERN private cloud testbed. The paper is organized as follows: the first section will explain the integration of the experiment workload management systems (WMS) with the cloud resources. The second section will revisit the performance and stress testing performed with HammerCloud in order to evaluate and compare the suitability for the experiment workloads. The third section will go deeper into the dynamic provisioning techniques, such as the use of the cloud APIs directly by the WMS. The paper finishes with a review of the conclusions and the challenges ahead.

HammerCloud: A Stress Testing System for Distributed Analysis

NASA Astrophysics Data System (ADS)

van der Ster, Daniel C.; Elmsheuser, Johannes; Úbeda García, Mario; Paladin, Massimo

2011-12-01

Distributed analysis of LHC data is an I/O-intensive activity which places large demands on the internal network, storage, and local disks at remote computing facilities. Commissioning and maintaining a site to provide an efficient distributed analysis service is therefore a challenge which can be aided by tools to help evaluate a variety of infrastructure designs and configurations. HammerCloud is one such tool; it is a stress testing service which is used by central operations teams, regional coordinators, and local site admins to (a) submit arbitrary number of analysis jobs to a number of sites, (b) maintain at a steady-state a predefined number of jobs running at the sites under test, (c) produce web-based reports summarizing the efficiency and performance of the sites under test, and (d) present a web-interface for historical test results to both evaluate progress and compare sites. HammerCloud was built around the distributed analysis framework Ganga, exploiting its API for grid job management. HammerCloud has been employed by the ATLAS experiment for continuous testing of many sites worldwide, and also during large scale computing challenges such as STEP'09 and UAT'09, where the scale of the tests exceeded 10,000 concurrently running and 1,000,000 total jobs over multi-day periods. In addition, HammerCloud is being adopted by the CMS experiment; the plugin structure of HammerCloud allows the execution of CMS jobs using their official tool (CRAB).

Cardiometabolic syndrome and its association with education, smoking, diet, physical activity, and social support: findings from the Pennsylvania 2007 BRFSS Survey.

PubMed

Liu, Longjian; Núñez, Ana E

2010-07-01

The authors aimed to examine the prevalence of cardiometabolic syndrome (CMS) and its association with education, smoking, diet, physical activity, and social support among white, black, and Hispanic adults using data from the 2007 Pennsylvania Behavior Risk Factor Surveillance System (BRFSS) survey, the largest population-based survey in the state. The authors examined associations between CMS and associated factors cross-sectionally using univariate and multivariate methods. The study included a representative sample of 12,629 noninstitutionalized Pennsylvanians aged > or =18. Components of CMS included obesity, hypercholesterolemia, angina (as a surrogate for decreased high-density lipoprotein), prehypertension or hypertension, and prediabetes or diabetes. CMS was identified as the presence of > or =3 CMS components. The results show that the prevalence of CMS was 20.48% in blacks, followed by Hispanics (19.14%) and whites (12.26%), (P<.01). Multivariate logistic regression analyses indicated that physical inactivity, lower educational levels, smoking, daily consumption of vegetables and/or fruits <3 servings, and lack of social support were significantly associated with the odds of having CMS. In conclusion, black and Hispanic adults have a significantly higher prevalence of CMS than whites. The significant association between CMS and risk factors provides new insights in the direction of health promotion to prevent and control CMS in those who are at high risk.

The mitochondrial gene orfH79 plays a critical role in impairing both male gametophyte development and root growth in CMS-Honglian rice.

PubMed

Peng, Xiaojue; Wang, Kun; Hu, Chaofeng; Zhu, Youlin; Wang, Ting; Yang, Jing; Tong, Jiping; Li, Shaoqing; Zhu, Yingguo

2010-06-24

Cytoplasmic male sterility (CMS) has often been associated with abnormal mitochondrial open reading frames. The mitochondrial gene orfH79 is a candidate gene for causing the CMS trait in CMS-Honglian (CMS-HL) rice. However, whether the orfH79 expression can actually induce CMS in rice remains unclear. Western blot analysis revealed that the ORFH79 protein is mainly present in mitochondria of CMS-HL rice and is absent in the fertile line. To investigate the function of ORFH79 protein in mitochondria, this gene was fused to a mitochondrial transit peptide sequence and used to transform wild type rice, where its expression induced the gametophytic male sterile phenotype. In addition, excessive accumulation of reactive oxygen species (ROS) in the microspore, a reduced ATP/ADP ratio, decreased mitochondrial membrane potential and a lower respiration rate in the transgenic plants were found to be similar to those in CMS-HL rice. Moreover, retarded growth of primary and lateral roots accompanied by abnormal accumulation of ROS in the root tip was observed in both transgenic rice and CMS-HL rice (YTA). These results suggest that the expression of orfH79 in mitochondria impairs mitochondrial function, which affects the development of both male gametophytes and the roots of CMS-HL rice.

CDX2 prognostic value in stage II/III resected colon cancer is related to CMS classification.

PubMed

Pilati, C; Taieb, J; Balogoun, R; Marisa, L; de Reyniès, A; Laurent-Puig, P

2017-05-01

Caudal-type homeobox transcription factor 2 (CDX2) is involved in colon cancer (CC) oncogenesis and has been proposed as a prognostic biomarker in patients with stage II or III CC. We analyzed CDX2 expression in a series of 469 CC typed for the new international consensus molecular subtype (CMS) classification, and we confirmed results in a series of 90 CC. Here, we show that lack of CDX2 expression is only present in the mesenchymal subgroup (CMS4) and in MSI-immune tumors (CMS1) and not in CMS2 and CMS3 colon cancer. Although CDX2 expression was a globally independent prognostic factor, loss of CDX2 expression is not associated with a worse prognosis in the CMS1 group, but is highly prognostic in CMS4 patients for both relapse free and overall survival. Similarly, lack of CDX2 expression was a bad prognostic factor in MSS patients, but not in MSI. Our work suggests that combination of the consensual CMS classification and lack of CDX2 expression could be a useful marker to identify CMS4/CDX2-negative patients with a very poor prognosis. © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease

PubMed Central

Azad, Priti; Zhao, Huiwen W.; Ronen, Roy; Zhou, Dan; Poulsen, Orit; Hsiao, Yu Hsin; Bafna, Vineet

2016-01-01

In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology. PMID:27821551

Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease.

PubMed

Azad, Priti; Zhao, Huiwen W; Cabrales, Pedro J; Ronen, Roy; Zhou, Dan; Poulsen, Orit; Appenzeller, Otto; Hsiao, Yu Hsin; Bafna, Vineet; Haddad, Gabriel G

2016-11-14

In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge's disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology. © 2016 Azad et al.

High Energy Physics Research with the CMS Experiment at CERN

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

Hanson, Gail G.

2013-05-31

The highlight of our last budget period, June 1, 2010, to May 31, 2013, was the discovery of the Higgs boson by the ATLAS and CMS experiments at the CERN Large Hadron Collider (LHC), announced on July 4, 2012, and for which François Englert and Peter Higgs were awarded the 2013 Nobel Prize in Physics on October 8, 2013. The Higgs boson was postulated in 1964 to explain how elementary particles obtain mass and was the missing piece of the Standard Model. However, the Standard Model does not describe everything that we know. There are many unanswered questions, such asmore » how can the Higgs boson have the mass that we have observed, are there more Higgs bosons, why is there more matter than antimatter, and what is the invisible dark matter, which constitutes about 85% of the matter in the universe. Our group played a significant role in the discovery of the Higgs boson and in subsequent analyses. We also carried out searches for new physics, in ways that could help elucidate some of the remaining questions. Our role in the CMS detector focused on the Tracker, a silicon strip outer tracker and pixel inner tracker.« less

Unintended Consequences in Cancer Care Delivery Created by the Medicare Part B Proposal: Is the Clinical Rationale for the Experiment Flawed?

PubMed

Gordan, Lucio; Grogg, Amy; Blazer, Marlo; Fortner, Barry

2017-02-01

Medicare currently enrolls ≥ 45 million adults, and by 2030 this is projected to increase to ≥ 80 million beneficiaries. With this growth, the Centers for Medicare & Medicaid Services (CMS) issued a proposal, the Medicare Part B Drug Payment Model, to shrink drug expenditures, a major contributor to overall health care costs. For this to not adversely affect patient outcomes, lower-cost alternative medications with equivalent efficacy and no increased toxicity must be available. This is often not true in the treatment of cancer. Herein, we examine the flaws in the rationale of the CMS and the potential unintended consequences of this experiment. We identified the top three oncology expenditures (rituximab, bevacizumab, and trastuzumab) and their vetted alternatives (per the National Comprehensive Cancer Network guidelines) to ascertain whether lower-cost equivalent alternatives are available. Drug cost was based on April 2016 average sale price. We explored both efficacy of the agents and, when applicable, toxicity to compare alternatives to these high-dollar medications. For the largest Medicare oncology drug expenditures, there is not a lower-cost option with equal efficacy for their primary indications. Without lower-cost alternatives, the unintended consequence of this CMS experiment may include curtailing access to care or an increase in patient/program costs. The CMS proposal, by simply lowering reimbursement for drugs, does not acknowledge the value of these agents and could unintentionally reduce quality of care. Alternative approaches to value-based care, such as the Oncology Care Model and similar frameworks, should be explored.

Enabling opportunistic resources for CMS Computing Operations

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

Hufnagel, Dirk

With the increased pressure on computing brought by the higher energy and luminosity from the LHC in Run 2, CMS Computing Operations expects to require the ability to utilize opportunistic resources resources not owned by, or a priori configured for CMS to meet peak demands. In addition to our dedicated resources we look to add computing resources from non CMS grids, cloud resources, and national supercomputing centers. CMS uses the HTCondor/glideinWMS job submission infrastructure for all its batch processing, so such resources will need to be transparently integrated into its glideinWMS pool. Bosco and parrot wrappers are used to enablemore » access and bring the CMS environment into these non CMS resources. Finally, we describe our strategy to supplement our native capabilities with opportunistic resources and our experience so far using them.« less

Enabling opportunistic resources for CMS Computing Operations

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

Hufnagel, Dick

With the increased pressure on computing brought by the higher energy and luminosity from the LHC in Run 2, CMS Computing Operations expects to require the ability to utilize “opportunistic” resources — resources not owned by, or a priori configured for CMS — to meet peak demands. In addition to our dedicated resources we look to add computing resources from non CMS grids, cloud resources, and national supercomputing centers. CMS uses the HTCondor/glideinWMS job submission infrastructure for all its batch processing, so such resources will need to be transparently integrated into its glideinWMS pool. Bosco and parrot wrappers are usedmore » to enable access and bring the CMS environment into these non CMS resources. Here we describe our strategy to supplement our native capabilities with opportunistic resources and our experience so far using them.« less

Enabling opportunistic resources for CMS Computing Operations

DOE PAGES

Hufnagel, Dirk

2015-12-23

With the increased pressure on computing brought by the higher energy and luminosity from the LHC in Run 2, CMS Computing Operations expects to require the ability to utilize opportunistic resources resources not owned by, or a priori configured for CMS to meet peak demands. In addition to our dedicated resources we look to add computing resources from non CMS grids, cloud resources, and national supercomputing centers. CMS uses the HTCondor/glideinWMS job submission infrastructure for all its batch processing, so such resources will need to be transparently integrated into its glideinWMS pool. Bosco and parrot wrappers are used to enablemore » access and bring the CMS environment into these non CMS resources. Finally, we describe our strategy to supplement our native capabilities with opportunistic resources and our experience so far using them.« less

Standard duplex criteria overestimate the degree of stenosis after eversion carotid endarterectomy.

PubMed

Benzing, Travis; Wilhoit, Cameron; Wright, Sharee; McCann, P Aaron; Lessner, Susan; Brothers, Thomas E

2015-06-01

The eversion technique for carotid endarterectomy (eCEA) offers an alternative to longitudinal arteriotomy and patch closure (pCEA) for open carotid revascularization. In some reports, eCEA has been associated with a higher rate of >50% restenosis of the internal carotid when it is defined as peak systolic velocity (PSV) >125 cm/s by duplex imaging. Because the conformation of the carotid bifurcation may differ after eCEA compared with native carotid arteries, it was hypothesized that standard duplex criteria might not accurately reflect the presence of restenosis after eCEA. In a case-control study, the outcomes of all patients undergoing carotid endarterectomy by one surgeon during the last 10 years were analyzed retrospectively, with a primary end point of PSV >125 cm/s. Duplex flow velocities were compared with luminal diameter measurements for any carotid computed tomography arteriography or magnetic resonance angiography study obtained within 2 months of duplex imaging, with the degree of stenosis calculated by the methodology used in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) as well as cross-sectional area (CSA) reduction. Simulations were generated and analyzed by computational model simulations of the eCEA and pCEA arteries. Eversion and longitudinal arteriotomy with patch techniques were used in 118 and 177 carotid arteries, respectively. Duplex follow-up was available in 90 eCEA arteries at a median of 16 (range, 2-136) months and in 150 pCEA arteries at a median of 41 (range, 3-115) months postoperatively. PSV >125 cm/s was present at some time during follow-up in 31% of eCEA and pCEA carotid arteries, each, and in the most recent duplex examination in 7% after eCEA and 21% after pCEA (P = .003), with no eCEA and two pCEA arteries occluding completely during follow-up (P = .29). In 19 carotid arteries with PSV >125 cm/s after angle correction (median, 160 cm/s; interquartile range, 146-432 cm/s) after eCEA that were subsequently examined by axial imaging, the mean percentage stenosis was 8% ± 11% by NASCET, 11% ± 5% by ECST, and 20% ± 9% by CSA criteria. For eight pCEA arteries with PSV >125 cm/s (median velocity, 148 cm/s; interquartile range, 139-242 cm/s), the corresponding NASCET, ECST, and CSA stenoses were 8% ± 35%, 26% ± 32%, and 25% ± 33%, respectively. NASCET internal carotid diameter reduction of at least 50% was noted by axial imaging after two of the eight pCEAs, and the PSV exceeded 200 cm/s in each case. The presence of hemodynamically significant carotid artery restenosis may be overestimated by standard duplex criteria after eCEA and perhaps after pCEA. Insufficient information currently exists to determine what PSV does correspond to hemodynamically significant restenosis. Published by Elsevier Inc.

78 FR 56710 - Agency Information Collection Activities: Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

... the following transmissions: OMB, Office of Information and Regulatory Affairs Attention: CMS Desk... Identifiers: CMS-10199 and CMS-10266] Agency Information Collection Activities: Submission for OMB Review... an opportunity for the public to comment on CMS' intention to collect information from the public...

42 CFR 422.510 - Termination of contract by CMS.

Code of Federal Regulations, 2012 CFR

2012-10-01

...: (1) Termination of contract by CMS. (i) CMS notifies the MA organization in writing 90 days before... organization; or (B) The MA organization experiences financial difficulties so severe that its ability to make...) of this section. (ii) CMS notifies the MA organization in writing that its contract will be...

42 CFR 422.510 - Termination of contract by CMS.

Code of Federal Regulations, 2011 CFR

2011-10-01

...: (1) Termination of contract by CMS. (i) CMS notifies the MA organization in writing 90 days before... organization; or (B) The MA organization experiences financial difficulties so severe that its ability to make...) of this section. (ii) CMS notifies the MA organization in writing that its contract will be...

42 CFR 422.510 - Termination of contract by CMS.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Termination of contract by CMS. (i) CMS notifies the MA organization in writing 90 days before the intended...; or (B) The MA organization experiences financial difficulties so severe that its ability to make...) of this section. (ii) CMS notifies the MA organization in writing that its contract will be...

42 CFR 401.108 - CMS rulings.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false CMS rulings. 401.108 Section 401.108 Public Health... GENERAL ADMINISTRATIVE REQUIREMENTS Confidentiality and Disclosure § 401.108 CMS rulings. (a) After... regulations, but which has been adopted by CMS as having precedent, may be published in the Federal Register...

45 CFR 150.319 - Determining the amount of the penalty-mitigating circumstances.

Code of Federal Regulations, 2010 CFR

2010-10-01

... RELATING TO HEALTH CARE ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement... guidelines for taking into account the factors listed in § 150.317, CMS considers the following: (a) Record... noncompliance without notice from CMS and voluntarily reported that noncompliance, provided that the responsible...

42 CFR 401.625 - Effect of CMS claims collection decisions on appeals.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Effect of CMS claims collection decisions on... Compromise § 401.625 Effect of CMS claims collection decisions on appeals. Any action taken under this..., is not an initial determination for purposes of CMS appeal procedures. ...

42 CFR 403.248 - Administrative review of CMS determinations.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false Administrative review of CMS determinations. 403... Certification Program: General Provisions § 403.248 Administrative review of CMS determinations. (a) This section provides for administrative review if CMS determines— (1) Not to certify a policy; or (2) That a...

78 FR 67149 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-08

... Identifier: CMS-R-216] Agency Information Collection Activities: Proposed Collection; Comment Request AGENCY... & Medicaid Services (CMS) is announcing an opportunity for the public to comment on CMS' intention to collect... accepting comments. 2. By regular mail. You may mail written comments to the following address: CMS, Office...

42 CFR 493.571 - Disclosure of accreditation, State and CMS validation inspection results.

Code of Federal Regulations, 2013 CFR

2013-10-01

... validation inspection results. 493.571 Section 493.571 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Program § 493.571 Disclosure of accreditation, State and CMS validation inspection results. (a... licensure program, in accordance with State law. (c) CMS validation inspection results. CMS may disclose the...

42 CFR 493.571 - Disclosure of accreditation, State and CMS validation inspection results.

Code of Federal Regulations, 2011 CFR

2011-10-01

... validation inspection results. 493.571 Section 493.571 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Program § 493.571 Disclosure of accreditation, State and CMS validation inspection results. (a... licensure program, in accordance with State law. (c) CMS validation inspection results. CMS may disclose the...

42 CFR 493.571 - Disclosure of accreditation, State and CMS validation inspection results.

Code of Federal Regulations, 2012 CFR

2012-10-01

... validation inspection results. 493.571 Section 493.571 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Program § 493.571 Disclosure of accreditation, State and CMS validation inspection results. (a... licensure program, in accordance with State law. (c) CMS validation inspection results. CMS may disclose the...

42 CFR 493.571 - Disclosure of accreditation, State and CMS validation inspection results.

Code of Federal Regulations, 2010 CFR

2010-10-01

... validation inspection results. 493.571 Section 493.571 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Program § 493.571 Disclosure of accreditation, State and CMS validation inspection results. (a... licensure program, in accordance with State law. (c) CMS validation inspection results. CMS may disclose the...

42 CFR 493.571 - Disclosure of accreditation, State and CMS validation inspection results.

Code of Federal Regulations, 2014 CFR

2014-10-01

... validation inspection results. 493.571 Section 493.571 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... Program § 493.571 Disclosure of accreditation, State and CMS validation inspection results. (a... licensure program, in accordance with State law. (c) CMS validation inspection results. CMS may disclose the...

42 CFR § 512.900 - Termination of an episode payment model.

Code of Federal Regulations, 2010 CFR

2017-10-01

... 42 Public Health 5 2017-10-01 2017-10-01 false Termination of an episode payment model. § 512.900... SERVICES (CONTINUED) HEALTH CARE INFRASTRUCTURE AND MODEL PROGRAMS EPISODE PAYMENT MODEL Model Termination § 512.900 Termination of an episode payment model. CMS may terminate any EPM for reasons including but...

Registration of cytoplasmic male-sterile oilseed sunflower genetic stocks CMS GIG2 and CMS GIG2-RV, and fertility restoration lines RF GIG2-MAX 1631 and RF GIG2-MAX 1631-RV

USDA-ARS?s Scientific Manuscript database

Two cytoplasmic male-sterile (CMS) oilseed sunflower (Helianthus annuus L.) genetic stocks, CMS GIG2 (Reg. No. xxx, PI xxxx), and CMS GIG2-RV (Reg. No. xxx, PI xxxx), and corresponding fertility restoration lines RF GIG2-MAX 1631 (Reg. No. xxx, PI xxxx) and RF GIG2-MAX 1631-RV (Reg. No. xxx, PI xxx...

Numerical modeling of the autumnal thermal bar

NASA Astrophysics Data System (ADS)

Tsydenov, Bair O.

2018-03-01

The autumnal riverine thermal bar of Kamloops Lake has been simulated using atmospheric data from December 1, 2015, to January 4, 2016. The nonhydrostatic 2.5D mathematical model developed takes into account the diurnal variability of the heat fluxes and wind on the lake surface. The average values for shortwave and longwave radiation and latent and sensible heat fluxes were 19.7 W/m2, - 95.9 W/m2, - 11.8 W/m2, and - 32.0 W/m2 respectively. Analysis of the wind regime data showed prevailing easterly winds and maximum speed of 11 m/s on the 8th and 19th days. Numerical experiments with different boundary conditions at the lake surface were conducted to evaluate effects of variable heat flux and wind stress. The results of modeling demonstrated that the variable heat flux affects the process of thermal bar evolution, especially during the lengthy night cooling. However, the wind had the greatest impact on the behavior of the autumnal thermal bar: The easterly winds contributed to an earlier appearance of the thermal bar, but the strong winds generating the intensive circulations (the velocity of the upper lake flow increased to 6 cm/s) may destroy the thermal bar front.

Evaluation of NASA's Carbon Monitoring System (CMS) Flux Pilot: Terrestrial CO2 Fluxes

NASA Astrophysics Data System (ADS)

Fisher, J. B.; Polhamus, A.; Bowman, K. W.; Collatz, G. J.; Potter, C. S.; Lee, M.; Liu, J.; Jung, M.; Reichstein, M.

2011-12-01

NASA's Carbon Monitoring System (CMS) flux pilot project combines NASA's Earth System models in land, ocean and atmosphere to track surface CO2 fluxes. The system is constrained by atmospheric measurements of XCO2 from the Japanese GOSAT satellite, giving a "big picture" view of total CO2 in Earth's atmosphere. Combining two land models (CASA-Ames and CASA-GFED), two ocean models (ECCO2 and NOBM) and two atmospheric chemistry and inversion models (GEOS-5 and GEOS-Chem), the system brings together the stand-alone component models of the Earth System, all of which are run diagnostically constrained by a multitude of other remotely sensed data. Here, we evaluate the biospheric land surface CO2 fluxes (i.e., net ecosystem exchange, NEE) as estimated from the atmospheric flux inversion. We compare against the prior bottom-up estimates (e.g., the CASA models) as well. Our evaluation dataset is the independently derived global wall-to-wall MPI-BGC product, which uses a machine learning algorithm and model tree ensemble to "scale-up" a network of in situ CO2 flux measurements from 253 globally-distributed sites in the FLUXNET network. The measurements are based on the eddy covariance method, which uses observations of co-varying fluxes of CO2 (and water and energy) from instruments on towers extending above ecosystem canopies; the towers integrate fluxes over large spatial areas (~1 km2). We present global maps of CO2 fluxes and differences between products, summaries of fluxes by TRANSCOM region, country, latitude, and biome type, and assess the time series, including timing of minimum and maximum fluxes. This evaluation shows both where the CMS is performing well, and where improvements should be directed in further work.

CMS Centres Worldwide - a New Collaborative Infrastructure

NASA Astrophysics Data System (ADS)

Taylor, Lucas

2011-12-01

The CMS Experiment at the LHC has established a network of more than fifty inter-connected "CMS Centres" at CERN and in institutes in the Americas, Asia, Australasia, and Europe. These facilities are used by people doing CMS detector and computing grid operations, remote shifts, data quality monitoring and analysis, as well as education and outreach. We present the computing, software, and collaborative tools and videoconferencing systems. These include permanently running "telepresence" video links (hardware-based H.323, EVO and Vidyo), Webcasts, and generic Web tools such as CMS-TV for broadcasting live monitoring and outreach information. Being Web-based and experiment-independent, these systems could easily be extended to other organizations. We describe the experiences of using CMS Centres Worldwide in the CMS data-taking operations as well as for major media events with several hundred TV channels, radio stations, and many more press journalists simultaneously around the world.

Relations between the Test of Variables of Attention (TOVA) and the Children's Memory Scale (CMS).

PubMed

Riccio, Cynthia A; Garland, Beth H; Cohen, Morris J

2007-09-01

There is considerable overlap in the constructs of attention and memory. The objective of this study was to examine the relationship between the Test of Variables of Attention (TOVA), a measure of attention, to components of memory and learning as measured by the Children's Memory Scale (CMS). Participants (N = 105) were consecutive referrals to an out-patient facility, generally for learning or behavior problems, who were administered both the TOVA and the CMS. Significant correlations were found between the omissions score on the TOVA and subscales of the CMS. TOVA variability and TOVA reaction time correlated significantly with subscales of the CMS as well. TOVA commission errors did not correlate significantly with any CMS Index. Although significant, the correlation coefficients indicate that the CMS and TOVA are measuring either different constructs or similar constructs but in different ways. As such, both measures may be useful in distinguishing memory from attention problems.

42 CFR 423.509 - Termination of contract by CMS.

Code of Federal Regulations, 2014 CFR

2014-10-01

...: (1) Termination of contract by CMS. (i) CMS notifies the Part D plan sponsor in writing at least 45... experiences financial difficulties so severe that its ability to make necessary health services available is...) CMS notifies the Part D plan sponsor in writing that its contract will be terminated on a date...

77 FR 70445 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-26

...-wide set of credentials and single sign-on capability for multiple CMS applications. In order to prove... and answers); 4. Provide the user a single sign-on, federated CMS EIDM ID and Password; 5... Terms of Service and CMS Privacy Statement on the Web. Form Numbers: CMS-10452 (OCN: 0938-New...

Increasing Honest Responding on Cognitive Distortions in Child Molesters: The Bogus Pipeline Procedure

ERIC Educational Resources Information Center

Gannon, Theresa A.

2006-01-01

Professionals conclude that child molesters (CMs) hold offense-supportive beliefs (or cognitive distortions) from CMs' questionnaire responses. Because questionnaires are easily faked, we asked 32 CMs to complete a cognitive distortion scale under standard conditions (Time 1). A week later (Time 2), the same CMs completed the scale again. This…

42 CFR 417.801 - Agreements between CMS and health care prepayment plans.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 3 2010-10-01 2010-10-01 false Agreements between CMS and health care prepayment... CMS and health care prepayment plans. (a) General requirement. (1) In order to participate and receive... written agreement with CMS. (2) An existing group practice prepayment plan (GPPP) that continues as an...

45 CFR 150.347 - Failure to request a hearing.

Code of Federal Regulations, 2010 CFR

2010-10-01

... CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement With Respect to Issuers and....343, CMS may assess the proposed civil money penalty, a less severe penalty, or a more severe penalty. CMS notifies the responsible entity in writing of any penalty that has been assessed and of the means...