Suicides, homicides, accidents, and other external causes of death among blacks and whites in the Southern Community Cohort Study.

PubMed

Sonderman, Jennifer S; Munro, Heather M; Blot, William J; Tarone, Robert E; McLaughlin, Joseph K

2014-01-01

Prior studies of risk factors associated with external causes of death have been limited in the number of covariates investigated and external causes examined. Herein, associations between numerous demographic, lifestyle, and health-related factors and the major causes of external mortality, such as suicide, homicide, and accident, were assessed prospectively among 73,422 black and white participants in the Southern Community Cohort Study (SCCS). Hazard ratios (HR) and 95% confidence intervals (CI) were calculated in multivariate regression analyses using the Cox proportional hazards model. Men compared with women (HR = 2.32; 95% CI: 1.87-2.89), current smokers (HR = 1.74; 95% CI: 1.40-2.17), and unemployed/never employed participants at the time of enrollment (HR = 1.67; 95% CI 1.38-2.02) had increased risk of dying from all external causes, with similarly elevated HRs for suicide, homicide, and accidental death among both blacks and whites. Blacks compared with whites had lower risk of accidental death (HR = 0.46; 95% CI: 0.38-0.57) and suicide (HR = 0.55; 95% CI: 0.31-0.99). Blacks and whites in the SCCS had comparable risks of homicide death (HR = 1.05; 95% CI: 0.63-1.76); however, whites in the SCCS had unusually high homicide rates compared with all whites who were resident in the 12 SCCS states, while black SCCS participants had homicide rates similar to those of all blacks residing in the SCCS states. Depression was the strongest risk factor for suicide, while being married was protective against death from homicide in both races. Being overweight/obese at enrollment was associated with reduced risks in all external causes of death, and the number of comorbid conditions was a risk factor for iatrogenic deaths. Most risk factors identified in earlier studies of external causes of death were confirmed in the SCCS cohort, in spite of the low SES of SCCS participants. Results from other epidemiologic cohorts are needed to confirm the novel findings identified in this study.

Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample

PubMed Central

Kalvin, Carla B.; Bierman, Karen L.; Gatzke-Kopp, Lisa M.

2016-01-01

Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher-rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems. PMID:26943804

Decompression Sickness After Air Break in Prebreathe Described with a Survival Model

NASA Technical Reports Server (NTRS)

Conkin, J.; Pilmanis, A. A.

2010-01-01

Data from Brooks City-Base show the decompression sickness (DCS) and venous gas emboli (VGE) consequences of air breaks in a resting 100% O2 prebreathe (PB) prior to a hypobaric exposure. METHODS: DCS and VGE survival times from 95 controls for a 60 min PB prior to 2-hr or 4-hr exposures to 4.37 psia are statistically compared to 3 break in PB conditions: a 10 min (n=40), 20 min (n=40), or 60 min break (n=32) 30 min into the PB followed by 30 min of PB. Ascent rate was 1,524 meters / min and all exposures included light exercise and 4 min of VGE monitoring of heart chambers at 16 min intervals. DCS survival time for combined control and air breaks were described with an accelerated log logistic model where exponential N2 washin during air break was described with a 10 min half-time and washout during PB with a 60 min half-time. RESULTS: There was no difference in VGE or DCS survival times among 3 different air breaks, or when air breaks were compared to control VGE times. However, 10, 20, and 60 min air breaks had significantly earlier survival times compared to control DCS times, certainly early in the exposures. CONCLUSION: Air breaks of 10, 20, and 60 min after 30 min of a 60 min PB reduced DCS survival time. The survival model combined discrete comparisons into a global description mechanistically linked to asymmetrical N2 washin and washout kinetics based on inspired pN2. Our unvalidated regression is used to compute additional PB time needed to compensate for an air break in PB within the range of tested conditions.

Emotional Reactivity, Behavior Problems, and Social Adjustment at School Entry in a High-risk Sample.

PubMed

Kalvin, Carla B; Bierman, Karen L; Gatzke-Kopp, Lisa M

2016-11-01

Prior research suggests that heightened emotional reactivity to emotionally distressing stimuli may be associated with elevated internalizing and externalizing behaviors, and contribute to impaired social functioning. These links were explored in a sample of 169 economically-disadvantaged kindergarteners (66 % male; 68 % African American, 22 % Hispanic, 10 % Caucasian) oversampled for elevated aggression. Physiological measures of emotional reactivity (respiratory sinus arrhythmia [RSA], heart rate [HR], and cardiac pre-ejection period [PEP]) were collected, and teachers and peers provided ratings of externalizing and internalizing behavior, prosocial competence, and peer rejection. RSA withdrawal, HR reactivity, and PEP shortening (indicating increased arousal) were correlated with reduced prosocial competence, and RSA withdrawal and HR reactivity were correlated with elevated internalizing problems. HR reactivity was also correlated with elevated externalizing problems and peer rejection. Linear regressions controlling for age, sex, race, verbal proficiency, and resting physiology showed that HR reactivity explained unique variance in both teacher-rated prosocial competence and peer rejection, and contributed indirectly to these outcomes through pathways mediated by internalizing and externalizing problems. A trend also emerged for the unique contribution of PEP reactivity to peer-rated prosocial competence. These findings support the contribution of emotional reactivity to behavior problems and social adjustment among children living in disadvantaged urban contexts, and further suggest that elevated reactivity may confer risk for social difficulties in ways that overlap only partially with internalizing and externalizing behavior problems.

Presynaptic Filament Dynamics in Homologous Recombination and DNA Repair

PubMed Central

Liu, Jie; Ehmsen, Kirk T.; Heyer, Wolf-Dietrich; Morrical, Scott W.

2014-01-01

Homologous Recombination (HR) is an essential genome stability mechanism used for high-fidelity repair of DNA double-strand breaks and for the recovery of stalled or collapsed DNA replication forks. The crucial homology search and DNA strand exchange steps of HR are catalyzed by presynaptic filaments—helical filaments of a recombinase enzyme bound to single-stranded DNA. Presynaptic filaments are fundamentally dynamic structures, the assembly, catalytic turnover, and disassembly of which must be closely coordinated with other elements of the DNA recombination, repair, and replication machinery in order for genome maintenance functions to be effective. Here, we review the major dynamic elements controlling the assembly, activity, and disassembly of presynaptic filaments: some intrinsic such as recombinase ATP binding and hydrolytic activities, others extrinsic such as ssDNA-binding proteins, mediator proteins, and DNA motor proteins. We examine dynamic behavior on multiple levels, including atomic- and filament-level structural changes associated with ATP binding and hydrolysis as evidenced in crystal structures, as well as subunit binding and dissociation events driven by intrinsic and extrinsic factors. We examine the biochemical properties of recombination proteins from four model systems (T4 phage, E. coli, S. cerevisiae, and H. sapiens), demonstrating how their properties are tailored for the context-specific requirements in these diverse species. We propose that the presynaptic filament has evolved to rely on multiple external factors for increased multi-level regulation of HR processes in genomes with greater structural and sequence complexity. PMID:21599536

Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase.

PubMed

Xia, Jun; Chen, Li-Tzu; Mei, Qian; Ma, Chien-Hui; Halliday, Jennifer A; Lin, Hsin-Yu; Magnan, David; Pribis, John P; Fitzgerald, Devon M; Hamilton, Holly M; Richters, Megan; Nehring, Ralf B; Shen, Xi; Li, Lei; Bates, David; Hastings, P J; Herman, Christophe; Jayaram, Makkuni; Rosenberg, Susan M

2016-11-01

DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution. However, the main kinds and sources of DNA damage repaired by HR in somatic cells and the roles of important HR proteins remain elusive. We present engineered proteins that trap, map, and quantify Holliday junctions (HJs), a central DNA intermediate in HR, based on catalytically deficient mutant RuvC protein of Escherichia coli . We use RuvCDefGFP (RDG) to map genomic footprints of HR at defined DNA breaks in E. coli and demonstrate genome-scale directionality of double-strand break (DSB) repair along the chromosome. Unexpectedly, most spontaneous HR-HJ foci are instigated, not by DSBs, but rather by single-stranded DNA damage generated by replication. We show that RecQ, the E. coli ortholog of five human cancer proteins, nonredundantly promotes HR-HJ formation in single cells and, in a novel junction-guardian role, also prevents apparent non-HR-HJs promoted by RecA overproduction. We propose that one or more human RecQ orthologs may act similarly in human cancers overexpressing the RecA ortholog RAD51 and find that cancer genome expression data implicate the orthologs BLM and RECQL4 in conjunction with EME1 and GEN1 as probable HJ reducers in such cancers. Our results support RecA-overproducing E. coli as a model of the many human tumors with up-regulated RAD51 and provide the first glimpses of important, previously elusive reaction intermediates in DNA replication and repair in single living cells.

Magnetic-field-induced DNA strand breaks in brain cells of the rat.

PubMed Central

Lai, Henry; Singh, Narendra P

2004-01-01

In previous research, we found that rats acutely (2 hr) exposed to a 60-Hz sinusoidal magnetic field at intensities of 0.1-0.5 millitesla (mT) showed increases in DNA single- and double-strand breaks in their brain cells. Further research showed that these effects could be blocked by pretreating the rats with the free radical scavengers melatonin and N-tert-butyl-alpha-phenylnitrone, suggesting the involvement of free radicals. In the present study, effects of magnetic field exposure on brain cell DNA in the rat were further investigated. Exposure to a 60-Hz magnetic field at 0.01 mT for 24 hr caused a significant increase in DNA single- and double-strand breaks. Prolonging the exposure to 48 hr caused a larger increase. This indicates that the effect is cumulative. In addition, treatment with Trolox (a vitamin E analog) or 7-nitroindazole (a nitric oxide synthase inhibitor) blocked magnetic-field-induced DNA strand breaks. These data further support a role of free radicals on the effects of magnetic fields. Treatment with the iron chelator deferiprone also blocked the effects of magnetic fields on brain cell DNA, suggesting the involvement of iron. Acute magnetic field exposure increased apoptosis and necrosis of brain cells in the rat. We hypothesize that exposure to a 60-Hz magnetic field initiates an iron-mediated process (e.g., the Fenton reaction) that increases free radical formation in brain cells, leading to DNA strand breaks and cell death. This hypothesis could have an important implication for the possible health effects associated with exposure to extremely low-frequency magnetic fields in the public and occupational environments. PMID:15121512

Chaotic dynamics and its analysis of Hindmarsh-Rose neurons by Shil’nikov approach

NASA Astrophysics Data System (ADS)

Wei, Wei; Zuo, Min

2015-08-01

In this paper, the relationship between external current stimulus and chaotic behaviors of a Hindmarsh-Rose (HR) neuron is considered. In order to find out the range of external current stimulus which will produce chaotic behaviors of an HR neuron, the Shil’nikov technique is employed. The Cardano formula is taken to obtain the threshold of the chaotic motion, and series solution to a differential equation is utilized to obtain the homoclinic orbit of HR neurons. This analysis establishes mathematically the value of external current input in generating chaotic motion of HR neurons by the Shil’nikov method. The numerical simulations are performed to support the theoretical results. Project supported by the Beijing Natural Science Foundation, China (Grant No. 4132005), the National Natural Science Foundation of China (Grant No. 61403006), the Importation and Development of High-Caliber Talents Project of Beijing Municipal Institutions, China (Grant No. YETP1449), and the Project of Scientific and Technological Innovation Platform, China (Grant No. PXM2015_014213_000063).

Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

PubMed Central

Bolderson, Emma; Tomimatsu, Nozomi; Richard, Derek J.; Boucher, Didier; Kumar, Rakesh; Pandita, Tej K.; Burma, Sandeep; Khanna, Kum Kum

2010-01-01

DNA double-strand break (DSB) repair via the homologous recombination pathway is a multi-stage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability. PMID:20019063

Holliday junction trap shows how cells use recombination and a junction-guardian role of RecQ helicase

PubMed Central

Xia, Jun; Chen, Li-Tzu; Mei, Qian; Ma, Chien-Hui; Halliday, Jennifer A.; Lin, Hsin-Yu; Magnan, David; Pribis, John P.; Fitzgerald, Devon M.; Hamilton, Holly M.; Richters, Megan; Nehring, Ralf B.; Shen, Xi; Li, Lei; Bates, David; Hastings, P. J.; Herman, Christophe; Jayaram, Makkuni; Rosenberg, Susan M.

2016-01-01

DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution. However, the main kinds and sources of DNA damage repaired by HR in somatic cells and the roles of important HR proteins remain elusive. We present engineered proteins that trap, map, and quantify Holliday junctions (HJs), a central DNA intermediate in HR, based on catalytically deficient mutant RuvC protein of Escherichia coli. We use RuvCDefGFP (RDG) to map genomic footprints of HR at defined DNA breaks in E. coli and demonstrate genome-scale directionality of double-strand break (DSB) repair along the chromosome. Unexpectedly, most spontaneous HR-HJ foci are instigated, not by DSBs, but rather by single-stranded DNA damage generated by replication. We show that RecQ, the E. coli ortholog of five human cancer proteins, nonredundantly promotes HR-HJ formation in single cells and, in a novel junction-guardian role, also prevents apparent non-HR–HJs promoted by RecA overproduction. We propose that one or more human RecQ orthologs may act similarly in human cancers overexpressing the RecA ortholog RAD51 and find that cancer genome expression data implicate the orthologs BLM and RECQL4 in conjunction with EME1 and GEN1 as probable HJ reducers in such cancers. Our results support RecA-overproducing E. coli as a model of the many human tumors with up-regulated RAD51 and provide the first glimpses of important, previously elusive reaction intermediates in DNA replication and repair in single living cells. PMID:28090586

REV7 counteracts DNA double-strand break resection and impacts PARP inhibition

PubMed Central

Xu, Guotai; Yuan, Jingsong; Mistrik, Martin; Bouwman, Peter; Bartkova, Jirina; Gogola, Ewa; Warmerdam, Daniël; Barazas, Marco; Jaspers, Janneke E.; Watanabe, Kenji; Pieterse, Mark; Kersbergen, Ariena; Sol, Wendy; Celie, Patrick H. N.; Schouten, Philip C.; van den Broek, Bram; Salman, Ahmed; Nieuwland, Marja; de Rink, Iris; de Ronde, Jorma; Jalink, Kees; Boulton, Simon J.; Chen, Junjie; van Gent, Dik C.; Bartek, Jiri; Jonkers, Jos; Borst, Piet; Rottenberg, Sven

2015-01-01

Summary Error-free repair of DNA double-strand breaks (DSB) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway1. In the absence of BRCA1-mediated HR, administration of PARP inhibitors induces synthetic lethality of tumor cells of patients with breast or ovarian cancers2,3. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration4. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases5. In particular, little is known about BRCA1-independent restoration of HR. Here, we show that loss of REV7 (also known as MAD2L2) re-establishes CtIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and appears to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance6. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining (NHEJ) during immunoglobulin class switch recombination. Our results reveal an unexpected critical function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells. PMID:25799992

Mediation of Sensation Seeking and Behavioral Inhibition on the Relationship between Heart Rate and Antisocial Behavior: The TRAILS Study

ERIC Educational Resources Information Center

Sijtsema, Jelle J.; Veenstra, Rene; Lindenberg, Siegwart; van Roon, Arie M.; Verhulst, Frank C.; Ormel, Johan; Riese, Harriette

2010-01-01

Objective: Why is low resting heart rate (HR) associated with antisocial behavior (ASB), i.e., aggression and rule breaking, in adolescence? Theory suggests that personality traits mediate this relationship but differently with age. In the present study this age-effect hypothesis is tested; we expected that the relationship between HR and…

Predicting survival of men with recurrent prostate cancer after radical prostatectomy.

PubMed

Dell'Oglio, Paolo; Suardi, Nazareno; Boorjian, Stephen A; Fossati, Nicola; Gandaglia, Giorgio; Tian, Zhe; Moschini, Marco; Capitanio, Umberto; Karakiewicz, Pierre I; Montorsi, Francesco; Karnes, R Jeffrey; Briganti, Alberto

2016-02-01

To develop and externally validate a novel nomogram aimed at predicting cancer-specific mortality (CSM) after biochemical recurrence (BCR) among prostate cancer (PCa) patients treated with radical prostatectomy (RP) with or without adjuvant external beam radiotherapy (aRT) and/or hormonal therapy (aHT). The development cohort included 689 consecutive PCa patients treated with RP between 1987 and 2011 with subsequent BCR, defined as two subsequent prostate-specific antigen values >0.2 ng/ml. Multivariable competing-risks regression analyses tested the predictors of CSM after BCR for the purpose of 5-year CSM nomogram development. Validation (2000 bootstrap resamples) was internally tested. External validation was performed into a population of 6734 PCa patients with BCR after treatment with RP at the Mayo Clinic from 1987 to 2011. The predictive accuracy (PA) was quantified using the receiver operating characteristic-derived area under the curve and the calibration plot method. The 5-year CSM-free survival rate was 83.6% (confidence interval [CI]: 79.6-87.2). In multivariable analyses, pathologic stage T3b or more (hazard ratio [HR]: 7.42; p = 0.008), pathologic Gleason score 8-10 (HR: 2.19; p = 0.003), lymph node invasion (HR: 3.57; p = 0.001), time to BCR (HR: 0.99; p = 0.03) and age at BCR (HR: 1.04; p = 0.04), were each significantly associated with the risk of CSM after BCR. The bootstrap-corrected PA was 87.4% (bootstrap 95% CI: 82.0-91.7%). External validation of our nomogram showed a good PA at 83.2%. We developed and externally validated the first nomogram predicting 5-year CSM applicable to contemporary patients with BCR after RP with or without adjuvant treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

Relationships Between Results Of An Internal And External Match Load Determining Method In Male, Singles Badminton Players.

PubMed

Abdullahi, Yahaya; Coetzee, Ben; Van den Berg, Linda

2017-07-03

The study purpose was to determine relationships between results of internal and external match load determining methods. Twenty-one players, who participated in selected badminton championships during the 2014/2015 season served as subjects. The heart rate (HR) values and GPS data of each player were obtained via a fix Polar HR Transmitter Belt and MinimaxX GPS device. Moderate significant Spearman's rank correlations were found between HR and absolute duration (r = 0.43 at a low intensity (LI) and 0.44 at a high intensity (HI)), distance covered (r = 0.42 at a HI) and player load (PL) (r = 0.44 at a HI). Results also revealed an opposite trend for external and internal measures of load as the average relative HR value was found to be the highest for the HI zone (54.1%) compared to the relative measures of external load where average values (1.29-9.89%) were the lowest for the HI zone. In conclusion, our findings show that results of an internal and external badminton match load determining method are more related to each other in the HI zone than other zones and that the strength of relationships depend on the duration of activities that are performed in especially LI and HI zones. Overall, trivial to moderate relationships between results of an internal and external match load determining method in male, singles badminton players reaffirm the conclusions of others that these constructs measure distinctly different demands and should therefore be measured concurrently to fully understand the true requirements of badminton match play.

The Effect of Augmenting OPTN Data With External Death Data on Calculating Patient Survival Rates After Organ Transplantation.

PubMed

Wilk, Amber R; Edwards, Leah B; Edwards, Erick B

2017-04-01

Although the Organ Procurement and Transplantation Network (OPTN) database contains a rich set of data on United States transplant recipients, follow-up data may be incomplete. It was of interest to determine if augmenting OPTN data with external death data altered patient survival estimates. Solitary kidney, liver, heart, and lung transplants performed between January 1, 2011, and January 31, 2013, were queried from the OPTN database. Unadjusted Kaplan-Meier 3-year patient survival rates were computed using 4 nonmutually exclusive augmented datasets: OPTN only, OPTN + verified external deaths, OPTN + verified + unverified external deaths (OPTN + all), and an additional source extending recipient survival time if no death was found in OPTN + all (OPTN + all [Assumed Alive]). Pairwise comparisons were made using unadjusted Cox Proportional Hazards analyses applying Bonferroni adjustments. Although differences in patient survival rates across data sources were small (≤1 percentage point), OPTN only data often yielded slightly higher patient survival rates than sources including external death data. No significant differences were found, including comparing OPTN + verified (hazard ratio [HR], 1.05; 95% confidence interval [95% CI], 1.00-1.10); P = 0.0356), OPTN + all (HR, 1.06; 95% CI, 1.01-1.11; P = 0.0243), and OPTN + all (Assumed Alive) (HR, 1.00; 95% CI, 0.96-1.05; P = 0.8587) versus OPTN only, or OPTN + verified (HR, 1.05; 95% CI, 1.00-1.10; P = 0.0511), and OPTN + all (HR, 1.05; 95% CI, 1.00-1.10; P = 0.0353) versus OPTN + all (Assumed Alive). Patient survival rates varied minimally with augmented data sources, although using external death data without extending the survival time of recipients not identified in these sources results in a biased estimate. It remains important for transplant centers to maintain contact with transplant recipients and obtain necessary follow-up information, because this information can improve the transplantation process for future recipients.

Bloom DNA Helicase Facilitates Homologous Recombination between Diverged Homologous Sequences*

PubMed Central

Kikuchi, Koji; Abdel-Aziz, H. Ismail; Taniguchi, Yoshihito; Yamazoe, Mitsuyoshi; Takeda, Shunichi; Hirota, Kouji

2009-01-01

Bloom syndrome caused by inactivation of the Bloom DNA helicase (Blm) is characterized by increases in the level of sister chromatid exchange, homologous recombination (HR) associated with cross-over. It is therefore believed that Blm works as an anti-recombinase. Meanwhile, in Drosophila, DmBlm is required specifically to promote the synthesis-dependent strand anneal (SDSA), a type of HR not associating with cross-over. However, conservation of Blm function in SDSA through higher eukaryotes has been a matter of debate. Here, we demonstrate the function of Blm in SDSA type HR in chicken DT40 B lymphocyte line, where Ig gene conversion diversifies the immunoglobulin V gene through intragenic HR between diverged homologous segments. This reaction is initiated by the activation-induced cytidine deaminase enzyme-mediated uracil formation at the V gene, which in turn converts into abasic site, presumably leading to a single strand gap. Ig gene conversion frequency was drastically reduced in BLM−/− cells. In addition, BLM−/− cells used limited donor segments harboring higher identity compared with other segments in Ig gene conversion event, suggesting that Blm can promote HR between diverged sequences. To further understand the role of Blm in HR between diverged homologous sequences, we measured the frequency of gene targeting induced by an I-SceI-endonuclease-mediated double-strand break. BLM−/− cells showed a severer defect in the gene targeting frequency as the number of heterologous sequences increased at the double-strand break site. Conversely, the overexpression of Blm, even an ATPase-defective mutant, strongly stimulated gene targeting. In summary, Blm promotes HR between diverged sequences through a novel ATPase-independent mechanism. PMID:19661064

Complete response in a patient with gynecological hidradenocarcinoma treated with exclusive external beam radiotherapy and brachytherapy: a case report.

PubMed

Giannelli, Flavio; Chiola, Ilaria; Belgioia, Liliana; Garelli, Stefania; Pastorino, Alice; Marcenaro, Michela; Mammoliti, Serafina; Costantini, Sergio; Bizzarri, Nicolò; Vellone, Valerio; Barra, Salvina; Corvò, Renzo

2017-12-01

Hidradenocarcinoma (HC) is a very rare disease. This case report illustrates a successful treatment of a 60-year-old woman with vulvo-vaginal localization of hidradenocarcinoma treated with external beam radiotherapy delivered by helical tomotherapy with a simultaneous integrated boost (SIB), followed by brachytherapy. External beam radiotherapy dose prescription was 50.4 Gy in 28 fractions, five fractions per week to whole pelvis (planning target volume 1 - PTV1), 60.2 Gy in 28 fractions to SIB1 (fundus of uterus and right inguinal node), and 58.8 Gy in 28 fractions to SIB2 (lower/middle third of vagina, paraurethral region and right inguinal lymph nodes). Brachytherapy dose prescription was 28 Gy in 4 fractions for cervix, fundus of uterus and upper third of vagina (HR-CTV1), and 22 Gy in 4 fractions to middle third of vagina and paraurethral region (HR-CTV2). D 90 for whole treatment was 91.9 Gy and 86.0 Gy for HR-CTV1 and HR-CTV2, respectively. Patient remained 12-months disease-free without treatment related side effects.

Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.

PubMed

Delabaere, Laetitia; Ertl, Henry A; Massey, Dashiell J; Hofley, Carolyn M; Sohail, Faraz; Bienenstock, Elisa J; Sebastian, Hans; Chiolo, Irene; LaRocque, Jeannine R

2017-04-01

Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8 days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

PubMed Central

Truong, Lan N.; Li, Yongjiang; Shi, Linda Z.; Hwang, Patty Yi-Hwa; He, Jing; Wang, Hailong; Razavian, Niema; Berns, Michael W.; Wu, Xiaohua

2013-01-01

Microhomology-mediated end joining (MMEJ) is a major pathway for Ku-independent alternative nonhomologous end joining, which contributes to chromosomal translocations and telomere fusions, but the underlying mechanism of MMEJ in mammalian cells is not well understood. In this study, we demonstrated that, distinct from Ku-dependent classical nonhomologous end joining, MMEJ—even with very limited end resection—requires cyclin-dependent kinase activities and increases significantly when cells enter S phase. We also showed that MMEJ shares the initial end resection step with homologous recombination (HR) by requiring meiotic recombination 11 homolog A (Mre11) nuclease activity, which is needed for subsequent recruitment of Bloom syndrome protein (BLM) and exonuclease 1 (Exo1) to DNA double-strand breaks (DSBs) to promote extended end resection and HR. MMEJ does not require S139-phosphorylated histone H2AX (γ-H2AX), suggesting that initial end resection likely occurs at DSB ends. Using a MMEJ and HR competition repair substrate, we demonstrated that MMEJ with short end resection is used in mammalian cells at the level of 10–20% of HR when both HR and nonhomologous end joining are available. Furthermore, MMEJ is used to repair DSBs generated at collapsed replication forks. These studies suggest that MMEJ not only is a backup repair pathway in mammalian cells, but also has important physiological roles in repairing DSBs to maintain cell viability, especially under genomic stress. PMID:23610439

NF-κB regulates DNA double-strand break repair in conjunction with BRCA1-CtIP complexes.

PubMed

Volcic, Meta; Karl, Sabine; Baumann, Bernd; Salles, Daniela; Daniel, Peter; Fulda, Simone; Wiesmüller, Lisa

2012-01-01

NF-κB is involved in immune responses, inflammation, oncogenesis, cell proliferation and apoptosis. Even though NF-κB can be activated by DNA damage via Ataxia telangiectasia-mutated (ATM) signalling, little was known about an involvement in DNA repair. In this work, we dissected distinct DNA double-strand break (DSB) repair mechanisms revealing a stimulatory role of NF-κB in homologous recombination (HR). This effect was independent of chromatin context, cell cycle distribution or cross-talk with p53. It was not mediated by the transcriptional NF-κB targets Bcl2, BAX or Ku70, known for their dual roles in apoptosis and DSB repair. A contribution by Bcl-xL was abrogated when caspases were inhibited. Notably, HR induction by NF-κB required the targets ATM and BRCA2. Additionally, we provide evidence that NF-κB interacts with CtIP-BRCA1 complexes and promotes BRCA1 stabilization, and thereby contributes to HR induction. Immunofluorescence analysis revealed accelerated formation of replication protein A (RPA) and Rad51 foci upon NF-κB activation indicating HR stimulation through DSB resection by the interacting CtIP-BRCA1 complex and Rad51 filament formation. Taken together, these results define multiple NF-κB-dependent mechanisms regulating HR induction, and thereby providing a novel intriguing explanation for both NF-κB-mediated resistance to chemo- and radiotherapies as well as for the sensitization by pharmaceutical intervention of NF-κB activation.

A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice.

PubMed

Pai, Chen-Chun; Deegan, Rachel S; Subramanian, Lakxmi; Gal, Csenge; Sarkar, Sovan; Blaikley, Elizabeth J; Walker, Carol; Hulme, Lydia; Bernhard, Eric; Codlin, Sandra; Bähler, Jürg; Allshire, Robin; Whitehall, Simon; Humphrey, Timothy C

2014-06-09

DNA double-strand break (DSB) repair is a highly regulated process performed predominantly by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. How these pathways are coordinated in the context of chromatin is unclear. Here we uncover a role for histone H3K36 modification in regulating DSB repair pathway choice in fission yeast. We find Set2-dependent H3K36 methylation reduces chromatin accessibility, reduces resection and promotes NHEJ, while antagonistic Gcn5-dependent H3K36 acetylation increases chromatin accessibility, increases resection and promotes HR. Accordingly, loss of Set2 increases H3K36Ac, chromatin accessibility and resection, while Gcn5 loss results in the opposite phenotypes following DSB induction. Further, H3K36 modification is cell cycle regulated with Set2-dependent H3K36 methylation peaking in G1 when NHEJ occurs, while Gcn5-dependent H3K36 acetylation peaks in S/G2 when HR prevails. These findings support an H3K36 chromatin switch in regulating DSB repair pathway choice.

Synthetic lethality in DNA repair network: A novel avenue in targeted cancer therapy and combination therapeutics.

PubMed

Bhattacharjee, Sonali; Nandi, Saikat

2017-12-01

Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable. Many DNA double strand break repair (DSBR) genes have synthetic lethal relationships with oncogenes and tumor suppressor genes, which can be exploited for targeted cancer therapy, an approach referred to as combination therapy. DNA double-strand breaks (DSBs) are one of the most toxic lesions to a cell and can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). HR and NHEJ genes are particularly attractive targets for cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing cancer cells. Here, we review recent advances in the development of small molecule inhibitors against HR and NHEJ genes to induce synthetic lethality and address the future directions and clinical relevance of this approach. © 2017 IUBMB Life, 69(12):929-937, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice

PubMed Central

Tomimatsu, Nozomi; Mukherjee, Bipasha; Hardebeck, Molly Catherine; Ilcheva, Mariya; Camacho, Cristel Vanessa; Harris, Janelle Louise; Porteus, Matthew; Llorente, Bertrand; Khanna, Kum Kum; Burma, Sandeep

2014-01-01

Resection of DNA double-strand breaks (DSBs) is a pivotal step during which the choice between NHEJ and HR DNA repair pathways is made. While CDKs are known to control initiation of resection, their role in regulating long-range resection remains elusive. Here we show that CDKs 1/2 phosphorylate the long-range resection nuclease EXO1 at four C-terminal S/TP sites during S/G2 phases of the cell cycle. Impairment of EXO1 phosphorylation attenuates resection, chromosomal integrity, cell survival, and HR, but augments NHEJ upon DNA damage. In contrast, cells expressing phospho-mimic EXO1 are proficient in resection even after CDK inhibition and favor HR over NHEJ. Mutation of cyclin-binding sites on EXO1 attenuates CDK binding and EXO1 phosphorylation, causing a resection defect that can be rescued by phospho-mimic mutations. Mechanistically, phosphorylation of EXO1 augments its recruitment to DNA breaks possibly via interactions with BRCA1. In sum, phosphorylation of EXO1 by CDKs is a novel mechanism regulating repair pathway choice. PMID:24705021

Deficient Event-Related Theta Oscillations in Individuals at Risk for Alcoholism: A Study of Reward Processing and Impulsivity Features

PubMed Central

Kamarajan, Chella; Pandey, Ashwini K.; Chorlian, David B.; Manz, Niklas; Stimus, Arthur T.; Anokhin, Andrey P.; Bauer, Lance O.; Kuperman, Samuel; Kramer, John; Bucholz, Kathleen K.; Schuckit, Marc A.; Hesselbrock, Victor M.; Porjesz, Bernice

2015-01-01

Background Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism. Methods EROs were recorded during a monetary gambling task (MGT) in 12–25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups. Results HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects. Conclusions As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders. PMID:26580209

Deficient Event-Related Theta Oscillations in Individuals at Risk for Alcoholism: A Study of Reward Processing and Impulsivity Features.

PubMed

Kamarajan, Chella; Pandey, Ashwini K; Chorlian, David B; Manz, Niklas; Stimus, Arthur T; Anokhin, Andrey P; Bauer, Lance O; Kuperman, Samuel; Kramer, John; Bucholz, Kathleen K; Schuckit, Marc A; Hesselbrock, Victor M; Porjesz, Bernice

2015-01-01

Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism. EROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups. HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects. As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders.

Changes in Physiological Parameters Induced by Indoor Simulated Driving: Effect of Lower Body Exercise at Mid-Term Break

PubMed Central

Liang, Wen Chieh; Yuan, John; Sun, Deh Chuan; Lin, Ming Han

2009-01-01

The study monitored physiological parameter changes after 120-min of simulated driving. Blood pressures, heart rate (HR), heart rate variability (HRV) and palm temperatures were measured using an ANSWatch® monitor. Subjects were divided into two groups (A & B). Both groups performed 2-hour driving, but group B additionally took a 15-min exercise break. Heart rate, systolic pressure, LF/HF, and palm temperature decreased for group A after driving; for group B only HR and palm temperatures decreased. HRV and parasympathetic indices HF(AU) and HF(NU) increased for group A, while HRV and sympathetic index LF(AU) increased in group B. Group A had higher fatigue scores than group B. ANS activation may overcome some fatigue symptoms, but the recovery is nonetheless incomplete. Exercise break is proven to be an effective remedy, especially if accompanied by the ANS actions. The normalized parasympathetic index HF(NU), the normalized sympathetic index LF(NU), and the sympatho-vagal balance index LF/HF are three most promising parameters that could be further developed to monitor driver fatigue. PMID:22399979

Complete response in a patient with gynecological hidradenocarcinoma treated with exclusive external beam radiotherapy and brachytherapy: a case report

PubMed Central

Giannelli, Flavio; Chiola, Ilaria; Garelli, Stefania; Pastorino, Alice; Marcenaro, Michela; Mammoliti, Serafina; Costantini, Sergio; Bizzarri, Nicolò; Vellone, Valerio; Barra, Salvina; Corvò, Renzo

2017-01-01

Hidradenocarcinoma (HC) is a very rare disease. This case report illustrates a successful treatment of a 60-year-old woman with vulvo-vaginal localization of hidradenocarcinoma treated with external beam radiotherapy delivered by helical tomotherapy with a simultaneous integrated boost (SIB), followed by brachytherapy. External beam radiotherapy dose prescription was 50.4 Gy in 28 fractions, five fractions per week to whole pelvis (planning target volume 1 – PTV1), 60.2 Gy in 28 fractions to SIB1 (fundus of uterus and right inguinal node), and 58.8 Gy in 28 fractions to SIB2 (lower/middle third of vagina, paraurethral region and right inguinal lymph nodes). Brachytherapy dose prescription was 28 Gy in 4 fractions for cervix, fundus of uterus and upper third of vagina (HR-CTV1), and 22 Gy in 4 fractions to middle third of vagina and paraurethral region (HR-CTV2). D90 for whole treatment was 91.9 Gy and 86.0 Gy for HR-CTV1 and HR-CTV2, respectively. Patient remained 12-months disease-free without treatment related side effects. PMID:29441103

Behavior modification after inactivation of cerebellar dentate nuclei.

PubMed

Peterson, Todd C; Villatoro, Lee; Arneson, Tom; Ahuja, Brittany; Voss, Stephanie; Swain, Rodney A

2012-08-01

Effort-based decision making occurs when subjects are given a choice between a reward available at a high response cost and a reward available at a low response cost and is altered in individuals with disorders such as autism or particular patterns of brain injury. The current study explored the relationship between effort-based decision making and reinforcement characteristics in the T maze. This was done using both normal animals and animals with bilateral inactivation of the cerebellar dentate nuclei. Rats chose between alternatives in which one arm contained high-density reinforcement (HR) and the other arm contained low-density reinforcement (LR). During training, the HR arm was obstructed and the point at which the animal no longer worked for reinforcement (breaking point) was determined. The cerebellar dentate nuclei were then transiently inactivated and once again breaking points were assessed. The results indicated that inactivation of the dentate nucleus disrupted effort-based decision making. Additionally, altering both the palatability and the magnitude of the reinforcement were assessed in an attempt to reestablish the original preinactivation breaking point. It was hypothesized that an increase in the strength or magnitude of the reinforcement would promote an increase in the breaking point of the animal even when the cerebellum was inactivated. The results indicated that with both strategies animals effectively reestablished original breaking points. The results of this study will inform the current literature regarding the modification of behavior after brain injury and further the understanding of the behavioral deficits associated with cerebellar dysfunction.

Reward processing deficits and impulsivity in high-risk offspring of alcoholics: A study of event-related potentials during a monetary gambling task.

PubMed

Kamarajan, Chella; Pandey, Ashwini K; Chorlian, David B; Manz, Niklas; Stimus, Arthur T; Bauer, Lance O; Hesselbrock, Victor M; Schuckit, Marc A; Kuperman, Samuel; Kramer, John; Porjesz, Bernice

2015-11-01

Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. The goal of the present study is to elucidate reward processing deficits, externalizing disorders, and impulsivity as elicited by electrophysiological, clinical and behavioral measures in subjects at high risk for alcoholism from families densely affected by alcoholism in the context of brain maturation across age groups and gender. Event-related potentials (ERPs) and current source density (CSD) during a monetary gambling task (MGT) were measured in 12-25 year old offspring (N=1864) of families in the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective study; the high risk (HR, N=1569) subjects were from families densely affected with alcoholism and the low risk (LR, N=295) subjects were from community families. Externalizing disorders and impulsivity scores were also compared between LR and HR groups. HR offspring from older (16-25 years) male and younger (12-15 years) female subgroups showed lower P3 amplitude than LR subjects. The amplitude decrement was most prominent in HR males during the loss condition. Overall, P3 amplitude increase at anterior sites and decrease at posterior areas were seen in older compared to younger subjects, suggesting frontalization during brain maturation. The HR subgroups also exhibited hypofrontality manifested as weaker CSD activity during both loss and gain conditions at frontal regions. Further, the HR subjects had higher impulsivity scores and increased prevalence of externalizing disorders. P3 amplitudes during the gain condition were negatively correlated with impulsivity scores. Older male and younger female HR offspring, compared to their LR counterparts, manifested reward processing deficits as indexed by lower P3 amplitude and weaker CSD activity, along with higher prevalence of externalizing disorders and higher impulsivity scores. Reward related P3 is a valuable measure reflecting neurocognitive dysfunction in subjects at risk for alcoholism, as well as to characterize reward processing and brain maturation across gender and age group. Copyright © 2015 Elsevier B.V. All rights reserved.

Homologous Recombination Repair Protects Against Particulate Chromate-induced Chromosome Instability in Chinese Hamster Cells

PubMed Central

Stackpole, Megan M.; Wise, Sandra S.; Duzevik, Eliza Grlickova; Munroe, Ray C.; Thompson, W. Douglas; Thacker, John; Thompson, Larry H.; Hinz, John M.; Wise, John Pierce

2008-01-01

Particulate hexavalent chromium [Cr(VI)] compounds are well-established human carcinogens. Cr(VI)-induced tumors are characterized by chromosomal instability (CIN); however, the mechanisms of this effect are unknown. We investigated the hypothesis that homologous recombination (HR) repair of DNA double strand breaks protect cells from Cr(VI)-induced CIN by focusing on the XRCC3 and RAD51C genes, which play an important role in cellular resistance to DNA double strand breaks. We used Chinese hamster cells defective in each HR gene (irs3 for RAD51C and irs1SF for XRCC3) and compared with their wildtype parental and cDNA-complemented controls. We found that the intracellular Cr ion levels varied among the cell lines after particulate chromate treatment. Importantly, accounting for differences in Cr ion levels, we discovered that XRCC3 and RAD51C cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, relative to wild-type and cDNA-complimented cells. We also observed the emergence of high levels of chromatid exchanges in the two mutant cell lines. For example, 1 ug/cm2 lead chromate induced 20 and 32 exchanges in XRCC3- and RAD51C-deficient cells, respectively, whereas no exchanges were detected in the wildtype and cDNA-complemented cells. These observations suggest that HR protects cells from Cr(VI)-induced CIN, consistent with the ability of particulate Cr(VI) to induce double strand breaks. PMID:17662313

Verification and Validation of the Coastal Modeling System. Report 3: CMS-Flow: Hydrodynamics

DTIC Science & Technology

2011-12-01

Jansen (1978) Spectrum TMA Directional spreading distribution Cosine Power Directional spreading parameter γ 3.3 Bottom friction Off (default...Ramp duration 3 hr The wave breaking formula applied was Battjes and Jansen (1978) because it is the recommended wave breaking formula when using...Li, Z.H., K.D. Nguyen , J.C. Brun-Cottan and J.M. Martin. 1994. Numerical simulation of the turbidity maximum transport in the Gironde Estuary (France

Monitoring external and internal loads of brazilian soccer referees during official matches.

PubMed

Costa, Eduardo C; Vieira, Caio M A; Moreira, Alexandre; Ugrinowitsch, Carlos; Castagna, Carlo; Aoki, Marcelo S

2013-01-01

This study aimed to assess the external and internal loads of Brazilian soccer referees during official matches. A total of 11 field referees (aged 36.2 ± 7.5 years) were monitored during 35 matches. The external (distance covered, mean and maximal speed) and internal load parameters (session ratings of perceived exertion [RPE] training load [TL], Edwards' TL, and time spent in different heart rate [HR] zones) were assessed in 3-4 matches per referee. External load parameters were measured using a wrist Global Positioning System (GPS) receiver. No differences in distance covered (5.219 ± 205 vs. 5.230 ± 237 m) and maximal speed (19.3 ± 1.0 vs. 19.4 ± 1.4 km·h(-1)) were observed between the halves of the matches (p > 0.05). However, the mean speed was higher in the first half of the matches (6.6 ± 0.4 vs. 6.4 ± 0.3 km·h(-1)) (p < 0.05) than in the second half. The mean HR during the matches was ~89% of HRmax. In ~95% of the matches, the referees demonstrated a HR ≥ 80% of HRmax. Nonetheless, the time spent at 90-100% of HRmax was higher in the first half (59.9 vs. 52.3%) (p < 0.05). Significant correlations between session RPE TL and distance covered at 90-100% of HRmax (r = 0.62) and session RPE TL and maximal speed (r = 0.54) (p < 0.05) were noted. Furthermore, there was a positive correlation between session RPE TL and Edwards' TL (r = 0.61) (p < 0.05). Brazilian soccer referees demonstrated high external and internal load demands during official matches. The portable GPS/HR monitors and session RPE method can provide relevant information regarding the magnitude of the physiological strain during official matches. Key PointsHigh external and internal loads were imposed on Brazilian soccer referees during official matches.There was a high positive correlation between a subjective marker of internal load (session RPE) and parameters of external load (distance covered between 90-100% of HRmax and maximal speed).There was a high positive correlation between session RPE method and Edwards' method.Session RPE seems to be a reliable marker of internal load.The portable GPS/HR monitors and the session RPE method can provide relevant information regarding the magnitude of external and internal loads of soccer referees during official matches.

Influence of extended incubation time on Human sperm chromatin condensation, sperm DNA strand breaks and their effect on fertilisation rate.

PubMed

Ahmed, I; Abdelateef, S; Laqqan, M; Amor, H; Abdel-Lah, M A; Hammadeh, M E

2018-02-14

The purpose of this study was to determine influence of extended incubation time on sperm chromatin condensation and DNA strand breaks and their effect on fertilisation rate. Forty couples undergoing ICSI therapy were included. Semen was prepared by PureSperm gradient centrifugation and divided into two parts. The first part (G1) was used immediately for ICSI, whereas the second part (G2) was kept in the incubator at 37°C, 5% and 90% Humidity for 5 hr, and thereafter, the capacitated spermatozoa were used for ICSI. The TUNEL test and chromomycin CMA3 were used to evaluate the DNA strand breaks and chromatin condensation respectively. The percentage of condensed chromatin was 73.92 ± 12.70 in the group 1 and 81.13 ± 10.31% in group 2 (p = .001). However, the double-strand breaks were 11.15 ± 8.67% in G.1 and 16.30 ± 11.12% in G.2. (p = .001). Fertilisation rate in the (Group 1) was 62.45% and 69.17% in (Group 2). There was a positive correlation between condensed chromatin and fertilisation rate (r = 0.846, p = .001) and a negative correlation with DNA double-strand breaks (r = -0.802; p = .001). In conclusion, the prolonged sperm incubation (5 hr) leads to a higher chromatin condensation and to a significantly increased number of DNA strands double breaks with no influence on fertilisation rates. © 2018 Blackwell Verlag GmbH.

Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites

PubMed Central

Kato, Takamitsu A.; Suzuki, Takehiro; Dohmae, Naoshi; Takizawa, Kazuya; Nakazawa, Yuka; Genet, Matthew D.; Saotome, Mika; Hama, Michio; Nakajima, Nakako Izumi; Hazawa, Masaharu; Tomita, Masanori; Koike, Manabu; Noshiro, Katsuko; Tomiyama, Kenichi; Obara, Chizuka; Gotoh, Takaya; Ui, Ayako; Fujimori, Akira; Nakayama, Fumiaki; Sugasawa, Kaoru; Okayasu, Ryuichi; Tajima, Katsushi

2018-01-01

The p300 and CBP histone acetyltransferases are recruited to DNA double-strand break (DSB) sites where they induce histone acetylation, thereby influencing the chromatin structure and DNA repair process. Whether p300/CBP at DSB sites also acetylate non-histone proteins, and how their acetylation affects DSB repair, remain unknown. Here we show that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DSB sites. Using in vitro acetylated RAD52, we identified 13 potential acetylation sites in RAD52 by a mass spectrometry analysis. An immunofluorescence microscopy analysis revealed that RAD52 acetylation at DSBs sites is counteracted by SIRT2- and SIRT3-mediated deacetylation, and that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, inhibition of ataxia telangiectasia mutated (ATM) protein by siRNA or inhibitor treatment demonstrated that the acetylation of RAD52 at DSB sites is dependent on the ATM protein kinase activity, through the formation of RAD52, p300/CBP, SIRT2, and SIRT3 foci at DSB sites. Our findings clarify the importance of RAD52 acetylation in HR and its underlying mechanism. PMID:29590107

Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

PubMed Central

Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

2015-01-01

Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice.

PubMed

Gupta, Arun; Hunt, Clayton R; Hegde, Muralidhar L; Chakraborty, Sharmistha; Chakraborty, Sharmistha; Udayakumar, Durga; Horikoshi, Nobuo; Singh, Mayank; Ramnarain, Deepti B; Hittelman, Walter N; Namjoshi, Sarita; Asaithamby, Aroumougame; Hazra, Tapas K; Ludwig, Thomas; Pandita, Raj K; Tyler, Jessica K; Pandita, Tej K

2014-07-10

Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Parenting and children's externalizing problems in substance-abusing families.

PubMed

Stanger, Catherine; Dumenci, Levent; Kamon, Jody; Burstein, Marcy

2004-09-01

This study tested associations in path models among positive and negative parenting and children's rule-breaking behavior, aggressive and oppositional behavior, and attention problems for families with a drug-dependent parent. A structural model tested relations between parenting and children's externalizing problems for 251 families with 399 children between the ages of 6 and 18, controlling for nonindependence of ratings at the family level. The model also tested potential moderators, including child age, gender, and ethnicity (White vs. other), and caregiver gender (families with a female substance-abusing caregiver vs. families with a male substance-abusing caregiver). Results indicated that caregiver ratings of monitoring predicted rule-breaking behavior and use of inconsistent discipline predicted ratings of all 3 externalizing syndromes, after controlling parenting and externalizing problems for the effects of the moderators and after controlling significant relations among types of parenting and types of externalizing problems.

Individualized Internal and External Training Load Relationships in Elite Wheelchair Rugby Players.

PubMed

Paulson, Thomas A W; Mason, Barry; Rhodes, James; Goosey-Tolfrey, Victoria L

2015-01-01

The quantification and longitudinal monitoring of athlete training load (TL) provides a scientific explanation for changes in performance and helps manage injury/illness risk. Therefore, accurate and reliable monitoring tools are essential for the optimization of athletic performance. The aim of the present study was to establish the relationship between measures of internal [heart rate (HR) and session RPE (sRPE)] and external TL specific to wheelchair rugby (WR). Fourteen international WR athletes (age = 29 ± 7 years; body mass = 58.9 ± 10.9 kg) were monitored during 18 training sessions over a 3 month period during the competitive phase of the season. Activity profiles were collected during each training session using a radio-frequency based indoor tracking system (ITS). External TL was quantified by total distance (m) covered as well as time spent and distance covered in a range of classification-specific arbitrary speed zones. Banister's TRIMP, Edwards's summated HR zone (SHRZ), and Lucia's TRIMP methods were used to quantify physiological internal TL. sRPE was calculated as the product of session duration multiplied by perceived exertion using the Borg CR10 scale. Relationships between external and internal TL were examined using correlation coefficients and the 90% confidence intervals (90% CI). sRPE (r = 0.59) and all HR-based (r > 0.80) methods showed large and very large relationships with the total distance covered during training sessions, respectively. Large and very large correlations (r = 0.56 - 0.82) were also observed between all measures of internal TL and times spent and distances covered in low and moderate intensity speed zones. HR-based methods showed very large relationships with time (r = 0.71-0.75) and distance (r = 0.70-0.73) in the very high speed zone and a large relationship with the number of high intensity activities (HIA) performed (r = 0.56-0.62). Weaker relationships (r = 0.32-0.35) were observed between sRPE and all measures of high intensity activity. A large variation of individual correlation co-efficient was observed between sRPE and all external TL measures. The current findings suggest that sRPE and HR-based internal TL measures provide a valid tool for quantifying volume of external TL during WR training but may underestimate HIA. It is recommended that both internal and external TL measures are employed for the monitoring of overall TL during court-based training in elite WR athletes.

Individualized Internal and External Training Load Relationships in Elite Wheelchair Rugby Players

PubMed Central

Paulson, Thomas A. W.; Mason, Barry; Rhodes, James; Goosey-Tolfrey, Victoria L.

2015-01-01

Aim: The quantification and longitudinal monitoring of athlete training load (TL) provides a scientific explanation for changes in performance and helps manage injury/illness risk. Therefore, accurate and reliable monitoring tools are essential for the optimization of athletic performance. The aim of the present study was to establish the relationship between measures of internal [heart rate (HR) and session RPE (sRPE)] and external TL specific to wheelchair rugby (WR). Methods: Fourteen international WR athletes (age = 29 ± 7 years; body mass = 58.9 ± 10.9 kg) were monitored during 18 training sessions over a 3 month period during the competitive phase of the season. Activity profiles were collected during each training session using a radio-frequency based indoor tracking system (ITS). External TL was quantified by total distance (m) covered as well as time spent and distance covered in a range of classification-specific arbitrary speed zones. Banister's TRIMP, Edwards's summated HR zone (SHRZ), and Lucia's TRIMP methods were used to quantify physiological internal TL. sRPE was calculated as the product of session duration multiplied by perceived exertion using the Borg CR10 scale. Relationships between external and internal TL were examined using correlation coefficients and the 90% confidence intervals (90% CI). Results: sRPE (r = 0.59) and all HR-based (r > 0.80) methods showed large and very large relationships with the total distance covered during training sessions, respectively. Large and very large correlations (r = 0.56 − 0.82) were also observed between all measures of internal TL and times spent and distances covered in low and moderate intensity speed zones. HR-based methods showed very large relationships with time (r = 0.71−0.75) and distance (r = 0.70−0.73) in the very high speed zone and a large relationship with the number of high intensity activities (HIA) performed (r = 0.56−0.62). Weaker relationships (r = 0.32−0.35) were observed between sRPE and all measures of high intensity activity. A large variation of individual correlation co-efficient was observed between sRPE and all external TL measures. Conclusion: The current findings suggest that sRPE and HR-based internal TL measures provide a valid tool for quantifying volume of external TL during WR training but may underestimate HIA. It is recommended that both internal and external TL measures are employed for the monitoring of overall TL during court-based training in elite WR athletes. PMID:26733881

Disrupted resting brain graph measures in individuals at high risk for alcoholism.

PubMed

Holla, Bharath; Panda, Rajanikant; Venkatasubramanian, Ganesan; Biswal, Bharat; Bharath, Rose Dawn; Benegal, Vivek

2017-07-30

Familial susceptibility to alcoholism is likely to be linked to the externalizing diathesis seen in high-risk offspring from high-density alcohol use disorder (AUD) families. The present study aimed at comparing resting brain functional connectivity and their association with externalizing symptoms and alcoholism familial density in 40 substance-naive high-risk (HR) male offspring from high-density AUD families and 30 matched healthy low-risk (LR) males without a family history of substance dependence using graph theory-based network analysis. The HR subjects from high-density AUD families compared with LR, showed significantly reduced clustering, small-worldness, and local network efficiency. The frontoparietal, cingulo-opercular, sensorimotor and cerebellar networks exhibited significantly reduced functional segregation. These disruptions exhibited independent incremental value in predicting the externalizing symptoms over and above the demographic variables. The reduction of functional segregation in HR subjects was significant across both the younger and older age groups and was proportional to the family loading of AUDs. Detection and estimation of these developmentally relevant disruptions in small-world architecture at critical brain regions sub-serving cognitive, affective, and sensorimotor processes are vital for understanding the familial risk for early onset alcoholism as well as for understanding the pathophysiological mechanism of externalizing behaviors. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Scaling and Instabilities in Bubble Pinch-Off

NASA Astrophysics Data System (ADS)

Burton, J. C.; Waldrep, R.; Taborek, P.

2005-05-01

We have used a 100 000 frame-per-second video to analyze the pinch-off of nitrogen gas bubbles in fluids with a wide range of viscosity. If the external fluid is highly viscous (ηext>100 cP), the bubble neck radius is proportional to the time before break, τ, and decreases smoothly to zero. If the external fluid has low viscosity (ηext<10 cP), the radius scales as τ1/2 until an instability develops in the gas bubble, which causes the neck to rupture and tear apart. Finally, if the viscosity of the external fluid is in an intermediate range, an elongated thread is formed, which breaks apart into micron-sized bubbles.

Simulations of Gamma-Ray Burst Jets in a Stratified External Medium: Dynamics, Afterglow Light Curves, Jet Breaks, and Radio Calorimetry

NASA Astrophysics Data System (ADS)

De Colle, Fabio; Ramirez-Ruiz, Enrico; Granot, Jonathan; Lopez-Camara, Diego

2012-05-01

The dynamics of gamma-ray burst (GRB) jets during the afterglow phase is most reliably and accurately modeled using hydrodynamic simulations. All published simulations so far, however, have considered only a uniform external medium, while a stratified external medium is expected around long duration GRB progenitors. Here, we present simulations of the dynamics of GRB jets and the resulting afterglow emission for both uniform and stratified external media with ρextvpropr -k for k = 0, 1, 2. The simulations are performed in two dimensions using the special relativistic version of the Mezcal code. Common to all calculations is the initiation of the GRB jet as a conical wedge of half-opening angle θ0 = 0.2 whose radial profile is taken from the self-similar Blandford-McKee solution. The dynamics for stratified external media (k = 1, 2) are broadly similar to those derived for expansion into a uniform external medium (k = 0). The jet half-opening angle is observed to start increasing logarithmically with time (or radius) once the Lorentz factor Γ drops below θ-1 0. For larger k values, however, the lateral expansion is faster at early times (when Γ > θ-1 0) and slower at late times with the jet expansion becoming Newtonian and slowly approaching spherical symmetry over progressively longer timescales. We find that, contrary to analytic expectations, there is a reasonably sharp jet break in the light curve for k = 2 (a wind-like external medium), although the shape of the break is affected more by the viewing angle (for θobs <= θ0) than by the slope of the external density profile (for 0 <= k <= 2). Steeper density profiles (i.e., increasing k values) are found to produce more gradual jet breaks while larger viewing angles cause smoother and later appearing jet breaks. The counterjet becomes visible as it becomes sub-relativistic, and for k = 0 this results in a clear bump-like feature in the light curve. However, for larger k values the jet decelerates more gradually, causing only a mild flattening in the radio light curve that might be hard to discern when k = 2. Late-time radio calorimetry, which makes use of a spherical flow approximation near the non-relativistic transition, is likely to consistently overestimate the true energy by up to a factor of a few for k = 2, but likely to either overpredict or underpredict it by a smaller factor for k = 0, 1.

Shaping HR8799's outer dust belt with an unseen planet

NASA Astrophysics Data System (ADS)

Read, M. J.; Wyatt, M. C.; Marino, S.; Kennedy, G. M.

2018-04-01

HR8799 is a benchmark system for direct imaging studies. It hosts two debris belts, which lie internally and externally to four giant planets. This paper considers how the four known planets and a possible fifth planet interact with the external population of debris through N-body simulations. We find that when only the known planets are included, the inner edge of the outer belt predicted by our simulations is much closer to the outermost planet than recent ALMA observations suggest. We subsequently include a fifth planet in our simulations with a range of masses and semimajor axes, which is external to the outermost known planet. We find that a fifth planet with a mass and semimajor axis of 0.1 MJ and 138 au predicts an outer belt that agrees well with ALMA observations, whilst remaining stable for the lifetime of HR8799 and lying below current direct imaging detection thresholds. We also consider whether inward scattering of material from the outer belt can input a significant amount of mass into the inner belt. We find that for the current age of HR8799, only ˜1 per cent of the mass-loss rate of the inner disc can be replenished by inward scattering. However, we find that the higher rate of inward scattering during the first ˜10 Myr of HR8799 would be expected to cause warm dust emission at a level similar to that currently observed, which may provide an explanation for such bright emission in other systems at ˜10 Myr ages.

Separable Roles for a Caenorhabditis elegans RMI1 Homolog in Promoting and Antagonizing Meiotic Crossovers Ensure Faithful Chromosome Inheritance

PubMed Central

Jagut, Marlène; Hamminger, Patricia; Woglar, Alexander; Millonigg, Sophia; Paulin, Luis; Mikl, Martin; Dello Stritto, Maria Rosaria; Tang, Lois; Habacher, Cornelia; Tam, Angela; Gallach, Miguel; von Haeseler, Arndt; Villeneuve, Anne M.; Jantsch, Verena

2016-01-01

During the first meiotic division, crossovers (COs) between homologous chromosomes ensure their correct segregation. COs are produced by homologous recombination (HR)-mediated repair of programmed DNA double strand breaks (DSBs). As more DSBs are induced than COs, mechanisms are required to establish a regulated number of COs and to repair remaining intermediates as non-crossovers (NCOs). We show that the Caenorhabditis elegans RMI1 homolog-1 (RMH-1) functions during meiosis to promote both CO and NCO HR at appropriate chromosomal sites. RMH-1 accumulates at CO sites, dependent on known pro-CO factors, and acts to promote CO designation and enforce the CO outcome of HR-intermediate resolution. RMH-1 also localizes at NCO sites and functions in parallel with SMC-5 to antagonize excess HR-based connections between chromosomes. Moreover, RMH-1 also has a major role in channeling DSBs into an NCO HR outcome near the centers of chromosomes, thereby ensuring that COs form predominantly at off-center positions. PMID:27011106

The impact of delivery style on doctors' experience of stress during simulated bad news consultations.

PubMed

Shaw, Joanne; Brown, Rhonda; Dunn, Stewart

2015-10-01

The purpose of this study was to investigate the relationship between doctors' bad news delivery style and their experience of physiological stress during simulated bad news consultations. 31 doctors participated in two simulated breaking bad news (BBN) consultations. Delivery style was categorized as either blunt, forecasting or stalling (i.e. avoidant), based on the time to deliver the bad news and qualitative analysis of the interaction content and doctor's language style. Doctors' heart rate (HR) and skin conductance (SC) were recorded in consecutive 30s epochs. Doctors experienced a significant decrease in HR (F(1,36)=44.9, p<.0001) and SC (F(1,48)=5.6, p<.001) between the pre- and post-news delivery phases of the consultation. Between-group comparisons for the three delivery styles did not identify any significant differences in HR (F(2,36)=2.2, p>.05) or SC (F(2,48)=.66, p>.05). Doctors experience heightened stress in the pre-news delivery phase of breaking bad news interactions. Delaying the delivery of bad news exposes doctors to a longer period of increased stress.This suggests that medical students and doctors should be taught to deliver bad news without delay, to help mitigate their response to this stressful encounter. Copyright © 2015. Published by Elsevier Ireland Ltd.

Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

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

Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin

2013-03-15

Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likelymore » to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.« less

Validation of a new mortality risk prediction model for people 65 years and older in northwest Russia: The Crystal risk score.

PubMed

Turusheva, Anna; Frolova, Elena; Bert, Vaes; Hegendoerfer, Eralda; Degryse, Jean-Marie

2017-07-01

Prediction models help to make decisions about further management in clinical practice. This study aims to develop a mortality risk score based on previously identified risk predictors and to perform internal and external validations. In a population-based prospective cohort study of 611 community-dwelling individuals aged 65+ in St. Petersburg (Russia), all-cause mortality risks over 2.5 years follow-up were determined based on the results obtained from anthropometry, medical history, physical performance tests, spirometry and laboratory tests. C-statistic, risk reclassification analysis, integrated discrimination improvement analysis, decision curves analysis, internal validation and external validation were performed. Older adults were at higher risk for mortality [HR (95%CI)=4.54 (3.73-5.52)] when two or more of the following components were present: poor physical performance, low muscle mass, poor lung function, and anemia. If anemia was combined with high C-reactive protein (CRP) and high B-type natriuretic peptide (BNP) was added the HR (95%CI) was slightly higher (5.81 (4.73-7.14)) even after adjusting for age, sex and comorbidities. Our models were validated in an external population of adults 80+. The extended model had a better predictive capacity for cardiovascular mortality [HR (95%CI)=5.05 (2.23-11.44)] compared to the baseline model [HR (95%CI)=2.17 (1.18-4.00)] in the external population. We developed and validated a new risk prediction score that may be used to identify older adults at higher risk for mortality in Russia. Additional studies need to determine which targeted interventions improve the outcomes of these at-risk individuals. Copyright © 2017 Elsevier B.V. All rights reserved.

LEAD SEVERING CONTRIVANCE

DOEpatents

Widmaier, W.

1958-04-01

A means for breaking an electrical circuit within an electronic tube during the process of manufacture is described. Frequently such circuits must be employed for gettering or vapor coating purposes, however, since an external pair of corector pins having no use after manufacture, is undesirable, this invention permits the use of existing leads to form a temporary circuit during manufacture, and severing it thereafter. One portion of the temporary circuit, made from a springy material such as tungsten, is spot welded to a fusable member. To cut the circuit an external radiant heat source melts the fusable member, allowing the tensed tungsten spring to contract and break the circuit. This inexpensive arrangement is particularly useful when the tube has a great many external leads crowded into the tube base.

Histone Variant Regulates DNA Repair via Chromatin Condensation | Center for Cancer Research

Cancer.gov

Activating the appropriate DNA repair pathway is essential for maintaining the stability of the genome after a break in both strands of DNA. How a pathway is selected, however, is not well understood. Since these double strand breaks (DSBs) occur while DNA is packaged as chromatin, changes in its organization are necessary for repair to take place. Numerous alterations have been associated with DSBs, including modifications of histone tails and exchange of histone variants, some increasing chromatin accessibility, others reducing it. In fact, distinct domains flanking a single DSB have been observed that are bound by opposing repair pathway proteins 53BP1and BRCA1, which promote non-homologous end joining (NHEJ) and homologous recombination (HR), respectively. To investigate whether DSB-proximal chromatin reorganization affects repair pathway selection, Philipp Oberdoerffer, Ph.D., of CCR’s Laboratory of Receptor Biology and Gene Expression, and his colleagues performed a high-throughput RNA interference (RNAi) screen for chromatin-related genes that modulate HR.

Pretreatment Endorectal Coil Magnetic Resonance Imaging Findings Predict Biochemical Tumor Control in Prostate Cancer Patients Treated With Combination Brachytherapy and External-Beam Radiotherapy

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

Riaz, Nadeem; Afaq, Asim; Akin, Oguz

Purpose: To investigate the utility of endorectal coil magenetic resonance imaging (eMRI) in predicting biochemical relapse in prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Methods and Materials: Between 2000 and 2008, 279 men with intermediate- or high-risk prostate cancer underwent eMRI of their prostate before receiving brachytherapy and supplemental intensity-modulated radiotherapy. Endorectal coil MRI was performed before treatment and retrospectively reviewed by two radiologists experienced in genitourinary MRI. Image-based variables, including tumor diameter, location, number of sextants involved, and the presence of extracapsular extension (ECE), were incorporated with other established clinical variables to predict biochemical control outcomes.more » The median follow-up was 49 months (range, 1-13 years). Results: The 5-year biochemical relapse-free survival for the cohort was 92%. Clinical findings predicting recurrence on univariate analysis included Gleason score (hazard ratio [HR] 3.6, p = 0.001), PSA (HR 1.04, p = 0.005), and National Comprehensive Cancer Network risk group (HR 4.1, p = 0.002). Clinical T stage and the use of androgen deprivation therapy were not correlated with biochemical failure. Imaging findings on univariate analysis associated with relapse included ECE on MRI (HR 3.79, p = 0.003), tumor size (HR 2.58, p = 0.04), and T stage (HR 1.71, p = 0.004). On multivariate analysis incorporating both clinical and imaging findings, only ECE on MRI and Gleason score were independent predictors of recurrence. Conclusions: Pretreatment eMRI findings predict for biochemical recurrence in intermediate- and high-risk prostate cancer patients treated with combination brachytherapy and external-beam radiotherapy. Gleason score and the presence of ECE on MRI were the only significant predictors of biochemical relapse in this group of patients.« less

Frequency-dependent left ventricular performance in women and men.

PubMed

Wainstein, Rodrigo V; Sasson, Zion; Mak, Susanna

2012-06-01

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.

Inhibitors of the proteasome suppress homologous DNA recombination in mammalian cells.

PubMed

Murakawa, Yasuhiro; Sonoda, Eiichiro; Barber, Louise J; Zeng, Weihua; Yokomori, Kyoko; Kimura, Hiroshi; Niimi, Atsuko; Lehmann, Alan; Zhao, Guang Yu; Hochegger, Helfrid; Boulton, Simon J; Takeda, Shunichi

2007-09-15

Proteasome inhibitors are novel antitumor agents against multiple myeloma and other malignancies. Despite the increasing clinical application, the molecular basis of their antitumor effect has been poorly understood due to the involvement of the ubiquitin-proteasome pathway in multiple cellular metabolisms. Here, we show that treatment of cells with proteasome inhibitors has no significant effect on nonhomologous end joining but suppresses homologous recombination (HR), which plays a key role in DNA double-strand break (DSB) repair. In this study, we treat human cells with proteasome inhibitors and show that the inhibition of the proteasome reduces the efficiency of HR-dependent repair of an artificial HR substrate. We further show that inhibition of the proteasome interferes with the activation of Rad51, a key factor for HR, although it does not affect the activation of ATM, gammaH2AX, or Mre11. These data show that the proteasome-mediated destruction is required for the promotion of HR at an early step. We suggest that the defect in HR-mediated DNA repair caused by proteasome inhibitors contributes to antitumor effect, as HR plays an essential role in cellular proliferation. Moreover, because HR plays key roles in the repair of DSBs caused by chemotherapeutic agents such as cisplatin and by radiotherapy, proteasome inhibitors may enhance the efficacy of these treatments through the suppression of HR-mediated DNA repair pathways.

What do prostate cancer patients die of?

PubMed

Riihimäki, Matias; Thomsen, Hauke; Brandt, Andreas; Sundquist, Jan; Hemminki, Kari

2011-01-01

A recent rise in the incidence of prostate cancer and a more favorable outcome have increased the proportions of other causes of death in affected men. Extending the survival of prostate cancer patients thus requires knowledge of all causes of death. Data on the population, cancers, and causes of death were gathered from the nationwide Swedish Family-Cancer Database. A Cox regression model, comparing prostate cancer patients with all other men, was applied. Hazard ratios (HR) were calculated both for the underlying cause and for dying with a specific cause listed among multiple causes of death. Among 686,500 observed deaths, 62,500 were prostate cancer patients. For underlying causes other than prostate cancer, the highest cause-specific HRs were found for external causes (HR, 1.24; 95% confidence interval [CI], 1.16-1.31), diseases of the pulmonary circulation (HR, 1.22; 95% CI, 1.09-1.37), and heart failure (HR, 1.18; 95% CI, 1.11-1.24). For specific multiple causes, the highest HRs were found for anemia (HR, 2.28; 95% CI, 2.14-2.42), diseases of the pulmonary circulation (HR, 1.61; 95% CI, 1.55-1.68), and urinary system disease (HR, 1.90; 95% CI, 1.84-1.96). Prostate cancer patients have a higher risk for dying from various causes other than prostate cancer, including external causes and heart failure. Mechanisms have been proposed linking these elevated risks to both cancer and treatment. More attention should be paid to comorbidities in men with prostate cancer. The present study fulfills a gap in the knowledge of death causes in prostate cancer patients.

Fumarase is involved in DNA double-strand break resection through a functional interaction with Sae2.

PubMed

Leshets, Michael; Ramamurthy, Dharanidharan; Lisby, Michael; Lehming, Norbert; Pines, Ophry

2018-06-01

One of the most severe forms of DNA damage is the double-strand break (DSB). Failure to properly repair the damage can cause mutation, gross chromosomal rearrangements and lead to the development of cancer. In eukaryotes, homologous recombination (HR) and non-homologous end joining (NHEJ) are the main DSB repair pathways. Fumarase is a mitochondrial enzyme which functions in the tricarboxylic acid cycle. Intriguingly, the enzyme can be readily detected in the cytosolic compartment of all organisms examined, and we have shown that cytosolic fumarase participates in the DNA damage response towards DSBs. In human cells, fumarase was shown to be involved in NHEJ, but it is still unclear whether fumarase is also important for the HR pathway. Here we show that the depletion of cytosolic fumarase in yeast prolongs the presence of Mre11 at the DSBs, and decreases the kinetics of repair by the HR pathway. Overexpression of Sae2 endonuclease reduced the DSB sensitivity of the cytosolic fumarase depleted yeast, suggesting that Sae2 and fumarase functionally interact. Our results also suggest that Sae2 and cytosolic fumarase physically interact in vivo. Sae2 has been shown to be important for the DSB resection process, which is essential for the repair of DSBs by the HR pathway. Depletion of cytosolic fumarase inhibited DSB resection, while the overexpression of cytosolic fumarase or Sae2 restored resection. Together with our finding that cytosolic fumarase depletion reduces Sae2 cellular amounts, our results suggest that cytosolic fumarase is important for the DSB resection process by regulating Sae2 levels.

Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair.

PubMed

Lu, Wei-Ting; Hawley, Ben R; Skalka, George L; Baldock, Robert A; Smith, Ewan M; Bader, Aldo S; Malewicz, Michal; Watts, Felicity Z; Wilczynska, Ania; Bushell, Martin

2018-02-07

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells.

A comparison of methods to quantify the in-season training load of professional soccer players.

PubMed

Scott, Brendan R; Lockie, Robert G; Knight, Timothy J; Clark, Andrew C; Janse de Jonge, Xanne A K

2013-03-01

To compare various measures of training load (TL) derived from physiological (heart rate [HR]), perceptual (rating of perceived exertion [RPE]), and physical (global positioning system [GPS] and accelerometer) data during in-season field-based training for professional soccer. Fifteen professional male soccer players (age 24.9 ± 5.4 y, body mass 77.6 ± 7.5 kg, height 181.1 ± 6.9 cm) were assessed in-season across 97 individual training sessions. Measures of external TL (total distance [TD], the volume of low-speed activity [LSA; <14.4 km/h], high-speed running [HSR; >14.4 km/h], very high-speed running [VHSR; >19.8 km/h], and player load), HR and session-RPE (sRPE) scores were recorded. Internal TL scores (HR-based and sRPE-based) were calculated, and their relationships with measures of external TL were quantified using Pearson product-moment correlations. Physical measures of TD, LSA volume, and player load provided large, significant (r = .71-.84; P < .01) correlations with the HR-based and sRPE-based methods. Volume of HSR and VHSR provided moderate to large, significant (r = .40-.67; P < .01) correlations with measures of internal TL. While the volume of HSR and VHSR provided significant relationships with internal TL, physical-performance measures of TD, LSA volume, and player load appear to be more acceptable indicators of external TL, due to the greater magnitude of their correlations with measures of internal TL.

Exposure to Family Violence and Internalizing and Externalizing Problems Among Spanish Adolescents.

PubMed

Izaguirre, Ainhoa; Calvete, Esther

2018-04-01

Exposure to intimate partner violence (IPV) and child maltreatment may have devastating consequences on children's development. The aim of this research was to examine the predictive associations between exposure to violence at home (witnessing violence against the mother and/or direct victimization by the parents) and adolescent internalizing and externalizing problems. A total of 613 Spanish adolescents (13-18 years) took part in this study. Results indicate that psychological victimization by the parents predicted an increase in anxious/depressive symptoms, aggressive and rule-breaking behavior, and substance abuse at Time 2. In addition, rule-breaking behavior predicted an increase in adolescents' substance abuse at Time 2. Concerning gender, psychological victimization predicted an increase in anxiety/depression, aggressive behavior, rule-breaking behavior, and substance abuse in boys; whereas in girls, psychological victimization only predicted an increase in anxiety/depression.

Personal Values and Moral Disengagement Promote Aggressive and Rule-Breaking Behaviours in Adolescents With Disruptive Behaviour Disorders: A Pilot Study.

PubMed

Paciello, Marinella; Muratori, Pietro; Ruglioni, Laura; Milone, Annarita; Buonanno, Carlo; Capo, Rosario; Lochman, John E; Barcaccia, Barbara

2017-01-01

The pilot study presented in this article investigated the role of moral-cognitive features in understanding aggressive and rule-breaking behaviours in adolescents with Disruptive Behaviour Disorder (DBD). We collected two samples. The community sample was composed of 85 adolescents, whereas the DBD sample was composed of 30 adolescents. Compared with a community sample, adolescents with DBD are more inclined to use moral disengagement (MD) to legitimize their aggressive and rule-breaking behaviours. Moreover, regression models showed that self-enhancement values and MD foster externalizing behaviours taking into account both gender and the group they belonged to, that is, either clinical or community sample. Instead, self-transcendence values could prevent externalizing problems by inhibiting MD. Implications of these findings for assessment and therapeutic interventions are discussed. © The Author(s) 2015.

Gas Bubble Pinch-off in Viscous and Inviscid Liquids

NASA Astrophysics Data System (ADS)

Taborek, P.

2005-11-01

We have used high-speed video to analyze pinch-off of nitrogen gas bubbles in fluids with a wide range of viscosity. If the external fluid is highly viscous (ηext>100 cP), the radius is proportional to the time before break, τ, and decreases smoothly to zero. If the external fluid has low viscosity (ηext<10 cP), the neck radius scales as &1/2circ; until an instability develops in the gas bubble which causes the neck to rupture and tear apart. Finally, if the viscosity of the external fluid is in an intermediate range, an elongated thread is formed which breaks apart into micron-sized bubbles. 100,000 frame-per-second videos will be presented which illustrate each of these flow regimes.

Rosa26-GFP Direct Repeat (RaDR-GFP) Mice Reveal Tissue- and Age-Dependence of Homologous Recombination in Mammals In Vivo

PubMed Central

Kay, Jennifer E.; Na, Li; Rowland, Elizabeth A.; Winther, Kelly E.; Chow, Danielle N.; Kimoto, Takafumi; Matsuguchi, Tetsuya; Jonnalagadda, Vidya S.; Maklakova, Vilena I.; Singh, Vijay R.; Wadduwage, Dushan N.; Rajapakse, Jagath; So, Peter T. C.; Collier, Lara S.; Engelward, Bevin P.

2014-01-01

Homologous recombination (HR) is critical for the repair of double strand breaks and broken replication forks. Although HR is mostly error free, inherent or environmental conditions that either suppress or induce HR cause genomic instability. Despite its importance in carcinogenesis, due to limitations in our ability to detect HR in vivo, little is known about HR in mammalian tissues. Here, we describe a mouse model in which a direct repeat HR substrate is targeted to the ubiquitously expressed Rosa26 locus. In the Rosa26 Direct Repeat-GFP (RaDR-GFP) mice, HR between two truncated EGFP expression cassettes can yield a fluorescent signal. In-house image analysis software provides a rapid method for quantifying recombination events within intact tissues, and the frequency of recombinant cells can be evaluated by flow cytometry. A comparison among 11 tissues shows that the frequency of recombinant cells varies by more than two orders of magnitude among tissues, wherein HR in the brain is the lowest. Additionally, de novo recombination events accumulate with age in the colon, showing that this mouse model can be used to study the impact of chronic exposures on genomic stability. Exposure to N-methyl-N-nitrosourea, an alkylating agent similar to the cancer chemotherapeutic temozolomide, shows that the colon, liver and pancreas are susceptible to DNA damage-induced HR. Finally, histological analysis of the underlying cell types reveals that pancreatic acinar cells and liver hepatocytes undergo HR and also that HR can be specifically detected in colonic somatic stem cells. Taken together, the RaDR-GFP mouse model provides new understanding of how tissue and age impact susceptibility to HR, and enables future studies of genetic, environmental and physiological factors that modulate HR in mammals. PMID:24901438

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells.

PubMed

Kumar, S; Peng, X; Daley, J; Yang, L; Shen, J; Nguyen, N; Bae, G; Niu, H; Peng, Y; Hsieh, H-J; Wang, L; Rao, C; Stephan, C C; Sung, P; Ira, G; Peng, G

2017-04-17

Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. DNA2 nuclease is an evolutionarily conserved essential enzyme in replication and HR repair. Here we demonstrate that DNA2 is overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA double strand break end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anticancer drugs by targeting druggable nuclease DNA2. We propose DNA2 inhibition as new strategy in cancer therapy by targeting replication stress, a molecular property of cancer cells that is acquired as a result of oncogene activation instead of targeting currently undruggable oncoprotein itself such as KRAS.

Childhood internalizing and externalizing problems predict the onset of clinical panic attacks over adolescence: the TRAILS study.

PubMed

Mathyssek, Christina M; Olino, Thomas M; Verhulst, Frank C; van Oort, Floor V A

2012-01-01

Panic attacks are a source of individual suffering and are an independent risk factor for later psychopathology. However, much less is known about risk factors for the development of panic attacks, particularly during adolescence when the incidence of panic attacks increases dramatically. We examined whether internalizing and externalizing problems in childhood predict the onset of panic attacks in adolescence. This study is part of the TRacking Adolescents' Individual Lives Survey (TRAILS), a Dutch longitudinal population cohort study (N = 1,584). Internalizing and Externalizing Problems were collected using the Youth Self-Report (YSR) and the parent-report Child Behavior Checklist (CBCL) at baseline (age 10-12). At age 18-20, DSM-IV defined panic attacks since baseline were assessed with the Composite International Diagnostic Interview (CIDI). We investigated whether early adolescent Internalizing and Externalizing Problems predicted panic attacks between ages 10-20 years, using survival analysis in univariate and multivariate models. There were N = 314 (19.8%) cases who experienced at least one DSM-IV defined panic attack during adolescence and N = 18 (1.2%) who developed panic disorder during adolescence. In univariate analyses, CBCL Total Problems, Internalizing Problems and three of the eight syndrome scales predicted panic attack onset, while on the YSR all broad-band problem scales and each narrow-band syndrome scale predicted panic attack onset. In multivariate analyses, CBCL Social Problems (HR 1.19, p<.05), and YSR Thought Problems (HR 1.15, p<.05) and Social Problems (HR 1.26, p<.01) predicted panic attack onset. Risk indicators of panic attack include the wide range of internalizing and externalizing problems. Yet, when adjusted for co-occurring problem behaviors, Social Problems were the most consistent risk factor for panic attack onsets in adolescence.

Externalizing and Internalizing Problems in Relation to Autonomic Function: A Population-Based Study in Preadolescents

ERIC Educational Resources Information Center

Dietrich, Andrea; Riese, Harriette; Sondeijker, Frouke E. P. L.; Greaves-Lord, Kirstin; van Roon, Arie M.; Ormel, Johan; Neeleman, Jan; Rosmalen, Judith G. M.

2007-01-01

Objective: To investigate whether externalizing and internalizing problems are related to lower and higher heart rate (HR), respectively, and to explore the relationship of these problems with respiratory sinus arrhythmia (RSA) and baroreflex sensitivity (BRS). Moreover, to study whether problems present at both preschool and preadolescent age…

The oxygen-conserving potential of the diving response: A kinetic-based analysis.

PubMed

Costalat, Guillaume; Coquart, Jeremy; Castres, Ingrid; Joulia, Fabrice; Sirost, Olivier; Clua, Eric; Lemaître, Frédéric

2017-04-01

We investigated the oxygen-conserving potential of the human diving response by comparing trained breath-hold divers (BHDs) to non-divers (NDs) during simulated dynamic breath-holding (BH). Changes in haemodynamics [heart rate (HR), stroke volume (SV), cardiac output (CO)] and peripheral muscle oxygenation [oxyhaemoglobin ([HbO 2 ]), deoxyhaemoglobin ([HHb]), total haemoglobin ([tHb]), tissue saturation index (TSI)] and peripheral oxygen saturation (SpO 2 ) were continuously recorded during simulated dynamic BH. BHDs showed a breaking point in HR kinetics at mid-BH immediately preceding a more pronounced drop in HR (-0.86 bpm.% -1 ) while HR kinetics in NDs steadily decreased throughout BH (-0.47 bpm.% -1 ). By contrast, SV remained unchanged during BH in both groups (all P > 0.05). Near-infrared spectroscopy (NIRS) results (mean ± SD) expressed as percentage changes from the initial values showed a lower [HHb] increase for BHDs than for NDs at the cessation of BH (+24.0 ± 10.1 vs. +39.2 ± 9.6%, respectively; P < 0.05). As a result, BHDs showed a [tHb] drop that NDs did not at the end of BH (-7.3 ± 3.2 vs. -3.0 ± 4.7%, respectively; P < 0.05). The most striking finding of the present study was that BHDs presented an increase in oxygen-conserving efficiency due to substantial shifts in both cardiac and peripheral haemodynamics during simulated BH. In addition, the kinetic-based approach we used provides further credence to the concept of an "oxygen-conserving breaking point" in the human diving response.

Immunofluorescence-based methods to monitor DNA end resection

PubMed Central

Mukherjee, Bipasha; Tomimatsu, Nozomi; Burma, Sandeep

2017-01-01

Summary Double-strand breaks (DSBs) are the most deleterious amongst all types of DNA damage that can occur in the cell. These breaks arise from both endogenous (for example, DNA replication stress) as well as exogenous insults (for example, ionizing radiation). DSBs are principally repaired by one of two major pathways: non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ is an error-prone process that can occur in all phases of the cell cycle, while HR is limited to the S and G2 phases of the cell cycle when a sister chromatid is available as a template for error-free repair. The first step in HR is “DNA end resection”, a process during which the broken DNA end is converted into a long stretch of 3′-ended single-stranded DNA (ssDNA). In recent years, DNA end resection has been identified as a pivotal step that controls “repair pathway choice” i.e., the appropriate choice between NHEJ and HR for DSB repair. Therefore, methods to quantitatively or semi-quantitatively assess DNA end resection have gained importance in laboratories working on DNA repair. In this chapter, we describe two simple immunofluorescence-based techniques to monitor DNA end resection in mammalian cells. The first technique involves immuno-detection of Replication Protein A (RPA), a ssDNA-binding protein that binds to resected DNA. The second technique involves labeling of genomic DNA with 5-bromo-2′-deoxyuridine (BrdU) that can be detected by anti-BrdU antibody only after the DNA becomes single stranded due to resection. These methods are not complicated, do not involve sophisticated instrumentation or reporter constructs, and can be applied to most mammalian cell lines, and therefore, should be of broad utility as simple ways of monitoring DNA end resection in vivo. PMID:25804748

Low heart rate: a marker of stress resilience. The TRAILS study.

PubMed

Oldehinkel, Albertine J; Verhulst, Frank C; Ormel, Johan

2008-06-15

The stimulation-seeking theory posits that individuals with low habitual autonomic arousal levels will seek stimulation to increase their arousal to more optimal levels. Because of their assumed high optimal stimulation levels, persons characterized by low autonomic arousal may be better able to endure stressors than those with higher levels. In this study, we tested the hypothesis that low resting heart rate (HR) and high respiratory sinus arrhythmia (RSA) protect against the detrimental effects of stressors on mental health in early adolescents from the general population. Data were collected as part of TRacking Adolescents' Individual Lives Survey (TRAILS), a large prospective cohort of Dutch (pre)adolescents (N = 1478), with measurements at approximately age 11 (T1) and age 13.5 (T2). Internalizing and externalizing mental health problems were assessed at both waves, using multiple informants. Resting HR and RSA were assessed at T1 and the amount of parent-reported stressors and long-term difficulties at T2. Stressors predicted mental health problems in adolescents with intermediate and high HR, but not in those with low HR. These findings were consistent regardless of the measure used to assess stressors and of adjustment for T1 mental health problems. Furthermore, the stress-buffering effects of low HR pertained to both externalizing problems and internalizing problems. No stress-buffering effects were found for RSA, suggesting predominantly sympathetic influences. Our study, which linked physiologic measures to stress sensitivity in real life, suggests that low HR is a marker of resilience to the effects of environmental challenges in early adolescence.

Mortality, Causes of Death and Associated Factors Relate to a Large HIV Population-Based Cohort.

PubMed

Garriga, César; García de Olalla, Patricia; Miró, Josep M; Ocaña, Inma; Knobel, Hernando; Barberá, Maria Jesús; Humet, Victoria; Domingo, Pere; Gatell, Josep M; Ribera, Esteve; Gurguí, Mercè; Marco, Andrés; Caylà, Joan A

2015-01-01

Antiretroviral therapy has led to a decrease in HIV-related mortality and to the emergence of non-AIDS defining diseases as competing causes of death. This study estimates the HIV mortality rate and their risk factors with regard to different causes in a large city from January 2001 to June 2013. We followed-up 3137 newly diagnosed HIV non-AIDS cases. Causes of death were classified as HIV-related, non-HIV-related and external. We examined the effect of risk factors on survival using mortality rates, Kaplan-Meier plots and Cox models. Finally, we estimated survival for each main cause of death groups through Fine and Gray models. 182 deaths were found [14.0/1000 person-years of follow-up (py); 95% confidence interval (CI):12.0-16.1/1000 py], 81.3% of them had a known cause of death. Mortality rate by HIV-related causes and non-HIV-related causes was the same (4.9/1000 py; CI:3.7-6.1/1000 py), external was lower [1.7/1000 py; (1.0-2.4/1000 py)]. Kaplan-Meier estimate showed worse survival in intravenous drug user (IDU) and heterosexuals than in men having sex with men (MSM). Factors associated with HIV-related causes of death include: IDU male (subHazard Ratio (sHR):3.2; CI:1.5-7.0) and <200 CD4 at diagnosis (sHR:2.7; CI:1.3-5.7) versus ≥500 CD4. Factors associated with non-HIV-related causes of death include: ageing (sHR:1.5; CI:1.4-1.7) and heterosexual female (sHR:2.8; CI:1.1-7.3) versus MSM. Factors associated with external causes of death were IDU male (sHR:28.7; CI:6.7-123.2) and heterosexual male (sHR:11.8; CI:2.5-56.4) versus MSM. There are important differences in survival among transmission groups. Improved treatment is especially necessary in IDUs and heterosexual males.

Genetic variation in a DNA double strand break repair gene in saudi population: a comparative study with worldwide ethnic groups.

PubMed

Areeshi, Mohammed Yahya

2013-01-01

DNA repair capacity is crucial in maintaining cellular functions and homeostasis. However, it can be altered based on DNA sequence variations in DNA repair genes and this may lead to the development of many diseases including malignancies. Identification of genetic polymorphisms responsible for reduced DNA repair capacity is necessary for better prevention. Homologous recombination (HR), a major double strand break repair pathway, plays a critical role in maintaining the genome stability. The present study was performed to determine the frequency of the HR gene XRCC3 Exon 7 (C18067T, rs861539) polymorphisms in Saudi Arabian population in comparison with epidemiological studies by "MEDLINE" search to equate with global populations. The variant allelic (T) frequency of XRCC3 (C>T) was found to be 39%. Our results suggest that frequency of XRCC3 (C>T) DNA repair gene exhibits distinctive patterns compared with the Saudi Arabian population and this might be attributed to ethnic variation. The present findings may help in high-risk screening of humans exposed to environmental carcinogens and cancer predisposition in different ethnic groups.

Promotion of Homologous Recombination and Genomic Stability byRAD51AP1 via RAD51 Recombinase Enhancement

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

Wiese, Claudia; Dray, Eloise; Groesser, Torsten

2007-04-11

Homologous recombination (HR) repairs chromosome damage and is indispensable for tumor suppression in humans. RAD51 mediates the DNA strand pairing step in HR. RAD51AP1 (RAD51 Associated Protein 1) is a RAD51-interacting protein whose function has remained elusive. Knockdown of RAD51AP1 in human cells by RNA interference engenders sensitivity to different types of genotoxic stress. Moreover, RAD51AP1-depleted cells are impaired for the recombinational repair of a DNA double-strand break and exhibit chromatid breaks both spontaneously and upon DNA damaging treatment. Purified RAD51AP1 binds dsDNA and RAD51, and it greatly stimulates the RAD51-mediated D-loop reaction. Biochemical and cytological results show that RAD51AP1more » functions at a step subsequent to the assembly of the RAD51-ssDNA nucleoprotein filament. Our findings provide the first evidence that RAD51AP1 helps maintain genomic integrity via RAD51 recombinase enhancement.« less

Towards 24/7 continuous heart rate monitoring.

PubMed

Tarniceriu, Adrian; Parak, Jakub; Renevey, Philippe; Nurmi, Marko; Bertschi, Mattia; Delgado-Gonzalo, Ricard; Korhonen, Ilkka

2016-08-01

Heart rate (HR) and HR variability (HRV) carry rich information about physical activity, mental and physical load, physiological status, and health of an individual. When combined with activity monitoring and personalized physiological modelling, HR/HRV monitoring may be used for monitoring of complex behaviors and impact of behaviors and external factors on the current physiological status of an individual. Optical HR monitoring (OHR) from wrist provides a comfortable and unobtrusive method for HR/HRV monitoring and is better adhered by users than traditional ECG electrodes or chest straps. However, OHR power consumption is significantly higher than that for ECG based methods due to the measurement principle based on optical illumination of the tissue. We developed an algorithmic approach to reduce power consumption of the OHR in 24/7 HR trending. We use continuous activity monitoring and a fast converging frequency domain algorithm to derive a reliable HR estimate in 7.1s (during outdoor sports, in average) to 10.0s (during daily life). The method allows >80% reduction in power consumption in 24/7 OHR monitoring when average HR monitoring is targeted, without significant reduction in tracking accuracy.

Daytime napping and mortality, with a special reference to cardiovascular disease: the JACC study.

PubMed

Tanabe, Naohito; Iso, Hiroyasu; Seki, Nao; Suzuki, Hiroshi; Yatsuya, Hiroshi; Toyoshima, Hideaki; Tamakoshi, Akiko

2010-02-01

Daytime napping is associated with elevated risk of all-cause mortality in the elderly. However, the association with cardiovascular disease (CVD) risk is inconsistent. From 1988 to 1990, a total of 67 129 Japanese non-workers or daytime workers (27 755 men and 39 374 women) aged 40-79 years, without a history of stroke, heart disease or cancer, completed a lifestyle questionnaire. They were followed for mortality until the end of 2003. During the 879 244 person-year follow-up, 9643 deaths (2852 from CVD, 3643 from cancer, 2392 from other internal causes, 738 from external causes and 18 from unspecified causes) were observed. After adjustment for possible confounders, subjects with a daytime napping habit had elevated hazard ratios (HRs) for mortality from all causes [HR 1.19, 95% confidence interval (CI) 1.14-1.24, P < 0.001], CVD (HR 1.31, 95% CI 1.22-1.42, P < 0.001), non-cardiovascular/non-cancer internal diseases (HR 1.26, 95% CI 1.16-1.37, P < 0.001) and external causes (HR 1.28, 95% CI 1.10-1.50, P = 0.001), but not for cancer death (HR 1.03, 95% CI 0.96-1.10, P = 0.400). The risk of CVD mortality associated with daytime napping was diminished among overweight subjects, but pronounced in those with weight loss after age 20 years, with non-regular employment, with lower education level and with a follow-up period <5 years. Daytime napping is associated with elevated risk of CVD mortality as well as non-cardiovascular/non-cancer and external deaths. Daytime napping may elevate risk of CVD death through some biological effects but, to a larger extent, some comorbid disorders causing weight loss or associated with non-regular employment and low education level could explain this association.

DNA Damage Response Factors from Diverse Pathways, Including DNA Crosslink Repair, Mediate Alternative End Joining

PubMed Central

Howard, Sean M.; Yanez, Diana A.; Stark, Jeremy M.

2015-01-01

Alternative end joining (Alt-EJ) chromosomal break repair involves bypassing classical non-homologous end joining (c-NHEJ), and such repair causes mutations often with microhomology at the repair junction. Since the mediators of Alt-EJ are not well understood, we have sought to identify DNA damage response (DDR) factors important for this repair event. Using chromosomal break reporter assays, we surveyed an RNAi library targeting known DDR factors for siRNAs that cause a specific decrease in Alt-EJ, relative to an EJ event that is a composite of Alt-EJ and c-NHEJ (Distal-EJ between two tandem breaks). From this analysis, we identified several DDR factors that are specifically important for Alt-EJ relative to Distal-EJ. While these factors are from diverse pathways, we also found that most of them also promote homologous recombination (HR), including factors important for DNA crosslink repair, such as the Fanconi Anemia factor, FANCA. Since bypass of c-NHEJ is likely important for both Alt-EJ and HR, we disrupted the c-NHEJ factor Ku70 in Fanca-deficient mouse cells and found that Ku70 loss significantly diminishes the influence of Fanca on Alt-EJ. In contrast, an inhibitor of poly ADP-ribose polymerase (PARP) causes a decrease in Alt-EJ that is enhanced by Ku70 loss. Additionally, the helicase/nuclease DNA2 appears to have distinct effects from FANCA and PARP on both Alt-EJ, as well as end resection. Finally, we found that the proteasome inhibitor Bortezomib, a cancer therapeutic that has been shown to disrupt FANC signaling, causes a significant reduction in both Alt-EJ and HR, relative to Distal-EJ, as well as a substantial loss of end resection. We suggest that several distinct DDR functions are important for Alt-EJ, which include promoting bypass of c-NHEJ and end resection. PMID:25629353

Parenting and Children's Externalizing Problems in Substance-Abusing Families

ERIC Educational Resources Information Center

Stanger, Catherine; Dumenci, Levent; Kamon, Jody; Burstein, Marcy

2004-01-01

This study tested associations in path models among positive and negative parenting and children's rule-breaking behavior, aggressive and oppositional behavior, and attention problems for families with a drug-dependent parent. A structural model tested relations between parenting and children's externalizing problems for 251 families with 399…

The Mechanism of Gene Targeting in Human Somatic Cells

PubMed Central

Kan, Yinan; Ruis, Brian; Lin, Sherry; Hendrickson, Eric A.

2014-01-01

Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells. PMID:24699519

The Chilling Optimum of Idaho and Arizona Ponderosa Pine Buds

Treesearch

David L. Wenny; Daniel J. Swanson; R. Kasten Dumroese

2002-01-01

Ponderosa pine (Pinus ponderosa) seedlings from Idaho (var. ponderosa) and Arizona (var. scopulorum) grown in a container nursery received optimum chilling [2,010 hr (84 days) of temperatures below 5°C]. While seedlings were in the greenhouse, days required for 50% of the population to break bud were similar for both seed sources...

Genetic variation in GABRA2 moderates peer influence on externalizing behavior in adolescents.

PubMed

Villafuerte, Sandra; Trucco, Elisa M; Heitzeg, Mary M; Burmeister, Margit; Zucker, Robert A

2014-01-01

Genetic predisposition and environmental influences are both important factors in the development of problematic behavior leading to substance use in adolescence. Involvement with delinquent peers also strongly predicts adolescent externalizing behavior. Several lines of evidence support a role of GABRA2 on externalizing behavior related to disinhibition. However, whether this genetic association is influenced by the environment such as peer behavior remains unknown. We examined the moderating role of GABRA2 genetic variation on the socialization model of delinquent peer affiliation (at ages 12-14 years) on externalizing behavior (at ages 15-17 years) in the Michigan Longitudinal Study (MLS) adolescent sample. The sample consisted of 244 adolescents (75 females and 152 with at least one parent with a DSM-IV lifetime alcohol dependence/abuse diagnosis). Peer delinquent activity reported by the participant and teacher-reported adolescent externalizing behavior (Teacher Report Form (TRF) were assessed. No main effect of the GABRA2 SNP rs279826, which tags a large haplotype, on externalizing behavior was observed. However, there was a statistically reliable GABRA2 × peer delinquency interaction. The effect of peer delinquent involvement on externalizing scores and the rule breaking subscale is significantly stronger for those with the GG genotype compared to A-carriers, whereas there was no effect of genotype on externalizing in the absence of peer delinquent involvement. No interaction was observed for the aggression subscale. Our results suggest that the genetic effect of GABRA2 on externalizing behavior, more specifically on rule breaking is, at least in part, due to its effect on susceptibility to environmental exposure (i.e., peer delinquency).

Serum Gamma-Glutamyl-Transferase Independently Predicts Outcome After Transarterial Chemoembolization of Hepatocellular Carcinoma: External Validation

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

Guiu, Boris, E-mail: boris.guiu@chu-dijon.fr; Deschamps, Frederic; Boulin, Mathieu

Purpose: An Asian study showed that gamma glutamyl transpeptidase (GGT) can predict survival after transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). This study was designed to validate in a European population this biomarker as an independent predictor of outcome after TACE of HCC and to determine a threshold value for clinical use. Methods: In 88 consecutive patients treated by TACE for HCC, the optimal threshold for GGT serum level was determined by a ROC analysis. Endpoints were time-to-treatment failure (TTTF) and overall survival (OS). All multivariate models were internally validated using bootstrapping (90 replications). Results: Median follow-up lasted 373 days,more » and median overall survival was 748 days. The optimal threshold for GGT was 165 U/L (sensitivity: 89.3%; specificity: 56.7%; area under the ROC curve: 0.7515). Median TTTF was shorter when GGT was {>=}165 U/L (281 days vs. 850 days; P < 0.001). GGT {>=}165 U/L (hazard ratio (HR) = 2.06; P = 0.02), WHO PS of 2 (HR = 5.4; P = 0.002), and tumor size (HR = 1.12; P = 0.014) were independently associated with shorter TTTF. Median OS was shorter when GGT was {>=}165 U/L (508 days vs. not reached; P < 0.001). GGT {>=} 165 U/L (HR = 3.05; P = 0.029), WHO PS of 2 (HR = 12.95; P < 0.001), alfa-fetoprotein (HR = 2.9; P = 0.01), and tumor size (HR = 1.096; P = 0.013) were independently associated with shorter OS. The results were confirmed by bootstrapping. Conclusions: Our results provide in a European population the external validation of GGT as an independent predictor of outcome after TACE of HCC. A serum level of GGT {>=} 165 U/L is independently associated with both shorter TTTF and OS.« less

Advantages and Disadvantages for Receiving Internet-Based HIV/AIDS Interventions at Home or at Community Based Organization

PubMed Central

Green, Shana M.; Lockhart, Elizabeth; Marhefka, Stephanie L.

2015-01-01

Within recent years public health interventions have become technologically based to reflect the digital age we currently live in and appeal to the public in innovative and novel ways. The Internet breaks down boundaries distance imposes and increases our ability to reach and connect with people. Internet-based interventions have the potential to expand access to effective behavioral interventions. The US National HIV/AIDS Strategy states that people living with HIV should have access to effective behavioral interventions like Healthy Relationships (HR) to help them develop safe sex and disclosure skills. However, access to HR is limited across the country, especially for people in remote or rural areas. Internet-based Healthy Relationships Video Groups (HR-VG) delivered at home or community based organizations (CBOs) can possibly expand access. This study assesses the preferences of women living with HIV (WLH) for participation in HR-VG among 21 WLH who participated in a randomized control trial (RCT) testing HR-VG and completed open-ended semi-structured telephone interviews. Transcripts were thematically analyzed to determine advantages, disadvantages and overall preference for home or agency delivery of HR-VG. Themes relating to convenience, technology access, privacy, distractions, HIV serostatus disclosure and social opportunities were identified as advantages or disadvantages to participating in HR-VG at each location. Overall privacy was the most salient concern of accessing HR-VG at home or at a CBO. Considering the concerns expressed by WLH, further studies are needed to assess how an Internet-based intervention delivered at home for WLH can maintain privacy while being cost effective. PMID:26357907

Advantages and disadvantages for receiving Internet-based HIV/AIDS interventions at home or at community-based organizations.

PubMed

Green, Shana M; Lockhart, Elizabeth; Marhefka, Stephanie L

2015-01-01

Within recent years, public health interventions have become technology based to reflect the digital age we currently live in and appeal to the public in innovative and novel ways. The Internet breaks down boundaries distance imposes and increases our ability to reach and connect with people. Internet-based interventions have the potential to expand access to effective behavioral interventions (EBIs). The US National HIV/AIDS Strategy states that people living with HIV should have access to EBIs such as healthy relationships (HR) to help them develop safe sex and disclosure skills. However, access to HR is limited across the country, especially for people in remote or rural areas. Internet-based healthy relationships video groups (HR-VG) delivered at home or community-based organizations (CBOs) can possibly expand access. This study assesses the preferences of women living with HIV (WLH) for participation in HR-VG among 21 WLH who participated in a randomized control trial (RCT) testing HR-VG and completed open-ended semi-structured telephone interviews. Transcripts were thematically analyzed to determine advantages and disadvantages of home or CBO delivery of HR-VG. Themes relating to convenience, technology access, privacy, distractions, HIV serostatus disclosure, and social opportunities were identified as advantages or disadvantages to participating in HR-VG at each location. Overall, privacy was the most salient concern of accessing HR-VG at home or at a CBO. Considering the concerns expressed by WLH, further studies are needed to assess how an Internet-based intervention delivered at home for WLH can maintain privacy while being cost effective.

Childhood Internalizing and Externalizing Problems Predict the Onset of Clinical Panic Attacks over Adolescence: The TRAILS Study

PubMed Central

Mathyssek, Christina M.; Olino, Thomas M.; Verhulst, Frank C.; van Oort, Floor V. A.

2012-01-01

Background Panic attacks are a source of individual suffering and are an independent risk factor for later psychopathology. However, much less is known about risk factors for the development of panic attacks, particularly during adolescence when the incidence of panic attacks increases dramatically. We examined whether internalizing and externalizing problems in childhood predict the onset of panic attacks in adolescence. Method This study is part of the TRacking Adolescents’ Individual Lives Survey (TRAILS), a Dutch longitudinal population cohort study (N = 1,584). Internalizing and Externalizing Problems were collected using the Youth Self-Report (YSR) and the parent-report Child Behavior Checklist (CBCL) at baseline (age 10–12). At age 18–20, DSM-IV defined panic attacks since baseline were assessed with the Composite International Diagnostic Interview (CIDI). We investigated whether early adolescent Internalizing and Externalizing Problems predicted panic attacks between ages 10–20 years, using survival analysis in univariate and multivariate models. Results There were N = 314 (19.8%) cases who experienced at least one DSM-IV defined panic attack during adolescence and N = 18 (1.2%) who developed panic disorder during adolescence. In univariate analyses, CBCL Total Problems, Internalizing Problems and three of the eight syndrome scales predicted panic attack onset, while on the YSR all broad-band problem scales and each narrow-band syndrome scale predicted panic attack onset. In multivariate analyses, CBCL Social Problems (HR 1.19, p<.05), and YSR Thought Problems (HR 1.15, p<.05) and Social Problems (HR 1.26, p<.01) predicted panic attack onset. Conclusion Risk indicators of panic attack include the wide range of internalizing and externalizing problems. Yet, when adjusted for co-occurring problem behaviors, Social Problems were the most consistent risk factor for panic attack onsets in adolescence. PMID:23251576

Results from a blind and a non-blind randomised trial run in parallel: experience from the Estonian Postmenopausal Hormone Therapy (EPHT) Trial.

PubMed

Veerus, Piret; Fischer, Krista; Hakama, Matti; Hemminki, Elina

2012-04-04

The Estonian Postmenopausal Hormone Therapy (EPHT) Trial assigned 4170 potential participants prior to recruitment to blind or non-blind hormone therapy (HT), with placebo or non-treatment the respective alternatives. Before having to decide on participation, women were told whether they had been randomised to the blind or non-blind trial. Eligible women who were still willing to join the trial were recruited. After recruitment participants in the non-blind trial (N = 1001) received open-label HT or no treatment, participants in the blind trial (N = 777) remained blinded until the end of the trial. The aim of this paper is to analyse the effect of blinding on internal and external validity of trial outcomes. Effect of blinding was calculated as the hazard ratio of selected chronic diseases, total mortality and all outcomes. For analysing the effect of blinding on external validity, the hazard ratios from women recruited to the placebo arm and to the non-treatment arm were compared with those not recruited; for analysing the effect of blinding on internal validity, the hazard ratios from the blind trial were compared with those from the non-blind trial. The women recruited to the placebo arm had less cerebrovascular disease events (HR 0.43; 95% CI: 0.26-0.71) and all outcomes combined (HR 0.76; 95% CI: 0.63-0.91) than those who were not recruited. Among women recruited or not recruited to the non-treatment arm, no differences were observed for any of the outcomes studied.Among women recruited to the trial, the risk for coronary heart disease events (HR 0.77; 95% CI: 0.64-0.93), cerebrovascular disease events (HR 0.66; 95%CI: 0.47-0.92), and all outcomes combined (HR 0.82; 95% CI: 0.72-0.94) was smaller among participants in the blind trial than in the non-blind trial. There was no difference between the blind and the non-blind trial for total cancer (HR 0.95; 95% CI: 0.64-1.42), bone fractures (0.93; 95% CI: 0.74-1.16), and total mortality (HR 1.03; 95% CI: 0.53-1.98). The results from blind and non-blind trials may differ, even if the target population is the same. Blinding may influence both internal and external validity. The effect of blinding may vary for different outcome events. [ISRCTN35338757].

The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy

PubMed Central

2013-01-01

Germ line mutations in breast cancer gene 1 (BRCA1) predispose women to breast and ovarian cancers. Although BRCA1 is involved in many important biological processes, the function of BRCA1 in homologous recombination (HR) mediated repair is considered one of the major mechanisms contributing to its tumor suppression activity, and the cause of hypersensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors when BRCA1 is defective. Mounting evidence suggests that the mechanism of repairing DNA double strand breaks (DSBs) by HR is different than the mechanism operating when DNA replication is blocked. Although BRCA1 has been recognized as a central component in HR, the precise role of BRCA1 in HR, particularly under replication stress, has remained largely unknown. Given the fact that DNA lesions caused by replication blockages are the primary substrates for HR in mitotic cells, functional analysis of BRCA1 in HR repair in the context of replication stress should benefit our understanding of the molecular mechanisms underlying tumorigenesis associated with BRCA1 deficiencies, as well as the development of therapeutic approaches for cancer patients carrying BRCA1 mutations or reduced BRCA1 expression. This review focuses on the current advances in this setting and also discusses the significance in tumorigenesis and cancer therapy. PMID:23388117

Brachytherapy improves biochemical failure-free survival in low- and intermediate-risk prostate cancer compared with conventionally fractionated external beam radiation therapy: a propensity score matched analysis.

PubMed

Smith, Graham D; Pickles, Tom; Crook, Juanita; Martin, Andre-Guy; Vigneault, Eric; Cury, Fabio L; Morris, Jim; Catton, Charles; Lukka, Himu; Warner, Andrew; Yang, Ying; Rodrigues, George

2015-03-01

To compare, in a retrospective study, biochemical failure-free survival (bFFS) and overall survival (OS) in low-risk and intermediate-risk prostate cancer patients who received brachytherapy (BT) (either low-dose-rate brachytherapy [LDR-BT] or high-dose-rate brachytherapy with external beam radiation therapy [HDR-BT+EBRT]) versus external beam radiation therapy (EBRT) alone. Patient data were obtained from the ProCaRS database, which contains 7974 prostate cancer patients treated with primary radiation therapy at four Canadian cancer institutions from 1994 to 2010. Propensity score matching was used to obtain the following 3 matched cohorts with balanced baseline prognostic factors: (1) low-risk LDR-BT versus EBRT; (2) intermediate-risk LDR-BT versus EBRT; and (3) intermediate-risk HDR-BT+EBRT versus EBRT. Kaplan-Meier survival analysis was performed to compare differences in bFFS (primary endpoint) and OS in the 3 matched groups. Propensity score matching created acceptable balance in the baseline prognostic factors in all matches. Final matches included 2 1:1 matches in the intermediate-risk cohorts, LDR-BT versus EBRT (total n=254) and HDR-BT+EBRT versus EBRT (total n=388), and one 4:1 match in the low-risk cohort (LDR-BT:EBRT, total n=400). Median follow-up ranged from 2.7 to 7.3 years for the 3 matched cohorts. Kaplan-Meier survival analysis showed that all BT treatment options were associated with statistically significant improvements in bFFS when compared with EBRT in all cohorts (intermediate-risk EBRT vs LDR-BT hazard ratio [HR] 4.58, P=.001; intermediate-risk EBRT vs HDR-BT+EBRT HR 2.08, P=.007; low-risk EBRT vs LDR-BT HR 2.90, P=.004). No significant difference in OS was found in all comparisons (intermediate-risk EBRT vs LDR-BT HR 1.27, P=.687; intermediate-risk EBRT vs HDR-BT+EBRT HR 1.55, P=.470; low-risk LDR-BT vs EBRT HR 1.41, P=.500). Propensity score matched analysis showed that BT options led to statistically significant improvements in bFFS in low- and intermediate-risk prostate cancer patient populations. Copyright © 2015 Elsevier Inc. All rights reserved.

Brachytherapy Improves Biochemical Failure–Free Survival in Low- and Intermediate-Risk Prostate Cancer Compared With Conventionally Fractionated External Beam Radiation Therapy: A Propensity Score Matched Analysis

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

Smith, Graham D.; Pickles, Tom; Crook, Juanita

2015-03-01

Purpose: To compare, in a retrospective study, biochemical failure-free survival (bFFS) and overall survival (OS) in low-risk and intermediate-risk prostate cancer patients who received brachytherapy (BT) (either low-dose-rate brachytherapy [LDR-BT] or high-dose-rate brachytherapy with external beam radiation therapy [HDR-BT+EBRT]) versus external beam radiation therapy (EBRT) alone. Methods and Materials: Patient data were obtained from the ProCaRS database, which contains 7974 prostate cancer patients treated with primary radiation therapy at four Canadian cancer institutions from 1994 to 2010. Propensity score matching was used to obtain the following 3 matched cohorts with balanced baseline prognostic factors: (1) low-risk LDR-BT versus EBRT; (2)more » intermediate-risk LDR-BT versus EBRT; and (3) intermediate-risk HDR-BT+EBRT versus EBRT. Kaplan-Meier survival analysis was performed to compare differences in bFFS (primary endpoint) and OS in the 3 matched groups. Results: Propensity score matching created acceptable balance in the baseline prognostic factors in all matches. Final matches included 2 1:1 matches in the intermediate-risk cohorts, LDR-BT versus EBRT (total n=254) and HDR-BT+EBRT versus EBRT (total n=388), and one 4:1 match in the low-risk cohort (LDR-BT:EBRT, total n=400). Median follow-up ranged from 2.7 to 7.3 years for the 3 matched cohorts. Kaplan-Meier survival analysis showed that all BT treatment options were associated with statistically significant improvements in bFFS when compared with EBRT in all cohorts (intermediate-risk EBRT vs LDR-BT hazard ratio [HR] 4.58, P=.001; intermediate-risk EBRT vs HDR-BT+EBRT HR 2.08, P=.007; low-risk EBRT vs LDR-BT HR 2.90, P=.004). No significant difference in OS was found in all comparisons (intermediate-risk EBRT vs LDR-BT HR 1.27, P=.687; intermediate-risk EBRT vs HDR-BT+EBRT HR 1.55, P=.470; low-risk LDR-BT vs EBRT HR 1.41, P=.500). Conclusions: Propensity score matched analysis showed that BT options led to statistically significant improvements in bFFS in low- and intermediate-risk prostate cancer patient populations.« less

PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.

PubMed

Clarke, Thomas L; Sanchez-Bailon, Maria Pilar; Chiang, Kelly; Reynolds, John J; Herrero-Ruiz, Joaquin; Bandeiras, Tiago M; Matias, Pedro M; Maslen, Sarah L; Skehel, J Mark; Stewart, Grant S; Davies, Clare C

2017-03-02

Protein post-translation modification plays an important role in regulating DNA repair; however, the role of arginine methylation in this process is poorly understood. Here we identify the arginine methyltransferase PRMT5 as a key regulator of homologous recombination (HR)-mediated double-strand break (DSB) repair, which is mediated through its ability to methylate RUVBL1, a cofactor of the TIP60 complex. We show that PRMT5 targets RUVBL1 for methylation at position R205, which facilitates TIP60-dependent mobilization of 53BP1 from DNA breaks, promoting HR. Mechanistically, we demonstrate that PRMT5-directed methylation of RUVBL1 is critically required for the acetyltransferase activity of TIP60, promoting histone H4K16 acetylation, which facilities 53BP1 displacement from DSBs. Interestingly, RUVBL1 methylation did not affect the ability of TIP60 to facilitate ATM activation. Taken together, our findings reveal the importance of PRMT5-mediated arginine methylation during DSB repair pathway choice through its ability to regulate acetylation-dependent control of 53BP1 localization. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

PubMed Central

Schanz, Julie; Tüchler, Heinz; Solé, Francesc; Mallo, Mar; Luño, Elisa; Cervera, José; Granada, Isabel; Hildebrandt, Barbara; Slovak, Marilyn L.; Ohyashiki, Kazuma; Steidl, Christian; Fonatsch, Christa; Pfeilstöcker, Michael; Nösslinger, Thomas; Valent, Peter; Giagounidis, Aristoteles; Aul, Carlo; Lübbert, Michael; Stauder, Reinhard; Krieger, Otto; Garcia-Manero, Guillermo; Faderl, Stefan; Pierce, Sherry; Le Beau, Michelle M.; Bennett, John M.; Greenberg, Peter; Germing, Ulrich; Haase, Detlef

2012-01-01

Purpose The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. Patients and Methods Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. Results In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. Conclusion In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories. PMID:22331955

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

Hamilton, Sarah Nicole; Tyldesley, Scott; Department of Radiation Oncology, British Columbia Cancer Agency–Vancouver Centre, Vancouver, British Columbia

Purpose: To compare the second malignancy incidence in prostate cancer patients treated with brachytherapy (BT) relative to radical prostatectomy (RP) and to compare both groups with the cancer incidence in the general population. Methods and Materials: From 1998 to 2010, 2418 patients were treated with Iodine 125 prostate BT monotherapy at the British Columbia Cancer Agency, and 4015 referred patients were treated with RP. Cancer incidence was compared with the age-matched general population using standardized incidence ratios (SIRs). Pelvic malignancies included invasive and noninvasive bladder cancer and rectal cancer. Cox multivariable analysis was performed with adjustment for covariates to determinemore » whether treatment (RP vs BT) was associated with second malignancy risk. Results: The median age at BT was 66 years and at RP 62 years. The SIR comparing BT patients with the general population was 1.06 (95% confidence interval [CI] 0.91-1.22) for second malignancy and was 1.53 (95% CI 1.12-2.04) for pelvic malignancy. The SIR comparing RP patients with the general population was 1.11 (95% CI 0.98-1.25) for second malignancy and was 1.11 (95% CI 0.82-1.48) for pelvic malignancy. On multivariable analysis, older age (hazard ratio [HR] 1.05) and smoking (HR 1.65) were associated with increased second malignancy risk (P<.0001). Radical prostatectomy was not associated with a decreased second malignancy risk relative to BT (HR 0.90, P=.43), even when excluding patients who received postprostatectomy external beam radiation therapy (HR 1.13, P=.25). Older age (HR 1.09, P<.0001) and smoking (HR 2.17, P=.0009) were associated with increased pelvic malignancy risk. Radical prostatectomy was not associated with a decreased pelvic malignancy risk compared with BT (HR 0.57, P=.082), even when excluding postprostatectomy external beam radiation therapy patients (HR 0.87, P=.56). Conclusions: After adjustment for covariates, BT patients did not have an increased second malignancy risk compared with RP patients. Further follow-up of this cohort is needed given the potential latency of radiation-induced malignancies.« less

External Validity of a Risk Stratification Score Predicting Early Distant Brain Failure and Salvage Whole Brain Radiation Therapy After Stereotactic Radiosurgery for Brain Metastases.

PubMed

Press, Robert H; Boselli, Danielle M; Symanowski, James T; Lankford, Scott P; McCammon, Robert J; Moeller, Benjamin J; Heinzerling, John H; Fasola, Carolina E; Burri, Stuart H; Patel, Kirtesh R; Asher, Anthony L; Sumrall, Ashley L; Curran, Walter J; Shu, Hui-Kuo G; Crocker, Ian R; Prabhu, Roshan S

2017-07-01

A scoring system using pretreatment factors was recently published for predicting the risk of early (≤6 months) distant brain failure (DBF) and salvage whole brain radiation therapy (WBRT) after stereotactic radiosurgery (SRS) alone. Four risk factors were identified: (1) lack of prior WBRT; (2) melanoma or breast histologic features; (3) multiple brain metastases; and (4) total volume of brain metastases <1.3 cm 3 , with each factor assigned 1 point. The purpose of this study was to assess the validity of this scoring system and its appropriateness for clinical use in an independent external patient population. We reviewed the records of 247 patients with 388 brain metastases treated with SRS between 2010 at 2013 at Levine Cancer Institute. The Press (Emory) risk score was calculated and applied to the validation cohort population, and subsequent risk groups were analyzed using cumulative incidence. The low-risk (LR) group had a significantly lower risk of early DBF than did the high-risk (HR) group (22.6% vs 44%, P=.004), but there was no difference between the HR and intermediate-risk (IR) groups (41.2% vs 44%, P=.79). Total lesion volume <1.3 cm 3  (P=.004), malignant melanoma (P=.007), and multiple metastases (P<.001) were validated as predictors for early DBF. Prior WBRT and breast cancer histologic features did not retain prognostic significance. Risk stratification for risk of early salvage WBRT were similar, with a trend toward an increased risk for HR compared with LR (P=.09) but no difference between IR and HR (P=.53). The 3-level Emory risk score was shown to not be externally valid, but the model was able to stratify between 2 levels (LR and not-LR [combined IR and HR]) for early (≤6 months) DBF. These results reinforce the importance of validating predictive models in independent cohorts. Further refinement of this scoring system with molecular information and in additional contemporary patient populations is warranted. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic variation in GABRA2 moderates peer influence on externalizing behavior in adolescents

PubMed Central

Villafuerte, Sandra; Trucco, Elisa M; Heitzeg, Mary M; Burmeister, Margit; Zucker, Robert A

2014-01-01

Background Genetic predisposition and environmental influences are both important factors in the development of problematic behavior leading to substance use in adolescence. Involvement with delinquent peers also strongly predicts adolescent externalizing behavior. Several lines of evidence support a role of GABRA2 on externalizing behavior related to disinhibition. However, whether this genetic association is influenced by the environment such as peer behavior remains unknown. Methods We examined the moderating role of GABRA2 genetic variation on the socialization model of delinquent peer affiliation (at ages 12–14 years) on externalizing behavior (at ages 15–17 years) in the Michigan Longitudinal Study (MLS) adolescent sample. The sample consisted of 244 adolescents (75 females and 152 with at least one parent with a DSM-IV lifetime alcohol dependence/abuse diagnosis). Peer delinquent activity reported by the participant and teacher-reported adolescent externalizing behavior (Teacher Report Form (TRF) were assessed. Results No main effect of the GABRA2 SNP rs279826, which tags a large haplotype, on externalizing behavior was observed. However, there was a statistically reliable GABRA2 × peer delinquency interaction. The effect of peer delinquent involvement on externalizing scores and the rule breaking subscale is significantly stronger for those with the GG genotype compared to A-carriers, whereas there was no effect of genotype on externalizing in the absence of peer delinquent involvement. No interaction was observed for the aggression subscale. Conclusion Our results suggest that the genetic effect of GABRA2 on externalizing behavior, more specifically on rule breaking is, at least in part, due to its effect on susceptibility to environmental exposure (i.e., peer delinquency). PMID:25365806

Integration of Externally Carried Weapon Systems with Military Helicopters (L’Integration des Systemes d’Armes Transportes en Charge Externe sur les Helicopteres Militaires)

DTIC Science & Technology

1990-04-01

Np - Yaw to Roll Derivative (Yaw/Roll Coupling) Hr - Yaw to Yaw Rate Derivative (Yaw Damping) M - Pitch to Incidence Derivative (Incidence Stability) F...system is installed in the same configuration as used on the land based vehicle, simply by bolting-on to the limited number of available hard points...helicopters not originally designed to take external loads. The limited number of hard points on the fuselage structure leads to define supports of complex

KSC-99pp0199

NASA Image and Video Library

1999-02-09

KENNEDY SPACE CENTER, FLA. -- An external tank is suspended in the transfer aisle of the Vehicle Assembly Building before being placed into its storage compartment. The largest and heaviest element of the Space Shuttle, an external tank contains the liquid hydrogen fuel and liquid oxygen oxidizer for the three Space Shuttle main engines (SSMEs) in the orbiter during liftoff and ascent. When the SSMEs are shut down, the external tank is jettisoned, breaking up as it enters the Earth's atmopshere and impacting in a remote ocean area. It is not recovered

Resistance-breaking population of Meloidogyne incognita utilizes plant peroxidase to scavenge reactive oxygen species, thereby promoting parasitism on tomato carrying Mi-1 gene.

PubMed

Guan, Tinglong; Shen, Jinhua; Fa, Yang; Su, Yishi; Wang, Xuan; Li, Hongmei

2017-01-01

Resistance conferred by the Mi-1 gene from Solanum peruvianum is effective and widely used for controlling root-knot nematodes (RKNs, Meloidogyne spp.). However, breakdown of resistance by RKNs seriously threatens the durable application of the resistance resource. Here, a resistance-breaking population of M. incognita was selected from an avirulent population by continuously inoculating on Mi-1-carrying tomato. Histological observations showed the resistance-breaking population would not induce hypersensitive response (HR) when infecting Mi-1-carrying tomato, while avirulent population did. A total of 308 differentially expressed genes (DEGs) were identified from Mi-1-carrying tomato upon infection with resistance-breaking versus avirulent populations by RNA-seq. The expression patterns of 23 selected DEGs were validated by quantitative real-time PCR (qRT-PCR). Subsequently, seven out of nine highly up-regulated DEGs were successfully knocked down in Mi-1-carrying tomato by tobacco rattle virus (TRV) mediated RNAi. The TRV line targeting a peroxidase gene showed a much higher magnitude of reactive oxygen species (ROS) and distinct reduction of pathogenicity upon infection of the resistance-breaking population compared with that of TRV::gfp line. Our results suggested that plant peroxidase might be exploited by resistance-breaking population of M. incognita to scavenge ROS, so as to overcome Mi-1-mediated resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Preclinical evaluation of the PARP inhibitor BMN-673 for the treatment of ovarian clear cell cancer

PubMed Central

Samartzis, Eleftherios Pierre; Dedes, Ioannis; Lambros, Maryou B; Natrajan, Rachael; Gauthier, Arnaud; Piscuoglio, Salvatore; Töpfer, Chantal; Vukovic, Vesna; Daley, Frances; Weigelt, Britta; Reis-Filho, Jorge S

2017-01-01

Purpose To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition. Experimental Design The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry. Results A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 –9.4 (SD +/− 0.29) vs –8.1 (SD +/− 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases. Conclusions A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs. PMID:28002809

Prolonged particulate chromate exposure does not inhibit homologous recombination repair in North Atlantic right whale (Eubalaena glacialis) lung cells.

PubMed

Browning, Cynthia L; Wise, Catherine F; Wise, John Pierce

2017-09-15

Chromosome instability is a common feature of cancers that forms due to the misrepair of DNA double strand breaks. Homologous recombination (HR) repair is a high fidelity DNA repair pathway that utilizes a homologous DNA sequence to accurately repair such damage and protect the genome. Prolonged exposure (>72h) to the human lung carcinogen, particulate hexavalent chromium (Cr(VI)), inhibits HR repair, resulting in increased chromosome instability in human cells. Comparative studies have shown acute Cr(VI) exposure induces less chromosome damage in whale cells than human cells, suggesting investigating the effect of this carcinogen in other species may inform efforts to prevent Cr(VI)-induced chromosome instability. Thus, the goal of this study was to determine the effect of prolonged Cr(VI) exposure on HR repair and clastogenesis in North Atlantic right whale (Eubalaena glacialis) lung cells. We show particulate Cr(VI) induces HR repair activity after both acute (24h) and prolonged (120h) exposure in North Atlantic right whale cells. Although the RAD51 response was lower following prolonged Cr(VI) exposure compared to acute exposure, the response was sufficient for HR repair to occur. In accordance with active HR repair, no increase in Cr(VI)-induced clastogenesis was observed with increased exposure time. These results suggest prolonged Cr(VI) exposure affects HR repair and genomic stability differently in whale and human lung cells. Future investigation of the differences in how human and whale cells respond to chemical carcinogens may provide valuable insight into mechanisms of preventing chemical carcinogenesis. Copyright © 2017. Published by Elsevier Inc.

Individually Coded Telemetry: a Tool for Studying Heart Rate and Behaviour in Reindeer Calves

PubMed Central

Eloranta, E; Norberg, H; Nilsson, A; Pudas, T; Säkkinen, H

2002-01-01

The aim of the study was to test the performance of a silver wire modified version of the coded telemetric heart rate monitor Polar Vantage NV™ (PVNV) and to measure heart rate (HR) in a group of captive reindeer calves during different behaviour. The technical performance of PVNV HR monitors was tested in cold conditions (-30°C) using a pulse generator and the correlation between generated pulse and PVNV values was high (r = 0.9957). The accuracy was tested by comparing the HR obtained with the PVNV monitor with the standard ECG, and the correlation was significant (r = 0.9965). Both circadian HR and HR related to behavioural pattern were recorded. A circadian rhythm was observed in the HR in reindeer with a minimum during night and early morning hours and maximum at noon and during the afternoon, the average HR of the reindeer calves studied being 42.5 beats/min in February. The behaviour was recorded by focal individual observations and the data was synchronized with the output of the HR monitors. Running differed from all other behavioural categories in HR. Inter-individual differences were seen expressing individual responses to external and internal stimuli. The silver wire modified Polar Vantage NV™ provides a suitable and reliable tool for measuring heart rate in reindeer, also in natural conditions. PMID:12564543

Nasal Dilators (Breathe Right Strips and NoZovent) for Snoring and OSA: A Systematic Review and Meta-Analysis

PubMed Central

Malu, Omojo O.; Kram, Yoseph A.; Song, Sungjin A.; Tolisano, Anthony M.; Kushida, Clete A.

2016-01-01

Objective. To systematically review the international literature for studies evaluating internal (NoZovent) and external (Breathe Right Strips) nasal dilators as treatment for obstructive sleep apnea (OSA). Study Design. Systematic review with meta-analysis. Methods. Four databases, including PubMed/MEDLINE, were searched through September 29, 2016. Results. One-hundred twelve studies were screened, fifty-eight studies were reviewed, and fourteen studies met criteria. In 147 patients, the apnea-hypopnea index (AHI) was reported, and there was an improvement from a mean ± standard deviation (M ± SD) of 28.7 ± 24.0 to 27.4 ± 23.3 events/hr, p value 0.64. There was no significant change in AHI, lowest oxygen saturation, or snoring index in OSA patients when using nasal dilators. However, a subanalysis demonstrated a slight reduction in apnea index (AI) with internal nasal dilators (decrease by 4.87 events/hr) versus minimal change for external nasal dilators (increase by 0.64 events/hr). Conclusion. Although nasal dilators have demonstrated improved nasal breathing, they have not shown improvement in obstructive sleep apnea outcomes, with the exception of mild improvement in apnea index when internal nasal dilators were used. PMID:28070421

Supramolecular Systems and Chemical Reactions in Single-Molecule Break Junctions.

PubMed

Li, Xiaohui; Hu, Duan; Tan, Zhibing; Bai, Jie; Xiao, Zongyuan; Yang, Yang; Shi, Jia; Hong, Wenjing

2017-04-01

The major challenges of molecular electronics are the understanding and manipulation of the electron transport through the single-molecule junction. With the single-molecule break junction techniques, including scanning tunneling microscope break junction technique and mechanically controllable break junction technique, the charge transport through various single-molecule and supramolecular junctions has been studied during the dynamic fabrication and continuous characterization of molecular junctions. This review starts from the charge transport characterization of supramolecular junctions through a variety of noncovalent interactions, such as hydrogen bond, π-π interaction, and electrostatic force. We further review the recent progress in constructing highly conductive molecular junctions via chemical reactions, the response of molecular junctions to external stimuli, as well as the application of break junction techniques in controlling and monitoring chemical reactions in situ. We suggest that beyond the measurement of single molecular conductance, the single-molecule break junction techniques provide a promising access to study molecular assembly and chemical reactions at the single-molecule scale.

Direct Measure of Radiative and Dynamical Properties of an Exoplanet Atmosphere

NASA Astrophysics Data System (ADS)

de Wit, Julien; Lewis, Nikole K.; Langton, Jonathan; Laughlin, Gregory; Deming, Drake; Batygin, Konstantin; Fortney, Jonathan J.

2016-04-01

Two decades after the discovery of 51 Peg b, the formation processes and atmospheres of short-period gas giants remain poorly understood. Observations of eccentric systems provide key insights on those topics as they can illuminate how a planet’s atmosphere responds to changes in incident flux. We report here the analysis of multi-day multi-channel photometry of the eccentric (e∼ 0.93) hot Jupiter HD 80606 b obtained with the Spitzer Space Telescope. The planet’s extreme eccentricity combined with the long coverage and exquisite precision of new periastron-passage observations allow us to break the degeneracy between the radiative and dynamical timescales of HD 80606 b’s atmosphere and constrain its global thermal response. Our analysis reveals that the atmospheric layers probed heat rapidly (∼4 hr radiative timescale) from \\lt 500 to 1400 K as they absorb ∼ 20% of the incoming stellar flux during the periastron passage, while the planet’s rotation period is {93}-35+85 hr, which exceeds the predicted pseudo-synchronous period (40 hr).

DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair

PubMed Central

Serrano, Moises A.; Li, Zhengke; Dangeti, Mohan; Musich, Phillip R.; Patrick, Steve; Roginskaya, Marina; Cartwright, Brian; Zou, Yue

2012-01-01

Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are two distinct DNA double-strand break (DSB) repair pathways. Here we report that DNA-dependent protein kinase (DNA-PK), the core component of NHEJ, partnering with DNA-damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), regulates HR repair of DSBs. The regulation was accomplished through modulation of the p53 and replication protein A (RPA) interaction. We show that upon DNA damage, p53 and RPA were freed from a p53-RPA complex by simultaneous phosphorylations of RPA at the N-terminus of RPA32 subunit by DNA-PK and of p53 at Ser37 and Ser46 in a Chk1/Chk2-independent manner by ATR and ATM, respectively. Neither the phosphorylation of RPA nor of p53 alone could dissociate p53 and RPA. Furthermore, disruption of the release significantly compromised HR repair of DSBs. Our results reveal a mechanism for the crosstalk between HR repair and NHEJ through the co-regulation of p53-RPA interaction by DNA-PK, ATM and ATR. PMID:22797063

DNA-PK, ATM and ATR collaboratively regulate p53-RPA interaction to facilitate homologous recombination DNA repair.

PubMed

Serrano, M A; Li, Z; Dangeti, M; Musich, P R; Patrick, S; Roginskaya, M; Cartwright, B; Zou, Y

2013-05-09

Homologous recombination (HR) and nonhomologous end joining (NHEJ) are two distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-dependent protein kinase (DNA-PK), the core component of NHEJ, partnering with DNA-damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), regulates HR repair of DSBs. The regulation was accomplished through modulation of the p53 and replication protein A (RPA) interaction. We show that upon DNA damage, p53 and RPA were freed from a p53-RPA complex by simultaneous phosphorylations of RPA at the N-terminus of RPA32 subunit by DNA-PK and of p53 at Ser37 and Ser46 in a Chk1/Chk2-independent manner by ATR and ATM, respectively. Neither the phosphorylation of RPA nor of p53 alone could dissociate p53 and RPA. Furthermore, disruption of the release significantly compromised HR repair of DSBs. Our results reveal a mechanism for the crosstalk between HR repair and NHEJ through the co-regulation of p53-RPA interaction by DNA-PK, ATM and ATR.

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer

PubMed Central

Bosch, Linda J.W.; Coupé, Veerle M.H.; Mongera, Sandra; Haan, Josien C.; Richman, Susan D.; Koopman, Miriam; Tol, Jolien; de Meyer, Tim; Louwagie, Joost; Dehaspe, Luc; van Grieken, Nicole C.T.; Ylstra, Bauke; Verheul, Henk M.W.; van Engeland, Manon; Nagtegaal, Iris D.; Herman, James G.; Quirke, Philip; Seymour, Matthew T.; Punt, Cornelis J.A.; van Criekinge, Wim; Carvalho, Beatriz; Meijer, Gerrit A.

2017-01-01

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 (DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p=0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p=0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p=0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p=0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1: HR=0.7 (95%CI 0.5-0.9, p=0.01), unmethylated DCR1: HR=0.8 (95%CI 0.6-1.2, p=0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials. PMID:28968978

Is modern external beam radiotherapy with androgen deprivation therapy still a viable alternative for prostate cancer in an era of robotic surgery and brachytherapy: a comparison of Australian series.

PubMed

Wilcox, Shea William; Aherne, Noel J; McLachlan, Craig Steven; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2015-02-01

We compare the results of modern external-beam radiotherapy (EBRT), using combined androgen deprivation and dose-escalated intensity-modulated radiotherapy with MRI-CT fusion and daily image guidance with fiducial markers (DE-IG-IMRT), with recently published Australian series of brachytherapy and surgery. Five-year actuarial biochemical disease-free survival (bDFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCaSS) were calculated for 675 patients treated with DE-IG-IMRT and androgen deprivation therapy (ADT). Patients had intermediate-risk (IR) and high-risk (HR) disease. A search was conducted identifying Australian reports from 2005 onwards of IR and HR patients treated with surgery or brachytherapy, reporting actuarial outcomes at 3 years or later. With a median follow-up of 59 months, our 5-year bDFS was 93.3% overall: 95.5% for IR and 91.3% for HR disease. MFS was 96.9% overall (99.0% IR, 94.9% HR), and PCaSS was 98.8% overall (100% IR, 97.7% HR). Prevalence of Grade 2 genitourinary and gastrointestinal toxicity at 5 years was 1.3% and 1.6%, with 0.3% Grade 3 genitourinary toxicity and no Grade 3 gastrointestinal toxicity. Eight reports of brachytherapy and surgery were identified. The HDR brachytherapy series' median 5-year bDFS was 82.5%, MFS 90.0% and PCaSS 97.9%. One surgical series reported 5-year bDFS of 65.5% for HR patients. One LDR series reported 5-year bDFS of 85% for IR patients. Modern EBRT is at least as effective as modern Australian surgical and brachytherapy techniques. All patients considering treatment for localised prostate cancer should be referred to a radiation oncologist to discuss EBRT as an equivalent option. © 2015 The Royal Australian and New Zealand College of Radiologists.

Decoy receptor 1 (DCR1) promoter hypermethylation and response to irinotecan in metastatic colorectal cancer.

PubMed

Bosch, Linda J W; Trooskens, Geert; Snaebjornsson, Petur; Coupé, Veerle M H; Mongera, Sandra; Haan, Josien C; Richman, Susan D; Koopman, Miriam; Tol, Jolien; de Meyer, Tim; Louwagie, Joost; Dehaspe, Luc; van Grieken, Nicole C T; Ylstra, Bauke; Verheul, Henk M W; van Engeland, Manon; Nagtegaal, Iris D; Herman, James G; Quirke, Philip; Seymour, Matthew T; Punt, Cornelis J A; van Criekinge, Wim; Carvalho, Beatriz; Meijer, Gerrit A

2017-09-08

Diversity in colorectal cancer biology is associated with variable responses to standard chemotherapy. We aimed to identify and validate DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of metastatic CRC patients. Candidate genes were selected from 389 genes involved in DNA Damage Repair by correlation analyses between gene methylation status and drug response in 32 cell lines. A large series of samples (n=818) from two phase III clinical trials was used to evaluate these candidate genes by correlating methylation status to progression-free survival after treatment with first-line single-agent fluorouracil (Capecitabine or 5-fluorouracil) or combination chemotherapy (Capecitabine or 5-fluorouracil plus irinotecan (CAPIRI/FOLFIRI)). In the discovery (n=185) and initial validation set (n=166), patients with methylated Decoy Receptor 1 ( DCR1) did not benefit from CAPIRI over Capecitabine treatment (discovery set: HR=1.2 (95%CI 0.7-1.9, p =0.6), validation set: HR=0.9 (95%CI 0.6-1.4, p =0.5)), whereas patients with unmethylated DCR1 did (discovery set: HR=0.4 (95%CI 0.3-0.6, p =0.00001), validation set: HR=0.5 (95%CI 0.3-0.7, p =0.0008)). These results could not be replicated in the external data set (n=467), where a similar effect size was found in patients with methylated and unmethylated DCR1 for FOLFIRI over 5FU treatment (methylated DCR1 : HR=0.7 (95%CI 0.5-0.9, p =0.01), unmethylated DCR1 : HR=0.8 (95%CI 0.6-1.2, p =0.4)). In conclusion, DCR1 promoter hypermethylation status is a potential predictive biomarker for response to treatment with irinotecan, when combined with capecitabine. This finding could not be replicated in an external validation set, in which irinotecan was combined with 5FU. These results underline the challenge and importance of extensive clinical evaluation of candidate biomarkers in multiple trials.

Handball load and shoulder injury rate: a 31-week cohort study of 679 elite youth handball players.

PubMed

Møller, M; Nielsen, R O; Attermann, J; Wedderkopp, N; Lind, M; Sørensen, H; Myklebust, G

2017-02-01

Knowledge of injury patterns, an essential step towards injury prevention, is lacking in youth handball. To investigate if an increase in handball load is associated with increased shoulder injury rates compared with a minor increase or decrease, and if an association is influenced by scapular control, isometric shoulder strength or glenohumeral range of motion (ROM). 679 players (14-18 years) provided weekly reports on shoulder injury and handball load (training and competition hours) over 31 weeks using the SMS, phone and medical examination system. Handball load in a given week was categorised into (1) <20% increase or decrease (reference), (2) increase between 20% and 60% and (3) increase >60% relative to the weekly average amount of handball load the preceding 4 weeks. Assessment of shoulder isometric rotational and abduction strength, ROM and scapular control was performed at baseline and midseason. An increase in handball load by >60% was associated with greater shoulder injury rate (HR 1.91; 95% CI 1.00 to 3.70, p=0.05) compared with the reference group. The effect of an increase in handball load between 20% and 60% was exacerbated among players with reduced external rotational strength (HR 4.0; 95% CI 1.1 to 15.2, p=0.04) or scapular dyskinesis (HR 4.8; 95% CI 1.3 to 18.3, p=0.02). Reduced external rotational strength exacerbated the effect of an increase above 60% (HR 4.2; 95% CI 1.4 to 12.8, p=0.01). A large increase in weekly handball load increases the shoulder injury rate in elite youth handball players; particularly, in the presence of reduced external rotational strength or scapular dyskinesis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Environmental applications of single collector high resolution ICP-MS.

PubMed

Krachler, Michael

2007-08-01

The number of environmental applications of single collector high resolution ICP-MS (HR-ICP-MS) has increased rapidly in recent years. There are many factors that contribute to make HR-ICP-MS a very powerful tool in environmental analysis. They include the extremely low detection limits achievable, tremendously high sensitivity, the ability to separate ICP-MS signals of the analyte from spectral interferences, enabling the reliable determination of many trace elements, and the reasonable precision of isotope ratio measurements. These assets are improved even further using high efficiency sample introduction systems. Therefore, external factors such as the stability of laboratory blanks are frequently the limiting factor in HR-ICP-MS analysis rather than the detection power. This review aims to highlight the most recent applications of HR-ICP-MS in this sector, focusing on matrices and applications where the superior capabilities of the instrumental technique are most useful and often ultimately required.

Breakdown of String Perturbation Theory for Many External Particles.

PubMed

Ghosh, Sudip; Raju, Suvrat

2017-03-31

We consider massless string scattering amplitudes in a limit where the number of external particles becomes very large, while the energy of each particle remains small. Using the growth of the volume of the relevant moduli space, and by means of independent numerical evidence, we argue that string perturbation theory breaks down in this limit. We discuss some remarkable implications for the information paradox.

A new method for stable lead isotope extraction from seawater.

PubMed

Zurbrick, Cheryl M; Gallon, Céline; Flegal, A Russell

2013-10-24

A new technique for stable lead (Pb) isotope extraction from seawater is established using Toyopearl AF-Chelate 650M(®) resin (Tosoh Bioscience LLC). This new method is advantageous because it is semi-automated and relatively fast; in addition it introduces a relatively low blank by minimizing the volume of chemicals used in the extraction. Subsequent analyses by HR ICP-MS have a good relative external precision (2σ) of 3.5‰ for (206)Pb/(207)Pb, while analyses by MC-ICP-MS have a better relative external precision of 0.6‰. However, Pb sample concentrations limit MC-ICP-MS analyses to (206)Pb, (207)Pb, and (208)Pb. The method was validated by processing the common Pb isotope reference material NIST SRM-981 and several GEOTRACES intercalibration samples, followed by analyses by HR ICP-MS, all of which showed good agreement with previously reported values. Copyright © 2013 Elsevier B.V. All rights reserved.

A comparison of laser ablation-inductively coupled plasma-mass spectrometry and high-resolution continuum source graphite furnace molecular absorption spectrometry for the direct determination of bromine in polymers

NASA Astrophysics Data System (ADS)

de Gois, Jefferson S.; Van Malderen, Stijn J. M.; Cadorim, Heloisa R.; Welz, Bernhard; Vanhaecke, Frank

2017-06-01

This work describes the development and comparison of two methods for the direct determination of Br in polymer samples via solid sampling, one using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and the other using high-resolution continuum source graphite furnace molecular absorption spectrometry with direct solid sample analysis (HR-CS SS-GF MAS). The methods were optimized and their accuracy was evaluated by comparing the results obtained for 6 polymeric certified reference materials (CRMs) with the corresponding certified values. For Br determination with LA-ICP-MS, the 79Br+ signal could be monitored interference-free. For Br determination via HR-CS SS-GF MAS, the CaBr molecule was monitored at 625.315 nm with integration of the central pixel ± 1. Bromine quantification by LA-ICP-MS was performed via external calibration against a single CRM while using the 12C+ signal as an internal standard. With HR-CS SS-GF MAS, Br quantification could be accomplished using external calibration against aqueous standard solutions. Except for one LA-ICP-MS result, the concentrations obtained with both techniques were in agreement with the certified values within the experimental uncertainty as evidenced using a t-test (95% confidence level). The limit of quantification was determined to be 100 μg g- 1 Br for LA-ICP-MS and 10 μg g- 1 Br for HR-CS SS-GF MAS.

In Vitro Expansion of Bone Marrow Derived Mesenchymal Stem Cells Alters DNA Double Strand Break Repair of Etoposide Induced DNA Damage.

PubMed

Hare, Ian; Gencheva, Marieta; Evans, Rebecca; Fortney, James; Piktel, Debbie; Vos, Jeffrey A; Howell, David; Gibson, Laura F

2016-01-01

Mesenchymal stem cells (MSCs) are of interest for use in diverse cellular therapies. Ex vivo expansion of MSCs intended for transplantation must result in generation of cells that maintain fidelity of critical functions. Previous investigations have identified genetic and phenotypic alterations of MSCs with in vitro passage, but little is known regarding how culturing influences the ability of MSCs to repair double strand DNA breaks (DSBs), the most severe of DNA lesions. To investigate the response to DSB stress with passage in vitro, primary human MSCs were exposed to etoposide (VP16) at various passages with subsequent evaluation of cellular damage responses and DNA repair. Passage number did not affect susceptibility to VP16 or the incidence and repair kinetics of DSBs. Nonhomologous end joining (NHEJ) transcripts showed little alteration with VP16 exposure or passage; however, homologous recombination (HR) transcripts were reduced following VP16 exposure with this decrease amplified as MSCs were passaged in vitro. Functional evaluations of NHEJ and HR showed that MSCs were unable to activate NHEJ repair following VP16 stress in cells after successive passage. These results indicate that ex vivo expansion of MSCs alters their ability to perform DSB repair, a necessary function for cells intended for transplantation.

Structural Continuum Modeling of Space Shuttle External Tank Foam Insulation

NASA Technical Reports Server (NTRS)

Steeve, Brian; Ayala, Sam; Purlee, T. Eric; Shaw, Phillip

2006-01-01

This document is a viewgraph presentation reporting on work in modeling the foam insulation of the Space Shuttle External Tank. An analytical understanding of foam mechanics is required to design against structural failure. The Space Shuttle External Tank is covered primarily with closed cell foam to: Prevent ice, Protect structure from ascent aerodynamic and engine plume heating, and Delay break-up during re-entry. It is important that the foam does not shed unacceptable debris during ascent environment. Therefore a modeling of the foam insulation was undertaken.

An examination of a modified Yo-Yo test to measure intermittent running performance in rugby players.

PubMed

Dobbin, Nick; Moss, Samantha Louise; Highton, Jamie; Twist, Craig

2018-06-17

This study examined how starting each shuttle in the prone position altered the internal, external and perceptual responses to the Yo-Yo Intermittent Recovery Test Level 1 (Yo-Yo IR1). Using a randomized crossover design, 17 male rugby players completed the Yo-Yo IR1 and prone Yo-Yo IR1 on two separate occasions. External loads (via microtechnology), [Formula: see text], heart rate (HR) and rating of perceived exertion (RPE) were measured at 160, 280 and 440 m (sub-maximal) and when the test was terminated (peak). The pre-to-post change in blood lactate concentration (Δ[La] b ) was determined for both tests. All data were analysed using effect sizes (ES) and magnitude-based inferences. Between-trial differences (ES ± 90% CL) indicated that total distance was most likely lower (-1.87 ± 0.19), whereas other measures of peak external load were likely to very likely higher during the prone Yo-Yo IR1 (0.62-1.80). Sub-maximal RPE was likely to most likely higher (0.40-0.96) and peak RPE very likely higher (0.63 ± 0.41) in the prone Yo-Yo IR1. The change in [La] b was likely higher after the prone Yo-Yo IR1. Mean HR was possibly lower at 440 m (-0.25 ± 0.29) as was peak HR (-0.26 ± 0.25) in the prone Yo-Yo IR1. [Formula: see text], [Formula: see text] and [Formula: see text] were likely to very likely higher at 280 and 440 m (ES = 0.36-1.22), while peak values were possibly to likely higher (ES = 0.23-0.37) in the prone Yo-Yo IR1. Adopting a prone position during the Yo-Yo IR1 increases the internal, external and perceptual responses, placing greater emphasis on metabolically demanding actions typical of rugby.

Developmental transitions in presentations of externalizing problems among boys and girls at risk for child maltreatment.

PubMed

Villodas, Miguel T; Litrownik, Alan J; Thompson, Richard; Jones, Deborah; Roesch, Scott C; Hussey, Jon M; Block, Stephanie; English, Diana J; Dubowitz, Howard

2015-02-01

The present study examined the impact of children's maltreatment experiences on the emergence of externalizing problem presentations among children during different developmental periods. The sample included 788 youth and their caregivers who participated in a multisite, prospective study of youth at-risk for maltreatment. Externalizing problems were assessed at ages 4, 8, and 12, and symptoms and diagnoses of attention-deficit/hyperactivity disorder, oppositional defiant disorder, and conduct disorder were assessed at age 14, during interviews with youth and caregivers. Information about maltreatment allegations was coded from official records. Latent transition analysis identified three groups of youth with similar presentations of externalizing problems ("well adjusted," "hyperactive/oppositional," and "aggressive/rule-breaking") and transitions between groups from ages 4, 8, and 12. A "defiant/deceitful" group also emerged at age 12. Girls were generally more likely to present as well adjusted than boys. Children with recent physical abuse allegations had an increased risk for aggressive/rule-breaking presentations during the preschool and preadolescent years, while children with sexual abuse or neglect allegations had lower probabilities of having well-adjusted presentations during middle childhood. These findings indicate that persistently severe aggressive conduct problems, which are related to the most concerning outcomes, can be identified early, particularly among neglected and physically and sexually abused children.

Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells.

PubMed

Renaud, Emilie; Barascu, Aurelia; Rosselli, Filippo

2016-01-29

To rescue collapsed replication forks cells utilize homologous recombination (HR)-mediated mechanisms to avoid the induction of gross chromosomal abnormalities that would be generated by non-homologous end joining (NHEJ). Using DNA interstrand crosslinks as a replication barrier, we investigated how the Fanconi anemia (FA) pathway promotes HR at stalled replication forks. FA pathway inactivation results in Fanconi anemia, which is associated with a predisposition to cancer. FANCD2 monoubiquitination and assembly in subnuclear foci appear to be involved in TIP60 relocalization to the chromatin to acetylates histone H4K16 and prevents the binding of 53BP1 to its docking site, H4K20Me2. Thus, FA pathway loss-of-function results in accumulation of 53BP1, RIF1 and RAP80 at damaged chromatin, which impair DNA resection at stalled replication fork-associated DNA breaks and impede HR. Consequently, DNA repair in FA cells proceeds through the NHEJ pathway, which is likely responsible for the accumulation of chromosome abnormalities. We demonstrate that the inhibition of NHEJ or deacetylase activity rescue HR in FA cells. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Characterization of Brca2-Deficient Plants Excludes the Role of NHEJ and SSA in the Meiotic Chromosomal Defect Phenotype

PubMed Central

Dumont, Marilyn; Massot, Sophie; Doutriaux, Marie-Pascale; Gratias, Ariane

2011-01-01

In somatic cells, three major pathways are involved in the repair of DNA double-strand breaks (DBS): Non-Homologous End Joining (NHEJ), Single-Strand Annealing (SSA) and Homologous Recombination (HR). In somatic and meiotic HR, DNA DSB are 5′ to 3′ resected, producing long 3′ single-stranded DNA extensions. Brca2 is essential to load the Rad51 recombinase onto these 3′ overhangs. The resulting nucleofilament can thus invade a homologous DNA sequence to copy and restore the original genetic information. In Arabidopsis, the inactivation of Brca2 specifically during meiosis by an RNAi approach results in aberrant chromosome aggregates, chromosomal fragmentation and missegregation leading to a sterility phenotype. We had previously suggested that such chromosomal behaviour could be due to NHEJ. In this study, we show that knock-out plants affected in both BRCA2 genes show the same meiotic phenotype as the RNAi-inactivated plants. Moreover, it is demonstrated that during meiosis, neither NHEJ nor SSA compensate for HR deficiency in BRCA2-inactivated plants. The role of the plant-specific DNA Ligase6 is also excluded. The possible mechanism(s) involved in the formation of these aberrant chromosomal bridges in the absence of HR during meiosis are discussed. PMID:22039535

Modification of Electron Cyclotron Maser Operation by Application of an External Signal.

DTIC Science & Technology

1987-03-31

start-up phase jitter in the presence of this external priming signal can be estimated by using the method of David [30]. A lumped circuit representation...27. K.E. Kreischer, R.J. Temkin, H.R. Fetterman , and W.I. Mulligan, IEEE Trans. Microwave Theory Tech. MTT-32, 481 (1984). 28. I.G. Zarnitsyna and G.S...Nusinovich, Radiophys. Quant. Electron. 17, 1418 (1974). 29. G.S. Nusinovich, Radiophys. Quant. Electron. 19, 1301 (1976). 30. E.E. David Jr., Proc

KSC-99pp0198

NASA Image and Video Library

1999-02-09

KENNEDY SPACE CENTER, FLA. -- In the transfer aisle of the Vehicle Assembly Building, Atlantis awaits a vacancy in one of the Orbiter Processing Facility bays. Seen behind the left wing is an external tank being raised to a vertical position. The largest and heaviest element of the Space Shuttle, an external tank contains the liquid hydrogen fuel and liquid oxygen oxidizer for the three Space Shuttle main engines (SSMEs) in the orbiter during liftoff and ascent. When the SSMEs are shut down, the external tank is jettisoned, breaking up as it enters the Earth's atmopshere and impacting in a remote ocean area. It is not recovered

KSC-99pp0197

NASA Image and Video Library

1999-02-09

KENNEDY SPACE CENTER, FLA. -- In the transfer aisle of the Vehicle Assembly Building, Atlantis awaits a vacancy in one of the Orbiter Processing Facility bays. Seen behind the right wing is an external tank being raised to a vertical position. The largest and heaviest element of the Space Shuttle, an external tank contains the liquid hydrogen fuel and liquid oxygen oxidizer for the three Space Shuttle main engines (SSMEs) in the orbiter during liftoff and ascent. When the SSMEs are shut down, the external tank is jettisoned, breaking up as it enters the Earth's atmopshere and impacting in a remote ocean area. It is not recovered

Smartphone-Based Cardiac Rehabilitation Program: Feasibility Study.

PubMed

Chung, Heewon; Ko, Hoon; Thap, Tharoeun; Jeong, Changwon; Noh, Se-Eung; Yoon, Kwon-Ha; Lee, Jinseok

2016-01-01

We introduce a cardiac rehabilitation program (CRP) that utilizes only a smartphone, with no external devices. As an efficient guide for cardiac rehabilitation exercise, we developed an application to automatically indicate the exercise intensity by comparing the estimated heart rate (HR) with the target heart rate zone (THZ). The HR is estimated using video images of a fingertip taken by the smartphone's built-in camera. The introduced CRP app includes pre-exercise, exercise with intensity guidance, and post-exercise. In the pre-exercise period, information such as THZ, exercise type, exercise stage order, and duration of each stage are set up. In the exercise with intensity guidance, the app estimates HR from the pulse obtained using the smartphone's built-in camera and compares the estimated HR with the THZ. Based on this comparison, the app adjusts the exercise intensity to shift the patient's HR to the THZ during exercise. In the post-exercise period, the app manages the ratio of the estimated HR to the THZ and provides a questionnaire on factors such as chest pain, shortness of breath, and leg pain during exercise, as objective and subjective evaluation indicators. As a key issue, HR estimation upon signal corruption due to motion artifacts is also considered. Through the smartphone-based CRP, we estimated the HR accuracy as mean absolute error and root mean squared error of 6.16 and 4.30bpm, respectively, with signal corruption due to motion artifacts being detected by combining the turning point ratio and kurtosis.

Smartphone-Based Cardiac Rehabilitation Program: Feasibility Study

PubMed Central

Chung, Heewon; Yoon, Kwon-Ha; Lee, Jinseok

2016-01-01

We introduce a cardiac rehabilitation program (CRP) that utilizes only a smartphone, with no external devices. As an efficient guide for cardiac rehabilitation exercise, we developed an application to automatically indicate the exercise intensity by comparing the estimated heart rate (HR) with the target heart rate zone (THZ). The HR is estimated using video images of a fingertip taken by the smartphone’s built-in camera. The introduced CRP app includes pre-exercise, exercise with intensity guidance, and post-exercise. In the pre-exercise period, information such as THZ, exercise type, exercise stage order, and duration of each stage are set up. In the exercise with intensity guidance, the app estimates HR from the pulse obtained using the smartphone’s built-in camera and compares the estimated HR with the THZ. Based on this comparison, the app adjusts the exercise intensity to shift the patient’s HR to the THZ during exercise. In the post-exercise period, the app manages the ratio of the estimated HR to the THZ and provides a questionnaire on factors such as chest pain, shortness of breath, and leg pain during exercise, as objective and subjective evaluation indicators. As a key issue, HR estimation upon signal corruption due to motion artifacts is also considered. Through the smartphone-based CRP, we estimated the HR accuracy as mean absolute error and root mean squared error of 6.16 and 4.30bpm, respectively, with signal corruption due to motion artifacts being detected by combining the turning point ratio and kurtosis. PMID:27551969

Tunable spin splitting and spin lifetime in polar WSTe monolayer

NASA Astrophysics Data System (ADS)

Adhib Ulil Absor, Moh.; Kotaka, Hiroki; Ishii, Fumiyuki; Saito, Mineo

2018-04-01

The established spin splitting with out-of-plane Zeeman spin polarizations in the monolayer (ML) of transition metal dichalcogenides (TMDs) is dictated by inversion symmetry breaking together with mirror symmetry in the surface plane. Here, by density functional theory calculations, we find that mirror symmetry breaking in the polar WSTe ML leads to large spin splitting exhibiting in-plane Rashba spin polarizations. We also find that the interplay between the out-of-plane Zeeman- and in-plane Rashba spin-polarized states sensitively affects the spin lifetime, which can be effectively controlled by in-plane strain. In addition, the tunability of spin splitting using an external electric field is also demonstrated. Our study clarifies that the use of in-plane strain and an external electric field is effective for tuning the spin splitting and spin lifetime of the polar WSTe ML; thus, it is useful for designing spintronic devices.

Spontaneous decoherence of coupled harmonic oscillators confined in a ring

NASA Astrophysics Data System (ADS)

Gong, ZhiRui; Zhang, ZhenWei; Xu, DaZhi; Zhao, Nan; Sun, ChangPu

2018-04-01

We study the spontaneous decoherence of coupled harmonic oscillators confined in a ring container, where the nearest-neighbor harmonic potentials are taken into consideration. Without any external symmetry-breaking field or surrounding environment, the quantum superposition state prepared in the relative degrees of freedom gradually loses its quantum coherence spontaneously. This spontaneous decoherence is interpreted by the gauge couplings between the center-of-mass and the relative degrees of freedoms, which actually originate from the symmetries of the ring geometry and the corresponding nontrivial boundary conditions. In particular, such spontaneous decoherence does not occur at all at the thermodynamic limit because the nontrivial boundary conditions become the trivial Born-von Karman boundary conditions when the perimeter of the ring container tends to infinity. Our investigation shows that a thermal macroscopic object with certain symmetries has a chance for its quantum properties to degrade even without applying an external symmetry-breaking field or surrounding environment.

MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems.

PubMed

Sakuma, Tetsushi; Nakade, Shota; Sakane, Yuto; Suzuki, Ken-Ichi T; Yamamoto, Takashi

2016-01-01

Programmable nucleases enable engineering of the genome by utilizing endogenous DNA double-strand break (DSB) repair pathways. Although homologous recombination (HR)-mediated gene knock-in is well established, it cannot necessarily be applied in every cell type and organism because of variable HR frequencies. We recently reported an alternative method of gene knock-in, named the PITCh (Precise Integration into Target Chromosome) system, assisted by microhomology-mediated end-joining (MMEJ). MMEJ harnesses independent machinery from HR, and it requires an extremely short homologous sequence (5-25 bp) for DSB repair, resulting in precise gene knock-in with a more easily constructed donor vector. Here we describe a streamlined protocol for PITCh knock-in, including the design and construction of the PITCh vectors, and their delivery to either human cell lines by transfection or to frog embryos by microinjection. The construction of the PITCh vectors requires only a few days, and the entire process takes ∼ 1.5 months to establish knocked-in cells or ∼ 1 week from injection to early genotyping in frog embryos.

G9a coordinates with the RPA complex to promote DNA damage repair and cell survival.

PubMed

Yang, Qiaoyan; Zhu, Qian; Lu, Xiaopeng; Du, Yipeng; Cao, Linlin; Shen, Changchun; Hou, Tianyun; Li, Meiting; Li, Zhiming; Liu, Chaohua; Wu, Di; Xu, Xingzhi; Wang, Lina; Wang, Haiying; Zhao, Ying; Yang, Yang; Zhu, Wei-Guo

2017-07-25

Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs. This mechanism facilitates homologous recombination (HR) and cell survival. We confirmed the interaction between RPA and G9a to be critical for RPA foci formation and HR upon DNA damage. Collectively, our findings demonstrate a regulatory pathway based on CK2-G9a-RPA that permits HR in cancer cells and provide further rationale for the use of G9a inhibitors as a cancer therapeutic.

Match-play activity profile in professional soccer players during official games and the relationship between external and internal load.

PubMed

Suarez-Arrones, L; Torreño, N; Requena, B; Sáez De Villarreal, E; Casamichana, D; Barbero-Alvarez, J C; Munguía-Izquierdo, D

2015-12-01

The aim was to quantify for the first time the physical and physiological profile of professional soccer players in official games using GPS and heart rate (HR) response. Thirty professional soccer players were investigated during a half in competitive club level matches (N.=348) using GPS devices. The relative total distance was 118.9±10.7 m∙min(-1) and player's Work-To-Rest Ratio was 2.1:1. Defenders covered the lowest total distance, while Second-Strikers (2(nd)S) and Wide-Midfielders (W-MD) traveled the greatest total distance. Defenders presented the lowest Work-To-Rest Ratio values. Playing position also impacted on all sprinting performance results, except in average sprint distance and time of sprint. The number of sprints and repeated-sprint sequences recorded by the W-MD and Strikers (S) were significantly greater than any other group. The average HR recorded was 87.1%HRmax and the relationship between the external and internal load value (Effindex) was 1.4 with significant differences in both between playing positions. W-MD recorded a significantly smaller average HR than any other group and Centre-Backs showed a significantly smaller Effindex value than any other group. Conversely, W-MD showed a significantly greater Effindex value than any other group, except the 2(nd)S. This study has verified a number of statistically significant differences between the different playing positions. Coaches should be focused on the specific physical and physiological requirements of the playing positions to optimize the training prescription in soccer. The relationships between external and internal load measures among position-specific indicates that players with less overall running performance during match-play were the worst in Effindex.

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

PubMed

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

2014-02-01

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

Progress towards understanding the nature of chromatid breakage.

PubMed

Bryant, P E; Gray, L J; Peresse, N

2004-01-01

The wide range of sensitivities of stimulated T-cells from different individuals to radiation-induced chromatid breakage indicates the involvement of several low penetrance genes that appear to link elevated chromatid breakage to cancer susceptibility. The mechanisms of chromatid breakage are not yet fully understood. However, evidence is accumulating that suggests chromatid breaks are not simply expanded DNA double-strand breaks (DSB). Three models of chromatid breakage are considered. The classical breakage-first and the Revell "exchange" models do not accord with current evidence. Therefore a derivative of Revell's model has been proposed whereby both spontaneous and radiation-induced chromatid breaks result from DSB signaling and rearrangement processes from within large looped chromatin domains. Examples of such rearrangements can be observed by harlequin staining whereby an exchange of strands occurs immediately adjacent to the break site. However, these interchromatid rearrangements comprise less than 20% of the total breaks. The rest are thought to result from intrachromatid rearrangements, including a very small proportion involving complete excision of a looped domain. Work is in progress with the aim of revealing these rearrangements, which may involve the formation of inversions adjacent to the break sites. It is postulated that the disappearance of chromatid breaks with time results from the completion of such rearrangements, rather than from the rejoining of DSB. Elevated frequencies of chromatid breaks occur in irradiated cells with defects in both nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways, however there is little evidence of a correlation between reduced DSB rejoining and disappearance of chromatid breaks. Moreover, at least one treatment which abrogates the disappearance of chromatid breaks with time leaves DSB rejoining unaffected. The I-SceI DSB system holds considerable promise for the elucidation of these mechanisms, although the break frequency is relatively low in the cell lines so far derived. Techniques to study and improve such systems are under way in different cell lines. Clearly, much remains to be done to clarify the mechanisms involved in chromatid breakage, but the experimental models are becoming available with which we can begin to answer some of the key questions. Copyright 2003 S. Karger AG, Basel

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

Lin, M; Choi, E; Chuong, M

Purpose: To evaluate weather the current radiobiological models can predict the normal liver complications of radioactive Yttrium-90 ({sup 90}Y) selective-internal-radiation-treatment (SIRT) for metastatic liver lesions based on the post-infusion {sup 90}Y PET images. Methods: A total of 20 patients with metastatic liver tumors treated with SIRT that received a post-infusion {sup 90}Y-PET/CT scan were analyzed in this work. The 3D activity distribution of the PET images was converted into a 3D dose distribution via a kernel convolution process. The physical dose distribution was converted into the equivalent dose (EQ2) delivered at 2 Gy based on the linear-quadratic (LQ) model consideringmore » the dose rate effect. The biological endpoint of this work was radiation-induce liver disease (RILD). The NTCPs were calculated with four different repair-times (T1/2-Liver-Repair= 0,0.5,1.0,2.0 hr) and three published NTCP models (Lyman-external-RT, Lyman 90Y-HCC-SIRT, parallel model) were compared to the incidence of RILD of the recruited patients to evaluate their ability of outcome prediction. Results: The mean normal liver physical dose (avg. 51.9 Gy, range 31.9–69.8 Gy) is higher than the suggested liver dose constraint for external beam treatment (∼30 Gy). However, none of the patients in our study developed RILD after the SIRT. The estimated probability of ‘no patient developing RILD’ obtained from the two Lyman models are 46.3% to 48.3% (T1/2-Liver-Repair= 0hr) and <1% for all other repair times. For the parallel model, the estimated probability is 97.3% (0hr), 51.7% (0.5hr), 2.0% (1.0hr) and <1% (2.0hr). Conclusion: Molecular-images providing the distribution of {sup 90}Y enable the dose-volume based dose/outcome analysis for SIRT. Current NTCP models fail to predict RILD complications in our patient population, unless a very short repair-time for the liver is assumed. The discrepancy between the Lyman {sup 90}Y-HCC-SIRT model predicted and the clinically observed outcomes further demonstrates the need of an NTCP model specific to the metastatic liver SIRT.« less

Go Long, Go Deep: Finding Optical Jet Breaks for Swift-Era GRBs with the LBT

NASA Astrophysics Data System (ADS)

Dai, X.; Garnavich, P. M.; Prieto, J. L.; Stanek, K. Z.; Kochanek, C. S.; Bechtold, J.; Bouche, N.; Buschkamp, P.; Diolaiti, E.; Fan, X.; Giallongo, E.; Gredel, R.; Hill, J. M.; Jiang, L.; McClelland, C.; Milne, P.; Pedichini, F.; Pogge, R. W.; Ragazzoni, R.; Rhoads, J.; Smareglia, R.; Thompson, D.; Wagner, R. M.

2008-08-01

Using the 8.4 m Large Binocular Telescope, we observed six GRB afterglows from 2.8 hr to 30.8 days after the burst triggers to systematically probe the late-time behaviors of afterglows including jet breaks, flares, and supernova bumps. We detected five afterglows with Sloan r' magnitudes ranging from 23.0 to 26.3 mag. The depth of our observations allows us to extend the temporal baseline for measuring jet breaks by another decade in timescale. We detected two jet breaks and a third candidate, all of which are not detectable without deep, late-time optical observations. In the other three cases, we do not detect the jet breaks either because of contamination from the host galaxy light, the presence of a supernova bump, or the intrinsic faintness of the optical afterglow. This suggests that the basic picture that GRBs are collimated is still valid and that the apparent lack of Swift jet breaks is due to poorly sampled afterglow light curves, particularly at late times. Based on data acquired using the Large Binocular Telescope (LBT). The LBT is an international collaboration among institutions in the United States, Italy, and Germany. LBT Corporation partners are the University of Arizona on behalf of the Arizona university system; Istituto Nazionale di Astrofisica, Italy; LBT Beteiligungsgesellschaft, Germany, representing the Max Planck Society, the Astrophysical Institute Potsdam, and Heidelberg University; the Ohio State University; and the Research Corporation, on behalf of the University of Notre Dame, the University of Minnesota, and the University of Virginia.

Generation of Aggregates of Mouse Embryonic Stem Cells that Show Symmetry Breaking, Polarization and Emergent Collective Behaviour In Vitro.

PubMed

Baillie-Johnson, Peter; van den Brink, Susanne Carina; Balayo, Tina; Turner, David Andrew; Martinez Arias, Alfonso

2015-11-24

We have developed a protocol improving current Embryoid Body (EB) culture which allows the study of self-organization, symmetry breaking, axial elongation and cell fate specification using aggregates of mouse embryonic stem cells (mESCs) in suspension culture. Small numbers of mESCs are aggregated in basal medium for 48 hr in non-tissue-culture-treated, U-bottomed 96-well plates, after which they are competent to respond to experimental signals. Following treatment, these aggregates begin to show signs of polarized gene expression and gradually alter their morphology from a spherical mass of cells to an elongated, well organized structure in the absence of external asymmetry cues. These structures are not only able to display markers of the three germ layers, but actively display gastrulation-like movements, evidenced by a directional dislodgement of individual cells from the aggregate, which crucially occurs at one region of the elongated structure. This protocol provides a detailed method for the reproducible formation of these aggregates, their stimulation with signals such as Wnt/β-Catenin activation and BMP inhibition and their analysis by single time-point or time-lapse fluorescent microscopy. In addition, we describe modifications to current whole-mount mouse embryo staining procedures for immunocytochemical analysis of specific markers within fixed aggregates. The changes in morphology, gene expression and length of the aggregates can be quantitatively measured, providing information on how signals can alter axial fates. It is envisaged that this system can be applied both to the study of early developmental events such as axial development and organization, and more broadly, the processes of self-organization and cellular decision-making. It may also provide a suitable niche for the generation of cell types present in the embryo that are unobtainable from conventional adherent culture such as spinal cord and motor neurones.

Development of the Radiation Stabilized Distributed Flux Burner. Phase 1, final report

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

Sullivan, J.D.; Duret, M.J.

1997-06-01

The RSB was first developed for Thermally Enhanced Oil Recovery steamers which fire with a single 60 MMBtu/hr burner; the California Energy Commission and Chevron USA were involved in the burner development. The burner has also since found applications in refinery and chemical plant process heaters. All Phase I goals were successfully met: the RSB achieved sub-9 ppM NOx and sub-50 ppM CO emissions using high excess air, external flue gas recirculation (FGR), and fuel staging in the 3 MMBtu/hr laboratory watertube boiler. In a test in a 50,000 lb/hr oil field steamer with fuel staging, it consistently achieved sub-20more » ppM NOx and as low as 10 ppM NOx. With high CO{sub 2} casing gas in this steamer, simulating external FGR, sub-20 ppM NOx and as low as 5 ppM NOx were achieved. Burner material cost was reduced by 25% on a per Btu basis by increasing the effective surface firing rate at the burner; further reductions will occur in Phase II. The market for 30 ppM and 9 ppM low NOx burners has been identified as package boilers in the 50,000 to 250,000 lb/hr size range (the 30 ppM is for retrofit, the 9 ppM for the new boiler market). Alzeta and Babcock & Wilcox have teamed to sell both boiler retrofits and new boilers; they have identified boiler designs which use the compact flame shape of the RSB and can increase steam capacity while maintaining the same boiler footprint. Alzeta, Chevron, and B & W have teamed to identify sites to demonstrate the RSB in Phases II and III. In Phase II, the RSB will be demonstrated in a 100,000 lb/hr industrial watertube boiler.« less

3-DIMENSIONAL EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER INCREASES THE RISK OF HIP FRACTURE

PubMed Central

Elliott, Sean P.; Jarosek, Stephanie L.; Alanee, Shaheen R.; Konety, Badrinath R.; Dusenbery, Kathryn E.; Virnig, Beth A.

2011-01-01

Background Hip fracture is associated with high morbidity and mortality. Pelvic external beam radiotherapy (EBRT) is known to increase the risk of hip fractures in women but the effect in men is unknown. Methods 45,662 men aged ≥66 years, diagnosed with prostate cancer in 1992–2004 were identified from the SEER-Medicare database. Using Kaplan-Meier methods and Cox proportional hazards models, the primary outcome of hip fracture risk was compared among men who received radical prostatectomy (RP), EBRT, EBRT+androgen suppression therapy (AST) or AST alone, controlling for age, osteoporosis, race and other comorbidities. A secondary outcome was distal forearm fractures as an indicator of fragility fracture risk outside the radiation field. Results After controlling for covariates, EBRT increased the risk of hip fractures by 76% (HR 1.76, 95% CI 1.38–2.40) without increasing the risk of distal forearm fractures (HR 0.80, 95% CI 0.56–1.14). Combination therapy with EBRT+AST increased the risk of hip fracture 145% relative to RP (HR 2.45, 95% CI 1.88–3.19) and by 40% relative to EBRT (HR 1.40, 95% CI 1.17–1.68). EBRT+AST increased the risk of distal forearm fracture by 43% relative to RP (HR 1.43, 95% CI 0.97–2.10). The number needed to treat to result in 1 hip fracture through 10 years was 51 (95% CI 31–103). Conclusion In men with prostate cancer, pelvic 3-D conformal EBRT is associated with a 76% increased risk of hip fracture. This risk is slightly increased further by the addition of short-course AST to EBRT. This risk associated with EBRT is site-specific as there is no increase in the risk of fall-related fractures outside the radiation field. PMID:21412999

Extracellular enzyme kinetics scale with resource availability

EPA Science Inventory

Microbial community metabolism relies on external digestion, mediated by extracellular enzymes that break down complex organic matter into molecules small enough for cells to assimilate. We analyzed the kinetics of 40 extracellular enzymes that mediate the degradation and assimi...

Index extraction for electromagnetic field evaluation of high power wireless charging system.

PubMed

Park, SangWook

2017-01-01

This paper presents the precise dosimetry for highly resonant wireless power transfer (HR-WPT) system using an anatomically realistic human voxel model. The dosimetry for the HR-WPT system designed to operate at 13.56 MHz frequency, which one of the ISM band frequency band, is conducted in the various distances between the human model and the system, and in the condition of alignment and misalignment between transmitting and receiving circuits. The specific absorption rates in the human body are computed by the two-step approach; in the first step, the field generated by the HR-WPT system is calculated and in the second step the specific absorption rates are computed with the scattered field finite-difference time-domain method regarding the fields obtained in the first step as the incident fields. The safety compliance for non-uniform field exposure from the HR-WPT system is discussed with the international safety guidelines. Furthermore, the coupling factor concept is employed to relax the maximum allowable transmitting power. Coupling factors derived from the dosimetry results are presented. In this calculation, the external magnetic field from the HR-WPT system can be relaxed by approximately four times using coupling factor in the worst exposure scenario.

Rule breaking mediates the developmental association between GABRA2 and adolescent substance abuse.

PubMed

Trucco, Elisa M; Villafuerte, Sandra; Heitzeg, Mary M; Burmeister, Margit; Zucker, Robert A

2014-12-01

This study's primary aim was to examine age-specific associations between GABRA2, rule breaking, problematic alcohol use, and substance abuse symptomatology. The secondary aim was to examine the extent to which rule breaking mediates the GABRA2-substance abuse relationship. A sample (n = 518) of primarily male (70.9%) and White (88.8%) adolescents from the Michigan Longitudinal Study was assessed from ages 11-18. Age-specific effects of GABRA2 on rule breaking, problematic alcohol use, and substance abuse symptomatology were examined using nested path models. The role of rule breaking as a mediator in the association between GABRA2 and substance abuse outcomes was tested using prospective cross-lagged path models. GABRA2 is significantly (p < 0.05) associated with rule breaking in mid- to late-adolescence, but not substance abuse symptomatology across adolescence. GABRA2 effects on problematic alcohol use and substance abuse symptomatology operate largely (45.3% and 71.1%, respectively, p < 0.05) via rule breaking in midadolescence. GABRA2 represents an early risk factor for an externalizing pathway to the development of problematic alcohol and drug use. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

Cytogenetic Monitoring of Farmers exposed to pesticides in Colombia.

PubMed Central

Hoyos, L S; Carvajal, S; Solano, L; Rodriguez, J; Orozco, L; López, Y; Au, W W

1996-01-01

We have monitored 30 pesticide-exposed workers and 30 matched controls for expression of chromosome aberrations (CA) and sister chromatid exchanges (SCE) in their lymphocytes. Peripheral blood cultures were set up within 3 hr after the collection of samples, and four cultures were set up from each donor. For CA analysis, 100 complete metaphase cells from each donor were evaluated. For the SCE assay, 50 complete metaphase cells from each donor were analyzed. The CA and SCE data were analyzed for differences between the two groups using the chi 2 and the Student's t-test, respectively. From the CA analysis it was obvious that the overwhelming majority of aberrations were chromatid breaks and isochromatid breaks; therefore, only these data are presented and used for statistical analysis. Isochromatid breaks were counted as two breaks each and chromatid breaks as one in calculating the total chromatid break frequencies. Statistical evaluation of the data indicates that there is no significant difference (p > 0.05; chi 2 test) between the exposed and the nonexposed groups based on chromatid breaks per 100 cells (1.2 +/- 0.3 and 1.5 +/- 0.2, respectively) and total chromatid breaks per 100 cells (1.7 +/- 0.3 and 2.1 +/- 0.2, respectively). No significantly difference between the two groups (p > 0.05, Student's t-test) was observed with SCE frequencies (5.0 +/- 1.1 and 4.8 +/- 0.9, respectively). Linear regression analysis indicates that the data were not influenced by age, cigarette smoking, or alcohol consumption. It is assuring that the exposure conditions among these Indian farmers have not caused detectable increases of chromosome damage using standard assays; this suggests the lack of serious long-term health problems. However, periodic monitoring of such exposed populations should be conducted using the same or other more sensitive assays. In addition, other populations with exposure to different types of pesticides in Colombia should also be investigated. PMID:8781378

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.

PubMed

Claret, Laurent; Zheng, Jenny; Mercier, Francois; Chanu, Pascal; Chen, Ying; Rosbrook, Brad; Yazdi, Pithavala; Milligan, Peter A; Bruno, Rene

2016-09-01

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

Immunohistochemical and molecular imaging biomarker signature for the prediction of failure site after chemoradiation for head and neck squamous cell carcinoma.

PubMed

Rasmussen, Gregers Brünnich; Håkansson, Katrin E; Vogelius, Ivan R; Rasmussen, Jacob H; Friborg, Jeppe T; Fischer, Barbara M; Schumaker, Lisa; Cullen, Kevin; Therkildsen, Marianne H; Bentzen, Søren M; Specht, Lena

2017-11-01

To identify a failure site-specific prognostic model by combining immunohistochemistry (IHC) and molecular imaging information to predict long-term failure type in squamous cell carcinoma of the head and neck. Tissue microarray blocks of 196 head and neck squamous cell carcinoma cases were stained for a panel of biomarkers using IHC. Gross tumor volume (GTV) from the PET/CT radiation treatment planning CT scan, maximal Standard Uptake Value (SUVmax) of fludeoxyglucose (FDG) and clinical information were included in the model building using Cox proportional hazards models, stratified for p16 status in oropharyngeal carcinomas. Separate models were built for time to locoregional failure and time to distant metastasis. Higher than median p53 expression on IHC tended toward a risk factor for locoregional failure but was protective for distant metastasis, χ 2 for difference p = .003. The final model for locoregional failure included p53 (HR: 1.9; p: .055), concomitant cisplatin (HR: 0.41; p: .008), β-tubulin-1 (HR: 1.8; p: .08), β-tubulin-2 (HR: 0.49; p: .057) and SUVmax (HR: 2.1; p: .046). The final model for distant metastasis included p53 (HR: 0.23; p: .025), Bcl-2 (HR: 2.6; p: .08), SUVmax (HR: 3.5; p: .095) and GTV (HR: 1.7; p: .063). The models successfully distinguished between risk of locoregional failure and risk of distant metastasis, which is important information for clinical decision-making. High p53 expression has opposite prognostic effects for the two endpoints; increasing risk of locoregional failure, but decreasing the risk of metastatic failure, but external validation of this finding is needed.

Analysing a cycling grand tour: Can we monitor fatigue with intensity or load ratios?

PubMed

Sanders, Dajo; Heijboer, Mathieu; Hesselink, Matthijs K C; Myers, Tony; Akubat, Ibrahim

2018-06-01

This study evaluated the changes in ratios of different intensity (rating of perceived exertion; RPE, heart rate; HR, power output; PO) and load measures (session-RPE; sRPE, individualized TRIMP; iTRIMP, Training Stress Score™; TSS) in professional cyclists. RPE, PO and HR data was collected from twelve professional cyclists (VO 2max 75 ± 6 ml∙min∙kg -1 ) during a two-week baseline training period and during two cycling Grand Tours. Subjective:objective intensity (RPE:HR, RPE:PO) and load (sRPE:iTRIMP, sRPE:TSS) ratios and external:internal intensity (PO:HR) and load (TSS:iTRIMP) ratios were calculated for every session. Moderate to large increases in the RPE:HR, RPE:PO and sRPE:TSS ratios (d = 0.79-1.79) and small increases in the PO:HR and sRPE:iTRIMP ratio (d = 0.21-0.41) were observed during Grand Tours compared to baseline training data. Differences in the TSS:iTRIMP ratio were trivial to small (d = 0.03-0.27). Small to moderate week-to-week changes (d = 0.21-0.63) in the PO:HR, RPE:PO, RPE:HR, TSS:iTRIMP, sRPE:iTRIMP and sRPE:TSS were observed during the Grand Tour. Concluding, this study shows the value of using ratios of intensity and load measures in monitoring cyclists. Increases in ratios could reflect progressive fatigue that is not readily detected by changes in solitary intensity/load measures.

Human resource processes and the role of the human resources function during mergers and acquisitions in the electricity industry

NASA Astrophysics Data System (ADS)

Dass, Ted K.

Mergers and acquisitions (M&A) have been a popular strategy for organizations to consolidate and grow for more than a century. However, research in this field indicates that M&A are more likely to fail than succeed, with failure rates estimated to be as high as 75%. People-related issues have been identified as important causes for the high failure rate, but these issues are largely neglected until after the deal is closed. One explanation for this neglect is the low involvement of human resource (HR) professionals and the HR function during the M&A process. The strategic HR management literature suggests that a larger role for HR professionals in the M&A process would enable organizations to identify potential problems early and devise appropriate solutions. However, empirical research from an HR perspective has been scarce in this area. This dissertation examines the role of the HR function and the HR processes followed in organizations during M&A. Employing a case-study research design, this study examines M&A undertaken by two large organizations in the electricity industry through the lens of a "process" perspective. Based on converging evidence, the case studies address three sets of related issues: (1) how do organizations undertake and manage M&A; (2) what is the extent of HR involvement in M&A and what role does it play in the M&A process; and (3) what factors explain HR involvement in the M&A process and, more generally, in the formulation of corporate goals and strategies. Results reveal the complexity of issues faced by organizations in undertaking M&A, the variety of roles played by HR professionals, and the importance of several key contextual factors---internal and external to the organization---that influence HR involvement in the M&A process. Further, several implications for practice and future research are explored.

[Occupational stress and the risk of sickness absence in customer service workers].

PubMed

Szubert, Zuzanna; Merecz-Kot, Dorota; Sobala, Wojciech

2009-01-01

The aim of this study was to indicate psychosocial stressors at work that significantly affect sickness absence a workers. Study subjects included a group of 233 randomly selected women employed as post-office clerks. Sickness absence data covered the period of 2004-2006. The psychosocial factors were assessed by means of the Subjective Work Characteristics Questionnaire. The hazard ratio (HR) of sickness absence was analysed using the Cox regression model, separately for short- (1-9 days) medium- (10-29 days) and long-term (30 days and above) sickness absence. The shortterm sickness absence risk was significantly related with the post-office size--in the offices employing 8-12 workers, the risk was by 50% lower compared to those employing a smaller number of workers (HR = 0.49; 95% CI: 0.27-0.90) and unpleasant working conditions (dirt), which contributed to the increased risk (HR = 1.30; 95% CI: 1.12-1.50). In the case of a 10-29-day absence, the risk was slightly elevated by the demand of long-term vigilance, financial responsibility, and strictly determined breaks at work In the model of long-term sickness absence, a significantly higher risk was noted when the number of employees was 16-25 compared to a smaller number of employees (HR = 2.92; 95% CI: 1.09-7.82), non-occupational, self-assessed workload was high (HR = 2.97; 95% CI: 1.34-6.62) or moderate (HR = 2.22; 95% CI: 1.11-4.44) compared to self-assessed low workload, and the work space was limited (HR = 1.21; 95% CI: 1.00-1.47). Our analysis showed a significant effect of stressogenic work conditions on the patterns of sickness absence. Our findings may help in developing programs intended to reduce sickness absence through limiting the prevalence of unfavourable conditions at workplaces.

A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest

PubMed Central

Feng, Zhihui; Zhang, Junran

2012-01-01

Homologous recombination (HR) is a major mechanism utilized to repair blockage of DNA replication forks. Here, we report that a sister chromatid exchange (SCE) generated by crossover-associated HR efficiently occurs in response to replication fork stalling before any measurable DNA double-strand breaks (DSBs). Interestingly, SCE produced by replication fork collapse following DNA DSBs creation is specifically suppressed by ATR, a central regulator of the replication checkpoint. BRCA1 depletion leads to decreased RPA2 phosphorylation (RPA2-P) following replication fork stalling but has no obvious effect on RPA2-P following replication fork collapse. Importantly, we found that BRCA1 promotes RAD51 recruitment and SCE induced by replication fork stalling independent of ATR. In contrast, BRCA1 depletion leads to a more profound defect in RAD51 recruitment and SCE induced by replication fork collapse when ATR is depleted. We concluded that BRCA1 plays a dual role in two distinct HR-mediated repair upon replication fork stalling and collapse. Our data established a molecular basis for the observation that defective BRCA1 leads to a high sensitivity to agents that cause replication blocks without being associated with DSBs, and also implicate a novel mechanism by which loss of cell cycle checkpoints promotes BRCA1-associated tumorigenesis via enhancing HR defect resulting from BRCA1 deficiency. PMID:21954437

NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

DOE PAGES

Parplys, Ann C.; Zhao, Weixing; Sharma, Neelam; ...

2015-08-31

NUCKS1 (nuclear casein kinase and cyclin-dependent kinase substrate 1) is a 27 kD chromosomal, vertebrate-specific protein, for which limited functional data exist. Here, we demonstrate that NUCKS1 shares extensive sequence homology with RAD51AP1 (RAD51 associated protein 1), suggesting that these two proteins are paralogs. Similar to the phenotypic effects of RAD51AP1 knockdown, we find that depletion of NUCKS1 in human cells impairs DNA repair by homologous recombination (HR) and chromosome stability. Depletion of NUCKS1 also results in greatly increased cellular sensitivity to mitomycin C (MMC), and in increased levels of spontaneous and MMC-induced chromatid breaks. NUCKS1 is critical to maintainingmore » wild type HR capacity, and, as observed for a number of proteins involved in the HR pathway, functional loss of NUCKS1 leads to a slow down in DNA replication fork progression with a concomitant increase in the utilization of new replication origins. Interestingly, recombinant NUCKS1 shares the same DNA binding preference as RAD51AP1, but binds to DNA with reduced affinity when compared to RAD51AP1. Finally, our results show that NUCKS1 is a chromatin-associated protein with a role in the DNA damage response and in HR, a DNA repair pathway critical for tumor suppression.« less

Cellular Dynamics of Rad51 and Rad54 in Response to Postreplicative Stress and DNA Damage in HeLa Cells.

PubMed

Choi, Eui-Hwan; Yoon, Seobin; Hahn, Yoonsoo; Kim, Keun P

2017-02-01

Homologous recombination (HR) is necessary for maintenance of genomic integrity and prevention of various mutations in tumor suppressor genes and proto-oncogenes. Rad51 and Rad54 are key HR factors that cope with replication stress and DNA breaks in eukaryotes. Rad51 binds to single-stranded DNA (ssDNA) to form the presynaptic filament that promotes a homology search and DNA strand exchange, and Rad54 stimulates the strand-pairing function of Rad51. Here, we studied the molecular dynamics of Rad51 and Rad54 during the cell cycle of HeLa cells. These cells constitutively express Rad51 and Rad54 throughout the entire cell cycle, and the formation of foci immediately increased in response to various types of DNA damage and replication stress, except for caffeine, which suppressed the Rad51-dependent HR pathway. Depletion of Rad51 caused severe defects in response to postreplicative stress. Accordingly, HeLa cells were arrested at the G2-M transition although a small amount of Rad51 was steadily maintained in HeLa cells. Our results suggest that cell cycle progression and proliferation of HeLa cells can be tightly controlled by the abundance of HR proteins, which are essential for the rapid response to postreplicative stress and DNA damage stress.

Behavioral and emotional problems in a Kuala Lumpur children's home.

PubMed

Abd Rahman, Fairuz Nazri; Mohd Daud, Tuti Iryani; Nik Jaafar, Nik Ruzyanei; Shah, Shamsul Azhar; Tan, Susan Mooi Koon; Wan Ismail, Wan Salwina

2013-08-01

There is a dearth of studies on behavioral and emotional problems in residential care children in Malaysia. This study describes the behavioral and emotional problems in a sample of children in a government residential care home and compares them with their classmates living with their birth parents. A comparative cross-sectional study was carried out where carers from both groups were asked to fill in the translated Bahasa Melayu version of the Child Behavior Check List. Forms for 53 residential care children and 61 classmates were completed. The residential care children had significantly higher scores on the rule-breaking (P < 0.001) and Diagnostic and Statistical Manual of Mental Disorders (DSM) conduct problem subscales (P < 0.001). Residential care children's age significantly correlated with DSM somatic problems (P = 0.03) and post-traumatic stress (P = 0.023). Duration of care was significantly positively correlated with rule-breaking (P = 0.008), DSM conduct problems (P = 0.018) and externalizing scores (P = 0.017). Abuse and neglect cases had higher anxiety and depression scores (P = 0.024). Number of reasons in care positively correlated with several subscales, including total behavioral problem score (P = 0.005). Logistic regression revealed the greater number of reasons for placement a child had was significantly associated with having externalizing scores in the clinical range (P = 0.016). However, after Bonferroni correction, only the initial findings regarding rule-breaking and DSM conduct problem scores remained significant. Challenges exist in managing residential care children in Malaysia, especially regarding externalizing behavior. More studies are required to describe the Malaysian scene. © 2013 The Authors. Pediatrics International © 2013 Japan Pediatric Society.

Tankyrases Promote Homologous Recombination and Check Point Activation in Response to DSBs

PubMed Central

Furst, Audrey; Koch, Marc; Fischer, Benoit; Soutoglou, Evi

2016-01-01

DNA lesions are sensed by a network of proteins that trigger the DNA damage response (DDR), a signaling cascade that acts to delay cell cycle progression and initiate DNA repair. The Mediator of DNA damage Checkpoint protein 1 (MDC1) is essential for spreading of the DDR signaling on chromatin surrounding Double Strand Breaks (DSBs) by acting as a scaffold for PI3K kinases and for ubiquitin ligases. MDC1 also plays a role both in Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) repair pathways. Here we identify two novel binding partners of MDC1, the poly (ADP-ribose) Polymerases (PARPs) TNKS1 and 2. We find that TNKSs are recruited to DNA lesions by MDC1 and regulate DNA end resection and BRCA1A complex stabilization at lesions leading to efficient DSB repair by HR and proper checkpoint activation. PMID:26845027

Behavioral response to a just-in-time adaptive intervention (JITAI) to reduce sedentary behavior in obese adults: Implications for JITAI optimization.

PubMed

Thomas, J Graham; Bond, Dale S

2015-12-01

Just-in-time adaptive interventions (JITAIs) use mobile computers, sensors, and software analytics to automatically detect behavior and deliver tailored treatment. However, little is known about how JITAIs influence patterns of behavior or how best to design JITAIs for maximum effect. This study examined prompts and behavioral response to the B-MOBILE JITAI for reducing sedentary behavior (SB) in overweight/obese individuals. Thirty participants (83% women; 67% White, mean ± SD body mass index = 36.2 kg/m2) tested 3 conditions presented in a randomized counterbalanced order involving smartphone-based prompts for walking breaks of (a) 3 min after 30 SB min, (b) 6 min after 60 SB min, and (c) 12 min after 120 SB min. Participants carried the smartphone an average of 6.90 days during each 7-day condition, for an average of 14.94 hr per day. The 3- and 6-min conditions resulted in the greatest number of prompts, walking breaks, the best adherence to prompts, the greatest amount of daily time spent in walking breaks, and fastest adherence to prompts (ps < .01). Small but statistically significant decreases in the number of daily walking breaks, adherence to prompts, and minutes per day spent in walking breaks were observed as a function of the number of days spent in a condition (ps < .05). The B-MOBILE JITAI was effective in prompting breaks in sedentary behavior when it was most clinically relevant. Frequent prompts for small change may be an optimal strategy for shaping sedentary behavior, although more research is needed to determine how best to promote long-term adherence. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

To Nick or Not to Nick: Comparison of I-SceI Single- and Double-Strand Break-Induced Recombination in Yeast and Human Cells

PubMed Central

Katz, Samantha S.; Gimble, Frederick S.; Storici, Francesca

2014-01-01

Genetic modification of a chromosomal locus to replace an existing dysfunctional allele with a corrected sequence can be accomplished through targeted gene correction using the cell's homologous recombination (HR) machinery. Gene targeting is stimulated by generation of a DNA double-strand break (DSB) at or near the site of correction, but repair of the break via non-homologous end-joining without using the homologous template can lead to deleterious genomic changes such as in/del mutations, or chromosomal rearrangements. By contrast, generation of a DNA single-strand break (SSB), or nick, can stimulate gene correction without the problems of DSB repair because the uncut DNA strand acts as a template to permit healing without alteration of genetic material. Here, we examine the ability of a nicking variant of the I-SceI endonuclease (K223I I-SceI) to stimulate gene targeting in yeast Saccharomyces cerevisiae and in human embryonic kidney (HEK-293) cells. K223I I-SceI is proficient in both yeast and human cells and promotes gene correction up to 12-fold. We show that K223I I-SceI-driven recombination follows a different mechanism than wild-type I-SceI-driven recombination, thus indicating that the initial DNA break that stimulates recombination is not a low-level DSB but a nick. We also demonstrate that K223I I-SceI efficiently elevates gene targeting at loci distant from the break site in yeast cells. These findings establish the capability of the I-SceI nickase to enhance recombination in yeast and human cells, strengthening the notion that nicking enzymes could be effective tools in gene correction strategies for applications in molecular biology, biotechnology, and gene therapy. PMID:24558436

Relative contribution of homologous recombination and non-homologous end-joining to DNA double-strand break repair after oxidative stress in Saccharomyces cerevisiae.

PubMed

Letavayová, Lucia; Marková, Eva; Hermanská, Katarína; Vlcková, Viera; Vlasáková, Danusa; Chovanec, Miroslav; Brozmanová, Jela

2006-05-10

Oxidative damage to DNA seems to be an important factor in developing many human diseases including cancer. It involves base and sugar damage, base-free sites, DNA-protein cross-links and DNA single-strand (SSB) and double-strand (DSB) breaks. Oxidative DSB can be formed in various ways such as their direct induction by the drug or their generation either through attempted and aborted repair of primary DNA lesions or through DNA replication-dependent conversion of SSB. In general, two main pathways are responsible for repairing DSB, homologous recombination (HR) and non-homologous end-joining (NHEJ), with both of them being potential candidates for the repair of oxidative DSB. We have examined relative contribution of HR and NHEJ to cellular response after oxidative stress in Saccharomyces cerevisiae. Therefore, cell survival, mutagenesis and DSB induction and repair in the rad52, yku70 and rad52 yku70 mutants after hydrogen peroxide (H(2)O(2)), menadione (MD) or bleomycin (BLM) exposure were compared to those obtained for the corresponding wild type. We show that MD exposure does not lead to observable DSB induction in yeast, suggesting that the toxic effects of this agent are mediated by other types of DNA damage. Although H(2)O(2) treatment generates some DSB, their yield is relatively low and hence DSB may only partially be responsible for toxicity of H(2)O(2), particularly at high doses of the agent. On the other hand, the basis of the BLM toxicity resides primarily in DSB induction. Both HR and NHEJ act on BLM-induced DSB, although their relative participation in the process is not equal. Based on our results we suggest that the complexity and/or the quality of the BLM-induced DSB might represent an obstacle for the NHEJ pathway.

Quantum anomalous Hall effect in time-reversal-symmetry breaking topological insulators

NASA Astrophysics Data System (ADS)

Chang, Cui-Zu; Li, Mingda

2016-03-01

The quantum anomalous Hall effect (QAHE), the last member of Hall family, was predicted to exhibit quantized Hall conductivity {σyx}=\\frac{{{e}2}}{h} without any external magnetic field. The QAHE shares a similar physical phenomenon with the integer quantum Hall effect (QHE), whereas its physical origin relies on the intrinsic topological inverted band structure and ferromagnetism. Since the QAHE does not require external energy input in the form of magnetic field, it is believed that this effect has unique potential for applications in future electronic devices with low-power consumption. More recently, the QAHE has been experimentally observed in thin films of the time-reversal symmetry breaking ferromagnetic (FM) topological insulators (TI), Cr- and V- doped (Bi,Sb)2Te3. In this topical review, we review the history of TI based QAHE, the route to the experimental observation of the QAHE in the above two systems, the current status of the research of the QAHE, and finally the prospects for future studies.

Time-reversal symmetry-breaking superconductivity in epitaxial bismuth/nickel bilayers.

PubMed

Gong, Xinxin; Kargarian, Mehdi; Stern, Alex; Yue, Di; Zhou, Hexin; Jin, Xiaofeng; Galitski, Victor M; Yakovenko, Victor M; Xia, Jing

2017-03-01

Superconductivity that spontaneously breaks time-reversal symmetry (TRS) has been found, so far, only in a handful of three-dimensional (3D) crystals with bulk inversion symmetry. We report an observation of spontaneous TRS breaking in a 2D superconducting system without inversion symmetry: the epitaxial bilayer films of bismuth and nickel. The evidence comes from the onset of the polar Kerr effect at the superconducting transition in the absence of an external magnetic field, detected by the ultrasensitive loop-less fiber-optic Sagnac interferometer. Because of strong spin-orbit interaction and lack of inversion symmetry in a Bi/Ni bilayer, superconducting pairing cannot be classified as singlet or triplet. We propose a theoretical model where magnetic fluctuations in Ni induce the superconducting pairing of the [Formula: see text] orbital symmetry between the electrons in Bi. In this model, the order parameter spontaneously breaks the TRS and has a nonzero phase winding number around the Fermi surface, thus making it a rare example of a 2D topological superconductor.

The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats.

PubMed

Vogelaar, Pieter C; Roorda, Maurits; de Vrij, Edwin L; Houwertjes, Martin C; Goris, Maaike; Bouma, Hjalmar; van der Graaf, Adrianus C; Krenning, Guido; Henning, Robert H

2018-04-11

Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 µg/kg/h) undergoing H/R at 15°C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed. H/R injury in vitro lowered cell viability by 94 ± 1%, which was counteracted dose-dependently by multiple 6-hydroxychomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 5'-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols limit DNA damage, but only SUL-109 also prevented protein nitrosylation in tubular cells. Therefore SUL-109 offers a promising therapeutic strategy to preserve kidney mitochondrial function.

Waves: Internal Tides

NASA Technical Reports Server (NTRS)

Ray, Richard D.

1999-01-01

Oceanic internal tides are internal waves with tidal periodicities. They are ubiquitous throughout the ocean, although generally more pronounced near large bathymetric features such as mid-ocean ridges and continental slopes. The internal vertical displacements associated with these waves can be extraordinarily large. Near some shelf breaks where the surface tides are strong, internal displacements (e.g., of an isothermal surface) can exceed 200 meters. Displacements of 10 meters in the open ocean are not uncommon. The associated current velocities are usually comparable to or larger than the currents of the surface tide. On continental shelves internal tides can occasionally generate packets of internal solitons, which are detectable in remote sensing imagery. Other common nonlinear features are generation of higher harmonics (e.g., 6-hr waves) and wave breaking. Internal tides are known to be an important energy source for mixing of shelf waters. Recent research suggests that they may also be a significant energy source for deep-ocean mixing.

Impact of an external radiation field on handheld XRF measurements for nuclear forensics applications

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

Steeb, Jennifer L.; Mertz, Carol J.; Finck, Martha R.

X-ray fluorescence (XRF) is an attractive technique for nuclear forensics applications. We evaluated a handheld, portable XRF device by applying an external radiation field (10 mR/h to 17 R/h) using two types of radiography sources: a 60Co radiography camera to observe effects from high-energy gamma emissions and an 192Ir radiography camera to observe effects from several low-energy gamma (0.604, 0.468, and 0.317 MeV) and decay daughter x-ray emissions. External radiation tests proved that radiation, in general, has a significant effect on the dead time or background at dose rates over 1 R/hr for both the 192Ir and 60Co sources.

Polyakov loop fluctuations in the presence of external fields

NASA Astrophysics Data System (ADS)

Lo, Pok Man; Szymański, Michał; Redlich, Krzysztof; Sasaki, Chihiro

2018-06-01

We study the implications of the spontaneous and explicit Z(3) center symmetry breaking for the Polyakov loop susceptibilities. To this end, ratios of the susceptibilities of the real and imaginary parts, as well as of the modulus of the Polyakov loop are computed within an effective model using a color group integration scheme. We show that the essential features of the lattice QCD results of these ratios can be successfully captured by the effective approach. Furthermore we discuss a novel scaling relation in one of these ratios involving the explicit breaking field, volume, and temperature.

Stereotactic radiosurgery of World Health Organization grade II and III intracranial meningiomas: treatment results on the basis of a 22-year experience.

PubMed

Pollock, Bruce E; Stafford, Scott L; Link, Michael J; Garces, Yolanda I; Foote, Robert L

2012-02-15

A study was undertaken to define the variables associated with tumor control and survival after single-session stereotactic radiosurgery (SRS) for patients with atypical and malignant intracranial meningiomas. Fifty patients with World Health Organization (WHO) grade II (n = 37) or grade III (n = 13) meningiomas underwent SRS from 1990 to 2008. Most tumors were located in the falx/parasagittal region or cerebral convexities (n = 35, 70%). Twenty patients (40%) had progressing tumors despite prior external beam radiation therapy (EBRT) (median dose, 54.0 grays [Gy]). The median treatment volume was 14.6 cm(3) ; the median tumor margin dose was 15.0 Gy. Seven patients (14%) received concurrent EBRT (median dose, 50.4 Gy). Follow-up (median, 38 months) was censored at last evaluation (n = 28) or death (n = 22). Tumor grade correlated with disease-specific survival (DSS) (hazard ratio [HR], 3.4; P = .008), local tumor control (HR, 2.4; P = .02), and progression-free survival (PFS) (HR, 2.6; P = .02) on univariate analysis, but not on multivariate analysis. Multivariate analysis showed that having failed EBRT and tumor volume >14.6 cm(3) were negative predictors of DSS and local control (HR, 3.0; P = .02 and HR, 4.4; P = .01; HR, 3.3; P = .001 and HR, 2.3; P = .02;, respectively). Having failed EBRT was a negative predictor of PFS (HR, 3.5; P = .002). Thirteen patients (26%) had radiation-related complications at a median of 6 months after radiosurgery. Tumor progression despite prior EBRT and larger tumor volume are negative predictors of tumor control and survival for patients having SRS for WHO grade II and III intracranial meningiomas. Copyright © 2011 American Cancer Society.

Index extraction for electromagnetic field evaluation of high power wireless charging system

PubMed Central

2017-01-01

This paper presents the precise dosimetry for highly resonant wireless power transfer (HR-WPT) system using an anatomically realistic human voxel model. The dosimetry for the HR-WPT system designed to operate at 13.56 MHz frequency, which one of the ISM band frequency band, is conducted in the various distances between the human model and the system, and in the condition of alignment and misalignment between transmitting and receiving circuits. The specific absorption rates in the human body are computed by the two-step approach; in the first step, the field generated by the HR-WPT system is calculated and in the second step the specific absorption rates are computed with the scattered field finite-difference time-domain method regarding the fields obtained in the first step as the incident fields. The safety compliance for non-uniform field exposure from the HR-WPT system is discussed with the international safety guidelines. Furthermore, the coupling factor concept is employed to relax the maximum allowable transmitting power. Coupling factors derived from the dosimetry results are presented. In this calculation, the external magnetic field from the HR-WPT system can be relaxed by approximately four times using coupling factor in the worst exposure scenario. PMID:28708840

Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing's Sarcoma.

PubMed

Gill, Sonja J; Travers, Jon; Pshenichnaya, Irina; Kogera, Fiona A; Barthorpe, Syd; Mironenko, Tatiana; Richardson, Laura; Benes, Cyril H; Stratton, Michael R; McDermott, Ultan; Jackson, Stephen P; Garnett, Mathew J

2015-01-01

Ewing's sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing's sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing's sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing's sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing's sarcoma patients with PARP inhibitors.

Acetylsalicylic acid does not reduce the intraocular pressure variation in ocular hypertension or glaucoma.

PubMed

Lindén, C; Alm, A

2000-03-01

The purpose of this study was to measure if intraocular pressure (IOP) and IOP variations in patients with ocular hypertension and glaucoma are decreased by acetylsalicylic acid (ASA). The hypothesis to be tested was that short-term fluctuations in the IOP are caused by breaks of the inner wall of Schlemm's canal that are repaired by platelets inducing a cycle of breaks and repair. Furthermore, prostaglandins affect uveoscleral outflow and ASA inhibits prostaglandin biosynthesis and platelet aggregation. This implies that ASA may have complex effects on the IOP and its variations.In 28 patients with ocular hypertension or glaucoma the IOP was measured seven times during 2 hr on two succeeding days. Five hundred mg ASA or placebo was administrated orally in a masked fashion 15 hr prior to the second session. After wash-out, this procedure was repeated with a cross-over design. The same study outline was used in 28 glaucoma patients except for the cross-over design. There were no statistically significant differences in the mean IOP or in the IOP variations between the placebo treated and the ASA treated eyes in either group, and there were no significant differences between the day before and after treatment in any group. The results suggest that ASA does not affect IOP variations in a clinically significant way and that a single dose of ASA has no significant effect on mean IOP. Copyright 2000 Academic Press.

Gravitating lepton bag model

NASA Astrophysics Data System (ADS)

Burinskii, A.

2015-08-01

The Kerr-Newman (KN) black hole (BH) solution exhibits the external gravitational and electromagnetic field corresponding to that of the Dirac electron. For the large spin/mass ratio, a ≫ m, the BH loses horizons and acquires a naked singular ring creating two-sheeted topology. This space is regularized by the Higgs mechanism of symmetry breaking, leading to an extended particle that has a regular spinning core compatible with the external KN solution. We show that this core has much in common with the known MIT and SLAC bag models, but has the important advantage of being in accordance with the external gravitational and electromagnetic fields of the KN solution. A peculiar two-sheeted structure of Kerr's gravity provides a framework for the implementation of the Higgs mechanism of symmetry breaking in configuration space in accordance with the concept of the electroweak sector of the Standard Model. Similar to other bag models, the KN bag is flexible and pliant to deformations. For parameters of a spinning electron, the bag takes the shape of a thin rotating disk of the Compton radius, with a ring-string structure and a quark-like singular pole formed at the sharp edge of this disk, indicating that the considered lepton bag forms a single bag-string-quark system.

Initiation of Coronal Mass Ejections by Tether-Cutting Reconnection

NASA Technical Reports Server (NTRS)

Moore, Ronald L.; Sterling, Alphonse C.; Falconer, David A.; Six, N. Frank (Technical Monitor)

2002-01-01

We present and interpret examples of the eruptive motion and flare brightening observed in the onset of magnetic explosions that produce coronal mass ejections. The observations are photospheric magnetograms and sequences of coronal and/or chromospheric images. In our examples, the explosion is apparently driven by the ejective eruption of a sigmoidal sheared-field flux rope from the core of an initially closed bipole. This eruption is initiated (triggered and unleashed) by reconnection located either (1) internally, low in the sheared core field, or (2) externally, at a magnetic null above the closed bipole. The internal reconnection is commonly called 'tether-cutting" reconnection, and the external reconnection is commonly called "break-out' reconnection. We point out that break-out reconnection amounts to external tether cutting. In one example, the eruptive motion of the sheared core field starts several minutes prior to any detectable brightening in the coronal images. We suggest that in this case the eruption is triggered by internal tether-cutting reconnection that at first is too slow and/or too localized to produce detectable heating in the coronal images. This work is supported by NASA's Office of Space Science through its Solar & Heliospheric Physics Supporting Research & Technology program and its Sun-Earth Connection Guest Investigator program.

Gravitating lepton bag model

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

Burinskii, A., E-mail: burinskii@mail.ru

The Kerr–Newman (KN) black hole (BH) solution exhibits the external gravitational and electromagnetic field corresponding to that of the Dirac electron. For the large spin/mass ratio, a ≫ m, the BH loses horizons and acquires a naked singular ring creating two-sheeted topology. This space is regularized by the Higgs mechanism of symmetry breaking, leading to an extended particle that has a regular spinning core compatible with the external KN solution. We show that this core has much in common with the known MIT and SLAC bag models, but has the important advantage of being in accordance with the external gravitationalmore » and electromagnetic fields of the KN solution. A peculiar two-sheeted structure of Kerr’s gravity provides a framework for the implementation of the Higgs mechanism of symmetry breaking in configuration space in accordance with the concept of the electroweak sector of the Standard Model. Similar to other bag models, the KN bag is flexible and pliant to deformations. For parameters of a spinning electron, the bag takes the shape of a thin rotating disk of the Compton radius, with a ring–string structure and a quark-like singular pole formed at the sharp edge of this disk, indicating that the considered lepton bag forms a single bag–string–quark system.« less

Do post-trauma symptoms mediate the relation between neurobiological stress parameters and conduct problems in girls?

PubMed

Babel, Kimberly A; Jambroes, Tijs; Oostermeijer, Sanne; van de Ven, Peter M; Popma, Arne; Vermeiren, Robert R J M; Doreleijers, Theo A H; Jansen, Lucres M C

2016-01-01

Attenuated activity of stress-regulating systems has consistently been reported in boys with conduct problems. Results in studies of girls are inconsistent, which may result from the high prevalence of comorbid post-trauma symptoms. Therefore, the aim of the present study is to investigate post-trauma symptoms as a potential mediator in the relation between stress-regulation systems functioning and conduct problems in female adolescents. The sample consisted of 78 female adolescents (mean age 15.4; SD 1.1) admitted to a closed treatment institution. The diagnosis of disruptive behaviour disorder (DBD) was assessed by a structured interview-the diagnostic interview schedule for children version IV (DISC-IV). To assess post-trauma symptoms and externalizing behaviour problems, self-report questionnaires, youth self report (YSR) and the trauma symptom checklist for Children (TSCC) were used. The cortisol awakenings response (CAR) measured hypothalamic-pituitary-adrenal (HPA) axis activity, whereas autonomous nervous system (ANS) activity was assessed by heart rate (HR), pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA). Independent t-tests were used to compare girls with and without DBD, while path analyses tested for the mediating role of post- trauma symptoms in the relation between stress regulating systems and externalizing behaviour. Females with DBD (n = 37) reported significantly higher rates of post-trauma symptoms and externalizing behaviour problems than girls without DBD (n = 39). Path analysis found no relation between CAR and externalizing behaviour problems. With regard to ANS activity, positive direct effects on externalizing behaviour problems were present for HR (standardized β = 0.306, p = 0.020) and PEP (standardized β = -0.323, p = 0.031), though not for RSA. Furthermore, no relation-whether direct or indirect-could be determined from post-trauma symptoms. Present findings demonstrate that the neurobiological characteristics of female externalizing behaviour differ from males, since girls showed heightened instead of attenuated ANS activity. While the prevalence of post-trauma symptoms was high in girls with DBD, it did not mediate the relation between stress parameters and externalizing behaviour. Clinical implications and future directions are discussed.

Childhood Bipolar Disorder: A Difficult Diagnosis

ERIC Educational Resources Information Center

Sutton, Kimberly Kode

2014-01-01

Identifying children with emotional or behavior disorders has long been problematic. In a general sense, those children who are most likely to be noticed by teachers and, therefore, referred for possible special education placement are those who exhibit externalizing behaviors, including physical aggression, noncompliance, and rule-breaking. It is…

Clean Break

ERIC Educational Resources Information Center

Peterson, Erin

2011-01-01

An interim president has to perform a particularly difficult balancing act. He or she shoulders the burdens from--or legacy of--the previous president and must also provide a foundation of stability for the new president. Throughout the process, effective communication--both internally and externally--is critical to ensuring a smooth transition.…

Three-dimensional external beam radiotherapy for prostate cancer increases the risk of hip fracture.

PubMed

Elliott, Sean P; Jarosek, Stephanie L; Alanee, Shaheen R; Konety, Badrinath R; Dusenbery, Kathryn E; Virnig, Beth A

2011-10-01

Hip fracture is associated with high morbidity and mortality. Pelvic external beam radiotherapy (EBRT) is known to increase the risk of hip fractures in women, but the effect in men is unknown. From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, 45,662 men who were aged ≥66 years and diagnosed with prostate cancer in 1992-2004 were identified. By using Kaplan-Meier methods and Cox proportional hazards models, the primary outcome of hip fracture risk was compared among men who received radical prostatectomy (RP), EBRT, EBRT plus androgen suppression therapy (AST), or AST alone. Age, osteoporosis, race, and other comorbidities were statistically controlled. A secondary outcome was distal forearm fracture as an indicator of the risk of fall-related fracture outside the radiation field. After covariates were statistically controlled, the findings showed that EBRT increased the risk of hip fractures by 76% (hazards ratio [HR], 1.76; 95% confidence interval [CI], 1.38-2.40) without increasing the risk of distal forearm fractures (HR, 0.80; 95% CI, 0.56-1.14). Combination therapy with EBRT plus AST increased the risk of hip fracture 145% relative to RP alone (HR, 2.45; 95% CI, 1.88-3.19) and by 40% relative to EBRT alone (HR, 1.40; 95% CI, 1.17-1.68). EBRT plus AST increased the risk of distal forearm fracture by 43% relative to RP alone (HR, 1.43; 95% CI, 0.97-2.10). The number needed to treat to result in 1 hip fracture during a 10-year period was 51 patients (95% CI, 31-103). In men with prostate cancer, pelvic 3-D conformal EBRT was associated with a 76% increased risk of hip fracture. This risk was slightly increased further by the addition of short-course AST to EBRT. This risk associated with EBRT must be site-specific as there was no increase in the risk of fall-related fractures in bones that were outside the radiation field. Copyright © 2011 American Cancer Society.

Parenting practices and problem behavior across three generations: monitoring, harsh discipline, and drug use in the intergenerational transmission of externalizing behavior.

PubMed

Bailey, Jennifer A; Hill, Karl G; Oesterle, Sabrina; Hawkins, J David

2009-09-01

Using data from grandparents (G1), parents (G2), and children (G3), this study examined continuity in parental monitoring, harsh discipline, and child externalizing behavior across generations, and the contribution of parenting practices and parental drug use to intergenerational continuity in child externalizing behavior. Structural equation and path modeling of prospective, longitudinal data from 808 G2 participants, their G1 parents, and their school-age G3 children (n = 136) showed that parental monitoring and harsh discipline demonstrated continuity from G1 to G2. Externalizing behavior demonstrated continuity from G2 to G3. Continuity in parenting practices did not explain the intergenerational continuity in externalizing behavior. Rather, G2 adolescent externalizing behavior predicted their adult substance use, which was associated with G3 externalizing behavior. A small indirect effect of G1 harsh parenting on G3 was observed. Interparental abuse and socidemographic risk were included as controls but did not explain the intergenerational transmission of externalizing behavior. Results highlight the need for preventive interventions aimed at breaking intergenerational cycles in poor parenting practices. More research is required to identify parental mechanisms influencing the continuity of externalizing behavior across generations.

Verbs in the lexicon: Why is hitting easier than breaking?

PubMed

McKoon, Gail; Love, Jessica

2011-11-01

Adult speakers use verbs in syntactically appropriate ways. For example, they know implicitly that the boy hit at the fence is acceptable but the boy broke at the fence is not. We suggest that this knowledge is lexically encoded in semantic decompositions. The decomposition for break verbs (e.g. crack, smash) is hypothesized to be more complex than that for hit verbs (e.g. kick, kiss). Specifically, the decomposition of a break verb denotes that "an entity changes state as the result of some external force" whereas the decomposition for a hit verb denotes only that "an entity potentially comes in contact with another entity." In this article, verbs of the two types were compared in a lexical decision experiment - Experiment 1 - and they were compared in sentence comprehension experiments with transitive sentences (e.g. the car hit the bicycle and the car broke the bicycle) - Experiments 2 and 3. In Experiment 1, processing times were shorter for the hit than the break verbs and in Experiments 2 and 3, processing times were shorter for the hit sentences than the break sentences, results that are in accord with the complexities of the postulated semantic decompositions.

Vital signs and their cross-correlation in sepsis and NEC: A study of 1065 very low birth weight infants in two NICUs

PubMed Central

Fairchild, Karen D.; Lake, Douglas E.; Kattwinkel, John; Moorman, J. Randall; Bateman, David A; Grieve, Philip G; Isler, Joseph R; Sahni, Rakesh

2016-01-01

Background Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment. Methods For 1065 very low birth weight (VLBW) infants in two NICUs, mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO2) were analyzed hourly (131 infant-years’ data). Cross-correlation (co-trending) between two vital signs was measured allowing a lag of +/− 30 seconds. Cases of LOS and NEC were identified retrospectively (n=186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24h. Results The best single illness predictor within and between institutions was cross-correlation of HR-SpO2. The best combined model (mean SpO2, SD HR, and cross correlation of HR-SpO2,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement 0.25, 95% CI 0.113, 0.328). Conclusion Despite minor inter-institutional differences in vital sign patterns of VLBW infants, cross-correlation of HR-SpO2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC. PMID:28001143

Occasional Papers in Distance Education. Number 9.

ERIC Educational Resources Information Center

Roberts, David, Ed.; Meacham, David, Ed.

This collection of documents contains four papers: (1) "An Orientation Seminar for Prospective Wine Science and Viticulture Students" (A. V. Hood), which describes an innovation organized by staff involved in the external teaching of wine science and viticulture who sought to break down the barriers and concerns of prospective students…

Gas pressure in sealed electrochemical cells measured externally

NASA Technical Reports Server (NTRS)

Sherfey, J. M.

1967-01-01

Piezoresistive transducer measures gas pressure inside sealed secondary electrochemical cells without breaking the seal. This method is based on the observed fact that the force exerted by the cell faces on the clamp tightening them against the transducer is a function of the gas pressure inside the cell.

Distinct RAD51 Associations with RAD52 and BCCIP in Response to DNA Damage and Replication Stress

PubMed Central

Wray, Justin; Liu, Jingmei; Nickoloff, Jac A.; Shen, Zhiyuan

2009-01-01

RAD51 has critical roles in homologous recombination (HR) repair of DNA double-strand breaks (DSB) and restarting stalled or collapsed replication forks. In yeast, Rad51 function is facilitated by Rad52 and other “mediators.” Mammalian cells express RAD52, but BRCA2 may have supplanted RAD52 in mediating RAD51 loading onto ssDNA. BCCIP interacts with BRCA2, and both proteins are important for RAD51 focus formation after ionizing radiation and HR repair of DSBs. Nonetheless, mammalian RAD52 shares biochemical activities with yeast Rad52, including RAD51 binding and single-strand annealing, suggesting a conserved role in HR. Because RAD52 and RAD51 associate, and RAD51 and BCCIP associate, we investigated the colocalization of RAD51 with BCCIP and RAD52 in human cells. We found that RAD51 colocalizes with BCCIP early after ionizing radiation, with RAD52 later, and there was little colocalization of BCCIP and RAD52. RAD52 foci are induced to a greater extent by hydroxyurea, which stalls replication forks, than by ionizing radiation. Using fluorescence recovery after photo bleaching, we show that RAD52 mobility is reduced to a greater extent by hydroxyurea than ionizing radiation. However, BCCIP showed no changes in mobility after hydroxyurea or ionizing radiation. We propose that BCCIP-dependent repair of DSBs by HR is an early RAD51 response to ionizing radiation–induced DNA damage, and that RAD52-dependent HR occurs later to restart a subset of blocked or collapsed replication forks. RAD52 and BRCA2 seem to act in parallel pathways, suggesting that targeting RAD52 in BRCA2-deficient tumors may be effective in treating these tumors. PMID:18413737

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

PubMed

Lim, Yi Chieh; Roberts, Tara L; Day, Bryan W; Stringer, Brett W; Kozlov, Sergei; Fazry, Shazrul; Bruce, Zara C; Ensbey, Kathleen S; Walker, David G; Boyd, Andrew W; Lavin, Martin F

2014-12-01

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival. Copyright © 2014. Published by Elsevier B.V.

Effects of Health Insurance Interruption on Loss of Hypertension Control in Women With and Women Without HIV.

PubMed

Edmonds, Andrew; Ludema, Christina; Eron, Joseph J; Cole, Stephen R; Adedimeji, Adebola A; Cohen, Mardge H; Cooper, Hannah L; Fischl, Margaret; Johnson, Mallory O; Krause, Denise D; Merenstein, Dan; Milam, Joel; Wilson, Tracey E; Adimora, Adaora A

2017-12-01

Among low-income women with and without HIV, it is a priority to reduce age-related comorbidities, including hypertension and its sequelae. Because consistent health insurance access has been identified as an important factor in controlling many chronic diseases, we estimated the effects of coverage interruption on loss of hypertension control in a cohort of women in the United States. We analyzed prospective, longitudinal data from the Women's Interagency HIV Study. HIV-infected and HIV-uninfected women were included between 2005 and 2014 when they reported health insurance at consecutive biannual visits and had controlled hypertension, and were followed for any insurance break and loss of hypertension control. We estimated hazard ratios (HRs) by Cox proportional hazards regression with inverse-probability-of-treatment-and censoring weights (marginal structural models), and plotted the cumulative incidence of hypertension control loss. Among 890 HIV-infected women, the weighted HR for hypertension control loss comparing health insurance interruption to uninterrupted coverage was 1.37 (95% confidence interval [CI], 0.99-1.91). Inclusion of AIDS Drug Assistance Program (ADAP) participation with health insurance modestly increased the HR (1.47; 95% CI, 1.04-2.07). Analysis of 272 HIV-uninfected women yielded a similar HR (1.39; 95% CI, 0.88-2.21). Additionally, there were indications of uninterrupted coverage having a protective effect on hypertension when compared with the natural course in HIV-infected (HR, 0.82; 95% CI, 0.61-1.11) and HIV-uninfected (HR, 0.78; 95% CI, 0.52-1.19) women. This study provides evidence that health insurance continuity promotes hypertension control in key populations. Interventions that ensure coverage stability and ADAP access should be a policy priority.

Immortalization capacity of HPV types is inversely related to chromosomal instability.

PubMed

Schütze, Denise M; Krijgsman, Oscar; Snijders, Peter J F; Ylstra, Bauke; Weischenfeldt, Joachim; Mardin, Balca R; Stütz, Adrian M; Korbel, Jan O; de Winter, Johan P; Meijer, Chris J L M; Quint, Wim G V; Bosch, Leontien; Wilting, Saskia M; Steenbergen, Renske D M

2016-06-21

High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs.Twenty five cell cultures obtained by transduction of ten hrHPV types (i.e. HPV16/18/31/33/35/45/51/59/66/70 E6E7) in two or three HFK donors each were studied.All hrHPV-transduced HFKs showed an increased number of double strand DNA breaks compared to controls, without exhibiting significant differences between types. However, immortal descendants of HPV-transduced HFKs that underwent a prior crisis period (HPV45/51/59/66/70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without crisis (HPV16/18/31/33/35-transduced HFKs). Notably, the hTERT locus at 5p was exclusively gained in cells with a history of crisis and coincided with increased expression. Chromothripsis was detected in one cell line in which multiple rearrangements within chromosome 8 resulted in a gain of MYC.Together we demonstrated that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the viral immortalization capacity. We propose that hrHPV types with reduced immortalization capacity in vitro, reflected by a crisis period, require more genetic host cell aberrations to facilitate immortalization than types that can immortalize without crisis. This may in part explain the observed differences in HPV-type prevalence in cervical cancers and emphasizes that changes in the host cell genome contribute to HPV-induced carcinogenesis.

Immortalization capacity of HPV types is inversely related to chromosomal instability

PubMed Central

Schütze, Denise M.; Krijgsman, Oscar; Snijders, Peter J.F.; Ylstra, Bauke; Weischenfeldt, Joachim; Mardin, Balca R.; Stütz, Adrian M.; Korbel, Jan O.; Meijer, Chris J.L.M.; Quint, Wim G.V.; Bosch, Leontien; Wilting, Saskia M.; Steenbergen, Renske D.M.

2016-01-01

High-risk human papillomavirus (hrHPV) types induce immortalization of primary human epithelial cells. Previously we demonstrated that immortalization of human foreskin keratinocytes (HFKs) is HPV type dependent, as reflected by the presence or absence of a crisis period before reaching immortality. This study determined how the immortalization capacity of ten hrHPV types relates to DNA damage induction and overall genomic instability in HFKs. Twenty five cell cultures obtained by transduction of ten hrHPV types (i.e. HPV16/18/31/33/35/45/51/59/66/70 E6E7) in two or three HFK donors each were studied. All hrHPV-transduced HFKs showed an increased number of double strand DNA breaks compared to controls, without exhibiting significant differences between types. However, immortal descendants of HPV-transduced HFKs that underwent a prior crisis period (HPV45/51/59/66/70-transduced HFKs) showed significantly more chromosomal aberrations compared to those without crisis (HPV16/18/31/33/35-transduced HFKs). Notably, the hTERT locus at 5p was exclusively gained in cells with a history of crisis and coincided with increased expression. Chromothripsis was detected in one cell line in which multiple rearrangements within chromosome 8 resulted in a gain of MYC. Together we demonstrated that upon HPV-induced immortalization, the number of chromosomal aberrations is inversely related to the viral immortalization capacity. We propose that hrHPV types with reduced immortalization capacity in vitro, reflected by a crisis period, require more genetic host cell aberrations to facilitate immortalization than types that can immortalize without crisis. This may in part explain the observed differences in HPV-type prevalence in cervical cancers and emphasizes that changes in the host cell genome contribute to HPV-induced carcinogenesis. PMID:26993771

Improved methods of AAV-mediated gene targeting for human cell lines using ribosome-skipping 2A peptide

PubMed Central

Karnan, Sivasundaram; Ota, Akinobu; Konishi, Yuko; Wahiduzzaman, Md; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2016-01-01

The adeno-associated virus (AAV)-based targeting vector has been one of the tools commonly used for genome modification in human cell lines. It allows for relatively efficient gene targeting associated with 1–4-log higher ratios of homologous-to-random integration of targeting vectors (H/R ratios) than plasmid-based targeting vectors, without actively introducing DNA double-strand breaks. In this study, we sought to improve the efficiency of AAV-mediated gene targeting by introducing a 2A-based promoter-trap system into targeting constructs. We generated three distinct AAV-based targeting vectors carrying 2A for promoter trapping, each targeting a GFP-based reporter module incorporated into the genome, PIGA exon 6 or PIGA intron 5. The absolute gene targeting efficiencies and H/R ratios attained using these vectors were assessed in multiple human cell lines and compared with those attained using targeting vectors carrying internal ribosome entry site (IRES) for promoter trapping. We found that the use of 2A for promoter trapping increased absolute gene targeting efficiencies by 3.4–28-fold and H/R ratios by 2–5-fold compared to values obtained with IRES. In CRISPR-Cas9-assisted gene targeting using plasmid-based targeting vectors, the use of 2A did not enhance the H/R ratios but did upregulate the absolute gene targeting efficiencies compared to the use of IRES. PMID:26657635

Progressive Return to Activity Following Acute Concussion/Mild Traumatic Brain Injury: Guidance for the Rehabilitation Provider in Deployed and Non-deployed Settings

DTIC Science & Technology

2014-01-01

activity requires minimum 2 hours of rest • Video games , driving simulation ― 20 minutes to maximum of 40 minutes, followed by 80 minutes cognitive...as breath-holding, exertion, playing video games and driving. He is encouraged to monitor his HR before and during activity (not to exceed 40 percent...walking at low speed b) Shopping in the exchange for a single item c) Video games d) Television with rest breaks each hour Knowledge Test

Modulation of the poly (ADP-ribose) polymerase inhibitor response and DNA recombination in breast cancer cells by drugs affecting endogenous wild-type p53.

PubMed

Ireno, Ivanildce Cristiane; Wiehe, Rahel Stephanie; Stahl, Andreea Iulia; Hampp, Stephanie; Aydin, Sevtap; Troester, Melissa A; Selivanova, Galina; Wiesmüller, Lisa

2014-10-01

Synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) and homologous recombination (HR) repair pathways have been exploited for the development of novel mono- and combination cancer therapies. The tumor suppressor p53 was demonstrated to exhibit indirect and direct regulatory activities in DNA repair, particularly in DNA double-strand break (DSB)-induced and replication-associated HR. In this study, we tested a potential influence of the p53 status on the response to PARP inhibition, which is known to cause replication stress. Silencing endogenous or inducibly expressing p53 we found a protective effect of p53 on PARP inhibitor (PARPi)-mediated cytotoxicities. This effect was specific for wild-type versus mutant p53 and observed in cancer but not in non-transformed cell lines. Enhanced cytotoxicities after treatment with the p53-inhibitory drug Pifithrinα further supported p53-mediated resistance to PARP inhibition. Surprisingly, we equally observed increased PARPi sensitivity in the presence of the p53-activating compound Nutlin-3. As a common denominator, both drug responses correlated with decreased HR activities: Pifithrinα downregulated spontaneous HR resulting in damage accumulation. Nutlin-3 induced a decrease of DSB-induced HR, which was accompanied by a severe drop in RAD51 protein levels. Thus, we revealed a novel link between PARPi responsiveness and p53-controlled HR activities. These data expand the concept of cell and stress type-dependent healer and killer functions of wild-type p53 in response to cancer therapeutic treatment. Our findings have implications for the individualized design of cancer therapies using PARPi and the potentially combined use of p53-modulatory drugs. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Influence of Yo-Yo IR2 Scores on Internal and External Workloads and Fatigue Responses of Tag Football Players during Tournament Competition

PubMed Central

2015-01-01

The purpose of this study was to: a) identify changes in jump height and perceived well-being as indirect markers of fatigue, b) determine the internal and external workloads performed by players, and c) examine the influence of Yo-Yo IR2 on changes in jump height, perceived well-being and internal and external workloads during a tag football tournament. Microtechnology devices combined with heart rate (HR) chest straps provided external and internal measures of match work-rate and workload for twelve male tag football players during the 2014 Australian National Championships. Jump height and perceived well-being were assessed prior to and during the tournament as indirect measures of fatigue. Changes in work-rate, workload and fatigue measures between high- and low-fitness groups were examined based on players’ Yo-Yo IR2 score using a median split technique. The low- and high-fitness groups reported similar mean HR, PlayerloadTM/min, and distance/min for matches, however the low-fitness group reported higher perceived match-intensities (ES = 0.90–1.35) for several matches. Further, the high-fitness group reported higher measures of tournament workload, including distance (ES = 0.71), PlayerloadTM (ES = 0.85) and Edwards’ training impulse (TRIMP) (ES = 1.23) than the low-fitness group. High- and low-fitness groups both showed large decreases (ES = 1.46–1.49) in perceived well-being during the tournament, although jump height did not decrease below pre-tournament values. Increased Yo-Yo IR2 appears to offer a protective effect against player fatigue despite increased workloads during a tag football tournament. It is vital that training programs adequately prepare tag football players for tournament competition to maximise performance and minimise player fatigue. PMID:26465599

Calcium and calmodulin are involved in blue light induction of the gsa gene for an early chlorophyll biosynthetic step in Chlamydomonas.

PubMed Central

Im, C S; Matters, G L; Beale, S I

1996-01-01

The Chlamydomonas reinhardtii nuclear gene gsa, which encodes the early chlorophyll biosynthetic enzyme glutamate 1-semialdehyde aminotransferase (GSAT), is specifically induced by blue light in cells synchronized in a 12-hr-light and 12-hr-dark regime. Light induction required the presence of a nitrogen source in the incubation medium. Maximal induction also required acetate. However, in the absence of acetate, partial induction occurred when Ca2+ was present in the medium at concentrations of > or = 1 microM. The Ca2+ channel-blocking agents Nd3+ and nifedipine partially inhibited the external Ca(2+)-supported induction of GSAT mRNA but did not inhibit acetate-supported induction. The calmodulin antagonists trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide inhibited both external Ca(2+)-supported and acetate-supported induction. The Ca2+ ionophore A23187 caused a transient induction in the dark. These results suggest that Ca2+ and calmodulin are involved in the signal transduction pathway linking blue light perception to the induction of GSAT mRNA. The electron transport uncoupler carbonyl cyanide m-chlorophenylhydrazone inhibited acetate-supported induction of GSAT mRNA but did not inhibit external Ca(2+)-supported induction. It is proposed that in the presence of acetate, an internal pool of Ca2+ can be mobilized as a second message, whereas in the absence of acetate, internal Ca2+ is not available but the requirement for Ca2+ can be partially met by an external Ca2+ source. The mobilization of internal Ca2+ may require energy derived from metabolism of acetate. PMID:8989881

An initial study of family accommodation in children and adolescents with chronic tic disorders.

PubMed

Storch, Eric A; Johnco, Carly; McGuire, Joseph F; Wu, Monica S; McBride, Nicole M; Lewin, Adam B; Murphy, Tanya K

2017-01-01

This initial study examined the nature, incidence, and clinical correlates of family accommodation in youth with tic disorders, and validated a brief self-report measure of tic-related family accommodation, the Tic Family Accommodation Scale (TFAS). Seventy-five youth aged 6-18 who were diagnosed with a tic disorder and their parent completed a diagnostic clinical interview, and clinician and parent-report measures of tic severity, depressive symptoms, anxiety symptoms, behavioral problems, family accommodation and impairment. An exploratory factor analysis of the TFAS showed a two-factor structure, with good internal consistency for the Total score, Modification of Child Environment and Modification of Parent Environment subscales (α = 0.88, 0.86, and 0.81, respectively). Family accommodation was not associated with tic severity. Family accommodation was associated with increased anxiety and depressive symptoms, higher externalizing, rule breaking, aggressive behaviors and social problems, and with greater tic-related functional impairment. Anxiety and externalizing problems (but not depressive symptoms) predicted family accommodation when controlling for tic severity. Family accommodation predicted high levels of functional impairment over and above the effect of tic severity, anxiety, depression and externalizing problems. Family accommodation is a common phenomenon for youth with tic disorders, with modifications typically encompassing changes to the child and/or parent environments. Accommodation was not associated with tic severity, but was related to higher levels of anxiety, depressive symptoms, externalizing symptoms, aggression, and rule breaking behaviors. Results suggest that other emotional symptoms are more likely to drive accommodation practices than the tic symptoms per se.

Blood acid-base changes during experimental emersion and reimmersion of the intertidal crab Carcinus maenas (L.).

PubMed

Truchot, J P

1975-04-01

The time course of blood acid-base changes was studied in Carcinus maenas during experimental emersion and reimmersion at 15 degrees C by measuring pH and PCO2 and calculating bicarbonate concentration. During the first 4 hr of the emersion period, a marked rise of PCO2 entails a respiratory acidosis which is progressively compensated by a slow increase of the bicarbonate concentration; this compensation is completed after about 100 hr and the steady state mean pH value approximates that found for the immersed controls. Return to aquatic conditions is characterized by a rapid decrease of both PCO2 and blood bicarbonate concentration. During the first 2 hr of the reimmersion period, the decrease of blood bicarbonate concentration is accompanied by excretion of a significant amount of base in water, thus suggesting that readjustments of acid-base balance take place at least in part by ionic exchanges between the blood and the external milieu. Initial status was restored after 9 hr. These finding agree with the general views concerning the blood acid-base changes which must occur at transition from water-to air-breathing.

Ferromagnetic mass fixed on a spring and subjected to an electromagnet powered by self-sustained oscillators

NASA Astrophysics Data System (ADS)

Abobda, L. T.; Woafo, P.

2014-12-01

The study of a ferromagnetic mass, fixed on a spring and subjected to an electromagnet powered by a Van der Pol (VDP) oscillator and by a Hindmarsh-Rose (HR) oscillator is performed, to serve as an electromechanical devices, but also to mimic the action of a natural pacemaker and nerves on a cardiac assist device or artificial heart. The excitation with the VDP oscillator shows in the mechanical part the transition from harmonic, periodic, biperiodic up to bursting oscillations, high displacement without pull-in instability in the free dynamics regime. Under DC plus square wave excitation, there is a coexistence of the bursting oscillations of the free dynamics and the one of the modulated dynamics. Considering the action of a HR oscillator, it is found transition from spikes, bursting oscillations, relaxation spikes, multiperiodic and sinusoidal oscillations under DC or DC plus square wave excitation. These electrical behaviors are transferred to the mechanical part which can then adopt spiking or bursting dynamics as the HR oscillator. For this electromechanical model, the VDP oscillator is more efficient than the HR oscillator to induce pulsatile pumping function with higher amplitude and to react to external influences without pull-in.

A scanning tunneling microscope break junction method with continuous bias modulation.

PubMed

Beall, Edward; Yin, Xing; Waldeck, David H; Wierzbinski, Emil

2015-09-28

Single molecule conductance measurements on 1,8-octanedithiol were performed using the scanning tunneling microscope break junction method with an externally controlled modulation of the bias voltage. Application of an AC voltage is shown to improve the signal to noise ratio of low current (low conductance) measurements as compared to the DC bias method. The experimental results show that the current response of the molecule(s) trapped in the junction and the solvent media to the bias modulation can be qualitatively different. A model RC circuit which accommodates both the molecule and the solvent is proposed to analyze the data and extract a conductance for the molecule.

Quantum anharmonic oscillator plus delta-function potential: a molecular view of pairing formation and breaking in the coordinate space

NASA Astrophysics Data System (ADS)

Sumaryada, Tony; Maha Putra, Bima; Pramudito, Sidikrubadi

2017-05-01

We propose an alternative way to describe the pairing formation and breaking via a quantum anharmonic oscillator with a delta-function potential model. Unlike BCS theory, which describes the pairing formation in the momentum space, this model works in the coordinate space and is able to give a molecular view of pairing formation and breaking in the coordinate space. By exploring the dynamical interplay between the intrinsic factor (dissociation energy) and external factor (pairing strength) of this system additional information was gained, including the critical pairing strength and critical scattering length, which might relate to the BCS-BEC crossover phenomena and halo state formation. Although only the energetic aspect of pairing is described by this model, its simplicity and pedagogical steps might help undergraduate students to understand the pairing problem in a simple way.

Biomolecular structure manipulation using tailored electromagnetic radiation: a proof of concept on a simplified model of the active site of bacterial DNA topoisomerase.

PubMed

Jarukanont, Daungruthai; Coimbra, João T S; Bauerhenne, Bernd; Fernandes, Pedro A; Patel, Shekhar; Ramos, Maria J; Garcia, Martin E

2014-10-21

We report on the viability of breaking selected bonds in biological systems using tailored electromagnetic radiation. We first demonstrate, by performing large-scale simulations, that pulsed electric fields cannot produce selective bond breaking. Then, we present a theoretical framework for describing selective energy concentration on particular bonds of biomolecules upon application of tailored electromagnetic radiation. The theory is based on the mapping of biomolecules to a set of coupled harmonic oscillators and on optimal control schemes to describe optimization of temporal shape, the phase and polarization of the external radiation. We have applied this theory to demonstrate the possibility of selective bond breaking in the active site of bacterial DNA topoisomerase. For this purpose, we have focused on a model that was built based on a case study. Results are given as a proof of concept.

Time-reversal symmetry-breaking superconductivity in epitaxial bismuth/nickel bilayers

DOE PAGES

Gong, Xinxin; Kargarian, Mehdi; Stern, Alex; ...

2017-03-31

Superconductivity that spontaneously breaks time-reversal symmetry (TRS) has been found, so far, only in a handful of three-dimensional (3D) crystals with bulk inversion symmetry. We report an observation of spontaneous TRS breaking in a 2D superconducting system without inversion symmetry: the epitaxial bilayer films of bismuth and nickel. The evidence comes from the onset of the polar Kerr effect at the superconducting transition in the absence of an external magnetic field, detected by the ultrasensitive loop-less fiber-optic Sagnac interferometer. Because of strong spin-orbit interaction and lack of inversion symmetry in a Bi/Ni bilayer, superconducting pairing cannot be classified as singletmore » or triplet.We propose a theoretical model where magnetic fluctuations in Ni induce the superconducting pairing of the d xy ± id x2-y2 orbital symmetry between the electrons in Bi. In this model, the order parameter spontaneously breaks the TRS and has a nonzero phase winding number around the Fermi surface, thus making it a rare example of a 2D topological superconductor.« less

Janus monolayers of transition metal dichalcogenides.

PubMed

Lu, Ang-Yu; Zhu, Hanyu; Xiao, Jun; Chuu, Chih-Piao; Han, Yimo; Chiu, Ming-Hui; Cheng, Chia-Chin; Yang, Chih-Wen; Wei, Kung-Hwa; Yang, Yiming; Wang, Yuan; Sokaras, Dimosthenis; Nordlund, Dennis; Yang, Peidong; Muller, David A; Chou, Mei-Yin; Zhang, Xiang; Li, Lain-Jong

2017-08-01

Structural symmetry-breaking plays a crucial role in determining the electronic band structures of two-dimensional materials. Tremendous efforts have been devoted to breaking the in-plane symmetry of graphene with electric fields on AB-stacked bilayers or stacked van der Waals heterostructures. In contrast, transition metal dichalcogenide monolayers are semiconductors with intrinsic in-plane asymmetry, leading to direct electronic bandgaps, distinctive optical properties and great potential in optoelectronics. Apart from their in-plane inversion asymmetry, an additional degree of freedom allowing spin manipulation can be induced by breaking the out-of-plane mirror symmetry with external electric fields or, as theoretically proposed, with an asymmetric out-of-plane structural configuration. Here, we report a synthetic strategy to grow Janus monolayers of transition metal dichalcogenides breaking the out-of-plane structural symmetry. In particular, based on a MoS 2 monolayer, we fully replace the top-layer S with Se atoms. We confirm the Janus structure of MoSSe directly by means of scanning transmission electron microscopy and energy-dependent X-ray photoelectron spectroscopy, and prove the existence of vertical dipoles by second harmonic generation and piezoresponse force microscopy measurements.

Heart rate-left ventricular ejection time relations - Variations during postural change and cardiovascular challenges

NASA Technical Reports Server (NTRS)

Lance, V. Q.; Spodick, D. H.

1976-01-01

Experiments were conducted on healthy human subjects to determine HR-LVET (Heart Rate-Left Ventricular Ejection Time) regression relations in different postures, including tilt, and during isometric exercise. The subjects were tested in the resting state in supine and sitting positions, during isometric handgrip in supine and sitting positions and during 70 deg headup tilt. The recordings included a bipolar electrocardiogram and a right external carotid pulse curve. Comparison of the HR-LVET relation for the conditions under analysis revealed differences among the respective regression equations, which can be explained by the well-established differences in stroke volume and ejection rate among these states. These differences appear to account for the fact that under conditions in which stroke volume variations should be the major determinant, slopes will be similar but intercepts will vary. Since substantial differences among intercepts are observed, caution should be exercised whenever the intercept factor is used to predict LVET for HR.

Aortic Wave Dynamics and Its Influence on Left Ventricular Workload

PubMed Central

Pahlevan, Niema M.; Gharib, Morteza

2011-01-01

The pumping mechanism of the heart is pulsatile, so the heart generates pulsatile flow that enters into the compliant aorta in the form of pressure and flow waves. We hypothesized that there exists a specific heart rate at which the external left ventricular (LV) power is minimized. To test this hypothesis, we used a computational model to explore the effects of heart rate (HR) and aortic rigidity on left ventricular (LV) power requirement. While both mean and pulsatile parts of the pressure play an important role in LV power requirement elevation, at higher rigidities the effect of pulsatility becomes more dominant. For any given aortic rigidity, there exists an optimum HR that minimizes the LV power requirement at a given cardiac output. The optimum HR shifts to higher values as the aorta becomes more rigid. To conclude, there is an optimum condition for aortic waves that minimizes the LV pulsatile load and consequently the total LV workload. PMID:21853075

Parental Problem Drinking and Adolescent Externalizing Behaviors: The Mediating Role of Family Functioning

PubMed Central

Schulz, Jessica; Gordon, Mellissa S.; Ohannessian, Christine McCauley

2015-01-01

This study explored relationships among parental problem drinking, family functioning, and adolescent externalizing behaviors. The unique effects of maternal and paternal drinking were examined separately for girls and boys. The sample included 14-19 year old U.S. adolescents (Mage=16.15; SD=.75; 52.5% female) and their parents. Participants completed surveys in the spring of 2007 and 2008. Structural equation modelling was used to conduct path analysis models. Results showed the distinctive and adverse effects of parental problem drinking on adolescent alcohol use, drug use, rule breaking, and aggressive behavior over time. Findings also highlighted the indirect and mediating roles of family functioning. For both girls and boys, family cohesion mediated the relationship between parental problem drinking and adolescent externalizing behaviors. For girls, adolescent-father communication predicted increased externalizing behaviors over time. These findings draw attention to the importance of exploring adolescent and parent gender when examining parental problem drinking, family functioning, and externalizing behaviors. PMID:26073673

Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta.

PubMed

Nicolay, Nils H; Carter, Rebecca; Hatch, Stephanie B; Schultz, Niklas; Prevo, Remko; McKenna, W Gillies; Helleday, Thomas; Sharma, Ricky A

2012-11-01

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt's lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control.

Homologous recombination and non-homologous end-joining repair pathways in bovine embryos with different developmental competence

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

Henrique Barreta, Marcos; Laboratorio de Biotecnologia e Reproducao Animal-BioRep, Universidade Federal de Santa Maria, Santa Maria, RS; Garziera Gasperin, Bernardo

2012-10-01

This study investigated the expression of genes controlling homologous recombination (HR), and non-homologous end-joining (NHEJ) DNA-repair pathways in bovine embryos of different developmental potential. It also evaluated whether bovine embryos can respond to DNA double-strand breaks (DSBs) induced with ultraviolet irradiation by regulating expression of genes involved in HR and NHEJ repair pathways. Embryos with high, intermediate or low developmental competence were selected based on the cleavage time after in vitro insemination and were removed from in vitro culture before (36 h), during (72 h) and after (96 h) the expected period of embryonic genome activation. All studied genes weremore » expressed before, during and after the genome activation period regardless the developmental competence of the embryos. Higher mRNA expression of 53BP1 and RAD52 was found before genome activation in embryos with low developmental competence. Expression of 53BP1, RAD51 and KU70 was downregulated at 72 h and upregulated at 168 h post-insemination in response to DSBs induced by ultraviolet irradiation. In conclusion, important genes controlling HR and NHEJ DNA-repair pathways are expressed in bovine embryos, however genes participating in these pathways are only regulated after the period of embryo genome activation in response to ultraviolet-induced DSBs.« less

Assessment of genetic mutations in the XRCC2 coding region by high resolution melting curve analysis and the risk of differentiated thyroid carcinoma in Iran

PubMed Central

Fayaz, Shima; Fard-Esfahani, Pezhman; Fard-Esfahani, Armaghan; Mostafavi, Ehsan; Meshkani, Reza; Mirmiranpour, Hossein; Khaghani, Shahnaz

2012-01-01

Homologous recombination (HR) is the major pathway for repairing double strand breaks (DSBs) in eukaryotes and XRCC2 is an essential component of the HR repair machinery. To evaluate the potential role of mutations in gene repair by HR in individuals susceptible to differentiated thyroid carcinoma (DTC) we used high resolution melting (HRM) analysis, a recently introduced method for detecting mutations, to examine the entire XRCC2 coding region in an Iranian population. HRM analysis was used to screen for mutations in three XRCC2 coding regions in 50 patients and 50 controls. There was no variation in the HRM curves obtained from the analysis of exons 1 and 2 in the case and control groups. In exon 3, an Arg188His polymorphism (rs3218536) was detected as a new melting curve group (OR: 1.46; 95%CI: 0.432–4.969; p = 0.38) compared with the normal melting curve. We also found a new Ser150Arg polymorphism in exon 3 of the control group. These findings suggest that genetic variations in the XRCC2 coding region have no potential effects on susceptibility to DTC. However, further studies with larger populations are required to confirm this conclusion. PMID:22481871

An adaptive supramolecular hydrogel comprising self-sorting double nanofibre networks

NASA Astrophysics Data System (ADS)

Shigemitsu, Hajime; Fujisaku, Takahiro; Tanaka, Wataru; Kubota, Ryou; Minami, Saori; Urayama, Kenji; Hamachi, Itaru

2018-02-01

Novel soft materials should comprise multiple supramolecular nanostructures whose responses (for example, assembly and disassembly) to external stimuli can be controlled independently. Such multicomponent systems are present in living cells and control the formation and break-up of a variety of supramolecular assemblies made of proteins, lipids, DNA and RNA in response to external stimuli; however, artificial counterparts are challenging to make. Here, we present a hybrid hydrogel consisting of a self-sorting double network of nanofibres in which each network responds to an applied external stimulus independent of the other. The hydrogel can be made to change its mechanical properties and rates of release of encapsulated proteins by adding Na2S2O4 or bacterial alkaline phosphatase. Notably, the properties of the gel depend on the order in which the external stimuli are applied. Multicomponent hydrogels comprising orthogonal stimulus-responsive supramolecular assemblies would be suitable for designing novel adaptive materials.

Survival Outcomes of Whole-Pelvic Versus Prostate-Only Radiation Therapy for High-Risk Prostate Cancer Patients With Use of the National Cancer Data Base

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

Amini, Arya; Jones, Bernard L.; Yeh, Norman

Purpose/Objectives: The addition of whole pelvic (WP) compared with prostate-only (PO) radiation therapy (RT) for clinically node-negative prostate cancer remains controversial. The purpose of our study was to evaluate the survival benefit of adding WPRT versus PO-RT for high-risk, node-negative prostate cancer, using the National Cancer Data Base (NCDB). Methods and Materials: Patients with high-risk prostate cancer treated from 2004 to 2006, with available data for RT volume, coded as prostate and pelvis (WPRT) or prostate alone (PO-RT) were included. Multivariate analysis (MVA) and propensity-score matched analysis (PSM) were performed. Recursive partitioning analysis (RPA) based on overall survival (OS) usingmore » Gleason score (GS), T stage, and pretreatment prostate-specific antigen (PSA) was also conducted. Results: A total of 14,817 patients were included: 7606 (51.3%) received WPRT, and 7211 (48.7%) received PO-RT. The median follow-up time was 81 months (range, 2-122 months). Under MVA, the addition of WPRT for high-risk patients had no OS benefit compared with PO-RT (HR 1.05; P=.100). On subset analysis, patients receiving dose-escalated RT also did not benefit from WPRT (HR 1.01; P=.908). PSM confirmed no survival benefit with the addition of WPRT for high-risk patients (HR 1.05; P=.141). In addition, RPA was unable to demonstrate a survival benefit of WPRT for any subset. Other prognostic factors for inferior OS under MVA included older age (HR 1.25; P<.001), increasing comorbidity scores (HR 1.46; P<.001), higher T stage (HR 1.17; P<.001), PSA (HR 1.81; P<.001), and GS (HR 1.29; P<.001), and decreasing median county household income (HR 1.15; P=.011). Factors improving OS included the addition of androgen deprivation therapy (HR 0.92; P=.033), combination external beam RT plus brachytherapy boost (HR 0.71; P<.001), and treatment at an academic/research institution (HR 0.84; P=.002). Conclusion: In the largest reported analysis of WPRT for patients with high-risk prostate cancer treated in the dose-escalated era, the addition of WPRT demonstrated no survival advantage compared with PO-RT.« less

APT Blanket System Loss-of-Coolant Accident (LOCA) Based on Initial Conceptual Design - Case 4: External Pressurizer Surge Line Break Near Inlet Header

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

Hamm, L.L.

1998-10-07

This report is one of a series of reports documenting accident scenario simulations for the Accelerator Production of Tritium (APT) blanket heat removal systems. The simulations were performed in support of the Preliminary Safety Analysis Report (PSAR) for the APT.

Combinations of PARP Inhibitors with Temozolomide Drive PARP1 Trapping and Apoptosis in Ewing’s Sarcoma

PubMed Central

Pshenichnaya, Irina; Kogera, Fiona A.; Barthorpe, Syd; Mironenko, Tatiana; Richardson, Laura; Benes, Cyril H.; Stratton, Michael R.; McDermott, Ultan; Jackson, Stephen P.; Garnett, Mathew J.

2015-01-01

Ewing’s sarcoma is a malignant pediatric bone tumor with a poor prognosis for patients with metastatic or recurrent disease. Ewing’s sarcoma cells are acutely hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition and this is being evaluated in clinical trials, although the mechanism of hypersensitivity has not been directly addressed. PARP inhibitors have efficacy in tumors with BRCA1/2 mutations, which confer deficiency in DNA double-strand break (DSB) repair by homologous recombination (HR). This drives dependence on PARP1/2 due to their function in DNA single-strand break (SSB) repair. PARP inhibitors are also cytotoxic through inhibiting PARP1/2 auto-PARylation, blocking PARP1/2 release from substrate DNA. Here, we show that PARP inhibitor sensitivity in Ewing’s sarcoma cells is not through an apparent defect in DNA repair by HR, but through hypersensitivity to trapped PARP1-DNA complexes. This drives accumulation of DNA damage during replication, ultimately leading to apoptosis. We also show that the activity of PARP inhibitors is potentiated by temozolomide in Ewing’s sarcoma cells and is associated with enhanced trapping of PARP1-DNA complexes. Furthermore, through mining of large-scale drug sensitivity datasets, we identify a subset of glioma, neuroblastoma and melanoma cell lines as hypersensitive to the combination of temozolomide and PARP inhibition, potentially identifying new avenues for therapeutic intervention. These data provide insights into the anti-cancer activity of PARP inhibitors with implications for the design of treatment for Ewing’s sarcoma patients with PARP inhibitors. PMID:26505995

Human cell toxicogenomic analysis of bromoacetic acid: a regulated drinking water disinfection by-product.

PubMed

Muellner, Mark G; Attene-Ramos, Matias S; Hudson, Matthew E; Wagner, Elizabeth D; Plewa, Michael J

2010-04-01

The disinfection of drinking water is a major achievement in protecting the public health. However, current disinfection methods also generate disinfection by-products (DBPs). Many DBPs are cytotoxic, genotoxic, teratogenic, and carcinogenic and represent an important class of environmentally hazardous chemicals that may carry long-term human health implications. The objective of this research was to integrate in vitro toxicology with focused toxicogenomic analysis of the regulated DBP, bromoacetic acid (BAA) and to evaluate modulation of gene expression involved in DNA damage/repair and toxic responses, with nontransformed human cells. We generated transcriptome profiles for 168 genes with 30 min and 4 hr exposure times that did not induce acute cytotoxicity. Using qRT-PCR gene arrays, the levels of 25 transcripts were modulated to a statistically significant degree in response to a 30 min treatment with BAA (16 transcripts upregulated and nine downregulated). The largest changes were observed for RAD9A and BRCA1. The majority of the altered transcript profiles are genes involved in DNA repair, especially the repair of double strand DNA breaks, and in cell cycle regulation. With 4 hr of treatment the expression of 28 genes was modulated (12 upregulated and 16 downregulated); the largest fold changes were in HMOX1 and FMO1. This work represents the first nontransformed human cell toxicogenomic study with a regulated drinking water disinfection by-product. These data implicate double strand DNA breaks as a feature of BAA exposure. Future toxicogenomic studies of DBPs will further strengthen our limited knowledge in this growing area of drinking water research. Copyright 2009 Wiley-Liss, Inc.

Repair pathways independent of the Fanconi anemia nuclear core complex play a predominant role in mitigating formaldehyde-induced DNA damage

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

Noda, Taichi; Department of Dermatology, School of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521; Takahashi, Akihisa

2011-01-07

The role of the Fanconi anemia (FA) repair pathway for DNA damage induced by formaldehyde was examined in the work described here. The following cell types were used: mouse embryonic fibroblast cell lines FANCA{sup -/-}, FANCC{sup -/-}, FANCA{sup -/-}C{sup -/-}, FANCD2{sup -/-} and their parental cells, the Chinese hamster cell lines FANCD1 mutant (mt), FANCGmt, their revertant cells, and the corresponding wild-type (wt) cells. Cell survival rates were determined with colony formation assays after formaldehyde treatment. DNA double strand breaks (DSBs) were detected with an immunocytochemical {gamma}H2AX-staining assay. Although the sensitivity of FANCA{sup -/-}, FANCC{sup -/-} and FANCA{sup -/-}C{sup -/-}more » cells to formaldehyde was comparable to that of proficient cells, FANCD1mt, FANCGmt and FANCD2{sup -/-} cells were more sensitive to formaldehyde than the corresponding proficient cells. It was found that homologous recombination (HR) repair was induced by formaldehyde. In addition, {gamma}H2AX foci in FANCD1mt cells persisted for longer times than in FANCD1wt cells. These findings suggest that formaldehyde-induced DSBs are repaired by HR through the FA repair pathway which is independent of the FA nuclear core complex. -- Research highlights: {yields} We examined to clarify the repair pathways of formaldehyde-induced DNA damage. Formaldehyde induces DNA double strand breaks (DSBs). {yields} DSBs are repaired through the Fanconi anemia (FA) repair pathway. {yields} This pathway is independent of the FA nuclear core complex. {yields} We also found that homologous recombination repair was induced by formaldehyde.« less

Analysis of illegitimate genomic integration mediated by zinc-finger nucleases: implications for specificity of targeted gene correction

PubMed Central

2010-01-01

Background Formation of site specific genomic double strand breaks (DSBs), induced by the expression of a pair of engineered zinc-finger nucleases (ZFNs), dramatically increases the rates of homologous recombination (HR) between a specific genomic target and a donor plasmid. However, for the safe use of ZFN induced HR in practical applications, possible adverse effects of the technology such as cytotoxicity and genotoxicity need to be well understood. In this work, off-target activity of a pair of ZFNs has been examined by measuring the ratio between HR and illegitimate genomic integration in cells that are growing exponentially, and in cells that have been arrested in the G2/M phase. Results A reporter cell line that contained consensus ZFN binding sites in an enhanced green fluorescent protein (EGFP) reporter gene was used to measure ratios between HR and non-homologous integration of a plasmid template. Both in human cells (HEK 293) containing the consensus ZFN binding sites and in cells lacking the ZFN binding sites, a 3.5 fold increase in the level of illegitimate integration was observed upon ZFN expression. Since the reporter gene containing the consensus ZFN target sites was found to be intact in cells where illegitimate integration had occurred, increased rates of illegitimate integration most likely resulted from the formation of off-target genomic DSBs. Additionally, in a fraction of the ZFN treated cells the co-occurrence of both specific HR and illegitimate integration was observed. As a mean to minimize unspecific effects, cell cycle manipulation of the target cells by induction of a transient G2/M cell cycle arrest was shown to stimulate the activity of HR while having little effect on the levels of illegitimate integration, thus resulting in a nearly eight fold increase in the ratio between the two processes. Conclusions The demonstration that ZFN expression, in addition to stimulating specific gene targeting by HR, leads to increased rates of illegitimate integration emphasizes the importance of careful characterization of ZFN treated cells. In order to reduce off-target events, reversible cell cycle arrest of the target cells in the G2/M phase is an efficient way for increasing the ratio between specific HR and illegitimate integration. PMID:20459736

The key role of CYC2 during meiosis in Tetrahymena thermophila.

PubMed

Xu, Qianlan; Wang, Ruoyu; Ghanam, A R; Yan, Guanxiong; Miao, Wei; Song, Xiaoyuan

2016-04-01

Meiotic recombination is carried out through a specialized pathway for the formation and repair of DNA double-strand breaks (DSBs) made by the Spo11 protein. The present study shed light on the functional role of cyclin, CYC2, in Tetrahymena thermophila which has transcriptionally high expression level during meiosis process. Knocking out the CYC2 gene results in arrest of meiotic conjugation process at 2.5-3.5 h after conjugation initiation, before the meiosis division starts, and in company with the absence of DSBs. To investigate the underlying mechanism of this phenomenon, a complete transcriptome profile was performed between wild-type strain and CYC2 knock-out strain. Functional analysis of RNA-Seq results identifies related differentially expressed genes (DEGs) including SPO11 and these DEGs are enriched in DNA repair/mismatch repair (MMR) terms in homologous recombination (HR), which indicates that CYC2 could play a crucial role in meiosis by regulating SPO11 and participating in HR.

The helicase domain of Polθ counteracts RPA to promote alt-NHEJ.

PubMed

Mateos-Gomez, Pedro A; Kent, Tatiana; Deng, Sarah K; McDevitt, Shane; Kashkina, Ekaterina; Hoang, Trung M; Pomerantz, Richard T; Sfeir, Agnel

2017-12-01

Mammalian polymerase theta (Polθ) is a multifunctional enzyme that promotes error-prone DNA repair by alternative nonhomologous end joining (alt-NHEJ). Here we present structure-function analyses that reveal that, in addition to the polymerase domain, Polθ-helicase activity plays a central role during double-strand break (DSB) repair. Our results show that the helicase domain promotes chromosomal translocations by alt-NHEJ in mouse embryonic stem cells and also suppresses CRISPR-Cas9- mediated gene targeting by homologous recombination (HR). In vitro assays demonstrate that Polθ-helicase activity facilitates the removal of RPA from resected DSBs to allow their annealing and subsequent joining by alt-NHEJ. Consistent with an antagonistic role for RPA during alt-NHEJ, inhibition of RPA1 enhances end joining and suppresses recombination. Taken together, our results reveal that the balance between HR and alt-NHEJ is controlled by opposing activities of Polθ and RPA, providing further insight into the regulation of repair-pathway choice in mammalian cells.

Intermediate-term results of image-guided brachytherapy and high-technology external beam radiotherapy in cervical cancer: Chiang Mai University experience.

PubMed

Tharavichitkul, Ekkasit; Chakrabandhu, Somvilai; Wanwilairat, Somsak; Tippanya, Damrongsak; Nobnop, Wannapha; Pukanhaphan, Nantaka; Galalae, Razvan M; Chitapanarux, Imjai

2013-07-01

To evaluate the outcomes of image-guided brachytherapy combined with 3D conformal or intensity modulated external beam radiotherapy (3D CRT/IMRT) in cervical cancer at Chiang Mai University. From 2008 to 2011, forty-seven patients with locally advanced cervical cancer were enrolled in this study. All patients received high-technology (3D CRT/IMRT) whole pelvic radiotherapy with a total dose of 45-46 Gy plus image-guided High-Dose-Rate intracavitary brachytherapy 6.5-7 Gy × 4 fractions to a High-Risk Clinical Target Volume (HR-CTV) according to GEC-ESTRO recommendations. The dose parameters of the HR-CTV for bladder, rectum and sigmoid colon were recorded, as well as toxicity profiles. In addition, the endpoints for local control, disease-free, metastasis-free survival and overall survival were calculated. At the median follow-up time of 26 months, the local control, disease-free survival, and overall survival rates were 97.9%, 85.1%, and 93.6%, respectively. The mean dose of HR-CTV, bladder, rectum and sigmoid were 93.1, 88.2, 69.6, and 72 Gy, respectively. In terms of late toxicity, the incidence of grade 3-4 bladder and rectum morbidity was 2.1% and 2.1%, respectively. A combination of image-guided brachytherapy and IMRT/3D CRT showed very promising results of local control, disease-free survival, metastasis-free survival and overall survival rates. It also caused a low incidence of grade 3-4 toxicity in treated study patients. Copyright © 2013 Elsevier Inc. All rights reserved.

External validation of the PROFUND index in polypathological patients from internal medicine and acute geriatrics departments in Aragón.

PubMed

Díez-Manglano, Jesús; Cabrerizo García, José Luis; García-Arilla Calvo, Ernesto; Jimeno Saínz, Araceli; Calvo Beguería, Eva; Martínez-Álvarez, Rosa M; Bejarano Tello, Esperanza; Caudevilla Martínez, Aránzazu

2015-12-01

The objective of the study was to validate externally and prospectively the PROFUND index to predict survival of polypathological patients after a year. An observational, prospective and multicenter study was performed. Polypathological patients admitted to an internal medicine or geriatrics department and attended by investigators consecutively between March 1 and June 30, 2011 were included. Data concerning age, gender, comorbidity, Barthel and Lawton-Brody indexes, Pfeiffer questionnaire, socio-familial Gijon scale, delirium, number of drugs and number of admissions during the previous year were gathered for each patient. The PROFUND index was calculated. The follow-up lasted 1 year. A Cox proportional regression model was calculated, and was used to analyze the association of the variables to mortality and C-statistic. 465 polypathological patients, 333 from internal medicine and 132 from geriatrics, were included. One-year mortality is associated with age [hazard ratio (HR) 1.52 95 % CI 1.04-2.12; p = 0.01], presence of neoplasia [HR 2.68 95 % CI 1.71-4.18; p = 0.0001] and dependence for basic activities of daily living [HR 2.34 95 % CI 1.61-3.40; p = 0.0009]. In predicting mortality, the PROFUND index shows good discrimination in patients from internal medicine (C-statistics 0.725 95 % CI 0.670-0.781), but a poor one in those from geriatrics (0.546 95 % CI 0.448-0.644). The PROFUND index is a reliable tool for predicting mortality in internal medicine PP patients.

Temperature modulation with an esophageal heat transfer device - a pediatric swine model study.

PubMed

Kulstad, Erik B; Naiman, Melissa; Shanley, Patrick; Garrett, Frank; Haryu, Todd; Waller, Donald; Azarafrooz, Farshid; Courtney, Daniel Mark

2015-01-01

An increasing number of conditions appear to benefit from control and modulation of temperature, but available techniques to control temperature often have limitations, particularly in smaller patients with high surface to mass ratios. We aimed to evaluate a new method of temperature modulation with an esophageal heat transfer device in a pediatric swine model, hypothesizing that clinically significant modulation in temperature (both increases and decreases of more than 1°C) would be possible. Three female Yorkshire swine averaging 23 kg were anesthetized with inhalational isoflurane prior to placement of the esophageal device, which was powered by a commercially available heat exchanger. Swine temperature was measured rectally and cooling and warming were performed by selecting the appropriate external heat exchanger mode. Temperature was recorded over time in order to calculate rates of temperature change. Histopathology of esophageal tissue was performed after study completion. Average swine baseline temperature was 38.3°C. Swine #1 exhibited a cooling rate of 3.5°C/hr; however, passive cooling may have contributed to this rate. External warming blankets maintained thermal equilibrium in swine #2 and #3, demonstrating maximum temperature decrease of 1.7°C/hr. Warming rates averaged 0.29°C/hr. Histopathologic analysis of esophageal tissue showed no adverse effects. An esophageal heat transfer device successfully modulated the temperature in a pediatric swine model. This approach to temperature modulation may offer a useful new modality to control temperature in conditions warranting temperature management (such as maintenance of normothermia, induction of hypothermia, fever control, or malignant hyperthermia).

Parental training and externalizing behaviors of children with severe hearing loss.

PubMed

Movallali, Guita; Amiri, Mohsen; Nesayan, Abas; Assady Gandomani, Roghaye

2017-01-01

Background: Externalizing behavior in deaf children causes many psychological problems for their parents. Aggression and rule breaking behaviors in children with severe hearing loss may cause psychological problems in parents and in managing children's behavior. Consequently, the present study aimed at investigating the effect of parental behavioral training of mothers on reducing the externalized behaviors (aggression and rule breaking behavior) of their 9- to 10- year old children with severe hearing loss. Methods: This was an experimental study with pretest, posttest, and a control group. The research population included all students with severe hearing loss and their mothers. Thus, 30 mothers whose children had the most severe hearing loss were selected as our main sample among 80 mothers who had completed the Child Behavior Checklist. Then, they were placed into the experimental (n=15) and control groups (n=15) after being matched based on age, educational level, and socioeconomic status. The research tool was Child Behavior Checklist-Persian Version. The parental behavior training was provided for the experimental group in nine 90- minute sessions. Results: The results of the present study indicated the effectiveness of experimental treatment on decreasing the aggressive behaviors of children of mothers in the experimental group compared to mothers of the control group (p=0.001). Moreover, the results revealed a decrease in rule breaking behaviors (p= 0.007) in children of mothers of the experimental group compared to mothers of the control group. Conclusion: Parents' behavioral training is important in decreasing the aggressive and offensive behaviors in children with severe hearing loss who are at risk of behavioral problems. Furthermore, some research has highlighted the necessity of such trainings for parents of these children. Thus, the present study, emphasizing the importance of childhood problems, found that mothers' behavioral training could prevent behavioral problems of school-aged children with hearing loss and reduce the recurrence of such problems.

Deformed Materials: Towards a Theory of Materials Morphology Dynamics

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

Sethna, James P

This grant supported work on the response of crystals to external stress. Our primary work described how disordered structural materials break in two (statistical models of fracture in disordered materials), studied models of deformation bursts (avalanches) that mediate deformation on the microscale, and developed continuum dislocation dynamics models for plastic deformation (as when scooping ice cream bends a spoon, Fig. 9). Glass is brittle -- it breaks with almost atomically smooth fracture surfaces. Many metals are ductile -- when they break, the fracture surface is locally sheared and stretched, and it is this damage that makes them hard to break.more » Bone and seashells are made of brittle material, but they are strong because they are disordered -- lots of little cracks form as they are sheared and near the fracture surface, diluting the external force. We have studied materials like bone and seashells using simulations, mathematical tools, and statistical mechanics models from physics. In particular, we studied the extreme values of fracture strengths (how likely will a beam in a bridge break far below its design strength), and found that the traditional engineering tools could be improved greatly. We also studied fascinating crackling-noise precursors -- systems which formed microcracks of a broad range of sizes before they broke. Ductile metals under stress undergo irreversible plastic deformation -- the planes of atoms must slide across one another (through the motion of dislocations) to change the overall shape in response to the external force. Microscopically, the dislocations in crystals move in bursts of a broad range of sizes (termed 'avalanches' in the statistical mechanics community, whose motion is deemed 'crackling noise'). In this grant period, we resolved a longstanding mystery about the average shape of avalanches of fixed duration (using tools related to an emergent scale invariance), we developed the fundamental theory describing the shapes of avalanches and how they are affected by the edges of the microscope viewing window, we found that slow creep of dislocations can trigger an oscillating response explaining recent experiments, we explained avalanches under external voltage, and we have studied how avalanches in experiments on the microscale relate to deformation of large samples. Inside the crystals forming the metal, the dislocations arrange into mysterious cellular structures, usually ignored in theories of plasticity. Writing a natural continuum theory for dislocation dynamics, we found that it spontaneously formed walls -- much like models of traffic jams and sonic booms. These walls formed rather realistic cellular structures, which we examined in great detail -- our walls formed fractal structures with fascinating scaling properties, related to those found in turbulent fluids. We found, however, that the numerical and mathematical tools available to solve our equations were not flexible enough to incorporate materials-specific information, and our models did not show the dislocation avalanches seen experimentally. In the last year of this grant, we wrote an invited review article, explaining how plastic flow in metals shares features with other stressed materials, and how tools of statistical physics used in these other systems might be crucial for understanding plasticity.« less

Effect of different external attention of focus instruction on learning of golf putting skill.

PubMed

Shafizadeh, Mohsen; McMorris, Terry; Sproule, John

2011-10-01

The effect of different sources of external attentional focus on learning a motor skill was assessed in the present study. 30 students (12 men, 18 women) participated voluntarily and were divided, according to type of external focus, into target, club swing, and target-club swing groups. The task was a golf putting skill. The target focus group attended to the target (hole), the club swing focus group attended to the execution of the club's swing, and the target-club swing focus group attended to both. All participants performed 50 trials of the putting skill in the acquisition phase and 10 trials in the 24-hr. delayed retention phase. The dependent variable was the error in the putting skill measured as the distance from the hole to the ball after each strike. Results showed the target-club swing focus group had better scores in the acquisition and retention phases than the other groups. It was concluded that external focus instruction helped the learners to integrate target cue with action cue and is more effective in skill learning than other external-focus instructions. These results support the claims of ecological psychology theorists concerning the effects of external focus of attention.

Broadband Spectral Modeling of the Extreme Gigahertz-peaked Spectrum Radio Source PKS B0008-421

NASA Astrophysics Data System (ADS)

Callingham, J. R.; Gaensler, B. M.; Ekers, R. D.; Tingay, S. J.; Wayth, R. B.; Morgan, J.; Bernardi, G.; Bell, M. E.; Bhat, R.; Bowman, J. D.; Briggs, F.; Cappallo, R. J.; Deshpande, A. A.; Ewall-Wice, A.; Feng, L.; Greenhill, L. J.; Hazelton, B. J.; Hindson, L.; Hurley-Walker, N.; Jacobs, D. C.; Johnston-Hollitt, M.; Kaplan, D. L.; Kudrayvtseva, N.; Lenc, E.; Lonsdale, C. J.; McKinley, B.; McWhirter, S. R.; Mitchell, D. A.; Morales, M. F.; Morgan, E.; Oberoi, D.; Offringa, A. R.; Ord, S. M.; Pindor, B.; Prabu, T.; Procopio, P.; Riding, J.; Srivani, K. S.; Subrahmanyan, R.; Udaya Shankar, N.; Webster, R. L.; Williams, A.; Williams, C. L.

2015-08-01

We present broadband observations and spectral modeling of PKS B0008-421 and identify it as an extreme gigahertz-peaked spectrum (GPS) source. PKS B0008-421 is characterized by the steepest known spectral slope below the turnover, close to the theoretical limit of synchrotron self-absorption, and the smallest known spectral width of any GPS source. Spectral coverage of the source spans from 0.118 to 22 GHz, which includes data from the Murchison Widefield Array and the wide bandpass receivers on the Australia Telescope Compact Array. We have implemented a Bayesian inference model fitting routine to fit the data with internal free-free absorption (FFA), single- and double-component FFA in an external homogeneous medium, FFA in an external inhomogeneous medium, or single- and double-component synchrotron self-absorption models, all with and without a high-frequency exponential break. We find that without the inclusion of a high-frequency break these models cannot accurately fit the data, with significant deviations above and below the peak in the radio spectrum. The addition of a high-frequency break provides acceptable spectral fits for the inhomogeneous FFA and double-component synchrotron self-absorption models, with the inhomogeneous FFA model statistically favored. The requirement of a high-frequency spectral break implies that the source has ceased injecting fresh particles. Additional support for the inhomogeneous FFA model as being responsible for the turnover in the spectrum is given by the consistency between the physical parameters derived from the model fit and the implications of the exponential spectral break, such as the necessity of the source being surrounded by a dense ambient medium to maintain the peak frequency near the gigahertz region. This implies that PKS B0008-421 should display an internal H i column density greater than 1020 cm-2. The discovery of PKS B0008-421 suggests that the next generation of low radio frequency surveys could reveal a large population of GPS sources that have ceased activity, and that a portion of the ultra-steep-spectrum source population could be composed of these GPS sources in a relic phase.

Schoolyard physical activity in 14-year-old adolescents assessed by mobile GPS and heart rate monitoring analysed by GIS.

PubMed

Fjørtoft, Ingunn; Löfman, Owe; Halvorsen Thorén, Kine

2010-11-01

Environmental settings seem to influence the activity patterns of children in neighbourhoods and schoolyards, the latter being an important arena to promote physical activity (PA) in school children. New technology has made it possible to describe free-living PA in interaction with the environment. This study focused on how schoolyard environments influenced the activity patterns and intensity levels in 14-year-old children and whether PA levels in adolescents complied with official recommendations. Another objective was to introduce methodology of using a mobile global positioning system (GPS) device with synchronous heart rate (HR) recordings as a proxy for PA level and a geographical information system (GIS) for spatial analyses. The sample constituted of 81 children (aged 14 years) from two schools. Movement patterns and activity levels were recorded during lunch break applying a GPS Garmin Forerunner 305 with combined HR monitoring and analysed in a GIS by an overlaid grid and kriging interpolation. Spatial data from GPS recordings showed particular movement patterns in the schoolyards. Low activity levels (mean HR < 120 bpm) dominated in both schools with no gender differences. Activities located to a handball goal area showed the highest monitored HR (>160 bpm) with higher intensity in girls than in boys. Movement patterns and PA generated in GIS for visualisation and analysis enabled direct and realistic description of utilising of schoolyard facilities and activity levels. Linking GPS data and PA levels to spatial structures made it possible to visualise the environmental interaction with PA and which environments promoted low or high PA.

Pseudosynapsis and Decreased Stringency of Meiotic Repair Pathway Choice on the Hemizygous Sex Chromosome of Caenorhabditis elegans Males

PubMed Central

Checchi, Paula M.; Lawrence, Katherine S.; Van, Mike V.; Larson, Braden J.; Engebrecht, JoAnne

2014-01-01

During meiosis, accurate chromosome segregation relies on homology to mediate chromosome pairing, synapsis, and crossover recombination. Crossovers are dependent upon formation and repair of double-strand breaks (DSBs) by homologous recombination (HR). In males of many species, sex chromosomes are largely hemizygous, yet DSBs are induced along nonhomologous regions. Here we analyzed the genetic requirements for meiotic DSB repair on the completely hemizygous X chromosome of Caenorhabditis elegans males. Our data reveal that the kinetics of DSB formation, chromosome pairing, and synapsis are tightly linked in the male germ line. Moreover, DSB induction on the X is concomitant with a brief period of pseudosynapsis that may allow X sister chromatids to masquerade as homologs. Consistent with this, neither meiotic kleisins nor the SMC-5/6 complex are essential for DSB repair on the X. Furthermore, early processing of X DSBs is dependent on the CtIP/Sae2 homolog COM-1, suggesting that as with paired chromosomes, HR is the preferred pathway. In contrast, the X chromosome is refractory to feedback mechanisms that ensure crossover formation on autosomes. Surprisingly, neither RAD-54 nor BRC-2 are essential for DSB repair on the X, suggesting that unlike autosomes, the X is competent for repair in the absence of HR. When both RAD-54 and the structure-specific nuclease XPF-1 are abrogated, X DSBs persist, suggesting that single-strand annealing is engaged in the absence of HR. Our findings indicate that alteration in sister chromatid interactions and flexibility in DSB repair pathway choice accommodate hemizygosity on sex chromosomes. PMID:24939994

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

PubMed Central

Chappell, William H.; Gautam, Dipendra; Ok, Suzan T.; Johnson, Bryan A.; Anacker, Daniel C.

2015-01-01

ABSTRACT High-risk human papillomavirus 31 (HPV31)-positive cells exhibit constitutive activation of the ATM-dependent DNA damage response (DDR), which is necessary for productive viral replication. In response to DNA double-strand breaks (DSBs), ATM activation leads to DNA repair through homologous recombination (HR), which requires the principal recombinase protein Rad51, as well as BRCA1. Previous studies from our lab demonstrated that Rad51 and BRCA1 are expressed at high levels in HPV31-positive cells and localize to sites of viral replication. These results suggest that HPV may utilize ATM activity to increase HR activity as a means to facilitate viral replication. In this study, we demonstrate that high-risk HPV E7 expression alone is sufficient for the increase in Rad51 and BRCA1 protein levels. We have found that this increase occurs, at least in part, at the level of transcription. Studies analyzing protein stability indicate that HPV may also protect Rad51 and BRCA1 from turnover, contributing to the overall increase in cellular levels. We also demonstrate that Rad51 is bound to HPV31 genomes, with binding increasing per viral genome upon productive replication. We have found that depletion of Rad51 and BRCA1, as well as inhibition of Rad51's recombinase activity, abrogates productive viral replication upon differentiation. Overall, these results indicate that Rad51 and BRCA1 are required for the process of HPV31 genome amplification and suggest that productive replication occurs in a manner dependent upon recombination. IMPORTANCE Productive replication of HPV31 requires activation of an ATM-dependent DNA damage response, though how ATM activity contributes to replication is unclear. Rad51 and BRCA1 play essential roles in repair of double-strand breaks, as well as the restart of stalled replication forks through homologous recombination (HR). Given that ATM activity is required to initiate HR repair, coupled with the requirement of Rad51 and BRCA1 for productive viral replication, our findings suggest that HPV may utilize ATM activity to ensure localization of recombination factors to productively replicating viral genomes. The finding that E7 increases the levels of Rad51 and BRCA1 suggests that E7 contributes to productive replication by providing DNA repair factors required for viral DNA synthesis. Our studies not only imply a role for recombination in the regulation of productive HPV replication but provide further insight into how HPV manipulates the DDR to facilitate the productive phase of the viral life cycle. PMID:26699641

Chromosome End Repair and Genome Stability in Plasmodium falciparum.

PubMed

Calhoun, Susannah F; Reed, Jake; Alexander, Noah; Mason, Christopher E; Deitsch, Kirk W; Kirkman, Laura A

2017-08-08

The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells, where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double-stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR), due to a lack of efficient nonhomologous end joining. However, given that the parasite is haploid during this stage of its life cycle, the mechanisms involved in maintaining genome stability are poorly understood. Of particular interest are the subtelomeric regions of the chromosomes, which contain the majority of the multicopy variant antigen-encoding genes responsible for virulence and disease severity. Here, we show that parasites utilize a competitive balance between de novo telomere addition, also called "telomere healing," and HR to stabilize chromosome ends. Products of both repair pathways were observed in response to DSBs that occurred spontaneously during routine in vitro culture or resulted from experimentally induced DSBs, demonstrating that both pathways are active in repairing DSBs within subtelomeric regions and that the pathway utilized was determined by the DNA sequences immediately surrounding the break. In combination, these two repair pathways enable parasites to efficiently maintain chromosome stability while also contributing to the generation of genetic diversity. IMPORTANCE Malaria is a major global health threat, causing approximately 430,000 deaths annually. This mosquito-transmitted disease is caused by Plasmodium parasites, with infection with the species Plasmodium falciparum being the most lethal. Mechanisms underlying DNA repair and maintenance of genome integrity in P. falciparum are not well understood and represent a gap in our understanding of how parasites survive the hostile environment of their vertebrate and insect hosts. Our work examines DNA repair in real time by using single-molecule real-time (SMRT) sequencing focused on the subtelomeric regions of the genome that harbor the multicopy gene families important for virulence and the maintenance of infection. We show that parasites utilize two competing molecular mechanisms to repair double-strand breaks, homologous recombination and de novo telomere addition, with the pathway used being determined by the surrounding DNA sequence. In combination, these two pathways balance the need to maintain genome stability with the selective advantage of generating antigenic diversity. Copyright © 2017 Calhoun et al.

Dimer motion on a periodic substrate: spontaneous symmetry breaking and absolute negative mobility.

PubMed

Speer, David; Eichhorn, Ralf; Evstigneev, Mykhaylo; Reimann, Peter

2012-06-01

We consider two coupled particles moving along a periodic substrate potential with negligible inertia effects (overdamped limit). Even when the particles are identical and the substrate spatially symmetric, a sinusoidal external driving of appropriate amplitude and frequency may lead to spontaneous symmetry breaking in the form of a permanent directed motion of the dimer. Thermal noise restores ergodicity and thus zero net velocity, but entails arbitrarily fast diffusion of the dimer for sufficiently weak noise. Moreover, upon application of a static bias force, the dimer exhibits a motion opposite to that force (absolute negative mobility). The key requirement for all these effects is a nonconvex interaction potential of the two particles.

Quantification by aberration corrected (S)TEM of boundaries formed by symmetry breaking phase transformations.

PubMed

Schryvers, D; Salje, E K H; Nishida, M; De Backer, A; Idrissi, H; Van Aert, S

2017-05-01

The present contribution gives a review of recent quantification work of atom displacements, atom site occupations and level of crystallinity in various systems and based on aberration corrected HR(S)TEM images. Depending on the case studied, picometer range precisions for individual distances can be obtained, boundary widths at the unit cell level determined or statistical evolutions of fractions of the ordered areas calculated. In all of these cases, these quantitative measures imply new routes for the applications of the respective materials. Copyright © 2017 Elsevier B.V. All rights reserved.

Maltreated Children's Thoughts and Emotions as Behavioral Predictors: Evidence for Social Work Action

ERIC Educational Resources Information Center

Maschi, Tina; Morgen, Keith; Hatcher, Schnavia Smith; Rosato, Nancy Scotto; Violette, Nancy M.

2009-01-01

The purpose of this secondary data analysis was to explore the mediating influence of internalizing behavior on the link between child maltreatment and externalizing behavior (for example, rule-breaking behavior and aggressive behavior) among children. Using a longitudinal comparison group design and a sample of 300 youths (56 percent maltreated),…

Vital signs and their cross-correlation in sepsis and NEC: a study of 1,065 very-low-birth-weight infants in two NICUs.

PubMed

Fairchild, Karen D; Lake, Douglas E; Kattwinkel, John; Moorman, J Randall; Bateman, David A; Grieve, Philip G; Isler, Joseph R; Sahni, Rakesh

2017-02-01

Subtle changes in vital signs and their interactions occur in preterm infants prior to overt deterioration from late-onset septicemia (LOS) or necrotizing enterocolitis (NEC). Optimizing predictive algorithms may lead to earlier treatment. For 1,065 very-low-birth-weight (VLBW) infants in two neonatal intensive care units (NICUs), mean, SD, and cross-correlation of respiratory rate, heart rate (HR), and oxygen saturation (SpO 2 ) were analyzed hourly (131 infant-years' data). Cross-correlation (cotrending) between two vital signs was measured allowing a lag of ± 30 s. Cases of LOS and NEC were identified retrospectively (n = 186) and vital sign models were evaluated for ability to predict illness diagnosed in the ensuing 24 h. The best single illness predictor within and between institutions was cross-correlation of HR-SpO 2 . The best combined model (mean SpO 2 , SDHR, and cross-correlation of HR-SpO 2 ,) trained at one site with ROC area 0.695 had external ROC area of 0.754 at the other site, and provided additive value to an established HR characteristics index for illness prediction (Net Reclassification Improvement: 0.205; 95% confidence interval (CI): 0.113, 0.328). Despite minor inter-institutional differences in vital sign patterns of VLBW infants, cross-correlation of HR-SpO 2 and a 3-variable vital sign model performed well at both centers for preclinical detection of sepsis or NEC.

Definition of Small Gram Quantity Contents for Type B Radioactive Material Transportation Packages: Activity-Based Content Limitations

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

Sitaraman, S; Kim, S; Biswas, D

2010-10-27

Since the 1960's, the Department of Transportation Specification (DOT Spec) 6M packages have been used extensively for transportation of Type B quantities of radioactive materials between Department of Energy (DOE) facilities, laboratories, and productions sites. However, due to the advancement of packaging technology, the aging of the 6M packages, and variability in the quality of the packages, the DOT implemented a phased elimination of the 6M specification packages (and other DOT Spec packages) in favor of packages certified to meet federal performance requirements. DOT issued the final rule in the Federal Register on October 1, 2004 requiring that use ofmore » the DOT Specification 6M be discontinued as of October 1, 2008. A main driver for the change was the fact that the 6M specification packagings were not supported by a Safety Analysis Report for Packaging (SARP) that was compliant with Title 10 of the Code of Federal Regulations part 71 (10 CFR 71). Therefore, materials that would have historically been shipped in 6M packages are being identified as contents in Type B (and sometimes Type A fissile) package applications and addenda that are to be certified under the requirements of 10 CFR 71. The requirements in 10 CFR 71 include that the Safety Analysis Report for Packaging (SARP) must identify the maximum radioactivity of radioactive constituents and maximum quantities of fissile constituents (10 CFR 71.33(b)(1) and 10 CFR 71.33(b)(2)), and that the application (i.e., SARP submittal or SARP addendum) demonstrates that the external dose rate (due to the maximum radioactivity of radioactive constituents and maximum quantities of fissile constituents) on the surface of the packaging (i.e., package and contents) not exceed 200 mrem/hr (10 CFR 71.35(a), 10 CFR 71.47(a)). It has been proposed that a 'Small Gram Quantity' of radioactive material be defined, such that, when loaded in a transportation package, the dose rates at external points of an unshielded packaging not exceed the regulatory limits prescribed by 10 CFR 71 for non-exclusive shipments. The mass of each radioisotope presented in this paper is limited by the radiation dose rate on the external surface of the package, which per the regulatory limit should not exceed 200 mrem/hr. The results presented are a compendium of allowable masses of a variety of different isotopes (with varying impurity levels of beryllium in some of the actinide isotopes) that, when loaded in an unshielded packaging, do not result in an external dose rate on the surface of the package that exceeds 190 mrem/hr (190 mrem/hr was chosen to provide 5% conservatism relative to the regulatory limit). These mass limits define the term 'Small Gram Quantity' (SGQ) contents in the context of radioactive material transportation packages. The term SGQ is isotope-specific and pertains to contents in radioactive material transportation packages that do not require shielding and still satisfy the external dose rate requirements. Since these calculated mass limits are for contents without shielding, they are conservative for packaging materials that provide some limited shielding or if the contents are placed into a shielded package. The isotopes presented in this paper were chosen as the isotopes that Department of Energy (DOE) sites most likely need to ship. Other more rarely shipped isotopes, along with industrial and medical isotopes, are planned to be included in subsequent extensions of this work.« less

Plasma concentrations of remoxipride and the gastrointestinal transit of 111In-marked extended-release coated spheres

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

Graffner, C.; Wagner, Z.; Nilsson, M.I.

1990-01-01

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in 111In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules withinmore » the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again extended distribution of the microcapsules. A mean Cmax of 2.7 microM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 mumol.L-1.hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation.« less

Insulative laser shell coupler

DOEpatents

Arnold, Phillip A.; Anderson, Andrew T.; Alger, Terry W.

1994-01-01

A segmented coaxial laser shell assembly having at least two water jacket sections, two pairs of interconnection half rings, a dialectric break ring, and a pair of threaded ring sections. Each water jacket section with an inner tubular section that defines an inner laser cavity with water paths adjacent to at least a portion of the exterior of the inner tubular section, and mating faces at the end of the water jacket section through which the inner laser cavity opens and which defines at least one water port therethrough in communication with the water jackets. The water paths also define in their external surface a circumferential notch set back from and in close proximity to the mating face. The dielectric break ring has selected thickness and is placed between, and in coaxial alignment with, the mating faces of two of the adjacent water jacket sections. The break ring also defines an inner laser cavity of the same size and shape as the inner laser cavity of the water jacket sections and at least one water passage through the break ring to communicate with at least one water port through the mating faces of the water jacket sections.

Insulative laser shell coupler

DOEpatents

Arnold, P.A.; Anderson, A.T.; Alger, T.W.

1994-09-20

A segmented coaxial laser shell assembly having at least two water jacket sections, two pairs of interconnection half rings, a dielectric break ring, and a pair of threaded ring sections is disclosed. Each water jacket section with an inner tubular section that defines an inner laser cavity with water paths adjacent to at least a portion of the exterior of the inner tubular section, and mating faces at the end of the water jacket section through which the inner laser cavity opens and which defines at least one water port therethrough in communication with the water jackets. The water paths also define in their external surface a circumferential notch set back from and in close proximity to the mating face. The dielectric break ring has selected thickness and is placed between, and in coaxial alignment with, the mating faces of two of the adjacent water jacket sections. The break ring also defines an inner laser cavity of the same size and shape as the inner laser cavity of the water jacket sections and at least one water passage through the break ring to communicate with at least one water port through the mating faces of the water jacket sections. 4 figs.

[Effect of external abdominal aorta compression on circulation during anesthesia induction in elderly patients].

PubMed

Li, Xiuman; Wang, Lixiang

2017-07-01

To investigate the effect of external abdominal aorta compression on circulation during anesthetic induction in elderly patients. A prospective randomized controlled trial was conducted. Patients with age of 60-75 years old, requiring a general anesthesia for non-abdominal surgery, and with II-III class of American Society of Anesthesiologists (ASA) physical status classification, and admitted to General Hospital of Chinese People's Armed Police Forces from January to April in 2017 were enrolled. They were divided into abdominal aorta pressure group and control group according to random number method, with 20 patients in each group. In both groups, anesthesia was induced with midazolam, propofol, fentanyl and cisatracurium, and was maintained with propofol, remifentanil and cisatracurium. After successful intubation, the anesthesia machine was changed into mechanical ventilation. The patients in abdominal aorta pressure group were given abdominal aorta pressure 1 minute after induction of general anesthesia with midazolam till 5 minutes after intubation. The mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO 2 ) were observed before anesthesia induction, immediately after anesthesia induction, immediately after intubation, 5 minutes and 10 minutes after intubation, respectively. The incidence of hypotension or bradycardia, and usage of ephedrine or atropine were recorded. There were no significant differences in MAP [mmHg (1 mmHg = 0.133 kPa): 83.6±4.7 vs. 82.9±4.7], HR (bpm: 67.3±5.9 vs. 65.9±5.7) and SpO 2 (0.962±0.007 vs. 0.960±0.009) before anesthesia induction between abdominal aorta pressure group and control group (all P > 0.05). Immediately after anesthesia induction, the MAP and HR in control group were significantly decreased as compared with those before anesthesia induction [MAP (mmHg): 70.0±8.7 vs. 82.9±4.7, HR (bpm): 60.7±6.7 vs. 65.9±5.7, both P < 0.05], and they were also significantly lower than those of abdominal aorta pressure group [MAP (mmHg): 83.1±3.9, HR (bpm): 66.8±4.9, both P < 0.05]. Immediately after intubation, the MAP and HR in control group were significantly increased as compared with those immediately after anesthesia induction [MAP (mmHg): 78.9±7.9 vs. 70.0±8.7, HR (bpm): 67.3±2.7 vs. 60.7±6.7, both P < 0.05], but the changes in MAP and HR in abdominal aorta pressure group were not obvious. During the anesthesia induction period, there was no statistical difference in SpO 2 change between the two groups. During induction of anesthesia, no adverse reaction was found in the abdominal aorta pressure group, but 4 patients with hypotension and 2 patients with bradycardia were found in the control group. Two patients with hypotension were treated with ephedrine, and 2 patients with bradycardia were treated with atropine. Anesthesia induction of elderly patients with abdominal aorta pressure can help maintain hemodynamic stability.

The sex-specific internal and external demands imposed on players during Ultimate Frisbee game-play.

PubMed

Madueno, Maria C; Kean, Crystal O; Scanlan, Aaron T

2017-11-01

Despite the growing popularity of Ultimate Frisbee (UF) across sexes, the game demands imposed on players have been predominately examined in males. This study aimed to compare the internal and external demands of UF game-play in males and females. Male (N.=10) and female (N.=10) recreational UF players competed in separate sex-specific, indoor UF games. Internal responses (blood lactate concentration [BLa-], rating of perceived exertion [RPE], and heart rate [HR]) and external responses (direction-specific and total relative PlayerLoad™ [PL], and estimated equivalent distance [EED]) were measured. Data were analyzed using mixed ANOVAs with Cohen's effect sizes (d). During male game-play, significantly (P<0.01) higher BLa- (d=1.30, large), HR (d=0.40, small), PL (d=0.80-1.24, moderate-large), and EED (d=0.93, moderate) were apparent during the first half compared to the second half in males. During female game-play, a significantly (P<0.001) larger RPE (d=0.93, moderate) was evident during the second compared to the first half. In addition, females exhibited significantly (P<0.05) lower BLa- (d=1.43, large) in the first half and higher medio-lateral PL (d=1.10, moderate) in the second half compared to males. While similar global responses were observed between sexes across UF game-play, males experienced greater declines in physiological intensity and multi-directional activity than females. These data indicate overlap in game demands and training recommendations across sexes, with activity maintenance a focus, particularly in males.

Modulating immunogenic properties of HIV-1 gp41 membrane-proximal external region by destabilizing six-helix bundle structure

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

Banerjee, Saikat; Shi, Heliang; Habte, Habtom H.

The C-terminal alpha-helix of gp41 membrane-proximal external region (MPER; {sup 671}NWFDITNWLWYIK{sup 683}) encompassing 4E10/10E8 epitopes is an attractive target for HIV-1 vaccine development. We previously reported that gp41-HR1-54Q, a trimeric protein comprised of the MPER in the context of a stable six-helix bundle (6HB), induced strong immune responses against the helix, but antibodies were directed primarily against the non-neutralizing face of the helix. To better target 4E10/10E8 epitopes, we generated four putative fusion intermediates by introducing double point mutations or deletions in the heptad repeat region 1 (HR1) that destabilize 6HB in varying degrees. One variant, HR1-∆10-54K, elicited antibodies inmore » rabbits that targeted W672, I675 and L679, which are critical for 4E10/10E8 recognition. Overall, the results demonstrated that altering structural parameters of 6HB can influence immunogenic properties of the MPER and antibody targeting. Further exploration of this strategy could allow development of immunogens that could lead to induction of 4E10/10E8-like antibodies. - Highlights: • Four gp41 MPER-based immunogens that resemble fusion intermediates were generated. • C-terminal region of MPER that contains 4E10/10E8 epitopes was highly immunogenic. • Altering 6HB structure can influence immunogenic properties of the MPER. • Induced antibodies targeted multiple residues critical for 4E10/10E8 binding. • Development of immunogens based on fusion intermediates is a promising strategy.« less

The Cancer of the Prostate Risk Assessment (CAPRA) score predicts biochemical recurrence in intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT) dose escalation or low-dose rate (LDR) brachytherapy.

PubMed

Krishnan, Vimal; Delouya, Guila; Bahary, Jean-Paul; Larrivée, Sandra; Taussky, Daniel

2014-12-01

To study the prognostic value of the University of California, San Francisco Cancer of the Prostate Risk Assessment (CAPRA) score to predict biochemical failure (bF) after various doses of external beam radiotherapy (EBRT) and/or permanent seed low-dose rate (LDR) prostate brachytherapy (PB). We retrospectively analysed 345 patients with intermediate-risk prostate cancer, with PSA levels of 10-20 ng/mL and/or Gleason 7 including 244 EBRT patients (70.2-79.2 Gy) and 101 patients treated with LDR PB. The minimum follow-up was 3 years. No patient received primary androgen-deprivation therapy. bF was defined according to the Phoenix definition. Cox regression analysis was used to estimate the differences between CAPRA groups. The overall bF rate was 13% (45/345). The CAPRA score, as a continuous variable, was statistically significant in multivariate analysis for predicting bF (hazard ratio [HR] 1.37, 95% confidence interval [CI] 1.10-1.72, P = 0.006). There was a trend for a lower bF rate in patients treated with LDR PB when compared with those treated by EBRT ≤ 74 Gy (HR 0.234, 95% CI 0.05-1.03, P = 0.055) in multivariate analysis. In the subgroup of patients with a CAPRA score of 3-5, CAPRA remained predictive of bF as a continuous variable (HR 1.51, 95% CI 1.01-2.27, P = 0.047) in multivariate analysis. The CAPRA score is useful for predicting biochemical recurrence in patients treated for intermediate-risk prostate cancer with EBRT or LDR PB. It could help in treatment decisions. © 2013 The Authors. BJU International © 2013 BJU International.

Validation of the 2014 European Society of Cardiology Sudden Cardiac Death Risk Prediction Model in Hypertrophic Cardiomyopathy in a Reference Center in South America.

PubMed

Fernández, Adrián; Quiroga, Alejandro; Ochoa, Juan Pablo; Mysuta, Mauricio; Casabé, José Horacio; Biagetti, Marcelo; Guevara, Eduardo; Favaloro, Liliana E; Fava, Agostina M; Galizio, Néstor

2016-07-01

Sudden cardiac death (SCD) is a common cause of death in hypertrophic cardiomyopathy (HC). Our aim was to conduct an external and independent validation in South America of the 2014 European Society of Cardiology (ESC) SCD risk prediction model to identify patients requiring an implantable cardioverter defibrillator. This study included 502 consecutive patients with HC followed from March, 1993 to December, 2014. A combined end point of SCD or appropriate implantable cardioverter defibrillator therapy was assessed. For the quantitative estimation of individual 5-year SCD risk, we used the formula: 1 - 0.998(exp(Prognostic index)). Our database also included the abnormal blood pressure response to exercise as a risk marker. We analyzed the 3 categories of 5-year risk proposed by the ESC: low risk (LR) <4%; intermediate risk (IR) ≥4% to <6%, and high risk (HR) ≥6%. The LR group included 387 patients (77%); the IR group 39 (8%); and the HR group 76 (15%). Fourteen patients (3%) had SCD/appropriate implantable cardioverter defibrillator therapy (LR: 0%; IR: 2 of 39 [5%]; and HR: 12 of 76 [16%]). In a receiver-operating characteristic curve, the new model proved to be an excellent predictor because the area under the curve for the estimated risk is 0.925 (statistical C: 0.925; 95% CI 0.8884 to 0.9539, p <0.0001). In conclusion, the SCD risk prediction model in HC proposed by the 2014 ESC guidelines was validated in our population and represents an improvement compared with previous approaches. A larger multicenter, independent and external validation of the model with long-term follow-up would be advisable. Copyright © 2016 Elsevier Inc. All rights reserved.

Observation of a Discrete Time Crystal

NASA Astrophysics Data System (ADS)

Kyprianidis, A.; Zhang, J.; Hess, P.; Becker, P.; Lee, A.; Smith, J.; Pagano, G.; Potter, A.; Vishwanath, A.; Potirniche, I.-D.; Yao, N.; Monroe, C.

2017-04-01

Spontaneous symmetry breaking is a key concept in the understanding of many physical phenomena, such as the formation of spatial crystals and the phase transition from paramagnetism to magnetic order. While the breaking of time translation symmetry is forbidden in equilibrium systems, it is possible for non-equilibrium Floquet driven systems to break a discrete time translation symmetry, and we present clear signatures of the formation of such a discrete time crystal. We apply a time periodic Hamiltonian to a chain of interacting spins under many-body localization conditions and observe the system's sub-harmonic response at twice that period. This spontaneous doubling of the periodicity is robust to external perturbations. We represent the spins with a linear chain of trapped 171Yb+ ions in an rf Paul trap, generate spin-spin interactions through spin-dependent optical dipole forces, and measure each spin using state-dependent fluorescence. This work is supported by the ARO Atomic Physics Program, the AFOSR MURI on Quantum Measurement and Verification, and the NSF Physics Frontier Center at JQI.

Symmetry-breaking dynamics of the finite-size Lipkin-Meshkov-Glick model near ground state

NASA Astrophysics Data System (ADS)

Huang, Yi; Li, Tongcang; Yin, Zhang-qi

2018-01-01

We study the dynamics of the Lipkin-Meshkov-Glick (LMG) model with a finite number of spins. In the thermodynamic limit, the ground state of the LMG model with an isotropic Hamiltonian in the broken phase breaks to a mean-field ground state with a certain direction. However, when the spin number N is finite, the exact ground state is always unique and is not given by a classical mean-field ground state. Here, we prove that when N is large but finite, through a tiny external perturbation, a localized state which is close to a mean-field ground state can be prepared, which mimics spontaneous symmetry breaking. Also, we find the localized in-plane spin polarization oscillates with two different frequencies ˜O (1 /N ) , and the lifetime of the localized state is long enough to exhibit this oscillation. We numerically test the analytical results and find that they agree very well with each other. Finally, we link the phenomena to quantum time crystals and time quasicrystals.

Cyclotron resonance of the magnetic ratchet effect and second harmonic generation in bilayer graphene

NASA Astrophysics Data System (ADS)

Kheirabadi, Narjes; McCann, Edward; Fal'ko, Vladimir I.

2018-02-01

We model the magnetic ratchet effect in bilayer graphene in which a dc electric current is produced by an ac electric field of frequency ω in the presence of a steady in-plane magnetic field and inversion-symmetry breaking. In bilayer graphene, the ratchet effect is tunable by an external metallic gate which breaks inversion symmetry. For zero in-plane magnetic field, we show that trigonal warping and inversion-symmetry breaking are able to produce a large dc valley current, but not a nonzero total dc charge current. For the magnetic ratchet in a tilted magnetic field, the perpendicular field component induces cyclotron motion with frequency ωc and we find that the dc current displays cyclotron resonance at ωc=ω , although this peak in the current is actually smaller than its value at ωc=0 . Second harmonic generation, however, is greatly enhanced by resonances at ωc=ω and ωc=2 ω for which the current is generally much larger than at ωc=0 .

A developmental approach to dimensional expression of psychopathology in child and adolescent offspring of parents with bipolar disorder.

PubMed

Morón-Nozaleda, María Goretti; Díaz-Caneja, Covadonga M; Rodríguez-Toscano, Elisa; Arango, Celso; Castro-Fornieles, Josefina; de la Serna, Elena; Espliego, Ana; Sanchez-Gistau, Vanessa; Romero, Soledad; Baeza, Immaculada; Sugranyes, Gisela; Moreno, Carmen; Moreno, Dolores

2017-10-01

The aim of this is to describe psychopathology, functioning and symptom dimensions accounting for subthreshold manifestations and developmental status in child and adolescent offspring of parents with bipolar disorder ("high-risk offspring"). The study population comprised 90 high-risk offspring (HR-offspring) and 107 offspring of community control parents (CC-offspring). Direct clinical observations and parental and offspring reports based on selected standardized clinical scales were used to assess offspring threshold and subthreshold diagnoses, symptoms and functioning. All outcomes were compared between the whole HR-offspring and CC-offspring samples and then by developmental status. After controlling for potential confounders, HR-offspring showed significantly poorer adjustment for childhood (r = 0.18, p = 0.014) and adolescence (r = 0.21, p = 0.048) than CC-offspring, as well as more emotional problems (r = 0.24, p = 0.001) and higher depression scores (r = 0.16, p = 0.021). As for differences in lifetime categorical diagnoses (threshold and subthreshold) between HR-offspring and CC-offspring, the prevalence of disruptive disorders was higher in pre-pubertal HR-offspring (OR 12.78 [1.45-112.42]), while prevalence of mood disorders was higher in post-pubertal HR-offspring (OR 3.39 [1.14-10.06]). Post-pubertal HR-offspring presented more prodromal (r = 0.40, p = 0.001), negative (r = 0.38, p = 0.002), manic (r = 0.22, p = 0.035) and depressive (r = 0.23, p = 0.015) symptoms than pre-pubertal HR-offspring, as well as more peer relationship problems (r = 0.31, p = 0.004), poorer childhood adjustment (r = 0.22, p = 0.044) and worse current psychosocial functioning (r = 0.27, p = 0.04). Externalizing psychopathology is more prevalent in pre-pubertal HR-offspring, while depressive and prodromal symptoms leading to functional impairment are more prominent in post-pubertal HR-offspring. Developmental approaches and dimensional measures may be useful for identifying children at high risk of developing bipolar disorder and help guide specific preventive strategies.

Mayo Alliance Prognostic Model for Myelodysplastic Syndromes: Integration of Genetic and Clinical Information.

PubMed

Tefferi, Ayalew; Gangat, Naseema; Mudireddy, Mythri; Lasho, Terra L; Finke, Christy; Begna, Kebede H; Elliott, Michelle A; Al-Kali, Aref; Litzow, Mark R; Hook, C Christopher; Wolanskyj, Alexandra P; Hogan, William J; Patnaik, Mrinal M; Pardanani, Animesh; Zblewski, Darci L; He, Rong; Viswanatha, David; Hanson, Curtis A; Ketterling, Rhett P; Tang, Jih-Luh; Chou, Wen-Chien; Lin, Chien-Chin; Tsai, Cheng-Hong; Tien, Hwei-Fang; Hou, Hsin-An

2018-06-01

To develop a new risk model for primary myelodysplastic syndromes (MDS) that integrates information on mutations, karyotype, and clinical variables. Patients with World Health Organization-defined primary MDS seen at Mayo Clinic (MC) from December 28, 1994, through December 19, 2017, constituted the core study group. The National Taiwan University Hospital (NTUH) provided the validation cohort. Model performance, compared with the revised International Prognostic Scoring System, was assessed by Akaike information criterion and area under the curve estimates. The study group consisted of 685 molecularly annotated patients from MC (357) and NTUH (328). Multivariate analysis of the MC cohort identified monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6), "non-MK abnormalities other than single/double del(5q)" (HR, 1.8; 95% CI, 1.3-2.6), RUNX1 (HR, 2.0; 95% CI, 1.2-3.1) and ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations, absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4), age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1), hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1), platelet count less than 75 × 10 9 /L (HR, 1.5; 95% CI, 1.1-2.1), and 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8) as predictors of inferior overall survival. Based on HR-weighted risk scores, a 4-tiered Mayo alliance prognostic model for MDS was devised: low (89 patients), intermediate-1 (104), intermediate-2 (95), and high (69); respective median survivals (5-year overall survival rates) were 85 (73%), 42 (34%), 22 (7%), and 9 months (0%). The Mayo alliance model was subsequently validated by using the external NTUH cohort and, compared with the revised International Prognostic Scoring System, displayed favorable Akaike information criterion (1865 vs 1943) and area under the curve (0.87 vs 0.76) values. We propose a simple and contemporary risk model for MDS that is based on a limited set of genetic and clinical variables. Copyright © 2018. Published by Elsevier Inc.

Homologous recombination mediates S-phase-dependent radioresistance in cells deficient in DNA polymerase eta

PubMed Central

Sharma, Ricky A.

2012-01-01

DNA polymerase eta (pol η) is the only DNA polymerase causally linked to carcinogenesis in humans. Inherited deficiency of pol η in the variant form of xeroderma pigmentosum (XPV) predisposes to UV-light-induced skin cancer. Pol η-deficient cells demonstrate increased sensitivity to cisplatin and oxaliplatin chemotherapy. We have found that XP30R0 fibroblasts derived from a patient with XPV are more resistant to cell kill by ionising radiation (IR) than the same cells complemented with wild-type pol η. This phenomenon has been confirmed in Burkitt’s lymphoma cells, which either expressed wild-type pol η or harboured a pol η deletion. Pol η deficiency was associated with accumulation of cells in S-phase, which persisted after IR. Cells deficient in pol η demonstrated increased homologous recombination (HR)-directed repair of double strand breaks created by IR. Depletion of the HR protein, X-ray repair cross-complementing protein 3 (XRCC3), abrogated the radioresistance observed in pol η-deficient cells as compared with pol η-complemented cells. These findings suggest that HR mediates S-phase-dependent radioresistance associated with pol η deficiency. We propose that pol η protein levels in tumours may potentially be used to identify patients who require treatment with chemo-radiotherapy rather than radiotherapy alone for adequate tumour control. PMID:22822095

Effect of tocolytic drugs on fetal heart rate variability: a systematic review.

PubMed

Verdurmen, Kim M J; Hulsenboom, Alexandra D J; van Laar, Judith O E H; Oei, S Guid

2017-10-01

Tocolytics may cause changes in fetal heart rate (HR) pattern, while fetal heart rate variability (HRV) is an important marker of fetal well-being. We aim to systematically review the literature on how tocolytic drugs affect fetal HRV. We searched CENTRAL, PubMed and EMBASE up to June 2016. Studies published in English, using computerized or visual analysis to describe the effect of tocolytics on HRV in human fetuses were included. Studies describing tocolytics during labor, external cephalic version, pre-eclampsia and infection were excluded. Eventually, we included six studies, describing 169 pregnant women. Nifedipine, atosiban and indomethacin administration show no clinically important effect on fetal HRV. Following administration of magnesium sulfate decreased variability and cases of bradycardia are described. Fenoterol administration results in a slight increase in fetal HR with no changes in variability. After ritodrine administration increased fetal HR and decreased variability is seen. The effect of co-administration of corticosteroids should be taken into account. In order to prevent iatrogenic preterm labor, the effects of tocolytic drugs on fetal HRV should be taken into account when monitoring these fetuses.

Natural Mentoring Processes Deter Externalizing Problems Among Rural African American Emerging Adults: A Prospective Analysis

PubMed Central

Kogan, Steven M.; Brody, Gene H.; Chen, Yi-fu

2011-01-01

A 3-wave model linking natural mentoring relationships to externalizing behavior was tested with 345 rural African American emerging adults in their final year of high school. Structural equation models were executed linking multi-informant reports of mentor-emerging adult relationship quality with youths’ externalizing behavior 18 months later. Consistent with our primary hypotheses, emerging adults whose relationships with their natural mentors were characterized by instrumental and emotional support and affectively positive interactions reported lower levels of anger, rule-breaking behavior, and aggression. These effects emerged independent of the influences of family support and youth gender. Two intrapersonal processes, a future orientation and self-regulation, emerged as mediators of the influence of natural mentoring relationships. The influence of natural mentors was most pronounced for emerging adults experiencing high levels of life stress. PMID:21293917

Coupled Brownian motors: Anomalous hysteresis and zero-bias negative conductance

NASA Astrophysics Data System (ADS)

Reimann, P.; Kawai, R.; Van den Broeck, C.; Hänggi, P.

1999-03-01

We introduce a model of interacting Brownian particles in a symmetric, periodic potential that undergoes a noise-induced non-equilibrium phase transition. The associated spontaneous symmetry breaking entails a ratchet-like transport mechanism. In response to an external force we identify several novel features; among the most prominent being a zero-bias negative conductance and a prima facie counterintuitive, anomalous hysteresis.

Prenatal and childhood antecedents of suicide: 50-year follow-up of the 1958 British Birth Cohort study.

PubMed

Geoffroy, M-C; Gunnell, D; Power, C

2014-04-01

We aimed to elucidate early antecedents of suicide including possible mediation by early child development. Using the 1958 birth cohort, based on British births in March 1958, individuals were followed up to adulthood. We used data collected at birth and at age 7 years from various informants. Suicides occurring up to 31 May 2009 were identified from linked national death certificates. Multivariable Cox proportional hazard models were used to investigate risk factors. Altogether 12399 participants (n = 44 suicides) had complete data. The strongest prenatal risk factors for suicide were: birth order, with risk increasing in later-born children [p trend = 0.063, adjusted hazard ratio (HR)], e.g. for fourth- or later-born children [HR = 2.27, 95% confidence interval (CI) 0.90-5.75]; young maternal age (HR = 1.18, 95% CI 0.34-4.13 for ⩽19 years and HR = 0.41, 95% CI 0.19-0.91 for >29 years, p trend = 0.034); and low (<2.5 kg) birth weight (HR = 2.48, 95% CI 1.03-5.95). The strongest risk factors at 7 years were externalizing problems in males (HR = 2.96, 95% CI 1.03-8.47, p trend = 0.050) and number of emotional adversities (i.e. parental death, neglected appearance, domestic tension, institutional care, contact with social services, parental divorce/separation and bullying) for which there was a graded association with risk of suicide (p trend = 0.033); the highest (HR = 3.12, 95% CI 1.01-9.62) was for persons with three or more adversities. Risk factors recorded at birth and at 7 years may influence an individual's long-term risk of suicide, suggesting that trajectories leading to suicide have roots in early life. Some factors are amenable to intervention, but for others a better understanding of causal mechanisms may provide new insights for intervention to reduce suicide risk.

Markets, Herding and Response to External Information.

PubMed

Carro, Adrián; Toral, Raúl; San Miguel, Maxi

2015-01-01

We focus on the influence of external sources of information upon financial markets. In particular, we develop a stochastic agent-based market model characterized by a certain herding behavior as well as allowing traders to be influenced by an external dynamic signal of information. This signal can be interpreted as a time-varying advertising, public perception or rumor, in favor or against one of two possible trading behaviors, thus breaking the symmetry of the system and acting as a continuously varying exogenous shock. As an illustration, we use a well-known German Indicator of Economic Sentiment as information input and compare our results with Germany's leading stock market index, the DAX, in order to calibrate some of the model parameters. We study the conditions for the ensemble of agents to more accurately follow the information input signal. The response of the system to the external information is maximal for an intermediate range of values of a market parameter, suggesting the existence of three different market regimes: amplification, precise assimilation and undervaluation of incoming information.

High-Risk Alphapapillomavirus Oncogenes Impair the Homologous Recombination Pathway

PubMed Central

Khanal, Sujita; Robinson, Kristin L.; Wendel, Sebastian O.; Messer, Joshua J.; Galloway, Denise A.

2017-01-01

ABSTRACT Persistent high-risk genus human Alphapapillomavirus (HPV) infections cause nearly every cervical carcinoma and a subset of tumors in the oropharyngeal tract. During the decades required for HPV-associated tumorigenesis, the cellular genome becomes significantly destabilized. Our analysis of cervical tumors from four separate data sets found a significant upregulation of the homologous-recombination (HR) pathway genes. The increased abundance of HR proteins can be replicated in primary cells by expression of the two HPV oncogenes (E6 and E7) required for HPV-associated transformation. HPV E6 and E7 also enhanced the ability of HR proteins to form repair foci, and yet both E6 and E7 reduce the ability of the HR pathway to complete double-strand break (DSB) repair by about 50%. The HPV oncogenes hinder HR by allowing the process to begin at points in the cell cycle when the lack of a sister chromatid to serve as a homologous template prevents completion of the repair. Further, HPV E6 attenuates repair by causing RAD51 to be mislocalized away from both transient and persistent DSBs, whereas HPV E7 is only capable of impairing RAD51 localization to transient lesions. Finally, we show that the inability to robustly repair DSBs causes some of these lesions to be more persistent, a phenotype that correlates with increased integration of episomal DNA. Together, these data support our hypothesis that HPV oncogenes contribute to the genomic instability observed in HPV-associated malignancies by attenuating the repair of damaged DNA. IMPORTANCE This study expands the understanding of HPV biology, establishing a direct role for both HPV E6 and E7 in the destabilization of the host genome by blocking the homologous repair of DSBs. To our knowledge, this is the first time that both viral oncogenes were shown to disrupt this DSB repair pathway. We show that HPV E6 and E7 allow HR to initiate at an inappropriate part of the cell cycle. The mislocalization of RAD51 away from DSBs in cells expressing HPV E6 and E7 hinders HR through a distinct mechanism. These observations have broad implications. The impairment of HR by HPV oncogenes may be targeted for treatment of HPV+ malignancies. Further, this attenuation of repair suggests HPV oncogenes may contribute to tumorigenesis by promoting the integration of the HPV genome, a common feature of HPV-transformed cells. Our data support this idea since HPV E6 stimulates the integration of episomes. PMID:28768872

Symmetry-Breaking Bifurcation in the Nonlinear Schrödinger Equation with Symmetric Potentials

NASA Astrophysics Data System (ADS)

Kirr, E.; Kevrekidis, P. G.; Pelinovsky, D. E.

2011-12-01

We consider the focusing (attractive) nonlinear Schrödinger (NLS) equation with an external, symmetric potential which vanishes at infinity and supports a linear bound state. We prove that the symmetric, nonlinear ground states must undergo a symmetry breaking bifurcation if the potential has a non-degenerate local maxima at zero. Under a generic assumption we show that the bifurcation is either a subcritical or supercritical pitchfork. In the particular case of double-well potentials with large separation, the power of nonlinearity determines the subcritical or supercritical character of the bifurcation. The results are obtained from a careful analysis of the spectral properties of the ground states at both small and large values for the corresponding eigenvalue parameter.

Ergodicity breaking and ageing of underdamped Brownian dynamics with quenched disorder

NASA Astrophysics Data System (ADS)

Guo, Wei; Li, Yong; Song, Wen-Hua; Du, Lu-Chun

2018-03-01

The dynamics of an underdamped Brownian particle moving in one-dimensional quenched disorder under the action of an external force is investigated. Within the tailored parameter regime, the transiently anomalous diffusion and ergodicity breaking, spanning several orders of magnitude in time, have been obtained. The ageing nature of the system weakens as the dissipation of the system increases for other given parameters. Its origin is ascribed to the highly local heterogeneity of the disorder. Two kinds of approximations (in the stationary state), respectively, for large bias and large damping are derived. These results may be helpful in further understanding the nontrivial response of nonlinear dynamics, and also have potential applications to experiments and activities of biological processes.

Topological sound in active-liquid metamaterials

NASA Astrophysics Data System (ADS)

Souslov, Anton

Active liquids can flow spontaneously even in the absence of an external drive. Recently, such liquids have been experimentally realized using molecular, colloidal, or macroscopic self-propelled constituents. Using active liquids as a building material, we lay out design principles for artificial structures termed topological active metamaterials. Such metamaterials break time-reversal symmetry and can be designed using periodic lattices composed of annular channels filled with a spontaneously flowing active liquid. We show that these active metamaterials support topologically protected sound modes that propagate unidirectionally (without backscattering) along either sample edges or domain walls, and despite overdamped particle dynamics. Our work illustrates how parity-symmetry breaking in metamaterial structure combined with microscopic irreversibility of active matter leads to novel functionalities that cannot be achieved using only passive materials.

EVALUATION OF INTERNALLY STAGED COAL BURNERS AND SORBENT JET AERODYNAMICS FOR COMBINED SO2/NOX CONTROL IN UTILITY BOILERS, VOLUME 1, TESTING IN A 10 MILLION BTU/HR EXPERIMENTAL FURNACE

EPA Science Inventory

The document gives results of tests conducted in a 2 MWt experimental furnace to: (1) investigate ways to reduce NOx emissions from utility coal burners without external air ports (i.e., with internal fuel/air staging); and (2) improve the performance of calcium-based sorbents fo...

TALEN-Mediated Homologous Recombination Produces Site-Directed DNA Base Change and Herbicide-Resistant Rice.

PubMed

Li, Ting; Liu, Bo; Chen, Chih Ying; Yang, Bing

2016-05-20

Over the last decades, much endeavor has been made to advance genome editing technology due to its promising role in both basic and synthetic biology. The breakthrough has been made in recent years with the advent of sequence-specific endonucleases, especially zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPRs) guided nucleases (e.g., Cas9). In higher eukaryotic organisms, site-directed mutagenesis usually can be achieved through non-homologous end-joining (NHEJ) repair to the DNA double-strand breaks (DSBs) caused by the exogenously applied nucleases. However, site-specific gene replacement or genuine genome editing through homologous recombination (HR) repair to DSBs remains a challenge. As a proof of concept gene replacement through TALEN-based HR in rice (Oryza sativa), we successfully produced double point mutations in rice acetolactate synthase gene (OsALS) and generated herbicide resistant rice lines by using TALENs and donor DNA carrying the desired mutations. After ballistic delivery into rice calli of TALEN construct and donor DNA, nine HR events with different genotypes of OsALS were obtained in T0 generation at the efficiency of 1.4%-6.3% from three experiments. The HR-mediated gene edits were heritable to the progeny of T1 generation. The edited T1 plants were as morphologically normal as the control plants while displayed strong herbicide resistance. The results demonstrate the feasibility of TALEN-mediated genome editing in rice and provide useful information for further genome editing by other nuclease-based genome editing platforms. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

The extent and distribution of inequalities in childhood mortality by cause of death according to parental socioeconomic positions: a birth cohort study in South Korea.

PubMed

Kim, Jongoh; Son, Mia; Kawachi, Ichiro; Oh, Juhwan

2009-10-01

It has been shown that childhood mortality is affected by parental socioeconomic positions; in this article, we investigate the extent and distribution of inequalities across major causes of childhood death. We built a retrospective birth cohort using individually linked national birth and death records in South Korea. 1,329,540 children were followed up to exact age eight from 1995 to 1996 and total observed person-years were 10,594,168.18. Causes of death were identified from death records while parental education, occupation and birth characteristics were identified from birth records. Survival analysis was performed according to parental socioeconomic positions. Cox proportional hazard analysis was done according to parental education and occupation with adjustment of birth characteristics such as sex, parental age, gestational age, birth weight, multiple birth, the number of total births, and previous death of children. Cumulative incidence of mortality by age was obtained through a competing-risk method in each cause according to maternal education. From these results, distribution of inequalities across major causes of death was calculated. In total, 7018 deaths occurred during the eight years and mortality rate was 66.24 per 100,000 person-years. External cause was the most common cause of death followed by congenital malformations, nervous system diseases, perinatal diseases, cancer, respiratory, cardiovascular, infectious and gastrointestinal diseases. For all-cause mortality, hazard ratios (HR) were 1.98 (95% CI: 1.83-2.13) for paternal education, 1.90 (1.75-2.07) for maternal education, 1.40 (1.33-1.47) for paternal occupation and 2.33(1.98-2.73) for maternal occupation (between middle school graduation or lower and university or more for education, between manual and non-manual for occupation). Mortality differentials were found in every cause of death. External cause, respiratory, cardiovascular and infectious diseases showed larger HR than all-cause mortality: 2.20 (1.90-2.56), 2.87 (2.02-4.08), 2.50 (1.67-3.75) and 2.12 (1.43-3.15) respectively according to maternal education. On the contrary, congenital malformations and cancer had smaller HR than all-cause mortality: 1.49 (1.22-1.82) and 1.43 (1.00-2.05) respectively according to maternal education. In all-cause mortality and most of the causes, cumulative incidence of mortality increased rapidly until one or two years after birth and then slowed down. But in external cause and cancer, cumulative incidence of mortality accumulated at a constant pace. Thus, inequalities in these causes of death consistently widened. External cause was the leading cause of overall inequalities and its proportion was 36-42% followed by congenital malformations, respiratory diseases etc. We conclude that there were inequalities of childhood mortality in every major cause of death. External cause was the leading cause of both all-cause mortality and overall inequalities. Public health interventions to reduce inequalities are necessary and external cause should be primarily considered.

Attenuating homologous recombination stimulates an AID-induced antileukemic effect

PubMed Central

Lamont, Kristin R.; Hasham, Muneer G.; Donghia, Nina M.; Branca, Jane; Chavaree, Margaret; Chase, Betsy; Breggia, Anne; Hedlund, Jacquelyn; Emery, Ivette; Cavallo, Francesca; Jasin, Maria; Rüter, Jens

2013-01-01

Activation-induced cytidine deaminase (AID) is critical in normal B cells to initiate somatic hypermutation and immunoglobulin class switch recombination. Accumulating evidence suggests that AID is also prooncogenic, inducing cancer-promoting mutations or chromosome rearrangements. In this context, we find that AID is expressed in >40% of primary human chronic lymphocytic leukemia (CLL) cases, consistent with other reports. Using a combination of human B lymphoid leukemia cells and mouse models, we now show that AID expression can be harnessed for antileukemic effect, after inhibition of the RAD51 homologous recombination (HR) factor with 4,4′-diisothiocyanatostilbene-2-2′-disulfonic acid (DIDS). As a proof of principle, we show that DIDS treatment inhibits repair of AID-initiated DNA breaks, induces apoptosis, and promotes cytotoxicity preferentially in AID-expressing human CLL. This reveals a novel antineoplastic role of AID that can be triggered by inhibition of HR, suggesting a potential new paradigm to treat AID-expressing tumors. Given the growing list of tumor types with aberrant AID expression, this novel therapeutic approach has potential to impact a significant patient population. PMID:23589568

Utilizing Laser-Induced Breakdown Spectroscopy Method to recognize chemical composition of low-carbon steel in NH3(NO)4 material

NASA Astrophysics Data System (ADS)

Saud Oraibi, Nissan

2018-05-01

A standoff laser Induced Break down Spectroscopy (L.I.B.S) technique has been used to characterization the organic material such as NH3(NO)4, a Q-switched Nd:YAG laser (1064 nm wavelength, 9 ns pulse width and 1 Hz repetition rate, 300 mJ is focused to the targets to generate plasma. HR 4000 CG-UV-NIR spectrum analyzer was used to collect the generated plasma emissions, specific signature of each targets material can be obtained by analysis the plasma emission spectrum Peak ratio analysis technique is used for the identification of energetic materials.

The fine print on HSAs.

PubMed

Coyle, Dan

2008-01-01

A health savings account (HSA) plan, when properly understood, can be a great tool for managing health care costs for employers. It also can be a great tool for employees who want to save for future medical costs. Unfortunately, most presentations and articles about HSA plans skip the details and there are many administrative and compliance complexities, as would be expected with any plan that involves a tax break. This article provides ten points human resource (HR) and benefit professionals should know when considering whether to add an HSA plan. In this collective learning curve, the more accurately employers address questions, the happier their employees will be with their new plans.

The effect of food on gastrointestinal (GI) transit of sustained-release ibuprofen tablets as evaluated by gamma scintigraphy

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

Borin, M.T.; Khare, S.; Beihn, R.M.

1990-03-01

The GI transit of radiolabeled sustained-release ibuprofen 800-mg tablets in eight healthy, fed volunteers was monitored using external gamma scintigraphy. Ibuprofen serum concentrations were determined from blood samples drawn over 36 hr following dosing. Sustained-release ibuprofen tablets containing 0.18% of 170Er2O3 (greater than 96% 170Er) in the bulk formulation were manufactured under pilot-scale conditions and were radiolabeled utilizing a neutron activation procedure which converted stable 170Er to radioactive 171Er (t1/2 = 7.5 hr). At the time of dosing, each tablet contained 50 mu Ci of 171Er. Dosage form position were reported at various time intervals. In five subjects the sustained-releasemore » tablet remained in the stomach and eroded slowly over 7-12 hr, resulting in gradual increases in small bowel radioactivity. In the remaining three subjects, the intact tablet was ejected from the stomach and a gastric residence time of approximately 4 hr was measured. This is in marked contrast to a previous study conducted in fasted volunteers in which gastric retention time ranged from 10 to 60 min. Differences in GI transit between fed and fasted volunteers had little effect on ibuprofen bioavailability. AUC and Tmax were unaltered and Cmax was increased by 24%, which is in agreement with results from a previous, crossover-design food effect study.« less

Postmastectomy Radiation Therapy Is Associated With Improved Survival in Node-Positive Male Breast Cancer: A Population Analysis.

PubMed

Abrams, Matthew J; Koffer, Paul P; Wazer, David E; Hepel, Jaroslaw T

2017-06-01

Because of its rarity, there are no randomized trials investigating postmastectomy radiation therapy (PMRT) in male breast cancer. This study retrospectively examines the impact of PMRT in male breast cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. The SEER database 8.3.2 was queried for men ages 20+ with a diagnosis of localized or regional nonmetastatic invasive ductal/lobular carcinoma from 1998 to 2013. Included patients were treated by modified radical mastectomy (MRM), with or without adjuvant external beam radiation. Univariate and multivariate analyses evaluated predictors for PMRT use after MRM. Kaplan-Meier overall survival (OS) curves of the entire cohort and a case-matched cohort were calculated and compared by the log-rank test. Cox regression was used for multivariate survival analyses. A total of 1933 patients were included in the unmatched cohort. There was no difference in 5-year OS between those who received PMRT and those who did not (78% vs 77%, respectively, P=.371); however, in the case-matched analysis, PMRT was associated with improved OS at 5 years (83% vs 54%, P<.001). On subset analysis of the unmatched cohort, PMRT was associated with improved OS in men with 1 to 3 positive nodes (5-year OS 79% vs 72% P=.05) and those with 4+ positive nodes (5-year OS 73% vs 53% P<.001). On multivariate analysis of the unmatched cohort, independent predictors for improved OS were use of PMRT: HR=0.551 (0.412-0.737) and estrogen receptor-positive disease: HR=0.577 (0.339-0.983). Predictors for a survival detriment were higher grade 3/4: HR=1.825 (1.105-3.015), larger tumor T2: HR=1.783 (1.357-2.342), T3/T4: HR=2.683 (1.809-3.978), higher N-stage: N1 HR=1.574 (1.184-2.091), N2/N3: HR=2.328 (1.684-3.218), black race: HR=1.689 (1.222-2.336), and older age 81+: HR=4.164 (1.497-11.582). There may be a survival benefit with the addition of PMRT for male breast cancer with node-positive disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Postmastectomy Radiation Therapy Is Associated With Improved Survival in Node-Positive Male Breast Cancer: A Population Analysis

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

Abrams, Matthew J., E-mail: mabrams@tuftsmedicalcenter.org; Koffer, Paul P.; Wazer, David E.

Purpose: Because of its rarity, there are no randomized trials investigating postmastectomy radiation therapy (PMRT) in male breast cancer. This study retrospectively examines the impact of PMRT in male breast cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Methods and Materials: The SEER database 8.3.2 was queried for men ages 20+ with a diagnosis of localized or regional nonmetastatic invasive ductal/lobular carcinoma from 1998 to 2013. Included patients were treated by modified radical mastectomy (MRM), with or without adjuvant external beam radiation. Univariate and multivariate analyses evaluated predictors for PMRT use after MRM. Kaplan-Meier overallmore » survival (OS) curves of the entire cohort and a case-matched cohort were calculated and compared by the log-rank test. Cox regression was used for multivariate survival analyses. Results: A total of 1933 patients were included in the unmatched cohort. There was no difference in 5-year OS between those who received PMRT and those who did not (78% vs 77%, respectively, P=.371); however, in the case-matched analysis, PMRT was associated with improved OS at 5 years (83% vs 54%, P<.001). On subset analysis of the unmatched cohort, PMRT was associated with improved OS in men with 1 to 3 positive nodes (5-year OS 79% vs 72% P=.05) and those with 4+ positive nodes (5-year OS 73% vs 53% P<.001). On multivariate analysis of the unmatched cohort, independent predictors for improved OS were use of PMRT: HR=0.551 (0.412-0.737) and estrogen receptor–positive disease: HR=0.577 (0.339-0.983). Predictors for a survival detriment were higher grade 3/4: HR=1.825 (1.105-3.015), larger tumor T2: HR=1.783 (1.357-2.342), T3/T4: HR=2.683 (1.809-3.978), higher N-stage: N1 HR=1.574 (1.184-2.091), N2/N3: HR=2.328 (1.684-3.218), black race: HR=1.689 (1.222-2.336), and older age 81+: HR=4.164 (1.497-11.582). Conclusions: There may be a survival benefit with the addition of PMRT for male breast cancer with node-positive disease.« less

Adiabatic photo-steering theory in topological insulators.

PubMed

Inoue, Jun-Ichi

2014-12-01

Feasible external control of material properties is a crucial issue in condensed matter physics. A new approach to achieving this aim, named adiabatic photo-steering, is reviewed. The core principle of this scheme is that several material constants are effectively turned into externally tunable variables by irradiation of monochromatic laser light. Two-dimensional topological insulators are selected as the optimal systems that exhibit a prominent change in their properties following the application of this method. Two specific examples of photo-steered quantum phenomena, which reflect topological aspects of the electronic systems at hand, are presented. One is the integer quantum Hall effect described by the Haldane model, and the other is the quantum spin Hall effect described by the Kane-Mele model. The topological quantities associated with these phenomena are the conventional Chern number and spin Chern number, respectively. A recent interesting idea, time-reversal symmetry breaking via a temporary periodic external stimulation, is also discussed.

Adiabatic photo-steering theory in topological insulators

NASA Astrophysics Data System (ADS)

Inoue, Jun-ichi

2014-12-01

Feasible external control of material properties is a crucial issue in condensed matter physics. A new approach to achieving this aim, named adiabatic photo-steering, is reviewed. The core principle of this scheme is that several material constants are effectively turned into externally tunable variables by irradiation of monochromatic laser light. Two-dimensional topological insulators are selected as the optimal systems that exhibit a prominent change in their properties following the application of this method. Two specific examples of photo-steered quantum phenomena, which reflect topological aspects of the electronic systems at hand, are presented. One is the integer quantum Hall effect described by the Haldane model, and the other is the quantum spin Hall effect described by the Kane-Mele model. The topological quantities associated with these phenomena are the conventional Chern number and spin Chern number, respectively. A recent interesting idea, time-reversal symmetry breaking via a temporary periodic external stimulation, is also discussed.

Multiple-exciton generation in lead selenide nanorod solar cells with external quantum efficiencies exceeding 120%

PubMed Central

Davis, Nathaniel J. L. K.; Böhm, Marcus L.; Tabachnyk, Maxim; Wisnivesky-Rocca-Rivarola, Florencia; Jellicoe, Tom C.; Ducati, Caterina; Ehrler, Bruno; Greenham, Neil C.

2015-01-01

Multiple-exciton generation—a process in which multiple charge-carrier pairs are generated from a single optical excitation—is a promising way to improve the photocurrent in photovoltaic devices and offers the potential to break the Shockley–Queisser limit. One-dimensional nanostructures, for example nanorods, have been shown spectroscopically to display increased multiple exciton generation efficiencies compared with their zero-dimensional analogues. Here we present solar cells fabricated from PbSe nanorods of three different bandgaps. All three devices showed external quantum efficiencies exceeding 100% and we report a maximum external quantum efficiency of 122% for cells consisting of the smallest bandgap nanorods. We estimate internal quantum efficiencies to exceed 150% at relatively low energies compared with other multiple exciton generation systems, and this demonstrates the potential for substantial improvements in device performance due to multiple exciton generation. PMID:26411283

External Validation of Bifactor Model of ADHD: Explaining Heterogeneity in Psychiatric Comorbidity, Cognitive Control, and Personality Trait Profiles Within DSM-IV ADHD

PubMed Central

Martel, Michelle M.; Roberts, Bethan; Gremillion, Monica; von Eye, Alexander; Nigg, Joel T.

2011-01-01

The current paper provides external validation of the bifactor model of ADHD by examining associations between ADHD latent factor/profile scores and external validation indices. 548 children (321 boys; 302 with ADHD), 6 to 18 years old, recruited from the community participated in a comprehensive diagnostic procedure. Mothers completed the Child Behavior Checklist, Early Adolescent Temperament Questionnaire, and California Q-Sort. Children completed the Stop and Trail-Making Task. Specific inattention was associated with depression/withdrawal, slower cognitive task performance, introversion, agreeableness, and high reactive control; specific hyperactivity-impulsivity was associated with rule-breaking/aggressive behavior, social problems, errors during set-shifting, extraversion, disagreeableness, and low reactive control. It is concluded that the bifactor model provides better explanation of heterogeneity within ADHD than DSM-IV ADHD symptom counts or subtypes. PMID:21735050

Deep Keck u-Band Imaging of the Hubble Ultra Deep Field: A Catalog of z ~ 3 Lyman Break Galaxies

NASA Astrophysics Data System (ADS)

Rafelski, Marc; Wolfe, Arthur M.; Cooke, Jeff; Chen, Hsiao-Wen; Armandroff, Taft E.; Wirth, Gregory D.

2009-10-01

We present a sample of 407 z ~ 3 Lyman break galaxies (LBGs) to a limiting isophotal u-band magnitude of 27.6 mag in the Hubble Ultra Deep Field. The LBGs are selected using a combination of photometric redshifts and the u-band drop-out technique enabled by the introduction of an extremely deep u-band image obtained with the Keck I telescope and the blue channel of the Low Resolution Imaging Spectrometer. The Keck u-band image, totaling 9 hr of integration time, has a 1σ depth of 30.7 mag arcsec-2, making it one of the most sensitive u-band images ever obtained. The u-band image also substantially improves the accuracy of photometric redshift measurements of ~50% of the z ~ 3 LBGs, significantly reducing the traditional degeneracy of colors between z ~ 3 and z ~ 0.2 galaxies. This sample provides the most sensitive, high-resolution multi-filter imaging of reliably identified z ~ 3 LBGs for morphological studies of galaxy formation and evolution and the star formation efficiency of gas at high redshift.

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

Seo, Dong-Kyun; Medpelli, Dinesh; Ladd, Danielle

A product formed from a first material including a geopolymer resin material, a geopolymer material, or a combination thereof by contacting the first material with a fluid and removing at least some of the fluid to yield a product. The first material may be formed by heating and/or aging an initial geopolymer resin material to yield the first material before contacting the first material with the fluid. In some cases, contacting the first material with the fluid breaks up or disintegrates the first material (e.g., in response to contact with the fluid and in the absence of external mechanical stress),more » thereby forming particles having an external dimension in a range between 1 nm and 2 cm.« less

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

Seo, Dong-Kyun; Medpelli, Dinesh; Ladd, Danielle

A product formed from a first material including a geopolymer resin material, a geopolymer resin, or a combination thereof by contacting the first material with a fluid and removing at least some of the fluid to yield a product. The first material may be formed by heating and/or aging an initial geopolymer resin material to yield the first material before contacting the first material with the fluid. In some cases, contacting the first material with the fluid breaks up or disintegrates the first material (e.g., in response to contact with the fluid and in the absence of external mechanical stress),more » thereby forming particles having an external dimension in a range between 1 nm and 2 cm.« less

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31.

PubMed

Chappell, William H; Gautam, Dipendra; Ok, Suzan T; Johnson, Bryan A; Anacker, Daniel C; Moody, Cary A

2015-12-23

High-risk human papillomavirus 31 (HPV31)-positive cells exhibit constitutive activation of the ATM-dependent DNA damage response (DDR), which is necessary for productive viral replication. In response to DNA double-strand breaks (DSBs), ATM activation leads to DNA repair through homologous recombination (HR), which requires the principal recombinase protein Rad51, as well as BRCA1. Previous studies from our lab demonstrated that Rad51 and BRCA1 are expressed at high levels in HPV31-positive cells and localize to sites of viral replication. These results suggest that HPV may utilize ATM activity to increase HR activity as a means to facilitate viral replication. In this study, we demonstrate that high-risk HPV E7 expression alone is sufficient for the increase in Rad51 and BRCA1 protein levels. We have found that this increase occurs, at least in part, at the level of transcription. Studies analyzing protein stability indicate that HPV may also protect Rad51 and BRCA1 from turnover, contributing to the overall increase in cellular levels. We also demonstrate that Rad51 is bound to HPV31 genomes, with binding increasing per viral genome upon productive replication. We have found that depletion of Rad51 and BRCA1, as well as inhibition of Rad51's recombinase activity, abrogates productive viral replication upon differentiation. Overall, these results indicate that Rad51 and BRCA1 are required for the process of HPV31 genome amplification and suggest that productive replication occurs in a manner dependent upon recombination. Productive replication of HPV31 requires activation of an ATM-dependent DNA damage response, though how ATM activity contributes to replication is unclear. Rad51 and BRCA1 play essential roles in repair of double-strand breaks, as well as the restart of stalled replication forks through homologous recombination (HR). Given that ATM activity is required to initiate HR repair, coupled with the requirement of Rad51 and BRCA1 for productive viral replication, our findings suggest that HPV may utilize ATM activity to ensure localization of recombination factors to productively replicating viral genomes. The finding that E7 increases the levels of Rad51 and BRCA1 suggests that E7 contributes to productive replication by providing DNA repair factors required for viral DNA synthesis. Our studies not only imply a role for recombination in the regulation of productive HPV replication but provide further insight into how HPV manipulates the DDR to facilitate the productive phase of the viral life cycle. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Self-organization of magnetic particles at fluid interfaces

NASA Astrophysics Data System (ADS)

Belkin, Maxim

Understanding principles that govern emergent behavior in systems with complex interactions has puzzled scientists for many years. In my work I studied seemingly simple but highly non-trivial system of magnetic micro-particles suspended at fluid interface and energized by an external vertical AC magnetic field. It can be considered as a prototype for probing the interplay of individual interactions on the collective response of system to the external driving. The first part of this work is focused on experimental study of self-organization in this system. In a certain region of parameters formation of localized snake-like structures with accompanying large-scale symmetric surface flows is observed. Characteristics of the self-organized structure as well as flows strongly depend on parameters of the external driving. Increased driving leads to a spontaneous symmetry breaking of the surface flows which results in a self-propulsion of the "snake". This observation leads to an idea of controlled design of a self-propelled swimmer. Numerical calculations based on a phenomenological model proposed for the description of such system successfully reproduces self-organization of the snake-like structures, self-propulsion under spontaneous and artificial symmetry breaking. Increase in the number of the particles promotes a formation of multiple snakes which are in turn unstable with respect to self-induced flows and become mobile swimmers. Such ensemble effectively mixes the surface of liquid. Experimental study of such two-dimensional mixing is the focus of the second part of this work. Results of molecular-dynamics simulations based on proposed theoretical model are reported.

Autonomic and Adrenocortical Interactions Predict Mental Health in Late Adolescence: The TRAILS Study.

PubMed

Nederhof, Esther; Marceau, Kristine; Shirtcliff, Elizabeth A; Hastings, Paul D; Oldehinkel, Albertine J

2015-07-01

The present study is informed by the theory of allostatic load to examine how multiple stress responsive biomarkers are related to mental health outcomes. Data are from the TRAILS study, a large prospective population study of 715 Dutch adolescents (50.9 % girls), assessed at 16.3 and 19.1 years. Reactivity measures of the hypothalamic pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) biomarkers (heart rate, HR; respiratory sinus arrhythmia, RSA; and pre-ejection period, PEP) to a social stress task were used to predict concurrent and longitudinal changes in internalizing and externalizing symptoms. Hierarchical linear modeling revealed relatively few single effects for each biomarker with the exception that high HR reactivity predicted concurrent internalizing problems in boys. More interestingly, interactions were found between HPA-axis reactivity and sympathetic and parasympathetic reactivity. Boys with high HPA reactivity and low RSA reactivity had the largest increases in internalizing problems from 16 to 19 years. Youth with low HPA reactivity along with increased ANS activation characterized by both decreases in RSA and decreases in PEP had the most concurrent externalizing problems, consistent with broad theories of hypo-arousal. Youth with high HPA reactivity along with increases in RSA but decreases in PEP also had elevated concurrent externalizing problems, which increased over time, especially within boys. This profile illustrates the utility of examining the parasympathetic and sympathetic components of the ANS which can act in opposition to one another to achieve, overall, stress responsivity. The framework of allostasis and allostatic load is supported in that examination of multiple biomarkers working together in concert was of value in understanding mental health problems concurrently and longitudinally. Findings argue against an additive panel of risk and instead illustrate the dynamic interplay of stress physiology systems.

Comparison of athlete-coach perceptions of internal and external load markers for elite junior tennis training.

PubMed

Murphy, Alistair P; Duffield, Rob; Kellett, Aaron; Reid, Machar

2014-09-01

To investigate the discrepancy between coach and athlete perceptions of internal load and notational analysis of external load in elite junior tennis. Fourteen elite junior tennis players and 6 international coaches were recruited. Ratings of perceived exertion (RPEs) were recorded for individual drills and whole sessions, along with a rating of mental exertion, coach rating of intended session exertion, and athlete heart rate (HR). Furthermore, total stroke count and unforced-error count were notated using video coding after each session, alongside coach and athlete estimations of shots and errors made. Finally, regression analyses explained the variance in the criterion variables of athlete and coach RPE. Repeated-measures analyses of variance and interclass correlation coefficients revealed that coaches significantly (P < .01) underestimated athlete session RPE, with only moderate correlation (r = .59) demonstrated between coach and athlete. However, athlete drill RPE (P = .14; r = .71) and mental exertion (P = .44; r = .68) were comparable and substantially correlated. No significant differences in estimated stroke count were evident between athlete and coach (P = .21), athlete notational analysis (P = .06), or coach notational analysis (P = .49). Coaches estimated significantly greater unforced errors than either athletes or notational analysis (P < .01). Regression analyses found that 54.5% of variance in coach RPE was explained by intended session exertion and coach drill RPE, while drill RPE and peak HR explained 45.3% of the variance in athlete session RPE. Coaches misinterpreted session RPE but not drill RPE, while inaccurately monitoring error counts. Improved understanding of external- and internal-load monitoring may help coach-athlete relationships in individual sports like tennis avoid maladaptive training.

Effects of Bout Duration on Players' Internal and External Loads During Small-Sided Games in Young Soccer Players.

PubMed

Köklü, Yusuf; Alemdaroğlu, Utku; Cihan, Hamit; Wong, Del P

2017-11-01

To investigate the effects of different bout durations on internal and external loads of young soccer players during different small-sided games (SSGs). Fifteen young male soccer players (average age 17 ± 1 y) participated in 2 vs 2, 3 vs 3, and 4 vs 4 SSGs. All games lasted 12 min playing time in total, but each SSG format further consisted of 4 bout durations: continuous (CON: 1 bout × 12 min) or interval with short (SBD: 6 bouts  × 2 min), medium (MBD: 3 bouts × 4 min), or long (LBD: 2 bouts × 6 min) bout durations. During the SSGs, heart-rate (HR) responses and distance covered in different speed zones (walking and low-intensity, moderate-intensity, and high-intensity running) were measured. Rating of perceived exertion (RPE) and blood lactate (La - ) were determined at the end of each SSG. The SBD format elicited significantly lower %HR max responses compared to LBD and CON in all formats (P < .05). The SBD format also showed significantly shorter distances covered in walking and greater distances covered in moderate-intensity running, as well as significantly greater total distance covered compared to LBD and CON in all formats (P < .05). In addition, LBD produced significantly lower La - and RPE responses than SBD and CON in all formats (P < .05). These results suggest that coaches and sport scientists who want to achieve higher internal loads could use SBD and CON timing protocols, while those who want to achieve higher external loads might prefer to use SBD and MBD when planning all SSG formats.

Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine.

PubMed

Latimer, Nicholas R; Abrams, Keith R; Amonkar, Mayur M; Stapelkamp, Ceilidh; Swann, R Suzanne

2015-07-01

Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS. Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect. A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well. RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making. Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib. ©AlphaMed Press.

Adjusting for the Confounding Effects of Treatment Switching—The BREAK-3 Trial: Dabrafenib Versus Dacarbazine

PubMed Central

Abrams, Keith R.; Amonkar, Mayur M.; Stapelkamp, Ceilidh; Swann, R. Suzanne

2015-01-01

Background. Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48–1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS. Materials and Methods. Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, “treatment group” (assumes treatment effect could continue until death) and “on-treatment observed” (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect. Results. A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE “treatment group” and “on-treatment observed” analyses performed similarly well. Conclusion. RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching—a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making. Implications for Practice: Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib. PMID:26040620

Family Violence Pathways and Externalizing Behavior in Youth.

PubMed

Bozzay, Melanie L; Joy, Lendi N; Verona, Edelyn

2017-08-01

While studies suggest that youth who experience violence in the home are more likely to engage in externalizing behaviors (e.g., aggression, substance use, rule breaking), research is needed to understand factors that may explain how family violence is linked to externalizing, and whether there may be gender-specific trajectories to this outcome. The present study used a cross-sectional design and multigroup, path analytic modeling to test the degree to which personality traits (negative emotionality, constraint) in boys and girls (Model 1), as well as status offending primarily in girls (Model 2), may help explain relationships between exposure to familial adversity (witnessing family violence and child abuse) and adolescent externalizing behaviors in a mixed-gender, community sample with both caregiver and youth reports ( N = 237, 57% female, 10-17 years old). Results indicated that personality traits fully explained the relationship between witnessing family violence and externalizing and partially explained the relationship between child abuse and externalizing among youth. Despite theory suggesting a female-specific trajectory involving status offenses, both models were similarly relevant for boys and girls. These findings have implications for understanding processes by which adverse family circumstances may relate to externalizing behavior in youth. Preliminary suggestions are provided for future longitudinal research, policy changes, and clinical techniques that may be essential in preventing the progression to long-term adverse outcomes among youth.

Ad libitum fluid consumption via self- or external administration.

PubMed

Yeargin, Susan W; Finn, Megan E; Eberman, Lindsey E; Gage, Matthew J; McDermott, Brendon P; Niemann, Andrew

2015-01-01

During team athletic events, athletic trainers commonly provide fluids with water bottles. When a limited number of water bottles exist, various techniques are used to deliver fluids. To determine whether fluid delivered via water-bottle administration influenced fluid consumption and hydration status. Crossover study. Outdoor field (22.2°C ± 3.5°C). Nineteen participants (14 men, 5 women, age = 30 ± 10 years, height = 176 ± 8 cm, mass = 72.5 ± 10 kg) were recruited from the university and local running clubs. The independent variable was fluid delivery with 3 levels: self-administration with mouth-to-bottle direct contact (SA-DC), self-administration with no contact between mouth and bottle (SA-NC), and external administration with no contact between the mouth and the bottle (EA-NC). Participants warmed up for 10 minutes before completing 5 exercise stations, after which an ad libitum fluid break was given, for a total of 6 breaks. We measured the fluid variables of total volume consumed, total number of squirts, and average volume per squirt. Hydration status via urine osmolality and body-mass loss, and perceptual variables for thirst and fullness were recorded. We calculated repeated-measures analyses of variance to assess hydration status, fluid variables, and perceptual measures to analyze conditions across time. The total volume consumed for EA-NC was lower than for SA-DC (P = .001) and SA-NC (P = .001). The total number of squirts for SA-DC was lower than for SA-NC (P = .009). The average volume per squirt for EA-NC was lower than for SA-DC (P = .020) and SA-NC (P = .009). Participants arrived (601.0 ± 21.3 mOsm/L) and remained (622.3 ± 38.3 mOsm/L) hydrated, with no difference between conditions (P = .544); however, the EA-NC condition lost more body mass than did the SA-DC condition (P = .001). There was no main effect for condition on thirst (P = .147) or fullness (P = .475). External administration of fluid decreased total volume consumed via a decreased average volume per squirt. The SA-DC method requires fewer squirts within a specific time frame. Fluid breaks every 15 minutes resulted in maintenance of euhydration; however, loss of body mass was influenced by fluid administration. Athletic trainers should avoid external administration to promote positive hydration behaviors. When fluid is self-administered, individual bottles may be the best clinical practice because more volume can be consumed per squirt.

FIRST PRECISION LIGHT CURVE ANALYSIS OF THE NEGLECTED EXTREME MASS RATIO SOLAR-TYPE BINARY HR BOOTIS

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

Samec, Ronald G.; Benkendorf, Barry; Dignan, James B.

2015-04-15

HR Bootis is a neglected binary that is found to be a solar-type (G2V) extreme mass ratio binary (EMRB). It was discovered by Hanley and Shapley in 1940. Surprisingly, little has been published in the intervening years. In 1999 it was characterized by a 0.31587 day orbital period. Since that time it has been observed by various observers who have determined ∼20 timings of minimum light over the past ∼15,000 orbits. Our observations in 2012 represent the first precision curves in the BVR{sub c}I{sub c} Johnson–Cousins wavelength bands. The light curves have rather low amplitudes, averaging some 0.5 magnitudes, yetmore » they exhibit total eclipses, which is typical of the rare group of solar-type EMRBs. An improved linear ephemeris was computed along with a quadratic ephemeris showing a decaying orbit, which indicates magnetic breaking may be occurring. The light curve solution reveals that HR Boo is a contact system with a somewhat low 21% Roche-lobe fill-out but a mass ratio of q = 4.09 (0.2444), which defines it as an EMRB. Two spots, both hot, were allowed to iterate to fit the light curve asymmetries. Their radii are 32° and 16°. Both are high-latitude polar spots indicative of strong magnetic activity. The shallow contact yet nearly equal component temperatures makes it an unusual addition to this group.« less

Assessment of the hydrogen external tank pressure decay anomaly on Space Transportation System (STS) 51-L

NASA Technical Reports Server (NTRS)

Buckley, Theresa M.

1988-01-01

Following the Challenger tragedy, an evaluation of the integrated main propulsion system flight data revealed a premature decay in the hydrogen external tank ullage pressure. A reconstruction of predicted ullage pressure versus time indicated an inconsistency between predicted and measured ullage pressure starting at approximately 65.5 seconds into the flight and reaching a maximum value between 72 and 72.9 seconds. This discrepancy could have been caused by a hydrogen gas leak or by a liquied hydrogen leak that occurred either in the pressurization system or in the external tank. The corresponding leak rates over the time interval from 65.5 to 72.9 seconds were estimated to range from 0.28 kg/s (0.62 lbm/s) + or - 41 percent to between 0.43 and 0.51kg/s (0.94 and 1.12lbs/s) + or - 1 percent for a gas leak and from 72.9 kg/s (160.5 lbs/s) + or - 41 percent to between 111.6 and 133.2 kg/s (245.8 and 293.3 lbs/s) + or - 1 percent for a liquid leak. No speculation is made to ascertain whether the leak is liquid or gas, as this cannot be determined from the analysis performed. Four structural failures in the hydrogen external tank were considered to explain the leak rates. A break in the 5-cm (2 in) pressurization line, in the 13-cm (5 in) vent line, or in the 43-cm (17 in) feedline is not likely. A break in the 10-cm (4 in) recirculation line with a larger structural failure occurring in the 72 to 73-second time period, the time of the visibly identified premature pressure decay, does seem plausible and the most likely of the four modes considered. These modes are not all-inclusive and do not preclude the possibility of a leak elsewhere in the tank.

Modeling and simulation of maintenance treatment in first-line non-small cell lung cancer with external validation.

PubMed

Han, Kelong; Claret, Laurent; Sandler, Alan; Das, Asha; Jin, Jin; Bruno, Rene

2016-07-13

Maintenance treatment (MTx) in responders following first-line treatment has been investigated and practiced for many cancers. Modeling and simulation may support interpretation of interim data and development decisions. We aimed to develop a modeling framework to simulate overall survival (OS) for MTx in NSCLC using tumor growth inhibition (TGI) data. TGI metrics were estimated using longitudinal tumor size data from two Phase III first-line NSCLC studies evaluating bevacizumab and erlotinib as MTx in 1632 patients. Baseline prognostic factors and TGI metric estimates were assessed in multivariate parametric models to predict OS. The OS model was externally validated by simulating a third independent NSCLC study (n = 253) based on interim TGI data (up to progression-free survival database lock). The third study evaluated pemetrexed + bevacizumab vs. bevacizumab alone as MTx. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, baseline tumor size, ECOG score, Asian ethnicity, age, and gender were significant covariates in the final OS model. The OS model was qualified by simulating OS distributions and hazard ratios (HR) in the two studies used for model-building. Simulations of the third independent study based on interim TGI data showed that pemetrexed + bevacizumab MTx was unlikely to significantly prolong OS vs. bevacizumab alone given the current sample size (predicted HR: 0.81; 95 % prediction interval: 0.59-1.09). Predicted median OS was 17.3 months and 14.7 months in both arms, respectively. These simulations are consistent with the results of the final OS analysis published 2 years later (observed HR: 0.87; 95 % confidence interval: 0.63-1.21). Final observed median OS was 17.1 months and 13.2 months in both arms, respectively, consistent with our predictions. A robust TGI-OS model was developed for MTx in NSCLC. TTG captures treatment effect. The model successfully predicted the OS outcomes of an independent study based on interim TGI data and thus may facilitate trial simulation and interpretation of interim data. The model was built based on erlotinib data and externally validated using pemetrexed data, suggesting that TGI-OS models may be treatment-independent. The results supported the use of longitudinal tumor size and TTG as endpoints in early clinical oncology studies.

Enhanced carotid-cardiac baroreflex response and elimination of orthostatic hypotension 24 hours after acute exercise in paraplegics

NASA Technical Reports Server (NTRS)

Engelke, K. A.; Shea, J. D.; Doerr, D. F.; Convertino, V. A.

1992-01-01

To test the hypothesis that an acute bout of maximal exercise can ameliorate orthostatic hypotension consequent to prolonged wheelchair confinement, we evaluated heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure responses during 15 minutes of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects 24 hours after arm crank exercise designed to elicit maximal effort, and during a control (no exercise) conditions. Additionally, the carotid baroreceptor stimulus-cardiac response relationship was determined by measurement of R-R interval during external application of graded pressures to the carotid sinuses. One week separated the treatment conditions. The maximum slope of the carotid-cardiac baroreflex response was increased (p = 0.049) by exercise (6.2 +/- 1.7 msec/mmHg) compared to control (3.3 +/- 0.6). During control HUT, HR increased from 61 +/- 1 to 90 +/- 7 bpm (p = 0.001) while SBP decreased from 118 +/- 5 to 106 +/- 9 mmHg (p = 0.025). During HUT 24 hours after exercise, HR increased from 60 +/- 2 to 90 +/- 4 bpm (p = 0.001), but the reduction in SBP was essentially eliminated (116 +/- 5 to 113 +/- 5 mmHg).

Observation of a discrete time crystal

NASA Astrophysics Data System (ADS)

Zhang, J.; Hess, P. W.; Kyprianidis, A.; Becker, P.; Lee, A.; Smith, J.; Pagano, G.; Potirniche, I.-D.; Potter, A. C.; Vishwanath, A.; Yao, N. Y.; Monroe, C.

2017-03-01

Spontaneous symmetry breaking is a fundamental concept in many areas of physics, including cosmology, particle physics and condensed matter. An example is the breaking of spatial translational symmetry, which underlies the formation of crystals and the phase transition from liquid to solid. Using the analogy of crystals in space, the breaking of translational symmetry in time and the emergence of a ‘time crystal’ was recently proposed, but was later shown to be forbidden in thermal equilibrium. However, non-equilibrium Floquet systems, which are subject to a periodic drive, can exhibit persistent time correlations at an emergent subharmonic frequency. This new phase of matter has been dubbed a ‘discrete time crystal’. Here we present the experimental observation of a discrete time crystal, in an interacting spin chain of trapped atomic ions. We apply a periodic Hamiltonian to the system under many-body localization conditions, and observe a subharmonic temporal response that is robust to external perturbations. The observation of such a time crystal opens the door to the study of systems with long-range spatio-temporal correlations and novel phases of matter that emerge under intrinsically non-equilibrium conditions.

Observation of a discrete time crystal.

PubMed

Zhang, J; Hess, P W; Kyprianidis, A; Becker, P; Lee, A; Smith, J; Pagano, G; Potirniche, I-D; Potter, A C; Vishwanath, A; Yao, N Y; Monroe, C

2017-03-08

Spontaneous symmetry breaking is a fundamental concept in many areas of physics, including cosmology, particle physics and condensed matter. An example is the breaking of spatial translational symmetry, which underlies the formation of crystals and the phase transition from liquid to solid. Using the analogy of crystals in space, the breaking of translational symmetry in time and the emergence of a 'time crystal' was recently proposed, but was later shown to be forbidden in thermal equilibrium. However, non-equilibrium Floquet systems, which are subject to a periodic drive, can exhibit persistent time correlations at an emergent subharmonic frequency. This new phase of matter has been dubbed a 'discrete time crystal'. Here we present the experimental observation of a discrete time crystal, in an interacting spin chain of trapped atomic ions. We apply a periodic Hamiltonian to the system under many-body localization conditions, and observe a subharmonic temporal response that is robust to external perturbations. The observation of such a time crystal opens the door to the study of systems with long-range spatio-temporal correlations and novel phases of matter that emerge under intrinsically non-equilibrium conditions.

Ultra-high speed visualization of the flashing instability under vacuum conditions

NASA Astrophysics Data System (ADS)

Hernández Sánchez, Jose Federico; Al-Ghamdi, Tariq; Thoroddsen, Sigurdur T.

2017-11-01

We investigated experimentally the flashing instability of a jet of perfluoro-n-hexane (PFnH) released into a low-pressure environment. Using a ultra-high speed camera we observed the jet fragmentation occurring close to the nozzle. Using a fixed total driving pressure, we decreased systematically the vacuum pressure, investigating the transition from a laminar jet to a fully flashing jet. Our high temporal resolution allowed to visualize the detailed dynamics of external flash-boiling for the first time. We identified different mechanisms of jet break-up. At chamber pressures lower than the vapor pressure the laminar jet evolves to a meandering stream. In this stage, bubbles start to nucleate and violently expand upstream the nozzle. At lower vacuum pressures the initially cylindrical jet elongates, forming a liquid sheet that breaks in branches and later in drops. At very low pressures both mechanisms are responsible for the jet breaking. We calculated the size distribution of the ejected droplets, their individual trajectories, velocities as well as the spray angle as a function of the dimensionless vacuum pressure.

Influence of pellet seating on the external ballistic parameters of spring-piston air guns.

PubMed

Werner, Ronald; Schultz, Benno; Frank, Matthias

2016-09-01

In firearm examiners' and forensic specialists' casework as well as in air gun proof testing, reliable measurement of the weapon's muzzle velocity is indispensable. While there are standardized and generally accepted procedures for testing the performance of air guns, the method of seating the diabolo pellets deeper into the breech of break barrel spring-piston air guns has not found its way into standardized test procedures. The influence of pellet seating on the external ballistic parameters was investigated using ten different break barrel spring-piston air guns. Test shots were performed with the diabolo pellets seated 2 mm deeper into the breech using a pellet seater. The results were then compared to reference shots with conventionally loaded diabolo pellets. Projectile velocity was measured with a high-precision redundant ballistic speed measurement system. In eight out of ten weapons, the muzzle energy increased significantly when the pellet seater was used. The average increase in kinetic energy was 31 % (range 9-96 %). To conclude, seating the pellet even slightly deeper into the breech of spring-piston air guns might significantly alter the muzzle energy. Therefore, it is strongly recommended that this effect is taken into account when accurate and reliable measurements of air gun muzzle velocity are necessary.

Spontaneous chiral symmetry breaking in two-dimensional aggregation

NASA Astrophysics Data System (ADS)

Sandler, Ilya Moiseevich

Recently, unusual and strikingly beautiful seahorse-like growth patterns have been discovered. These patterns possess a spontaneously broken chiral (left/right) symmetry. To explain this spontaneous chiral symmetry breaking, we develop a model for the growth of the aggregate, assuming that the latter is charged, and that the incoming particles are polarizable, and hence drawn preferentially to regions of strong electric field. This model is used both for numerical simulation and theoretical analysis of the aggregation process. We find that the broken symmetry (typically, an 'S' shape) appears in our simulations for some parameter values. Its origin is the long-range interaction (competition and repulsion) among growing branches of the aggregate, such that a right or left side consistently dominates the growth process. We show that the electrostatic interaction may account for the other geometrical properties of the aggregates, such as the existence of only 2 main arms, and the "finned" external edge of the main arms. The results of our simulations of growth in the presence of the external electric field are also in a good agreement with the results of new experiments, motivated by our ideas. Thus, we believe that our growth model provides a plausible explanation of the origin of the broken symmetry in the experimental patterns.

Subwavelength resolution from multilayered structure (Conference Presentation)

NASA Astrophysics Data System (ADS)

Cheng, Bo Han; Jen, Yi-Jun; Liu, Wei-Chih; Lin, Shan-wen; Lan, Yung-Chiang; Tsai, Din Ping

2016-10-01

Breaking optical diffraction limit is one of the most important issues needed to be overcome for the demand of high-density optoelectronic components. Here, a multilayered structure which consists of alternating semiconductor and dielectric layers for breaking optical diffraction limitation at THz frequency region are proposed and analyzed. We numerically demonstrate that such multilayered structure not only can act as a hyperbolic metamaterial but also a birefringence material via the control of the external temperature (or magnetic field). A practical approach is provided to control all the diffraction signals toward a specific direction by using transfer matrix method and effective medium theory. Numerical calculations and computer simulation (based on finite element method, FEM) are carried out, which agree well with each other. The temperature (or magnetic field) parameter can be tuned to create an effective material with nearly flat isofrequency feature to transfer (project) all the k-space signals excited from the object to be resolved to the image plane. Furthermore, this multilayered structure can resolve subwavelength structures at various incident THz light sources simultaneously. In addition, the resolution power for a fixed operating frequency also can be tuned by only changing the magnitude of external magnetic field. Such a device provides a practical route for multi-functional material, photolithography and real-time super-resolution image.

Far-from-equilibrium magnetic granular layers: dynamic patterns, magnetic order and self-assembled swimmers

NASA Astrophysics Data System (ADS)

Snezhko, Alexey

2010-03-01

Ensembles of interacting particles subject to an external periodic forcing often develop nontrivial collective behavior and self-assembled dynamic patterns. We study emergent phenomena in magnetic granular ensembles suspended at a liquid-air and liquid-liquid interfaces and subjected to a transversal alternating magnetic field. Experiments reveal a new type of nontrivially ordered dynamic self-assembled structures (in particular, ``magnetic snakes'', ``asters'', ``clams'') emerging in such systems in a certain range of excitation parameters. These non-equilibrium dynamic structures emerge as a result of the competition between magnetic and hydrodynamic forces and have complex magnetic ordering. Transition between different self-assembled phases with parameters of external driving magnetic field is observed. I will show that above some frequency threshold magnetic snakes spontaneously break the symmetry of the self-induced surface flows (symmetry breaking instability) and turn into swimmers. Self-induced surface flows symmetry can be also broken in a controlled fashion by introduction of a large bead to a magnetic snake (bead-snake hybrid), that transforms it into a robust self-locomoting entity. Some features of the self-localized structures can be understood in the framework of an amplitude equation for parametric waves coupled to the conservation law equation describing the evolution of the magnetic particle density and the Navier-Stokes equation for hydrodynamic flows.

Markets, Herding and Response to External Information

PubMed Central

Carro, Adrián; Toral, Raúl; San Miguel, Maxi

2015-01-01

We focus on the influence of external sources of information upon financial markets. In particular, we develop a stochastic agent-based market model characterized by a certain herding behavior as well as allowing traders to be influenced by an external dynamic signal of information. This signal can be interpreted as a time-varying advertising, public perception or rumor, in favor or against one of two possible trading behaviors, thus breaking the symmetry of the system and acting as a continuously varying exogenous shock. As an illustration, we use a well-known German Indicator of Economic Sentiment as information input and compare our results with Germany’s leading stock market index, the DAX, in order to calibrate some of the model parameters. We study the conditions for the ensemble of agents to more accurately follow the information input signal. The response of the system to the external information is maximal for an intermediate range of values of a market parameter, suggesting the existence of three different market regimes: amplification, precise assimilation and undervaluation of incoming information. PMID:26204451

Survival After Conservative Management Versus External Beam Radiation Therapy in Elderly Patients With Localized Prostate Cancer

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

Dell'Oglio, Paolo, E-mail: paolo.delloglio@gmail.com; Department of Urology and Division of Experimental Oncology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan; Boehm, Katharina

Purpose: To compare survival in elderly men with clinically localized prostate cancer (PCa) according to treatment type, defined as radiation therapy (RT) with or without androgen deprivation therapy (ADT) versus conservative management (observation). Methods and Materials: In the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database, we identified 23,790 patients aged 80 years or more with clinically localized PCa treated with either RT or observation between 1991 and 2009. Competing risks analyses focused on cancer-specific mortality and other-cause mortality, after accounting for confounders. All analyses were repeated after stratification according to grade (well-differentiated vs moderately differentiated vs poorly differentiated disease), race, andmore » United States region, in patients with no comorbidities and in patients with at least 1 comorbidity. Analyses were repeated within most contemporary patients, namely those treated between 2001 and 2009. Results: Radiation therapy was associated with more favorable cancer-specific mortality rates than observation in patients with moderately differentiated disease (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66-0.94; P=.009) and in patients with poorly differentiated disease (HR 0.58; 95% CI 0.49-0.69; P<.001). Conversely, the benefit of RT was not observed in well-differentiated disease. The benefit of RT was confirmed in black men (HR 0.54; 95% CI 0.35-0.83; P=.004), across all United States regions (all P≤.004), in the subgroups of the healthiest patients (HR 0.67; 95% CI 0.57-0.78; P<.001), in patients with at least 1 comorbidity (HR 0.69; 95% CI 0.56-0.83; P<.001), and in most contemporary patients (HR 0.55; 95% CI 0.46-0.66; P<.001). Conclusions: Radiation therapy seems to be associated with a reduction in the risk of death from PCa relative to observation in elderly patients with clinically localized PCa, except for those with well-differentiated disease.« less

Predictive factors for severe and febrile neutropenia during docetaxel chemotherapy for castration-resistant prostate cancer.

PubMed

Shigeta, Keisuke; Kosaka, Takeo; Yazawa, Satoshi; Yasumizu, Yota; Mizuno, Ryuichi; Nagata, Hirohiko; Shinoda, Kazunobu; Morita, Shinya; Miyajima, Akira; Kikuchi, Eiji; Nakagawa, Ken; Hasegawa, Shintaro; Oya, Mototsugu

2015-06-01

The aim of this study is to identify factors that increase the occurrence of severe neutropenia (SN) and febrile neutropenia (FN) during docetaxel treatment for castration-resistant prostate cancer (CRPC). We retrospectively reviewed 258 courses during the first three cycles among 95 patients. Docetaxel at a dose of 75 mg/m(2) was administered every 3 or 4 weeks. Patient background, laboratory data, and bone scan results were collected to assess predictive factors for SN and FN. We defined SN as an absolute neutrophil count (ANC) of <500/mm(3) and defined FN as an ANC of <1000/mm(3) with a body temperature of >38.3 °C. The mean age of the patients was 72.6 ± 6.4 years and the mean prostate-specific antigen was 135.4 ± 290.9 ng/ml. During the first three courses of treatment, SN occurred in 72.6% of patients and FN occurred in 9.5 % of patients. Univariate analysis demonstrated that age ≥ 75 years (p = 0.002), number of comorbidities ≥ 1.2 (p = 0.008 and p = 0.006) and previous external beam radiation therapy (EBRT) (p = 0.001) were predictive factors for the development of SN or FN. In multivariate analysis, significant predictors of SN or FN were age ≥ 75 years (hazard ratio [HR] 5.77; p = 0.004) and previous EBRT (HR 14.5; p = 0.012). According to the subgroup analysis dividing SN and FN separately, multivariate analysis also revealed that age ≥ 75 years and previous EBRT were also significant predictors for developing SN (HR 5.09; p = 0.023, HR 12.7; p = 0.020, respectively) and for developing FN (HR 5.45; p = 0.042, HR 7.72; p = 0.015, respectively). Patients aged ≥ 75 years and with a history of localized radiation therapy are at higher risk for significant neutropenic events and require closer surveillance.

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

Urushihara, Yusuke; Kobayashi, Junya; Matsumoto, Yoshihisa

Highlights: Black-Right-Pointing-Pointer We investigated the effect of DNA-PK inhibition on DSB repair using fish cells. Black-Right-Pointing-Pointer A radiation sensitive mutant RIC1 strain showed a low level of DNA-PK activity. Black-Right-Pointing-Pointer DNA-PK dysfunction leads defects in HR repair and DNA-PKcs autophosphorylation. Black-Right-Pointing-Pointer DNA-PK dysfunction leads a slight increase in the number of 53BP1 foci after DSBs. Black-Right-Pointing-Pointer DNA-PK dysfunction leads an alternative NHEJ that depends on 53BP1. -- Abstract: Nonhomologous end joining (NHEJ) and homologous recombination (HR) are known as DNA double-strand break (DSB) repair pathways. It has been reported that DNA-PK, a member of PI3 kinase family, promotes NHEJ andmore » aberrant DNA-PK causes NHEJ deficiency. However, in this study, we demonstrate that a wild-type cell line treated with DNA-PK inhibitor and a mutant cell line with dysfunctional DNA-PK showed decreased HR efficiency in fish cells (Medaka, Oryzias latipes). Previously, we reported that the radiation-sensitive mutant RIC1 strain has a defect in the Histone H2AX phosphorylation after {gamma}-irradiation. Here, we showed that a DNA-PK inhibitor, NU7026, treatment resulted in significant reduction in the number of {gamma}H2AX foci after {gamma}-irradiation in wild-type cells, but had no significant effect in RIC1 cells. In addition, RIC1 cells showed significantly lower levels of DNA-PK kinase activity compared with wild-type cells. We investigated NHEJ and HR efficiency after induction of DSBs. Wild-type cells treated with NU7026 and RIC1 cells showed decreased HR efficiency. These results indicated that aberrant DNA-PK causes the reduction in the number of {gamma}H2AX foci and HR efficiency in RIC1 cells. We performed phosphorylated DNA-PKcs (Thr2609) and 53BP1 focus assay after {gamma}-irradiation. RIC1 cells showed significant reduction in the number of phosphorylated DNA-PKcs foci and no deference in the number of 53BP1 foci compared with wild-type cells. These results suggest that low level of DNA-PK activity causes aberrant DNA-PKcs autophosphorylation in RIC1 cells. It is known that 53BP1 is involved in both DNA-PK dependent and independent NHEJ. Therefore we suggest that DNA-PK independent NHEJ repair DSBs under the condition of decreased DNA-PK activity, which causes reduction of HR efficiency.« less

The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions

PubMed Central

Gerelchuluun, Ariungerel; Manabe, Eri; Ishikawa, Takaaki; Sun, Lue; Itoh, Kazuya; Sakae, Takeji; Suzuki, Kenshi; Hirayama, Ryoichi; Asaithamby, Aroumougame; Chen, David J.; Tsuboi, Koji

2017-01-01

The purpose of this study was to identify the roles of non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways in repairing DNA double-strand breaks (DSBs) induced by exposure to high-energy protons and carbon ions (C ions) versus gamma rays in Chinese hamster cells. Two Chinese hamster cell lines, ovary AA8 and lung fibroblast V79, as well as various mutant sublines lacking DNA-PKcs (V3), X-ray repair cross-complementing protein-4 [XRCC4 (XR1), XRCC3 (irs1SF) and XRCC2 (irs1)] were exposed to gamma rays (137Cs), protons (200 MeV; 2.2 keV/μm) and C ions (290 MeV; 50 keV/μm). V3 and XR1 cells lack the NHEJ pathway, whereas irs1 and irs1SF cells lack the HR pathway. After each exposure, survival was measured using a clonogenic survival assay, in situ DSB induction was evaluated by immunocytochemical analysis of histone H2AX phosphorylation at serine 139 (γ-H2AX foci) and chromosome aberrations were examined using solid staining. The findings from this study showed that clonogenic survival clearly depended on the NHEJ and HR pathway statuses, and that the DNA-PKcs−/− cells (V3) were the most sensitive to all radiation types. While protons and γ rays yielded almost the same biological effects, C-ion exposure greatly enhanced the sensitivity of wild-type and HR-deficient cells. However, no significant enhancement of sensitivity in cell killing was seen after C-ion irradiation of NHEJ deficient cells. Decreases in the number of γ-H2AX foci after irradiation occurred more slowly in the NHEJ deficient cells. In particular, V3 cells had the highest number of residual γ-H2AX foci at 24 h after C-ion irradiation. Chromosomal aberrations were significantly higher in both the NHEJ- and HR-deficient cell lines than in wild-type cell lines in response to all radiation types. Protons and gamma rays induced the same aberration levels in each cell line, whereas C ions introduced higher but not significantly different aberration levels. Our results suggest that the NHEJ pathway plays an important role in repairing DSBs induced by both clinical proton and C-ion beams. Furthermore, in C ions the HR pathway appears to be involved in the repair of DSBs to a greater extent compared to gamma rays and protons. PMID:25738894

A Swiss paradox? Higher income inequality of municipalities is associated with lower mortality in Switzerland.

PubMed

Clough-Gorr, Kerri M; Egger, Matthias; Spoerri, Adrian

2015-08-01

It has long been surmised that income inequality within a society negatively affects public health. However, more recent studies suggest there is no association, especially when analyzing small areas. This study aimed to evaluate the effect of income inequality on mortality in Switzerland using the Gini index on municipality level. The study population included all individuals >30 years at the 2000 Swiss census (N = 4,689,545) living in 2,740 municipalities with 35.5 million person-years of follow-up and 456,211 deaths over follow-up. Cox proportional hazard regression models were adjusted for age, gender, marital status, nationality, urbanization, and language region. Results were reported as hazard ratios (HR) with 95% confidence intervals. The mean Gini index across all municipalities was 0.377 (standard deviation 0.062, range 0.202-0.785). Larger cities, high-income municipalities and tourist areas had higher Gini indices. Higher income inequality was consistently associated with lower mortality risk, except for death from external causes. Adjusting for sex, marital status, nationality, urbanization and language region only slightly attenuated effects. In fully adjusted models, hazards of all-cause mortality by increasing Gini index quintile were HR = 0.99 (0.98-1.00), HR = 0.98 (0.97-0.99), HR = 0.95 (0.94-0.96), HR = 0.91 (0.90-0.92) compared to the lowest quintile. The relationship of income inequality with mortality in Switzerland is contradictory to what has been found in other developed high-income countries. Our results challenge current beliefs about the effect of income inequality on mortality on small area level. Further investigation is required to expose the underlying relationship between income inequality and population health.

Divorce and the Onset of Alcohol Use Disorders: A Swedish Population-Based Longitudinal Cohort and Co-Relative Study

PubMed Central

Kendler, Kenneth S.; Larsson Lönn, Sara; Salvatore, Jessica; Sundquist, Jan; Sundquist, Kristina

2017-01-01

Objective To clarify the magnitude and nature of the relationship between divorce and risk for alcohol use disorder (AUD). Method In a population-based Swedish sample of married individuals (n=942,366), we examined the association between divorce or widowhood and risk for first registration for AUD. AUD was assessed using medical, criminal and pharmacy registries. Results Divorce was strongly associated with risk for first AUD onset in both men (HR=5.98, 95% CI, 5.65–6.33) and women (HR=7.29, 6.72–7.91). We estimated the HR for AUD onset given divorce in discordant monozygotic twins to equal 3.45 and 3.62 in men and women, respectively. Divorce was also associated with an AUD recurrence in those with AUD registrations before marriage. Furthermore, widowhood increased risk for AUD in men (HR=3.85, 2.81–5.28) and women (HR=4.10, 2.98–5.64). Among divorced individuals, remarriage was associated with a large decline in AUD in both sexes: males 0.56, 0.62–0.64 and females 0.61, 0.55–0.69. Divorce produced a greater increase in first AUD onset in those with a family history of AUD or with prior externalizing behaviors. Conclusions Spousal loss through divorce or bereavement is associated with a large enduring increased AUD risk. This association likely reflects both causal and non-causal processes. That the AUD status of the spouse alters this association highlights the importance of spouse characteristics for the behavioral health consequences of spousal loss. The pronounced elevation in AUD risk following divorce or widowhood, and the protective effect of remarriage against subsequent AUD, speaks to the profound impact of marriage on problematic alcohol use. PMID:28103713

Causal effect of education on mortality in a quasi-experiment on 1.2 million Swedes.

PubMed

Lager, Anton Carl Jonas; Torssander, Jenny

2012-05-29

In 1949-1962, Sweden implemented a 1-y increase in compulsory schooling as a quasi-experiment. Each year, children in a number of municipalities were exposed to the reform and others were kept as controls, allowing us to test the hypothesis that education is causally related to mortality. We studied all children born between 1943 and 1955, in 900 Swedish municipalities, with control for birth-cohort and area differences. Primary outcome measures are all-cause and cause-specific mortality until the end of 2007. The analyses include 1,247,867 individuals, of whom 92,351 died. We found lower all-cause mortality risk in the experimental group after age 40 [hazard ratio (HR) = 0.96, 95% confidence interval (CI) 0.93-0.99] but not before (HR = 1.03, 95% CI 0.98-1.07) or during the whole follow-up (HR = 0.98, 95% CI 0.95-1.01). After age 40, the experimental group had lower mortality from overall cancer, lung cancer, and accidents. In addition, exposed women had lower mortality from ischemic heart disease, and exposed men lower mortality from overall external causes. In analyses stratified for final educational level, we found lower mortality in the experimental group within the strata that settled for compulsory schooling only (HR = 0.94, 95% CI 0.89-0.99) and compulsory schooling plus vocational training (HR = 0.92, 95% CI 0.88-0.97). Thus, the experimental group had lower mortality from causes known to be related to education. Lower mortality in the experimental group was also found among the least educated, a group that clearly benefited from the reform in terms of educational length. However, all estimates are small and there was no evident impact of the reform on all-cause mortality in all ages.

Factors influencing long-term urinary symptoms following prostate brachytherapy.

PubMed

Stone, Nelson N; Winoker, Jared S; Kaplan, Steven A; Stock, Richard G

2018-05-03

To determine which patient and treatment related factors were associated with increased AUA symptom score (AUASS) in men who presented with minimal symptoms prior to treatment for prostate cancer by permanent seed implantation. Of 1842 men with a minimum follow-up of 5 years (mean 9.4) 1110 (60.3%) had initial AUASS of 0-7 and were treated with BT alone (n=491) or BT with hormone therapy (NHT) and or external beam irradiation (EBRT, n=619). Median prostate volume (PV) was 37 cc. Data was prospectively collected on comorbidities. Initial AUASS was compared to last by student-t test (2-tailed). Freedom from increasing from minimal to moderate or severe symptoms was determined by Kaplan-Meier method with comparisons by log rank and Cox Hazard Rates (HR). The change from pre-treatment score for the minimal, moderate and severe symptom groups was: 3.6 to 7.3 (p<0.001), 11.6 to 11.3 (p=0.426) and 24.1 to 16.9 (p<0.001). For those with minimal symptoms the 10 and 15-year estimates for freedom from worse symptoms were 72.9 and 39.1%, respectively. Cox hazard rates were significant for EBRT boost (HR 1.45, p=0.004), radiation dose > 200 Gy (HR 1.25, p=0.024), hypertension (HR 1.37, p=0.006) and alcohol use (HR 1.46, p=0.001). A substantial number of men with initial low AUASS treated by BT experience worsening urinary symptoms with long-term follow. Use of EBRT, radiation dose, hypertension and alcohol use are risk factors for an increase in urinary symptom score. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Continued Benefit to Androgen Deprivation Therapy for Prostate Cancer Patients Treated With Dose-Escalated Radiation Therapy Across Multiple Definitions of High-Risk Disease

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

Stenmark, Matthew H.; Blas, Kevin; Halverson, Schuyler

2011-11-15

Purpose: To analyze prognostic factors in patients with high-risk prostate cancer treated with dose-escalated external-beam radiation therapy (EBRT) and androgen deprivation (ADT). Methods and Materials: Between 1998 and 2008 at University of Michigan Medical Center, 718 men were consecutively treated with EBRT to at least 75 Gy. Seven definitions of high-risk prostate cancer, applying to 11-33% of patients, were evaluated. Biochemical failure (BF), salvage ADT use, metastatic progression, and prostate cancer-specific mortality (PCSM) were estimated by the Kaplan-Meier method and Cox proportional hazards regression. Results: Each high-risk definition was associated with increased BF (hazard ratio [HR] 2.8-3.9, p < 0.0001),more » salvage ADT use (HR 3.9-6.3, p < 0.0001), metastasis (HR 3.7-6.6, p < 0.0001), and PCSM (HR 3.7-16.2, p < 0.0001). Furthermore, an increasing number of high-risk features predicted worse outcome. Adjuvant ADT yielded significant reductions in both metastases (HR 0.19-0.38, p < 0.001) and PCSM (HR 0.38-0.50, p < 0.05) for all high-risk definitions (with the exception of clinical Stage T3-4 disease) but improved BF only for those with elevated Gleason scores (p < 0.03, HR 0.25-0.48). When treated with ADT and dose-escalated EBRT, patients with Gleason scores 8 to 10, without other high-risk features, had 8-year freedom from BF of 74%, freedom from distant metastases of 93%, and cause-specific survival of 92%, with salvage ADT used in 16% of patients. Conclusion: Adjuvant ADT results in a significant improvement in clinical progression and PCSM across multiple definitions of high-risk disease even with dose-escalated EBRT. There is a subset of patients, characterized by multiple high-risk features or the presence of Gleason Pattern 5, who remain at significant risk for metastasis and PCSM despite current treatment.« less

Association of Patient Age at Gastric Bypass Surgery With Long-term All-Cause and Cause-Specific Mortality.

PubMed

Davidson, Lance E; Adams, Ted D; Kim, Jaewhan; Jones, Jessica L; Hashibe, Mia; Taylor, David; Mehta, Tapan; McKinlay, Rodrick; Simper, Steven C; Smith, Sherman C; Hunt, Steven C

2016-07-01

Bariatric surgery is effective in reducing all-cause and cause-specific long-term mortality. Whether the long-term mortality benefit of surgery applies to all ages at which surgery is performed is not known. To examine whether gastric bypass surgery is equally effective in reducing mortality in groups undergoing surgery at different ages. All-cause and cause-specific mortality rates and hazard ratios (HRs) were estimated from a retrospective cohort within 4 categories defined by age at surgery: younger than 35 years, 35 through 44 years, 45 through 54 years, and 55 through 74 years. Mean follow-up was 7.2 years. Patients undergoing gastric bypass surgery seen at a private surgical practice from January 1, 1984, through December 31, 2002, were studied. Data analysis was performed from June 12, 2013, to September 6, 2015. A cohort of 7925 patients undergoing gastric bypass surgery and 7925 group-matched, severely obese individuals who did not undergo surgery were identified through driver license records. Matching criteria included year of surgery to year of driver license application, sex, 5-year age groups, and 3 body mass index categories. Roux-en-Y gastric bypass surgery. All-cause and cause-specific mortality compared between those undergoing and not undergoing gastric bypass surgery using HRs. Among the 7925 patients who underwent gastric bypass surgery, the mean (SD) age at surgery was 39.5 (10.5) years, and the mean (SD) presurgical body mass index was 45.3 (7.4). Compared with 7925 matched individuals not undergoing surgery, adjusted all-cause mortality after gastric bypass surgery was significantly lower for patients 35 through 44 years old (HR, 0.54; 95% CI, 0.38-0.77), 45 through 54 years old (HR, 0.43; 95% CI, 0.30-0.62), and 55 through 74 years old (HR, 0.50; 95% CI, 0.31-0.79; P < .003 for all) but was not lower for those younger than 35 years (HR, 1.22; 95% CI, 0.82-1.81; P = .34). The lack of mortality benefit in those undergoing gastric bypass surgery at ages younger than 35 years primarily derived from a significantly higher number of externally caused deaths (HR, 2.53; 95% CI, 1.27-5.07; P = .009), particularly among women (HR, 3.08; 95% CI, 1.4-6.7; P = .005). Patients undergoing gastric bypass surgery had a significantly lower age-related increase in mortality than severely obese individuals not undergoing surgery (P = .001). Gastric bypass surgery was associated with improved long-term survival for all patients undergoing surgery at ages older than 35 years, with externally caused deaths only elevated in younger women. Gastric bypass surgery is protective against mortality even for older patients and also reduces the age-related increase in mortality observed in severely obese individuals not undergoing surgery.

[Accidents and violence in childhood and adolescence: risk and protective factors].

PubMed

Martins, Christine Baccarat de Godoy

2013-01-01

Singled out by statistics as the third leading cause of mortality in our country, external causes (accidents and violence) entail a great impact with economic, social and emotional rebound. Knowing the factors related to the event is essential, because it allows identifying and breaking the web that determines morbidity and mortality from external causes. The study aims to analyze the existing publications on the factors associated with accidents and violence, in order to provide theoretical support for professionals in their practices. This is a bibliographical study of the Liliacs, Medline and Scielo databanks. The knowledge of the risk and protection factors discussed in the present study enables subsidize the practice of social actors engaged in transforming the conditions that lead to accidents and violence.

Competing orders in the Hofstadter t -J model

NASA Astrophysics Data System (ADS)

Tu, Wei-Lin; Schindler, Frank; Neupert, Titus; Poilblanc, Didier

2018-01-01

The Hofstadter model describes noninteracting fermions on a lattice in the presence of an external magnetic field. Motivated by the plethora of solid-state phases emerging from electron interactions, we consider an interacting version of the Hofstadter model, including a Hubbard repulsion U . We investigate this model in the large-U limit corresponding to a t -J Hamiltonian with an external (orbital) magnetic field. By using renormalized mean-field theory supplemented by exact diagonalization calculations of small clusters, we find evidence for competing symmetry-breaking phases, exhibiting (possibly coexisting) charge, bond, and superconducting orders. Topological properties of the states are also investigated, and some of our results are compared to related experiments involving ultracold atoms loaded on optical lattices in the presence of a synthetic gauge field.

An experimental investigation of the NASA space shuttle external tank at hypersonic Mach numbers

NASA Technical Reports Server (NTRS)

Wittliff, C. E.

1975-01-01

Pressure and heat transfer tests were conducted simulating flight conditions which the space shuttle external tank will experience prior to break-up. The tests were conducted in the Calspan 48-inch Hypersonic Shock Tunnel and simulated entry conditions for nominal, abort-once-around (AOA), and return to launch site (RTLS) launch occurrences. Surface pressure and heat-transfer-rate distributions were obtained with and without various protuberences (or exterior hardware) on the model at Mach numbers from 15.2 to 17.7 at angles of attack from -15 deg to -180 deg and at several roll angles. The tests were conducted over a Reynolds number range from 1300 to 58,000, based on model length.

Localized and delocalized motion of colloidal particles on a magnetic bubble lattice.

PubMed

Tierno, Pietro; Johansen, Tom H; Fischer, Thomas M

2007-07-20

We study the motion of paramagnetic colloidal particles placed above magnetic bubble domains of a uniaxial garnet film and driven through the lattice by external magnetic field modulation. An external tunable precessing field propels the particles either in localized orbits around the bubbles or in superdiffusive or ballistic motion through the bubble array. This motion results from the interplay between the driving rotating signal, the viscous drag force and the periodic magnetic energy landscape. We explain the transition in terms of the incommensurability between the transit frequency of the particle through a unit cell and the modulation frequency. Ballistic motion dynamically breaks the symmetry of the array and the phase locked particles follow one of the six crystal directions.

Cracks dynamics under tensional stress - a DEM approach

NASA Astrophysics Data System (ADS)

Debski, Wojciech; Klejment, Piotr; Kosmala, Alicja; Foltyn, Natalia; Szpindler, Maciej

2017-04-01

Breaking and fragmentation of solid materials is an extremely complex process involving scales ranging from an atomic scale (breaking inter-atomic bounds) up to thousands of kilometers in case of catastrophic earthquakes (in energy scale it ranges from single eV up to 1024 J). Such a large scale span of breaking processes opens lot of questions like, for example, scaling of breaking processes, existence of factors controlling final size of broken area, existence of precursors, dynamics of fragmentation, to name a few. The classical approach to study breaking process at seismological scales, i.e., physical processes in earthquake foci, is essentially based on two factors: seismic data (mostly) and the continuum mechanics (including the linear fracture mechanics). Such approach has been gratefully successful in developing kinematic (first) and dynamic (recently) models of seismic rupture and explaining many of earthquake features observed all around the globe. However, such approach will sooner or latter face a limitation due to a limited information content of seismic data and inherit limitations of the fracture mechanics principles. A way of avoiding this expected limitation is turning an attention towards a well established in physics method of computational simulations - a powerful branch of contemporary physics. In this presentation we discuss preliminary results of analysis of fracturing dynamics under external tensional forces using the Discrete Element Method approach. We demonstrate that even under a very simplified tensional conditions, the fragmentation dynamics is a very complex process, including multi-fracturing, spontaneous fracture generation and healing, etc. We also emphasis a role of material heterogeneity on the fragmentation process.

The chiral magnetic effect and chiral symmetry breaking in SU(3) quenched lattice gauge theory

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

Braguta, V. V., E-mail: braguta@mail.ru; Buividovich, P. V., E-mail: buividovich@itep.ru; Kalaydzhyan, T., E-mail: tigran.kalaydzhyan@desy.de

2012-04-15

We study some properties of the non-Abelian vacuum induced by strong external magnetic field. We perform calculations in the quenched SU(3) lattice gauge theory with tadpole-improved Luescher-Weisz action and chirally invariant lattice Dirac operator. The following results are obtained: The chiral symmetry breaking is enhanced by the magnetic field. The chiral condensate depends on the strength of the applied field as a power function with exponent {nu} = 1.6 {+-} 0.2. There is a paramagnetic polarization of the vacuum. The corresponding susceptibility and other magnetic properties are calculated and compared with the theoretical estimations. There are nonzero local fluctuations ofmore » the chirality and electromagnetic current, which grow with the magnetic field strength. These fluctuations can be a manifestation of the Chiral Magnetic Effect.« less

A model to study finite-size and magnetic effects on the phase transition of a fermion interacting system

NASA Astrophysics Data System (ADS)

Corrêa, Emerson B. S.; Linhares, César A.; Malbouisson, Adolfo P. C.

2018-03-01

We present a model to study the effects from external magnetic field, chemical potential and finite size on the phase structures of a massive four- and six-fermion interacting systems. These effects are introduced by a method of compactification of coordinates, a generalization of the standard Matsubara prescription. Through the compactification of the z-coordinate and of imaginary time, we describe a heated system with the shape of a film of thickness L, at temperature β-1 undergoing first- or second-order phase transition. We have found a strong dependence of the temperature transition on the coupling constants λ and η. Besides inverse magnetic catalysis and symmetry breaking for both kinds of transition, we have found an inverse symmetry breaking phenomenon with respect to first-order phase transition.

Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (the ASCENDE-RT Trial): An Analysis of Survival Endpoints for a Randomized Trial Comparing a Low-Dose-Rate Brachytherapy Boost to a Dose-Escalated External Beam Boost for High- and Intermediate-risk Prostate Cancer

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

Morris, W. James, E-mail: jmorris@bccancer.bc.ca; BC Cancer Agency–Vancouver Centre, Vancouver, British Columbia; Tyldesley, Scott

Purpose: To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for intermediate- and high-risk prostate cancer. Methods and Materials: ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398more » trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years. Results: In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis [MVA] hazard ratio [HR] 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62). Conclusions: Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.« less

Impact of physical fitness and biometric data on the quality of external chest compression: a randomised, crossover trial

PubMed Central

2011-01-01

Background During circulatory arrest, effective external chest compression (ECC) is a key element for patient survival. In 2005, international emergency medical organisations changed their recommended compression-ventilation ratio (CVR) from 15:2 to 30:2 to acknowledge the vital importance of ECC. We hypothesised that physical fitness, biometric data and gender can influence the quality of ECC. Furthermore, we aimed to determine objective parameters of physical fitness that can reliably predict the quality of ECC. Methods The physical fitness of 30 male and 10 female healthcare professionals was assessed by cycling and rowing ergometry (focussing on lower and upper body, respectively). During ergometry, continuous breath-by-breath ergospirometric measurements and heart rate (HR) were recorded. All participants performed two nine-minute sequences of ECC on a manikin using CVRs of 30:2 and 15:2. We measured the compression and decompression depths, compression rates and assessed the participants' perception of exhaustion and comfort. The median body mass index (BMI; male 25.4 kg/m2 and female 20.4 kg/m2) was used as the threshold for subgroup analyses of participants with higher and lower BMI. Results HR during rowing ergometry at 75 watts (HR75) correlated best with the quality of ECC (r = -0.57, p < 0.05). Participants with a higher BMI and better physical fitness performed better and showed less fatigue during ECC. These results are valid for the entire cohort, as well as for the gender-based subgroups. The compressions of female participants were too shallow and more rapid (mean compression depth was 32 mm and rate was 117/min with a CVR of 30:2). For participants with a lower BMI and higher HR75, the compression depth decreased over time, beginning after four minutes for the 15:2 CVR and after three minutes for the 30:2 CVR. Although found to be more exhausting, a CVR of 30:2 was rated as being more comfortable. Conclusion The quality of the ECC and fatigue can both be predicted by BMI and physical fitness. An evaluation focussing on the upper body may be a more valid predictor of ECC quality than cycling based tests. Our data strongly support the recommendation to relieve ECC providers after two minutes. PMID:22053981

Zimbabwe: Internally or Externally Driven Meltdown

DTIC Science & Technology

2010-06-01

front of parliament” were removed by “riot police us[ing] dogs , batons and tear gas.”202 Though the civil society strikes and protests in this period...Mugabe recognized ZAPU’s unwillingness to be muzzled in their opposition of his policies. He then moved to marginalize ZAPU, even in its own home...similar response to other protests, with police breaking up any protests using dogs , batons, or clubs as necessary to disperse protesters whether they

Development and validation of a gene expression-based signature to predict distant metastasis in locoregionally advanced nasopharyngeal carcinoma: a retrospective, multicentre, cohort study.

PubMed

Tang, Xin-Ran; Li, Ying-Qin; Liang, Shao-Bo; Jiang, Wei; Liu, Fang; Ge, Wen-Xiu; Tang, Ling-Long; Mao, Yan-Ping; He, Qing-Mei; Yang, Xiao-Jing; Zhang, Yuan; Wen, Xin; Zhang, Jian; Wang, Ya-Qin; Zhang, Pan-Pan; Sun, Ying; Yun, Jing-Ping; Zeng, Jing; Li, Li; Liu, Li-Zhi; Liu, Na; Ma, Jun

2018-03-01

Gene expression patterns can be used as prognostic biomarkers in various types of cancers. We aimed to identify a gene expression pattern for individual distant metastatic risk assessment in patients with locoregionally advanced nasopharyngeal carcinoma. In this multicentre, retrospective, cohort analysis, we included 937 patients with locoregionally advanced nasopharyngeal carcinoma from three Chinese hospitals: the Sun Yat-sen University Cancer Center (Guangzhou, China), the Affiliated Hospital of Guilin Medical University (Guilin, China), and the First People's Hospital of Foshan (Foshan, China). Using microarray analysis, we profiled mRNA gene expression between 24 paired locoregionally advanced nasopharyngeal carcinoma tumours from patients at Sun Yat-sen University Cancer Center with or without distant metastasis after radical treatment. Differentially expressed genes were examined using digital expression profiling in a training cohort (Guangzhou training cohort; n=410) to build a gene classifier using a penalised regression model. We validated the prognostic accuracy of this gene classifier in an internal validation cohort (Guangzhou internal validation cohort, n=204) and two external independent cohorts (Guilin cohort, n=165; Foshan cohort, n=158). The primary endpoint was distant metastasis-free survival. Secondary endpoints were disease-free survival and overall survival. We identified 137 differentially expressed genes between metastatic and non-metastatic locoregionally advanced nasopharyngeal carcinoma tissues. A distant metastasis gene signature for locoregionally advanced nasopharyngeal carcinoma (DMGN) that consisted of 13 genes was generated to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter distant metastasis-free survival (hazard ratio [HR] 4·93, 95% CI 2·99-8·16; p<0·0001), disease-free survival (HR 3·51, 2·43-5·07; p<0·0001), and overall survival (HR 3·22, 2·18-4·76; p<0·0001) than patients with low-risk scores. The prognostic accuracy of DMGN was validated in the internal and external cohorts. Furthermore, among patients with low-risk scores in the combined training and internal cohorts, concurrent chemotherapy improved distant metastasis-free survival compared with those patients who did not receive concurrent chemotherapy (HR 0·40, 95% CI 0·19-0·83; p=0·011), whereas patients with high-risk scores did not benefit from concurrent chemotherapy (HR 1·03, 0·71-1·50; p=0·876). This was also validated in the two external cohorts combined. We developed a nomogram based on the DMGN and other variables that predicted an individual's risk of distant metastasis, which was strengthened by adding Epstein-Barr virus DNA status. The DMGN is a reliable prognostic tool for distant metastasis in patients with locoregionally advanced nasopharyngeal carcinoma and might be able to predict which patients benefit from concurrent chemotherapy. It has the potential to guide treatment decisions for patients at different risk of distant metastasis. The National Natural Science Foundation of China, the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period, the Natural Science Foundation of Guang Dong Province, the National Key Research and Development Program of China, the Innovation Team Development Plan of the Ministry of Education, the Health & Medical Collaborative Innovation Project of Guangzhou City, China, and the Program of Introducing Talents of Discipline to Universities. Copyright © 2018 Elsevier Ltd. All rights reserved.

Quadrilinear CCD sensors for the multispectral channel of spaceborne imagers

NASA Astrophysics Data System (ADS)

Materne, Alex; Gili, Bruno; Laubier, David; Gimenez, Thierry

2001-12-01

The PLEIADES-HR Earth Observation satellites will combine a high resolution panchromatic channel -- 0.7 m at nadir -- and a multispectral channel allowing a 2.8 m resolution. This paper presents the main specifications, design and performances of a 52 microns pitch quadrilinear CCD sensor developed by ATMEL under CNES contract, for the multispectral channel of the PLEIADES-HR instrument. The monolithic CCD device includes four lines of 1500 pixels, each line dedicated to a narrow spectral band within blue to near infra red spectrum. The design of the photodiodes and CCD registers, with larger size than those developed up to now for CNES spaceborne imagers, needed some specific structures to break the large equipotential areas where charge do not flow properly. Results are presented on the options which were experimented to improve sensitivity, maintain transfer efficiency and reduce power dissipation. The four spectral bands are achieved by four stripe filters made by SAGEM-REOSC PRODUCTS on a glass substrate, to be assembled on the sensor window. Line to line spacing on the silicon die takes into account the results of straylight analysis. A mineral layer, with high optical absorption performances is deposited between photosensitive lines to further reduce straylight.

Theory of vibratory mobilization and break-up of non-wetting fluids entrapped in pore constrictions

NASA Astrophysics Data System (ADS)

Beresnev, I.; Li, W.; Vigil, D.

2006-12-01

Quantitative dynamics of a non-wetting (e. g., NAPL) ganglion entrapped in a pore constriction and subjected to vibrations can be approximated by the equation of motion of an oscillator moving under the effect of the external pressure gradient, inertial oscillatory force, and restoring capillary force. The solution of the equation provides the conditions under which the droplet experiences forced oscillations without being mobilized or is liberated upon the acceleration of the wall exceeding an "unplugging" threshold. This solution provides a quantitative tool for the estimation of the parameters of vibratory fields needed to liberate entrapped non-wetting fluids. For typical pore sizes encountered in reservoirs and aquifers, wall accelerations must exceed at least several m/sec2 and even higher levels to mobilize the droplets of NAPL; however, in the populations of ganglia entrapped in natural porous environments, many may reside very near their mobilization thresholds and may be mobilized by extremely low accelerations as well. For given acceleration, lower seismic frequencies are more efficient. The ganglia may also break up into smaller pieces when passing through pore constrictions. The snap-off is governed by the geometry only; for constrictions with sinusoidal profile (spatial wavelength of L and maximum and minimum radii of rmax and rmin, the break-up occurs if L > 2π(rmin rmax)1/2. Computational fluid dynamics shows the details of the break-up process.

The highest-ranking rooster has priority to announce the break of dawn.

PubMed

Shimmura, Tsuyoshi; Ohashi, Shosei; Yoshimura, Takashi

2015-07-23

The "cock-a-doodle-doo" crowing of roosters, which symbolizes the break of dawn in many cultures, is controlled by the circadian clock. When one rooster announces the break of dawn, others in the vicinity immediately follow. Chickens are highly social animals, and they develop a linear and fixed hierarchy in small groups. We found that when chickens were housed in small groups, the top-ranking rooster determined the timing of predawn crowing. Specifically, the top-ranking rooster always started to crow first, followed by its subordinates, in descending order of social rank. When the top-ranking rooster was physically removed from a group, the second-ranking rooster initiated crowing. The presence of a dominant rooster significantly reduced the number of predawn crows in subordinates. However, the number of crows induced by external stimuli was independent of social rank, confirming that subordinates have the ability to crow. Although the timing of subordinates' predawn crowing was strongly dependent on that of the top-ranking rooster, free-running periods of body temperature rhythms differed among individuals, and crowing rhythm did not entrain to a crowing sound stimulus. These results indicate that in a group situation, the top-ranking rooster has priority to announce the break of dawn, and that subordinate roosters are patient enough to wait for the top-ranking rooster's first crow every morning and thus compromise their circadian clock for social reasons.

Early Adolescent Friendship Selection Based on Externalizing Behavior: the Moderating Role of Pubertal Development. The SNARE Study.

PubMed

Franken, Aart; Prinstein, Mitchell J; Dijkstra, Jan Kornelis; Steglich, Christian E G; Harakeh, Zeena; Vollebergh, Wilma A M

2016-11-01

This study examined friendship (de-)selection processes in early adolescence. Pubertal development was examined as a potential moderator. It was expected that pubertal development would be associated with an increased tendency for adolescents to select their friends based on their similarities in externalizing behavior engagement (i.e., delinquency, alcohol use, and tobacco use). Data were used from the first three waves of the SNARE (Social Network Analysis of Risk behavior in Early adolescence) study (N = 1144; 50 % boys; M age  = 12.7; SD = 0.47), including students who entered the first year of secondary school. The hypothesis was tested using Stochastic Actor-Based Modeling in SIENA. While taking the network structure into account, and controlling for peer influence effects, the results supported this hypothesis. Early adolescents with higher pubertal development were as likely as their peers to select friends based on similarity in externalizing behavior and especially likely to remain friends with peers who had a similar level of externalizing behavior, and thus break friendship ties with dissimilar friends in this respect. As early adolescents are actively engaged in reorganizing their social context, adolescents with a higher pubertal development are especially likely to lose friendships with peers who do not engage in externalizing behavior, thus losing an important source of adaptive social control (i.e., friends who do not engage in externalizing behavior).

High Speed Modulation, Beam Steering and Control of High Power Diode Lasers

DTIC Science & Technology

2000-03-03

designing the interactive simulator in such a way that the user will be able to probe the system and change parameters on the fly. Pull -down menus will...AR and HR coatings, beam splitters, external cavities, etc) can be built and accessed via pull -down menus within an optical systems graphical GUI...supported in part by the National Science Foundation’s GOALI program under grant number DM59811466 and AFOSR under contract number F49620-97-1-0002 and

Fuel magnetization without external field coils (AutoMag)

NASA Astrophysics Data System (ADS)

Slutz, Stephen; Jennings, Christopher; Awe, Thomas; Shipley, Gabe; Lamppa, Derek; McBride, Ryan

2016-10-01

Magnetized Liner Inertial Fusion (MagLIF) has produced fusion-relevant plasma conditions on the Z accelerator where the fuel was magnetized using external field coils. We present a novel concept that does not need external field coils. This concept (AutoMag) magnetizes the fuel during the early part of the drive current by using a composite liner with helical conduction paths separated by insulating material. The drive is designed so the current rises slowly enough to avoid electrical breakdown of the insulators until a sufficiently strong magnetic field is established. Then the current rises more quickly, which causes the insulators to break down allowing the drive current to follow an axial path and implode the liner. Low inductance magnetically insulated power feeds can be used with AutoMag to increase the drive current without interfering with diagnostic access. Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin Company, for the United States Department of Energy's National Nuclear Security Administration under contract DE-AC04-94AL85000.

Swimming in external fields

NASA Astrophysics Data System (ADS)

Stark, Holger

2016-11-01

Microswimmers move autonomously but are subject to external fields, which influence their swimming path and their collective dynamics. With three concrete examples we illustrate swimming in external fields and explain the methodology to treat it. First, an active Brownian particle shows a conventional sedimentation profile in a gravitational field but with increased sedimentation length and some polar order along the vertical. Bottom-heavy swimmers are able to invert the sedimentation profile. Second, active Brownian particles interacting by hydrodynamic flow fields in a three-dimensional harmonic trap can spontaneously break the isotropic symmetry. They develop polar order, which one can describe by mean-field theory reminiscent to Weiss theory of ferromagnetism, and thereby pump fluid. Third, a single microswimmer shows interesting non-linear dynamics in Poiseuille flow including swinging and tumbling trajectories. For pushers, hydrodynamic interactions with bounding surfaces stabilize either straight swimming against the flow or tumbling close to the channel wall, while pushers always move on a swinging trajectory with a specific amplitude as limit cycle.

Hadronic Lorentz violation in chiral perturbation theory including the coupling to external fields

NASA Astrophysics Data System (ADS)

Kamand, Rasha; Altschul, Brett; Schindler, Matthias R.

2018-05-01

If any violation of Lorentz symmetry exists in the hadron sector, its ultimate origins must lie at the quark level. We continue the analysis of how the theories at these two levels are connected, using chiral perturbation theory. Considering a 2-flavor quark theory, with dimension-4 operators that break Lorentz symmetry, we derive a low-energy theory of pions and nucleons that is invariant under local chiral transformations and includes the coupling to external fields. The pure meson and baryon sectors, as well as the couplings between them and the couplings to external electromagnetic and weak gauge fields, contain forms of Lorentz violation which depend on linear combinations of quark-level coefficients. In particular, at leading order the electromagnetic couplings depend on the very same combinations as appear in the free particle propagators. This means that observations of electromagnetic processes involving hadrons—such as vacuum Cerenkov radiation, which may be allowed in Lorentz-violating theories—can only reliably constrain certain particular combinations of quark coefficients.

Depressive Symptoms and Externalizing Behaviors among Hispanic Immigrant Adolescents: Examining Longitudinal Effects of Cultural Stress

PubMed Central

Cano, Miguel Ángel; Schwartz, Seth J.; Castillo, Linda G.; Romero, Andrea J.; Huang, Shi; Lorenzo-Blanco, Elma I.; Unger, Jennifer B.; Zamboanga, Byron L.; Des Rosiers, Sabrina E.; Baezconde-Garbanati, Lourdes; Lizzi, Karina M.; Soto, Daniel W.; Oshri, Assaf; Villamar, Juan Andres; Pattarroyo, Monica; Szapocznik, José

2015-01-01

This study examined longitudinal effects of cultural stress (a latent factor comprised of bicultural stress, ethnic discrimination, and negative context of reception) on depressive symptoms and a range of externalizing behaviors among recently (≤5 years in the U.S. at baseline) immigrated Hispanic adolescents. A sample of 302 adolescents (53% boys; mean age 14.51 years) completed baseline measures of perceived ethnic discrimination, bicultural stress, and perceived negative context of reception; and outcome measures of depressive symptoms, cigarette smoking, alcohol use, aggressive behavior, and rule-breaking behavior six months post-baseline. A path analysis indicated that higher cultural stress scores predicted higher levels of all outcomes. These effects were consistent across genders, but varied by study site. Specifically, higher cultural stress scores increased depressive symptoms among participants in Miami, but not in Los Angeles. Findings suggest that cultural stress is a clinically relevant predictor of depressive symptoms and externalizing behaviors among Hispanic immigrant adolescents. PMID:25899132

Increasing potential predictability of Indian Summer monsoon active and break spells

NASA Astrophysics Data System (ADS)

Mani, N. J.; Goswami, B.

2009-12-01

An understanding of the limit on potential predictability is crucial for developing appropriate tools for extended range prediction of active/break spells of Indian summer monsoon (ISM). The global low frequency changes in climate modulate the annual cycle of the ISM and can influence the intrinsic predictability limit of the ISM intraseasonal oscillations (ISOs). Using 104 year (1901-2004) long daily rainfall data, the change in potential predictability of active and break spells are estimated by an empirical method. Using an ISO index based on 10-90 day filtered precipitation, Goswami and Xavier (2003)showed that the monsoon breaks are intrinsically more predictable (20-25 days) than the active conditions (10-15 days. In the present study, employing the same method in 15 year sliding windows, we found that the potential predictability of both active and break spells have undergone a rapid increase during the recent three decades. The potential predictability of active spells has shown an increase from 1 week to 2 weeks while that for break spells increased from 2 weeks to 3 weeks. This result is interesting and intriguing in the backdrop of recent finding that the potential predictability of monsoon weather has decreased substantially over the same period compared to earlier decades due to increased potential instability of the atmosphere. The possible role of internal dynamics and external forcing in producing this change has been explored. The variance among peak active/break conditions shows a steady decrease over the years, indicating a lesser event to event variability in the magnitude of ISO peak phases in recent years. The ISO predictability may be closely linked to the error energy cascading from the synoptic scales and the interaction between these scales. Computation of nonlinear kinetic energy exchange between synoptic and ISO scales in frequency domain, also support the notion of ineffectual influence of synoptic scale errors on the ISO scale.Ref: Goswami, B N and P K Xavier, 2003,GRL. 30(18), 1966, doi:10.1029/2003GL017,810, 2003. Fig 1. Change in potential predictability of rainfall ISO through a 15 year sliding window. a) potential predictability for evolution from active to break b) potential predictability for evolution from break to active.

Proteome analysis of Norway maple (Acer platanoides L.) seeds dormancy breaking and germination: influence of abscisic and gibberellic acids

PubMed Central

Pawłowski, Tomasz A

2009-01-01

Background Seed dormancy is controlled by the physiological or structural properties of a seed and the external conditions. It is induced as part of the genetic program of seed development and maturation. Seeds with deep physiological embryo dormancy can be stimulated to germinate by a variety of treatments including cold stratification. Hormonal imbalance between germination inhibitors (e.g. abscisic acid) and growth promoters (e.g. gibberellins) is the main cause of seed dormancy breaking. Differences in the status of hormones would affect expression of genes required for germination. Proteomics offers the opportunity to examine simultaneous changes and to classify temporal patterns of protein accumulation occurring during seed dormancy breaking and germination. Analysis of the functions of the identified proteins and the related metabolic pathways, in conjunction with the plant hormones implicated in seed dormancy breaking, would expand our knowledge about this process. Results A proteomic approach was used to analyse the mechanism of dormancy breaking in Norway maple seeds caused by cold stratification, and the participation of the abscisic (ABA) and gibberellic (GA) acids. Forty-four proteins showing significant changes were identified by mass spectrometry. Of these, eight spots were identified as water-responsive, 18 spots were ABA- and nine GA-responsive and nine spots were regulated by both hormones. The classification of proteins showed that most of the proteins associated with dormancy breaking in water were involved in protein destination. Most of the ABA- and GA-responsive proteins were involved in protein destination and energy metabolism. Conclusion In this study, ABA was found to mostly down-regulate proteins whereas GA up-regulated proteins abundance. Most of the changes were observed at the end of stratification in the germinated seeds. This is the most active period of dormancy breaking when seeds pass from the quiescent state to germination. Seed dormancy breaking involves proteins of various processes but the proteasome proteins, S-adenosylmethionine synthetase, glycine-rich RNA binding protein, ABI3-interacting protein 1, EF-2 and adenosylhomocysteinase are of particular importance. The effect of exogenously applied hormones was not a determining factor for total inhibition (ABA) or stimulation (GA) of Norway maple seed dormancy breaking and germination but proteomic data has proven these hormones play a role. PMID:19413897

Proteome analysis of Norway maple (Acer platanoides L.) seeds dormancy breaking and germination: influence of abscisic and gibberellic acids.

PubMed

Pawłowski, Tomasz A

2009-05-04

Seed dormancy is controlled by the physiological or structural properties of a seed and the external conditions. It is induced as part of the genetic program of seed development and maturation. Seeds with deep physiological embryo dormancy can be stimulated to germinate by a variety of treatments including cold stratification. Hormonal imbalance between germination inhibitors (e.g. abscisic acid) and growth promoters (e.g. gibberellins) is the main cause of seed dormancy breaking. Differences in the status of hormones would affect expression of genes required for germination. Proteomics offers the opportunity to examine simultaneous changes and to classify temporal patterns of protein accumulation occurring during seed dormancy breaking and germination. Analysis of the functions of the identified proteins and the related metabolic pathways, in conjunction with the plant hormones implicated in seed dormancy breaking, would expand our knowledge about this process. A proteomic approach was used to analyse the mechanism of dormancy breaking in Norway maple seeds caused by cold stratification, and the participation of the abscisic (ABA) and gibberellic (GA) acids. Forty-four proteins showing significant changes were identified by mass spectrometry. Of these, eight spots were identified as water-responsive, 18 spots were ABA- and nine GA-responsive and nine spots were regulated by both hormones. The classification of proteins showed that most of the proteins associated with dormancy breaking in water were involved in protein destination. Most of the ABA- and GA-responsive proteins were involved in protein destination and energy metabolism. In this study, ABA was found to mostly down-regulate proteins whereas GA up-regulated proteins abundance. Most of the changes were observed at the end of stratification in the germinated seeds. This is the most active period of dormancy breaking when seeds pass from the quiescent state to germination. Seed dormancy breaking involves proteins of various processes but the proteasome proteins, S-adenosylmethionine synthetase, glycine-rich RNA binding protein, ABI3-interacting protein 1, EF-2 and adenosylhomocysteinase are of particular importance. The effect of exogenously applied hormones was not a determining factor for total inhibition (ABA) or stimulation (GA) of Norway maple seed dormancy breaking and germination but proteomic data has proven these hormones play a role.

Analysis of heart rate deflection points to predict the anaerobic threshold by a computerized method.

PubMed

Marques-Neto, Silvio R; Maior, Alex S; Maranhão Neto, Geraldo A; Santos, Edil L

2012-07-01

Many studies have used the heart rate deflection points (HRDPs) during incremental exercise tests, because of their strong correlation with the anaerobic threshold. The aim of this study was to evaluate the profile of the HRDPs identified by a computerized method and compare them with ventilatory and lactate thresholds. Twenty-four professional soccer players (age, 22 ± 5 years; body mass, 74 ± 7 kg; height 177 ± 7 cm) volunteered for the study. The subjects completed a Bruce-protocol incremental treadmill exercise test to volitional fatigue. Heart rate (HR) and alveolar gas exchange were recorded continuously at ≥1 Hz during exercise testing. Subsequently, the time course of the HR was fit by a computer algorithm, and a set of lines yielding the lowest pooled residual sum of squares was chosen as the best fit. This procedure defined 2 HRDPs (HRDP1 and HRDP2). The HR break points averaged 43.9 ± 5.9 and 89.7 ± 7.5% of the VO2peak. The HRDP1 showed a poor correlation with ventilatory threshold (VT; r = 0.50), but HRDP2 was highly correlated to the respiratory compensation (RC) point (r = 0.98). Neither HRDP1 nor HRDP2 was correlated with LT1 (at VO2 = 2.26 ± 0.72 L·min(-1); r = 0.26) or LT2 (2.79 ± 0.59 L·min(-1); r = 0.49), respectively. LT1 and LT2 also were not well correlated with VT (2.93 ± 0.68 L·min(-1); r = 0.20) or RC (3.82 ± 0.60 L·min(-1); r = 0.58), respectively. Although the HR deflection points were not correlated to LT, HRDP2 could be identified in all the subjects and was strongly correlated with RC, consistent with a relationship to cardiorespiratory fatigue and endurance performance.

Validity of a basketball-specific complex test in female professional players.

PubMed

Schwesig, René; Hermassi, Souhail; Lauenroth, Andreas; Laudner, Kevin; Koke, Alexander; Bartels, Thomas; Delank, Stefan; Schulze, Stephan

2018-06-01

The purpose of this study was to assess the validity of a new basketball-specific complex test (BBCT) based on the ascertained match performance.Fourteen female professional basketball players (ages: 23.4 ± 1.8 years) performed the BBCT and a treadmill test (TT) at the beginning of pre-season training. Lactate, heart rate (HR), time, shooting precision and number of errors were measured during the four test sequences of the BBCT (short distance sprinting with direction changes, with and without a ball; fast break; lay-up parcours; sprint endurance test). In addition, lactate threshold (LT) and HR were assessed at selected times throughout the TT and the BBCT and over 6 (TT) or 10 (BBCT) minutes after the tests. The match performance score (mps) was calculated on specific parameters (e. g. points) collected during all matches during the subsequent season (22 matches). The mps served as the "gold standard" within the validation process for the BBCT and the TT.TT parameters demonstrated an explained variance (EV) between 0 % (HR recovery) and 11 % (running speed at 6 mmol/l LT). The EV from the BBCT was higher and ranged from 0 % (HR recovery 6 minutes after end of exercise) to 28 % (sprint endurance test after 8 of 10 sprints). Ten out of 21 BBCT parameters (48 %) and 2 out of 5 TT parameters (40 %) demonstrated an EV higher than 10 %. Average EV for all parameters was 12 % (BBCT) and 6 % (TT), respectively. The BBCT had a higher validity than the TT for predicting match performance. These findings suggest that coaches and scientists should consider using the BBCT testing protocol to estimate the match performance abilities of elite female players. © Georg Thieme Verlag KG Stuttgart · New York.

HOXC10 Expression Supports the Development of Chemotherapy Resistance by Fine Tuning DNA Repair in Breast Cancer Cells.

PubMed

Sadik, Helen; Korangath, Preethi; Nguyen, Nguyen K; Gyorffy, Balazs; Kumar, Rakesh; Hedayati, Mohammad; Teo, Wei Wen; Park, Sunju; Panday, Hardik; Munoz, Teresa Gonzalez; Menyhart, Otilia; Shah, Nilay; Pandita, Raj K; Chang, Jenny C; DeWeese, Theodore; Chang, Howard Y; Pandita, Tej K; Sukumar, Saraswati

2016-08-01

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR. ©2016 American Association for Cancer Research.

Forkhead-Associated Domain of Yeast Xrs2, a Homolog of Human Nbs1, Promotes Nonhomologous End Joining Through Interaction With a Ligase IV Partner Protein, Lif1

PubMed Central

Matsuzaki, Kenichiro; Shinohara, Akira; Shinohara, Miki

2008-01-01

DNA double-strand breaks (DSB) are repaired through two different pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ). Yeast Xrs2, a homolog of human Nbs1, is a component of the Mre11-Rad50-Xrs2 (MRX) complex required for both HR and NHEJ. Previous studies showed that the N-terminal forkhead-associated (FHA) domain of Xrs2/Nbs1 in yeast is not involved in HR, but is likely to be in NHEJ. In this study, we showed that the FHA domain of Xrs2 plays a critical role in efficient DSB repair by NHEJ. The FHA domain of Xrs2 specifically interacts with Lif1, a component of the ligase IV complex, Dnl4-Nej1-Lif1 (DNL). Lif1, which is phosphorylated in vivo, contains two Xrs2-binding regions. Serine 383 of Lif1 plays an important role in the interaction with Xrs2 as well as in NHEJ. Interestingly, the phospho-mimetic substitutions of serine 383 enhance the NHEJ activity of Lif1. Our results suggest that the phosphorylation of Lif1 at serine 383 is recognized by the Xrs2 FHA domain, which in turn may promote recruitment of the DNL complex to DSB for NHEJ. The interaction between Xrs2 and Lif1 through the FHA domain is conserved in humans; the FHA domain Nbs1 interacts with Xrcc4, a Lif1 homolog of human. PMID:18458108

Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs.

PubMed

Berte, Nancy; Piée-Staffa, Andrea; Piecha, Nadine; Wang, Mengwan; Borgmann, Kerstin; Kaina, Bernd; Nikolova, Teodora

2016-11-01

Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O 6 -chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665-78. ©2016 AACR. ©2016 American Association for Cancer Research.

Effects of depletion of dihydropyrimidine dehydrogenase on focus formation and RPA phosphorylation.

PubMed

Someya, Masanori; Sakata, Koh-ichi; Matsumoto, Yoshihisa; Tauchi, Hiroshi; Kai, Masahiro; Hareyama, Masato; Fukushima, Masakazu

2012-01-01

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell-killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization.

Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

PubMed

Kawano, Ken-Ichi; Umemura, Kazuo

2013-05-01

The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function. Copyright © 2012 John Wiley & Sons, Ltd.

Observation of backscattering-immune chiral electromagnetic modes without time reversal breaking.

PubMed

Chen, Wen-Jie; Hang, Zhi Hong; Dong, Jian-Wen; Xiao, Xiao; Wang, He-Zhou; Chan, C T

2011-07-08

A strategy is proposed to realize robust transport in a time reversal invariant photonic system. Using numerical simulation and a microwave experiment, we demonstrate that a chiral guided mode in the channel of a three-dimensional dielectric layer-by-layer photonic crystal is immune to the scattering of a square patch of metal or dielectric inserted to block the channel. The chirality based robust transport can be realized in nonmagnetic dielectric materials without any external field.

A reciprocity formulation for the EM scattering by an obstacle within a large open cavity

NASA Technical Reports Server (NTRS)

Pathak, Prabhakar H.; Burkholder, Robert J.

1993-01-01

A formulation based on a generalized reciprocity theorem is developed for analyzing the external high frequency EM scattering by a complex obstacle inside a relatively arbitrary open-ended waveguide cavity when it is illuminated by an external source. This formulation is also extended to include EM fields whose time dependence may be nonperiodic. A significant advantage of this formulation is that it allows one to break up the analysis into two independent parts; one deals with the waveguide cavity shape alone and the other with the obstacle alone. The external scattered field produced by the obstacle (in the presence of the waveguide cavity structure) is given in terms of a generalized reciprocity integral over a surface S(T) corresponding to the interior waveguide cavity cross section located conveniently but sufficiently close to the obstacle. Furthermore, the fields coupled into the cavity from the source in the exterior region generally need to propagate only one-way via the open front end (which is directly illuminated) to the interior surface S(T) in this approach, and not back, in order to find the external field scattered by the obstacle.

Magnetism and high magnetic-field-induced stability of alloy carbides in Fe-based materials.

PubMed

Hou, T P; Wu, K M; Liu, W M; Peet, M J; Hulme-Smith, C N; Guo, L; Zhuang, L

2018-02-14

Understanding the nature of the magnetic-field-induced precipitation behaviors represents a major step forward towards unravelling the real nature of interesting phenomena in Fe-based alloys and especially towards solving the key materials problem for the development of fusion energy. Experimental results indicate that the applied high magnetic field effectively promotes the precipitation of M 23 C 6 carbides. We build an integrated method, which breaks through the limitations of zero temperature and zero external field, to concentrate on the dependence of the stability induced by the magnetic effect, excluding the thermal effect. We investigate the intimate relationship between the external field and the origins of various magnetics structural characteristics, which are derived from the interactions among the various Wyckoff sites of iron atoms, antiparallel spin of chromium and Fe-C bond distances. The high-magnetic-field-induced exchange coupling increases with the strength of the external field, which then causes an increase in the parallel magnetic moment. The stability of the alloy carbide M 23 C 6 is more dependent on external field effects than thermal effects, whereas that of M 2 C, M 3 C and M 7 C 3 is mainly determined by thermal effects.

Modeling activity patterns of wildlife using time-series analysis.

PubMed

Zhang, Jindong; Hull, Vanessa; Ouyang, Zhiyun; He, Liang; Connor, Thomas; Yang, Hongbo; Huang, Jinyan; Zhou, Shiqiang; Zhang, Zejun; Zhou, Caiquan; Zhang, Hemin; Liu, Jianguo

2017-04-01

The study of wildlife activity patterns is an effective approach to understanding fundamental ecological and evolutionary processes. However, traditional statistical approaches used to conduct quantitative analysis have thus far had limited success in revealing underlying mechanisms driving activity patterns. Here, we combine wavelet analysis, a type of frequency-based time-series analysis, with high-resolution activity data from accelerometers embedded in GPS collars to explore the effects of internal states (e.g., pregnancy) and external factors (e.g., seasonal dynamics of resources and weather) on activity patterns of the endangered giant panda ( Ailuropoda melanoleuca ). Giant pandas exhibited higher frequency cycles during the winter when resources (e.g., water and forage) were relatively poor, as well as during spring, which includes the giant panda's mating season. During the summer and autumn when resources were abundant, pandas exhibited a regular activity pattern with activity peaks every 24 hr. A pregnant individual showed distinct differences in her activity pattern from other giant pandas for several months following parturition. These results indicate that animals adjust activity cycles to adapt to seasonal variation of the resources and unique physiological periods. Wavelet coherency analysis also verified the synchronization of giant panda activity level with air temperature and solar radiation at the 24-hr band. Our study also shows that wavelet analysis is an effective tool for analyzing high-resolution activity pattern data and its relationship to internal and external states, an approach that has the potential to inform wildlife conservation and management across species.

Isolation of pulmonary veins using a thermoreactive implantable device with external energy transfer: Evaluation in a porcine model.

PubMed

Boussy, Tim; Vandecasteele, Tim; Vera, Lisse; Schauvliege, Stijn; Philpott, Matthew; Clement, Eli; van Loon, Gunther; Willenz, Udi; Granada, Juan F; Stone, Gregg W; Reddy, Vivek Y; Van Langenhove, Glenn

2018-06-01

Pulmonary vein isolation (PVI) is a well-established method for the treatment of symptomatic paroxysmal atrial fibrillation, but is only partly successful with a high rate of electrical reconnection. We introduce a novel technique in which PVI is accomplished by noninvasive heating of a dedicated thermoresponse implant inserted into the pulmonary veins (PV), demonstrated in a porcine model. A self-expanding nitinol-based implant was positioned in the common inferior PV of 11 pigs, using a fluoroscopy-guided transatrial appendage approach. Ablation was performed through contactless energy transfer from a primary extracorporal coil to a secondary heat ring (HR) embedded in the proximal part of the implant. Electrophysiological conduction was assessed prior to and postablation, and at 3 months. Histological samples were obtained acutely (n  =  4) and after 3 months (n  =  7). In total, 13 PV implants were successfully positioned in the inferior PVs of 11 animals. Ablation was performed without injury of adjacent structures. PVI and bidirectional block was electrophysiologically confirmed in all cases immediately at the time of implantation and 3 months later in seven chronic animals in whom testing was repeated. Marked evidence of ablation around the proximal HR was evident at 3 months postprocedure, with scar tissue formation and only mild neointimal proliferation. Successful PVI can be obtained by external electromagnetic heat transfer to a novel pulmonary vein implant. © 2018 Wiley Periodicals, Inc.

Investigation of Factors Affecting Body Temperature Changes During Routine Clinical Head Magnetic Resonance Imaging

PubMed Central

Kim, Myeong Seong

2016-01-01

Background Pulsed radiofrequency (RF) magnetic fields, required to produce magnetic resonance imaging (MRI) signals from tissue during the MRI procedure have been shown to heat tissues. Objectives To investigate the relationship between body temperature rise and the RF power deposited during routine clinical MRI procedures, and to determine the correlation between this effect and the body’s physiological response. Patients and Methods We investigated 69 patients from the Korean national cancer center to identify the main factors that contribute to an increase in body temperature (external factors and the body’s response) during a clinical brain MRI. A routine protocol sequence of MRI scans (1.5 T and 3.0 T) was performed. The patient’s tympanic temperature was recorded before and immediately after the MRI procedure and compared with changes in variables related to the body’s physiological response to heat. Results Our investigation of the physiological response to RF heating indicated a link between increasing age and body temperature. A higher increase in body temperature was observed in older patients after a 3.0-T MRI (r = 0.07, P = 0.29 for 1.5-T MRI; r = 0.45, P = 0.002 for 3.0-T MRI). The relationship between age and body heat was related to the heart rate (HR) and changes in HR during the MRI procedure; a higher RF power combined with a reduction in HR resulted in an increase in body temperature. Conclusion A higher magnetic field strength and a decrease in the HR resulted in an increase in body temperature during the MRI procedure. PMID:27895872

Environment construction and bottleneck breakthrough in the improvement of wisdom exhibition

NASA Astrophysics Data System (ADS)

Zhang, Jiankang

2017-08-01

Wisdom exhibition is an inexorable trend in convention and exhibition industry in China. Information technology must be utilized by exhibition industry to achieve intelligent application and wisdom management, breaking the limitation of time as well as space, which raise the quality of exhibition service and level of operation to a totally new standard. Accordingly, exhibition industry should optimize mobile internet, a fundamental technology platform, during the advancing process of wisdom exhibition and consummate the combination among three plates including wisdom connection of information, wisdom exhibition environment and wisdom application of technology. Besides, the industry should realize the wisdom of external environment including wisdom of exhibition city, exhibition place, exhibition resource deal etc and break through bottle-neck in construction of wisdom exhibition industry, which includes construction of big data center, development of Mobile Internet application platform, promotion of information construction, innovative design of application scenarios.

Lattice field theory study of magnetic catalysis in graphene

DOE PAGES

DeTar, Carleton; Winterowd, Christopher; Zafeiropoulos, Savvas

2017-04-15

We discuss the simulation of the low-energy effective field theory (EFT) for graphene in the presence of an external magnetic field. Our fully nonperturbative calculation uses methods of lattice gauge theory to study the theory using a hybrid Monte Carlo approach. We investigate the phenomenon of magnetic catalysis in the context of graphene by studying the chiral condensate which is the order parameter characterizing the spontaneous breaking of chiral symmetry. In the EFT, the symmetry breaking pattern is given bymore » $$U(4) \\to U(2) \\times U(2)$$. We also comment on the difficulty, in this lattice formalism, of studying the time-reversal-odd condensate characterizing the ground state in the presence of a magnetic field. Lastly, we study the mass spectrum of the theory, in particular the Nambu-Goldstone (NG) mode as well as the Dirac quasiparticle, which is predicted to obtain a dynamical mass.« less

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

DeTar, Carleton; Winterowd, Christopher; Zafeiropoulos, Savvas

We discuss the simulation of the low-energy effective field theory (EFT) for graphene in the presence of an external magnetic field. Our fully nonperturbative calculation uses methods of lattice gauge theory to study the theory using a hybrid Monte Carlo approach. We investigate the phenomenon of magnetic catalysis in the context of graphene by studying the chiral condensate which is the order parameter characterizing the spontaneous breaking of chiral symmetry. In the EFT, the symmetry breaking pattern is given bymore » $$U(4) \\to U(2) \\times U(2)$$. We also comment on the difficulty, in this lattice formalism, of studying the time-reversal-odd condensate characterizing the ground state in the presence of a magnetic field. Lastly, we study the mass spectrum of the theory, in particular the Nambu-Goldstone (NG) mode as well as the Dirac quasiparticle, which is predicted to obtain a dynamical mass.« less

Topological sound in active-liquid metamaterials

NASA Astrophysics Data System (ADS)

Souslov, Anton; van Zuiden, Benjamin C.; Bartolo, Denis; Vitelli, Vincenzo

2017-11-01

Liquids composed of self-propelled particles have been experimentally realized using molecular, colloidal or macroscopic constituents. These active liquids can flow spontaneously even in the absence of an external drive. Unlike spontaneous active flow, the propagation of density waves in confined active liquids is not well explored. Here, we exploit a mapping between density waves on top of a chiral flow and electrons in a synthetic gauge field to lay out design principles for artificial structures termed topological active metamaterials. We design metamaterials that break time-reversal symmetry using lattices composed of annular channels filled with a spontaneously flowing active liquid. Such active metamaterials support topologically protected sound modes that propagate unidirectionally, without backscattering, along either sample edges or domain walls and despite overdamped particle dynamics. Our work illustrates how parity-symmetry breaking in metamaterial structure combined with microscopic irreversibility of active matter leads to novel functionalities that cannot be achieved using only passive materials.

High Resolution Manometry Correlates of Ineffective Esophageal Motility

PubMed Central

Xiao, Yinglian; Kahrilas, Peter J.; Kwasny, Mary J.; Roman, Sabine; Lin, Zhiyue; Nicodème, Frédéric; Lu, Chang; Pandolfino, John E.

2013-01-01

Background There are currently no criteria for ineffective esophageal motility (IEM) and ineffective swallow (IES) in High Resolution Manometry (HRM) and Esophageal Pressure Topography (EPT). Our aims were to utilize HRM metrics to define IEM within the Chicago Classification and to determine the distal contractile integral (DCI) threshold for IES. Methods The EPT of 150 patients with either dysphagia or reflux symptoms were reviewed for the breaks >2 cm in the proximal, middle and distal esophagus in the 20 mmHg isobaric contour (IBC). Peristaltic function in EPT was defined by the Chicago Classification, the corresponding conventional line tracing (CLT) were reviewed separately for IEM and IES. Generalized linear mixed models were used to find thresholds for DCI corresponding to traditionally determined IES and failed swallows. An external validation sample was used to confirm these thresholds. Results In terms of swallow subtypes, IES in CLT were a mixture of normal, weak and failed peristalsis in EPT. A DCI of 450mmHg-s-cm was determined to be optimal in predicting IES. In the validation sample, the threshold of 450 mmHg-s-cm showed strong agreement with CLT determination of IES (positive percent agreement 83%, negative percent agreement 90%) Thirty-three among 42 IEM patients in CLT had large peristaltic breaks, small peristaltic breaks or ‘frequent failed peristalsis’ in EPT; 87.2% (34/39) of patients classified as normal in CLT had proximal IBC-breaks in EPT. the patient level diagnostic agreement between CLT and EPT was good (78.6% positive percent agreement, 63.9% negative percent agreement), with negative agreement increasing to 92.0% if proximal breaks were excluded. Conclusions The manometric correlate of IEM in EPT is a mixture of failed swallows and IBC break in the middle/ distal troughs. A DCI value<450 mmHg-s-cm can be utilized to predict IES previously defined in CLT. IEM can be defined by >5 swallows with weak /failed peristalsis or with a DCI <450 mmHg-s-cm. PMID:22929758

Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both.

PubMed

Jarosek, Stephanie L; Virnig, Beth A; Chu, Haitao; Elliott, Sean P

2015-02-01

Prostate cancer is the second most common cancer in men and has high survivorship, yet little is known about the long-term risk of urinary adverse events (UAEs) after treatment. To compare the long-term UAE incidence across treatment and control groups. Using a matched-cohort design, we identified elderly men treated with external-beam radiotherapy (EBRT; n=44 318), brachytherapy (BT; n=14 259), EBRT+BT (n=11 835), radical prostatectomy (RP; n=26 970), RP+EBRT (n=1557), or cryotherapy (n=2115) for non-metastatic prostate cancer and 144 816 non-cancer control individuals from the population-based Surveillance, Epidemiology, and End Results-Medicare linked data from 1992-2007 with follow-up through 2009. The incidence of treated UAEs and time from cancer treatment to first UAE were analyzed in terms of propensity-weighted survival. Median follow-up was 4.14 yr. At 10 yr, all treatment groups experienced higher propensity-weighted cumulative UAE incidence than the control group (16.1%; hazard risk [HR] 1.0), with the highest incidence for RP+EBRT (37.8%; HR 3.19, 95% confidence interval [CI] 2.79-3.66), followed by BT+EBRT (28.4%; HR 1.97, CI 1.85-2.10), RP (26.6%; HR 2.44, CI 2.34-2.55), cryotherapy (23.4%; HR 1.56, CI 1.30-1.87), BT (19.8%; HR 1.43, CI 1.33-1.53), and EBRT (19.7%; HR 1.11, CI 1.07-1.16). Bladder outlet obstruction was the most common event. Men undergoing RP, RP+EBRT, and BT+EBRT experienced the highest UAE risk at 10 yr, although UAEs accrued differently over extended follow-up. The significant background UAE rate among non-cancer control individuals yields a risk attributable to prostate cancer treatment that is 17% lower than prior estimates. We show that treatment for prostate cancer, especially combinations of two treatments such as radiation and surgery, carries a significant risk of urinary adverse events such as urethral stricture. This risk increases with time since treatment, emphasizing that treatments have long-term effects. Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Unavailability of thymidine kinase does not preclude the use of German comprehensive prognostic index: results of an external validation analysis in early chronic lymphocytic leukemia and comparison with MD Anderson Cancer Center model.

PubMed

Molica, Stefano; Giannarelli, Diana; Mirabelli, Rosanna; Levato, Luciano; Russo, Antonio; Linardi, Maria; Gentile, Massimo; Morabito, Fortunato

2016-01-01

A comprehensive prognostic index that includes clinical (i.e., age, sex, ECOG performance status), serum (i.e., ß2-microglobulin, thymidine kinase [TK]), and molecular (i.e., IGVH mutational status, del 17p, del 11q) markers developed by the German CLL Study Group (GCLLSG) was externally validated in a prospective, community-based cohort consisting of 338 patients with early chronic lymphocytic leukemia (CLL) using as endpoint the time to first treatment (TTFT). Because serum TK was not available, a slightly modified version of the model based on seven instead of eight prognostic variables was used. By German index, 62.9% of patients were scored as having low-risk CLL (score 0-2), whereas 37.1% had intermediate-risk CLL (score 3-5). This stratification translated into a significant difference in the TTFT [HR = 4.21; 95% C.I. (2.71-6.53); P < 0.0001]. Also the 2007 MD Anderson Cancer Center (MDACC) score, barely based on traditional clinical parameters, showed comparable reliability [HR = 2.73; 95% C.I. (1.79-4.17); P < 0.0001]. A comparative performance assessment between the two models revealed that prediction of the TTFT was more accurate with German score. The c-statistic of the MDACC model was 0.65 (range, 0.53-0.78) a level below that of the German index [0.71 (range, 0.60-0.82)] and below the accepted 0.7 threshold necessary to have value at the individual patient level. Results of this external comparative validation analysis strongly support the German score as the benchmark for comparison of any novel prognostic scheme aimed at evaluating the TTFT in patients with early CLL even when a modified version which does not include TK is utilized. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or bladder-preservation therapy for muscle-invasive bladder cancer.

PubMed

Cahn, David B; Handorf, Elizabeth A; Ghiraldi, Eric M; Ristau, Benjamin T; Geynisman, Daniel M; Churilla, Thomas M; Horwitz, Eric M; Sobczak, Mark L; Chen, David Y T; Viterbo, Rosalia; Greenberg, Richard E; Kutikov, Alexander; Uzzo, Robert G; Smaldone, Marc C

2017-11-15

The current study was performed to examine temporal trends and compare overall survival (OS) in patients undergoing radical cystectomy (RC) or bladder-preservation therapy (BPT) for muscle-invasive urothelial carcinoma of the bladder. The authors reviewed the National Cancer Data Base to identify patients with AJCC stage II to III urothelial carcinoma of the bladder from 2004 through 2013. Patients receiving BPT were stratified as having received any external-beam radiotherapy (any XRT), definitive XRT (50-80 grays), and definitive XRT with chemotherapy (CRT). Treatment trends and OS outcomes for the BPT and RC cohorts were evaluated using Cochran-Armitage tests, unadjusted Kaplan-Meier curves, adjusted Cox multivariate regression, and propensity score matching, using increasingly stringent selection criteria. A total of 32,300 patients met the inclusion criteria and were treated with RC (22,680 patients) or BPT (9620 patients). Of the patients treated with BPT, 26.4% (2540 patients) and 15.5% (1489 patients), respectively, were treated with definitive XRT and CRT. Improved OS was observed for RC in all groups. After adjustments with more rigorous statistical models controlling for confounders and with more restrictive BPT cohorts, the magnitude of the OS benefit became attenuated on multivariate (any XRT: hazard ratio [HR], 2.115 [95% confidence interval [95% CI], 2.045-2.188]; definitive XRT: HR, 1.870 [95% CI, 1.773-1.972]; and CRT: HR, 1.578 [95% CI, 1.474-1.691]) and propensity score (any XRT: HR, 2.008 [95% CI, 1.871-2.154]; definitive XRT: HR, 1.606 [95% CI, 1.453-1.776]; and CRT: HR, 1.406 [95% CI, 1.235-1.601]) analyses. In the National Cancer Data Base, receipt of BPT was associated with decreased OS compared with RC in patients with stage II to III urothelial carcinoma. Increasingly stringent definitions of BPT and more rigorous statistical methods adjusting for selection biases attenuated observed survival differences. Cancer 2017;123:4337-45. © 2017 American Cancer Society. © 2017 American Cancer Society.

Brachytherapy Is Associated With Improved Survival in Inoperable Stage I Endometrial Adenocarcinoma: A Population-Based Analysis

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

Acharya, Sahaja; Perkins, Stephanie M.; DeWees, Todd

2015-11-01

Purpose: To assess the use of brachytherapy (BT) with or without external beam radiation (EBRT) in inoperable stage I endometrial adenocarcinoma in the United States and to determine the effect of BT on overall survival (OS) and cause-specific survival (CSS). Methods and Materials: Data between 1998 and 2011 from the National Cancer Institute's Surveillance, Epidemiology and End Results database were analyzed. Coarsened exact matching was used to adjust for differences in age and grade between patients who received BT and those who did not. Prognostic factors affecting OS and CSS were evaluated using the Kaplan-Meier product-limit method and a Coxmore » proportional hazards regression model. Results: A total of 460 patients with inoperable stage I endometrial adenocarcinoma treated with radiation therapy were identified. Radiation consisted of either EBRT (n=260) or BT with or without EBRT (n=200). The only factor associated with BT use was younger patient age (median age, 72 vs 76 years, P=.001). Patients who received BT had a higher 3-year OS (60% vs 47%, P<.001) and CSS (82% vs 74%, P=.032) compared with those who did not. On multivariate analysis, BT use was independently associated with an improved OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.52-0.87) and CSS (HR 0.61, 95% CI 0.39-0.93). When patients were matched on age, BT use remained significant on multivariate analysis for OS (HR 0.65, 95% CI 0.48-0.87) and CSS (HR 0.52, 95% CI 0.31-0.84). When matched on age and grade, BT remained independently associated with improved OS and CSS (OS HR 0.62, 95% CI 0.46-0.83; CSS HR 0.57, 95% CI 0.34-0.92). Conclusion: Brachytherapy is independently associated with improved OS and CSS. It should be considered as part of the treatment regimen for stage I inoperable endometrial cancer patients undergoing radiation.« less

Evidence for broken Galilean invariance at the quantum spin Hall edge

NASA Astrophysics Data System (ADS)

Geissler, Florian; Crépin, François; Trauzettel, Björn

2015-12-01

We study transport properties of the helical edge channels of a quantum spin Hall insulator, in the presence of electron-electron interactions and weak, local Rashba spin-orbit coupling. The combination of the two allows for inelastic backscattering that does not break time-reversal symmetry, resulting in interaction-dependent power-law corrections to the conductance. Here, we use a nonequilibrium Keldysh formalism to describe the situation of a long, one-dimensional edge channel coupled to external reservoirs, where the applied bias is the leading energy scale. By calculating explicitly the corrections to the conductance up to fourth order of the impurity strength, we analyze correlated single- and two-particle backscattering processes on a microscopic level. Interestingly, we show that the modeling of the leads together with the breaking of Galilean invariance has important effects on the transport properties. Such breaking occurs because the Galilean invariance of the bulk spectrum transforms into an emergent Lorentz invariance of the edge spectrum. With this broken Galilean invariance at the quantum spin Hall edge, we find a contribution to single-particle backscattering with a very low power scaling, while in the presence of Galilean invariance the leading contribution will be due to correlated two-particle backscattering only. This difference is further reflected in the different values of the Fano factor of the shot noise, an experimentally observable quantity. The described behavior is specific to the Rashba scatterer and does not occur in the case of backscattering off a time-reversal-breaking, magnetic impurity.

The highest-ranking rooster has priority to announce the break of dawn

PubMed Central

Shimmura, Tsuyoshi; Ohashi, Shosei; Yoshimura, Takashi

2015-01-01

The “cock-a-doodle-doo” crowing of roosters, which symbolizes the break of dawn in many cultures, is controlled by the circadian clock. When one rooster announces the break of dawn, others in the vicinity immediately follow. Chickens are highly social animals, and they develop a linear and fixed hierarchy in small groups. We found that when chickens were housed in small groups, the top-ranking rooster determined the timing of predawn crowing. Specifically, the top-ranking rooster always started to crow first, followed by its subordinates, in descending order of social rank. When the top-ranking rooster was physically removed from a group, the second-ranking rooster initiated crowing. The presence of a dominant rooster significantly reduced the number of predawn crows in subordinates. However, the number of crows induced by external stimuli was independent of social rank, confirming that subordinates have the ability to crow. Although the timing of subordinates’ predawn crowing was strongly dependent on that of the top-ranking rooster, free-running periods of body temperature rhythms differed among individuals, and crowing rhythm did not entrain to a crowing sound stimulus. These results indicate that in a group situation, the top-ranking rooster has priority to announce the break of dawn, and that subordinate roosters are patient enough to wait for the top-ranking rooster’s first crow every morning and thus compromise their circadian clock for social reasons. PMID:26203594

Breaking Bad News in Oncology: A Metasynthesis.

PubMed

Bousquet, Guilhem; Orri, Massimiliano; Winterman, Sabine; Brugière, Charlotte; Verneuil, Laurence; Revah-Levy, Anne

2015-08-01

The delivery of bad news by oncologists to their patients is a key moment in the physician-patient relationship. We performed a systematic review of qualitative studies (a metasynthesis) that focused on the experiences and points of view of oncologists about breaking bad news to patients. We searched international publications to identify relevant qualitative research exploring oncologists' perspectives about this topic. Thematic analysis, which compensates for the potential lack of generalizability of the primary studies by their conjoint interpretation, was used to identify key themes and synthesize them. NVivo qualitative analysis software was used. We identified 40 articles (> 600 oncologists) from 12 countries and assessed their quality as good according to the Critical Appraisal Skills Programme (CASP). Two main themes emerged: the patient-oncologist encounter during the breaking of bad news, comprising essential aspects of the communication, including the process of dealing with emotions; and external factors shaping the patient-oncologist encounter, composed of factors that influence the announcement beyond the physician-patient relationship: the family, systemic and institutional factors, and cultural factors. Breaking bad news is a balancing act that requires oncologists to adapt continually to different factors: their individual relationships with the patient, the patient's family, the institutional and systemic environment, and the cultural milieu. Extending the development of the ability to personalize and adapt therapeutic treatment to this realm of communications would be a major step forward from the stereotyped way that oncologists are currently trained in communication skills. © 2015 by American Society of Clinical Oncology.

Small helicopter could find niche in remote heavy lift operations

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

Not Available

1994-02-21

A new helicopter specifically designed for external vertical lift operations, such as moving transportable rig components or seismic equipment in remote locations, operates more efficiently than most other medium or heavy-lift helicopters, according to manufacturer Kaman Aerospace. The single-pilot helicopter was designed as an aerial truck for efficient lifting of heavy loads but with the operating costs of a light-lift craft. The K-Max helicopter can lift more pounds of cargo per gallon of fuel consumed than other similar helicopters, according to Kaman. For example, to transport a 5,000-lb load at an elevation of 8,000 ft, the K-Max helicopter consumes 85more » gal of fuel/hr. Under the same load conditions, the next most efficient commercially available helicopter consumes 160 gal of fuel/hr and requires two pilots. The 4,500-lb helicopter can lift 5,000 lb to an altitude of 8,000 ft or about 6,000 lb at low altitudes.« less

KSC-2010-4579

NASA Image and Video Library

2010-09-08

CAPE CANAVERAL, Fla. -- In the LC-39 Complex Turn Basin area across from the Vehicle Assembly Building at NASA's Kennedy Space Center in Florida, a major water main leak in a 24-inch pipe caused soil to wash away near the Press Site. The center was closed for the morning while workers assessed and repaired the break. In the background is the Pegasus barge docked at the Turn Basin which is used to deliver the space shuttle external fuel tank. Photo credit: NASA/Jack Pfaller

KSC-2010-4582

NASA Image and Video Library

2010-09-08

CAPE CANAVERAL, Fla. -- In the LC-39 Complex Turn Basin area across from the Vehicle Assembly Building at NASA's Kennedy Space Center in Florida, a major water main leak in a 24-inch pipe caused soil to wash away near the Press Site. The center was closed for the morning while workers assessed and repaired the break. In the background is the Pegasus barge docked at the Turn Basin which is used to deliver the space shuttle external fuel tank. Photo credit: NASA/Jack Pfaller

KSC-2010-4580

NASA Image and Video Library

2010-09-08

CAPE CANAVERAL, Fla. -- In the LC-39 Complex Turn Basin area across from the Vehicle Assembly Building at NASA's Kennedy Space Center in Florida, a major water main leak in a 24-inch pipe caused soil to wash away near the Press Site. The center was closed for the morning while workers assessed and repaired the break. In the background is the Pegasus barge docked at the Turn Basin which is used to deliver the space shuttle external fuel tank. Photo credit: NASA/Jack Pfaller

Operational Art in Theory and War: A Comparison of Soviet Theory and the Red Army’s Conduct in Operation BAGRATION 1944

DTIC Science & Technology

2013-03-22

overthrown landowners and bourgeoisie and externally against foreign aggression. 11 This ideological foundation inspired the dynamic and innovative...unsuccessfully trying to break the trench lines in France in World War I, but accomplished it in four days in World War II. The combination of speed...muse.jhu.edu/journals/journal_of_military_history/toc/jmh.72.3.html 21 Moreover, it was the stunning German attack on France in 1940 that opened

Numerical investigation of electron localization in polymer chains

NASA Astrophysics Data System (ADS)

Paulsson, Magnus; Stafström, Sven

1998-01-01

Using finite-size scaling, we have calculated the localization-delocalization phase diagrams for electronic wave functions in different disordered polymeric systems. The disorder considered here simulates finite polymer chain lengths, breaks in the conjugation, and disorder in an external potential. It is shown that a system of interacting chains, even at rather weak interchain interactions, allows for enough flexibility for the scattered waves to avoid dephasing and localization. Localization and the metal-insulator transition in highly conducting polymers are discussed in view of these results.

Further evidence for a potassium-like action of lithium ions on sodium efflux in frog skeletal muscle

PubMed Central

Beaugé, L. A.; Ortiz, Olga

1972-01-01

1. The efflux of labelled sodium as well as net sodium and lithium changes were studied in aged high sodium sartorius muscles of the South American frog Leptodactilus ocelatus. 2. In the presence of 2·5 mM potassium in the media, the replacement of external sodium with lithium or magnesium resulted in an increase in sodium efflux. The magnitude of such increase was always larger in lithium. 3. With the absence of potassium in the media, the response of sodium efflux to replacement of external sodium varied with the cation used as a substitute. In lithium Ringer there was always a noticeable increase, whereas in magnesium there was always a marked reduction. The same results were observed when calcium was substituted for magnesium. 4. The replacement of 60 mM external sodium with sucrose did not prevent the stimulating effect of 5 mM potassium on sodium efflux, nor the inhibitory action of 10-4 M ouabain. This indicates that neither sucrose by itself, nor the lowering of the ionic strength, modified to an appreciable extent the function of the sodium pump. 5. Net sodium extrusion took place against an electrochemical gradient in potassium-free — 50 mM sodium — mM lithium Ringer. About 75% of this efflux was ouabain sensitive. 6. Muscles made both sodium and lithium rich and incubated in potassium-free — 60 mM sodium — 50 mM lithium Ringer also showed net sodium extrusion against an electrochemical gradient, which was 85% ouabain sensitive. This extrusion took place even under conditions where the changes in free energy favouring lithium entry were always lower than the changes in free energy opposing sodium going out. This indicates that a sodium-lithium exchange by a counter-transport process is unlikely. 7. External potassium reduced the ouabain sensitive lithium influx in muscles incubated in lithium Ringer. The values found were 5·90 ± 0·39 μ-mole/g.hr and 2·66 ± 0·43 μmole/g.hr in potassium-free and 15 mM potassium respectively. At the same time potassium had no effect on the ouabain-insensitive lithium uptake. 8. Muscles incubated in potassium-free-magnesium Ringer had a residual sodium efflux which could not be accounted for by passive movement. About 40% of it was abolished by 10-4 M ouabain. This ouabain-sensitive part could be a consequence of some stimulation of the sodium pump by potassium leaking out of the cells. If this is correct it should be inhibited by external sodium and should not contribute to the total sodium efflux in potassium-free sodium media. 9. Magnesium was used as the reference cation to study the sodium-stimulated sodium efflux under potassium-free conditions. The total sodium efflux amounted to 0·668 hr-1 (rate constant) and was 71% ouabain sensitive. 10. The present experiments demonstrated that lithium ions have a direct stimulating effect on sodium efflux in high sodium skeletal muscle, and strongly support the notion that this effect is produced by an activation of the sodium pump through a potassium-like action. PMID:4637626

Key tasks in healthcare marketing: assessing importance and current level of knowledge.

PubMed

Kennett, Pamela A; Henson, Steve W; Crow, Stephen M; Hartman, Sandra J

2005-01-01

When examining the healthcare industry, the need for continuing education in internal functions (i.e., HR management) has been documented. However, equally important to success in the healthcare industry are external functions such as marketing. In an expansion of research on internally focused functions, we report findings from an exploratory study designed to examine the perceptions of executives about managerial skill needs in the externally focused area of marketing. Specifically, we examine eight key tasks in marketing and ask executives to rate the level of knowledge required for each and then to assess current, or actual, levels of knowledge in the field. Findings suggest that pricing strategy, product strategy, and segmentation and targeting were the tasks that require the most knowledge for healthcare marketers, and that they do, in fact, perceive various gaps in all of the areas examined. Implications and suggestions for future research are provided.

A description of the external and internal quiet daily variation currents at North American locations for a quiet-Sun year.

USGS Publications Warehouse

Campbell, W.H.

1983-01-01

An order 4, degree 12 spherical harmonic analysis of the smoothed quiet geomagnetic daily variations was used to separate the external and internal geomagnetic Sq field at North American locations for the quiet-Sun year, 1965. These fields were represented by a month-by-month display of equivalent current vortex systems with dominant, pre-noon foci. The focus reached 40o latitude near the June solstice and about 30o latitude near the December solstice. The daily range of Sq current amplitudes was largest in late July to early August and smallest in mid-December. Semi-annual variations of Sq currents dominated only the equatorial region. Daily maxima in mid-latitudes, occurred mostly near local noon in December to February and about 1 hr before noon in June to mid-October. -Author

Patterns of Sensitivity to Parenting and Peer Environments: Early Temperament and Adolescent Externalizing Behavior.

PubMed

Tung, Irene; Noroña, Amanda N; Morgan, Julia E; Caplan, Barbara; Lee, Steve S; Baker, Bruce L

2018-03-14

Although parenting behavior and friendship quality predict adolescent externalizing behaviors (EBs), individual differences in temperament may differentially affect susceptibility to these factors over time. In a multi-method and multi-informant study of 141 children followed prospectively from toddlerhood to adolescence, we tested the independent and interactive associations of age 3 reactive temperament (e.g., negative emotionality) and age 13 observed parenting (i.e., positive and negative behavior) and friendship (i.e., conflict and warmth), with multi-informant ratings of age 15 aggression and rule-breaking behavior. Negative parenting predicted growth in parent-rated EB, but only for adolescents with early reactive temperament. Temperament did not affect sensitivity to positive parenting or friendship. Results are discussed in the context of differential susceptibility theory and intervention implications for adolescents. © 2018 Society for Research on Adolescence.

GEN1/Yen1 and the SLX4 complex: solutions to the problem of Holliday junction resolution

PubMed Central

Svendsen, Jennifer M.; Harper, J. Wade

2010-01-01

Chromosomal double-strand breaks (DSBs) are considered to be among the most deleterious DNA lesions found in eukaryotic cells due to their propensity to promote genome instability. DSBs occur as a result of exogenous or endogenous DNA damage, and also occur during meiotic recombination. DSBs are often repaired through a process called homologous recombination (HR), which employs the sister chromatid in mitotic cells or the homologous chromosome in meiotic cells, as a template for repair. HR frequently involves the formation and resolution of four-way DNA structures referred to as the Holliday junction (HJ). Despite extensive study, the machinery and mechanisms used to process these structures in eukaryotes have remained poorly understood. Recent work has identified XPG and UvrC/GIY domain-containing structure-specific endonucleases that can symmetrically cleave HJs in vitro in a manner that allows for religation without additional processing, properties that are reminiscent of the classical RuvC HJ resolvase in bacteria. Genetic studies reveal potential roles for these HJ resolvases in repair after DNA damage and during meiosis. The stage is now set for a more comprehensive understanding of the specific roles these enzymes play in the response of cells to DSBs, collapsed replication forks, telomere dysfunction, and meiotic recombination. PMID:20203129

Adeno-associated virus inverted terminal repeats stimulate gene editing.

PubMed

Hirsch, M L

2015-02-01

Advancements in genome editing have relied on technologies to specifically damage DNA which, in turn, stimulates DNA repair including homologous recombination (HR). As off-target concerns complicate the therapeutic translation of site-specific DNA endonucleases, an alternative strategy to stimulate gene editing based on fragile DNA was investigated. To do this, an episomal gene-editing reporter was generated by a disruptive insertion of the adeno-associated virus (AAV) inverted terminal repeat (ITR) into the egfp gene. Compared with a non-structured DNA control sequence, the ITR induced DNA damage as evidenced by increased gamma-H2AX and Mre11 foci formation. As local DNA damage stimulates HR, ITR-mediated gene editing was investigated using DNA oligonucleotides as repair substrates. The AAV ITR stimulated gene editing >1000-fold in a replication-independent manner and was not biased by the polarity of the repair oligonucleotide. Analysis of additional human DNA sequences demonstrated stimulation of gene editing to varying degrees. In particular, inverted yet not direct, Alu repeats induced gene editing, suggesting a role for DNA structure in the repair event. Collectively, the results demonstrate that inverted DNA repeats stimulate gene editing via double-strand break repair in an episomal context and allude to efficient gene editing of the human chromosome using fragile DNA sequences.

Techniques for establishing schedules with wheel running as reinforcement in rats.

PubMed

Iversen, I H

1993-07-01

In three experiments, access to wheel running was contingent on lever pressing. In each experiment, the duration of access to running was reduced gradually to 4, 5, or 6 s, and the schedule parameters were expanded gradually. The sessions lasted 2 hr. In Experiment 1, a fixed-ratio 20 schedule controlled a typical break-and-run pattern of lever pressing that was maintained throughout the session for 3 rats. In Experiment 2, a fixed-interval schedule of 6 min maintained lever pressing throughout the session for 3 rats, and for 1 rat, the rate of lever pressing was positively accelerated between reinforcements. In Experiment 3, a variable-ratio schedule of 20 or 35 was in effect and maintained lever pressing at a very stable pace throughout the session for 2 of 3 rats; for 1 rat, lever pressing was maintained at an irregular rate. When the session duration was extended to successive 24-hr periods, with food and water accessible in Experiment 3, lever pressing settled into a periodic pattern occurring at a high rate at approximately the same time each day. In each experiment, the rats that developed the highest local rates of running during wheel access also maintained the most stable and highest rates of lever pressing.

FANCJ helicase controls the balance between short- and long-tract gene conversions between sister chromatids

PubMed Central

Nath, Sarmi; Somyajit, Kumar; Mishra, Anup; Scully, Ralph

2017-01-01

Abstract The FANCJ DNA helicase is linked to hereditary breast and ovarian cancers as well as bone marrow failure disorder Fanconi anemia (FA). Although FANCJ has been implicated in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), the molecular mechanism underlying the tumor suppressor functions of FANCJ remains obscure. Here, we demonstrate that FANCJ deficient human and hamster cells exhibit reduction in the overall gene conversions in response to a site-specific chromosomal DSB induced by I-SceI endonuclease. Strikingly, the gene conversion events were biased in favour of long-tract gene conversions in FANCJ depleted cells. The fine regulation of short- (STGC) and long-tract gene conversions (LTGC) by FANCJ was dependent on its interaction with BRCA1 tumor suppressor. Notably, helicase activity of FANCJ was essential for controlling the overall HR and in terminating the extended repair synthesis during sister chromatid recombination (SCR). Moreover, cells expressing FANCJ pathological mutants exhibited defective SCR with an increased frequency of LTGC. These data unravel the novel function of FANCJ helicase in regulating SCR and SCR associated gene amplification/duplications and imply that these functions of FANCJ are crucial for the genome maintenance and tumor suppression. PMID:28911102

The effects of near-UV radiation on elasmobranch lens cytoskeletal actin.

PubMed

Zigman, S; Rafferty, N S; Scholz, D L; Lowe, K

1992-08-01

The role of near-UV radiation as a cytoskeletal actin-damaging agent was investigated. Two procedures were used to analyse fresh smooth dogfish (Mustelus canis) eye lenses that were incubated for up to 22 hr in vitro, with elasmobranch Ringer's medium, and with or without exposure to a near-UV lamp (emission principally at 365 nm; irradiance of 2.5 mW cm-2). These were observed histologically using phalloidin-rhodamine specific staining and by transmission electron microscopy. In addition, solutions of purified polymerized rabbit muscle actin were exposed to the same UV conditions and depolymerization was assayed by ultracentrifugation and high-pressure liquid chromatography. While the two actins studied do differ very slightly in some amino acid sequences, they would react physically nearly identically. The results showed that dogfish lenses developed superficial opacities due to near-UV exposure. Whole mounts of lens epithelium exhibited breakdown of actin filaments in the basal region of the cells within 18 hr of UV exposure. TEM confirmed the breakdown of actin filaments due to UV exposure. SDS-PAGE and immunoblotting positively identified actin in these cells. Direct exposure of purified polymerized muscle actin in polymerizing buffer led to an increase in actin monomer of approximately 25% in the UV-exposed solutions within 3-18 hr, whether assayed by ultracentrifugation or HPLC. The above indicates that elasmobranch lens epithelial cells contain UV-labile actin filaments, and that near-UV radiation, as is present in the sunlit environment, can break down the actin structure in these cells. Furthermore, breakdown of purified polymerized muscle actin does occur due to near-UV light exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes.

PubMed

Wei, Lanlan; Griego, Anastacia M; Chu, Ming; Ozbun, Michelle A

2014-10-01

High-risk human papillomavirus (HR-HPV) infections are necessary but insufficient agents of cervical and other epithelial cancers. Epidemiological studies support a causal, but ill-defined, relationship between tobacco smoking and cervical malignancies. In this study, we used mainstream tobacco smoke condensate (MSTS-C) treatments of cervical cell lines that maintain either episomal or integrated HPV16 or HPV31 genomes to model tobacco smoke exposure to the cervical epithelium of the smoker. MSTS-C exposure caused a dose-dependent increase in viral genome replication and correspondingly higher early gene transcription in cells with episomal HPV genomes. However, MSTS-C exposure in cells with integrated HR-HPV genomes had no effect on genome copy number or early gene transcription. In cells with episomal HPV genomes, the MSTS-C-induced increases in E6 oncogene transcription led to decreased p53 protein levels and activity. As expected from loss of p53 activity in tobacco-exposed cells, DNA strand breaks were significantly higher but apoptosis was minimal compared with cells containing integrated viral genomes. Furthermore, DNA mutation frequencies were higher in surviving cells with HPV episomes. These findings provide increased understanding of tobacco smoke exposure risk in HPV infection and indicate tobacco smoking acts more directly to alter HR-HPV oncogene expression in cells that maintain episomal viral genomes. This suggests a more prominent role for tobacco smoke in earlier stages of HPV-related cancer progression. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib.

PubMed

Hudson, John M; Bailey, Colleen; Atri, Mostafa; Stanisz, Greg; Milot, Laurent; Williams, Ross; Kiss, Alex; Burns, Peter N; Bjarnason, Georg A

2018-06-01

To identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib. Thirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis. A higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used. DCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS. • DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy. • The change in blood volume measured by DCE-US was predictive of OS/PFS. • Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS.

In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases.

PubMed

Sebastiano, Vittorio; Maeder, Morgan L; Angstman, James F; Haddad, Bahareh; Khayter, Cyd; Yeo, Dana T; Goodwin, Mathew J; Hawkins, John S; Ramirez, Cherie L; Batista, Luis F Z; Artandi, Steven E; Wernig, Marius; Joung, J Keith

2011-11-01

The combination of induced pluripotent stem cell (iPSC) technology and targeted gene modification by homologous recombination (HR) represents a promising new approach to generate genetically corrected, patient-derived cells that could be used for autologous transplantation therapies. This strategy has several potential advantages over conventional gene therapy including eliminating the need for immunosuppression, avoiding the risk of insertional mutagenesis by therapeutic vectors, and maintaining expression of the corrected gene by endogenous control elements rather than a constitutive promoter. However, gene targeting in human pluripotent cells has remained challenging and inefficient. Recently, engineered zinc finger nucleases (ZFNs) have been shown to substantially increase HR frequencies in human iPSCs, raising the prospect of using this technology to correct disease causing mutations. Here, we describe the generation of iPSC lines from sickle cell anemia patients and in situ correction of the disease causing mutation using three ZFN pairs made by the publicly available oligomerized pool engineering method (OPEN). Gene-corrected cells retained full pluripotency and a normal karyotype following removal of reprogramming factor and drug-resistance genes. By testing various conditions, we also demonstrated that HR events in human iPSCs can occur as far as 82 bps from a ZFN-induced break. Our approach delineates a roadmap for using ZFNs made by an open-source method to achieve efficient, transgene-free correction of monogenic disease mutations in patient-derived iPSCs. Our results provide an important proof of principle that ZFNs can be used to produce gene-corrected human iPSCs that could be used for therapeutic applications. Copyright © 2011 AlphaMed Press.

The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling.

PubMed

Peng, Chenghao; Chen, Zhengxin; Wang, Shuai; Wang, Hong-Wei; Qiu, Wenjin; Zhao, Lin; Xu, Ran; Luo, Hui; Chen, Yuanyuan; Chen, Dan; You, Yongping; Liu, Ning; Wang, Huibo

2016-04-15

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol κ in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression. Further investigation of the relationship between Pol κ and temozolomide revealed that Pol κ inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. ©2016 AACR. ©2016 American Association for Cancer Research.

APO Time-resolved Color Photometry of Highly Elongated Interstellar Object 1I/‘Oumuamua

NASA Astrophysics Data System (ADS)

Bolin, Bryce T.; Weaver, Harold A.; Fernandez, Yanga R.; Lisse, Carey M.; Huppenkothen, Daniela; Jones, R. Lynne; Jurić, Mario; Moeyens, Joachim; Schambeau, Charles A.; Slater, Colin. T.; Ivezić, Željko; Connolly, Andrew J.

2018-01-01

We report on g-, r-, and i-band observations of the Interstellar Object 1I/‘Oumuamua (1I) taken on 2017 October 29 from 04:28 to 08:40 UTC by the Apache Point Observatory (APO) 3.5 m telescope’s ARCTIC camera. We find that 1I’s colors are g-r=0.41+/- 0.24 and r-i=0.23+/- 0.25, consistent with visible spectra and most comparable to the population of solar system C/D asteroids, Trojans, or comets. We find no evidence of any cometary activity at a heliocentric distance of 1.46 au, approximately 1.5 months after 1I’s closest approach distance to the Sun. Significant brightness variability was seen in the r observations, with the object becoming notably brighter toward the end of the run. By combining our APO photometric time series data with the Discovery Channel Telescope data of Knight et al., taken 20 hr later on 2017 October 30, we construct an almost complete lightcurve with a most probable single-peaked lightcurve period of P≃ 4 {hr}. Our results imply a double-peaked rotation period of 8.1 ± 0.02 hr, with a peak-to-trough amplitude of 1.5–2.1 mag. Assuming that 1I’s shape can be approximated by an ellipsoid, the amplitude constraint implies that 1I has an axial ratio of 3.5–10.3, which is strikingly elongated. Assuming that 1I is rotating above its critical break up limit, our results are compatible with 1I having modest cohesive strength and may have obtained its elongated shape during a tidal distortion event before being ejected from its home system.

Exposure to Ultrafine Particles from Ambient Air and Oxidative Stress–Induced DNA Damage

PubMed Central

Bräuner, Elvira Vaclavik; Forchhammer, Lykke; Møller, Peter; Simonsen, Jacob; Glasius, Marianne; Wåhlin, Peter; Raaschou-Nielsen, Ole; Loft, Steffen

2007-01-01

Background Particulate matter, especially ultrafine particles (UFPs), may cause health effects through generation of oxidative stress, with resulting damage to DNA and other macromolecules. Objective We investigated oxidative damage to DNA and related repair capacity in peripheral blood mononuclear cells (PBMCs) during controlled exposure to urban air particles with assignment of number concentration (NC) to four size modes with average diameters of 12, 23, 57, and 212 nm. Design Twenty-nine healthy adults participated in a randomized, two-factor cross-over study with or without biking exercise for 180 min and with exposure to particles (NC 6169-15362/cm3) or filtered air (NC 91-542/cm3) for 24 hr. Methods The levels of DNA strand breaks (SBs), oxidized purines as formamidopyrimidine DNA glycolase (FPG) sites, and activity of 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1) in PBMCs were measured by the Comet assay. mRNA levels of OGG1, nucleoside diphosphate linked moiety X-type motif 1 (NUDT1), and heme oxygenase-1 (HO1) were determined by real-time reverse transcriptase–polymerase chain reaction. Results Exposure to UFPs for 6 and 24 hr significantly increased the levels of SBs and FPG sites, with a further insignificant increase after physical exercise. The OGG1 activity and expression of OGG1, NUDT1, and HO1 were unaltered. There was a significant dose–response relationship between NC and DNA damage, with the 57-nm mode as the major contributor to effects. Concomitant exposure to ozone, nitrogen oxides, and carbon monoxide had no influence. Conclusion Our results indicate that UFPs, especially the 57-nm soot fraction from vehicle emissions, causes systemic oxidative stress with damage to DNA and no apparent compensatory up-regulation of DNA repair within 24 hr. PMID:17687444

Xrcc2 deficiency sensitizes cells to apoptosis by MNNG and the alkylating anticancer drugs temozolomide, fotemustine and mafosfamide.

PubMed

Tsaryk, Roman; Fabian, Kerstin; Thacker, John; Kaina, Bernd

2006-08-08

DNA double-strand breaks (DSBs) are potent killing lesions, and inefficient repair of DSBs does not only lead to cell death but also to genomic instability and tumorigenesis. DSBs are repaired by non-homologous end-joining and homologous recombination (HR). A key player in HR is Xrcc2, a Rad51-like protein. Cells deficient in Xrcc2 are hypersensitive to X-rays and mitomycin C and display increased chromosomal aberration frequencies. In order to elucidate the role of Xrcc2 in resistance to anticancer drugs, we compared Xrcc2 knockout (Xrcc2-/-) mouse embryonic fibroblasts with the corresponding isogenic wild-type and Xrcc2 complemented knockout cells. We show that Xrcc2-/- cells are hypersensitive to the killing effect of the simple methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). They undergo apoptosis after MNNG treatment while necrosis is only marginally enhanced. Complementation of Xrcc2 deficient cells by Xrcc2 cDNA transfection conferred resistance to the cytotoxic and apoptosis-inducing effect of MNNG. The hypersensitivity of Xrcc2-/- cells to MNNG prompted us to investigate their killing and apoptotic response to various methylating, chloroethylating and crosslinking drugs used in anticancer therapy. Xrcc2 deficient cells were found to be hypersensitive to temozolomide, fotemustine and mafosfamide. They were also hypersensitive to cisplatin but not to taxol. The data reveal that Xrcc2 plays a role in the protection against a wide range of anticancer drugs and, therefore, suggest Xrcc2 to be a determinant of anticancer drug resistance. They also indicate that HR is involved in the processing of DNA damage induced by simple alkylating agents.

Depressive symptoms and externalizing behaviors among Hispanic immigrant adolescents: Examining longitudinal effects of cultural stress.

PubMed

Cano, Miguel Ángel; Schwartz, Seth J; Castillo, Linda G; Romero, Andrea J; Huang, Shi; Lorenzo-Blanco, Elma I; Unger, Jennifer B; Zamboanga, Byron L; Des Rosiers, Sabrina E; Baezconde-Garbanati, Lourdes; Lizzi, Karina M; Soto, Daniel W; Oshri, Assaf; Villamar, Juan Andres; Pattarroyo, Monica; Szapocznik, José

2015-07-01

This study examined longitudinal effects of cultural stress (a latent factor comprised of bicultural stress, ethnic discrimination, and negative context of reception) on depressive symptoms and a range of externalizing behaviors among recently (≤5 years in the U.S. at baseline) immigrated Hispanic adolescents. A sample of 302 adolescents (53% boys; mean age 14.51 years) completed baseline measures of perceived ethnic discrimination, bicultural stress, and perceived negative context of reception; and outcome measures of depressive symptoms, cigarette smoking, alcohol use, aggressive behavior, and rule-breaking behavior six months post-baseline. A path analysis indicated that higher cultural stress scores predicted higher levels of all outcomes. These effects were consistent across genders, but varied by study site. Specifically, higher cultural stress scores increased depressive symptoms among participants in Miami, but not in Los Angeles. Findings suggest that cultural stress is a clinically relevant predictor of depressive symptoms and externalizing behaviors among Hispanic immigrant adolescents. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Arterial stress hormones during scuba diving with different breathing gases.

PubMed

Weist, Frank; Strobel, Günther; Hölzl, Mathias; Böning, Dieter

2012-07-01

The purpose of the study was to determine whether the conditions during scuba diving without exercise (e.g., submersion, restricted breathing) stimulate the activities of the sympathoadrenergic system and the hypothalamic-pituitary-adrenal axis. This might facilitate panic reactions in dangerous situations. Fifteen experienced rescue divers participated in three experiments with two submersions each in a diving tower where ambient pressure could be varied. During submersion (duration = 15 min), they were breathing either pure oxygen (ambient pressure = 1.1 bar) or air (1.1 and 5.3 bar) or Heliox21 (21% O(2) and 79% He, 1.1 and 5.3 bar). The subjects stayed upright immediately below the water surface holding one hand with a cannulated radial artery out in the air. Noradrenaline, adrenaline, and dopamine concentrations in arterial blood and heart rate (HR) variability as indicators of sympathoadrenergic activity and cortisol and adrenocorticotropic hormone concentrations as strain indicators were measured. [Noradrenaline] and [adrenaline] (initial values (mean ± SE) = 1616 ± 93 and 426 ± 38 pmol·L(-1)) decreased significantly by up to 30% and 50%, respectively, after 11 min of submersion, independent of pressure and inspired gas. HR variability showed roughly corresponding changes and also indications for parasympathetic stimulation, but artifacts by interference among HR monitors reduced the number of usable measurements. The other hormone concentrations did not change significantly. There was no increase of stress hormone concentrations in experienced subjects. The reduction of [noradrenaline] and [adrenaline] during scuba diving seems to be a reaction to orthostatic relief caused by external hydrostatic pressure on peripheral vasculature. The activity of the vegetative nervous system might be estimated from HR variability if interference among pulse watches can be avoided.

Prognostic value of circulating microRNAs in upper tract urinary carcinoma

PubMed Central

Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-01-01

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC. PMID:29682178

Increased risk of death immediately after losing a spouse: Cause-specific mortality following widowhood in Norway.

PubMed

Brenn, Tormod; Ytterstad, Elinor

2016-08-01

This paper examines the short-term risk of cause-specific death following widowhood. We followed all individuals registered as married in Norway in 1975 for marital status and mortality until 2006. Widowed individuals were followed for mortality for 7years following widowhood. Causes of death were categorized into five cause-groups. Life tables were used in survival analyses. Deaths among the widowed were most frequent in the week following widowhood. In this week and compared to married individuals, there were more deaths including those from malignant cancer in men (hazard ratio (HR) of 1.51; 95% CI: 1.12, 1.89), from external causes in men (HR=3.64; 95% CI: 2.01, 5.28), and from respiratory diseases (HR=2.18; 95% CI: 1.52, 2.84 in men and HR=3.18; 95% CI: 2.26, 4.09 in women). A majority of respiratory deaths were from pneumonia. Thereafter excess mortality among the widowed dropped gradually. Although these numbers stabilized, they were still elevated in year 7. Excess mortality was particularly high in the youngest age group considered (55-64years) and decreased with age, though more so in men than in women. Only a few more widowed individuals than expected died of a condition in the same cause-group as their spouses. A novel finding was that excess deaths in the week following widowhood also were from cancer and respiratory diseases. Men in the youngest age group seemed most vulnerable. Prevention should be considered directly after the death of a spouse, and measures should be aimed at virtually all causes of death. Copyright © 2016 Elsevier Inc. All rights reserved.

Prognostic value of circulating microRNAs in upper tract urinary carcinoma.

PubMed

Montalbo, Ruth; Izquierdo, Laura; Ingelmo-Torres, Mercedes; Lozano, Juan José; Capitán, David; Alcaraz, Antonio; Mengual, Lourdes

2018-03-30

The identification of upper tract urinary carcinoma (UTUC) prognostic biomarkers is urgently needed to predict tumour progression. This study aimed to identify serum microRNAs (miRNAs) that may be useful as minimally invasive predictive biomarkers of tumour progression and survival in UTUC patients. To this end, 33 UTUC patients who underwent radical nephroureterectomy at the Hospital Clinic of Barcelona were prospectively included. Expression of 800 miRNAs was evaluated in serum samples from these patients using nCounter® miRNA Expression Assays. The study was divided into an initial discovery phase (n=12) and a validation phase (n=21). Cox regression analysis was used for survival analysis. The median follow-up (range) of the series was 42 months (9-100 months). In the discovery phase, 38 differentially expressed miRNAs were identified between progressing and non-progressing UTUC patients (p<0.05). Validation of these 38 miRNAs in an independent set of UTUC patients confirmed the differential expression in 18 of them (p<0.05). Cox Regression analysis showed miR-151b and pathological stage as significant prognostic factors for tumour progression (HR=0.33, p<0.001 and HR=2.62, p=0.006, respectively) and cancer specific survival (HR=0.25, p<0.001 and HR=3.98, p=0.003, respectively). Survival curves revealed that miR-151b is able to discriminate between two groups of UTUC patients with a highly significant different probability of tumour progression (p=0.006) and cancer specific survival (p=0.034). Although the data needs to be externally validated, miRNA analysis in serum appears to be a valuable prognostic tool in UTUC patients. Particularly, differential expression of miR-151b in serum may serve as a minimally invasive prognostic tool in UTUC.

Suicide and unintentional injury mortality among homeless people: a Danish nationwide register-based cohort study.

PubMed

Feodor Nilsson, Sandra; Hjorthøj, Carsten Rygaard; Erlangsen, Annette; Nordentoft, Merete

2014-02-01

Homeless people have elevated mortality, especially due to external causes. We aimed to examine suicide and unintentional injury mortality levels and identify predictors in the homeless population. A nationwide, register-based cohort study of homeless people aged 16 years and older was carried out using the Danish Homeless Register, 1999-2008. In all, 32 010 homeless people (70.5% men) were observed. For men, the mortality rate was 174.4 [95% confidence interval (CI) = 150.6-198.1] per 100 000 person-years for suicide and 463.3 (95% CI = 424.6-502.0) for unintentional injury. For women, the corresponding rates were 111.4 (95% CI = 81.7-141.1) for suicide and 241.4 (95% CI = 197.6-285.1) for unintentional injury. Schizophrenia spectrum, affective, personality and substance use disorders were strongly associated with increased risk of suicide; the highest risk estimates were found for schizophrenia spectrum disorders among both men [hazard ratio (HR) = 3.1, 95% CI = 2.0-4.9] and women (HR = 15.5, 95% CI = 4.5-54.0). Alcohol and drug use disorders were predictors of death by unintentional injury for both men and women, whereas schizophrenia spectrum disorders and personality disorders were only significant predictors among men; the highest risk estimates were found for drug use disorders among men (HR = 2.2, 95% CI = 1.8-2.8) and women (HR = 3.1, 95% CI = 1.8-5.4). A history of psychiatric admission and emergency room contact were predictors for dying by suicide and unintentional injury. People in the homeless shelter population with a history of a psychiatric disorder constitute a high-risk group regarding the elevated suicide and unintentional injury mortality.

Transduction of Nonhuman Primate Brain with Adeno-Associated Virus Serotype 1: Vector Trafficking and Immune Response

PubMed Central

Forsayeth, John; Mirek, Hanna; Munson, Keith; Bringas, John; Pivirotto, Phil; McBride, Jodi L; Davidson, Beverly L.; Bankiewicz, Krystof S.

2009-01-01

Abstract We used convection-enhanced delivery (CED) to characterize gene delivery mediated by adeno-associated virus type 1 (AAV1) by tracking expression of hrGFP (humanized green fluorescent protein from Renilla reniformis) into the striatum, basal forebrain, and corona radiata of monkey brain. Four cynomolgus monkeys received single infusions into corona radiata, putamen, and caudate. The other group (n = 4) received infusions into basal forebrain. Thirty days after infusion animals were killed and their brains were processed for immunohisto-chemical evaluation. Volumetric analysis of GFP-positive brain areas was performed. AAV1-hrGFP infusions resulted in approximately 550, 700, and 73 mm3 coverage after infusion into corona radiata, striatum, and basal forebrain, respectively. Aside from targeted regions, other brain structures also showed GFP signal (internal and external globus pallidus, subthalamic nucleus), supporting the idea that AAV1 is actively trafficked to regions distal from the infusion site. In addition to neuronal transduction, a significant nonneuronal cell population was transduced by AAV1 vector; for example, oligodendrocytes in corona radiata and astrocytes in the striatum. We observed a strong humoral and cell-mediated response against AAV1-hrGFP in transduced monkeys irrespective of the anatomic location of the infusion, as evidenced by induction of circulating anti-AAV1 and anti-hrGFP antibodies, as well as infiltration of CD4+ lymphocytes and upregulation of MHC-II in regions infused with vector. We conclude that transduction of antigen-presenting cells within the CNS is a likely cause of this response and that caution is warranted when foreign transgenes are used as reporters in gene therapy studies with vectors with broader tropism than AAV2. PMID:19292604

Social inequalities in mental health and mortality among refugees and other immigrants to Sweden – epidemiological studies of register data

PubMed Central

Hollander, Anna-Clara

2013-01-01

The aim of this PhD project was to increase knowledge, using population-based registers, of how pre- and post-migration factors and social determinants of health are associated with inequalities in poor mental health and mortality among refugees and other immigrants to Sweden. Study I and II had cross-sectional designs and used logistic regression analysis to study differences in poor mental health (measured with prescribed psychotropic drugs purchased) between refugee and non-refugee immigrants. In Study I, there was a significant difference in poor mental health between female refugees and non-refugees (OR=1.27; CI=1.15–1.40) when adjusted for socio-economic factors. In Study II, refugees of most origins had a higher likelihood of poor mental health than non-refugees of the same origin. Study III and IV had cohort designs and used Cox regression analysis. Study III analysed mortality rates among non-labour immigrants. Male refugees had higher relative risks of mortality from cardiovascular disease (HR=1.53; CI=1.04–2.24) and external causes (HR=1.59; CI=1.01–2.50) than male non-refugees did, adjusted for socio-economic factors. Study IV included the population with a strong connection to the labour market in 1999 to analyse the relative risk of hospitalisation due to depressive disorder following unemployment. The lowest relative risk was found among employed Swedish-born men and the highest among foreign-born females who lost employment during follow-up (HR=3.47; CI=3.02–3.98). Immigrants, and particularly refugees, have poorer mental health than native Swedes. Refugee men have a higher relative mortality risk for cardiovascular disease and external causes of death than do non-refugees. The relative risk of hospitalisation due to depressive disorder following unemployment was highest among immigrant women. To promote mental health and reduce mortality among immigrants, it is important to consider pre- and post-migration factors and the general social determinants of health. PMID:23810108

Permeation-solid adsorbent sampling and GC analysis of formaldehyde.

PubMed

Muntuta-Kinyanta, C; Hardy, J K

1991-12-01

A passive method with membrane permeation sampling for the determination of time-weighted-average (TWA) concentration of formaldehyde in air is described. The sampling device was constructed by affixing an unbacked dimethyl silicone membrane to the base of a glass tube and by sealing the top with a rubber stopper. Formaldehyde permeates the membrane and reacts with 2-(hydroxymethyl)piperidine (2-HMP) coated on the surface of XAD-2. Sampling times from 15 min to 8 hr have been used. The formaldehyde-oxazolidine produced is thermally desorbed and determined by a packed column gas chromatograph equipped with a flame ionization detector (FID). The response of the monitor is directly proportional to the external concentration of formaldehyde over the concentration range 0.050-100 ppm. The permeation constant (the slope of the permeation curve) of the membrane is 0.333 mug ppm(-1). hr, and the detection limit of the method is 0.03 ppm for an 8-hr sampling period. Relative humidity (RH) (35-94%), temperature (0-82 degrees ) and storage period (0-25 days) do not affect the permeation process for sample collection. Moreover, potential chemical interferences, 10 ppm acetone or acrolein, respectively, have no detectable effect on the process. The method gives TWA concentration directly from the measurements, and the equipment is economical and convenient for personal or multi-location sample collections.

Broadly neutralizing antibodies from human survivors target a conserved site in the Ebola virus glycoprotein HR2-MPER region.

PubMed

Flyak, Andrew I; Kuzmina, Natalia; Murin, Charles D; Bryan, Christopher; Davidson, Edgar; Gilchuk, Pavlo; Gulka, Christopher P; Ilinykh, Philipp A; Shen, Xiaoli; Huang, Kai; Ramanathan, Palaniappan; Turner, Hannah; Fusco, Marnie L; Lampley, Rebecca; Kose, Nurgun; King, Hannah; Sapparapu, Gopal; Doranz, Benjamin J; Ksiazek, Thomas G; Wright, David W; Saphire, Erica Ollmann; Ward, Andrew B; Bukreyev, Alexander; Crowe, James E

2018-05-07

Ebola virus (EBOV) in humans causes a severe illness with high mortality rates. Several strategies have been developed in the past to treat EBOV infection, including the antibody cocktail ZMapp, which has been shown to be effective in nonhuman primate models of infection 1 and has been used under compassionate-treatment protocols in humans 2 . ZMapp is a mixture of three chimerized murine monoclonal antibodies (mAbs) 3-6 that target EBOV-specific epitopes on the surface glycoprotein 7,8 . However, ZMapp mAbs do not neutralize other species from the genus Ebolavirus, such as Bundibugyo virus (BDBV), Reston virus (RESTV) or Sudan virus (SUDV). Here, we describe three naturally occurring human cross-neutralizing mAbs, from BDBV survivors, that target an antigenic site in the canonical heptad repeat 2 (HR2) region near the membrane-proximal external region (MPER) of the glycoprotein. The identification of a conserved neutralizing antigenic site in the glycoprotein suggests that these mAbs could be used to design universal antibody therapeutics against diverse ebolavirus species. Furthermore, we found that immunization with a peptide comprising the HR2-MPER antigenic site elicits neutralizing antibodies in rabbits. Structural features determined by conserved residues in the antigenic site described here could inform an epitope-based vaccine design against infection caused by diverse ebolavirus species.

Preparation and Testing of Plant Seed Meal-based Wood Adhesives

PubMed Central

He, Zhongqi; Chapital, Dorselyn C.

2015-01-01

Recently, the interest in plant seed meal-based products as wood adhesives has steadily increased, as these plant raw materials are considered renewable and environment-friendly. These natural products may serve as alternatives to petroleum-based adhesives to ease environmental and sustainability concerns. This work demonstrates the preparation and testing of the plant seed-based wood adhesives using cottonseed and soy meal as raw materials. In addition to untreated meals, water washed meals and protein isolates are prepared and tested. Adhesive slurries are prepared by mixing a freeze-dried meal product with deionized water (3:25 w/w) for 2 hr. Each adhesive preparation is applied to one end of 2 wood veneer strips using a brush. The tacky adhesive coated areas of the wood veneer strips are lapped and glued by hot-pressing. Adhesive strength is reported as the shear strength of the bonded wood specimen at break. Water resistance of the adhesives is measured by the change in shear strength of the bonded wood specimens at break after water soaking. This protocol allows one to assess plant seed-based agricultural products as suitable candidates for substitution of synthetic-based wood adhesives. Adjustments to the adhesive formulation with or without additives and bonding conditions could optimize their adhesive properties for various practical applications. PMID:25867092

Loss of NEIL3 DNA glycosylase markedly increases replication associated double strand breaks and enhances sensitivity to ATR inhibitor in glioblastoma cells

PubMed Central

Klattenhoff, Alex W.; Thakur, Megha; Chu, Christopher S.; Ray, Debolina; Habib, Samy L.; Kidane, Dawit

2017-01-01

DNA endonuclease eight-like glycosylase 3 (NEIL3) is one of the DNA glycosylases that removes oxidized DNA base lesions from single-stranded DNA (ssDNA) and non-B DNA structures. Approximately seven percent of human tumors have an altered NEIL3 gene. However, the role of NEIL3 in replication-associated repair and its impact on modulating treatment response is not known. Here, we report that NEIL3 is localized at the DNA double-strand break (DSB) sites during oxidative DNA damage and replication stress. Loss of NEIL3 significantly increased spontaneous replication-associated DSBs and recruitment of replication protein A (RPA). In contrast, we observed a marked decrease in Rad51 on nascent DNA strands at the replication fork, suggesting that HR-dependent repair is compromised in NEIL3-deficient cells. Interestingly, NEIL3-deficient cells were sensitive to ataxia–telangiectasia and Rad3 related protein (ATR) inhibitor alone or in combination with PARP1 inhibitor. This study elucidates the mechanism by which NEIL3 is critical to overcome oxidative and replication-associated genotoxic stress. Our findings may have important clinical implications to utilize ATR and PARP1 inhibitors to enhance cytotoxicity in tumors that carry altered levels of NEIL3. PMID:29348879

Preparation and testing of plant seed meal-based wood adhesives.

PubMed

He, Zhongqi; Chapital, Dorselyn C

2015-03-05

Recently, the interest in plant seed meal-based products as wood adhesives has steadily increased, as these plant raw materials are considered renewable and environment-friendly. These natural products may serve as alternatives to petroleum-based adhesives to ease environmental and sustainability concerns. This work demonstrates the preparation and testing of the plant seed-based wood adhesives using cottonseed and soy meal as raw materials. In addition to untreated meals, water washed meals and protein isolates are prepared and tested. Adhesive slurries are prepared by mixing a freeze-dried meal product with deionized water (3:25 w/w) for 2 hr. Each adhesive preparation is applied to one end of 2 wood veneer strips using a brush. The tacky adhesive coated areas of the wood veneer strips are lapped and glued by hot-pressing. Adhesive strength is reported as the shear strength of the bonded wood specimen at break. Water resistance of the adhesives is measured by the change in shear strength of the bonded wood specimens at break after water soaking. This protocol allows one to assess plant seed-based agricultural products as suitable candidates for substitution of synthetic-based wood adhesives. Adjustments to the adhesive formulation with or without additives and bonding conditions could optimize their adhesive properties for various practical applications.

RPA accumulation during class switch recombination represents 5'-3' DNA-end resection during the S-G2/M phase of the cell cycle.

PubMed

Yamane, Arito; Robbiani, Davide F; Resch, Wolfgang; Bothmer, Anne; Nakahashi, Hirotaka; Oliveira, Thiago; Rommel, Philipp C; Brown, Eric J; Nussenzweig, Andre; Nussenzweig, Michel C; Casellas, Rafael

2013-01-31

Activation-induced cytidine deaminase (AID) promotes chromosomal translocations by inducing DNA double-strand breaks (DSBs) at immunoglobulin (Ig) genes and oncogenes in the G1 phase. RPA is a single-stranded DNA (ssDNA)-binding protein that associates with resected DSBs in the S phase and facilitates the assembly of factors involved in homologous repair (HR), such as Rad51. Notably, RPA deposition also marks sites of AID-mediated damage, but its role in Ig gene recombination remains unclear. Here, we demonstrate that RPA associates asymmetrically with resected ssDNA in response to lesions created by AID, recombination-activating genes (RAG), or other nucleases. Small amounts of RPA are deposited at AID targets in G1 in an ATM-dependent manner. In contrast, recruitment in the S-G2/M phase is extensive, ATM independent, and associated with Rad51 accumulation. In the S-G2/M phase, RPA increases in nonhomologous-end-joining-deficient lymphocytes, where there is more extensive DNA-end resection. Thus, most RPA recruitment during class switch recombination represents salvage of unrepaired breaks by homology-based pathways during the S-G2/M phase of the cell cycle. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Non-reciprocity in nonlinear elastodynamics

NASA Astrophysics Data System (ADS)

Blanchard, Antoine; Sapsis, Themistoklis P.; Vakakis, Alexander F.

2018-01-01

Reciprocity is a fundamental property of linear time-invariant (LTI) acoustic waveguides governed by self-adjoint operators with symmetric Green's functions. The break of reciprocity in LTI elastodynamics is only possible through the break of time reversal symmetry on the micro-level, and this can be achieved by imposing external biases, adding nonlinearities or allowing for time-varying system properties. We present a Volterra-series based asymptotic analysis for studying spatial non-reciprocity in a class of one-dimensional (1D), time-invariant elastic systems with weak stiffness nonlinearities. We show that nonlinearity is neither necessary nor sufficient for breaking reciprocity in this class of systems; rather, it depends on the boundary conditions, the symmetries of the governing linear and nonlinear operators, and the choice of the spatial points where the non-reciprocity criterion is tested. Extension of the analysis to higher dimensions and time-varying systems is straightforward from a mathematical point of view (but not in terms of new non-reciprocal physical phenomena), whereas the connection of non-reciprocity and time irreversibility can be studied as well. Finally, we show that suitably defined non-reciprocity measures enable optimization, and can provide physical understanding of the nonlinear effects in the dynamics, enabling one to establish regimes of "maximum nonlinearity." We highlight the theoretical developments by means of a numerical example.

The Synchrotron Spectrum of Fast Cooling Electrons Revisited.

PubMed

Granot; Piran; Sari

2000-05-10

We discuss the spectrum arising from synchrotron emission by fast cooling (FC) electrons, when fresh electrons are continually accelerated by a strong blast wave, into a power-law distribution of energies. The FC spectrum has so far been described by four power-law segments divided by three break frequencies nusa

Opening a band gap without breaking lattice symmetry: a new route toward robust graphene-based nanoelectronics.

PubMed

Kou, Liangzhi; Hu, Feiming; Yan, Binghai; Frauenheim, Thomas; Chen, Changfeng

2014-07-07

Developing graphene-based nanoelectronics hinges on opening a band gap in the electronic structure of graphene, which is commonly achieved by breaking the inversion symmetry of the graphene lattice via an electric field (gate bias) or asymmetric doping of graphene layers. Here we introduce a new design strategy that places a bilayer graphene sheet sandwiched between two cladding layers of materials that possess strong spin-orbit coupling (e.g., Bi2Te3). Our ab initio and tight-binding calculations show that a proximity enhanced spin-orbit coupling effect opens a large (44 meV) band gap in bilayer graphene without breaking its lattice symmetry, and the band gap can be effectively tuned by an interlayer stacking pattern and significantly enhanced by interlayer compression. The feasibility of this quantum-well structure is demonstrated by recent experimental realization of high-quality heterojunctions between graphene and Bi2Te3, and this design also conforms to existing fabrication techniques in the semiconductor industry. The proposed quantum-well structure is expected to be especially robust since it does not require an external power supply to open and maintain a band gap, and the cladding layers provide protection against environmental degradation of the graphene layer in its device applications.

Optical study of the counterpart to GRB 990712

NASA Astrophysics Data System (ADS)

Gorosabel, J.; Castro-Tirado, A. J.; Saizar, P.; Rattenbury, N. J.; Bond, I. A.; Yock, P.; Hearnshaw, J.; Kilmartin, P. M.; Muraki, Y.; Nakamura, T.; Ohnishi, K.; Reid, M.; Saito, To; Noda, S.

2000-09-01

Quasi-simultaneous BVR-band observations performed from New Zealand and Argentina ~16 hr after the burst clearly detected the optical counterpart to GR-B 990712. Based on these measurements we construct the optical multi-band spectrum. We report that the spectrum between the R and B bands follows a power law Fv~νβ with index β=-0.50+/-0.16. The spectrum is consistent with a stretch of an afterglow spectrum between the peak frequency, νm, and the cooling break, νc. The photon index derived following the model of Sari et al. (1998), p=2.36+/-0.08 is compatible with β and the power law decay, α, only if no absorption is introduced. Thus, our results support that GRB 990712 occurred in a low density region, resembling GRB 970508. .

The evaluation of upper body muscle activity during the performance of external chest compressions in simulated hypogravity

NASA Astrophysics Data System (ADS)

Krygiel, Rebecca G.; Waye, Abigail B.; Baptista, Rafael Reimann; Heidner, Gustavo Sandri; Rehnberg, Lucas; Russomano, Thais

2014-04-01

BACKGROUND: This original study evaluated the electromyograph (EMG) activity of four upper body muscles: triceps brachii, erector spinae, upper rectus abdominis, and pectoralis major, while external chest compressions (ECCs) were performed in simulated Martian hypogravity using a Body Suspension Device, counterweight system, and standard full body cardiopulmonary resuscitation (CPR) mannequin. METHOD: 20 young, healthy male subjects were recruited. One hundred compressions divided into four sets, with roughly six seconds between each set to indicate 'ventilation', were performed within approximately a 1.5 minute protocol. Chest compression rate, depth and number were measured along with the subject's heart rate (HR) and rating of perceived exertion (RPE). RESULTS: All mean values were used in two-tailed t-tests using SPSS to compare +1 Gz values (control) versus simulated hypogravity values. The AHA (2005) compression standards were maintained in hypogravity. RPE and HR increased by 32% (p < 0.001) and 44% (p = 0.002), respectively, when ECCs were performed during Mars simulation, in comparison to +1 Gz. In hypogravity, the triceps brachii showed significantly less activity (p < 0.001) when compared with the other three muscles studied. The comparison of all the other muscles showed no difference at +1 Gz or in hypogravity. CONCLUSIONS: This study was among the first of its kind, however several limitations were faced which hopefully will not exist in future studies. Evaluation of a great number of muscles will allow space crews to focus on specific strengthening exercises within their current training regimes in case of a serious cardiac event in hypogravity.

External validation of the modified Glasgow prognostic score for renal cancer

PubMed Central

Tai, Caroline G.; Johnson, Timothy V.; Abbasi, Ammara; Herrell, Lindsey; Harris, Wayne B.; Kucuk, Omer; Canter, Daniel J.; Ogan, Kenneth; Pattaras, John G.; Nieh, Peter T.; Master, Viraj A.

2014-01-01

Purpose: The modified Glasgow prognostic Score (mGPS) incorporates C-reactive protein and albumin as a clinically useful marker of tumor behavior. The ability of the mGPS to predict metastasis in localized renal cell carcinoma (RCC) remains unknown in an external validation cohort. Patients and Methods: Patients with clinically localized clear cell RCC were followed for 1 year post-operatively. Metastases were identified radiologically. Patients were categorized by mGPS score as low-risk (mGPS = 0 points), intermediate-risk (mGPS = 1 point) and high-risk (mGPS = 2 points). Univariate, Kaplan-Meier and multivariate Cox regression analyses examined Recurrence -free survival (RFS) across patient and disease characteristics. Results: Of the 129 patients in this study, 23.3% developed metastases. Of low, intermediate and high risk patients, 10.1%, 38.9% and 89.9% recurred during the study. After accounting for various patient and tumor characteristics in multivariate analysis including stage and grade, only mGPS was significantly associated with RFS. Compared with low-risk patients, intermediate- and high-risk patients experienced a 4-fold (hazard ratios [HR]: 4.035, 95% confidence interval [CI]: 1.312-12.415, P = 0.015) and 7-fold (HR: 7.012, 95% CI: 2.126-23.123 P < 0.001) risk of metastasis, respectively. Conclusions: mGPS is a robust predictor of metastasis following potentially curative nephrectomy for localized RCC. Clinicians may consider mGPS as an adjunct to identify high-risk patients for possible enrollment into clinical trials or for patient counseling PMID:24497679

Prognostic model based on nailfold capillaroscopy for identifying Raynaud's phenomenon patients at high risk for the development of a scleroderma spectrum disorder: PRINCE (prognostic index for nailfold capillaroscopic examination).

PubMed

Ingegnoli, Francesca; Boracchi, Patrizia; Gualtierotti, Roberta; Lubatti, Chiara; Meani, Laura; Zahalkova, Lenka; Zeni, Silvana; Fantini, Flavio

2008-07-01

To construct a prognostic index based on nailfold capillaroscopic examinations that is capable of predicting the 5-year transition from isolated Raynaud's phenomenon (RP) to RP secondary to scleroderma spectrum disorders (SSDs). The study involved 104 consecutive adult patients with a clinical history of isolated RP, and the index was externally validated in another cohort of 100 patients with the same characteristics. Both groups were followed up for 1-8 years. Six variables were examined because of their potential prognostic relevance (branching, enlarged and giant loops, capillary disorganization, microhemorrhages, and the number of capillaries). The only factors that played a significant prognostic role were the presence of giant loops (hazard ratio [HR] 2.64, P = 0.008) and microhemorrhages (HR 2.33, P = 0.01), and the number of capillaries (analyzed as a continuous variable). The adjusted prognostic role of these factors was evaluated by means of multivariate regression analysis, and the results were used to construct an algorithm-based prognostic index. The model was internally and externally validated. Our prognostic capillaroscopic index identifies RP patients in whom the risk of developing SSDs is high. This model is a weighted combination of different capillaroscopy parameters that allows physicians to stratify RP patients easily, using a relatively simple diagram to deduce the prognosis. Our results suggest that this index could be used in clinical practice, and its further inclusion in prospective studies will undoubtedly help in exploring its potential in predicting treatment response.

Impact of chitosan as a disintegrant on the bioavailability of furosemide tablets: in vitro evaluation and in vivo simulation of novel formulations.

PubMed

Rasool, Bazigha Kadhim Abdul; Fahmy, Sahar Abdelsattar; Galeel, Omar Waleed Abdul

2012-10-01

To determine the effect of chitosan, starch powder, polyvinylpyrrolidone (PVP), Avicel PH 101 powder, Avicel PH 102 granules as a function of different concentrations on the solubility, disintegration and hence dissolution of furosemide from immediate release tablet dosage forms. The tablets were prepared by the wet granulation method and evaluated for hardness, friability, disintegration and in vitro dissolution. Chitosan 7% w/w showed the fastest disintegration of furosemide tablets among the other disintegrants studied. This was attributed to its highest swelling properties and velocity constant of water uptake. The step of adding chitosan during tablet preparation had a great effect on the physical properties and dissolution profiles of the prepared tablets with external addition of chitosan showed best results compared to best results comparing to internal-external or internal addition. The most appropriate force of compression was 4ton/cm(2). The selected formula F15 containing 7% w/w chitosan was successful and showed a high significant (p<0.001) enhancement in disintegration and dissolution behaviors of furosemide tablets in comparison with the commercially available Furosemide ® tablets. These results were supported by the simulated data where F15 formula showed the highest plasma concentration C-max 1.89mcg/mL after 0.5 hr compared to C-max 1.05mcg/mL after 1hr for the reference. The present study demonstrated that chitosan is a very good candidate to be used as a tablet disintegrant and was able to enhance the dissolution of poorly absorbable drugs.

N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation.

PubMed

Kurashige, Tomomi; Shimamura, Mika; Nagayama, Yuji

2017-11-01

We evaluated the effect of the antioxidant N-acetyl-L-cysteine (NAC) on the levels of reactive oxygen species (ROS), DNA double strand breaks (DSB) and micronuclei (MN) induced by internal and external irradiation using a rat thyroid cell line PCCL3. In internal irradiation experiments, ROS and DSB levels increased immediately after 131 I addition and then gradually declined, resulting in very high levels of MN at 24 and 48 h. NAC administration both pre- and also post- 131 I addition suppressed ROS, DSB and MN. In external irradiation experiments with a low dose (0.5 Gy), ROS and DSB increased shortly and could be prevented by NAC administration pre-, but not post-irradiation. In contrast, external irradiation with a high dose (5 Gy) increased ROS and DSB in a bimodal way: ROS and DSB levels increased immediately after irradiation, quickly returned to the basal levels and gradually rose again after >24 h. The second phase was in parallel with an increase in 4-hydroxy-2-nonenal. The number of MN induced by the second wave of ROS/DSB elevations was much higher than that by the first peak. In this situation, NAC administered pre- and post-irradiation comparably suppressed MN induced by a delayed ROS elevation. In conclusion, a prolonged ROS increase during internal irradiation and a delayed ROS increase after external irradiation with a high dose caused serious DNA damage, which were efficiently prevented by NAC. Thus, NAC administration even both after internal or external irradiation prevents ROS increase and eventual DNA damage.

HTLV-I Tax Increases Genetic Instability by Inducing DNA Double Strand Breaks during DNA Replication and Switching Repair to NHEJ

PubMed Central

Baydoun, Hicham H.; Bai, Xue Tao; Shelton, Shary; Nicot, Christophe

2012-01-01

Background Appropriate responses to damaged DNA are indispensible for preserving genome stability and preventing cancer. Tumor viruses often target DNA repair machinery to achieve transformation. The Human T-cell leukemia virus type I (HTLV-I) is the only known transforming human retrovirus and the etiological agent of Adult T-cell Leukemia (ATLL). Although HTLV-I-transformed leukemic cells have numerous genetic lesions, the precise role of the viral tax gene in this process is not fully understood. Results Our results show a novel function of HTLV-I oncoprotein Tax as an inducer of genomic DNA double strand breaks (DDSB) during DNA replication. We also found that Tax acts as a potent inhibitor of homologous recombination (HR) DNA repair through the activation of the NF-kB pathway. These results were confirmed using HTLV-I molecular clones expressing Tax at physiological levels in a natural context. We further found that HTLV-I- and Tax-transformed cells are not more susceptible to DNA damaging agents and repair DNA lesions at a rate similar to that of normal cells. Finally, we demonstrated that during S phase, Tax-associated DDSB are preferentially repaired using the error-prone non-homologous end joining (NHEJ) pathway. Conclusions This study provides new insights in Tax effects on DNA repair and genome instability. Although it may not be self sufficient, the creation of DNA breaks and subsequent abnormal use of the non-conservative NHEJ DNA repair during the S phase in HTLV-I-infected Tax-expressing cells may cooperate with other factors to increase genetic and genome instability and favor transformation. PMID:22916124

Sedimentary structures formed under water surface waves: examples from a sediment-laden flash flood observed by remote camer

NASA Astrophysics Data System (ADS)

Froude, Melanie; Alexander, Jan; Cole, Paul; Barclay, Jenni

2014-05-01

On 13-14 October 2012, Tropical Storm Rafael triggered sediment-laden flash floods in the Belham Valley on Montserrat, West Indies. Rainfall was continuous for ~38 hours and intensity peaked at 48 mm/hr. Flow was strongly unsteady, turbulent with sediment concentrations varying up to hyperconcentrated. Time-lapse images captured at >1 frame per second by remote camera overlooking a surveyed valley section show the development of trains of water surface waves at multiple channel locations during different flow stages. Waves grew and diminished in height and remained stationary or migrated upstream. Trains of waves persisted for <5 minutes, until a single wave broke, sometimes initiating the breaking of adjacent waves within the train. Channel-wide surges (bores) propagating downstream with distinct turbulent flow fronts, were observed at irregular intervals during and up to 7 hours after peak stage. These bores are mechanically similar to breaking front tidal bores and arid flood bores, and resulted in a sudden increase in flow depth and velocity. When a bore front came into close proximity (within ~10 m) upstream of a train of water surface waves, the waves appeared to break simultaneously generating a localised surge of water upstream, that was covered by the bore travelling downstream. Those trains in which waves did not break during the passage of a bore temporarily reduced in height. In both cases, water surface waves reformed immediately after the surge in the same location. Deposits from the event, were examined in <4 m deep trenches ~0.5 km downstream of the remote camera. These contained laterally extensive lenticular and sheet-like units comprised of varying admixtures of sand and gravel that are attributed to antidunes, and associated transitions from upper-stage-plane-beds. Some of the structures are organised within concave upward sequences which contain downflow shifts between foreset and backset laminae; interpreted as trough fills from chute-and-pools or water surface wave breaking. At least 90% of the deposit is interpreted upper flow regime origin. The sequence, geometry and lamina-scale texture of the sedimentary structures will be discussed with reference to remote camera images of rapidly varying, unsteady and pulsatory flow behaviour.

Thorough subcells diagnosis in a multi-junction solar cell via absolute electroluminescence-efficiency measurements

PubMed Central

Chen, Shaoqiang; Zhu, Lin; Yoshita, Masahiro; Mochizuki, Toshimitsu; Kim, Changsu; Akiyama, Hidefumi; Imaizumi, Mitsuru; Kanemitsu, Yoshihiko

2015-01-01

World-wide studies on multi-junction (tandem) solar cells have led to record-breaking improvements in conversion efficiencies year after year. To obtain detailed and proper feedback for solar-cell design and fabrication, it is necessary to establish standard methods for diagnosing subcells in fabricated tandem devices. Here, we propose a potential standard method to quantify the detailed subcell properties of multi-junction solar cells based on absolute measurements of electroluminescence (EL) external quantum efficiency in addition to the conventional solar-cell external-quantum-efficiency measurements. We demonstrate that the absolute-EL-quantum-efficiency measurements provide I–V relations of individual subcells without the need for referencing measured I–V data, which is in stark contrast to previous works. Moreover, our measurements quantify the absolute rates of junction loss, non-radiative loss, radiative loss, and luminescence coupling in the subcells, which constitute the “balance sheets” of tandem solar cells. PMID:25592484

Coupling Functions Enable Secure Communications

NASA Astrophysics Data System (ADS)

Stankovski, Tomislav; McClintock, Peter V. E.; Stefanovska, Aneta

2014-01-01

Secure encryption is an essential feature of modern communications, but rapid progress in illicit decryption brings a continuing need for new schemes that are harder and harder to break. Inspired by the time-varying nature of the cardiorespiratory interaction, here we introduce a new class of secure communications that is highly resistant to conventional attacks. Unlike all earlier encryption procedures, this cipher makes use of the coupling functions between interacting dynamical systems. It results in an unbounded number of encryption key possibilities, allows the transmission or reception of more than one signal simultaneously, and is robust against external noise. Thus, the information signals are encrypted as the time variations of linearly independent coupling functions. Using predetermined forms of coupling function, we apply Bayesian inference on the receiver side to detect and separate the information signals while simultaneously eliminating the effect of external noise. The scheme is highly modular and is readily extendable to support different communications applications within the same general framework.

Slide Release Device. Shuttle Orbiter/External Tank Forward Attachment

NASA Technical Reports Server (NTRS)

1981-01-01

A prototype release mechanism is discussed which is interchangeable with the existing orbiter/external tank separation bolt and offers reduced weight, shock, and cost. The components are reuseable. The unit takes maximum advantage of the shank diameter and installs in the monoball just as does the shear bolt, by threading in the completely assembled condition. Actuation is different, in that instead of axially breaking the shank by very high pressure (on the order of 60,000 psi) using a very large force (over 235, 000 pounds), this mechanism releases the shank by cross-axis movement against a lubricated surface. Once free, the shank is driven out of the monoball by an axially precompressed spring. Final weight can be as low as 30 pounds, and the cartridge contains less than one gram of powder. The components show no significant wear after eleven actuations under load.

Open innovation as a new paradigm for global collaborations in health.

PubMed

Dandonoli, Patricia

2013-08-30

Open innovation, which refers to combining internal and external ideas and internal and external paths to market in order to achieve advances in processes or technologies, is an attractive paradigm for structuring collaborations between developed and developing country entities and people. Such open innovation collaborations can be designed to foster true co-creation among partners in rich and poor settings, thereby breaking down hierarchies and creating greater impact and value for each partner. Using an example from Concern Worldwide's Innovations for Maternal, Newborn &Child Health initiative, this commentary describes an early-stage pilot project built around open innovation in a low resource setting, which puts communities at the center of a process involving a wide range of partners and expertise, and considers how it could be adapted and make more impactful and sustainable by extending the collaboration to include developed country partners.

The Role of Fragile Sites in Sporadic Papillary Thyroid Carcinoma

PubMed Central

Dillon, Laura W.; Lehman, Christine E.; Wang, Yuh-Hwa

2012-01-01

The incidence of thyroid cancer is increasing, especially papillary thyroid carcinoma (PTC), making it currently the fastest-growing cancer among women. Reasons for this increase remain unclear, but several risk factors including radiation exposure and improved detection techniques have been suggested. Recently, the induction of chromosomal fragile site breakage was found to result in the formation of RET/PTC1 rearrangements, a common cause of PTC. Chromosomal fragile sites are regions of the genome with a high susceptibility to forming DNA breaks and are often associated with cancer. Exposure to a variety of external agents can induce fragile site breakage, which may account for some of the observed increase in PTC. This paper discusses the role of fragile site breakage in PTC development, external fragile site-inducing agents that may be potential risk factors for PTC, and how these factors are especially targeting women. PMID:22762011

Application of an automated natural language processing (NLP) workflow to enable federated search of external biomedical content in drug discovery and development.

PubMed

McEntire, Robin; Szalkowski, Debbie; Butler, James; Kuo, Michelle S; Chang, Meiping; Chang, Man; Freeman, Darren; McQuay, Sarah; Patel, Jagruti; McGlashen, Michael; Cornell, Wendy D; Xu, Jinghai James

2016-05-01

External content sources such as MEDLINE(®), National Institutes of Health (NIH) grants and conference websites provide access to the latest breaking biomedical information, which can inform pharmaceutical and biotechnology company pipeline decisions. The value of the sites for industry, however, is limited by the use of the public internet, the limited synonyms, the rarity of batch searching capability and the disconnected nature of the sites. Fortunately, many sites now offer their content for download and we have developed an automated internal workflow that uses text mining and tailored ontologies for programmatic search and knowledge extraction. We believe such an efficient and secure approach provides a competitive advantage to companies needing access to the latest information for a range of use cases and complements manually curated commercial sources. Copyright © 2016. Published by Elsevier Ltd.

Optical control of filamentation-induced damage to DNA by intense, ultrashort, near-infrared laser pulses

PubMed Central

Dharmadhikari, J. A.; Dharmadhikari, A. K.; Kasuba, K. C.; Bharambe, H.; D’Souza, J. S.; Rathod, K. D.; Mathur, D.

2016-01-01

We report on damage to DNA in an aqueous medium induced by ultrashort pulses of intense laser light of 800 nm wavelength. Focusing of such pulses, using lenses of various focal lengths, induces plasma formation within the aqueous medium. Such plasma can have a spatial extent that is far in excess of the Rayleigh range. In the case of water, the resulting ionization and dissociation gives rise to in situ generation of low-energy electrons and OH-radicals. Interactions of these with plasmid DNA produce nicks in the DNA backbone: single strand breaks (SSBs) are induced as are, at higher laser intensities, double strand breaks (DSBs). Under physiological conditions, the latter are not readily amenable to repair. Systematic quantification of SSBs and DSBs at different values of incident laser energy and under different external focusing conditions reveals that damage occurs in two distinct regimes. Numerical aperture is the experimental handle that delineates the two regimes, permitting simple optical control over the extent of DNA damage. PMID:27279565

How do you approach seizures in the high altitude traveler?

PubMed

Maa, Edward H

2011-01-01

Counseling patients who suffer first-time or break- through seizures can be difficult, particularly when controllable external factors may be contributing to the lowering of their seizure threshold. High altitude as a potential trigger for seizures is a common question in our epilepsy clinics in Colorado, and this article reviews the existing anecdotal literature, presents our local experience with high altitude seizures (HAS), offers possible mechanisms to explain how high altitude may trigger seizures, and suggests an initial work-up and prophylactic strategies for future high altitude exposures.

Negative Compressibility and Inverse Problem for Spinning Gas

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

Vasily Geyko and Nathaniel J. Fisch

2013-01-11

A spinning ideal gas in a cylinder with a smooth surface is shown to have unusual properties. First, under compression parallel to the axis of rotation, the spinning gas exhibits negative compressibility because energy can be stored in the rotation. Second, the spinning breaks the symmetry under which partial pressures of a mixture of gases simply add proportional to the constituent number densities. Thus, remarkably, in a mixture of spinning gases, an inverse problem can be formulated such that the gas constituents can be determined through external measurements only.

Gauged U(1) clockwork theory

NASA Astrophysics Data System (ADS)

Lee, Hyun Min

2018-03-01

We consider the gauged U (1) clockwork theory with a product of multiple gauge groups and discuss the continuum limit of the theory to a massless gauged U (1) with linear dilaton background in five dimensions. The localization of the lightest state of gauge fields on a site in the theory space naturally leads to exponentially small effective couplings of external matter fields localized away from the site. We discuss the implications of our general discussion with some examples, such as mediators of dark matter interactions, flavor-changing B-meson decays as well as D-term SUSY breaking.

Rectification of Spatial Disorder

NASA Astrophysics Data System (ADS)

Um, Jaegon; Hong, Hyunsuk; Marchesoni, Fabio; Park, Hyunggyu

2012-02-01

We demonstrate that a large ensemble of noiseless globally coupled-pinned oscillators is capable of rectifying spatial disorder with spontaneous current activated through a dynamical phase transition mechanism, either of first or second order, depending on the profile of the pinning potential. In the presence of an external weak drive, the same collective mechanism can result in an absolute negative mobility, which, though not immediately related to symmetry breaking, is most prominent at the phase transition. Our results apply to a tug-of-war by competing molecular motors for bidirectional cargo transport.

SU-F-19A-12: Split-Ring Applicator with Interstitial Needle for Improved Volumetric Coverage in HDR Brachytherapy for Cervical Cancer

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

Sherertz, T; Ellis, R; Colussi, V

2014-06-15

Purpose: To evaluate volumetric coverage of a Mick Radionuclear titanium Split-Ring applicator (SRA) with/without interstitial needle compared to an intracavitary Vienna applicator (VA), interstitial-intracavitary VA, and intracavitary ring and tandem applicator (RTA). Methods: A 57 year-old female with FIGO stage IIB cervical carcinoma was treated following chemoradiotherapy (45Gy pelvic and 5.4Gy parametrial boost) with highdose- rate (HDR) brachytherapy to 30Gy in 5 fractions using a SRA. A single interstitial needle was placed using the Ellis Interstitial Cap for the final three fractions to increase coverage of left-sided gross residual disease identified on 3T-MRI. High-risk (HR) clinical target volume (CTV) andmore » intermediate-risk (IR) CTV were defined using axial T2-weighted 2D and 3D MRI sequences (Philips PET/MRI unit). Organs-at-risks (OARs) were delineated on CT. Oncentra planning system was used for treatment optimization satisfying GEC-ESTRO guidelines for target coverage and OAR constraints. Retrospectively, treatment plans (additional 20 plans) were simulated using intracavitary SRA (without needle), intracavitary VA (without needle), interstitial-intracavitary VA, and intracavitary RTA with this same patient case. Plans were optimized for each fraction to maintain coverage to HR-CTV. Results: Interstitial-intracavitary SRA achieved the following combined coverage for external radiation and brachytherapy (EQD2): D90 HR-CTV =94.6Gy; Bladder-2cc =88.9Gy; Rectum-2cc =65.1Gy; Sigmoid-2cc =48.9Gy; Left vaginal wall (VW) =103Gy, Right VW =99.2Gy. Interstitial-intracavitary VA was able to achieve identical D90 HR-CTV =94.6Gy, yet Bladder-2cc =91.9Gy (exceeding GEC-ESTRO recommendations of 2cc<90Gy) and Left VW =120.8Gy and Right VW =115.5Gy. Neither the SRA nor VA without interstitial needle could cover HR-CTV adequately without exceeding dose to Bladder-2cc. Conventional RTA was unable to achieve target coverage for the HR-CTV >80Gy without severely overdosing OARs. Conclusion: The Ellis Interstitial Cap for the SRA offered superior dosimetric coverage as compared to the interstitialintracavitary VA. This represents the first reported use for this devise, and further investigation is warranted.« less

WE-AB-207B-04: A Preliminary Investigation of Indicators for Treatment Outcomes of CT Guided Cervical Cancer Brachytherapy

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

Meerschaert, R; Paul, A; Chen, W

Purpose: To identify indicators for recurrence in cervical cancer patients treated with high-dose-rate brachytherapy (HDR-BT). Methods: A total of 37 biopsy proven uterine cervical cancer patients of stage IB-IVA treated between 2011 and 2015 were included in this study. All patients were treated with 37.8–52.2Gy of external beam radiotherapy (EBRT) plus 5 × 5.0–6.5Gy of HDR-BT. Patient age, standard deviation of high-risk clinical tumor volume (HR-CTVSD) collected throughout HDR-BT, and D90 (EQD2, α/β=10Gy) of the HR-CTV were investigated as potential indicators for local/distant recurrence using ROC analysis. The optimal cutoff value was identified through the Youden index and was subsequentlymore » used to obtain a group assignment for all patients. Another two comparing groups were defined per evidence of post-EBRT tumor shrinkage based on the pre-HDR MR scan. Kaplan-Meier curves were generated for recurrence-free proportions for comparing groups where time was measured from the final HDR treatment date to the date of the final follow-up exam and compared through Cox regression. Results: Patients had a median follow-up of 12 months, where 16% had local pelvic recurrence and 16% had distant recurrence. HR-CTVSD was identified as a statistically significant indicator for recurrence (AUC=0.802, p=0.007) compared to D90 (AUC=0.655, p=0.167) and patient age (AUC=0.683, p=0.103). HR-CTVSD of 6.26cc was chosen as the optimal cutoff value, which was used as the basis for patient group assignment. Patients with HR-CTVSD>6.26cc had a hazard ratio of 3.92 (95% CI-1.37, 11.24; p=0.011) for recurrence compared to HRCTVSD≤ 6.26cc. Patients without evidence of post-EBRT tumor shrinkage compared to those with had a hazard ratio of 4.28 (95% CI-1.14, 16.15; p=0.032) for recurrence. Conclusion: HR-CTVSD was identified as an indicator for recurrence and an optimal value of 6.26cc was established in our study. In addition, patients without evidence of post-EBRT tumor shrinkage demonstrated an increased recurrence rate.« less

A Jet Break in the X-ray Light Curve of Short GRB 111020A: Implications for Energetics and Rates

NASA Technical Reports Server (NTRS)

Fong, W.; Berger, E.; Margutti, R.; Zauderer, B. A.; Troja, E.; Czekala, I.; Chornock, R.; Gehrels, N.; Sakamoto, T.; Fox, D. B.;

Outcomes in a multi-institutional cohort of patients treated with intraoperative radiation therapy for advanced or recurrent renal cell carcinoma.

PubMed

Paly, Jonathan J; Hallemeier, Christopher L; Biggs, Peter J; Niemierko, Andrzej; Roeder, Falk; Martínez-Monge, Rafael; Whitson, Jared; Calvo, Felipe A; Fastner, Gerd; Sedlmayer, Felix; Wong, William W; Ellis, Rodney J; Haddock, Michael G; Choo, Richard; Shipley, William U; Zietman, Anthony L; Efstathiou, Jason A

2014-03-01

This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. IORT was delivered during nephrectomy for advanced disease (28%) or during resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT. Copyright © 2014 Elsevier Inc. All rights reserved.

Breast Cancer Laterality Does Not Influence Survival in a Large Modern Cohort: Implications for Radiation-Related Cardiac Mortality

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

Rutter, Charles E., E-mail: charles.rutter@yale.edu; Chagpar, Anees B.; Cancer Outcomes, Public Policy and Effectiveness Research Center, Yale School of Medicine, New Haven, Connecticut

2014-10-01

Objectives: Radiation therapy for left-sided breast cancer has been associated with an elevated risk of cardiac mortality, based on studies predating treatment planning based on computed tomography. This study assessed the impact of tumor laterality on overall survival (OS) in a large cohort treated with modern techniques, to indirectly determine whether left-sided treatment remains associated with increased cardiac mortality. Methods and Materials: Patients treated for breast cancer with breast conserving surgery and adjuvant external beam radiation therapy were identified in the National Cancer Database, and OS was compared based on tumor laterality using Kaplan-Meier analysis. Separate analyses were performed formore » noninvasive and invasive carcinoma and for breast-only and breast plus regional nodal radiation therapy. Multivariate regression analysis of OS was performed with demographic, pathologic, and treatment variables as covariates to adjust for factors associated with breast cancer–specific survival. Results: We identified 344,831 patients whose cancer was diagnosed from 1998 to 2006 with a median follow-up time of 6.04 years (range, 0-14.17 years). Clinical, tumor, and treatment characteristics were similar between laterality groups. Regional nodal radiation was used in 14.2% of invasive cancers. No OS difference was noted based on tumor laterality for patients treated with breast-only (hazard ratio [HR] 0.984, P=.132) and breast plus regional nodal radiation therapy (HR 1.001, P=.957). In multivariate analysis including potential confounders, OS was identical between left and right sided cancers (HR 1.002, P=.874). No significant OS difference by laterality was observed when analyses were restricted to patients with at least 10 years of follow-up (n=27,725), both in patients treated with breast-only (HR 0.955, P=.368) and breast plus regional nodal radiation therapy (HR 0.859, P=.155). Conclusions: Radiation therapy for left-sided breast cancer does not appear to increase the risk of death in this national database relative to right-sided tumors. Consequently, radiation therapy–induced cardiac disease may be less prominent than previously demonstrated.« less

Outcomes in a Multi-institutional Cohort of Patients Treated With Intraoperative Radiation Therapy for Advanced or Recurrent Renal Cell Carcinoma

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

Paly, Jonathan J.; Hallemeier, Christopher L.; Biggs, Peter J.

2014-03-01

Purpose/Objective(s): This study aimed to analyze outcomes in a multi-institutional cohort of patients with advanced or recurrent renal cell carcinoma (RCC) who were treated with intraoperative radiation therapy (IORT). Methods and Materials: Between 1985 and 2010, 98 patients received IORT for advanced or locally recurrent RCC at 9 institutions. The median follow-up time for surviving patients was 3.5 years. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method. Chained imputation accounted for missing data, and multivariate Cox hazards regression tested significance. Results: IORT was delivered during nephrectomy for advanced disease (28%) or duringmore » resection of locally recurrent RCC in the renal fossa (72%). Sixty-nine percent of the patients were male, and the median age was 58 years. At the time of primary resection, the T stages were as follows: 17% T1, 12% T2, 55% T3, and 16% T4. Eighty-seven percent of the patients had a visibly complete resection of tumor. Preoperative or postoperative external beam radiation therapy was administered to 27% and 35% of patients, respectively. The 5-year OS was 37% for advanced disease and 55% for locally recurrent disease. The respective 5-year DSS was 41% and 60%. The respective 5-year DFS was 39% and 52%. Initial nodal involvement (hazard ratio [HR] 2.9-3.6, P<.01), presence of sarcomatoid features (HR 3.7-6.9, P<.05), and higher IORT dose (HR 1.3, P<.001) were statistically significantly associated with decreased survival. Adjuvant systemic therapy was associated with decreased DSS (HR 2.4, P=.03). For locally recurrent tumors, positive margin status (HR 2.6, P=.01) was associated with decreased OS. Conclusions: We report the largest known cohort of patients with RCC managed by IORT and have identified several factors associated with survival. The outcomes for patients receiving IORT in the setting of local recurrence compare favorably to similar cohorts treated by local resection alone suggesting the potential for improved DFS with IORT.« less

Disk Emission from Magnetohydrodynamic Simulations of Spinning Black Holes

NASA Technical Reports Server (NTRS)

Schnittman, Jeremy D.; Krolik, Julian H.; Noble, Scott C.

2016-01-01

We present the results of a new series of global, three-dimensional, relativistic magnetohydrodynamic (MHD) simulations of thin accretion disks around spinning black holes. The disks have aspect ratios of H/R approx. 0.05 and spin parameters of a/M = 0, 0.5, 0.9, and 0.99. Using the ray-tracing code Pandurata, we generate broadband thermal spectra and polarization signatures from the MHD simulations. We find that the simulated spectra can be well fit with a simple, universal emissivity profile that better reproduces the behavior of the emission from the inner disk, compared to traditional analyses carried out using a Novikov-Thorne thin disk model. Finally, we show how spectropolarization observations can be used to convincingly break the spin-inclination degeneracy well known to the continuum-fitting method of measuring black hole spin.

Dynamical responses to external stimuli for both cases of excitatory and inhibitory synchronization in a complex neuronal network.

PubMed

Kim, Sang-Yoon; Lim, Woochang

2017-10-01

For studying how dynamical responses to external stimuli depend on the synaptic-coupling type, we consider two types of excitatory and inhibitory synchronization (i.e., synchronization via synaptic excitation and inhibition) in complex small-world networks of excitatory regular spiking (RS) pyramidal neurons and inhibitory fast spiking (FS) interneurons. For both cases of excitatory and inhibitory synchronization, effects of synaptic couplings on dynamical responses to external time-periodic stimuli S ( t ) (applied to a fraction of neurons) are investigated by varying the driving amplitude A of S ( t ). Stimulated neurons are phase-locked to external stimuli for both cases of excitatory and inhibitory couplings. On the other hand, the stimulation effect on non-stimulated neurons depends on the type of synaptic coupling. The external stimulus S ( t ) makes a constructive effect on excitatory non-stimulated RS neurons (i.e., it causes external phase lockings in the non-stimulated sub-population), while S ( t ) makes a destructive effect on inhibitory non-stimulated FS interneurons (i.e., it breaks up original inhibitory synchronization in the non-stimulated sub-population). As results of these different effects of S ( t ), the type and degree of dynamical response (e.g., synchronization enhancement or suppression), characterized by the dynamical response factor [Formula: see text] (given by the ratio of synchronization degree in the presence and absence of stimulus), are found to vary in a distinctly different way, depending on the synaptic-coupling type. Furthermore, we also measure the matching degree between the dynamics of the two sub-populations of stimulated and non-stimulated neurons in terms of a "cross-correlation" measure [Formula: see text]. With increasing A , based on [Formula: see text], we discuss the cross-correlations between the two sub-populations, affecting the dynamical responses to S ( t ).

Enhanced magnetic field probe array for improved excluded flux calculations on the C-2U advanced beam-driven field-reversed configuration plasma experiment

NASA Astrophysics Data System (ADS)

Roche, T.; Thompson, M. C.; Mendoza, R.; Allfrey, I.; Garate, E.; Romero, J.; Douglass, J.

2016-11-01

External flux conserving coils were installed onto the exterior of the C-2U [M. W. Binderbauer et al., Phys. Plasmas 22, 056110 (2015)] confinement vessel to increase the flux confinement time of the system. The 0.5 in. stainless steel vessel wall has a skin time of ˜5 ms. The addition of the external copper coils effectively increases this time to ˜7 ms. This led to better-confined/longer-lived field-reversed configuration (FRC) plasmas. The fringing fields generated by the external coils have the side effect of rendering external field measurements invalid. Such measurements were key to the previous method of excluded flux calculation [M. C. Thompson et al., Rev. Sci. Instrum. 83, 10D709 (2012)]. A new array of B-dot probes and Rogowski coils were installed to better determine the amount of flux leaked out of the system and ultimately provide a more robust measurement of plasma parameters related to pressure balance including the excluded flux radius. The B-dot probes are surface mountable chip inductors with inductance of 33 μH capable of measuring the DC magnetic field and transient field, due to resistive current decay in the wall/coils, when coupled with active integrators. The Rogowski coils measure the total change in current in each external coil (150 A/2 ms). Currents were also actively driven in the external coils. This renders the assumption of total flux conservation invalid which further complicates the analysis process. The ultimate solution to these issues and the record breaking resultant FRC lifetimes will be presented.

External nutrient loading from land, sea and atmosphere to all 656 Swedish coastal water bodies.

PubMed

Bryhn, Andreas C; Dimberg, Peter H; Bergström, Lena; Fredriksson, Ronny E; Mattila, Johanna; Bergström, Ulf

2017-01-30

Identifying the main sources of nutrient loading is a key factor for efficient mitigation of eutrophication. This study has investigated the pathways of external nutrient loading to 656 coastal water bodies along the entire Swedish coastline. The studied water bodies have been delineated to meet requirements in the European Union's Water Framework Directive, and recent status assessments have shown that 57% of them fail to attain good or high ecological status with respect to nutrients. The analysis in the study was performed on data from mass-balance based nutrient budgets computed using the modelling framework Vattenwebb. The external nutrient contribution from the sea to the water bodies was highly variable, ranging from about 1% to nearly 100%, but the median contribution was >99% of the total external loading regarding both nitrogen and phosphorus. External loading from the atmosphere and local catchment area played a minor role in general. However, 45 coastal water bodies received >25% of the external nitrogen and phosphorus from their catchments. Loading from land typically peaked in April following ice-break and snow melting and was comparatively low during summer. The results indicate that for many eutrophicated Swedish coastal water bodies, nutrient abatement is likely to be optimally effective when potential measures in all of the catchment area of the concerned sea basin are considered. Local-scale mitigation in single water bodies will likely be locally effective only in the small proportion of areas where water and thereby also nutrient input from the catchment is high compared to the influx from the sea. Future studies should include nutrient reduction scenarios in order to refine these conclusions and to identify relevant spatial scales for coastal eutrophication mitigation measures from a water body perspective. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enhanced magnetic field probe array for improved excluded flux calculations on the C-2U advanced beam-driven field-reversed configuration plasma experiment.

PubMed

Roche, T; Thompson, M C; Mendoza, R; Allfrey, I; Garate, E; Romero, J; Douglass, J

2016-11-01

External flux conserving coils were installed onto the exterior of the C-2U [M. W. Binderbauer et al., Phys. Plasmas 22, 056110 (2015)] confinement vessel to increase the flux confinement time of the system. The 0.5 in. stainless steel vessel wall has a skin time of ∼5 ms. The addition of the external copper coils effectively increases this time to ∼7 ms. This led to better-confined/longer-lived field-reversed configuration (FRC) plasmas. The fringing fields generated by the external coils have the side effect of rendering external field measurements invalid. Such measurements were key to the previous method of excluded flux calculation [M. C. Thompson et al., Rev. Sci. Instrum. 83, 10D709 (2012)]. A new array of B-dot probes and Rogowski coils were installed to better determine the amount of flux leaked out of the system and ultimately provide a more robust measurement of plasma parameters related to pressure balance including the excluded flux radius. The B-dot probes are surface mountable chip inductors with inductance of 33 μH capable of measuring the DC magnetic field and transient field, due to resistive current decay in the wall/coils, when coupled with active integrators. The Rogowski coils measure the total change in current in each external coil (150 A/2 ms). Currents were also actively driven in the external coils. This renders the assumption of total flux conservation invalid which further complicates the analysis process. The ultimate solution to these issues and the record breaking resultant FRC lifetimes will be presented.

Enhanced magnetic field probe array for improved excluded flux calculations on the C-2U advanced beam-driven field-reversed configuration plasma experiment

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

Roche, T., E-mail: troche@trialphaenergy.com; Thompson, M. C.; Mendoza, R.

2016-11-15

External flux conserving coils were installed onto the exterior of the C-2U [M. W. Binderbauer et al., Phys. Plasmas 22, 056110 (2015)] confinement vessel to increase the flux confinement time of the system. The 0.5 in. stainless steel vessel wall has a skin time of ∼5 ms. The addition of the external copper coils effectively increases this time to ∼7 ms. This led to better-confined/longer-lived field-reversed configuration (FRC) plasmas. The fringing fields generated by the external coils have the side effect of rendering external field measurements invalid. Such measurements were key to the previous method of excluded flux calculation [M.more » C. Thompson et al., Rev. Sci. Instrum. 83, 10D709 (2012)]. A new array of B-dot probes and Rogowski coils were installed to better determine the amount of flux leaked out of the system and ultimately provide a more robust measurement of plasma parameters related to pressure balance including the excluded flux radius. The B-dot probes are surface mountable chip inductors with inductance of 33 μH capable of measuring the DC magnetic field and transient field, due to resistive current decay in the wall/coils, when coupled with active integrators. The Rogowski coils measure the total change in current in each external coil (150 A/2 ms). Currents were also actively driven in the external coils. This renders the assumption of total flux conservation invalid which further complicates the analysis process. The ultimate solution to these issues and the record breaking resultant FRC lifetimes will be presented.« less

Toxicological evaluation of hydrochlorofluorocarbon 142b.

PubMed

Seckar, J A; Trochimowicz, H J; Hogan, G K

1986-03-01

Groups of 110 rats of each sex were exposed by whole-body inhalation to 0, 1000, 10,000 or 20,000 ppm (v/v) of hydrochlorofluorocarbon 142b (CFC 142b or 1-chloro-1, 1-difluoroethane) for 6 hr/day, 5 days/wk for 104 wk (ten rats from each group were killed after 52 wk) in a combined chronic toxicity and oncogenicity study. Concurrently, ten male rats per group were exposed to the same concentrations for 13 wk in a bone-marrow cytogenicity study and another ten male rats per group were exposed for 15 wk in a dominant lethal study. No toxicologically significant compound-related effects were observed in behaviour, appearance, growth, clinical pathology, or gross and microscopic pathology. Respiratory infection and consequently higher than expected mortality during the first year did not compromise the studies or conclusions but may have contributed to the intergroup differences in the numbers of chromosome breaks and acentric fragments. No evidence for mutagenic potential was seen in either the dominant lethal or the cytogenetic assays. These data indicate the very low toxicity of CFC 142b with respect to chronic effects and genotoxic and oncogenic potential. The toxicological profile of CFC 142b is similar to that of other chlorofluorocarbons that have been assigned a threshold limit value (TLV) of 1000 ppm as a workplace 8-hr time-weighted average by the American Conference of Governmental Industrial Hygienists.

Doctors' stress responses and poor communication performance in simulated bad-news consultations.

PubMed

Brown, Rhonda; Dunn, Stewart; Byrnes, Karen; Morris, Richard; Heinrich, Paul; Shaw, Joanne

2009-11-01

No studies have previously evaluated factors associated with high stress levels and poor communication performance in breaking bad news (BBN) consultations. This study determined factors that were most strongly related to doctors' stress responses and poor communication performance during a simulated BBN task. In 2007, the authors recruited 24 doctors comprising 12 novices (i.e., interns/residents with 1-3 years' experience) and 12 experts (i.e., registrars, medical/radiation oncologists, or cancer surgeons, with more than 4 years' experience). Doctors participated in simulated BBN consultations and a number of control tasks. Five-minute-epoch heart rate (HR), HR variability, and communication performance were assessed in all participants. Subjects also completed a short questionnaire asking about their prior experience BBN, perceived stress, psychological distress (i.e., anxiety, depression), fatigue, and burnout. High stress responses were related to inexperience with BBN, fatigue, and giving bad versus good news. Poor communication performance in the consultation was related to high burnout and fatigue scores. These results suggest that BBN was a stressful experience for doctors even in a simulated encounter, especially for those who were inexperienced and/or fatigued. Poor communication performance was related to burnout and fatigue, but not inexperience with BBN. These results likely indicate that burnout and fatigue contributed to stress and poor work performance in some doctors during the simulated BBN task.

Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament

PubMed Central

Ma, Chu Jian; Gibb, Bryan; Kwon, YoungHo; Sung, Patrick; Greene, Eric C.

2017-01-01

Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair. Here, we use single-molecule imaging to visualize the interplay between human RPA (hRPA) and human RAD51 during presynaptic complex assembly and disassembly. We demonstrate that ssDNA-bound hRPA can undergo facilitated exchange, enabling hRPA to undergo rapid exchange between free and ssDNA-bound states only when free hRPA is present in solution. Our results also indicate that the presence of free hRPA inhibits RAD51 filament nucleation, but has a lesser impact upon filament elongation. This finding suggests that hRPA exerts important regulatory influence over RAD51 and may in turn affect the properties of the assembled RAD51 filament. These experiments provide an important basis for further investigations into the regulation of human presynaptic complex assembly. PMID:27903895

RNA-processing proteins regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA.

PubMed

Manfrini, Nicola; Trovesi, Camilla; Wery, Maxime; Martina, Marina; Cesena, Daniele; Descrimes, Marc; Morillon, Antonin; d'Adda di Fagagna, Fabrizio; Longhese, Maria Pia

2015-02-01

Eukaryotic cells respond to DNA double-strand breaks (DSBs) by activating a checkpoint that depends on the protein kinases Tel1/ATM and Mec1/ATR. Mec1/ATR is activated by RPA-coated single-stranded DNA (ssDNA), which arises upon nucleolytic degradation (resection) of the DSB. Emerging evidences indicate that RNA-processing factors play critical, yet poorly understood, roles in genomic stability. Here, we provide evidence that the Saccharomyces cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA. The lack of Xrn1 inhibits ssDNA generation at the DSB by preventing the loading of the MRX complex. By contrast, DSB resection is not affected in the absence of Rrp6 or Trf4, but their lack impairs the recruitment of RPA, and therefore of Mec1, to the DSB. Rrp6 and Trf4 inactivation affects neither Rad51/Rad52 association nor DSB repair by homologous recombination (HR), suggesting that full Mec1 activation requires higher amount of RPA-coated ssDNA than HR-mediated repair. Noteworthy, deep transcriptome analyses do not identify common misregulated gene expression that could explain the observed phenotypes. Our results provide a novel link between RNA processing and genome stability. © 2014 The Authors.

Adaptive Helmholtz resonators and passive vibration absorbers for cylinder interior noise control

NASA Astrophysics Data System (ADS)

Estève, Simon J.; Johnson, Marty E.

2005-12-01

This paper presents an adaptive-passive solution to control the broadband sound transmission into rocket payload fairings. The treatment is composed of passive distributed vibration absorbers (DVAs) and adaptive Helmholtz resonators (HR). Both the frequency domain and time-domain model of a simply supported cylinder excited by an external plane wave are developed. To tune vibration absorbers to tonal excitation, a tuning strategy, based on the phase information between the velocity of the absorber mass and the velocity of the host structure is used here in a new fashion to tune resonators to peaks in the broadband acoustic spectrum of a cavity. This tuning law, called the dot-product method, only uses two microphone signals local to each HR, which allows the adaptive Helmholtz resonator (AHR) to be manufactured as an autonomous device with power supply, sensor, actuator and controller integrated. Numerical simulations corresponding to a 2.8 m long 2.5 m diameter composite cylinder prototype demonstrate that, as long as the structure modes, which strongly couple to the acoustic cavity, are damped with a DVA treatment, the dot-product method tune multiple HRs to a near-optimal solution over a broad frequency range (40-160 Hz). An adaptive HR prototype with variable opening is built and characterized. Experiments conducted on the cylinder prototype with eight AHRs demonstrate the ability of resonators adapted with the dot-product method to converge to near-optimal noise attenuation in a frequency band including multiple resonances.

A comparison of the shuttle and 6 minute walking tests with measured peak oxygen consumption in patients with heart failure.

PubMed

Green, D J; Watts, K; Rankin, S; Wong, P; O'Driscoll, J G

2001-09-01

This study investigated the use of an incremental, externally-paced 10 m shuttle walk test (SWT) as an objective, reliable and predictive test of functional capacity in patients with heart failure (CHF). The SWT was compared to a 6 minute walk test (6WT) and a maximal symptom-limited treadmill peak oxygen consumption (VO2peak) test. Experiment 1 examined the reproducibility of the SWT. Two SWF trials were performed and distance ambulated (DA), heart rate (HR) and rate of perceived exertion (RPE) results compared. In experiment 2, SWT, 6WT, and VO2 peak tests were performed and HR. RPE and ambulatory VO2 compared. The SWT demonstrated strong test/retest reliability for DA (r = 0.98). HR (r = 0.96) and RPE (r = 0.89). Treadmill VO2 peak was significantly correlated with DA during the SWT (r = 0.83, P < 0.05), but not the 6WT. SWT peak VO2 (18.5 +/- 1.8 ml.kg(-1) x min(-1)) and treadmill VO2 peak (18.3 +/-2.0 ml.kg(-1) x min(-1)) were also highly correlated (r = 0.78, P < 0.05). Conversely, 6WT peak VO2 and treadmill VO2 peak were not significantly correlated. This study suggests the SWT is a reliable, objective test, highly predictive of VO2 peak which may be a more optimal field exercise test than the self paced 6WT.

Field-induced cluster spin glass and inverse symmetry breaking enhanced by frustration

NASA Astrophysics Data System (ADS)

Schmidt, M.; Zimmer, F. M.; Magalhaes, S. G.

2018-03-01

We consider a cluster disordered model to study the interplay between short- and long-range interactions in geometrically frustrated spin systems under an external magnetic field (h). In our approach, the intercluster long-range disorder (J) is analytically treated to get an effective cluster model that is computed exactly. The clusters follow a checkerboard lattice with first-neighbor (J1) and second-neighbor (J2) interactions. We find a reentrant transition from the cluster spin-glass (CSG) state to a paramagnetic (PM) phase as the temperature decreases for a certain range of h. This inverse symmetry breaking (ISB) appears as a consequence of both quenched disorder with frustration and h, that introduce a CSG state with higher entropy than the polarized PM phase. The competitive scenario introduced by antiferromagnetic (AF) short-range interactions increases the CSG state entropy, leading to continuous ISB transitions and enhancing the ISB regions, mainly in the geometrically frustrated case (J1 =J2). Remarkably, when strong AF intracluster couplings are present, field-induced CSG phases can be found. These CSG regions are strongly related to the magnetization plateaus observed in this cluster disordered system. In fact, it is found that each field-induced magnetization jump brings a CSG region. We notice that geometrical frustration, as well as cluster size, play an important role in the magnetization plateaus and, therefore, are also relevant in the field-induced glassy states. Our findings suggest that competing interactions support ISB and field-induced CSG phases in disordered cluster systems under an external magnetic field.

Premeditation moderates the relation between sensation seeking and risky substance use among young adults.

PubMed

McCabe, Connor J; Louie, Kristine A; King, Kevin M

2015-09-01

Young adulthood is a peak period for externalizing behaviors such as substance abuse and antisocial conduct. Evidence from developmental neuroscience suggests that externalizing conduct within this time period may be associated with a "developmental asymmetry" characterized by an early peak in sensation seeking combined with a relatively immature impulse control system. Trait measures of impulsivity-sensation seeking and premeditation-are psychological manifestations of these respective systems, and multiple prior studies suggest that high sensation seeking and low premeditation independently confer risk for distinct forms of externalizing behaviors. The goal of the present study was to test this developmental asymmetry hypothesis, examining whether trait premeditation moderates the effect of sensation seeking on substance use and problems, aggression, and rule-breaking behavior. Using a cross-sectional sample of college-enrolled adults (n = 491), we applied zero-inflated modeling strategies to examine the likelihood and level of risky externalizing behaviors. Results indicated that lower premeditation enhanced the effect of higher sensation seeking on higher levels of positive and negative alcohol consequences, more frequent drug use, and more problematic drug use, but was unrelated to individual differences in antisocial behaviors. Our findings indicate that the developmental asymmetry between sensation seeking and a lack of premeditation is a risk factor for individual differences in problematic substance use among young adults, and may be less applicable for antisocial behaviors among high functioning individuals. (c) 2015 APA, all rights reserved).

Performances of 250 Amp-hr lithium/thionyl chloride cells

NASA Technical Reports Server (NTRS)

Goualard, Jacques

1991-01-01

A 250 Ah lithium thionyl chloride battery is being developed for a booster rocket engine. Extensive cell testing is running to evaluate functional and safety performances. Some results are presented. The lithium/thionyl chloride batteries were selected for their high energy density (low weight) as compared to other sources. The temperature of a lower weight item will be more sensitive to variations of internal and external heat fluxes than a heavier one. The use of high energy density L/TC batteries is subjected to stringent thermal environments to have benefit of energy density and to stay safe in any conditions. The battery thermal environment and discharge rate have to be adjusted to obtain the right temperature range at cell level, to have the maximum performances. Voltage and capacity are very sensitive to temperature. This temperature is the cell internal actual temperature during discharge. This temperature is directed by external thermal environment and by cell internal heat dissipation, i.e., cell actual voltage.

Risk of Fatal Cerebrovascular Accidents after External Beam Radiation Therapy for Early Stage Glottic Larynx Cancer

PubMed Central

Swisher-McClure, Samuel; Mitra, Nandita; Lin, Alexander; Ahn, Peter; Wan, Fei; O’Malley, Bert; Weinstein, Gregory S.; Bekelman, Justin E.

2013-01-01

Background This study compared the risk of fatal cerebrovascular accidents (CVA) in patients with early stage glottic larynx cancer receiving surgery or external beam radiation therapy (EBRT). Methods and Materials Using a competing risks survival analysis, we compared the risk of death due to CVA among patients with early stage glottic larynx cancer receiving surgery or EBRT in the SEER database. Results The cumulative incidence of fatal CVA at 15 years was higher in patients receiving EBRT (2.8 %; 95% CI 2.3%–3.4%) compared to surgery (1.5 %; 95% CI 0.8 %–2.3%, p= 0.024). In multivariable competing risks regression models, EBRT remained associated with an increased risk of fatal CVA compared to surgery (adjusted HR 1.75; 95% CI 1.04–2.96, p= 0.037). Conclusion Treatment of early stage glottic larynx cancer with EBRT was associated with a small increase in the risk of late fatal CVA events relative to surgery. PMID:23595858

Enabling Long-Duration Lunar Equatorial Operations With Thermal Wadi Infrastructure

NASA Technical Reports Server (NTRS)

Jones, Heather L.; Thornton, John P.; Balasubramaniam, Ramaswamy; Gokoglu, Suleyman, A.; Sacksteder, Kurt R.; Whittaker, William L.

2011-01-01

Long duration missions on the Moon s equator must survive lunar nights. With 350 hr of cryogenic temperatures, lunar nights present a challenge to robotic survival. Insulation is imperfect, so it is not possible to passively contain enough heat to stay warm through the night. Components that enable mobility, environmental sensing and solar power generation must be exposed, and they leak heat. Small, lightweight rovers cannot store enough energy to warm components throughout the night without some external source of heat or power. Thermal wadis, however, can act as external heat sources to keep robots warm through the lunar night. Electrical power can also be provided to rovers during the night from batteries stored in the ground beside wadis. Buried batteries can be warmed by the wadi s heat. Results from analysis of the interaction between a rover and a wadi are presented. A detailed three-dimensional (3D) thermal model and an easily configurable two-dimensional (2D) thermal model are used for analysis.

Phenomenology of break-up modes in contact free externally heated nanoparticle laden fuel droplets

NASA Astrophysics Data System (ADS)

Pathak, Binita; Basu, Saptarshi

2016-12-01

We study thermally induced atomization modes in contact free (acoustically levitated) nanoparticle laden fuel droplets. The initial droplet size, external heat supplied, and suspended particle concentration (wt. %) in droplets govern the stability criterion which ultimately determines the dominant mode of atomization. Pure fuel droplets exhibit two dominant modes of breakup namely primary and secondary. Primary modes are rather sporadic and normally do not involve shape oscillations. Secondary atomization however leads to severe shape deformations and catastrophic intense breakup of the droplets. The dominance of these modes has been quantified based on the external heat flux, dynamic variation of surface tension, acoustic pressure, and droplet size. Addition of particles alters the regimes of the primary and secondary atomization and introduces bubble induced boiling and bursting. We analyze this new mode of atomization and estimate the time scale of bubble growth up to the point of bursting using energy balance to determine the criterion suitable for parent droplet rupture. All the three different modes of breakup have been well identified in a regime map determined in terms of Weber number and the heat utilization rate which is defined as the energy utilized for transient heating, vaporization, and boiling in droplets.

Space Shuttle Projects

NASA Image and Video Library

1976-01-01

This is a cutaway illustration of the Space Shuttle external tank (ET) with callouts. The giant cylinder, higher than a 15-story building, with a length of 154-feet (47-meters) and a diameter of 27.5-feet (8.4-meters), is the largest single piece of the Space Shuttle. During launch, the ET also acts as a backbone for the orbiter and solid rocket boosters. Separate pressurized tank sections within the external tank hold the liquid hydrogen fuel and liquid oxygen oxidizer for the Shuttle's three main engines. During launch, the ET feeds the fuel under pressure through 17-inch (43.2-centimeter) ducts that branch off into smaller lines that feed directly into the main engines. The main engines consume 64,000 gallons (242,260 liters) of fuel each minute. Machined from aluminum alloys, the Space Shuttle's external tank is currently the only part of the launch vehicle that is not reused. After its 526,000-gallons (1,991,071 liters) of propellants are consumed during the first 8.5-minutes of flight, it is jettisoned from the orbiter and breaks up in the upper atmosphere, its pieces falling into remote ocean waters. The Marshall Space Flight Center was responsible for developing the ET.

The creation of racks and nanopores creation in various allotropes of boron due to the mechanical loads

NASA Astrophysics Data System (ADS)

Sadeghzadeh, S.

2017-11-01

Two-dimensional (2D) materials have recently attracted a great attraction. This paper provides a detailed discussion on the rupture mechanisms of different allotropes of boron. As a new 2D material by using a reactive molecular dynamics model, probable types of rupture for borophene sheets were studied, among which two dominant mechanisms were observed: creation of the cracks and formation of nanopores. The results obtained are compared to those for graphene and h-BN nano sheets, although the rupture mechanism was completely different from the graphene and h-BN sheets. The simulations suggested that borophene might remain more stable against external mechanical loads than graphene and BN sheets. Cracking leads to larger strain along the loading direction, whereas the creation of local pores spends the imposed energy for breaking the internal bonds and so flowing the external energy into the various bonds increases the number of pores. For the armchair-types, cracking is a dominant mechanism while for the zigzag-type the common mechanism is the creation of nanopores. These interesting results may help to design a new class of semiconductors that remain stable even when are sustaining uncontrollable external stresses.

Physiological responses and external validity of a new setting for taekwondo combat simulation.

PubMed

Hausen, Matheus; Soares, Pedro Paulo; Araújo, Marcus Paulo; Porto, Flávia; Franchini, Emerson; Bridge, Craig Alan; Gurgel, Jonas

2017-01-01

Combat simulations have served as an alternative framework to study the cardiorespiratory demands of the activity in combat sports, but this setting imposes rule-restrictions that may compromise the competitiveness of the bouts. The aim of this study was to assess the cardiorespiratory responses to a full-contact taekwondo combat simulation using a safe and externally valid competitive setting. Twelve male national level taekwondo athletes visited the laboratory on two separate occasions. On the first visit, anthropometric and running cardiopulmonary exercise assessments were performed. In the following two to seven days, participants performed a full-contact combat simulation, using a specifically designed gas analyser protector. Oxygen uptake ([Formula: see text]), heart rate (HR) and capillary blood lactate measurements ([La-]) were obtained. Time-motion analysis was performed to compare activity profile. The simulation yielded broadly comparable activity profiles to those performed in competition, a mean [Formula: see text] of 36.6 ± 3.9 ml.kg-1.min-1 (73 ± 6% [Formula: see text]) and mean HR of 177 ± 10 beats.min-1 (93 ± 5% HRPEAK). A peak [Formula: see text] of 44.8 ± 5.0 ml.kg-1.min-1 (89 ± 5% [Formula: see text]), a peak heart rate of 190 ± 13 beats.min-1 (98 ± 3% HRmax) and peak [La-] of 12.3 ± 2.9 mmol.L-1 was elicited by the bouts. Regarding time-motion analysis, combat simulation presented a similar exchange time, a shorter preparation time and a longer exchange-preparation ratio. Taekwondo combats capturing the full-contact competitive elements of a bout elicit moderate to high cardiorespiratory demands on the competitors. These data are valuable to assist preparatory strategies within the sport.

Physiological responses and external validity of a new setting for taekwondo combat simulation

PubMed Central

2017-01-01

Combat simulations have served as an alternative framework to study the cardiorespiratory demands of the activity in combat sports, but this setting imposes rule-restrictions that may compromise the competitiveness of the bouts. The aim of this study was to assess the cardiorespiratory responses to a full-contact taekwondo combat simulation using a safe and externally valid competitive setting. Twelve male national level taekwondo athletes visited the laboratory on two separate occasions. On the first visit, anthropometric and running cardiopulmonary exercise assessments were performed. In the following two to seven days, participants performed a full-contact combat simulation, using a specifically designed gas analyser protector. Oxygen uptake (V˙O2), heart rate (HR) and capillary blood lactate measurements ([La-]) were obtained. Time-motion analysis was performed to compare activity profile. The simulation yielded broadly comparable activity profiles to those performed in competition, a mean V˙O2 of 36.6 ± 3.9 ml.kg-1.min-1 (73 ± 6% V˙O2PEAK) and mean HR of 177 ± 10 beats.min-1 (93 ± 5% HRPEAK). A peak V˙O2 of 44.8 ± 5.0 ml.kg-1.min-1 (89 ± 5% V˙O2PEAK), a peak heart rate of 190 ± 13 beats.min-1 (98 ± 3% HRmax) and peak [La-] of 12.3 ± 2.9 mmol.L–1 was elicited by the bouts. Regarding time-motion analysis, combat simulation presented a similar exchange time, a shorter preparation time and a longer exchange-preparation ratio. Taekwondo combats capturing the full-contact competitive elements of a bout elicit moderate to high cardiorespiratory demands on the competitors. These data are valuable to assist preparatory strategies within the sport. PMID:28158252

Excess mortality among people who report lifetime use of illegal drugs in the United States: A 20-year follow-up of a nationally representative survey.

PubMed

Walker, Elizabeth Reisinger; Pratt, Laura A; Schoenborn, Charlotte A; Druss, Benjamin G

2017-02-01

The purpose of this study was to determine the mortality risks, over 20 years of follow-up in a nationally representative sample, associated with illegal drug use and to describe risk factors for mortality. We analyzed data from the 1991 National Health Interview Survey, which is a nationally representative household survey in the United States, linked to the National Death Index through 2011. This study included 20,498 adults, aged 18-44 years in 1991, with 1047 subsequent deaths. A composite variable of self-reported lifetime illegal drug use was created (hierarchical categories of heroin, cocaine, hallucinogens/inhalants, and marijuana use). Mortality risk was significantly elevated among individuals who reported lifetime use of heroin (HR=2.40, 95% CI: 1.65-3.48) and cocaine (HR=1.27, 95% CI: 1.04-1.55), but not for those who used hallucinogens/inhalants or marijuana, when adjusting for demographic characteristics. Baseline health risk factors (smoking, alcohol use, physical activity, and BMI) explained the greatest amount of this mortality risk. After adjusting for all baseline covariates, the association between heroin or cocaine use and mortality approached significance. In models adjusted for demographics, people who reported lifetime use of heroin or cocaine had an elevated mortality risk due to external causes (poisoning, suicide, homicide, and unintentional injury). People who had used heroin, cocaine, or hallucinogens/inhalants had an elevated mortality risk due to infectious diseases. Heroin and cocaine are associated with considerable excess mortality, particularly due to external causes and infectious diseases. This association can be explained mainly by health risk behaviors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Molecular excitonic seesaws.

PubMed

Wilhelm, Philipp; Schedlbauer, Jakob; Hinderer, Florian; Hennen, Daniel; Höger, Sigurd; Vogelsang, Jan; Lupton, John M

2018-04-17

The breaking of molecular symmetry through photoexcitation is a ubiquitous but rather elusive process, which, for example, controls the microscopic efficiency of light harvesting in molecular aggregates. A molecular excitation within a π-conjugated segment will self-localize due to strong coupling to molecular vibrations, locally changing bond alternation in a process which is fundamentally nondeterministic. Probing such symmetry breaking usually relies on polarization-resolved fluorescence, which is most powerful on the level of single molecules. Here, we explore symmetry breaking by designing a large, asymmetric acceptor-donor-acceptor (A 1 -D-A 2 ) complex 10 nm in length, where excitation energy can flow from the donor, a π-conjugated oligomer, to either one of the two boron-dipyrromethene (bodipy) dye acceptors of different color. Fluorescence correlation spectroscopy (FCS) reveals a nondeterministic switching between the energy-transfer pathways from the oligomer to the two acceptor groups on the submillisecond timescale. We conclude that excitation energy transfer, and light harvesting in general, are fundamentally nondeterministic processes, which can be strongly perturbed by external stimuli. A simple demonstration of the relation between exciton localization within the extended π-system and energy transfer to the endcap is given by considering the selectivity of endcap emission through the polarization of the excitation light in triads with bent oligomer backbones. Bending leads to increased localization so that the molecule acquires bichromophoric characteristics in terms of its fluorescence photon statistics.

Biochemical Kinetics Model of DSB Repair and GammaH2AX FOCI by Non-homologous End Joining

NASA Technical Reports Server (NTRS)

Cucinotta, Francis, A.; Pluth, Janice M.; Anderson, Jennifer A.; Harper, Jane V.; O'Neill, Peter

2007-01-01

We developed a biochemical kinetics approach to describe the repair of double strand breaks (DSB) produced by low LET radiation by modeling molecular events associated with the mechanisms of non-homologous end-joining (NHEJ). A system of coupled non-linear ordinary differential equations describes the induction of DSB and activation pathways for major NHEJ components including Ku(sub 70/80), DNA-PK(sub cs), and the Ligase IV-XRCC4 hetero-dimer. The autophosphorylation of DNA-PK(sub cs and subsequent induction of gamma-H2AX foci observed after ionizing radiation exposure were modeled. A two-step model of DNA-PK(sub cs) regulation of repair was developed with the initial step allowing access of other NHEJ components to breaks, and a second step limiting access to Ligase IV-XRCC4. Our model assumes that the transition from the first to second-step depends on DSB complexity, with a much slower-rate for complex DSB. The model faithfully reproduced several experimental data sets, including DSB rejoining as measured by pulsed-field electrophoresis (PFGE), quantification of the induction of gamma-H2AX foci, and live cell imaging of the induction of Ku(sub 70/80). Predictions are made for the behaviors of NHEJ components at low doses and dose-rates, where a steady-state is found at dose-rates of 0.1 Gy/hr or lower.

Differential RPA-1 and RAD-51 recruitment in vivo throughout the C. elegans germline, as revealed by laser microirradiation.

PubMed

Koury, Emily; Harrell, Kailey; Smolikove, Sarit

2018-01-25

Studies of the repair pathways associated with DNA double strand breaks (DSBs) are numerous, and provide evidence for cell-cycle specific regulation of homologous recombination (HR) by the regulation of its associated proteins. Laser microirradiation is a well-established method to examine in vitro kinetics of repair and allows for live-imaging of DSB repair from the moment of induction. Here we apply this method to whole, live organisms, introducing an effective system to analyze exogenous, microirradiation-induced breaks in the Caenorhabditis elegans germline. Through this method we observed the sequential kinetics of the recruitment of ssDNA binding proteins RPA-1 and RAD-51 in vivo. We analyze these kinetics throughout different regions of the germline, and thus throughout a range of developmental stages of mitotic and meiotic nuclei. Our analysis demonstrates a largely conserved timing of recruitment of ssDNA binding proteins to DSBs throughout the germline, with a delay of RAD-51 recruitment at mid-pachytene nuclei. Microirradiated nuclei are viable and undergo a slow kinetics of resolution. We observe RPA-1 and RAD-51 colocalization for hours post-microirradiation throughout the germline, suggesting that there are mixed RPA-1/RAD-51 filaments. Finally, through live imaging analysis we observed RAD-51 foci movement with low frequency of coalescence. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Differential RPA-1 and RAD-51 recruitment in vivo throughout the C. elegans germline, as revealed by laser microirradiation

PubMed Central

Koury, Emily; Harrell, Kailey

2018-01-01

Abstract Studies of the repair pathways associated with DNA double strand breaks (DSBs) are numerous, and provide evidence for cell-cycle specific regulation of homologous recombination (HR) by the regulation of its associated proteins. Laser microirradiation is a well-established method to examine in vitro kinetics of repair and allows for live-imaging of DSB repair from the moment of induction. Here we apply this method to whole, live organisms, introducing an effective system to analyze exogenous, microirradiation-induced breaks in the Caenorhabditis elegans germline. Through this method we observed the sequential kinetics of the recruitment of ssDNA binding proteins RPA-1 and RAD-51 in vivo. We analyze these kinetics throughout different regions of the germline, and thus throughout a range of developmental stages of mitotic and meiotic nuclei. Our analysis demonstrates a largely conserved timing of recruitment of ssDNA binding proteins to DSBs throughout the germline, with a delay of RAD-51 recruitment at mid-pachytene nuclei. Microirradiated nuclei are viable and undergo a slow kinetics of resolution. We observe RPA-1 and RAD-51 colocalization for hours post-microirradiation throughout the germline, suggesting that there are mixed RPA-1/RAD-51 filaments. Finally, through live imaging analysis we observed RAD-51 foci movement with low frequency of coalescence. PMID:29244155

External Exposure to Short- and Medium-Chain Chlorinated Paraffins for the General Population in Beijing, China.

PubMed

Gao, Wei; Cao, Dandan; Wang, Yingjun; Wu, Jing; Wang, Ying; Wang, Yawei; Jiang, Guibin

2018-01-02

Chlorinated paraffins (CPs) are a class of compounds that are currently produced and used in large amounts in commercial products worldwide. In this study, food, indoor air, indoor dust, and drinking water samples were collected to evaluate the external exposure levels of CPs and possible pathway for the general population in Beijing, China. Short chain CPs (SCCPs) and medium chain CPs (MCCPs) in 199 samples were analyzed using a gas chromatography tandem time-of-flight high-resolution mass spectrometry (GC-TOF-HR-MS) method. High levels of CPs were observed in the indoor environment from residential houses, offices, and student dormitories. The geometric mean concentrations (GM) of ∑SCCPs and ∑MCCPs in indoor dust were 92 μg g -1 and 82 μg g -1 , respectively, while in indoor air, the concentrations were 80 ng m -3 and 3.4 ng m -3 , respectively. The GM of ∑SCCPs and ∑MCCPs in the diet were 83 ng g -1 dry weight (dw) and 56 ng g -1 dw, respectively. The most important external exposure routes to CPs to the general populations in Beijing were food intake and indoor dust ingestion. Indoor dust and indoor air posed higher risks for toddlers and infants than for adults.

Quantum information cannot be completely hidden in correlations: implications for the black-hole information paradox.

PubMed

Braunstein, Samuel L; Pati, Arun K

2007-02-23

Can quantum-information theory shed light on black-hole evaporation? By entangling the in-fallen matter with an external system we show that the black-hole information paradox becomes more severe, even for cosmologically sized black holes. We rule out the possibility that the information about the in-fallen matter might hide in correlations between the Hawking radiation and the internal states of the black hole. As a consequence, either unitarity or Hawking's semiclassical predictions must break down. Any resolution of the black-hole information crisis must elucidate one of these possibilities.

Study to develop improved methods to detect leakage in fluid systems, phase 2

NASA Technical Reports Server (NTRS)

Janus, J. C.; Cimerman, I.

1971-01-01

An ultrasonic contact sensor engineering prototype leak detection system was developed and its capabilities under cryogenic operations demonstrated. The results from tests indicate that the transducer performed well on liquid hydrogen plumbing, that flow and valve actuation could be monitored, and that the phase change from gaseous to liquid hydrogen could be detected by the externally mounted transducers. Tests also demonstrate the ability of the system to detect internal leaks past valve seats and to function as a flow meter. Such a system demonstrates that it is not necessary to break into welded systems to locate internal leaks.

Thermally induced secondary atomization of droplet in an acoustic field

NASA Astrophysics Data System (ADS)

Basu, Saptarshi; Saha, Abhishek; Kumar, Ranganathan

2012-01-01

We study the thermal effects that lead to instability and break up in acoustically levitated vaporizing fuel droplets. For selective liquids, atomization occurs at the droplet equator under external heating. Short wavelength [Kelvin-Helmholtz (KH)] instability for diesel and bio-diesel droplets triggers this secondary atomization. Vapor pressure, latent heat, and specific heat govern the vaporization rate and temperature history, which affect the surface tension gradient and gas phase density, ultimately dictating the onset of KH instability. We develop a criterion based on Weber number to define a condition for the inception of secondary atomization.

Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients.

PubMed

Romesser, Paul B; Pei, Xin; Shi, Weiji; Zhang, Zhigang; Kollmeier, Marisa; McBride, Sean M; Zelefsky, Michael J

2018-01-01

To evaluate the difference in prostate-specific antigen (PSA) recurrence-free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to ≥75 Gy with ≥5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a ≥0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

The range of thermal insulation in the tissues of the new-born baby

PubMed Central

Hey, E. N.; Katz, G.

1970-01-01

1. Rectal temperature and skin temperatures were measured in twenty-eight naked babies weighing 1·1-4·5 kg, lying supine in environments of 25-31 °C when air speed was 4-7 cm/sec. The ratio of external insulation to internal or tissue insulation for the whole body averaged 2·7 but varied inversely with body weight; the ratio was higher than this on the trunk, and five times lower than this on the hand and foot. The mean ratio rose threefold when environmental temperature was increased to 34-35° C. 2. Direct measurements of heat flow from the back of a hand placed in a water jacket maintained at 32° C were made in thirty-three babies. Heat loss averaged 3 kcal/m2.hr.° C at low environmental temperature, but the loss was often rather less than this in the first 24 hr of life. Heat loss from the hand increased three- to fourfold, during exposure to an environment of 35° C. 3. When babies more than 48 hr old were exposed to an environment of 34-35° C, heat loss from the hand only increased when rectal temperature reached between 36·6 and 37·3° C; a slightly higher rectal temperature was usually reached before heat loss rose in babies less than 24 hr old. 4. Similar methods were used to study specific tissue insulation in three babies with congenital defects of the brain who lacked evidence of temperature control. No changes in insulation were detected in these three babies following changes in environmental temperature. 5. It is concluded that the range and pattern of control that can be exerted over the specific thermal insulation of the tissues is essentially the same in babies 2-20 days old as it is in adult life. PMID:5499741

Dramatically Polarized Opinion on the Role of Brachytherapy Boost in Management of High-risk Prostate Cancer: A Survey of North American Genitourinary Expert Radiation Oncologists.

PubMed

McClelland, Shearwood; Sandler, Kiri A; Degnin, Catherine; Chen, Yiyi; Mitin, Timur

2018-06-01

Three randomized clinical trials have established brachytherapy (BT) boost in combination with external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) as superior to definitive EBRT and ADT alone in terms of biochemical control (but not overall survival) at the expense of increased toxicity in men with high-risk (HR) prostate cancer (PCa). The current view regarding these 2 treatment algorithms among North American genitourinary (GU) experts is not known. A survey was distributed to 88 practicing North American GU physicians serving on decision-making committees of cooperative group research organizations. Questions pertained to opinions regarding BT as monotherapy for low-risk PCa and BT boost for HR PCa. Responders were asked to self-identify as BT experts versus non-experts. Treatment recommendations were correlated with practice patterns using the Fisher exact test. Forty-two radiation oncologists completed the survey, of whom 23 (55%) recommend EBRT and ADT alone and 19 (45%) recommend addition of BT boost. Twenty-five participants (60%) identified themselves as BT experts. Nearly 90% of those recommending BT boost were BT experts versus approximately 10% of non-BT experts (P < .001). Responders who recommended BT monotherapy as first-choice treatment for low-risk PCa were more likely to recommend BT boost for HR PCa (P < .0001). There is a dramatic polarization in opinions regarding incorporation of BT boost into EBRT + ADT therapy for patients with HR PCa among North American GU radiation oncology experts, who serve on decision-making committees and influence the national treatment guidelines and future clinical trials. Those who identify themselves as BT experts are significantly more likely to recommend BT boost. These findings are likely to influence the national guidelines and implementation of BT boost in current and future North American PCa clinical studies. Copyright © 2018 Elsevier Inc. All rights reserved.

Multivariate assessment of the central-cardiorespiratory network structure in neuropathological disease.

PubMed

Schulz, Steffen; Haueisen, Jens; Bär, Karl-Juergen; Voss, Andreas

2018-06-22

The new interdisciplinary field of network physiology is getting more and more into the focus of interest in medicine. The autonomic nervous system (ANS) dysfunction is well described in schizophrenia (SZO). However, the linear and nonlinear coupling between the ANS and central nervous system (CNS) is only partly addressed until now. This coupling can be assumed as a feedback-feedforward network, reacting with flexible and adaptive responses to internal and external factors. Approach: For the first time, in this study, we investigated linear and nonlinear short-term central-cardiorespiratory couplings of 17 patients suffering from paranoid schizophrenia (SZO) in comparison to 17 age-gender matched healthy subjects (CON) analyzing heart rate (HR), respiration (RESP) and the power of frontal EEG activity (PEEG). The objective is to determine how the different regulatory aspects of the CNS-ANS compose the central-cardiorespiratory network (CCRN). To quantify these couplings within the CCRN the normalized short time partial directed coherence (NSTPDC) and the new multivariate high-resolution joint symbolic dynamics (mHRJSD) were applied. Main results: We found that the CCRN in SZO is characterized as a bidirectional one, with stronger central driving mechanisms (PEEG→HR) towards HR regulation than vice versa, and with stronger respiratory influence (RESP→PEEG) on central activity than vice versa. This suggests that the central-cardiorespiratory process (closed-loop) is mainly focusing on adapting the HR via the sinoatrial node than focusing on respiratory regulation. On the other side, the feedback-loop from ANS to CNS is strongly dominated via respiratory activity. Significance: We could demonstrate a considerably significantly different central-cardiorespiratory network structure in schizophrenia with strong central influence on the cardiac system and a strong respiratory influence on the central nervous system. Moreover, this study provides a more in-depth understanding of the interplay of the central and autonomic regulatory network in healthy subjects and schizophrenic patients. . © 2018 Institute of Physics and Engineering in Medicine.

Role of proline and pyrroline-5-carboxylate metabolism in plant defense against invading pathogens

PubMed Central

Qamar, Aarzoo; Mysore, Kirankumar S.; Senthil-Kumar, Muthappa

2015-01-01

Pyrroline-5-carboxylate (P5C) is an intermediate product of both proline biosynthesis and catabolism. Recent evidences indicate that proline-P5C metabolism is tightly regulated in plants, especially during pathogen infection and abiotic stress. However, role of P5C and its metabolism in plants has not yet been fully understood. Studies indicate that P5C synthesized in mitochondria has a role in both resistance (R)-gene-mediated and non-host resistance against invading pathogens. Proline dehydrogenase and delta-ornithine amino transferase-encoding genes, both involved in P5C synthesis in mitochondria are implicated in defense response of Nicotiana benthamiana and Arabidopsis thaliana against bacterial pathogens. Such defense response is proposed to involve salicylic acid-dependent pathway, reactive oxygen species (ROS) and hypersensitive response (HR)-associated cell death. Recently HR, a form of programmed cell death (PCD), has been proposed to be induced by changes in mitochondrial P5C synthesis or the increase in P5C levels per se in plants inoculated with either a host pathogen carrying suitable avirulent (Avr) gene or a non-host pathogen. Consistently, A. thaliana mutant plants deficient in P5C catabolism showed HR like cell death when grown in external P5C or proline supplemented medium. Similarly, yeast and plant cells under oxidative stress were shown to increase ROS production and PCD due to increase in P5C levels. Similar mechanism has also been reported as one of the triggers for apoptosis in mammalian cells. This review critically analyzes results from various studies and enumerates the pathways for regulation of P5C levels in the plant cell, especially in mitochondria, during pathogen infection. Further, mechanisms regulating P5C- mediated defense responses, namely HR are outlined. This review also provides new insights into the differential role of proline-P5C metabolism in plants exposed to pathogen infection. PMID:26217357

A dose-volume analysis of magnetic resonance imaging-aided high-dose-rate image-based interstitial brachytherapy for uterine cervical cancer.

PubMed

Yoshida, Ken; Yamazaki, Hideya; Takenaka, Tadashi; Kotsuma, Tadayuki; Yoshida, Mineo; Furuya, Seiichi; Tanaka, Eiichi; Uegaki, Tadaaki; Kuriyama, Keiko; Matsumoto, Hisanobu; Yamada, Shigetoshi; Ban, Chiaki

2010-07-01

To investigate the feasibility of our novel image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) for uterine cervical cancer, we evaluated the dose-volume histogram (DVH) according to the recommendations of the Gynecological GEC-ESTRO Working Group for image-based intracavitary brachytherapy (ICBT). Between June 2005 and June 2007, 18 previously untreated cervical cancer patients were enrolled. We implanted magnetic resonance imaging (MRI)-available plastic applicators by our unique ambulatory technique. Total treatment doses were 30-36 Gy (6 Gy per fraction) combined with external beam radiotherapy (EBRT). Treatment plans were created based on planning computed tomography with MRI as a reference. DVHs of the high-risk clinical target volume (HR CTV), intermediate-risk CTV (IR CTV), and the bladder and rectum were calculated. Dose values were biologically normalized to equivalent doses in 2-Gy fractions (EQD(2)). The median D90 (HR CTV) and D90 (IR CTV) per fraction were 6.8 Gy (range, 5.5-7.5) and 5.4 Gy (range, 4.2-6.3), respectively. The median V100 (HR CTV) and V100 (IR CTV) were 98.4% (range, 83-100) and 81.8% (range, 64-93.8), respectively. When the dose of EBRT was added, the median D90 and D100 of HR CTV were 80.6 Gy (range, 65.5-96.6) and 62.4 Gy (range, 49-83.2). The D(2cc) of the bladder was 62 Gy (range, 51.4-89) and of the rectum was 65.9 Gy (range, 48.9-76). Although the targets were advanced and difficult to treat effectively by ICBT, MRI-aided image-based ISBT showed favorable results for CTV and organs at risk compared with previously reported image-based ICBT results. (c) 2010 Elsevier Inc. All rights reserved.

Breeding biology of the golden-faced Tyrannulet (Zimmerius chrysops) in venezuela

USGS Publications Warehouse

Goulding, W.; Martin, T.E.

2010-01-01

We present the first detailed information on the breeding biology of the Golden-faced Tyrannulet (Zimmerius chrysops). Information was gathered from 96 nests in Yacamb National Park, Venezuela during the 2002 to 2008 breeding seasons. The enclosed nest was similar to descriptions of nests of other species in the genus. Eggs were laid on alternate days with mean (?? SE) clutch size of 1.98 ?? 0.02 (n 45) and fresh weight of 1.616 ?? 0.020 g (n 48). Only the female incubated and the incubation period averaged 16.9 ?? 0.3 days (n 10). Nest attentiveness ( time on the nest) averaged 66.0 ?? 1.6 (n 40) and increased from early to mid- and late-incubation. Incubation behavior yielded an average 24-hr egg temperature of 34.88 ?? 0.45?? C (n 7 nests, 43 days). The nestling growth rate constant for body mass (k 0.285 ?? 0.011) was slow even for tropical tyrannids. The nestling period for nests where exact hatch and fledging days were observed ranged from 17 to 19 days with an average of 18.0 ?? 0. 2 days (n 9). Both females and males fed nestlings at a rate that increased over the nestling period with a mean of 4.41 ?? 0.65 trips/hr (n 10) during days 1 and 2 after hatching, and 14.93 ?? 2.36 trips/hr (n 6) at pin-break (days 1011). Daily predation rates were similar in egg-laying (0.052 ?? 0.025; n 76.5 exposure days) and incubation periods (0.068 ?? 0.010; n 575.5 exposure days), but were lower during the nestling period (0.039 ?? 0.010; n 377.0 exposure days). The total daily predation rate (0.057 ?? 0.007; n 989.0 exposure days) indicated only 12 of nests were successful. These breeding biology parameters for Z. chrysops differ substantially from other tyrant-flycatchers and temperate species, further highlighting the diversity within the Tyrannidae. ?? 2010 by the Wilson Ornithological Society.

Novel poly (ADP-ribose) polymerase inhibitor, AZD2281, enhances radiosensitivity of both normoxic and hypoxic esophageal squamous cancer cells.

PubMed

Zhan, L; Qin, Q; Lu, J; Liu, J; Zhu, H; Yang, X; Zhang, C; Xu, L; Liu, Z; Cai, J; Ma, J; Dai, S; Tao, G; Cheng, H; Sun, X

2016-04-01

Radiotherapy plays an important role in the treatment of esophageal squamous cell carcinoma (ESCC). However, the outcome of radiotherapy in ESCC remains unsatisfactory because esophageal squamous cancer cells, particularly those under hypoxic condition, exhibit radioresistance. The aim of this study was to determine whether or not AZD2281, a potent poly (ADP-ribose) polymerase (PARP) inhibitor, could enhance the radiation sensitivity of two ESCC cell lines, namely ECA109 and TE13. The radiosensitizing effect of AZD2281 was evaluated on the basis of cell death, clonogenic survival and tumor xenograft progression. AZD2281 alone was slightly toxic to ESCC cell lines. Apoptosis was increased and clonogenic survival was decreased in both cell lines when AZD2281 was combined with ionizing radiation (IR) under normoxic condition. AZD2281 enhanced IR-induced apoptosis to a more significant level under chronic hypoxic condition (0.2% O(2), 48 hour) than under normoxic condition. AZD2281 also slightly enhanced clonogenic cell death under chronic hypoxic condition compared with that under normoxic condition. This result could be associated with increased radiation-induced DNA double-strand breaks (DSB), decreased DSB repair and increased apoptosis of ESCC cells. Furthermore, homologous recombination (HR) protein Rad51 expression and focus formation were decreased in ESCC cells exposed to moderate chronic hypoxic condition (0.2% O(2), 48 hour); this result indicated that chronic hypoxic ESCC cells were HR deficient, possibly causing contextual synthetic lethality with PARP inhibitor in radiation sensitization. AZD2281 was also a radiation sensitizer in ESCC tumor xenograft models. Hence, in vitro and in vivo findings provide evidence that AZD2281 potently sensitizes ESCC cells to X-ray irradiation. The selective cell killing of HR-defective hypoxic cells contributes to radiosensitization by PARP inhibitor in ESCC cells under hypoxic condition. © 2015 International Society for Diseases of the Esophagus.

Limitations of differential electrophoresis for measuring colloidal forces: a Brownian dynamics study.

PubMed

Holtzer, Gretchen L; Velegol, Darrell

2005-10-25

Differential electrophoresis experiments are often used to measure subpiconewton forces between two spheres of a heterodoublet. The experiments have been interpreted by solving the electrokinetic equations to obtain a simple Stokes law-type equation. However, for nanocolloids, the effects of Brownian motion alter the interpretation: (1) Brownian translation changes the rate of axial separation. (2) Brownian rotation reduces the alignment of the doublet with the applied electric field. (3) Particles can reaggregate by Brownian motion after they break, forming either heterodoublets or homodoublets, and because homodoublets cannot be broken by differential electrophoresis, this effectively terminates the experiment. We tackle points 1 and 2 using Brownian dynamics simulations (BDS) with electrophoresis as an external force, accounting for convective translation and rotation as well as Brownian translation and rotation. Our simulations identify the lower particle size limit of differential electrophoresis to be about 1 microm for desired statistical accuracy. Furthermore, our simulations predict that particles around 10 nm in size and at ambient conditions will break primarily by Brownian motion, with a negligible effect due to the electric field.

Dramatic change in a young woman's perception of her diabetes and remarkable reduction in HbA1c after an individual course of Guided Self-Determination

PubMed Central

Zoffmann, Vibeke; Prip, Anne; Christiansen, Anette Wendelboe

2015-01-01

A 24-year-old woman with type 1 diabetes participated in a randomised controlled trial proving effectiveness of a flexible Guided Self-Determination (GSD) intervention. She had for 10 years been living with a complex situation of eating disorder, poor glycaemic control, non-attendance and psychosocial distress. She managed to change her perception of diabetes dramatically and improved her glycaemic control. Considering the complexity of her case, we explored how she achieved these changes. A GSD-trained nurse delivered the intervention, which involves reflection sheets and advanced professional communication. Glycated hemoglobin was reported in the patient's record and an interview conducted by external interviewers was analysed thematically, indicating that a four-stage process of empowerment had taken place: ‘focusing on life prior to numbers’, ‘unpacking a heavy burden’, ‘breaking out of isolation through communication’ and ‘finding strength within oneself’. The article emphasises that GSD works by breaking isolation through communication as an appropriate way to achieve good diabetes control. PMID:26150632

Dynamic Balance of Excitation and Inhibition in Human and Monkey Neocortex

NASA Astrophysics Data System (ADS)

Dehghani, Nima; Peyrache, Adrien; Telenczuk, Bartosz; Le van Quyen, Michel; Halgren, Eric; Cash, Sydney S.; Hatsopoulos, Nicholas G.; Destexhe, Alain

2016-03-01

Balance of excitation and inhibition is a fundamental feature of in vivo network activity and is important for its computations. However, its presence in the neocortex of higher mammals is not well established. We investigated the dynamics of excitation and inhibition using dense multielectrode recordings in humans and monkeys. We found that in all states of the wake-sleep cycle, excitatory and inhibitory ensembles are well balanced, and co-fluctuate with slight instantaneous deviations from perfect balance, mostly in slow-wave sleep. Remarkably, these correlated fluctuations are seen for many different temporal scales. The similarity of these computational features with a network model of self-generated balanced states suggests that such balanced activity is essentially generated by recurrent activity in the local network and is not due to external inputs. Finally, we find that this balance breaks down during seizures, where the temporal correlation of excitatory and inhibitory populations is disrupted. These results show that balanced activity is a feature of normal brain activity, and break down of the balance could be an important factor to define pathological states.

The role of puberty in the making and breaking of young ballet dancers: Perspectives of dance teachers.

PubMed

Mitchell, Siobhan B; Haase, Anne M; Malina, Robert M; Cumming, Sean P

2016-02-01

Physical changes associated with puberty may conflict with functional and aesthetic ideals for a career in ballet. The dance teacher is in a position to guide young dancers through the pubertal transition, although dancers rather than teachers are often the focus of research. This study explores the social stimulus value of the female body in ballet as perceived by the dance teacher and how value may change during puberty. Ten UK dance teachers were interviewed; interpretative phenomenological analysis was used. Four main themes perceived by dance teachers emerged as central to the social stimulus value of the body among adolescent dancers: the ideal body; teacher approaches to managing puberty in the dance environment; puberty as a 'make or break' stage in ballet; and teacher awareness of pubertal onset and the implications of timing. Dance teachers can play an important role in moderating external and individual expectations during the pubertal transition. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Electron Acceleration and Efficiency in Nonthermal Gamma-Ray Sources

NASA Astrophysics Data System (ADS)

Bykov, A. M.; Meszaros, P.

1996-04-01

In energetic nonthermal sources such as gamma-ray bursts, active galactic nuclei, or galactic jets, etc., one expects both relativistic and transrelativistic shocks accompanied by violent motions of moderately relativistic plasma. We present general considerations indicating that these sites are electron and positron accelerators leading to a modified power-law spectrum. The electron (or e+/-) energy index is very hard, ~ gamma -1 or flatter, up to a comoving frame break energy gamma *, and becomes steeper above that. In the example of gamma-ray bursts, the Lorentz factor reaches gamma * ~ 103 for e+/- accelerated by the internal shock ensemble on subhydrodynamical timescales. For pairs accelerated on hydrodynamical timescales in the external shocks, similar hard spectra are obtained, and the break Lorentz factor can be as high as gamma * <~ 105. Radiation from the nonthermal electrons produces photon spectra with shapes and characteristic energies in qualitative agreement with observed generic gamma-ray burst and blazar spectra. The scenario described here provides a plausible way to solve one of the crucial problems of nonthermal high-energy sources, namely, the efficient transfer of energy from the proton flow to an appropriate nonthermal lepton component.

[The application of genome editing in identification of plant gene function and crop breeding].

PubMed

Zhou, Xiang-chun; Xing, Yong-zhong

2016-03-01

Plant genome can be modified via current biotechnology with high specificity and excellent efficiency. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system are the key engineered nucleases used in the genome editing. Genome editing techniques enable gene targeted mutagenesis, gene knock-out, gene insertion or replacement at the target sites during the endogenous DNA repair process, including non-homologous end joining (NHEJ) and homologous recombination (HR), triggered by the induction of DNA double-strand break (DSB). Genome editing has been successfully applied in the genome modification of diverse plant species, such as Arabidopsis thaliana, Oryza sativa, and Nicotiana tabacum. In this review, we summarize the application of genome editing in identification of plant gene function and crop breeding. Moreover, we also discuss the improving points of genome editing in crop precision genetic improvement for further study.

CRISPR-Cas9; an efficient tool for precise plant genome editing.

PubMed

Islam, Waqar

2018-06-01

Efficient plant genome editing is dependent upon induction of double stranded DNA breaks (DSBs) through site specified nucleases. These DSBs initiate the process of DNA repair which can either base upon homologous recombination (HR) or non-homologous end jointing (NHEJ). Recently, CRISPR-Cas9 mechanism got highlighted as revolutionizing genetic tool due to its simpler frame work along with the broad range of adaptability and applications. So, in this review, I have tried to sum up the application of this biotechnological tool in plant genome editing. Furthermore, I have tried to explain successful adaptation of CRISPR in various plant species where it is used for the successful generation of stable mutations in a steadily growing number of species through NHEJ. The review also sheds light upon other biotechnological approaches relying upon single DNA lesion induction such as genomic deletion or pair wise nickases for evasion of offsite effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

In situ analysis of DNA damage response and repair using laser microirradiation.

PubMed

Kim, Jong-Soo; Heale, Jason T; Zeng, Weihua; Kong, Xiangduo; Krasieva, Tatiana B; Ball, Alexander R; Yokomori, Kyoko

2007-01-01

A proper response to DNA damage is critical for the maintenance of genome integrity. However, it is difficult to study the in vivo kinetics and factor requirements of the damage recognition process in mammalian cells. In order to address how the cell reacts to DNA damage, we utilized a second harmonic (532 nm) pulsed Nd:YAG laser to induce highly concentrated damage in a small area in interphase cell nuclei and cytologically analyzed both protein recruitment and modification. Our results revealed for the first time the sequential recruitment of factors involved in two major DNA double-strand break (DSB) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR), and the cell cycle-specific recruitment of the sister chromatid cohesion complex cohesin to the damage site. In this chapter, the strategy developed to study the DNA damage response using the 532-nm Nd:YAG laser will be summarized.

KSC-99pp0477

NASA Image and Video Library

1999-04-29

The STS-96 crew pose for a group photo after emergency egress training at Launch Pad 39B. From left are Mission Specialist Ellen Ochoa (Ph.D.); Pilot Rick Douglas Husband; Mission Specialists Julie Payette, Daniel Barry (M.D., Ph.D.), and Tamara E. Jernigan (Ph.D.); Commander Kent V. Rominger; and Mission Specialist Valery Ivanovich Tokarev. Payette is with the Canadian Space Agency, and Ivanovich Tokarev with the Russian Space Agency. Behind them is the tip of the external tank, which is 153.8 feet high. The external tank provides fuel to the three space shuttle main engines in the orbiter during liftoff and ascent. It is eventually jettisoned, entering the Earth's atmosphere, breaking up and impacting a remote ocean area. STS-96, scheduled for liftoff on May 20 at 9:32 a.m., is a logistics and resupply mission for the International Space Station, carrying such payloads as a Russian crane, the Strela; a U.S.-built crane; the Spacehab Oceaneering Space System Box (SHOSS), a logistics items carrier; and STARSHINE, a student-led experiment

Power and empowerment: Fostering effective collaboration in meeting the needs of orphans and vulnerable children

PubMed Central

WALLIS, A.; DUKAY, V.; MELLINS, C.

2009-01-01

In sub-Saharan Africa, HIV/AIDS has resulted in a rapidly growing population of orphans and vulnerable children (OVC). These OVC have strained the traditional safety net provided by extended families to its breaking point. Increasingly, community-based initiatives are emerging to fill the gap. However, relatively little is known about these efforts and their effectiveness. This article looks at one such initiative in rural Tanzania, and explores the relationship between local communities that seek to empower themselves to address the needs of their OVC and external organisations that have the resources and power to help them. This case study describes the successful effort of a community to build a Centre housing its orphans, and the subsequent closure of that Centre despite its evident success, because of a conflict between internal and external interests. This case study is used as the basis of a broader discussion on how those with power, and communities seeking empowerment, are complexly intertwined. PMID:19626505

Electric field control of deterministic current-induced magnetization switching in a hybrid ferromagnetic/ferroelectric structure

NASA Astrophysics Data System (ADS)

Cai, Kaiming; Yang, Meiyin; Ju, Hailang; Wang, Sumei; Ji, Yang; Li, Baohe; Edmonds, Kevin William; Sheng, Yu; Zhang, Bao; Zhang, Nan; Liu, Shuai; Zheng, Houzhi; Wang, Kaiyou

2017-07-01

All-electrical and programmable manipulations of ferromagnetic bits are highly pursued for the aim of high integration and low energy consumption in modern information technology. Methods based on the spin-orbit torque switching in heavy metal/ferromagnet structures have been proposed with magnetic field, and are heading toward deterministic switching without external magnetic field. Here we demonstrate that an in-plane effective magnetic field can be induced by an electric field without breaking the symmetry of the structure of the thin film, and realize the deterministic magnetization switching in a hybrid ferromagnetic/ferroelectric structure with Pt/Co/Ni/Co/Pt layers on PMN-PT substrate. The effective magnetic field can be reversed by changing the direction of the applied electric field on the PMN-PT substrate, which fully replaces the controllability function of the external magnetic field. The electric field is found to generate an additional spin-orbit torque on the CoNiCo magnets, which is confirmed by macrospin calculations and micromagnetic simulations.

Tunable phase transition in single-layer TiSe2 via electric field

NASA Astrophysics Data System (ADS)

Liu, Lei; Zhuang, Houlong L.

2018-06-01

Phase transition represents an intriguing physical phenomenon that exists in a number of single-layer transition-metal dichalcogenides. This phenomenon often occurs below a critical temperature and breaks the long-range crystalline order leading to a reconstructed superstructure called the charge-density wave (CDW) structure, which can therefore be recovered by external stimuli such as temperature. Alternatively, we show here that another external stimulation, electric field can also result in the phase transition between the regular and CDW structures of a single-layer transition-metal dichalcogenide. We used single-layer TiSe2 as an example to elucidate the mechanism of the CDW followed by calculations of the electronic structure using a hybrid density functional. We found that applying electric field can tune the phase transition between the 1T and CDW phases of single-layer TiSe2. Our work opens up a route of tuning the phase transition of single-layer materials via electric field.

Tug of war in motility assay experiments

NASA Astrophysics Data System (ADS)

Hexner, Daniel; Kafri, Yariv

2009-09-01

The dynamics of two groups of molecular motors pulling in opposite directions on a rigid filament is studied theoretically. To this end we first consider the behavior of one set of motors pulling in a single direction against an external force using a new mean-field approach. Based on these results we analyze a similar setup with two sets of motors pulling in opposite directions in a tug of war in the presence of an external force. In both cases we find that the interplay of fluid friction and protein friction leads to a complex phase diagram where the force-velocity relations can exhibit regions of bistability and spontaneous symmetry breaking. Finally, motivated by recent work, we turn to the case of motility assay experiments where motors bound to a surface push on a bundle of filaments. We find that, depending on the absence or the presence of bistability in the force-velocity curve at zero force, the bundle exhibits anomalous or biased diffusion on long-time and large-length scales.

Cervical brachytherapy technique for locally advanced carcinoma of the cervix in a patient with septate uterus.

PubMed

Platta, Christopher S; Wallace, Charlie; Gondi, Vinai; Das, Rupak; Straub, Margaret; Al-Niaimi, Ahmed; Applegate, Glenn; Bradley, Kristin A

2014-03-01

To describe an approach to cervical brachytherapy in a patient with congenital septate uterus and locally advanced cervical carcinoma. The patient is a 34-year-old female with septate uterus presenting with pelvic pain. Workup demonstrated a stage IIB cervical adenocarcinoma with imaging evidence of an involved right external iliac lymph node. The patient received whole pelvic radiation, with concurrent weekly cisplatin (40 mg/m(2)), to a dose of 45 Gy in 25 fractions followed by a parametrial boost of 5.4 Gy and an additional nodal boost of 9 Gy. The patient was initiated on cervical brachytherapy following fraction 23 of pelvic radiation. To conform to her septated uterus, a Rotte-Y tandem was used. Additionally, 2 CT-compatible ovoids were placed in the vaginal apex to enhance dose distribution and coverage of the target volume. Each fraction of brachytherapy was performed with CT-based planning. A high-risk clinical target volume (HR-CTV) and normal structures were defined and constrained per American Brachytherapy Society (ABS) and Groupe Européen de Curiethérapie/European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) guidelines. The brachytherapy dose was 27.5 Gy in 5 fractions of 5.5 Gy each, prescribed to the HR-CTV. Herein, we report the first documented case of cervical brachytherapy in a patient with septate uterus and locally advanced cervical carcinoma. Using CT-guided planning, in conjunction with the ABS and GEC-ESTRO guidelines, the patient was effectively treated with adapted cervical brachytherapy, meeting criteria for HR-CTV coverage and normal tissue tolerances.

Large vasodilatations in skeletal muscle of resting conscious dogs and their contribution to blood pressure variability

PubMed Central

Just, Armin; Schneider, Christian; Ehmke, Heimo; Kirchheim, Hartmut R

2000-01-01

Large (up to +400 %) transient (∼20 s) increases of blood flow were observed in the external iliac arteries of resting conscious dogs (n = 10) in the absence of major alerting or muscular activity. At the same time arterial pressure (AP) fellslightly while heart rate (HR) rose. The vasodilatations were resistant to atropine, ganglionic, β-adrenergic and NO-synthase inhibition, but were suppressed by spinal or general anaesthesia. Vasodilatations of similar appearance were elicited by an alerting sound; these were abolished by atropine. The spontaneous vasodilatations occurred simultaneously and their magnitudes were well correlated between both legs, but were not correlated to the amount of concomitant activation of the surface electromyogram. The duration of this activation almost never outlasted 10 s. The reactive hyperaemia observed after a total occlusion of the artery even for 16 s was not large enough to explain the size of the spontaneous vasodilatations. Occlusion during peak flow of the vasodilatations did not affect the size of the reactive hyperaemia. Spectral analysis made separately for data segments with and without vasodilatation revealed that the vasodilatations substantially enhanced the variability of AP and HR at frequencies below ∼0.1 Hz. In conclusion, large coordinated skeletal muscle vasodilatations were identified in resting conscious dogs, which are initiated neurally, but not by sympathetic-cholinergic or nitroxidergic fibres and which do not show any clear correlation to muscular contraction. The vasodilatations substantially affect the regulation of skeletal muscle blood flow and explain a significant portion of AP and HR variability. PMID:10990545

Study of Mo (VI) removal from aqueous solution: application of different mathematical models to continuous biosorption data.

PubMed

Kafshgari, Fatemeh; Keshtkar, Ali Reza; Mousavian, Mohammad Ali

2013-01-25

Molybdenum (VI) biosorption process was investigated by marine algae Cystoseria indica pretreated with 0.1 M CaCl2 solution in a packed bed column. The biosorbent was characterized by FTIR, BET and SEM analyses. The results showed that Mo (VI) ions should be chelated with the hydroxyl, carboxyl and amine groups of the biomass. The effects of inlet metal concentration and flow rate on biosorption process were investigated and the experimental breakthrough curves were obtained. Results showed that the maximum biosorption capacity of Ca-pretreated C. indica for Mo (VI) was found to be 18.32 mg/g at optimum flow rate of (1.4 mL/min). The controlled-rate step shifted from external to internal mass transfer limitations, as the flow rate increased. Also, it was observed that the breakthrough and exhaustion time decreased from 17.14 hr to 9.05 hr and from 0.006 h to 0.002 hr respectively, with the increase of flow rate from 0.7 to 2.1 ML/min. The increase in the initial concentration of Mo (VI) solution from 30 to 95 ml min-1 increases the adsorption capacity from 18.32 to 30.19 mg/g and decreases the percentage of Mo (VI) removal from 61 to 38%. Also, the treated volume was the greatest (1.42 L) at the lowest inlet concentration. Column data obtained under different conditions were described using the Thomas, Yoon and Nelson, Yan and Belter models. The breakthrough curve predictions by Belter model were found to be very satisfactory.

Laboratory evaluation of compressor blades considered for use in CIP/CUP compressors. [GAT2, 214X, X224, and D-15Al alloys

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

Ritchie, K.L.

1976-04-30

Four die-casting alloys, the external-pressure-pin and conventional casting methods, an accelerated aging heat treatment, and an airfoil fillet modification were evaluated for 33F-S1 compressor blades considered for use in axial flow compressors installed during the Cascade Improvement and Uprating Programs at the three gaseous diffusion plants. Based on castability, resonant frequency, resistance to fatigue cracking, and shank breaking load, the ranking of the four alloys from highest to lowest is GAT2, 214X, X224, and D-15. The GAT2 alloy ranked highest in all categories except impact value; the impact values of both X224 and 214X alloys exceeded that of the GAT2more » alloy, thus indicating the latter is relatively more brittle. However, in view of its other excellent properties, including fatigue cracking resistance, GAT2 alloy is worthy of consideration for use in blades for CIP/CUP or Add-on Plant compressors, particularly if castability becomes a problem with the presently used 214X alloy. Use of the external-pressure-pin casting method is not recommended because the resulting casting difficulties cannot be justified by the small increases in shank breaking loads. The airfoil fillet modification, which is a change from the conventional circular fillet to an elliptical fillet, resulted in increases (1.5 to 4.0 percent) in the average resonant frequency and in resistance to fatigue cracking (15 to 100 percent). The results of giving the blades an accelerated aging heat treatment, designed to simulate in excess of 10,000 hours of cascade exposure, showed that overaging had no significant effect on average resonant frequency but that overaging improved blade quality by reducing residual casting stress. (auth)« less

Cyclic adenosine 3′,5′-monophosphate in human lymphocytes. Alterations after phytohemagglutinin stimulation

PubMed Central

Smith, Jay W.; Steiner, Alton L.; Newberry, W. Marcus; Parker, Charles W.

1971-01-01

We have studied cyclic adenosine 3′,5′-monophosphate (cyclic AMP) concentrations in human peripheral blood lymphocytes after stimulation with phytohemagglutinin (PHA), isoproterenol, prostaglandins, and aminophylline. Purified lymphocytes were obtained by nylon fiber chromatography, and low speed centrifugation to remove platelets. Cyclic AMP levels were determined by a highly sensitive radioimmunoassay. At concentrations of 0.1-1.0 mmoles/liter isoproterenol and aminophylline produced moderate increases in cyclic AMP concentrations, whereas prostaglandins produced marked elevations. High concentrations of PHA produced 25-300% increases in cyclic AMP levels, alterations being demonstrated within 1-2 min. The early changes in cyclic AMP concentration appear to precede previously reported metabolic changes in PHA-stimulated cells. After 6 hr cyclic AMP levels in PHA-stimulated cells had usually fallen to the levels of control cells. After 24 hr the level in PHA-stimulated cells was characteristically below that of the control cells. Adenyl cyclase, the enzyme which converts ATP to cyclic AMP, was measured in lymphocyte homogenates. Adenyl cyclase activity was rapidly stimulated by fluoride, isoproterenol, prostaglandins, and PHA. Since adenyl cyclase is characteristically localized in external cell membranes, our results are consistent with an initial action of PHA at this level. PMID:4395563

Graph state generation with noisy mirror-inverting spin chains

NASA Astrophysics Data System (ADS)

Clark, Stephen R.; Klein, Alexander; Bruderer, Martin; Jaksch, Dieter

2007-06-01

We investigate the influence of noise on a graph state generation scheme which exploits a mirror inverting spin chain. Within this scheme the spin chain is used repeatedly as an entanglement bus (EB) to create multi-partite entanglement. The noise model we consider comprises of each spin of this EB being exposed to independent local noise which degrades the capabilities of the EB. Here we concentrate on quantifying its performance as a single-qubit channel and as a mediator of a two-qubit entangling gate, since these are basic operations necessary for graph state generation using the EB. In particular, for the single-qubit case we numerically calculate the average channel fidelity and whether the channel becomes entanglement breaking, i.e. expunges any entanglement the transferred qubit may have with other external qubits. We find that neither local decay nor dephasing noise cause entanglement breaking. This is in contrast to local thermal and depolarizing noise where we determine a critical length and critical noise coupling, respectively, at which entanglement breaking occurs. The critical noise coupling for local depolarizing noise is found to exhibit a power-law dependence on the chain length. For two-qubits we similarly compute the average gate fidelity and whether the ability for this gate to create entanglement is maintained. The concatenation of these noisy gates for the construction of a five-qubit linear cluster state and a Greenberger Horne Zeilinger state indicates that the level of noise that can be tolerated for graph state generation is tightly constrained.

Time-Reversal Symmetry Breaking and Consequent Physical Responses Induced by All-In-All-Out Type Magnetic Order on the Pyrochlore Lattice

NASA Astrophysics Data System (ADS)

Arima, Taka-Hisa

2014-03-01

Pyrochlore-type 5d transition-metal oxide compounds Cd2Os2O7 and R2Ir2O7 (R =rare earth) undergo a metal-insulator transition accompanied by a magnetic transition. Recently, the magnetic structures of Cd2Os2O7 and Eu2Ir2O7 were investigated by means of resonant x-ray magnetic scattering. The x-ray data indicated the all-in/all-out type magnetic order. The all-in/all-out order breaks the time-reversal symmetry, while the spontaneous magnetization is essentially absent. The magnetic order can be viewed as ferroic magnetic octupolar order. The magnetic order is expected to provide several unique physical properties like quadratic magnetization. linear magneto-capacitance, linear magneto-resistance, linear magneto-mechanical coupling and so on. The symmetry breaking results in two non-equivalent domains, ``all-in/all-out'' and ``all-out/all-in.'' Interestingly, some theoretical works predict that a peculiar metallic state would appear on the domain wall. The observation and control of the domain distribution are essential for studying verious exotic physical responses. We have developed an x-ray technique for domain imaging and started studying the effects of external stimuli on the domain distribution. This work was performed in collaboration with S. Tardif, S. Takeshita, H. Ohsumi, D. Uematsu, H. Sagayama, J. J. Ishikawa, S. Nakatsuji, J. Yamaura, and Z. Hiroi.

Mesospheric gravity-wave climatology at Adelaide

NASA Technical Reports Server (NTRS)

Vincent, R. A.

1986-01-01

The MF Adelaide partial-reflection radar has been operating continuously since November 1983. This has enabled a climatology of gravity-wave activity to be constructed for the mesosphere. The data have been analyzed for a medium-period range of 1 to 8 hr. and a longer period range between 8 and 24 hr. covering the inertio-period waves. The tidal motions have been filtered out prior to analysis. For the data analyses so far (Nov. 1983 to Dec. 1984), a number of interesting features emerged. Firstly, the wave activity at heights above 80 km shows a small seimannual variation with season with the activity being strongest in summer and winter. At heights below 80 km however, there is a similar but more marked variation with the weakest amplitudes occurring at the time of the changeovers in the prevailing circulation. If breaking gravity waves are responsible for much of the turbulence in the mesosphere, then the periods March to April and September to October might also be expected to be periods of weak turbulence. The wave field appears to be partially polarized. The meridional amplitudes are larger than the zonal amplitudes, especially in water. It is found that the degree of polarization is about 15% in summer and 30% in winter. The polarized component is found to propagate in the opposite direction to the background flow in the stratosphere, which suggests that the polarization arises through directional filtering of the waves as they propagate up from below.

WAITING TIME DISTRIBUTION OF SOLAR ENERGETIC PARTICLE EVENTS MODELED WITH A NON-STATIONARY POISSON PROCESS

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

Li, C.; Su, W.; Fang, C.

2014-09-10

We present a study of the waiting time distributions (WTDs) of solar energetic particle (SEP) events observed with the spacecraft WIND and GOES. The WTDs of both solar electron events (SEEs) and solar proton events (SPEs) display a power-law tail of ∼Δt {sup –γ}. The SEEs display a broken power-law WTD. The power-law index is γ{sub 1} = 0.99 for the short waiting times (<70 hr) and γ{sub 2} = 1.92 for large waiting times (>100 hr). The break of the WTD of SEEs is probably due to the modulation of the corotating interaction regions. The power-law index, γ ∼more » 1.82, is derived for the WTD of the SPEs which is consistent with the WTD of type II radio bursts, indicating a close relationship between the shock wave and the production of energetic protons. The WTDs of SEP events can be modeled with a non-stationary Poisson process, which was proposed to understand the waiting time statistics of solar flares. We generalize the method and find that, if the SEP event rate λ = 1/Δt varies as the time distribution of event rate f(λ) = Aλ{sup –α}exp (– βλ), the time-dependent Poisson distribution can produce a power-law tail WTD of ∼Δt {sup α} {sup –3}, where 0 ≤ α < 2.« less

Corrosion investigation of fire-gilded bronze involving high surface resolution spectroscopic imaging

NASA Astrophysics Data System (ADS)

Masi, G.; Chiavari, C.; Avila, J.; Esvan, J.; Raffo, S.; Bignozzi, M. C.; Asensio, M. C.; Robbiola, L.; Martini, C.

2016-03-01

Gilded bronzes are often affected by severe corrosion, due to defects in the Au layer and Au/Cu alloy galvanic coupling, stimulated by large cathodic area of the gilded layer. Galvanic corrosion, triggered by gilding defects, leads to products growth at the Au/bronze interface, inducing blistering or break-up of the Au layer. In this context, fire-gilded bronze replicas prepared by ancient methods (use of spreadable Au-Hg paste) was specifically characterised by compiling complementary spectroscopic and imaging information before/after accelerated ageing with synthetic rain. Fire-gilded bronze samples were chemically imaged in cross-section at nano-metric scale (<200 nm) using high energy and lateral resolution synchrotron radiation photoemission (HR-SRPES) of core levels and valence band after conventional characterisation of the samples by Glow Discharge optical Emission Spectroscopy (GD-OES) and conventional X-ray photoelectron spectroscopy (XPS). We have found a net surface enrichment in Zn and Sn after fire-gilding and presence of metallic Hg, Pb and Cu within the Au layer. Moreover, the composition distribution of the elements together with their oxidation has been determined. It was also revealed that metallic phases including Hg and Pb remain in the gilding after corrosion. Moreover, selective dissolution of Zn and Cu occurs in the crater due to galvanic coupling, which locally induces relative Sn species enrichment (decuprification). The feasibility advantages and disadvantages of chemical imaging using HR-SRPES to study artworks have been investigated on representative replicas.

The purine scaffold Hsp90 inhibitor PU-H71 sensitizes cancer cells to heavy ion radiation by inhibiting DNA repair by homologous recombination and non-homologous end joining.

PubMed

Lee, Younghyun; Li, Huizi Keiko; Masaoka, Aya; Sunada, Shigeaki; Hirakawa, Hirokazu; Fujimori, Akira; Nickoloff, Jac A; Okayasu, Ryuichi

2016-10-01

PU-H71 is a purine-scaffold Hsp90 inhibitor developed to overcome limitations of conventional Hsp90 inhibitors. This study was designed to investigate the combined effect of PU-H71 and heavy ion irradiation on human tumor and normal cells. The effects of PU-H71 were determined by monitoring cell survival by colony formation, and DNA double-strand break (DSB) repair by γ-H2AX foci and immuno-blotting DSB repair proteins. The mode of cell death was evaluated by sub-G1 DNA content (as an indicator for apoptosis), and mitotic catastrophe. PU-H71 enhanced heavy ion irradiation-induced cell death in three human cancer cell lines, but the drug did not radiosensitize normal human fibroblasts. In irradiated tumor cells, PU-H71 increased the persistence of γ-H2AX foci, and it reduced RAD51 foci and phosphorylated DNA-PKcs, key DSB repair proteins involved in homologous recombination (HR) and non-homologous end joining (NHEJ). In some tumor cell lines, PU-H71 altered the sub-G1 cell fraction and mitotic catastrophe following carbon ion irradiation. Our results demonstrate that PU-H71 sensitizes human cancer cells to heavy ion irradiation by inhibiting both HR and NHEJ DSB repair pathways. PU-H71 holds promise as a radiosensitizer for enhancing the efficacy of heavy ion radiotherapy. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Protein dynamics of human RPA and RAD51 on ssDNA during assembly and disassembly of the RAD51 filament.

PubMed

Ma, Chu Jian; Gibb, Bryan; Kwon, YoungHo; Sung, Patrick; Greene, Eric C

2017-01-25

Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair. Here, we use single-molecule imaging to visualize the interplay between human RPA (hRPA) and human RAD51 during presynaptic complex assembly and disassembly. We demonstrate that ssDNA-bound hRPA can undergo facilitated exchange, enabling hRPA to undergo rapid exchange between free and ssDNA-bound states only when free hRPA is present in solution. Our results also indicate that the presence of free hRPA inhibits RAD51 filament nucleation, but has a lesser impact upon filament elongation. This finding suggests that hRPA exerts important regulatory influence over RAD51 and may in turn affect the properties of the assembled RAD51 filament. These experiments provide an important basis for further investigations into the regulation of human presynaptic complex assembly. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

GRB 120729A: External Shock Origin for Both the Prompt Gamma-Ray Emission and Afterglow

NASA Astrophysics Data System (ADS)

Huang, Li-Ye; Wang, Xiang-Gao; Zheng, WeiKang; Liang, En-Wei; Lin, Da-bin; Zhong, Shu-Qing; Zhang, Hai-Ming; Huang, Xiao-Li; Filippenko, Alexei V.; Zhang, Bing

2018-06-01

Gamma-ray burst (GRB) 120729A was detected by Swift/BAT and Fermi/GBM, and then rapidly observed by Swift/XRT, Swift/UVOT, and ground-based telescopes. It had a single long and smooth γ-ray emission pulse, which extends continuously to the X-rays. We report Lick/KAIT observations of the source, and make temporal and spectral joint fits of the multiwavelength light curves of GRB 120729A. It exhibits achromatic light-curve behavior, consistent with the predictions of the external shock model. The light curves are decomposed into four typical phases: onset bump (Phase I), normal decay (Phase II), shallow decay (Phase III), and post-jet break (Phase IV). The spectral energy distribution (SED) evolves from prompt γ-ray emission to the afterglow with a photon index from Γ γ = 1.36 to Γ ≈ 1.75. There is no obvious evolution of the SED during the afterglow. The multiwavelength light curves from γ-ray to optical can be well modeled with an external shock by considering energy injection, and a time-dependent microphysics model with {ε }B\\propto {t}{α B} for the emission at early times, T< {T}0+157 {{s}}. Therefore, we conclude that both the prompt γ-ray emission and afterglow of GRB 120729A have the same external shock physical origin. Our model indicates that the ɛ B evolution can be described as a broken power-law function with α B,1 = 0.18 ± 0.04 and α B,2 = 0.84 ± 0.04. We also systematically investigate single-pulse GRBs in the Swift era, finding that only a small fraction of GRBs (GRBs 120729A, 051111, and 070318) are likely to originate from an external shock for both the prompt γ-ray emission and afterglow.

A cross-sectional assessment of the long term effects of brief strategic family therapy for adolescent substance use.

PubMed

Horigian, Viviana E; Feaster, Daniel J; Robbins, Michael S; Brincks, Ahnalee M; Ucha, Jessica; Rohrbaugh, Michael J; Shoham, Varda; Bachrach, Ken; Miller, Michael; Burlew, A Kathleen; Hodgkins, Candace C; Carrion, Ibis S; Silverstein, Meredith; Werstlein, Robert; Szapocznik, José

2015-10-01

Young adult drug use and law-breaking behaviors often have roots in adolescence. These behaviors are predicted by early drug use, parental substance use disorders, and disrupted and conflict-ridden family environments. To examine long-term outcomes of Brief Strategic Family Therapy (BSFT) compared to treatment as usual (TAU) in the rates of drug use, number of arrests and externalizing behaviors in young adults who were randomized into treatment conditions as adolescents. 261 of 480 adolescents who had been randomized to BSFT or TAU in the BSFT effectiveness study were assessed at a single time, 3-7 years post randomization. Assessments of drug use, externalizing behaviors, arrests and incarcerations were conducted using Timeline Follow Back, Adult Self Report, and self-report, respectively. Drug use, arrests and incarcerations were examined using negative binomial models and externalizing behaviors were examined using linear regression. When compared with TAU, BSFT youth reported lower incidence of lifetime (IRR = 0.68, 95%CI [0.57, 0.81]) and past year (IRR = 0.54, 95%CI [0.40, 0.71]) arrests; lower rates of lifetime (IRR = 0.63, 95%CI [0.49, 0.81]) and past year (IRR = 0.70, 95%CI [0.53, 0.92]) incarcerations; and lower scores on externalizing behaviors at follow-up (B = -0.42, SE = .15, p = .005). There were no differences in drug use. BSFT may have long term effects in reducing the number of arrests, incarcerations and externalizing problems. These effects could be explained by the improvements in family functioning that occurred during the effectiveness study. This study contributes to the literature by reporting on the long term outcomes of family therapy for adolescent drug abuse. © American Academy of Addiction Psychiatry.

Training the Antifragile Athlete: A Preliminary Analysis of Neuromuscular Training Effects on Muscle Activation Dynamics.

PubMed

Kiefer, Adam W; Myer, Gregory D

2015-10-01

Athletic injuries typically occur when the stable, emergent coordination between behavioral processes breaks down due to external noise, or variability. A physiological system that operates at an optimal point on a spectrum of rigidity and flexibility may be better prepared to handle extreme external variability, and the purpose of the current experiment was to examine whether targeted neuromuscular training resulted in changes to the rigidity and flexibility of the gluteal muscle tonus signal as measured with electromyography prior to the landing phase of a drop vertical jump task. 10 adolescent female athletes who participated in a targeted 10-week neuromuscular training program and 6 controls participated, and their tonus dynamics were examined with recurrence quantification analysis prior to training and after the 10-week program. The dependent measures, percent laminarity (%LAM) and percent determinism (%DET) were hypothesized to decrease following training, and were submitted to a one tailed mixed-model ANOVA. The training group exhibited a decrease in %LAM and %DET after training compared to pre-training and controls. The present findings indicate increased metaflexibility (i.e., greater intermittency and an increase in internal randomness) in tonus dynamics following neuromuscular training, and have important implications for the prevention of musculoskeletal injury in sport, specifically within the context of external noise and antifragility.

Auto-magnetizing liners for magnetized inertial fusion

DOE PAGES

Slutz, S. A.; Jennings, C. A.; Awe, T. J.; ...

2017-01-20

Here, the MagLIF (Magnetized Liner Inertial Fusion) concept has demonstrated fusion-relevant plasma conditions on the Z accelerator using external field coils to magnetize the fuel before compression. We present a novel concept (AutoMag), which uses a composite liner with helical conduction paths separated by insulating material to provide fuel magnetization from the early part of the drive current, which by design rises slowly enough to avoid electrical breakdown of the insulators. Once the magnetization field is established, the drive current rises more quickly, which causes the insulators to break down allowing the drive current to follow an axial path andmore » implode the liner in the conventional z-pinch manner. There are two important advantages to AutoMag over external field coils for the operation of MagLIF. Low inductance magnetically insulated power feeds can be used to increase the drive current, and AutoMag does not interfere with diagnostic access. Also, AutoMag enables a pathway to energy applications for MagLIF, since expensive field coils will not be damaged each shot. Finally, it should be possible to generate Field Reversed Configurations (FRC) by using both external field coils and AutoMag in opposite polarities. This would provide a means to studying FRC liner implosions on the 100 ns time scale.« less

Stellarator Coil Design and Plasma Sensitivity

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

Long-Poe Ku and Allen H. Boozer

2010-11-03

The rich information contained in the plasma response to external magnetic perturbations can be used to help design stellarator coils more effectively. We demonstrate the feasibility by first devel- oping a simple, direct method to study perturbations in stellarators that do not break stellarator symmetry and periodicity. The method applies a small perturbation to the plasma boundary and evaluates the resulting perturbed free-boundary equilibrium to build up a sensitivity matrix for the important physics attributes of the underlying configuration. Using this sensitivity information, design methods for better stellarator coils are then developed. The procedure and a proof-of-principle application are givenmore » that (1) determine the spatial distributions of external normal magnetic field at the location of the unperturbed plasma boundary to which the plasma properties are most sen- sitive, (2) determine the distributions of external normal magnetic field that can be produced most efficiently by distant coils, (3) choose the ratios of the magnitudes of the the efficiently produced magnetic distributions so the sensitive plasma properties can be controlled. Using these methods, sets of modular coils are found for the National Compact Stellarator Experiment (NCSX) that are either smoother or can be located much farther from the plasma boundary than those of the present design.« less

Gyrokinetic Simulations with External Resonant Magnetic Perturbations: Island Torque and Nonambipolar Transport with Rotation

NASA Astrophysics Data System (ADS)

Waltz, R. E.; Waelbroeck, F. L.

2012-03-01

Static external resonant magnetic perturbations (RMPs) have been added to the δf gyrokinetic code GYRO. This allows nonlinear gyrokinetic simulations of the nonambipolar radial current flow jr and the corresponding plasma torque (density) R[jrBθ/c], induced by islands that break the toroidal symmetry of a tokamak. This extends previous GYRO simulations for the transport of toroidal angular momentum (TAM) [1,2]. The focus is on full torus radial slice electrostatic simulations of induced q=m/n=6/3 islands with widths 5% of the minor radius. The island torque scales with the radial electric field Er the island width w, and the intensity I of the high-n micro-turbulence, as wErI^1/2. The net island torque is null at zero Er rather than at zero toroidal rotation. This means that there is a small co-directed magnetic acceleration to the small diamagnetic co-rotation corresponding to the zero Er which can be called the residual stress [2] from an externally induced island. Finite-beta GYRO simulations of a core radial slice demonstrate island unlocking and the RMP screening. 6pt[1] R.E. Waltz, et al., Phys. Plasmas 14, 122507 (2007). [2] R.E. Waltz, et al., Phys. Plasmas 18, 042504 (2011).

Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections.

PubMed

Piano, Salvatore; Bartoletti, Michele; Tonon, Marta; Baldassarre, Maurizio; Chies, Giada; Romano, Antonietta; Viale, Pierluigi; Vettore, Elia; Domenicali, Marco; Stanco, Marialuisa; Pilutti, Chiara; Frigo, Anna Chiara; Brocca, Alessandra; Bernardi, Mauro; Caraceni, Paolo; Angeli, Paolo

2017-08-31

Patients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections. 259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients). Sepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p<0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3. Sepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Development and validation of a risk stratification score for ventral incisional hernia after abdominal surgery: hernia expectation rates in intra-abdominal surgery (the HERNIA Project).

PubMed

Goodenough, Christopher J; Ko, Tien C; Kao, Lillian S; Nguyen, Mylan T; Holihan, Julie L; Alawadi, Zeinab; Nguyen, Duyen H; Flores, Juan R; Arita, Nestor T; Roth, J Scott; Liang, Mike K

2015-04-01

Ventral incisional hernias (VIH) develop in up to 20% of patients after abdominal surgery. No widely applicable preoperative risk-assessment tool exists. We aimed to develop and validate a risk-assessment tool to predict VIH after abdominal surgery. A prospective study of all patients undergoing abdominal surgery was conducted at a single institution from 2008 to 2010. Variables were defined in accordance with the National Surgical Quality Improvement Project, and VIH was determined through clinical and radiographic evaluation. A multivariate Cox proportional hazard model was built from a development cohort (2008 to 2009) to identify predictors of VIH. The HERNIAscore was created by converting the hazards ratios (HR) to points. The predictive accuracy was assessed on the validation cohort (2010) using a receiver operator characteristic curve and calculating the area under the curve (AUC). Of 625 patients followed for a median of 41 months (range 0.3 to 64 months), 93 (13.9%) developed a VIH. The training cohort (n = 428, VIH = 70, 16.4%) identified 4 independent predictors: laparotomy (HR 4.77, 95% CI 2.61 to 8.70) or hand-assisted laparoscopy (HAL, HR 4.00, 95% CI 2.08 to 7.70), COPD (HR 2.35; 95% CI 1.44 to 3.83), and BMI ≥ 25 kg/m(2) (HR1.74; 95% CI 1.04 to 2.91). Factors that were not predictive included age, sex, American Society of Anesthesiologists (ASA) score, albumin, immunosuppression, previous surgery, and suture material or technique. The predictive score had an AUC = 0.77 (95% CI 0.68 to 0.86) using the validation cohort (n = 197, VIH = 23, 11.6%). Using the HERNIAscore: HERNIAscore = 4(∗)Laparotomy+3(∗)HAL+1(∗)COPD+1(∗) BMI ≥ 25, 3 classes stratified the risk of VIH: class I (0 to 3 points),5.2%; class II (4 to 5 points),19.6%; and class III (6 points), 55.0%. The HERNIAscore accurately identifies patients at increased risk for VIH. Although external validation is needed, this provides a starting point to counsel patients and guide clinical decisions. Increasing the use of laparoscopy, weight-loss programs, community smoking prevention programs, and incisional reinforcement may help reduce rates of VIH. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

PubMed Central

Wei, Caimiao; Gould, Rebekah; Yu, Xian; Zhang, Ya; Liu, Mei; Walls, Andrew; Bousamra, Alex; Ramineni, Maheshwari; Sinn, Bruno; Hunt, Kelly; Buchholz, Thomas A.; Valero, Vicente; Buzdar, Aman U.; Yang, Wei; Brewster, Abenaa M.; Moulder, Stacy; Pusztai, Lajos; Hatzis, Christos; Hortobagyi, Gabriel N.

2017-01-01

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)–targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor–negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor–negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated. PMID:28135148

Fifteen-Year Radiotherapy Outcomes of the Randomized PORTEC-1 Trial for Endometrial Carcinoma

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

Creutzberg, Carien L., E-mail: c.l.creutzberg@lumc.nl; Nout, Remi A.; Lybeert, Marnix L.M.

2011-11-15

Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. Patients and Methods: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. Results: 426 patients were alive at the date of analysis. The median follow-upmore » time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.« less

The Patient Burden of Bladder Outlet Obstruction after Prostate Cancer Treatment.

PubMed

Liberman, Daniel; Jarosek, Stephanie; Virnig, Beth A; Chu, Haitao; Elliott, Sean P

2016-05-01

Bladder outlet obstruction after prostate cancer therapy imposes a significant burden on health and quality of life in men. Our objective was to describe the burden of bladder outlet obstruction after prostate cancer therapy by detailing the type of procedures performed and how often those procedures were repeated in men with recurrent bladder outlet obstruction. Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data from 1992 to 2007 with followup through 2009 we identified 12,676 men who underwent at least 1 bladder outlet obstruction procedure after prostate cancer therapy, including external beam radiotherapy in 3,994, brachytherapy in 1,485, brachytherapy plus external beam radiotherapy in 1,847, radical prostatectomy in 4,736, radical prostatectomy plus external beam radiotherapy in 369 and cryotherapy in 245. Histogram, incidence rates and Cox proportional hazards models with repeat events analysis were done to describe the burden of repeat bladder outlet obstruction treatments stratified by prostate cancer therapy type. We describe the type of bladder outlet obstruction surgery grouped by level of invasiveness. At a median followup of 8.8 years 44.6% of men underwent 2 or more bladder outlet obstruction procedures. Compared to men who underwent radical prostatectomy those treated with brachytherapy and brachytherapy plus external beam radiotherapy were at increased adjusted risk for repeat bladder outlet obstruction treatment (HR 1.2 and 1.32, respectively, each p <0.05). After stricture incision the men treated with radical prostatectomy or radical prostatectomy plus external beam radiotherapy were most likely to undergo dilation at a rate of 34.7% to 35.0%. Stricture resection/ablation was more common after brachytherapy, external beam radiotherapy or brachytherapy plus external beam radiotherapy at a rate of 28.9% to 41.2%. Almost half of the men with bladder outlet obstruction after prostate cancer therapy undergo more than 1 procedure. Furthermore men with bladder outlet obstruction after radiotherapy undergo more invasive endoscopic therapies and are at higher risk for multiple treatments than men with bladder outlet obstruction after radical prostatectomy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Opening the black box of transfer systems in public sector health services in a Western state in India.

PubMed

Purohit, Bhaskar; Martineau, Tim; Sheikh, Kabir

2016-08-22

Limited research on Posting and Transfer (P&T) policies and systems in the public sector health services and the reluctance for an open debate on the issue makes P&T as a black box. Limited research on P&T in India suggests that P&T policies and systems are either non-existent, weak, poorly implemented or characterized by corruption. Hence the current study aimed at opening the "black box" of P&T systems in public sector health services in India by assessing the implementation gaps between P&T policies and their actual implementation. This was a qualitative study carried out in Department of Health, in a Western State in India. To understand the extant P&T policies, a systems map was first developed with the help of document review and Key Informant (KI) Interviews. Next systems audit was carried out to assess the actual implementation of transfer policies by interviewing Medical Officers (MOs), the group mainly affected by the P&T policies. Job histories were constructed from the interviews to understand transfer processes like frequencies of transfers and to assess if transfer rules were adhered. The analysis is based on a synthesis of document review, 19 in-depth interviews with MOs working with state health department and five in-depth interviews with Key Informants (KIs). Framework analysis approach was used to analyze data using NVIVO. The state has a generic transfer guideline applicable to all government officers but there is no specific transfer policy or guideline for government health personnel. The generic transfer guidelines are weakly implemented indicating a significant gap between policy and actual implementation. The formal transfer guidelines are undermined by a parallel system in which desirable posts are attained, retained or sometimes given up by the use of political connections and money. MOs' experiences of transfers were marked by perceptions of unfairness and irregularities reflected through interviews as well as the job histories. The generic transfer rules and ambiguity in how transfers are treated may explain the discrepancy between policy and implementation leading to systems abuse. This discrepancy could have negative influence on MOs' morale which could in turn affect distribution of MOs. Where possible, ambiguity in the rules should be avoided and a greater transparency on implementation of the transfer rules is needed. However, it may not be possible to make any significant improvements to P&T policies and how they are implemented until the external pressure that creates parallel systems is greatly reduced in translating HR policy into HR practice. Effective P&T policies and implementation may have important implications for organizational performance and may help to improve Human Resource (HR) policy and HR expertise. Also there is a greater need for transparency on implementation of the rules. However, it may not be possible to make any significant improvements to P&T policies and how they are implemented until the external pressure that creates parallel systems is greatly reduced.

Enhanced photocatalytic CO2 reduction to CH4 over separated dual co-catalysts Au and RuO2

NASA Astrophysics Data System (ADS)

Dong, Chunyang; Hu, Songchang; Xing, Mingyang; Zhang, Jinlong

2018-04-01

A spatially separated, dual co-catalyst photocatalytic system was constructed by the stepwise introduction of RuO2 and Au nanoparticles (NPs) at the internal and external surfaces of a three dimensional, hierarchically ordered TiO2-SiO2 (HTSO) framework (the final photocatalyst was denoted as Au/HRTSO). Characterization by HR-TEM, EDS-mapping, XRD and XPS confirmed the existence and spatially separated locations of Au and RuO2. In CO2 photocatalytic reduction (CO2PR), Au/HRTSO (0.8%) shows the optimal performance in both the activity and selectivity towards CH4; the CH4 yield is almost twice that of the singular Au/HTSO or HRTSO (0.8%, weight percentage of RuO2) counterparts. Generally, Au NPs at the external surface act as electron trapping agents and RuO2 NPs at the inner surface act as hole collectors. This advanced spatial configuration could promote charge separation and transfer efficiency, leading to enhanced CO2PR performance in both the yield and selectivity toward CH4 under simulated solar light irradiation.

Risk of fatal cerebrovascular accidents after external beam radiation therapy for early-stage glottic laryngeal cancer.

PubMed

Swisher-McClure, Samuel; Mitra, Nandita; Lin, Alexander; Ahn, Peter; Wan, Fei; O'Malley, Bert; Weinstein, Gregory S; Bekelman, Justin E

2014-05-01

This study compared the risk of fatal cerebrovascular accidents (CVAs) in patients with early-stage glottic laryngeal cancer receiving surgery or external beam radiation therapy (EBRT). Using a competing risks survival analysis, we compared the risk of death because of CVA among patients with early-stage glottic laryngeal cancer receiving surgery or EBRT in the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence of fatal CVA at 15 years was higher in patients receiving EBRT (2.8%; 95% confidence interval [CI], 2.3% to 3.4%) compared to surgery (1.5%; 95% CI, 0.8% to 2.3%; p = .024). In multivariable competing risks regression models, EBRT remained associated with an increased risk of fatal CVA compared to surgery (adjusted hazard ratio [HR], 1.75; 95% CI, 1.04-2.96; p = .037). Treatment for early-stage glottic laryngeal cancer with EBRT was associated with a small increase in the risk of late fatal CVA events relative to surgery. Copyright © 2013 Wiley Periodicals, Inc.

The impact of ART on union dissolution: a register-based study in Denmark 1994-2010.

PubMed

Martins, Mariana Veloso; Vassard, Ditte; Hougaard, Charlotte Ørsted; Schmidt, Lone

2018-01-23

Are couples initiating ART treatment at higher risk for future union dissolution compared to other couples? There is no effect of ART treatments in future marital dissolution over a period of 16 years when adjusting for all confounders. Findings regarding marital stability and infertility treatments have been sparse and controversial. While there is data showing higher divorce rates among women who go through infertility treatments, there is also some evidence of this experience bringing couples closer by forcing them to communicate more and to deal with the surrounding stigma. Using a population-based study and couple-level data, we investigated the extent to which ART treatment increases the risk for divorce/marital dissolution during up to 16 years of follow-up. Register-based national cohort study including all women registered with ART treatment in Denmark between 1 January 1994 and 30 September 2009 (n = 42 845). Marital/cohabiting status was confirmed by matching these women to partners who they were married to or shared an address with. To account for having a significant relationship at baseline (2 years), marital/cohabiting status was confirmed by accessing this variable before the establishment of the cohort back to 1 January 1992. A comparison group from the background population including five controls per case and matched to female age at baseline was prospectively sampled. Participants could change status during follow-up if they entered ART. The final sample had 148 972 couples, followed until marital dissolution, death of self/spouse, migration or until 31 December 2010. We used Cox regression models adjusting for female and male age, education, marriage, common child at baseline and live-born child during follow-up. At baseline, the majority of couples were married (69%). More non-ART couples opted for marriage (70% versus 64%; P < 0.0001) and already had common children at study entry (43% versus 9%; P < 0.0001). During the 16 years of follow-up the majority of couples had children with their baseline partners (56% non-ART versus 65% ART), and 22% ended up separated or divorced (20% ART versus 22% non-ART). Findings revealed a lower risk of break-up among ART couples (crude HR 0.84, 95% CI 0.82-0.86), even after adjusting for both partners' age, education, partnership status and having a common child at baseline (adj HR 0.83, 95% CI 0.80-0.86). However, when subsequent common children (time-dependent) was added to the model, no difference in the risk of dissolution was found (adj HR 1.00, 95% CI 0.99-1.01). A significant interaction between ART status and common children showed that the risk of break-up was attributed to childlessness regardless of having gone through ART treatment. This study did not control for involuntary childlessness, non-ART fertility care (ovulation induction, IUI) and biological parenthood. Additionally, there are important predictors of divorce that were not considered. We were unable to adjust for religion, existence of previous marital relationships, income, employment, health status of parents and child(ren), and quality of relationship. The finding that going through ART does not increase the risk of break up per se is reassuring for couples who underwent ART and have children or are contemplating to start ART. This work was supported by FCT (Portuguese Foundation for Science and Technology), grant ref. SFRH/BPD/85789/2012. The authors have no conflicts of interest. N/A. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com