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Sample records for regulation specifically older

  1. Treatment of specific phobia in older adults

    Directory of Open Access Journals (Sweden)

    Nancy A Pachana

    2007-10-01

    Full Text Available Nancy A Pachana1, Rana M Woodward1, Gerard JA Byrne21School of Psychology, University of Queensland, Brisbane, Australia 2School of Medicine, University of Queensland, Brisbane, AustraliaAbstract: Phobias are common in later life, yet treatment research in this population remains scant. The efficacy of exposure therapy, in combination with other Cognitive-Behavioral Therapy (CBT components, in the treatment of specific phobia with a middle and older aged sample was examined. Sixteen adults aged 45–68 with DSM-IV diagnosis of a specific phobia received a manualized intervention over ten weeks, and were compared with a control group. Results indicated significant time effects in the treatment group for the primary outcome variables of phobic severity and avoidance as well as secondary outcome variables including depression and anxiety. Symptom presence and severity also significantly declined in the treatment group. No significant changes in state anxiety were noted across the treatment period. Such results provide support for the efficacy of exposure combined with CBT treatment for specific phobia in middle to older aged adults.Keywords: anxiety, phobia, older adults, cognitive behavioral therapy

  2. Specific phobias in older adults: characteristics and differential diagnosis.

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    Coelho, Carlos M; Gonçalves, Daniela C; Purkis, Helena; Pocinho, Margarida; Pachana, Nancy A; Byrne, Gerard J

    2010-08-01

    Differential diagnosis implies identifying shared and divergent characteristics between clinical states. Clinical work with older adults demands not only the knowledge of nosological features associated with differential diagnosis, but also recognition of idiosyncratic factors associated with this population. Several factors can interfere with an accurate diagnosis of specific phobia in older cohorts. The goal of this paper is to review criteria for specific phobia and its differential diagnosis with panic disorder, agoraphobia, post-traumatic stress disorder and obsessive compulsive disorder, while stressing the specific factors associated with aging. A literature search regarding specific phobia in older adults was carried out using PubMed. Relevant articles were selected and scanned for further pertinent references. In addition, relevant references related to differential diagnosis and assessment were used. Etiologic factors, specificity of feared stimulus or situation, fear predictability and the nature of phobic situations are key points to be assessed when implementing a differential diagnosis of specific phobia. First, age-related sensory impairments are common and interfere both with information processing and communication. Second, medical illnesses create symptoms that might cause, interfere with, or mimic anxiety. Third, cohort effects might result in underreporting, through the inability to communicate or recognize anxiety symptoms, misattributing them to physical conditions. Finally, diagnostic criteria and screening instruments were usually developed using younger samples and are therefore not adapted to the functional and behavioral characteristics of older samples.

  3. Affect and person specificity in mood regulation

    OpenAIRE

    Corby, Emma Kate

    2007-01-01

    489 university students in three countries completed questionnaires in a study investigating affect and person specificity in the use of mood regulation strategies. The major aims of the study were to (1) describe the relationship between specific affective states and the strategies utilised, (2) explore the role that individual differences variables played in the tendency to use particular strategies, and (3) measure the impact that the use of different strategies had upon subjective well-b...

  4. Primary Auditory Cortex Regulates Threat Memory Specificity

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    Wigestrand, Mattis B.; Schiff, Hillary C.; Fyhn, Marianne; LeDoux, Joseph E.; Sears, Robert M.

    2017-01-01

    Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used…

  5. How do older adult drivers self-regulate? Characteristics of self-regulation classes defined by latent class analysis.

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    Bergen, Gwen; West, Bethany A; Luo, Feijun; Bird, Donna C; Freund, Katherine; Fortinsky, Richard H; Staplin, Loren

    2017-06-01

    Motor-vehicle crashes were the second leading cause of injury death for adults aged 65-84years in 2014. Some older drivers choose to self-regulate their driving to maintain mobility while reducing driving risk, yet the process remains poorly understood. Data from 729 older adults (aged ≥60years) who joined an older adult ride service program between April 1, 2010 and November 8, 2013 were analyzed to define and describe classes of driving self-regulation. Latent class analysis was employed to characterize older adult driving self-regulation classes using driving frequency and avoidance of seven driving situations. Logistic regression was used to explore associations between characteristics affecting mobility and self-regulation class. Three classes were identified (low, medium, and high self-regulation). High self-regulating participants reported the highest proportion of always avoiding seven risky driving situations and the lowest driving frequency followed by medium and low self-regulators. Those who were female, aged 80years or older, visually impaired, assistive device users, and those with special health needs were more likely to be high self-regulating compared with low self-regulating. Avoidance of certain driving situations and weekly driving frequency are valid indicators for describing driving self-regulation classes in older adults. Understanding the unique characteristics and mobility limitations of each class can guide optimal transportation strategies for older adults. Published by Elsevier Ltd.

  6. Positivity Effect Specific to Older Adults with Subclinical Memory Impairment

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    Leal, Stephanie L.; Noche, Jessica A.; Murray, Elizabeth A.; Yassa, Michael A.

    2016-01-01

    Numerous studies have suggested that older adults preferentially remember positive information ("positivity effect"), however others have reported mixed results. One potential source of conflict is that aging is not a unitary phenomenon and individual differences exist. We modified a standard neuropsychological test to vary emotional…

  7. Situation Selection and Modification for Emotion Regulation in Younger and Older Adults.

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    Livingstone, Kimberly M; Isaacowitz, Derek M

    2015-11-01

    This research investigated age differences in use and effectiveness of situation selection and situation modification for emotion regulation. Socioemotional selectivity theory suggests stronger emotional well-being goals in older age; emotion regulation may support this goal. Younger and older adults assigned to an emotion regulation or "just view" condition first freely chose to engage with negative, neutral, or positive material (situation selection), then chose to view or skip negative and positive material (situation modification), rating affect after each experience. In both tasks, older adults in both goal conditions demonstrated pro-hedonic emotion regulation, spending less time with negative material compared to younger adults. Younger adults in the regulate condition also engaged in pro-hedonic situation selection, but not modification. Whereas situation selection was related to affect, modification of negative material was not. This research supports more frequent pro-hedonic motivation in older age, as well as age differences in use of early-stage emotion regulation.

  8. A qualitative exploration of self-regulation behaviors among older drivers.

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    Donorfio, Laura K M; Mohyde, Maureen; Coughlin, Joseph; D'Ambrosio, Lisa

    2008-01-01

    While much of the research on aging and driving has focused on sensory and motor changes, little is known about older drivers and the actual self-regulation adjustments they employ to continue driving safely. This research looks at how older drivers have made changes to driving patterns and behaviors that have allowed them to continue to drive without compromising their perceived safety, independence, and quality of life. Nine focus groups were held with older men and women aged 58 to 89 years. Some of the major themes that emerged were the following: older adults are very aware of age-related changes to driving; they perceive that self-regulation behaviors change with age; and they view transportation alternatives as limited or nonexistent. Policy implications include developing functional transit programs for older adults and car manufacturer training workshops to educate older adults on the safety features of newly purchased automobiles.

  9. Balance Performance Is Task Specific in Older Adults

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    Ayelet Dunsky

    2017-01-01

    Full Text Available Balance ability among the elderly is a key component in the activities of daily living and is divided into two types: static and dynamic. For clinicians who wish to assess the risk of falling among their elderly patients, it is unclear if more than one type of balance test can be used to measure their balance impairment. In this study, we examined the association between static balance measures and two dynamic balance field tests. One hundred and twelve community-dwelling older adults (mean age 74.6 participated in the study. They underwent the Tetrax static postural assessment and then performed the Timed Up and Go (TUG and the Functional Reach (FR Test as dynamic balance tests. In general, low-moderate correlations were found between the two types of balance tests. For women, age and static balance parameters explained 28.1–40.4% of the variance of TUG scores and 14.6–24% of the variance of FR scores. For men, age and static balance parameters explained 9.5–31.2% of the variance of TUG scores and 23.9–41.7% of the variance of FR scores. Based on our findings, it is suggested that a combination of both static and dynamic tests be used for assessing postural balance ability.

  10. The Older Adult Positivity Effect in Evaluations of Trustworthiness: Emotion Regulation or Cognitive Capacity?

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    Zebrowitz, Leslie A; Boshyan, Jasmine; Ward, Noreen; Gutchess, Angela; Hadjikhani, Nouchine

    2017-01-01

    An older adult positivity effect, i.e., the tendency for older adults to favor positive over negative stimulus information more than do younger adults, has been previously shown in attention, memory, and evaluations. This effect has been attributed to greater emotion regulation in older adults. In the case of attention and memory, this explanation has been supported by some evidence that the older adult positivity effect is most pronounced for negative stimuli, which would motivate emotion regulation, and that it is reduced by cognitive load, which would impede emotion regulation. We investigated whether greater older adult positivity in the case of evaluative responses to faces is also enhanced for negative stimuli and attenuated by cognitive load, as an emotion regulation explanation would predict. In two studies, younger and older adults rated trustworthiness of faces that varied in valence both under low and high cognitive load, with the latter manipulated by a distracting backwards counting task. In Study 1, face valence was manipulated by attractiveness (low /disfigured faces, medium, high/fashion models' faces). In Study 2, face valence was manipulated by trustworthiness (low, medium, high). Both studies revealed a significant older adult positivity effect. However, contrary to an emotion regulation account, this effect was not stronger for more negative faces, and cognitive load increased rather than decreased the rated trustworthiness of negatively valenced faces. Although inconsistent with emotion regulation, the latter effect is consistent with theory and research arguing that more cognitive resources are required to process negative stimuli, because they are more cognitively elaborated than positive ones. The finding that increased age and increased cognitive load both enhanced the positivity of trustworthy ratings suggests that the older adult positivity effect in evaluative ratings of faces may reflect age-related declines in cognitive capacity rather

  11. Fluid cognitive ability is a resource for successful emotion regulation in older and younger adults

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    Opitz, Philipp C.; Lee, Ihno A.; Gross, James J.; Urry, Heather L.

    2014-01-01

    The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER) framework suggests that (1) emotion regulation (ER) strategies require resources and that (2) higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR), a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults) completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease) their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity), expressive behavior (corrugator muscle activity), and autonomic physiology (heart rate and electrodermal activity) as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger). As predicted, higher fluid cognitive ability—indexed by perceptual reasoning, processing speed, and working memory—was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation. PMID:24987387

  12. Fluid Cognitive Ability is a Resource for Successful Emotion Regulation in Older and Younger Adults

    Directory of Open Access Journals (Sweden)

    Philipp C. Opitz

    2014-06-01

    Full Text Available The Selection, Optimization, and Compensation with Emotion Regulation (SOC-ER framework suggests that (1 emotion regulation (ER strategies require resources and that (2 higher levels of relevant resources may increase ER success. In the current experiment, we tested the specific hypothesis that individual differences in one internal class of resources, namely cognitive ability, would contribute to greater success using cognitive reappraisal (CR, a form of ER in which one reinterprets the meaning of emotion-eliciting situations. To test this hypothesis, 60 participants (30 younger and 30 older adults completed standardized neuropsychological tests that assess fluid and crystallized cognitive ability, as well as a CR task in which participants reinterpreted the meaning of sad pictures in order to alter (increase or decrease their emotions. In a control condition, they viewed the pictures without trying to change how they felt. Throughout the task, we indexed subjective emotional experience (self-reported ratings of emotional intensity, expressive behavior (corrugator muscle activity, and autonomic physiology (heart rate and electrodermal activity as measures of emotional responding. Multilevel models were constructed to explain within-subjects variation in emotional responding as a function of ER contrasts comparing increase or decrease conditions with the view control condition and between-subjects variation as a function of cognitive ability and/or age group (older, younger. As predicted, higher fluid cognitive ability – indexed by perceptual reasoning, processing speed, and working memory – was associated with greater success using reappraisal to alter emotional responding. Reappraisal success did not vary as a function of crystallized cognitive ability or age group. Collectively, our results provide support for a key tenet of the SOC-ER framework that higher levels of relevant resources may confer greater success at emotion regulation.

  13. Dissecting specific and global transcriptional regulation of bacterial gene expression

    NARCIS (Netherlands)

    Gerosa, Luca; Kochanowski, Karl; Heinemann, Matthias; Sauer, Uwe

    Gene expression is regulated by specific transcriptional circuits but also by the global expression machinery as a function of growth. Simultaneous specific and global regulation thus constitutes an additional-but often neglected-layer of complexity in gene expression. Here, we develop an

  14. Combinatorial regulation of tissue specification by GATA and FOG factors

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    Chlon, Timothy M.; Crispino, John D.

    2012-01-01

    The development of complex organisms requires the formation of diverse cell types from common stem and progenitor cells. GATA family transcriptional regulators and their dedicated co-factors, termed Friend of GATA (FOG) proteins, control cell fate and differentiation in multiple tissue types from Drosophila to man. FOGs can both facilitate and antagonize GATA factor transcriptional regulation depending on the factor, cell, and even the specific gene target. In this review, we highlight recent studies that have elucidated mechanisms by which FOGs regulate GATA factor function and discuss how these factors use these diverse modes of gene regulation to control cell lineage specification throughout metazoans. PMID:23048181

  15. 77 FR 189 - Federal Acquisition Regulation; Brand-Name Specifications

    Science.gov (United States)

    2012-01-03

    ... 2006-0020, Sequence 26] RIN 9000-AK55 Federal Acquisition Regulation; Brand-Name Specifications... Management and Budget memoranda on brand-name specifications. DATES: Effective Date: February 2, 2012. FOR... brand- name specifications. Eight respondents submitted 32 comments in response to the interim rule. The...

  16. Active training and driving-specific feedback improve older drivers' visual search prior to lane changes

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    Lavallière Martin

    2012-03-01

    Full Text Available Abstract Background Driving retraining classes may offer an opportunity to attenuate some effects of aging that may alter driving skills. Unfortunately, there is evidence that classroom programs (driving refresher courses do not improve the driving performance of older drivers. The aim of the current study was to evaluate if simulator training sessions with video-based feedback can modify visual search behaviors of older drivers while changing lanes in urban driving. Methods In order to evaluate the effectiveness of the video-based feedback training, 10 older drivers who received a driving refresher course and feedback about their driving performance were tested with an on-road standardized evaluation before and after participating to a simulator training program (Feedback group. Their results were compared to a Control group (12 older drivers who received the same refresher course and in-simulator active practice as the Feedback group without receiving driving-specific feedback. Results After attending the training program, the Control group showed no increase in the frequency of the visual inspection of three regions of interests (rear view and left side mirrors, and blind spot. In contrast, for the Feedback group, combining active training and driving-specific feedbacks increased the frequency of blind spot inspection by 100% (32.3 to 64.9% of verification before changing lanes. Conclusions These results suggest that simulator training combined with driving-specific feedbacks helped older drivers to improve their visual inspection strategies, and that in-simulator training transferred positively to on-road driving. In order to be effective, it is claimed that driving programs should include active practice sessions with driving-specific feedbacks. Simulators offer a unique environment for developing such programs adapted to older drivers' needs.

  17. Active training and driving-specific feedback improve older drivers' visual search prior to lane changes.

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    Lavallière, Martin; Simoneau, Martin; Tremblay, Mathieu; Laurendeau, Denis; Teasdale, Normand

    2012-03-02

    Driving retraining classes may offer an opportunity to attenuate some effects of aging that may alter driving skills. Unfortunately, there is evidence that classroom programs (driving refresher courses) do not improve the driving performance of older drivers. The aim of the current study was to evaluate if simulator training sessions with video-based feedback can modify visual search behaviors of older drivers while changing lanes in urban driving. In order to evaluate the effectiveness of the video-based feedback training, 10 older drivers who received a driving refresher course and feedback about their driving performance were tested with an on-road standardized evaluation before and after participating to a simulator training program (Feedback group). Their results were compared to a Control group (12 older drivers) who received the same refresher course and in-simulator active practice as the Feedback group without receiving driving-specific feedback. After attending the training program, the Control group showed no increase in the frequency of the visual inspection of three regions of interests (rear view and left side mirrors, and blind spot). In contrast, for the Feedback group, combining active training and driving-specific feedbacks increased the frequency of blind spot inspection by 100% (32.3 to 64.9% of verification before changing lanes). These results suggest that simulator training combined with driving-specific feedbacks helped older drivers to improve their visual inspection strategies, and that in-simulator training transferred positively to on-road driving. In order to be effective, it is claimed that driving programs should include active practice sessions with driving-specific feedbacks. Simulators offer a unique environment for developing such programs adapted to older drivers' needs.

  18. An episodic specificity induction enhances means-end problem solving in young and older adults.

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    Madore, Kevin P; Schacter, Daniel L

    2014-12-01

    Episodic memory plays an important role not only in remembering past experiences, but also in constructing simulations of future experiences and solving means-end social problems. We recently found that an episodic specificity induction-brief training in recollecting details of past experiences-enhances performance of young and older adults on memory and imagination tasks. Here we tested the hypothesis that this specificity induction would also positively impact a means-end problem-solving task on which age-related changes have been linked to impaired episodic memory. Young and older adults received the specificity induction or a control induction before completing a means-end problem-solving task, as well as memory and imagination tasks. Consistent with previous findings, older adults provided fewer relevant steps on problem solving than did young adults, and their responses also contained fewer internal (i.e., episodic) details across the 3 tasks. There was no difference in the number of other (e.g., irrelevant) steps on problem solving or external (i.e., semantic) details generated on the 3 tasks as a function of age. Critically, the specificity induction increased the number of relevant steps and internal details (but not other steps or external details) that both young and older adults generated in problem solving compared with the control induction, as well as the number of internal details (but not external details) generated for memory and imagination. Our findings support the idea that episodic retrieval processes are involved in means-end problem solving, extend the range of tasks on which a specificity induction targets these processes, and show that the problem-solving performance of older adults can benefit from a specificity induction as much as that of young adults. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  19. Effects of Task Instruction on Autobiographical Memory Specificity in Young and Older Adults

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    Ford, Jaclyn Hennessey; Rubin, David C.; Giovanello, Kelly S.

    2013-01-01

    Older adults tend to retrieve autobiographical information that is overly general (i.e. not restricted to a single event, termed the overgenerality effect) relative to young adults’ specific memories. A vast majority of studies that have reported overgenerality effects explicitly instruct participants to retrieve specific memories, thereby requiring participants to maintain task goals, inhibit inappropriate responses, and control their memory search. Since these processes are impaired in healthy aging, it is important to determine whether such task instructions influence the magnitude of the overgenerality effect in older adults. In the current study, participants retrieved autobiographical memories during presentation of musical clips. Task instructions were manipulated to separate age-related differences in the specificity of underlying memory representations from age-related differences in following task instructions. Whereas young adults modulated memory specificity based on task demands, older adults did not. These findings suggest that reported rates of overgenerality in older adults’ memories may include age-related differences in memory representation, as well as differences in task compliance. Such findings provide a better understanding of the underlying cognitive mechanisms involved in age-related changes in autobiographical memory and may also be valuable for future research examining effects of overgeneral memory on general well-being. PMID:23915176

  20. Effects of task instruction on autobiographical memory specificity in young and older adults.

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    Ford, Jaclyn Hennessey; Rubin, David C; Giovanello, Kelly S

    2014-01-01

    Older adults tend to retrieve autobiographical information that is overly general (i.e., not restricted to a single event, termed the overgenerality effect) relative to young adults' specific memories. A vast majority of studies that have reported overgenerality effects explicitly instruct participants to retrieve specific memories, thereby requiring participants to maintain task goals, inhibit inappropriate responses, and control their memory search. Since these processes are impaired in healthy ageing, it is important to determine whether such task instructions influence the magnitude of the overgenerality effect in older adults. In the current study participants retrieved autobiographical memories during presentation of musical clips. Task instructions were manipulated to separate age-related differences in the specificity of underlying memory representations from age-related differences in following task instructions. Whereas young adults modulated memory specificity based on task demands, older adults did not. These findings suggest that reported rates of overgenerality in older adults' memories might include age-related differences in memory representation, as well as differences in task compliance. Such findings provide a better understanding of the underlying cognitive mechanisms involved in age-related changes in autobiographical memory and may also be valuable for future research examining effects of overgeneral memory on general well-being.

  1. Self-Regulation, Self-Efficacy and Health Behavior Change in Older Adults.

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    Purdie, Nola; McCrindle, Andrea

    2002-01-01

    Presents an overview of self-regulation models: theory of planned behavior, protection motivation theory, health belief model, action control theory, transtheoretical model of behavior change, health action process, and precaution adoption process. Applies models to health behavior change in older adults with cardiovascular disease or diabetes.…

  2. Memory for general and specific value information in younger and older adults: measuring the limits of strategic control.

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    Castel, Alan D; Farb, Norman A S; Craik, Fergus I M

    2007-06-01

    The ability to selectively remember important information is a critical function of memory. Although previous research has suggested that older adults are impaired in a variety of episodic memory tasks, recent work has demonstrated that older adults can selectively remember high-value information. In the present research, we examined how younger and older adults selectively remembered words with various assigned numeric point values, to see whether younger adults could remember more specific value information than could older adults. Both groups were equally good at recalling point values when recalling the range of high-value words, but younger adults outperformed older adults when recalling specific values. Although older adults were more likely to recognize negative value words, both groups exhibited control by not recalling negative value information. The findings suggest that although both groups retain high-value information, older adults rely more on gist-based encoding and retrieval operations, whereas younger adults are able to remember specific numeric value information.

  3. Effects of muscle composition and architecture on specific strength in obese older women.

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    Rastelli, F; Capodaglio, P; Orgiu, S; Santovito, C; Caramenti, M; Cadioli, M; Falini, A; Rizzo, G; Lafortuna, C L

    2015-10-01

    What is the central question of this study? Do obesity-specific factors affect skeletal muscle performance in older individuals? What is the main finding and its importance? Older obese women have a larger quadriceps femoris size but develop lower tension per unit of skeletal muscle than their normal-weight counterparts. Muscle impairment and excess body mass are very common among older people. Given that the effect of obesity on strength production has scarcely been studied in older individuals, we analysed functional and structural characteristics of quadriceps femoris (QF) in obese (OB) and normal-weight (NW) older women with comparable habitual physical activity. In five OB (body mass index 36.8 ± 1.9 kg m(-2), age 72.4 ± 2.3 years) and six NW well-functioning older women (body mass index 24.3 ± 1.8 kg m(-2), age 72.7 ± 1.9 years), peak knee-extension torque (KET) was measured in isometric (90 deg knee flexion) and isokinetic conditions (240, 180, 120 and 60 deg s(-1)). Mid-thigh QF cross-sectional area (CSA) and muscle tissue fat content (MF%) were determined with magnetic resonance imaging (Dixon sequence). Muscle fascicle length and pennation angle (PA) were assessed with ultrasonography for each muscle belly of the QF (vastus lateralis, vastus intermedius, rectus femoris and vastus intermedius). Despite similar values of KET, CSA was 17.0% larger in OB than in NW women (P Muscle composition and architecture seem to be important determinants of KET/CSA in elderly women. In fact, owing to the effect of obesity overload, OB women have a larger QF size than NW women, but unfavourable muscle composition and architecture. The higher MF% and steeper PA observed in OB women are associated with reduced levels of muscle specific strength. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

  4. Gender-Specific Differences in the Relationship between Autobiographical Memory and Intertemporal Choice in Older Adults.

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    Maayke Seinstra

    Full Text Available As the population of older adults grows, their economic choices will have increasing impact on society. Research on the effects of aging on intertemporal decisions shows inconsistent, often opposing results, indicating that yet unexplored factors might play an essential role in guiding one's choices. Recent studies suggest that episodic future thinking, which is based on the same neural network involved in episodic memory functions, leads to reductions in discounting of future rewards. As episodic memory functioning declines with normal aging, but to greatly variable degrees, individual differences in delay discounting might be due to individual differences in the vitality of this memory system in older adults. We investigated this hypothesis, using a sample of healthy older adults who completed an intertemporal choice task as well as two episodic memory tasks. We found no clear evidence for a relationship between episodic memory performance and delay discounting in older adults. However, when additionally considering gender differences, we found an interaction effect of gender and autobiographical memory on delay discounting: while men with higher memory scores showed less delay discounting, women with higher memory scores tended to discount the future more. We speculate that this gender effect might stem from the gender-specific use of different modal representation formats (i.e. temporal or visual during assessment of intertemporal choice options.

  5. Albumin levels and cause-specific mortality in community-dwelling older adults.

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    Wu, Chen-Yi; Hu, Hsiao-Yun; Huang, Nicole; Chou, Yi-Chang; Li, Chung-Pin; Chou, Yiing-Jenq

    2018-04-09

    To investigate the association between serum albumin levels and cause-specific mortality among community-dwelling older adults. This cohort study was based on data obtained from the government-sponsored Annual Geriatric Health Examination Program for the older adults in Taipei City between 2006 and 2010. The study sample consisted of 77,531 community-dwelling Taipei citizens (≥65 years old). Mortality was determined by matching the participants' medical records with national death files. Serum albumin levels were categorized into dwelling older adults had a mean albumin level of 4.3 g/dL, which significantly reduced by age. Compared to albumin levels ≥4.4 g/dL, mildly low albumin levels (4.2-4.3 g/dL) were associated with an increased mortality risk (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.05-1.28 for all-cause mortality), and albumin levels dwelling older adults, and mortality risk increased as the albumin level decreased. Copyright © 2017. Published by Elsevier Inc.

  6. TTP specifically regulates the internalization of the transferrin receptor

    DEFF Research Database (Denmark)

    Tosoni, Daniela; Puri, Claudia; Confalonieri, Stefano

    2005-01-01

    Different plasma membrane receptors are internalized through saturable/noncompetitive pathways, suggesting cargo-specific regulation. Here, we report that TTP (SH3BP4), a SH3-containing protein, specifically regulates the internalization of the transferrin receptor (TfR). TTP interacts...... with endocytic proteins, including clathrin, dynamin, and the TfR, and localizes selectively to TfR-containing coated-pits (CCP) and -vesicles (CCV). Overexpression of TTP specifically inhibits TfR internalization, and causes the formation of morphologically aberrant CCP, which are probably fission impaired....... This effect is mediated by the SH3 of TTP, which can bind to dynamin, and it is rescued by overexpression of dynamin. Functional ablation of TTP causes a reduction in TfR internalization, and reduced cargo loading and size of TfR-CCV. Tyrosine phosphorylation of either TTP or dynamin prevents...

  7. Is the Veterans Specific Activity Questionnaire Valid to Assess Older Adults Aerobic Fitness?

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    de Carvalho Bastone, Alessandra; de Souza Moreira, Bruno; Teixeira, Claudine Patrícia; Dias, João Marcos Domingues; Dias, Rosângela Corrêa

    2016-01-01

    Aerobic fitness in older adults is related to health status, incident disability, nursing home admission, and all-cause mortality. The most accurate quantification of aerobic fitness, expressed as peak oxygen consumption in mL·kg·min, is the cardiorespiratory exercise test; however, it is not feasible in all settings and might offer risk to patients. The Veterans Specific Activity Questionnaire (VSAQ) is a 13-item self-administered symptom questionnaire that estimates aerobic fitness expressed in metabolic equivalents (METs) and has been validated to cardiovascular patients. The purpose of this study was to assess the validity and reliability of the VSAQ in older adults without specific health conditions. A methodological study with a cross-sectional design was conducted with 28 older adults (66-86 years). The VSAQ was administered on 3 occasions by 2 evaluators. Aerobic capacity in METs as measured by the VSAQ was compared with the METs found in an incremental shuttle walk test (ISWT) performed with a portable metabolic measurement system and with accelerometer data. The validity of the VSAQ was found to be moderate-to-good when compared with the METs and distance measured by the ISWT and with the moderate activity per day and steps per day obtained by accelerometry. The Bland-Altman graph analysis showed no values outside the limits of agreement, suggesting good precision between the METs estimated by questionnaire and the METs measured by the ISWT. Also, the intrarater and interrater reliabilities of the instrument were good. The results showed that the VSAQ is a valuable tool to assess the aerobic fitness of older adults.

  8. Establishing a culturally specific nursing home for Finnish-speaking older persons in Sweden: A case study.

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    Hadziabdic, Emina; Hjelm, Katarina

    2018-04-01

    The study aims to describe the establishment of a culturally specific nursing home for Finnish-speaking older persons in Sweden. A descriptive qualitative study. A descriptive case study based on a review of 14 public documents and individual interviews with two experts in the area, analysed with qualitative content analysis. This study found that shared language, preservation of customs and habits and collaboration between the representatives of the municipality, Finnish-speaking migrant associations and staff at the nursing home influenced the development of the culturally specific nursing home for older Finnish-speaking people intended to avoid loneliness, isolation and misunderstandings among older Finnish-speaking. Collaboration between healthcare service for older persons and minority people resulted in an optimal culturally specific nursing home, simultaneously encountering the majority culture. Nursing and healthcare services need to be aware of positive effects of collaboration with stakeholders to achieve optimal culturally specific nursing homes.

  9. Do People With Psychosis Have Specific Difficulties Regulating Emotions?

    Science.gov (United States)

    Lincoln, Tania M; Hartmann, Maike; Köther, Ulf; Moritz, Steffen

    2015-01-01

    Difficulties in emotion regulation (ER) are present in psychotic disorders, but their precise nature is not yet fully understood and it is unclear which difficulties are unique to psychosis compared with other disorders. This study investigated whether ER difficulties in psychosis are more prominent for the ability to modify emotions or for the ability to tolerate and accept them. Furthermore, it investigated whether ER difficulties occur for sadness, anxiety, anger and shame likewise. ER skills were assessed in participants with psychotic disorders (n = 37), participants with depression (n = 30) and healthy controls (n = 28) using the Emotion Regulation Skill Questionnaire that asks participants to rate the intensity of different emotions over the past week and the skills employed to handle each of them. Compared with healthy controls, participants with psychosis showed reduced skills related to awareness, understanding and acceptance of potentially distressing emotions, but not in the ability to modify them. These differences remained significant after controlling for depression. Participants with psychosis showed reduced ER skills in regard to all of the assessed emotions compared with the healthy controls, despite the fact that they only reported sadness as being significantly more intense. The participants with depression showed a similar pattern of ER skills to the psychosis sample, although with a tendency towards even more pronounced difficulties. It is concluded that psychosis is characterized by difficulties in using specific ER skills related to awareness, understanding and acceptance to regulate anger, shame, anxiety and sadness. These difficulties are not unique to psychosis but nevertheless present a promising treatment target. The participants with psychosis found it more difficult to be aware of their emotions, to understand them and to accept them than the healthy control group. However, they reported equal skills when it came to

  10. The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

    Directory of Open Access Journals (Sweden)

    Justin W Walley

    2008-12-01

    Full Text Available Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD is required for the expression of selected genes downstream of the jasmonate (JA and ethylene (ET signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

  11. Specific transfer effects following variable priority dual-task training in older adults.

    Science.gov (United States)

    Lussier, Maxime; Bugaiska, Aurélia; Bherer, Louis

    2017-01-01

    Past divided attention training studies in older adults have suggested that variable priority training (VPT) tends to show larger improvement than fixed priority training (FPT). However, it remains unclear whether VPT leads to larger transfer effects. In this study, eighty-three older adults aged between 55 and 65 received five 1-hour sessions of VPT, FPT or of an active placebo. VPT and FPT subjects trained on a complex dual-task condition with variable stimulus timings in order to promote more flexible and self-guided strategies with regard to attentional priority devoted to the concurrent tasks. Real-time individualized feedback was provided to encourage improvement. The active placebo group attended computer classes. Near and far modality transfer tasks were used to assess the generalization of transfer effects. Results showed that VPT induced significantly larger transfer effects than FPT on a near modality transfer task. Evidence for larger transfer effects in VPT than FPT on a far modality transfer task was also observed. Furthermore, the superiority of VPT on FPT in transfer effects was specific to the ability to coordinate two concurrent tasks. Results of this study help better understand the benefits of VPT attentional training on transfer effects, which is an essential outcome for cognitive training effectiveness and relevancy.

  12. Do current national and international guidelines have specific recommendations for older adults with bipolar disorder?

    DEFF Research Database (Denmark)

    Dols, Annemiek; Kessing, Lars Vedel; Strejilevich, Sergio A

    2016-01-01

    a variety of sources have become available in recent years. It is expected that at least some of this emerging information on OABD would be incorporated into treatment guidelines available to clinicians around the world. METHODS: The International Society of Bipolar Disorders OABD task force compiled...... and compared recommendations from current national and international guidelines that specifically address geriatric or older individuals with BD (from year 2005 onwards). RESULTS: There were 34 guidelines, representing six continents and 19 countries. The majority of guidelines had no separate section on OABD....... General principles for treating OABD with medication are recommended to be similar to those for younger adults, with special caution for side effects due to somatic comorbidity and concomitant medications. Therapeutic lithium serum levels are suggested to be lower but recommendations are very general...

  13. Fat-specific protein 27 regulates storage of triacylglycerol

    DEFF Research Database (Denmark)

    Keller, P.; Petrie, J.T.; Rose, P. De

    2008-01-01

    FSP27 (fat-specific protein 27) is a member of the cell death-inducing DNA fragmentation factor-alpha-like effector (CIDE) family. Although Cidea and Cideb were initially characterized as activators of apoptosis, recent studies have demonstrated important metabolic roles for these proteins...... in several cell types without induction of adipocyte genes. Increased triacylglycerol is likely due to decreased beta-oxidation of nonesterified fatty acids. Altered flux of fatty acids into triacylglycerol may be a direct effect of FSP27 function, which is localized to lipid droplets in 293T cells and 3T3-L...... decreases with total fat mass but is not associated with measures of insulin resistance (e.g. homeostasis model assessment). Together, these data indicate that FSP27 binds to lipid droplets and regulates their enlargement Udgivelsesdato: 2008/5/23...

  14. Older drivers' self-assessed driving skills, driving-related stress and self-regulation in traffic

    DEFF Research Database (Denmark)

    Siren, Anu Kristiina; Meng, Annette

    2013-01-01

    Previous research on older drivers has indicated connections between self-rated driving ability, confidence in their own driving, driving-related stress, and self-regulatory behaviour. However, more systematic associations between older drivers' perceptions on their own driving and self......-regulation or driver stress and self-regulation behaviour, and possible gender differences in these, have not been obtained in previous studies. The aim of the present study was to gain a better understanding of older drivers' self-regulatory driving and the motivators behind this behaviour, by placing this behaviour...... and avoidance than situations related to infrastructure, and women were more likely to report discomfort and avoidance of driving situations. The results suggest that older drivers generally show good self-judgement of changes in their driving skills and acknowledge the different types of skills comprised...

  15. Age differences among older adults in the use of emotion regulation strategies. What happens among over 85s and centenarians?

    Science.gov (United States)

    Etxeberria, Igone; Etxebarria, Itziar; Urdaneta, Elena; Yanguas, Jose Javier

    2016-09-01

    Past research on emotion regulation strategies has concluded that older adults use more passive strategies than young adults. However, we found scarce research in this field focusing on the oldest old (i.e. those aged 85 and over). The aim of this study was to analyze whether or not differences exist in the way older adults aged 85 and over (centenarians included) use emotion regulation strategies, in comparison with younger age groups (65-74 and 75-84 years old). Participants were 257 older adults from Spain, all aged between 65 and 104. The sample was divided into four age groups: 65-74; 75-84; 85-94; and 95-104 years old. Participants completed the Strategy Questionnaire after reading each of the vignettes designed to elicit feelings of either sadness or anger. The questionnaire measures four types of regulation strategies: Passive, Express, Solve and Seek. The 85-94 age group and centenarians were found to use proactive (Express, Seek) and Solve strategies less in comparison with younger age groups when regulating sadness and anger. In contrast, an increased use of Passive strategies was observed in the regulation of both emotions in the 85-94 age group. Significant differences were also found between centenarians and younger age groups in the use of Passive strategies for sadness, although not for anger. Age differences were observed in the use of emotion regulation strategies, with older age groups using proactive strategies less and passive strategies more.

  16. Driving self-regulation and ride service utilization in a multicommunity, multistate sample of U.S. older adults.

    Science.gov (United States)

    Bird, Donna C; Freund, Katherine; Fortinsky, Richard H; Staplin, Loren; West, Bethany A; Bergen, Gwen; Downs, Jonathan

    2017-04-03

    This study examined a multicommunity alternative transportation program available 24 hours a day, 7 days a week, for any purpose, offering door-through-door service in private automobiles to members who either do not drive or are transitioning away from driving. Specific aims were to describe the characteristics of members by driving status and ride service usage of these members. Data came from administrative records maintained by a nonprofit ride service program and include 2,661 individuals aged 65+ residing in 14 states who joined the program between April 1, 2010, and November 8, 2013. Latent class analysis was used to group current drivers into 3 classes of driving status of low, medium, and high self-regulation, based on their self-reported avoidance of certain driving situations and weekly driving frequency. Demographics and ride service use rate for rides taken through March 31, 2014, by type of ride (e.g., medical, social, etc.) were calculated for nondrivers and drivers in each driving status class. The majority of ride service users were female (77%) and aged 65-74 years (82%). The primary method of getting around when enrolling for the transportation service was by riding with a friend or family member (60%). Among the 67,883 rides given, nondrivers took the majority (69%) of rides. Medical rides were the most common, accounting for 40% of all rides. Reported ride usage suggests that older adults are willing to use such ride services for a variety of trips when these services are not limited to specific types (e.g., medical). Further research can help tailor strategies to encourage both nondrivers and drivers to make better use of alternative transportation that meets the special needs of older people.

  17. Tissue specific regulation of lipogenesis by thyroid hormone

    Energy Technology Data Exchange (ETDEWEB)

    Blennemann, B.; Freake, H. (Univ. of Connecticut, Storrs (United States))

    1990-02-26

    Thyroid hormone stimulates long chain fatty acid synthesis in rat liver by increasing the amounts of key lipogenic enzymes. Sparse and conflicting data exist concerning its action on this pathway in other tissues. The authors recently showed that, in contrast to liver, hypothyroidism stimulates lipogenesis in brown adipose tissue and have now systematically examined the effects of thyroid state on fatty acid synthesis in other rat tissues. Lipogenesis was assessed by tritiated water incorporation. Euthyroid hepatic fatty acid synthesis (16.6um H/g/h) was reduced to 30% in hypothyroid rats and increased 3 fold in hyperthyroidism. Lipogenesis was detected in euthyroid kidney and heart and these levels were also stimulated by thyroid hormone treatment. Brown adipose tissue was unique in showing increased lipogenesis in the hypothyroid state. Hyperthyroid levels were not different from euthyroid. Effects in white adipose tissue were small and inconsistent. Brain, skin and lung were all lipogenically active, but did not respond to changes in thyroid state. Low but detectable levels of fatty acid synthesis were measured in muscle, which also were non-responsive. A wide spectrum of responses to thyroid hormone are seen in different rat tissues and thus the pathway of long chain fatty acid synthesis would appear to be an excellent model for examining the tissue specific regulation of gene expression by thyroid hormone.

  18. Tissue specific regulation of lipogenesis by thyroid hormone

    International Nuclear Information System (INIS)

    Blennemann, B.; Freake, H.

    1990-01-01

    Thyroid hormone stimulates long chain fatty acid synthesis in rat liver by increasing the amounts of key lipogenic enzymes. Sparse and conflicting data exist concerning its action on this pathway in other tissues. The authors recently showed that, in contrast to liver, hypothyroidism stimulates lipogenesis in brown adipose tissue and have now systematically examined the effects of thyroid state on fatty acid synthesis in other rat tissues. Lipogenesis was assessed by tritiated water incorporation. Euthyroid hepatic fatty acid synthesis (16.6um H/g/h) was reduced to 30% in hypothyroid rats and increased 3 fold in hyperthyroidism. Lipogenesis was detected in euthyroid kidney and heart and these levels were also stimulated by thyroid hormone treatment. Brown adipose tissue was unique in showing increased lipogenesis in the hypothyroid state. Hyperthyroid levels were not different from euthyroid. Effects in white adipose tissue were small and inconsistent. Brain, skin and lung were all lipogenically active, but did not respond to changes in thyroid state. Low but detectable levels of fatty acid synthesis were measured in muscle, which also were non-responsive. A wide spectrum of responses to thyroid hormone are seen in different rat tissues and thus the pathway of long chain fatty acid synthesis would appear to be an excellent model for examining the tissue specific regulation of gene expression by thyroid hormone

  19. Varicella-Zoster Virus-Specific Cellular Immune Responses to the Live Attenuated Zoster Vaccine in Young and Older Adults.

    Science.gov (United States)

    Weinberg, Adriana; Canniff, Jennifer; Rouphael, Nadine; Mehta, Aneesh; Mulligan, Mark; Whitaker, Jennifer A; Levin, Myron J

    2017-07-15

    The incidence and severity of herpes zoster (HZ) increases with age. The live attenuated zoster vaccine generates immune responses similar to HZ. We compared the immune responses to zoster vaccine in young and older to adults to increase our understanding of the immune characteristics that may contribute to the increased susceptibility to HZ in older adults. Young (25-40 y; n = 25) and older (60-80 y; n = 33) adults had similar magnitude memory responses to varicella-zoster virus (VZV) ex vivo restimulation measured by responder cell-frequency and flow cytometry, but the responses were delayed in older compared with young adults. Only young adults had an increase in dual-function VZV-specific CD4 + and CD8 + T cell effectors defined by coexpression of IFN-γ, IL-2, and CD107a after vaccination. In contrast, older adults showed marginal increases in VZV-specific CD8 + CD57 + senescent T cells after vaccination, which were already higher than those of young adults before vaccination. An increase in VZV-stimulated CD4 + CD69 + CD57 + PD1 + and CD8 + CD69 + CD57 + PD1 + T cells from baseline to postvaccination was associated with concurrent decreased VZV-memory and CD8 + effector responses, respectively, in older adults. Blocking the PD1 pathway during ex vivo VZV restimulation increased the CD4 + and CD8 + proliferation, but not the effector cytokine production, which modestly increased with TIM-3 blockade. We conclude that high proportions of senescent and exhausted VZV-specific T cells in the older adults contribute to their poor effector responses to a VZV challenge. This may underlie their inability to contain VZV reactivation and prevent the development of HZ. Copyright © 2017 by The American Association of Immunologists, Inc.

  20. Sensory-specific balance training in older adults: effect on proprioceptive reintegration and cognitive demands.

    Science.gov (United States)

    Westlake, Kelly P; Culham, Elsie G

    2007-10-01

    Age-related changes in the ability to adjust to alterations in sensory information contribute to impaired postural stability. The purpose of this randomized controlled trial was to investigate the effect of sensory-specific balance training on proprioceptive reintegration. The subjects of this study were 36 older participants who were healthy. Participants were randomly assigned to a balance exercise group (n=17) or a falls prevention education group (n=19). The primary outcome measure was the center-of-pressure (COP) velocity change score. This score represented the difference between COP velocity over 45 seconds of quiet standing and each of six 5-second intervals following proprioceptive perturbation through vibration with or without a secondary cognitive task. Clinical outcome measures included the Fullerton Advanced Balance (FAB) Scale and the Activities-specific Balance Confidence (ABC) Scale. Assessments were conducted at baseline, postintervention, and at an 8-week follow-up. Following the exercise intervention, there was less destabilization within the first 5 seconds following vibration with or without a secondary task than there was at baseline or in the falls prevention education group. These training effects were not maintained at the 8-week follow-up. Postintervention improvements also were seen on the FAB Scale and were maintained at follow-up. No changes in ABC Scale scores were identified in the balance exercise group, but ABC Scale scores indicated reduced balance confidence in the falls prevention education group postintervention. The results of this study support short-term enhanced postural responses to proprioceptive reintegration following a sensory-specific balance exercise program.

  1. Sex-specific effects of social networks on the prevalence, awareness, and control of hypertension among older Korean adults.

    Science.gov (United States)

    Baek, Jiwon; Hur, Nam Wook; Kim, Hyeon Chang; Youm, Yoosik

    2016-07-01

    Hypertension is a common chronic disease among older adults, and is associated with medical complications and mortality. This study aimed to examine the effects of social network characteristics on the prevalence, awareness, and control of hypertension among older adults. The Korean Social Life, Health, and Aging Project (KSHAP) interviewed 814 ≥ 60-year-old residents and their spouses from a rural township between December 2011 and March 2012 (response rate: 95%). We evaluated the data from 595 participants. Multivariate logistic regression models were used to assess the effects of network characteristics on hypertension. We observed strong sex-specific network effects on the prevalence, awareness, and control of hypertension. Among older women, network density was associated with hypertension awareness [odds ratio (OR): 2.63, 95% confidence interval (CI): 1.03-5.37] and control (OR: 1.72; 95% CI: 0.94-3.13). Among older men, large networks were associated with a lower prevalence of hypertension (OR: 0.75; 95% CI: 0.58-0.96). Compared to older women, older men with coarse networks exhibited better hypertension awareness (OR: 0.37; 95% CI: 0.14-0.95) and control (OR: 0.42; 95% CI: 0.19-0.91). Network size interacted with density for hypertension control (P = 0.051), with controlled hypertension being associated with large and course networks. A large network was associated with a lower risk for hypertension, and a coarse network was associated with hypertension awareness and control among older men. Older women with dense networks were most likely to exhibit hypertension awareness and control.

  2. Narrative Review of Dance-based Exercise and Its Specific Impact on Depressive Symptoms in Older Adults

    Directory of Open Access Journals (Sweden)

    Ray Marks

    2016-01-01

    Full Text Available Background: Depression is a chronic condition that results in considerable disability, and particularly in later life, severely impacts the life quality of the individual with this condition. The first aim of this review article was to summarize, synthesize, and evaluate the research base concerning the use of dance-based exercises on health status, in general, and secondly, specifically for reducing depressive symptoms, in older adults. A third was to provide directives for professionals who work or are likely to work with this population in the future. Methods: All English language peer reviewed publications detailing the efficacy of dance therapy as an intervention strategy for older people in general, and specifically for minimizing depression and dependence among the elderly were analyzed. Key words: dance therapy and depression were included. Databases used were Academic Search Complete, Cinahl, PubMed, Scopus, PsycINFO, and Web of Science. Results: Collectively, this data reveal dance therapy may be useful as a rehabilitation strategy for older adults, in general, as well as for elders with varying degrees of depression, regardless of strategy employed. Conclusions: Although more research is needed, older individuals with or without chronic depression or depressive symptoms can benefit emotionally from dance based exercise participation. Geriatric clinicians can expect this form of exercise will also heighten the life quality of the older individual with depression or subclinical depression.

  3. Activities-specific balance confidence scale for predicting future falls in Indian older adults

    Directory of Open Access Journals (Sweden)

    Moiz JA

    2017-04-01

    Full Text Available Jamal Ali Moiz,1 Vishal Bansal,2 Majumi M Noohu,1 Shailendra Nath Gaur,3 Mohammad Ejaz Hussain,1 Shahnawaz Anwer,4,5 Ahmad Alghadir4 1Centre for Physiotherapy and Rehabilitation Sciences, Jamia Millia Islamia, New Delhi, India; 2Department of Physiology, 3Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India; 4Rehabilitation Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia; 5Department of Musculoskeletal Science, Dr D.Y. Patil College of Physiotherapy, Dr D.Y. Patil Vidyapeeth, Pune, India Background: Activities-specific balance confidence (ABC scale is a subjective measure of confidence in performing various ambulatory activities without falling or experiencing a sense of unsteadiness. Objective: This study aimed to examine the ability of the Hindi version of the ABC scale (ABC-H scale to discriminate between fallers and non-fallers and to examine its predictive validity for prospective falls. Design: This was a prospective cohort study. Materials and methods: A total of 125 community-dwelling older adults (88 were men completed the ABC-H scale. The occurrence of falls over the follow-up period of 12 months was recorded. Discriminative validity was analyzed by comparing the total ABC-H scale scores between the faller and non-faller groups. A receiver operating characteristic curve analysis and a logistic regression analysis were used to examine the predictive accuracy of the ABC-H scale. Results: The mean ABC-H scale score of the faller group was significantly lower than that of the non-faller group (52.6±8.1 vs 73.1±12.2; P<0.001. The optimal cutoff value for distinguishing faller and non-faller adults was ≤58.13. The sensitivity, specificity, area under the curve, and positive and negative likelihood ratios of the cutoff score were 86.3%, 87.3%, 0.91 (P<0.001, 6.84, and 0.16, respectively. The percentage test accuracy and false-positive and

  4. Safety-specific benefit of the probabilistic evaluation of older nuclear power plants

    International Nuclear Information System (INIS)

    Hoertner, H.; Koeberlein, K.

    1991-01-01

    The report summarizes the experience of the GRS obtained within the framework of a probabilistic evaluation of older nuclear power plants and the German risk study. The applied methodology and the problems involved are explained first. After a brief summary of probabilistic analyses carried out for German nuclear power plants, reliability analyses for older systems are discussed in detail. The findings from the probabilistic safety analyses and the conclusions drawn are presented. (orig.) [de

  5. Impact of visual impairment on vision-specific quality of life among older adults living in nursing home.

    Science.gov (United States)

    Dev, Mahesh Kumar; Paudel, Nabin; Joshi, Niraj Dev; Shah, Dev Narayan; Subba, Shishir

    2014-03-01

    Visual impairment (VI) has a significant negative impact on quality of life (QoL) amongst older people living in nursing homes. The purpose of this study was to determine the prevalence of VI and blindness and to explore the association between severity of VI and vision-specific QoL among older people living in nursing homes of Kathmandu, Nepal. This cross-sectional study involved 158 residents aged 60 years or older residing in seven nursing homes of Kathmandu Valley, Nepal. Near acuity, presenting and the best corrected distance visual acuity (VA) were assessed in each eye and considered in the better eye after adequate refraction. A complete anterior and posterior segment examination was carried out. Face-to-face interviews were conducted using a 57-item Nursing Home Vision-Targeted Health-Related Quality of Life (NHVQoL) questionnaire. The mean age of residents was 75.60 ± 7.12 years and the majority were female (66.46%). The prevalence of VI and blindness was 45.57% and its leading cause was cataract, which was followed by age-related macular degeneration, corneal opacity, glaucoma and macular scar. The mean composite score of NHVQoL questionnaire was 52.22 ± 12.49. There was a consistent overall deterioration in the mean composite score as well as each subscale score of NHVQoL questionnaire with a worsening of VA. VI and blindness are highly prevalent among older people living in nursing homes. VI has a significant negative impact on vision-specific QoL. Vision-specific QoL is reduced, and the reduction in the QoL bears a positive association with severity of VI among older people living in nursing homes.

  6. Frailty Index Developed From a Cancer-Specific Geriatric Assessment and the Association With Mortality Among Older Adults With Cancer.

    Science.gov (United States)

    Guerard, Emily J; Deal, Allison M; Chang, YunKyung; Williams, Grant R; Nyrop, Kirsten A; Pergolotti, Mackenzi; Muss, Hyman B; Sanoff, Hanna K; Lund, Jennifer L

    2017-07-01

    Background: An objective measure is needed to identify frail older adults with cancer who are at increased risk for poor health outcomes. The primary objective of this study was to develop a frailty index from a cancer-specific geriatric assessment (GA) and evaluate its ability to predict all-cause mortality among older adults with cancer. Patients and Methods: Using a unique and novel data set that brings together GA data with cancer-specific and long-term mortality data, we developed the Carolina Frailty Index (CFI) from a cancer-specific GA based on the principles of deficit accumulation. CFI scores (range, 0-1) were categorized as robust (0-0.2), pre-frail (0.2-0.35), and frail (>0.35). The primary outcome for evaluating predictive validity was all-cause mortality. The Kaplan-Meier method and log-rank tests were used to compare survival between frailty groups, and Cox proportional hazards regression models were used to evaluate associations. Results: In our sample of 546 older adults with cancer, the median age was 72 years, 72% were women, 85% were white, and 47% had a breast cancer diagnosis. Overall, 58% of patients were robust, 24% were pre-frail, and 18% were frail. The estimated 5-year survival rate was 72% in robust patients, 58% in pre-frail patients, and 34% in frail patients (log-rank test, P older adults with cancer, a finding that was independent of age, sex, cancer type and stage, and number of medical comorbidities. The CFI has the potential to become a tool that oncologists can use to objectively identify frailty in older adults with cancer. Copyright © 2017 by the National Comprehensive Cancer Network.

  7. Older drivers with cognitive impairment: Perceived changes in driving skills, driving-related discomfort and self-regulation of driving

    DEFF Research Database (Denmark)

    Meng, A.; Siren, A.; Teasdale, Thomas William

    2013-01-01

    The results of a previous study indicate that in general, older drivers who recognise cognitive problems show realistic self-assessment of changes in their driving skills and that driving-related discomfort may function as an indirect monitoring of driving ability, contributing to their safe...... drivers may recognise cognitive problems, they tend not to recognise changes to their driving, which may reflect reluctance to acknowledge the impact of cognitive impairment on their driving. Furthermore, the results suggest that driving-related discomfort plays an important role in the self......-regulation of driving among cognitively impaired older drivers. However, it is less clear what triggers driving-related discomfort among cognitively impaired older drivers indicating that it may be a less reliable aspect of their self-monitoring of driving ability....

  8. 77 FR 3636 - Federal Acquisition Regulation; Brand-Name Specifications; Correction

    Science.gov (United States)

    2012-01-25

    ... 26] RIN 9000-AK55 Federal Acquisition Regulation; Brand-Name Specifications; Correction AGENCY... Regulation (FAR) to implement the Office of Management and Budget memoranda on brand-name specifications, FAR Case 2005-037, Brand-Name Specifications, which published in the Federal Register at 77 FR 189 on...

  9. Specific food preferences of older adults with a poor appetite. A forced-choice test conducted in various care settings.

    Science.gov (United States)

    van der Meij, Barbara S; Wijnhoven, Hanneke A H; Finlayson, Graham S; Oosten, Babette S H; Visser, Marjolein

    2015-07-01

    A poor appetite in older adults is an important determinant of reduced food intake and undernutrition. Food preferences may influence food intake. The aim of this study was to investigate food preferences of older adults with a poor appetite and compare these with preferences of older adults with a good appetite. Older adults (n = 349, aged 65-101 years) in nursing/residential care homes, hospitals or at home receiving home care participated in a computer-based forced-choice food preference assessment. Self-reported appetite in the past week was classified as 'good' or 'poor' using a validated instrument. Food preferences were determined by counting the relative frequency of choices for food images according to 11 dichotomous categories: high/low 1) protein; 2) fat; 3) carbohydrates; 4) fiber; 5) variation; and 6) animal/vegetarian proteins; 7) sweet/savory taste; 8) solid/liquid texture; 9) dairy/non-dairy; with/without 10) sauce or 11) color variation. Specific food preferences in participants with a poor appetite were identified by one-sample t-tests comparing frequencies to the expected value of 48. Preference differences between those with a good and a poor appetite were analyzed using GLM adjusting for confounders. The results showed that older adults with a poor appetite (n = 113; 32.4%) preferred variation (51.6 vs. 48, P food preferences. Their preference for variation differs from those with a good appetite. These results may be used to develop meals that are preferred by older adults with poor appetite in order to increase food intake and prevent undernutrition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. A Systematic Review of Culturally Specific Interventions to Increase Physical Activity for Older Asian Americans.

    Science.gov (United States)

    Katigbak, Carina; Flaherty, Erin; Chao, Ying-Yu; Nguyen, Tam; Cheung, Daphne; Yiu-Cho Kwan, Rick

    Physical activity (PA) is a significant modifiable risk factor for cardiovascular disease. For older adults, engaging in PA is shown to improve cardiac status, reduce cognitive, and functional decline, and improve overall quality of life. However, only 17% of Asian American adults meet the 2008 federal recommended guidelines for aerobic and muscle strengthening activity; and there is a paucity of data reporting on older Asian Americans - a rapidly growing, underserved group. While data pertaining to Asian Americans is frequently reported at the aggregate level, this masks differences (eg, language, culture, income) among Asian ethnic subgroups that may impact health behaviors. The purpose of this review was to identify intervention, and cultural adaptation strategies in studies promoting PA for older Asian Americans. A comprehensive literature search was performed to identify interventions published between 1996-2016 focused on improving PA among older Asian Americans (> 60 years old). Data were abstracted to examine intervention study designs, cultural adaptation strategies, theoretical frameworks, and physical activity measures. Nine studies met the review's inclusion criteria. Community-based recruitment approaches were widely used, and all studies employed cultural adaptation to varying degrees. Most studies reported improvements in PA outcomes, focused on Chinese Americans, and relied on self-reports of PA, while few aimed to increase PA using a multi-component approach. Future studies would benefit from larger sample sizes, a wider representation of Asian ethnic subgroups, and concentrated efforts to implement deep level adaptations that may increase the salience and sustainability of these interventions.

  11. Associations of Total and Domain-Specific Sedentary Time With Type 2 Diabetes in Taiwanese Older Adults

    Directory of Open Access Journals (Sweden)

    Ming-Chun Hsueh

    2016-07-01

    Full Text Available Background: The increasing prevalence of type 2 diabetes in older adults has become a public health concern. We investigated the associations of total and domain-specific sedentary time with risk of type 2 diabetes in older adults. Methods: The sample comprised 1046 older people (aged ≥65 years. Analyses were performed using crosssectional data collected via computer-assisted telephone-based interviews in 2014. Data on six self-reported domains of sedentary time (Measure of Older Adults’ Sedentary Time, type 2 diabetes status, and sociodemographic variables were included in the study. Binary logistic regression analysis was performed to calculate the adjusted odds ratios (ORs and 95% confidence intervals (CIs for total and individual sedentary behavior components and likelihood of type 2 diabetes. Results: A total of 17.5% of the participants reported type 2 diabetes. No significant associations were found between total sitting time and risk of type 2 diabetes, after controlling for confounding factors. After total sedentary behavior was stratified into six domains, only watching television for more than 2 hours per day was associated with higher odds of type 2 diabetes (OR 1.56; 95% CI, 1.10–2.21, but no significant associations were found between other domains of sedentary behavior (computer use, reading, socializing, transport, and hobbies and risk of type 2 diabetes. Conclusions: These findings suggest that, among domain-specific sedentary behavior, excessive television viewing might increase the risk of type 2 diabetes among older adults more than other forms of sedentary behavior.

  12. A passion for gambling: a generation-specific conceptual analysis and review of gambling among older adults in Canada.

    Science.gov (United States)

    Alberghetti, Alessandra; Collins, Patricia A

    2015-06-01

    The proliferation of gambling opportunities in Canada, coupled with an aging population, has led to an increased prevalence of gambling among older adults. Encouraged by this trend, gambling industries have modified their activities to attract and market to this group. Yet, older adults are not a homogeneous group. The life experiences, values, and attitudes shared by generations make a cohort-specific analysis of gambling among older adults a worthwhile pursuit. Drawing from the Dualistic Model of Passion (Vallerand et al. in J Pers Soc Psychol 85(4):756-767, 2003), we discuss the role of passion in shaping gambling behaviours, and the implications of a harmonious or obsessive passion on the benefits and risks to two distinct generations of older adults. Based on their generational attributes, we posit that members of the Silent Generation (those born between 1925 and 1942) stand to gain more from the benefits of recreational gambling, but also stand lose more from problem gambling, than their children's generation, the Baby Boomers (those born between 1942 and 1964). Preventative strategies to assist problem gambling seniors, along with recommendations for further research, are discussed.

  13. The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment.

    Science.gov (United States)

    Riby, L M; Marriott, A; Bullock, R; Hancock, J; Smallwood, J; McLaughlin, J

    2009-04-01

    Previous research investigating the impact of glucose ingestion and/or improvements in glucose regulation has found selective cognitive facilitation on episodic memory tasks in successful ageing and dementia. The present study aimed to extend this research to mild cognitive impairment (MCI). In a repeated-measures design, 24 older adults with and 24 older adults without MCI performed a battery of memory and attention tasks after 25 g of glucose or a sweetness matched placebo. In addition, to assess the impact of individual differences in glucose regulation, blood glucose measurements were taken throughout the testing session. Consistent with previous research, cognitive facilitation was observed for episodic memory tasks only in both successful ageing and MCI. Older adults with MCI had a similar glucose regulatory response as controls but their fasting levels were elevated. Notably, higher levels of blood glucose were associated with impaired memory performance in both the glucose and placebo conditions. Importantly, both blood glucose and memory performance indices were significant predictors of MCI status. The utility of glucose supplementation and the use of glucose regulation as a biological marker are discussed in relation to these data.

  14. Defining Alcohol-Specific Rules Among Parents of Older Adolescents: Moving Beyond No Tolerance

    OpenAIRE

    Bourdeau, Beth; Miller, Brenda; Vanya, Magdalena; Duke, Michael; Ames, Genevieve

    2012-01-01

    Parental beliefs and rules regarding their teen’s use of alcohol influence teen decisions regarding alcohol use. However, measurement of parental rules regarding adolescent alcohol use has not been thoroughly studied. This study used qualitative interviews with 174 parents of older teens from 100 families. From open-ended questions, themes emerged that describe explicit rules tied to circumscribed use, no tolerance, and “call me.” There was some inconsistency in explicit rules with and betwee...

  15. The development, factor structure and psychometric properties of driving self-regulation scales for older adults: Has self-regulation evolved in the last 15 years?

    Science.gov (United States)

    Wong, Ides Y; Smith, Simon S; Sullivan, Karen A

    2015-07-01

    The term driving self-regulation is typically used to describe the practice of drivers who avoid driving in situations that they regard as unsafe because of perceived physical impairment. Older adults report using this strategy to improve safety while retaining mobility. Self-regulation is typically assessed using the driving avoidance items from the driving habits questionnaire (DHQ) and the driver mobility questionnaire (DMQ-A). However, the psychometric properties of these measures are not well understood. Using data from 277 older drivers, exploratory factor analysis was used to test the homogeneity of three driving self-regulation scales: the DHQ, DMQ-A, and an extended DMQ-A. Good internal consistency for each of the scales was identified (all αs≥.9). A one factor solution was identified for two of the measures (DHQ, DMQ-A) and a two factor solution accounting for over 70% of the score variance was identified for the third measure. The two factors assessed situations that may be avoided while driving because of the "external" (e.g., weather-related) or "internal" (e.g., passenger-related) driving environments, respectively. The findings suggest that the interpretation of an overall summated scale score, or single-item interpretations, may not be appropriate. Instead, driving self-regulation may be a multifaceted construct comprised of distinct dimensions that have not been identified previously but can be reliably measured. These data have implications for our understanding of driving self-regulation by older adults and the way in which this behavior is measured. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. How can we characterize nano-specific soft regulation? Lessons from occupational health and safety governance

    NARCIS (Netherlands)

    Reichow, Aline; Dorbeck-Jung, Barbel R.; Konrad, Kornelia; Coenen, Christopher; Dijkstra, Anne; Milburn, Colin; van Lente, Harro

    2013-01-01

    Soft regulation is a widely used instrument in the governance of emerging technologies, especially in the governance of nanotechnologies. So far, evaluations on the effects of nano-specific soft regulation cannot build on a coherent and consistent typology. Characterization of soft regulation is

  17. Do older drivers with bilateral cataract self-regulate their driving while waiting for first eye cataract surgery?

    Directory of Open Access Journals (Sweden)

    Agramunt S

    2017-11-01

    Full Text Available Seraina Agramunt,1 Lynn B Meuleners,1 Michelle L Fraser,1 Kyle C Chow,1 Jonathon Q Ng,2,3 Vignesh Raja,4 Nigel Morlet2,3 1Curtin-Monash Accident Research Centre (C-MARC, Curtin University, Faculty of Health Sciences, Perth, Australia; 2Eye & Vision Epidemiology Research (EVER Group, Perth, Australia; 3School of Population and Global Health, The University of Western Australia, Perth, Australia; 4Sir Charles Gairdner Hospital, Perth, Australia Objectives: To analyze the association between visual impairment and driver self-regulation among a cohort of older drivers waiting for first eye cataract surgery.Methods: Ninety-six drivers with bilateral cataract aged 55+ years were assessed before first eye cataract surgery. Data collection consisted of a researcher-administered questionnaire, objective visual measures (visual acuity, contrast sensitivity and stereopsis, a visual attention test (the useful field of view test and a cognitive test (the Mini-Mental State Examination. Driver self-regulation practices were collected using the Driving Habits Questionnaire and were also measured with an in-vehicle monitoring device. Characteristics of self-regulators and non-self-regulators were compared and a logistic regression model was used to examine the association between 3 objective visual measures and driver self-regulation status.Results: After controlling for potential confounding factors, only binocular contrast sensitivity (p=0.01, age (p=0.03 and gender (p=0.03 were significantly associated with driver self-regulation status. The odds of participants with better contrast sensitivity scores (better vision self-regulating their driving in at least 1 driving situation decreased (odds ratio [OR]: 0.01, 95% CI: 0.00–0.28 while those of increasing age reported an increased odds of self-regulating their driving (OR: 1.08, 95% CI: 1.01–1.15. The odds of males self-regulating their driving was decreased compared with females (OR: 0.28, 95% CI: 0.09

  18. Do current national and international guidelines have specific recommendations for older adults with bipolar disorder? A brief report.

    Science.gov (United States)

    Dols, Annemiek; Kessing, Lars Vedel; Strejilevich, Sergio A; Rej, Soham; Tsai, Shang-Ying; Gildengers, Ariel G; Almeida, Osvaldo P; Shulman, Kenneth I; Sajatovic, Martha

    2016-12-01

    Older adults with bipolar disorder (OABD) are a growing segment of patients with bipolar disorder (BD) for which specific guidelines are warranted. Although, OABD are frequently excluded from randomized controlled trials due to their age or somatic comorbidity, more treatment data from a variety of sources have become available in recent years. It is expected that at least some of this emerging information on OABD would be incorporated into treatment guidelines available to clinicians around the world. The International Society of Bipolar Disorders OABD task force compiled and compared recommendations from current national and international guidelines that specifically address geriatric or older individuals with BD (from year 2005 onwards). There were 34 guidelines, representing six continents and 19 countries. The majority of guidelines had no separate section on OABD. General principles for treating OABD with medication are recommended to be similar to those for younger adults, with special caution for side effects due to somatic comorbidity and concomitant medications. Therapeutic lithium serum levels are suggested to be lower but recommendations are very general and mostly not informed by specific research evidence. There is a lack of emphasis of OABD-specific issues in existing guidelines. Given the substantial clinical heterogeneity in BD across the life span, along with the rapidly expanding population of older individuals worldwide, and limited mental health workforce with geriatric expertise, it is critical that additional effort and resources be devoted to studying treatment interventions specific to OABD and that treatment guidelines reflect research findings. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  19. Evidence for a Selectively Regulated Prioritization Shift Depending on Walking Situations in Older Adults

    OpenAIRE

    Salkovic, Dina; Hobert, Markus A.; Bellut, Carolin; Funer, Florian; Renno, Sarah; Haertner, Linda; Hasmann, Sandra E.; Staebler, Jana; Geritz, Johanna; Suenkel, Ulrike; Fallgatter, Andreas J.; Eschweiler, Gerhard W.; Berg, Daniela; Maetzler, Walter

    2017-01-01

    Background: Older adults have increased risks of balance issues and falls when walking and performing turns in daily situations. Changes of prioritization during different walking situations associated with dual tasking may contribute to these deficits. The objective of this study was therefore to investigate whether older adults demonstrate changes of prioritization during different walking paths. Methods: In total, 1,054 subjects with an age range from 50 to 83 years were selected from t...

  20. Self-Regulation and Recall: Growth Curve Modeling of Intervention Outcomes for Older Adults

    OpenAIRE

    West, Robin L.; Hastings, Erin C.

    2011-01-01

    Memory training has often been supported as a potential means to improve performance for older adults. Less often studied are the characteristics of trainees that benefit most from training. Using a self-regulatory perspective, the current project examined a latent growth curve model to predict training-related gains for middle-aged and older adult trainees from individual differences (e.g., education), information processing skills (strategy use) and self-regulatory factors such as self-effi...

  1. Gene program-specific regulation of PGC-1{alpha} activity

    DEFF Research Database (Denmark)

    Schmidt, Søren F; Mandrup, Susanne

    2011-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC-1α) activation coordinates induction of the hepatic fasting response through coactivation of numerous transcription factors and gene programs. In the June 15, 2011, issue of Genes & Development, Lustig and colleagues (pp....... 1232-1244) demonstrated that phosphorylation of PGC-1α by the p70 ribosomal protein S6 kinase 1 (S6K1) specifically interfered with the interaction between PGC-1α and HNF4α in liver and blocked the coactivation of the gluconeogenic target genes. This demonstrates how independent fine-tuning of gene...

  2. Cell-Type-Specific Splicing of Piezo2 Regulates Mechanotransduction

    Directory of Open Access Journals (Sweden)

    Marcin Szczot

    2017-12-01

    Full Text Available Summary: Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that Piezo2 is extensively spliced, producing different Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, whereas non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. Together, our results describe, at the molecular level, a potential mechanism by which transduction is tuned, permitting the detection of a variety of mechanosensory stimuli. : Szczot et al. find that the mechanoreceptor Piezo2 is extensively alternatively spliced, generating multiple distinct isoforms. Their findings indicate that these splice products have specific tissue and cell type expression patterns and exhibit differences in receptor properties. Keywords: Piezo, touch, sensation, ion-channel, splicing

  3. Plasticity Regulators Modulate Specific Root Traits in Discrete Nitrogen Environments

    Science.gov (United States)

    Gifford, Miriam L.; Banta, Joshua A.; Katari, Manpreet S.; Hulsmans, Jo; Chen, Lisa; Ristova, Daniela; Tranchina, Daniel; Purugganan, Michael D.; Coruzzi, Gloria M.; Birnbaum, Kenneth D.

    2013-01-01

    Plant development is remarkably plastic but how precisely can the plant customize its form to specific environments? When the plant adjusts its development to different environments, related traits can change in a coordinated fashion, such that two traits co-vary across many genotypes. Alternatively, traits can vary independently, such that a change in one trait has little predictive value for the change in a second trait. To characterize such “tunability” in developmental plasticity, we carried out a detailed phenotypic characterization of complex root traits among 96 accessions of the model Arabidopsis thaliana in two nitrogen environments. The results revealed a surprising level of independence in the control of traits to environment – a highly tunable form of plasticity. We mapped genetic architecture of plasticity using genome-wide association studies and further used gene expression analysis to narrow down gene candidates in mapped regions. Mutants in genes implicated by association and expression analysis showed precise defects in the predicted traits in the predicted environment, corroborating the independent control of plasticity traits. The overall results suggest that there is a pool of genetic variability in plants that controls traits in specific environments, with opportunity to tune crop plants to a given environment. PMID:24039603

  4. Dutasteride reduces prostate size and prostate specific antigen in older hypogonadal men with benign prostatic hyperplasia undergoing testosterone replacement therapy.

    Science.gov (United States)

    Page, Stephanie T; Hirano, Lianne; Gilchriest, Janet; Dighe, Manjiri; Amory, John K; Marck, Brett T; Matsumoto, Alvin M

    2011-07-01

    Benign prostatic hyperplasia and hypogonadism are common disorders in aging men. There is concern that androgen replacement in older men may increase prostate size and symptoms of benign prostatic hyperplasia. We examined whether combining dutasteride, which inhibits testosterone to dihydrotestosterone conversion, with testosterone treatment in older hypogonadal men with benign prostatic hyperplasia reduces androgenic stimulation of the prostate compared to testosterone alone. We conducted a double-blind, placebo controlled trial of 53 men 51 to 82 years old with symptomatic benign prostatic hyperplasia, prostate volume 30 cc or greater and serum total testosterone less than 280 ng/dl (less than 9.7 nmol/l). Subjects were randomized to daily transdermal 1% T gel plus oral placebo or dutasteride for 6 months. Testosterone dosing was adjusted to a serum testosterone of 500 to 1,000 ng/dl. The primary outcomes were prostate volume measured by magnetic resonance imaging, serum prostate specific antigen and androgen levels. A total of 46 subjects completed all procedures. Serum testosterone increased similarly into the mid-normal range in both groups. Serum dihydrotestosterone increased in the testosterone only but decreased in the testosterone plus dutasteride group. In the testosterone plus dutasteride group prostate volume and prostate specific antigen (mean ± SEM) decreased 12% ± 2.5% and 35% ± 5%, respectively, compared to the testosterone only group in which prostate volume and prostate specific antigen increased 7.5% ± 3.3% and 19% ± 7% (p = 0.03 and p = 0.008), respectively, after 6 months of treatment. Prostate symptom scores improved in both groups. Combined treatment with testosterone plus dutasteride reduces prostate volume and prostate specific antigen compared to testosterone only. Coadministration of a 5α-reductase inhibitor with testosterone appears to spare the prostate from androgenic stimulation during testosterone replacement in older

  5. Health literacy of older drivers and the importance of health experience for self-regulation of driving behaviour.

    Science.gov (United States)

    Sargent-Cox, K A; Windsor, T; Walker, J; Anstey, K J

    2011-05-01

    This study provides much needed information on the education level of older drivers regarding the impact of health conditions and medications on personal driving safety, where they source this information, and how this knowledge influences self-regulation of driving. Random and convenience sampling secured 322 Australian drivers (63.9% males) aged 65 years and over (M = 77.35 years, SD = 7.35) who completed a telephone interview. The majority of respondents (86%) had good knowledge about health conditions (health knowledge) and driving safety, however more than 50% was classified as having poor knowledge on the effects of certain medications (medication knowledge) and driving safety. Poorer health knowledge was associated with a reduced likelihood of driving over 100 km in adjusted models. Being older and having more than one medical condition was found to increase the likelihood of self-regulation of driving. Results indicate that health knowledge was less important for predicting driving behaviour than health experience. Of great interest was that up to 85.7% of respondents reported not receiving advice about the potential impact of their medical condition and driving from their doctor. The findings indicate a need for improved dissemination of evidence-based health information and education for older drivers and their doctors. Copyright © 2010 Elsevier Ltd. All rights reserved.

  6. Can specific transcriptional regulators assemble a universal cancer signature?

    Science.gov (United States)

    Roy, Janine; Isik, Zerrin; Pilarsky, Christian; Schroeder, Michael

    2013-10-01

    Recently, there is a lot of interest in using biomarker signatures derived from gene expression data to predict cancer progression. We assembled signatures of 25 published datasets covering 13 types of cancers. How do these signatures compare with each other? On one hand signatures answering the same biological question should overlap, whereas signatures predicting different cancer types should differ. On the other hand, there could also be a Universal Cancer Signature that is predictive independently of the cancer type. Initially, we generate signatures for all datasets using classical approaches such as t-test and fold change and then, we explore signatures resulting from a network-based method, that applies the random surfer model of Google's PageRank algorithm. We show that the signatures as published by the authors and the signatures generated with classical methods do not overlap - not even for the same cancer type - whereas the network-based signatures strongly overlap. Selecting 10 out of 37 universal cancer genes gives the optimal prediction for all cancers thus taking a first step towards a Universal Cancer Signature. We furthermore analyze and discuss the involved genes in terms of the Hallmarks of cancer and in particular single out SP1, JUN/FOS and NFKB1 and examine their specific role in cancer progression.

  7. TiGER: a database for tissue-specific gene expression and regulation.

    Science.gov (United States)

    Liu, Xiong; Yu, Xueping; Zack, Donald J; Zhu, Heng; Qian, Jiang

    2008-06-09

    Understanding how genes are expressed and regulated in different tissues is a fundamental and challenging question. However, most of currently available biological databases do not focus on tissue-specific gene regulation. The recent development of computational methods for tissue-specific combinational gene regulation, based on transcription factor binding sites, enables us to perform a large-scale analysis of tissue-specific gene regulation in human tissues. The results are stored in a web database called TiGER (Tissue-specific Gene Expression and Regulation). The database contains three types of data including tissue-specific gene expression profiles, combinatorial gene regulations, and cis-regulatory module (CRM) detections. At present the database contains expression profiles for 19,526 UniGene genes, combinatorial regulations for 7,341 transcription factor pairs and 6,232 putative CRMs for 2,130 RefSeq genes. We have developed and made publicly available a database, TiGER, which summarizes and provides large scale data sets for tissue-specific gene expression and regulation in a variety of human tissues. This resource is available at 1.

  8. TiGER: A database for tissue-specific gene expression and regulation

    Directory of Open Access Journals (Sweden)

    Zack Donald J

    2008-06-01

    Full Text Available Abstract Background Understanding how genes are expressed and regulated in different tissues is a fundamental and challenging question. However, most of currently available biological databases do not focus on tissue-specific gene regulation. Results The recent development of computational methods for tissue-specific combinational gene regulation, based on transcription factor binding sites, enables us to perform a large-scale analysis of tissue-specific gene regulation in human tissues. The results are stored in a web database called TiGER (Tissue-specific Gene Expression and Regulation. The database contains three types of data including tissue-specific gene expression profiles, combinatorial gene regulations, and cis-regulatory module (CRM detections. At present the database contains expression profiles for 19,526 UniGene genes, combinatorial regulations for 7,341 transcription factor pairs and 6,232 putative CRMs for 2,130 RefSeq genes. Conclusion We have developed and made publicly available a database, TiGER, which summarizes and provides large scale data sets for tissue-specific gene expression and regulation in a variety of human tissues. This resource is available at 1.

  9. Verbal responses, depressive symptoms, reminiscence functions and cognitive emotion regulation in older women receiving individual reminiscence therapy.

    Science.gov (United States)

    Wu, Dongmei; Chen, Taolin; Yang, Hao; Gong, Qiyong; Hu, Xiuying

    2018-07-01

    To examine the effectiveness of individual reminiscence therapy in community-dwelling older women with depressive symptoms and to explore the characteristics of participants' verbalisation in the process. Previous studies have found reminiscence was related to depression and anxiety. Although reminiscence therapy is widely used to reduce depression, little is known about how it works, and the content of verbalisations might provide one explanation. The study employed a one-group pretest-post-test design. Twenty-seven participants underwent 6-week interventions of individual reminiscence therapy at home that were conducted by one nurse and induced through seeing old photographs. The Geriatric Depression Scale, Zung Self-rating Anxiety Scale, Reminiscence Functions Scale and Cognitive Emotion Regulation Questionnaire were used to measure the emotional states, reminiscence functions and cognitive emotion regulation strategies. Participants' verbalisations were categorised using the Client Behavior System. Reminiscence therapy relieved depression and anxiety. Both the reminiscence function and cognitive emotion regulation became more favourable after interventions. Furthermore, higher frequencies of recounting, cognitive-behavioural exploration and affective exploration were noted in the process. Participants with more severe depressive symptoms tended to display a higher frequency of affective exploration. The reduction in depression, self-negative reminiscence and negative-focused emotion regulation were respectively associated with verbalisations. Individual reminiscence therapy might relieve negative emotion and improve reminiscence function and cognitive emotion regulation. The participants' verbalisation is worthy of our attention, due to its correlation with the severity of depression and its mitigating effects on the depression, anxiety, self-negative reminiscence and negative-focused regulation in older women. The results contribute to our understanding of

  10. Constructive episodic simulation: dissociable effects of a specificity induction on remembering, imagining, and describing in young and older adults.

    Science.gov (United States)

    Madore, Kevin P; Gaesser, Brendan; Schacter, Daniel L

    2014-05-01

    According to the constructive episodic simulation hypothesis (Schacter & Addis, 2007), both remembered past and imagined future events rely heavily on episodic memory. An alternative hypothesis is that observed similarities between remembering and imagining reflect the influence of broader factors such as descriptive ability, narrative style, or inhibitory control. We attempted to distinguish between these 2 hypotheses by examining the impact of an episodic specificity induction on memory, imagination, and picture description in young and older adults. In Experiment 1, participants received the specificity induction or a control induction prior to the memory, imagination, and description tasks. Older adults provided fewer internal (i.e., episodic) and more external (i.e., semantic) details than young adults across the 3 tasks irrespective of induction. Critically, however, the specificity induction selectively increased internal but not external details for memory and imagination in both age groups compared with the control induction. By contrast, the induction did not affect internal (or external) details for picture description. Experiment 2 replicated these results in young adults using a different control induction. Our findings point to a dissociation between episodic processes involved in memory and imagination and nonepisodic processes involved in picture description. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  11. Defining Alcohol-Specific Rules Among Parents of Older Adolescents: Moving Beyond No Tolerance.

    Science.gov (United States)

    Bourdeau, Beth; Miller, Brenda; Vanya, Magdalena; Duke, Michael; Ames, Genevieve

    2012-01-01

    Parental beliefs and rules regarding their teen's use of alcohol influence teen decisions regarding alcohol use. However, measurement of parental rules regarding adolescent alcohol use has not been thoroughly studied. This study used qualitative interviews with 174 parents of older teens from 100 families. From open-ended questions, themes emerged that describe explicit rules tied to circumscribed use, no tolerance, and "call me." There was some inconsistency in explicit rules with and between parents. Responses also generated themes relating to implicit rules such as expectations and preferences. Parents described their methods of communicating their position via conversational methods, role modeling their own behavior, teaching socially appropriate use of alcohol by offering their teen alcohol, and monitoring their teens' social activities. Findings indicate that alcohol rules are not adequately captured by current assessment measures.

  12. Self-rated health and all-cause and cause-specific mortality of older adults

    DEFF Research Database (Denmark)

    Bamia, Christina; Orfanos, Philippos; Juerges, Hendrik

    2017-01-01

    Objectives To evaluate, among the elderly, the association of self-rated health (SRH) with mortality, and to identify determinants of self-rating health as “at-least-good”. Study design Individual data on SRH and important covariates were obtained for 424,791 European and United States residents...... associations. Factors favourably associated with SRH were: sex (males), age (younger-old), education (high), marital status (married/cohabiting), physical activity (active), body mass index (non-obese), alcohol consumption (low to moderate) and previous morbidity (absence). Conclusion SRH provides a quick...... and simple tool for assessing health and identifying groups of elders at risk of early mortality that may be useful also in clinical settings. Modifying determinants of favourably rating health, e.g. by increasing physical activity and/or by eliminating obesity, may be important for older adults to “feel...

  13. A New Approach to Assessing Self-Regulation by Older Drivers: Development and Testing of a Questionnaire Instrument

    Science.gov (United States)

    2009-12-01

    Appropriate self-regulation of driving; that is, adjusting ones driving patterns by driving less or avoiding specific situations in which one feels unsafe or uncomfortable, shows considerable promise as a strategy for compensating for functional d...

  14. A new approach to assessing self-regulation by older drivers : development and testing of a questionnaire instrument.

    Science.gov (United States)

    2010-12-01

    Appropriate self-regulation of driving; that is, adjusting ones driving patterns by driving less or avoiding specific : situations in which one feels unsafe or uncomfortable, shows considerable promise as a strategy for compensating for : function...

  15. Specific expression of bioluminescence reporter gene in cardiomyocyte regulated by tissue specific promoter

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Vu Hong; Tae, Seong Ho; Le, Nguyen Uyen Chi; Min, Jung Joon [Chonnam National University Medical School, Gwangju (Korea, Republic of)

    2007-07-01

    As the human heart is not capable of regenerating the great numbers of cardiac cells that are lost after myocardial infarction, impaired cardiac function is the inevitable result of ischemic disease. Recently, human embryonic stem cells (hESCs) have gained popularity as a potentially ideal cell candidate for tissue regeneration. In particular, hESCs are capable of cardiac lineage-specific differentiation and confer improvement of cardiac function following transplantation into animal models. Although such data are encouraging, the specific strategy for in vivo and non-invasive detection of differentiated cardiac lineage is still limited. Therefore, in the present study, we established the gene construction in which the optical reporter gene Firefly luciferase was controlled by Myosin Heavy Chain promoter for specific expressing in heart cells. The vector consisting of - MHC promoter and a firefly luciferase coding sequence flanked by full-length bovine growth hormone (BGH) 3'-polyadenylation sequence based on pcDNA3.1- vector backbone. To test the specific transcription of this promoter in g of MHC-Fluc or CMV-Flue (for control) plasmid DNA in myocardial tissue, 20 phosphate-buffered saline was directly injected into mouse myocardium through a midline sternotomy and liver. After 1 week of injection, MHC-Fluc expression was detected from heart region which was observed under cooled CCD camera of in vivo imaging system but not from liver. In control group injected with CMV-Flue, the bioluminescence was detected from all these organs. The expression of Flue under control of Myosin Heavy Chain promoter may become a suitable optical reporter gene for stem cell-derived cardiac lineage differentiation study.

  16. 50 CFR 32.6 - What are the procedures for publication of refuge-specific sport fishing regulations?

    Science.gov (United States)

    2010-10-01

    ... refuge-specific sport fishing regulations? 32.6 Section 32.6 Wildlife and Fisheries UNITED STATES FISH... sport fishing regulations? (a) Refuge-specific fishing regulations are issued only at the time of or after the opening of a wildlife refuge area to sport fishing. (b) Refuge-specific fishing regulations...

  17. Specificity of emotion regulation deficits in social anxiety: an internet study.

    Science.gov (United States)

    Rusch, Silke; Westermann, Stefan; Lincoln, Tania M

    2012-09-01

    There is evidence for an association between social anxiety and emotion regulation difficulties. This study investigates that emotion regulation difficulties are specific to two domains of social anxiety. An explorative study was conducted to examine the associations between emotion regulation facets and social anxiety in the normal population. N= 149 healthy volunteers participated in an internet-based survey. Emotion regulation deficits were measured by the Difficulties in Emotion Regulation Scale which consists of six subscales. Social anxiety was measured by the Social Phobia Scale and the Social Interaction Anxiety Scale. Hierarchical regression analyses showed that anxiety of interactive social situations is associated with non-acceptance of negative emotions, impulse control difficulties, and lack of functional emotion regulation strategies over and above the impact of age and general psychopathology. In contrast, anxiety of being observed by others was not specifically associated with emotion regulation strategies. The results support the hypothesis that specific emotion regulation deficits are relevant to specific aspects of social anxiety. Implications for further research and therapy are discussed. © 2011 The British Psychological Society.

  18. 76 FR 59304 - 2011-2012 Refuge-Specific Hunting and Sport Fishing Regulations; Correction

    Science.gov (United States)

    2011-09-26

    ..., upland game hunting, big game hunting, and sport fishing for the 2011-2012 season. Inadvertently, this...-0038; 93270-1265-0000-4A] RIN 1018-AX54 2011-2012 Refuge-Specific Hunting and Sport Fishing Regulations... our regulations concerning hunting and sport fishing programs at national wildlife refuges...

  19. Obesity-specific neural cost of maintaining gait performance under complex conditions in community-dwelling older adults.

    Science.gov (United States)

    Osofundiya, Olufunmilola; Benden, Mark E; Dowdy, Diane; Mehta, Ranjana K

    2016-06-01

    Recent evidence of obesity-related changes in the prefrontal cortex during cognitive and seated motor activities has surfaced; however, the impact of obesity on neural activity during ambulation remains unclear. The purpose of this study was to determine obesity-specific neural cost of simple and complex ambulation in older adults. Twenty non-obese and obese individuals, 65years and older, performed three tasks varying in the types of complexity of ambulation (simple walking, walking+cognitive dual-task, and precision walking). Maximum oxygenated hemoglobin, a measure of neural activity, was measured bilaterally using a portable functional near infrared spectroscopy system, and gait speed and performance on the complex tasks were also obtained. Complex ambulatory tasks were associated with ~2-3.5 times greater cerebral oxygenation levels and ~30-40% slower gait speeds when compared to the simple walking task. Additionally, obesity was associated with three times greater oxygenation levels, particularly during the precision gait task, despite obese adults demonstrating similar gait speeds and performances on the complex gait tasks as non-obese adults. Compared to existing studies that focus solely on biomechanical outcomes, the present study is one of the first to examine obesity-related differences in neural activity during ambulation in older adults. In order to maintain gait performance, obesity was associated with higher neural costs, and this was augmented during ambulatory tasks requiring greater precision control. These preliminary findings have clinical implications in identifying individuals who are at greater risk of mobility limitations, particularly when performing complex ambulatory tasks. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Ecdysone signaling regulates specification of neurons with a male-specific neurite in Drosophila

    Directory of Open Access Journals (Sweden)

    Binglong Zhang

    2018-02-01

    Full Text Available Some mAL neurons in the male brain form the ipsilateral neurite (ILN[+] in a manner dependent on FruBM, a male-specific transcription factor. FruBM represses robo1 transcription, allowing the ILN to form. We found that the proportion of ILN[+]-mALs in all observed single cell clones dropped from ∼90% to ∼30% by changing the heat-shock timing for clone induction from 4-5 days after egg laying (AEL to 6-7 days AEL, suggesting that the ILN[+]-mALs are produced predominantly by young neuroblasts. Upon EcR-A knockdown, ILN[+]-mALs were produced at a high rate (∼60%, even when heat shocked at 6-7 days AEL, yet EcR-B1 knockdown reduced the proportion of ILN[+]-mALs to ∼30%. Immunoprecipitation assays in S2 cells demonstrated that EcR-A and EcR-B1 form a complex with FruBM. robo1 reporter transcription was repressed by FruBM and ecdysone counteracted FruBM. We suggest that ecdysone signaling modulates the FruBM action to produce an appropriate number of male-type neurons.

  1. Gender-specific associations between physical functioning, bone quality and fracture risk in older people

    NARCIS (Netherlands)

    Furrer, R.; van Schoor, N.M.; de Haan, A.; Lips, P.; de Jongh, R.T.

    2014-01-01

    The aim of this study was to investigate which parameters of physical functioning are associated with bone quality and fracture risk and whether gender-specific differences exist within these associations. We studied 1,486 participants of the Longitudinal Aging Study Amsterdam. As measures of

  2. The older, the better! Age-related differences in emotion regulation after psychological contract breach.

    NARCIS (Netherlands)

    Bal, P.M.; Smit, P.

    2012-01-01

    The aim of this paper was to investigate the role of emotion regulation and age in reactions to psychological contract breach towards positive and negative affect. The authors expected that in the context of contract breach, reappraisal emotion regulation mitigate the negative relation with affect.

  3. Geriatric-specific triage criteria are more sensitive than standard adult criteria in identifying need for trauma center care in injured older adults.

    Science.gov (United States)

    Ichwan, Brian; Darbha, Subrahmanyam; Shah, Manish N; Thompson, Laura; Evans, David C; Boulger, Creagh T; Caterino, Jeffrey M

    2015-01-01

    We evaluate the sensitivity of Ohio's 2009 emergency medical services (EMS) geriatric trauma triage criteria compared with the previous adult triage criteria in identifying need for trauma center care among older adults. We studied a retrospective cohort of injured patients aged 16 years or older in the 2006 to 2011 Ohio Trauma Registry. Patients aged 70 years or older were considered geriatric. We identified whether each patient met the geriatric and the adult triage criteria. The outcome measure was need for trauma center care, defined by surrogate markers: Injury Severity Score greater than 15, operating room in fewer than 48 hours, any ICU stay, and inhospital mortality. We calculated sensitivity and specificity of both triage criteria for both age groups. We included 101,577 patients; 33,379 (33%) were geriatric. Overall, 57% of patients met adult criteria and 68% met geriatric criteria. Using Injury Severity Score, for older adults geriatric criteria were more sensitive for need for trauma center care (93%; 95% confidence interval [CI] 92% to 93%) than adult criteria (61%; 95% CI 60% to 62%). Geriatric criteria decreased specificity in older adults from 61% (95% CI 61% to 62%) to 49% (95% CI 48% to 49%). Geriatric criteria in older adults (93% sensitivity, 49% specificity) performed similarly to the adult criteria in younger adults (sensitivity 87% and specificity 44%). Similar patterns were observed for other outcomes. Standard adult EMS triage guidelines provide poor sensitivity in older adults. Ohio's geriatric trauma triage guidelines significantly improve sensitivity in identifying Injury Severity Score and other surrogate markers of the need for trauma center care, with modest decreases in specificity for older adults. Copyright © 2014 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.

  4. Gender difference in older adult's utilization of gravitational and ground reaction force in regulation of angular momentum during stair descent.

    Science.gov (United States)

    Singhal, Kunal; Kim, Jemin; Casebolt, Jeffrey; Lee, Sangwoo; Han, Ki-Hoon; Kwon, Young-Hoo

    2015-06-01

    Angular momentum of the body is a highly controlled quantity signifying stability, therefore, it is essential to understand its regulation during stair descent. The purpose of this study was to investigate how older adults use gravity and ground reaction force to regulate the angular momentum of the body during stair descent. A total of 28 participants (12 male and 16 female; 68.5 years and 69.0 years of mean age respectively) performed stair descent from a level walk in a step-over-step manner at a self-selected speed over a custom made three-step staircase with embedded force plates. Kinematic and force data were used to calculate angular momentum, gravitational moment, and ground reaction force moment about the stance foot center of pressure. Women show a significantly greater change in normalized angular momentum (0.92Nms/Kgm; p=.004) as compared to men (0.45Nms/Kgm). Women produce higher normalized GRF (p=.031) during the double support phase. The angular momentum changes show largest backward regulation for Step 0 and forward regulation for Step 2. This greater difference in overall change in the angular momentum in women may explain their increased risk of fall over the stairs. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. A novel mammal-specific three partite enhancer element regulates node and notochord-specific Noto expression.

    Directory of Open Access Journals (Sweden)

    Leonie Alten

    Full Text Available The vertebrate organizer and notochord have conserved, essential functions for embryonic development and patterning. The restricted expression of developmental regulators in these tissues is directed by specific cis-regulatory modules (CRMs whose sequence conservation varies considerably. Some CRMs have been conserved throughout vertebrates and likely represent ancestral regulatory networks, while others have diverged beyond recognition but still function over a wide evolutionary range. Here we identify and characterize a mammalian-specific CRM required for node and notochord specific (NNC expression of NOTO, a transcription factor essential for node morphogenesis, nodal cilia movement and establishment of laterality in mouse. A 523 bp enhancer region (NOCE upstream the Noto promoter was necessary and sufficient for NNC expression from the endogenous Noto locus. Three subregions in NOCE together mediated full activity in vivo. Binding sites for known transcription factors in NOCE were functional in vitro but dispensable for NOCE activity in vivo. A FOXA2 site in combination with a novel motif was necessary for NOCE activity in vivo. Strikingly, syntenic regions in non-mammalian vertebrates showed no recognizable sequence similarities. In contrast to its activity in mouse NOCE did not drive NNC expression in transgenic fish. NOCE represents a novel, mammal-specific CRM required for the highly restricted Noto expression in the node and nascent notochord and thus regulates normal node development and function.

  6. A novel mammal-specific three partite enhancer element regulates node and notochord-specific Noto expression.

    Science.gov (United States)

    Alten, Leonie; Schuster-Gossler, Karin; Eichenlaub, Michael P; Wittbrodt, Beate; Wittbrodt, Joachim; Gossler, Achim

    2012-01-01

    The vertebrate organizer and notochord have conserved, essential functions for embryonic development and patterning. The restricted expression of developmental regulators in these tissues is directed by specific cis-regulatory modules (CRMs) whose sequence conservation varies considerably. Some CRMs have been conserved throughout vertebrates and likely represent ancestral regulatory networks, while others have diverged beyond recognition but still function over a wide evolutionary range. Here we identify and characterize a mammalian-specific CRM required for node and notochord specific (NNC) expression of NOTO, a transcription factor essential for node morphogenesis, nodal cilia movement and establishment of laterality in mouse. A 523 bp enhancer region (NOCE) upstream the Noto promoter was necessary and sufficient for NNC expression from the endogenous Noto locus. Three subregions in NOCE together mediated full activity in vivo. Binding sites for known transcription factors in NOCE were functional in vitro but dispensable for NOCE activity in vivo. A FOXA2 site in combination with a novel motif was necessary for NOCE activity in vivo. Strikingly, syntenic regions in non-mammalian vertebrates showed no recognizable sequence similarities. In contrast to its activity in mouse NOCE did not drive NNC expression in transgenic fish. NOCE represents a novel, mammal-specific CRM required for the highly restricted Noto expression in the node and nascent notochord and thus regulates normal node development and function.

  7. Specific food preferences of older adults with a poor appetite. A forced-choice test conducted in various care settings

    NARCIS (Netherlands)

    van der Meij, B.S.; Wijnhoven, H.A.H.; Finlayson, G.S.; Oosten, B.S.H.; Visser, M.

    2015-01-01

    A poor appetite in older adults is an important determinant of reduced food intake and undernutrition. Food preferences may influence food intake. The aim of this study was to investigate food preferences of older adults with a poor appetite and compare these with preferences of older adults with a

  8. Driving habits and risk exposure in older drivers: lessons learned from the implementation of a self-regulation curriculum.

    Science.gov (United States)

    Jones, Vanya C; Cho, Juhee; Abendschoen-Milani, Jackie; Gielen, Andrea

    2011-10-01

    This article describes the development and pilot testing of Seniors on the MOVE (Mature Operators Vehicular Education), a safe driving education program for older adults. The study aims are to describe driving experiences and habits of a community sample of older drivers and to determine whether the program reduces their driving risk exposures. A 2-group randomized design was used. Fifty-eight participants with an average age of 70 were randomly assigned to the MOVE program or a no treatment control group. MOVE is a 4-session program designed to help older drivers better understand and utilize self-regulation skills for safer driving. Baseline and 4-week follow-up questionnaires were completed by both groups, after which the control group received the MOVE program. In the total sample, 14 percent reported having ever been in a traffic crash where someone was injured, and 10 percent reported having received a traffic citation in the past 6 months. Almost one half of the sample (47%) reported thinking about reducing the amount of driving done at night. Nearly one third were thinking about reducing the amount of driving done in unfamiliar places (32%) and the number of miles driven each week (30%). Participants reported most frequently driving between 2 to 10 miles from home, on local roadways, and between 9:00 am and 4:00 pm. Based on responses to items that measured such driving habits, a risk exposure score was created by combining driving exposure variables. Participants were categorized into lower and higher driving risk exposure groups at baseline and follow-up. There were no statistical differences in changes in higher or lower risk driving exposure variables when comparing the 2 groups. Although the impact of this program on reported driving behaviors yielded null results, descriptions of older drivers' habits and plans are informative. Because many participants were thinking about making changes to their driving habits, and many already had, the need for more

  9. Age-specific reproductive success in a long-lived bird: do older parents resist stress better?

    Science.gov (United States)

    Angelier, Frederic; Moe, Børge; Weimerskirch, Henri; Chastel, Olivier

    2007-11-01

    In many vertebrates, reproductive performance increases with advancing age but mechanisms involved in such a pattern remain poorly studied. One potential mechanism may be the hormonal stress response, which shifts energy investment away from reproduction and redirects it towards survival. In birds, this stress response is achieved through a release of corticosterone and is also accompanied by a decrease in circulating prolactin, a hormone involved widely in regulating parental cares. It has been predicted that, when the value of the current reproduction is high relative to the value of future reproduction and survival, as it is expected to be in older adults, the stress response should be attenuated to ensure that reproduction is not inhibited. We tested this hypothesis by measuring the corticosterone and prolactin responses of known-age (8-36 years old) incubating snow petrels (Pagadroma nivea) to a standardized capture/handling stress protocol. We also investigated whether an attenuation of the stress responses will correlate with a lower occurrence of egg neglect, a frequently observed behaviour in snow petrels. The probability of successfully fledging a chick increased from 6 years to 12 years before stabilizing after 12 years of age. Corticosterone response to stress was unaffected by age. Prolactin response to stress, however, was influenced clearly by age: in both sexes older breeders had higher stress-induced prolactin levels than younger ones. This was due to an increasing attenuation of the prolactin response to stress with advancing age in females, and in males this was due to a probably higher intrinsic capacity of older males to secrete prolactin. Moreover, higher stress-induced prolactin levels were correlated with a lower probability of neglecting the egg. In young breeders, the combination of a robust corticosterone increase with a lower ability to maintain prolactin secretion during acute stress is probably one of the functional causes of their

  10. Self-regulation and recall: growth curve modeling of intervention outcomes for older adults.

    Science.gov (United States)

    West, Robin L; Hastings, Erin C

    2011-12-01

    Memory training has often been supported as a potential means to improve performance for older adults. Less often studied are the characteristics of trainees that benefit most from training. Using a self-regulatory perspective, the current project examined a latent growth curve model to predict training-related gains for middle-aged and older adult trainees from individual differences (e.g., education), information processing skills (strategy use) and self-regulatory factors such as self-efficacy, control, and active engagement in training. For name recall, a model including strategy usage and strategy change as predictors of memory gain, along with self-efficacy and self-efficacy change, showed comparable fit to a more parsimonious model including only self-efficacy variables as predictors. The best fit to the text recall data was a model focusing on self-efficacy change as the main predictor of memory change, and that model showed significantly better fit than a model also including strategy usage variables as predictors. In these models, overall performance was significantly predicted by age and memory self-efficacy, and subsequent training-related gains in performance were best predicted directly by change in self-efficacy (text recall), or indirectly through the impact of active engagement and self-efficacy on gains (name recall). These results underscore the benefits of targeting self-regulatory factors in intervention programs designed to improve memory skills.

  11. Sex-specific nonlinear associations between serum lipids and different domains of cognitive function in middle to older age individuals.

    Science.gov (United States)

    Lu, Yanhui; An, Yu; Yu, Huanling; Che, Fengyuan; Zhang, Xiaona; Rong, Hongguo; Xi, Yuandi; Xiao, Rong

    2017-08-01

    To examine how serum lipids relates to specific cognitive ability domains between the men and women in Chinese middle to older age individuals. A complete lipid panel was obtained from 1444 individuals, ages 50-65, who also underwent a selection of cognitive tests. Participants were 584 men and 860 women from Linyi city, Shandong province. Multiple linear regression analyses examined serum lipids level as quadratic predictors of sex-specific measure of performance in different cognitive domains, which were adjusted for sociodemographic and lifestyle characteristics. In men, a significant quadratic effect of total cholesterol (TC) was identified for Digit Symbol (B = -0.081, P = 0.044) and also quadratic effect of low density lipoprotein-cholesterol (LDL-C) was identified for Trail Making Test B (B = -0.082, P = 0.045). Differently in women, there were significant quadratic associations between high density lipoprotein-cholesterol (HDL-C) and multiple neuropsychological tests. The nonlinear lipid-cognition associations differed between men and women and were specific to certain cognitive domains and might be of potential relevance for prevention and therapy of cognitive decline.

  12. Tissue-specifically regulated site-specific excision of selectable marker genes in bivalent insecticidal, genetically-modified rice.

    Science.gov (United States)

    Hu, Zhan; Ding, Xuezhi; Hu, Shengbiao; Sun, Yunjun; Xia, Liqiu

    2013-12-01

    Marker-free, genetically-modified rice was created by the tissue-specifically regulated Cre/loxP system, in which the Cre recombinase gene and hygromycin phosphotransferase gene (hpt) were flanked by two directly oriented loxP sites. Cre expression was activated by the tissue-specific promoter OsMADS45 in flower or napin in seed, resulting in simultaneous excision of the recombinase and marker genes. Segregation of T1 progeny was performed to select recombined plants. The excision was confirmed by PCR, Southern blot and sequence analyses indicating that efficiency varied from 10 to 53 % for OsMADS45 and from 12 to 36 % for napin. The expression of cry1Ac and vip3A was detected by RT-PCR analysis in marker-free transgenic rice. These results suggested that our tissue-specifically regulated Cre/loxP system could auto-excise marker genes from transgenic rice and alleviate public concerns about the security of GM crops.

  13. Targeted Regression of Hepatocellular Carcinoma by Cancer-Specific RNA Replacement through MicroRNA Regulation.

    Science.gov (United States)

    Kim, Juhyun; Won, Ranhui; Ban, Guyee; Ju, Mi Ha; Cho, Kyung Sook; Young Han, Sang; Jeong, Jin-Sook; Lee, Seong-Wook

    2015-07-20

    Hepatocellular carcinoma (HCC) has a high fatality rate and limited therapeutic options with side effects and low efficacy. Here, we proposed a new anti-HCC approach based on cancer-specific post-transcriptional targeting. To this end, trans-splicing ribozymes from Tetrahymena group I intron were developed, which can specifically induce therapeutic gene activity through HCC-specific replacement of telomerase reverse transcriptase (TERT) RNA. To circumvent side effects due to TERT expression in regenerating liver tissue, liver-specific microRNA-regulated ribozymes were constructed by incorporating complementary binding sites for the hepatocyte-selective microRNA-122a (miR-122a), which is down-regulated in HCC. The ribozyme activity in vivo was assessed in mouse models orthotopically implanted with HCC. Systemic administration of adenovirus encoding the developed ribozymes caused efficient anti-cancer effect and the least hepatotoxicity with regulation of ribozyme expression by miR-122a in both xenografted and syngeneic orthotopic murine model of multifocal HCC. Of note, the ribozyme induced local and systemic antitumor immunity, thereby completely suppressing secondary tumor challenge in the syngeneic mouse. The cancer specific trans-splicing ribozyme system, which mediates tissue-specific microRNA-regulated RNA replacement, provides a clinically relevant, safe, and efficient strategy for HCC treatment.

  14. Daughter-specific transcription factors regulate cell size control in budding yeast.

    Science.gov (United States)

    Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M; Rosebrock, Adam P; Futcher, Bruce; Cross, Frederick R

    2009-10-01

    In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

  15. Daughter-Specific Transcription Factors Regulate Cell Size Control in Budding Yeast

    Science.gov (United States)

    Di Talia, Stefano; Wang, Hongyin; Skotheim, Jan M.; Rosebrock, Adam P.; Futcher, Bruce; Cross, Frederick R.

    2009-01-01

    In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle. PMID:19841732

  16. Daughter-specific transcription factors regulate cell size control in budding yeast.

    Directory of Open Access Journals (Sweden)

    Stefano Di Talia

    2009-10-01

    Full Text Available In budding yeast, asymmetric cell division yields a larger mother and a smaller daughter cell, which transcribe different genes due to the daughter-specific transcription factors Ace2 and Ash1. Cell size control at the Start checkpoint has long been considered to be a main regulator of the length of the G1 phase of the cell cycle, resulting in longer G1 in the smaller daughter cells. Our recent data confirmed this concept using quantitative time-lapse microscopy. However, it has been proposed that daughter-specific, Ace2-dependent repression of expression of the G1 cyclin CLN3 had a dominant role in delaying daughters in G1. We wanted to reconcile these two divergent perspectives on the origin of long daughter G1 times. We quantified size control using single-cell time-lapse imaging of fluorescently labeled budding yeast, in the presence or absence of the daughter-specific transcriptional regulators Ace2 and Ash1. Ace2 and Ash1 are not required for efficient size control, but they shift the domain of efficient size control to larger cell size, thus increasing cell size requirement for Start in daughters. Microarray and chromatin immunoprecipitation experiments show that Ace2 and Ash1 are direct transcriptional regulators of the G1 cyclin gene CLN3. Quantification of cell size control in cells expressing titrated levels of Cln3 from ectopic promoters, and from cells with mutated Ace2 and Ash1 sites in the CLN3 promoter, showed that regulation of CLN3 expression by Ace2 and Ash1 can account for the differential regulation of Start in response to cell size in mothers and daughters. We show how daughter-specific transcriptional programs can interact with intrinsic cell size control to differentially regulate Start in mother and daughter cells. This work demonstrates mechanistically how asymmetric localization of cell fate determinants results in cell-type-specific regulation of the cell cycle.

  17. Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling

    Science.gov (United States)

    Serafimidis, Ioannis; Rodriguez-Aznar, Eva; Lesche, Mathias; Yoshioka, Kazuaki; Takuwa, Yoh; Dahl, Andreas; Pan, Duojia; Gavalas, Anthony

    2017-01-01

    During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata, and genomics, we found that sphingosine-1-phosphate (S1p), signalling through the G protein coupled receptor (GPCR) S1pr2, plays a key role in pancreas development linking lineage allocation and specification. S1pr2 signalling promotes progenitor survival as well as acinar and endocrine specification. S1pr2-mediated stabilisation of the yes-associated protein (YAP) is essential for endocrine specification, thus linking a regulator of progenitor growth with specification. YAP stabilisation and endocrine cell specification rely on Gαi subunits, revealing an unexpected specificity of selected GPCR intracellular signalling components. Finally, we found that S1pr2 signalling posttranscriptionally attenuates Notch signalling levels, thus regulating lineage allocation. Both S1pr2-mediated YAP stabilisation and Notch attenuation are necessary for the specification of the endocrine lineage. These findings identify S1p signalling as a novel key pathway coordinating cell survival, lineage allocation, and specification and linking these processes by regulating YAP levels and Notch signalling. Understanding lineage allocation and specification in the pancreas will shed light in the origins of pancreatic diseases and may suggest novel therapeutic approaches. PMID:28248965

  18. Does Preschool Self-Regulation Predict Later Behavior Problems in General or Specific Problem Behaviors?

    Science.gov (United States)

    Lonigan, Christopher J; Spiegel, Jamie A; Goodrich, J Marc; Morris, Brittany M; Osborne, Colleen M; Lerner, Matthew D; Phillips, Beth M

    2017-11-01

    Findings from prior research have consistently indicated significant associations between self-regulation and externalizing behaviors. Significant associations have also been reported between children's language skills and both externalizing behaviors and self-regulation. Few studies to date, however, have examined these relations longitudinally, simultaneously, or with respect to unique clusters of externalizing problems. The current study examined the influence of preschool self-regulation on general and specific externalizing behavior problems in early elementary school and whether these relations were independent of associations between language, self-regulation, and externalizing behaviors in a sample of 815 children (44% female). Additionally, given a general pattern of sex differences in the presentations of externalizing behavior problems, self-regulation, and language skills, sex differences for these associations were examined. Results indicated unique relations of preschool self-regulation and language with both general externalizing behavior problems and specific problems of inattention. In general, self-regulation was a stronger longitudinal correlate of externalizing behavior for boys than it was for girls, and language was a stronger longitudinal predictor of hyperactive/impulsive behavior for girls than it was for boys.

  19. Rasch Analysis of the Activities-specific Balance Confidence (ABC) Scale in Older Adults Seeking Outpatient Rehabilitation Services.

    Science.gov (United States)

    Wang, Ying-Chih; Sindhu, Bhagwant; Lehman, Leigh; Li, Xiaoyan; Yen, Sheng-Che; Kapellusch, Jay

    2018-03-30

    Study Design Cross-sectional study of 5,012 older patients seeking outpatient rehabilitation therapy in 123 clinics. Background The Activities-Specific Balance Confidence (ABC) Scale measures confidence in performing various ambulatory activities without falling or experiencing a sense of unsteadiness. Objectives Our purposes were to: (1) examine the ABC Scale (0-100) using the Rasch analysis, (2) assess statistically reliable change, and (3) develop a functional staging to guide clinical interpretation of the patient's improvement. Methods We examined rating scale structure, item difficulty hierarchy, item fit, person-item match, separation index, differential item functioning (DIF), test precision, and unidimensionality. Additionally, we estimated the minimal detectable change (MDC) and developed a functional staging. Results Item 'walking outside on icy sidewalks' was the most difficult item, while 'reach for a small can off a shelf at eye level' was the easiest item. Overall, average patient ability estimates of 56.2 (20.3) was slightly higher than the average item difficulty estimates of 45.9 (7.8). With a separation index equaled to 3.65, the ABC items can differentiate persons into 5.2 statistically distinct strata. Most ABC items were free of DIF. For example, 'walk outside on icy sidewalks' was easier for patients who was underweight. Results supported unidimensionality of the ABC Scale, with the first factor explained 77% of the total variance. The estimated MDC was 15 points. We provided an example of functional staging application. Conclusion Results supported sound psychometric properties and clinical usage of the ABC Scale for older adults seeking outpatient rehabilitation therapy. Level of Evidence 2c. J Orthop Sports Phys Ther, Epub 30 Mar 2018. doi:10.2519/jospt.2018.8023.

  20. Tissue-specific 5' heterogeneity of PPARα transcripts and their differential regulation by leptin.

    Directory of Open Access Journals (Sweden)

    Emma S Garratt

    Full Text Available The genes encoding nuclear receptors comprise multiple 5'untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1 and liver (P2 transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3-13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors.

  1. Tissue-Specific 5′ Heterogeneity of PPARα Transcripts and Their Differential Regulation by Leptin

    Science.gov (United States)

    Garratt, Emma S.; Vickers, Mark H.; Gluckman, Peter D.; Hanson, Mark A.

    2013-01-01

    The genes encoding nuclear receptors comprise multiple 5′untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3–13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors. PMID:23825665

  2. Internet-Specific Epistemic Beliefs and Self-Regulated Learning in Online Academic Information Searching

    Science.gov (United States)

    Chiu, Yen-Lin; Liang, Jyh-Chong; Tsai, Chin-Chung

    2013-01-01

    Epistemic beliefs have been considered as important components of the self-regulatory model; however, their relationships with self-regulated learning processes in the Internet context need further research. The main purpose of this study was to examine the relationships between Internet-specific epistemic belief dimensions and self-regulated…

  3. TCR down-regulation controls virus-specific CD8+ T cell responses

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte Menné; Haks, Mariëlle; Nielsen, Bodil

    2008-01-01

    in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic...

  4. Tissue Specific Roles of Dynein Light Chain 1 in Regulating Germ Cell Apoptosis in Ceanorhabditis elegans

    DEFF Research Database (Denmark)

    Morthorst, Tine Hørning

    2015-01-01

    in the etiology of many diseases, including cancer, neurodegenerative, cardiovascular and autoimmune diseases. Several of the first genes found to regulate apoptosis were discovered in the nematode Caenorhabditis elegans. In this project, two different and tissue specific roles of C. elegans dynein light chain 1...

  5. Identity-specific motivation: How distinct identities direct self-regulation across distinct situations.

    Science.gov (United States)

    Browman, Alexander S; Destin, Mesmin; Molden, Daniel C

    2017-12-01

    Research on self-regulation has traditionally emphasized that people's thoughts and actions are guided by either (a) domain-general motivations that emerge from a cumulative history of life experiences, or (b) situation-specific motivations that emerge in immediate response to the incentives present in a particular context. However, more recent studies have illustrated the importance of understanding the interplay between such domain-general and situation-specific motivations across the types of contexts people regularly encounter. The present research, therefore, expands existing perspectives on self-regulation by investigating how people's identities -the internalized roles, relationships, and social group memberships that define who they are-systemically guide when and how different domain-general motivations are activated within specific types of situations. Using the motivational framework described by regulatory focus theory (Higgins, 1997), Studies 1 and 2 demonstrate that people indeed have distinct, identity-specific motivations that uniquely influence their current self-regulation when such identities are active. Studies 3-5 then begin to explore how identity-specific motivations are situated within people's larger self-concept. Studies 3a and 3b demonstrate that the less compatible people's specific identities, the more distinct are the motivations connected to those identities. Studies 4-5 then provide some initial, suggestive evidence that identity-specific motivations are not a separate, superordinate feature of people's identities that then alter how they pursue any subordinate, identity-relevant traits, but instead that such motivations emerge from the cumulative motivational significance of the subordinate traits to which the identities themselves become attached. Implications for understanding the role of the self-concept in self-regulation are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  6. Is this back pain killing me? All-cause and cardiovascular-specific mortality in older Danish twins with spinal pain

    DEFF Research Database (Denmark)

    Fernandez, M; Boyle, E; Hartvigsen, J

    2017-01-01

    of all-cause and disease-specific cardiovascular mortality in older Danish twins aged ≥70 years. Data from 4391 participants collected at baseline were linked with the Danish Cause of Death Registry with the study ending on 31 December 2014. Two crude and adjusted Cox proportional hazards regression......-significant, although greater in magnitude for monozygotic twins. Conclusions: Older people reporting spinal pain have 13% increased risk of mortality per years lived but the connection is not causal. We found no association between spinal pain and cardiovascular-specific mortality. The influence of shared familial...... factors is unlikely. Significance: Older people reporting spinal pain have 13% increased risk of mortality per year lived. However, this association is not likely to be causal, with the relevant confounders contributing to this relationship. Thus, pain in the spine may be part of a pattern of poor health...

  7. Specific DNA-binding proteins and DNA sequences involved in steroid hormone regulation of gene expression

    International Nuclear Information System (INIS)

    Spelsberg, T.; Hora, J.; Horton, M.; Goldberger, A.; Littlefield, B.; Seelke, R.; Toyoda, H.

    1987-01-01

    Steroid hormones circulate in the blood and are taken by target cells via complexes with intracellular binding proteins termed receptors, that are hormone and tissue specific. Each receptor binds it specific steroid with very high affinity, having an equilibrium dissociation constant (K/sub d/) in the range of 10 -9 to 10 -10 M. Once bound by their specific steroid hormones, the steroid receptors undergo a conformational change which allows them to bind with high affinity to sites on chromatin, termed nuclear acceptor sites. There are estimated 5,000 to 10,000 of these sites expressed with an equal number not expressed (''masked'') in intact chromatin. The result of the binding to nuclear acceptor sites is an alteration of gene transcription or, in some cases, gene expression as measured by the changing levels of specific RNAs and proteins in that target tissue. Each steroid regulates specific effects on the RNA and protein profiles. The chronology of the above mechanism of action after injection of radiolabelled steroid as is follows: Steroid-receptor complex formation (1 minute), nuclear acceptor sites (2 minutes), effects on RNA synthesis (10 to 30 minutes), and finally the changing protein profiles via changes in protein synthesis and protein turnover (1 to 6 hours). Thus steroid receptors represent one of the first identified intracellular gene regulation proteins. The receptor molecules themselves are regulated by the presence or absence of the steroid molecule

  8. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    Science.gov (United States)

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

  9. Epigenetic regulation of normal human mammary cell type-specific miRNAs

    Energy Technology Data Exchange (ETDEWEB)

    Vrba, Lukas [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center; Inst. of Plant Molecular Biology, Ceske Budejovice (Czech Republic). Biology Centre ASCR; Garbe, James C. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Center; Stampfer, Martha R. [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Center; Futscher, Bernard W. [Univ. of Arizona, Tucson, AZ (United States). Arizona Cancer Center and Dept. of Pharmacology & Toxicology

    2011-08-26

    Epigenetic mechanisms are important regulators of cell type–specific genes, including miRNAs. In order to identify cell type-specific miRNAs regulated by epigenetic mechanisms, we undertook a global analysis of miRNA expression and epigenetic states in three isogenic pairs of human mammary epithelial cells (HMEC) and human mammary fibroblasts (HMF), which represent two differentiated cell types typically present within a given organ, each with a distinct phenotype and a distinct epigenotype. While miRNA expression and epigenetic states showed strong interindividual concordance within a given cell type, almost 10% of the expressed miRNA showed a cell type–specific pattern of expression that was linked to the epigenetic state of their promoter. The tissue-specific miRNA genes were epigenetically repressed in nonexpressing cells by DNA methylation (38%) and H3K27me3 (58%), with only a small set of miRNAs (21%) showing a dual epigenetic repression where both DNA methylation and H3K27me3 were present at their promoters, such as MIR10A and MIR10B. Individual miRNA clusters of closely related miRNA gene families can each display cell type–specific repression by the same or complementary epigenetic mechanisms, such as the MIR200 family, and MIR205, where fibroblasts repress MIR200C/141 by DNA methylation, MIR200A/200B/429 by H3K27me3, and MIR205 by both DNA methylation and H3K27me3. Since deregulation of many of the epigenetically regulated miRNAs that we identified have been linked to disease processes such as cancer, it is predicted that compromise of the epigenetic control mechanisms is important for this process. Overall, these results highlight the importance of epigenetic regulation in the control of normal cell type–specific miRNA expression.

  10. Specification of Drosophila corpora cardiaca neuroendocrine cells from mesoderm is regulated by Notch signaling.

    Directory of Open Access Journals (Sweden)

    Sangbin Park

    2011-08-01

    Full Text Available Drosophila neuroendocrine cells comprising the corpora cardiaca (CC are essential for systemic glucose regulation and represent functional orthologues of vertebrate pancreatic α-cells. Although Drosophila CC cells have been regarded as developmental orthologues of pituitary gland, the genetic regulation of CC development is poorly understood. From a genetic screen, we identified multiple novel regulators of CC development, including Notch signaling factors. Our studies demonstrate that the disruption of Notch signaling can lead to the expansion of CC cells. Live imaging demonstrates localized emergence of extra precursor cells as the basis of CC expansion in Notch mutants. Contrary to a recent report, we unexpectedly found that CC cells originate from head mesoderm. We show that Tinman expression in head mesoderm is regulated by Notch signaling and that the combination of Daughterless and Tinman is sufficient for ectopic CC specification in mesoderm. Understanding the cellular, genetic, signaling, and transcriptional basis of CC cell specification and expansion should accelerate discovery of molecular mechanisms regulating ontogeny of organs that control metabolism.

  11. AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes.

    Science.gov (United States)

    Young, Nathan P; Kamireddy, Anwesh; Van Nostrand, Jeanine L; Eichner, Lillian J; Shokhirev, Maxim Nikolaievich; Dayn, Yelena; Shaw, Reuben J

    2016-03-01

    Faithful execution of developmental programs relies on the acquisition of unique cell identities from pluripotent progenitors, a process governed by combinatorial inputs from numerous signaling cascades that ultimately dictate lineage-specific transcriptional outputs. Despite growing evidence that metabolism is integrated with many molecular networks, how pathways that control energy homeostasis may affect cell fate decisions is largely unknown. Here, we show that AMP-activated protein kinase (AMPK), a central metabolic regulator, plays critical roles in lineage specification. Although AMPK-deficient embryonic stem cells (ESCs) were normal in the pluripotent state, these cells displayed profound defects upon differentiation, failing to generate chimeric embryos and preferentially adopting an ectodermal fate at the expense of the endoderm during embryoid body (EB) formation. AMPK(-/-) EBs exhibited reduced levels of Tfeb, a master transcriptional regulator of lysosomes, leading to diminished endolysosomal function. Remarkably, genetic loss of Tfeb also yielded endodermal defects, while AMPK-null ESCs overexpressing this transcription factor normalized their differential potential, revealing an intimate connection between Tfeb/lysosomes and germ layer specification. The compromised endolysosomal system resulting from AMPK or Tfeb inactivation blunted Wnt signaling, while up-regulating this pathway restored expression of endodermal markers. Collectively, these results uncover the AMPK pathway as a novel regulator of cell fate determination during differentiation. © 2016 Young et al.; Published by Cold Spring Harbor Laboratory Press.

  12. Specific microRNAs Regulate Heat Stress Responses in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Nehammer, Camilla; Podolska, Agnieszka; Mackowiak, Sebastian D

    2015-01-01

    have identified additional functions for already known players (mir-71 and mir-239) as well as identifying mir-80 and the mir-229 mir-64-66 cluster as important regulators of the heat stress response in C. elegans. These findings uncover an additional layer of complexity to the regulation of stress...... to heat stress in Caenorhabditis elegans and show that a discrete subset of miRNAs is thermoregulated. Using in-depth phenotypic analyses of miRNA deletion mutant strains we reveal multiple developmental and post-developmental survival and behavioral functions for specific miRNAs during heat stress. We...

  13. Short-Term Changes in General and Memory-Specific Control Beliefs and Their Relationship to Cognition in Younger and Older Adults

    Science.gov (United States)

    Bielak, Allison A. M.; Hultsch, David F.; Levy-Ajzenkopf, Judi; MacDonald, Stuart W. S.; Hunter, Michael A.; Strauss, Esther

    2007-01-01

    We examined short-term changes in younger and older adults' control beliefs. Participants completed measures of general and memory-specific competence and locus of control on 10 bi-monthly occasions. At each occasion, participants rated their control beliefs prior to and following completion of a battery of cognitive tasks. Exposure to the set of…

  14. Differential regulation of the transcriptional activity of the glucocorticoid receptor through site-specific phosphorylation

    Directory of Open Access Journals (Sweden)

    Raj Kumar

    2008-08-01

    Full Text Available Raj Kumar1, William J Calhoun21Division of Gastroenterology; 2Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep (APICS, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USAAbstract: Post-translational modifications such as phosphorylation are known to play an important role in the gene regulation by the transcription factors including the nuclear hormone receptor superfamily of which the glucocorticoid receptor (GR is a member. Protein phosphorylation often switches cellular activity from one state to another. Like many other transcription factors, the GR is a phosphoprotein, and phosphorylation plays an important role in the regulation of GR activity. Cell signaling pathways that regulate phosphorylation of the GR and its associated proteins are important determinants of GR function under various physiological conditions. While the role of many phosphorylation sites in the GR is still not fully understood, the role of others is clearer. Several aspects of transcription factor function, including DNA binding affinity, interaction of transactivation domains with the transcription initiation complex, and shuttling between the cytoplasmic compartments, have all been linked to site-specific phosphorylation. All major phosphorylation sites in the human GR are located in the N-terminal domain including the major transactivation domain, AF1. Available literature clearly indicates that many of these potential phosphorylation sites are substrates for multiple kinases, suggesting the potential for a very complex regulatory network. Phosphorylated GR interacts favorably with critical coregulatory proteins and subsequently enhances transcriptional activity. In addition, the activities and specificities of coregulators may be subject to similar regulation by phosphorylation. Regulation of the GR activity due to phosphorylation appears to be site-specific and dependent upon specific cell signaling cascade

  15. Annual overview report on the regulation of designated centres for older people - 2013

    LENUS (Irish Health Repository)

    Jones, Kelsey D J

    2015-01-01

    Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children\\'s PUFA status during treatment of severe acute malnutrition.

  16. Regulated expression of the neural cell adhesion molecule L1 by specific patterns of neural impulses.

    Science.gov (United States)

    Itoh, K; Stevens, B; Schachner, M; Fields, R D

    1995-11-24

    Development of the mammalian nervous system is regulated by neural impulse activity, but the molecular mechanisms are not well understood. If cell recognition molecules [for example, L1 and the neural cell adhesion molecule (NCAM)] were influenced by specific patterns of impulse activity, cell-cell interactions controlling nervous system structure could be regulated by nervous system function at critical stages of development. Low-frequency electrical pulses delivered to mouse sensory neurons in culture (0.1 hertz for 5 days) down-regulated expression of L1 messenger RNA and protein (but not NCAM). Fasciculation of neurites, adhesion of neuroblastoma cells, and the number of Schwann cells on neurites was reduced after 0.1-hertz stimulation, but higher frequencies or stimulation after synaptogenesis were without effect.

  17. Emergence of differentially regulated pathways associated with the development of regional specificity in chicken skin.

    Science.gov (United States)

    Chang, Kai-Wei; Huang, Nancy A; Liu, I-Hsuan; Wang, Yi-Hui; Wu, Ping; Tseng, Yen-Tzu; Hughes, Michael W; Jiang, Ting Xin; Tsai, Mong-Hsun; Chen, Chien-Yu; Oyang, Yen-Jen; Lin, En-Chung; Chuong, Cheng-Ming; Lin, Shau-Ping

    2015-01-23

    Regional specificity allows different skin regions to exhibit different characteristics, enabling complementary functions to make effective use of the integumentary surface. Chickens exhibit a high degree of regional specificity in the skin and can serve as a good model for when and how these regional differences begin to emerge. We used developing feather and scale regions in embryonic chickens as a model to gauge the differences in their molecular pathways. We employed cosine similarity analysis to identify the differentially regulated and co-regulated genes. We applied low cell techniques for expression validation and chromatin immunoprecipitation (ChIP)-based enhancer identification to overcome limited cell availabilities from embryonic chicken skin. We identified a specific set of genes demonstrating a high correlation as being differentially expressed during feather and scale development and maturation. Some members of the WNT, TGF-beta/BMP, and Notch family known to be involved in feathering skin differentiation were found to be differentially regulated. Interestingly, we also found genes along calcium channel pathways that are differentially regulated. From the analysis of differentially regulated pathways, we used calcium signaling pathways as an example for further verification. Some voltage-gated calcium channel subunits, particularly CACNA1D, are expressed spatio-temporally in the skin epithelium. These calcium signaling pathway members may be involved in developmental decisions, morphogenesis, or epithelial maturation. We further characterized enhancers associated with histone modifications, including H3K4me1, H3K27ac, and H3K27me3, near calcium channel-related genes and identified signature intensive hotspots that may be correlated with certain voltage-gated calcium channel genes. We demonstrated the applicability of cosine similarity analysis for identifying novel regulatory pathways that are differentially regulated during development. Our study

  18. LARP6 Meets Collagen mRNA: Specific Regulation of Type I Collagen Expression

    Directory of Open Access Journals (Sweden)

    Yujie Zhang

    2016-03-01

    Full Text Available Type I collagen is the most abundant structural protein in all vertebrates, but its constitutive rate of synthesis is low due to long half-life of the protein (60–70 days. However, several hundred fold increased production of type I collagen is often seen in reparative or reactive fibrosis. The mechanism which is responsible for this dramatic upregulation is complex, including multiple levels of regulation. However, posttranscriptional regulation evidently plays a predominant role. Posttranscriptional regulation comprises processing, transport, stabilization and translation of mRNAs and is executed by RNA binding proteins. There are about 800 RNA binding proteins, but only one, La ribonucleoprotein domain family member 6 (LARP6, is specifically involved in type I collagen regulation. In the 5′untranslated region (5’UTR of mRNAs encoding for type I and type III collagens there is an evolutionally conserved stem-loop (SL structure; this structure is not found in any other mRNA, including any other collagen mRNA. LARP6 binds to the 5′SL in sequence specific manner to regulate stability of collagen mRNAs and their translatability. Here, we will review current understanding of how is LARP6 involved in posttranscriptional regulation of collagen mRNAs. We will also discuss how other proteins recruited by LARP6, including nonmuscle myosin, vimentin, serine threonine kinase receptor associated protein (STRAP, 25 kD FK506 binding protein (FKBP25 and RNA helicase A (RHA, contribute to this process.

  19. Tissue-specific regulation of BMP signaling by Drosophila N-glycanase 1.

    Science.gov (United States)

    Galeone, Antonio; Han, Seung Yeop; Huang, Chengcheng; Hosomi, Akira; Suzuki, Tadashi; Jafar-Nejad, Hamed

    2017-08-04

    Mutations in the human N- glycanase 1 ( NGLY1 ) cause a rare, multisystem congenital disorder with global developmental delay. However, the mechanisms by which NGLY1 and its homologs regulate embryonic development are not known. Here we show that Drosophila Pngl encodes an N -glycanase and exhibits a high degree of functional conservation with human NGLY1. Loss of Pngl results in developmental midgut defects reminiscent of midgut-specific loss of BMP signaling. Pngl mutant larvae also exhibit a severe midgut clearance defect, which cannot be fully explained by impaired BMP signaling. Genetic experiments indicate that Pngl is primarily required in the mesoderm during Drosophila development. Loss of Pngl results in a severe decrease in the level of Dpp homodimers and abolishes BMP autoregulation in the visceral mesoderm mediated by Dpp and Tkv homodimers. Thus, our studies uncover a novel mechanism for the tissue-specific regulation of an evolutionarily conserved signaling pathway by an N -glycanase enzyme.

  20. Regulation and specificity of antifungal metapleural gland secretion in leaf-cutting ants

    DEFF Research Database (Denmark)

    Yek, Sze Huei; Nash, David Richard; Jensen, Annette Bruun

    2012-01-01

    significantly larger for ants challenged with virulent and mild pathogens/weeds than for controls and Escovopsis-challenged ants. We conclude that the MG defence system of leaf-cutting ants has characteristics reminiscent of an additional cuticular immune system, with specific and non-specific components......Ants have paired metapleural glands (MGs) to produce secretions for prophylactic hygiene. These exocrine glands are particularly well developed in leaf-cutting ants, but whether the ants can actively regulate MG secretion is unknown. In a set of controlled experiments using conidia of five fungi...

  1. Gender-specific hip fracture risk in community-dwelling and institutionalized seniors age 65 years and older.

    Science.gov (United States)

    Finsterwald, M; Sidelnikov, E; Orav, E J; Dawson-Hughes, B; Theiler, R; Egli, A; Platz, A; Simmen, H P; Meier, C; Grob, D; Beck, S; Stähelin, H B; Bischoff-Ferrari, H A

    2014-01-01

    In this study of acute hip fracture patients, we show that hip fracture rates differ by gender between community-dwelling seniors and seniors residing in nursing homes. While women have a significantly higher rate of hip fracture among the community-dwelling seniors, men have a significantly higher rate among nursing home residents. Differences in gender-specific hip fracture risk between community-dwelling and institutionalized seniors have not been well established, and seasonality of hip fracture risk has been controversial. We analyzed detailed data from 1,084 hip fracture patients age 65 years and older admitted to one large hospital center in Zurich, Switzerland. In a sensitivity analysis, we extend to de-personalized data from 1,265 hip fracture patients from the other two large hospital centers in Zurich within the same time frame (total n = 2,349). The denominators were person-times accumulated by the Zurich population in the corresponding age/gender/type of dwelling stratum in each calendar season for the period of the study. In the primary analysis of 1,084 hip fracture patients (mean age 85.1 years; 78% women): Among community-dwelling seniors, the risk of hip fracture was twofold higher among women compared with men (RR = 2.16; 95% CI, 1.74-2.69) independent of age, season, number of comorbidities, and cognitive function; among institutionalized seniors, the risk of hip fracture was 26% lower among women compared with men (RR = 0.77; 95% CI: 0.63-0.95) adjusting for the same confounders. In the sensitivity analysis of 2,349 hip fracture patients (mean age 85.0 years, 76% women), this pattern remained largely unchanged. There is no seasonal swing in hip fracture incidence. We confirm for seniors living in the community that women have a higher risk of hip fracture than men. However, among institutionalized seniors, men are at higher risk for hip fracture.

  2. Overview of OVATE FAMILY PROTEINS, a novel class of plant-specific growth regulators

    Directory of Open Access Journals (Sweden)

    Shucai eWang

    2016-03-01

    Full Text Available OVATE FAMILY PROTEINS (OFPs are a class of proteins with a conserved OVATE domain. OVATE protein was first identified in tomato as a key regulator of fruit shape. OFPs are plant-specific proteins that are widely distributed in the plant kingdom including mosses and lycophytes. Transcriptional activity analysis of Arabidopsis OFPs (AtOFPs in protoplasts suggests that they act as transcription repressors. Functional characterization of OFPs from different plant species including Arabidopsis, rice, tomato, pepper and banana suggests that OFPs regulate multiple aspects of plant growth and development, which is likely achieved by interacting with different types of transcription factors including the KNOX and BELL classes, and/or directly regulating the expression of target genes such as Gibberellin 20 oxidase (GA20ox. Here, we examine how OVATE was originally identified, summarize recent progress in elucidation of the roles of OFPs in regulating plant growth and development, and describe possible mechanisms underpinning this regulation. Finally, we review potential new research directions that could shed additional light on the functional biology of OFPs in plants.

  3. TCR Down-Regulation Controls Virus-Specific CD8+ T Cell Responses

    DEFF Research Database (Denmark)

    Bonefeld, Charlotte Menné; Haks, Mariëlle; Nielsen, Bodil

    2008-01-01

    The CD3gamma di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3gamma di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8(+) T cells is impaired...... in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic...... molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8(+) T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3gamma-mediated TCR down-regulation in virus...

  4. High-Throughput Screening to Identify Regulators of Meiosis-Specific Gene Expression in Saccharomyces cerevisiae.

    Science.gov (United States)

    Kassir, Yona

    2017-01-01

    Meiosis and gamete formation are processes that are essential for sexual reproduction in all eukaryotic organisms. Multiple intracellular and extracellular signals feed into pathways that converge on transcription factors that induce the expression of meiosis-specific genes. Once triggered the meiosis-specific gene expression program proceeds in a cascade that drives progress through the events of meiosis and gamete formation. Meiosis-specific gene expression is tightly controlled by a balance of positive and negative regulatory factors that respond to a plethora of signaling pathways. The budding yeast Saccharomyces cerevisiae has proven to be an outstanding model for the dissection of gametogenesis owing to the sophisticated genetic manipulations that can be performed with the cells. It is possible to use a variety selection and screening methods to identify genes and their functions. High-throughput screening technology has been developed to allow an array of all viable yeast gene deletion mutants to be screened for phenotypes and for regulators of gene expression. This chapter describes a protocol that has been used to screen a library of homozygous diploid yeast deletion strains to identify regulators of the meiosis-specific IME1 gene.

  5. PHF6 regulates phenotypic plasticity through chromatin organization within lineage-specific genes.

    Science.gov (United States)

    Soto-Feliciano, Yadira M; Bartlebaugh, Jordan M E; Liu, Yunpeng; Sánchez-Rivera, Francisco J; Bhutkar, Arjun; Weintraub, Abraham S; Buenrostro, Jason D; Cheng, Christine S; Regev, Aviv; Jacks, Tyler E; Young, Richard A; Hemann, Michael T

    2017-05-15

    Developmental and lineage plasticity have been observed in numerous malignancies and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the plant homeodomain finger protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B-cell- and T-cell-specific factors. Additionally, Phf6 KO cells show significant down-regulation of genes involved in the development and function of normal B cells, show up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition. © 2017 Soto-Feliciano et al.; Published by Cold Spring Harbor Laboratory Press.

  6. Regulating expressin of cell and tissue-specific genes by modifying transcription

    Energy Technology Data Exchange (ETDEWEB)

    Beachy, Roger N. [Donald Danforth Plant Science Center, St. Louis, MO (United States); Dai, Shunhong [Donald Danforth Plant Science Center, St. Louis, MO (United States)

    2009-12-15

    Transcriptional regulation is the primary step to control gene expression, therefore function. Such regulation is achieved primarily via a combination of the activities of the promoter cis regulatory DNA elements and trans regulatory proteins that function through binding to these DNA elements. Our research supported by this program has led to the identification of rice bZIP transcription factors RF2a, RF2b and RLP1 that play key roles in regulating the activity of a vascular tissue specific promoter isolated from Rice Tungro Bacilliform Virus (RTBV) through their interactions with the Box II essential cis element located in the promoter. RF2a, RF2b and RLP1 possess multiple regulatory domains. Functional characterization reveals that those domains can activate or repress the activity of the RTBV promoter. Studies of transcriptional regulation of the RTBV promoter by this group of bZIP proteins not only provide insights about gene expression in the vascular tissue, but also insights about general mechanisms of transcription activation and repression. The knowledge gained from this research will also enable us to develop a well-described set of tools that can be used to control expression of multiple genes in transgenic plants and to improve biofuel feedstock.

  7. The Candida albicans-specific gene EED1 encodes a key regulator of hyphal extension.

    LENUS (Irish Health Repository)

    Martin, Ronny

    2011-04-01

    The extension of germ tubes into elongated hyphae by Candida albicans is essential for damage of host cells. The C. albicans-specific gene EED1 plays a crucial role in this extension and maintenance of filamentous growth. eed1Δ cells failed to extend germ tubes into long filaments and switched back to yeast growth after 3 h of incubation during growth on plastic surfaces. Expression of EED1 is regulated by the transcription factor Efg1 and ectopic overexpression of EED1 restored filamentation in efg1Δ. Transcriptional profiling of eed1Δ during infection of oral tissue revealed down-regulation of hyphal associated genes including UME6, encoding another key transcriptional factor. Ectopic overexpression of EED1 or UME6 rescued filamentation and damage potential in eed1Δ. Transcriptional profiling during overexpression of UME6 identified subsets of genes regulated by Eed1 or Ume6. These data suggest that Eed1 and Ume6 act in a pathway regulating maintenance of hyphal growth thereby repressing hyphal-to-yeast transition and permitting dissemination of C. albicans within epithelial tissues.

  8. Development of a situation-specific theory for explaining health-related quality of life among older South Korean adults with type 2 diabetes.

    Science.gov (United States)

    Chang, Sun Ju; Im, Eun-Ok

    2014-01-01

    The purpose of the study was to develop a situation-specific theory for explaining health-related quality of life (QOL) among older South Korean adults with type 2 diabetes. To develop a situation-specific theory, three sources were considered: (a) the conceptual model of health promotion and QOL for people with chronic and disabling conditions (an existing theory related to the QOL in patients with chronic diseases); (b) a literature review using multiple databases including Cumulative Index for Nursing and Allied Health Literature (CINAHL), PubMed, PsycINFO, and two Korean databases; and (c) findings from our structural equation modeling study on health-related QOL in older South Korean adults with type 2 diabetes. The proposed situation-specific theory is constructed with six major concepts including barriers, resources, perceptual factors, psychosocial factors, health-promoting behaviors, and health-related QOL. The theory also provides the interrelationships among concepts. Health care providers and nurses could incorporate the proposed situation-specific theory into development of diabetes education programs for improving health-related QOL in older South Korean adults with type 2 diabetes.

  9. Regulating specific organic substances and heavy metals in industrial wastewater discharged to municipal wastewater treatment plants

    DEFF Research Database (Denmark)

    Grüttner, Henrik; Munk, L.; Pedersen, F.

    1994-01-01

    Due to the extension of wastewater treatment plants to nutrient removal and the development towards reuse of sludge m agriculture, new guidelines for regulating industrial discharges m Denmark were needed. The paper describes how a concept for regulating the discharge of specific organic substances...... substances, present knowledge of fate and effects in biological treatment plants is too scarce to underpin the setting of general standards. Therefore, it has been decided to base the developed priority system on the data used in the EEC-system for classification of hazardous chemicals. This includes ready...... degradability, defined by the OECD-test, bio-sorption and bio-accumulation, defined by the octanol/water distribution coefficient and toxic effects on water organisms. Several potential effects of seven heavy metals have been evaluated, and the most critical effects were found to be the quality criteria...

  10. Allele-specific physical interactions regulate the heterotic traits in hybrids of Arabidopsis thaliana ecotypes

    Directory of Open Access Journals (Sweden)

    Babita Singh

    2017-10-01

    Full Text Available Heterosis is an important phenomenon for the breeding in agricultural crops as it influences yield related traits such as biomass yield, seed number and weight, adaptive and reproductive traits. However, the level of heterosis greatly varies for different traits and different genotypes. The present study focuses on identification of physical interactions between alleles and their role in transcriptional regulation in heterotic plants. Here, we used two Arabidopsis ecotypes; Col-0 and C24 as parent for crosses. We performed crossing between these ecotypes and screened the F1 hybrids on the basis of different SSR markers. Further, we used Hi-C to capture intra- and inter-chromosomal physical interactions between alleles on genome-wide level. Then, we identified allele-specific chromatin interactions and constructed genome-wide allele-specific contact maps at different resolutions for the entire chromosome. We also performed RNA-seq of hybrids and their parents. RNA-seq analysis identified several differentially expressed genes and non-additively expressed genes in hybrids with respect to their parents. Further, to understand the biological significance of these chromatin interactions, we annotated these interactions and correlated with the transcriptome data. Thus, our study provides alleles-specific chromatin interactions in genome-wide fashion which play a crucial role in regulation of different genes that may be important for heterosis.

  11. Plasticity during Sleep Is Linked to Specific Regulation of Cortical Circuit Activity

    Directory of Open Access Journals (Sweden)

    Niels Niethard

    2017-09-01

    Full Text Available Sleep is thought to be involved in the regulation of synaptic plasticity in two ways: by enhancing local plastic processes underlying the consolidation of specific memories and by supporting global synaptic homeostasis. Here, we briefly summarize recent structural and functional studies examining sleep-associated changes in synaptic morphology and neural excitability. These studies point to a global down-scaling of synaptic strength across sleep while a subset of synapses increases in strength. Similarly, neuronal excitability on average decreases across sleep, whereas subsets of neurons increase firing rates across sleep. Whether synapse formation and excitability is down or upregulated across sleep appears to partly depend on the cell’s activity level during wakefulness. Processes of memory-specific upregulation of synapse formation and excitability are observed during slow wave sleep (SWS, whereas global downregulation resulting in elimination of synapses and decreased neural firing is linked to rapid eye movement sleep (REM sleep. Studies of the excitation/inhibition balance in cortical circuits suggest that both processes are connected to a specific inhibitory regulation of cortical principal neurons, characterized by an enhanced perisomatic inhibition via parvalbumin positive (PV+ cells, together with a release from dendritic inhibition by somatostatin positive (SOM+ cells. Such shift towards increased perisomatic inhibition of principal cells appears to be a general motif which underlies the plastic synaptic changes observed during sleep, regardless of whether towards up or downregulation.

  12. Specificity of the E. coli LysR-type transcriptional regulators.

    Directory of Open Access Journals (Sweden)

    Gwendowlyn S Knapp

    2010-12-01

    Full Text Available Families of paralogous oligomeric proteins are common in biology. How the specificity of assembly evolves is a fundamental question of biology. The LysR-Type Transcriptional Regulators (LTTR form perhaps the largest family of transcriptional regulators in bacteria. Because genomes often encode many LTTR family members, it is assumed that many distinct homooligomers are formed simultaneously in the same cell without interfering with each other's activities, suggesting specificity in the interactions. However, this assumption has not been systematically tested.A negative-dominant assay with λcI repressor fusions was used to evaluate the assembly of the LTTRs in E. coli K-12. Thioredoxin (Trx-LTTR fusions were used to challenge the homooligomeric interactions of λcI-LTTR fusions. Eight cI-LTTR fusions were challenged with twenty-eight Trx fusions. LTTRs could be divided into three classes based on their interactions with other LTTRs.Multimerization of LTTRs in E. coli K-12 is mostly specific. However, under the conditions of the assay, many LTTRs interact with more than one noncognate partner. The physiological significance and physical basis for these interactions are not known.

  13. Human muscle fibre type-specific regulation of AMPK and downstream targets by exercise

    DEFF Research Database (Denmark)

    Kristensen, Dorte Enggaard; Albers, Peter Hjorth; Prats, Clara

    2015-01-01

    are expressed in a fibre type-dependent manner and that fibre type-specific activation of AMPK and downstream targets is dependent on exercise intensity. Pools of type I and II fibres were prepared from biopsies of m. vastus lateralis from healthy men before and after two exercise trials; A) continuous cycling......AMP-activated protein kinase (AMPK) is a regulator of energy homeostasis during exercise. Studies suggest muscle fibre type-specific AMPK expression. However, fibre type-specific regulation of AMPK and downstream targets during exercise has not been proven. We hypothesized that AMPK subunits...... (CON) 30 min at 69 ± 1% VO2peak or B) interval cycling (INT) 30 min with 6 × 1.5 min high-intense bouts peaking at 95 ± 2% VO2peak . In type I vs. II fibres a higher β1 AMPK (+215%) and lower γ3 AMPK expression (-71%) was found. α1 , α2 , β2 and γ1 AMPK expression was similar between fibre types...

  14. High-Intensity Progressive Resistance Training Increases Strength With No Change in Cardiovascular Function and Autonomic Neural Regulation in Older Adults.

    Science.gov (United States)

    Kanegusuku, Hélcio; Queiroz, Andréia C; Silva, Valdo J; de Mello, Marco T; Ugrinowitsch, Carlos; Forjaz, Cláudia L

    2015-07-01

    The effects of high-intensity progressive resistance training (HIPRT) on cardiovascular function and autonomic neural regulation in older adults are unclear. To investigate this issue, 25 older adults were randomly divided into two groups: control (CON, N = 13, 63 ± 4 years; no training) and HIPRT (N = 12, 64 ± 4 years; 2 sessions/week, 7 exercises, 2–4 sets, 10–4 RM). Before and after four months, maximal strength, quadriceps cross-sectional area (QCSA), clinic and ambulatory blood pressures (BP), systemic hemodynamics, and cardiovascular autonomic modulation were measured. Maximal strength and QCSA increased in the HIPRT group and did not change in the CON group. Clinic and ambulatory BP, cardiac output, systemic vascular resistance, stroke volume, heart rate, and cardiac sympathovagal balance did not change in the HIPRT group or the CON group. In conclusion, HIPRT was effective at increasing muscle mass and strength without promoting changes in cardiovascular function or autonomic neural regulation.

  15. Tetracycline-inducible system for regulation of skeletal muscle-specific gene expression in transgenic mice

    Science.gov (United States)

    Grill, Mischala A.; Bales, Mark A.; Fought, Amber N.; Rosburg, Kristopher C.; Munger, Stephanie J.; Antin, Parker B.

    2003-01-01

    Tightly regulated control of over-expression is often necessary to study one aspect or time point of gene function and, in transgenesis, may help to avoid lethal effects and complications caused by ubiquitous over-expression. We have utilized the benefits of an optimized tet-on system and a modified muscle creatine kinase (MCK) promoter to generate a skeletal muscle-specific, doxycycline (Dox) controlled over-expression system in transgenic mice. A DNA construct was generated in which the codon optimized reverse tetracycline transactivator (rtTA) was placed under control of a skeletal muscle-specific version of the mouse MCK promoter. Transgenic mice containing this construct expressed rtTA almost exclusively in skeletal muscles. These mice were crossed to a second transgenic line containing a bi-directional promoter centered on a tet responder element driving both a luciferase reporter gene and a tagged gene of interest; in this case the calpain inhibitor calpastatin. Compound hemizygous mice showed high level, Dox dependent muscle-specific luciferase activity often exceeding 10,000-fold over non-muscle tissues of the same mouse. Western and immunocytochemical analysis demonstrated similar Dox dependent muscle-specific induction of the tagged calpastatin protein. These findings demonstrate the effectiveness and flexibility of the tet-on system to provide a tightly regulated over-expression system in adult skeletal muscle. The MCKrtTA transgenic lines can be combined with other transgenic responder lines for skeletal muscle-specific over-expression of any target gene of interest.

  16. Arabidopsis phosphoinositide-specific phospholipase C 4 negatively regulates seedling salt tolerance.

    Science.gov (United States)

    Xia, Keke; Wang, Bo; Zhang, Jiewei; Li, Yuan; Yang, Hailian; Ren, Dongtao

    2017-08-01

    Previous physiological and pharmacological studies have suggested that the activity of phosphoinositide-specific phospholipase C (PI-PLC) plays an important role in regulating plant salt stress responses by altering the intracellular Ca 2+ concentration. However, the individual members of plant PLCs involved in this process need to be identified. Here, the function of AtPLC4 in the salt stress response of Arabidopsis seedlings was analysed. plc4 mutant seedlings showed hyposensitivity to salt stress compared with Col-0 wild-type seedlings, and the salt hyposensitive phenotype could be complemented by the expression of native promoter-controlled AtPLC4. Transgenic seedlings with AtPLC4 overexpression (AtPLC4 OE) exhibited a salt-hypersensitive phenotype, while transgenic seedlings with its inactive mutant expression (AtPLC4m OE) did not exhibit this phenotype. Using aequorin as a Ca 2+ indicator in plc4 mutant and AtPLC4 OE seedlings, AtPLC4 was shown to positively regulate the salt-induced Ca 2+ increase. The salt-hypersensitive phenotype of AtPLC4 OE seedlings was partially rescued by EGTA. An analysis of salt-responsive genes revealed that the transcription of RD29B, MYB15 and ZAT10 was inversely regulated in plc4 mutant and AtPLC4 OE seedlings. Our findings suggest that AtPLC4 negatively regulates the salt tolerance of Arabidopsis seedlings, and Ca 2+ may be involved in regulating this process. © 2017 John Wiley & Sons Ltd.

  17. Ehd4 encodes a novel and Oryza-genus-specific regulator of photoperiodic flowering in rice.

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    He Gao

    Full Text Available Land plants have evolved increasingly complex regulatory modes of their flowering time (or heading date in crops. Rice (Oryza sativa L. is a short-day plant that flowers more rapidly in short-day but delays under long-day conditions. Previous studies have shown that the CO-FT module initially identified in long-day plants (Arabidopsis is evolutionary conserved in short-day plants (Hd1-Hd3a in rice. However, in rice, there is a unique Ehd1-dependent flowering pathway that is Hd1-independent. Here, we report isolation and characterization of a positive regulator of Ehd1, Early heading date 4 (Ehd4. ehd4 mutants showed a never flowering phenotype under natural long-day conditions. Map-based cloning revealed that Ehd4 encodes a novel CCCH-type zinc finger protein, which is localized to the nucleus and is able to bind to nucleic acids in vitro and transactivate transcription in yeast, suggesting that it likely functions as a transcriptional regulator. Ehd4 expression is most active in young leaves with a diurnal expression pattern similar to that of Ehd1 under both short-day and long-day conditions. We show that Ehd4 up-regulates the expression of the "florigen" genes Hd3a and RFT1 through Ehd1, but it acts independently of other known Ehd1 regulators. Strikingly, Ehd4 is highly conserved in the Oryza genus including wild and cultivated rice, but has no homologs in other species, suggesting that Ehd4 is originated along with the diversification of the Oryza genus from the grass family during evolution. We conclude that Ehd4 is a novel Oryza-genus-specific regulator of Ehd1, and it plays an essential role in photoperiodic control of flowering time in rice.

  18. Gender-Specific Associations of Serum Insulin-Like Growth Factor-1 With Bone Health and Fractures in Older Persons

    NARCIS (Netherlands)

    van Varsseveld, N.C.; Sohl, E.; Drent, M.L.; Lips, P.

    2015-01-01

    Context: IGF-1 plays a role in bone metabolism. Although IGF-1 and bone mass both decrease with advancing age, their relationship in older individuals remains to be elucidated. Objective: The objective was to investigate associations of serum IGF-1 cross-sectionally with quantitative ultrasound and

  19. Specific character of sustainable innovative development of transport construction in self-regulation conditions

    Science.gov (United States)

    Gumba, Khuta; Belyaeva, Svetlana

    2017-10-01

    The providing of sustainable development is impossible without activating the innovative activity of backbone economical sectors, in particular of transport construction. The system of self-regulation of activities is a specific feature of the transport industry development. The authors carried out the correlation analysis of innovative activity of construction enterprises, which proved the necessity of improving the normative and technical documents. The authors proposed and calculated the index of the legislation stability in the industry. The article suggests recommendations on the activation of innovative development in construction industry basing on the results of the modeling.

  20. Psychometric Properties of Persian Translated Version of Activities-specific Balance Confidence Scale (ABC in Arak Community-dwelling Older Adults

    Directory of Open Access Journals (Sweden)

    Daryoush Khajavi

    2017-11-01

    Full Text Available Abstract Background: Balance deficiency, falls and fear of fall are important problems that can resulted in reversed health outcomes including decreased quality of life. The purpose of this study was surveying factor structure, validation, and reliability determination of Persian translated version of Activities-specific Balance Confidence scale in community-dwelling older adults of Arak city. Materials and Methods: Research method was descriptive in form of psychometry. The statistic population was older adults of Arak in year 2012 and 308 subjects with mean age 69.38 years were selected availably. Data were collected by Persian translated version of Activities-specific Balance Confidence that is a 16-item scale and evaluates balance confidence in activities of daily living. Data were analyzed by Exploratory Factor Analysis. Test-retest and internal reliability were calculated by Pearson correlation coefficient and Chronbach’s Alpha. Data were analyzed with SPSS-16. Results: The findings resulted in extraction of one factor with eigenvalue over one that explained 82.89% of total variance. Test-retest reliability between 1 to 4 weeks and internal reliability (Chronbach’s alpha were 0.82 and 0.98, respectively. Gutmann split-half correlation coefficient and intra-class correlation coefficient were calculated 95% and 85%, respectively. Conclusion: Persian translated version of Activities-specific Balance Confidence (ABC-F is a valid and reliable tool for Iranian community-dwelling older adults that can be used in clinical and research purpose.

  1. The influence of age-related health difficulties and attitudes toward driving on driving self-regulation in the baby boomer and older adult generations.

    Science.gov (United States)

    Conlon, Elizabeth G; Rahaley, Nicole; Davis, Jessica

    2017-05-01

    Our study aimed to determine how age- and disease-related difficulties were associated with attitudes and beliefs about driving self-regulation in men and women in the baby boomer and older generations. Three hundred and ninety-nine men (n=204) and women (n=195) aged between 48 and 91 years participated in a cross-sectional study of Australian drivers. Demographic characteristics and measures of driving confidence, driving difficulty and driving self-regulation; perceptions of visual, physical and cognitive capacity; and attitudes and beliefs about driving were obtained. Driving self-regulation in men and women was explained by different mechanisms. For men, self-report of visual and cognitive difficulties and poor driving confidence predicted driving self-regulation. For women, negative attitudes toward driving mediated the associations found between health-related difficulties and driving self-regulation. Barriers to driving self-regulation were not associated with the driving self-regulatory practices of men or women. Regardless of generation, women reported poorer driving confidence, greater driving difficulty and more driving self-regulation than men. We concluded that age- and disease-related difficulties are related to increasing driving self-regulation in mature men and women. These results indicate that different pathways are needed in models of driving self-regulation for men and women regardless of generational cohort. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. First and second eye cataract surgery and driver self-regulation among older drivers with bilateral cataract: a prospective cohort study.

    Science.gov (United States)

    Agramunt, Seraina; Meuleners, Lynn B; Fraser, Michelle L; Chow, Kyle C; Ng, Jonathon Q; Raja, Vignesh

    2018-02-17

    Driving a car is the most common form of transport among the older population. Common medical conditions such as cataract, increase with age and impact on the ability to drive. To compensate for visual decline, some cataract patients may self-regulate their driving while waiting for cataract surgery. However, little is known about the self-regulation practices of older drivers throughout the cataract surgery process. The aim of this study is to assess the impact of first and second eye cataract surgery on driver self-regulation practices, and to determine which objective measures of vision are associated with driver self-regulation. Fifty-five older drivers with bilateral cataract aged 55+ years were assessed using the self-reported Driving Habits Questionnaire, the Mini-Mental State Examination and three objective visual measures in the month before cataract surgery, at least one to three months after first eye cataract surgery and at least one month after second eye cataract surgery. Participants' natural driving behaviour in four driving situations was also examined for one week using an in-vehicle monitoring device. Two separate Generalised Estimating Equation logistic models were undertaken to assess the impact of first and second eye cataract surgery on driver-self-regulation status and which changes in visual measures were associated with driver self-regulation status. The odds of being a self-regulator in at least one driving situation significantly decreased by 70% after first eye cataract surgery (OR: 0.3, 95% CI: 0.1-0.7) and by 90% after second eye surgery (OR: 0.1, 95% CI: 0.1-0.4), compared to before first eye surgery. Improvement in contrast sensitivity after cataract surgery was significantly associated with decreased odds of self-regulation (OR: 0.02, 95% CI: 0.01-0.4). The findings provide a strong rationale for providing timely first and second eye cataract surgery for older drivers with bilateral cataract, in order to improve their mobility and

  3. Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulation.

    Science.gov (United States)

    Wecksler, Aaron T; Kenyon, Victor; Deschamps, Joshua D; Holman, Theodore R

    2008-07-15

    Human reticulocyte 15-lipoxygenase (15-hLO-1) and epithelial 15-lipoxygenase (15-hLO-2) have been implicated in a number of human diseases, with differences in their substrate specificity potentially playing a central role. In this paper, we present a novel method for accurately measuring the substrate specificity of the two 15-hLO isozymes and demonstrate that both cholate and specific LO products affect substrate specificity. The linoleic acid (LA) product, 13-hydroperoxyoctadienoic acid (13-HPODE), changes the ( k cat/ K m) (AA)/( k cat/ K m) (LA) ratio more than 5-fold for 15-hLO-1 and 3-fold for 15-hLO-2, while the arachidonic acid (AA) product, 12-( S)-hydroperoxyeicosatetraenoic acid (12-HPETE), affects only the ratio of 15-hLO-1 (more than 5-fold). In addition, the reduced products, 13-( S)-hydroxyoctadecadienoic acid (13-HODE) and 12-( S)-hydroxyeicosatetraenoic acid (12-HETE), also affect substrate specificity, indicating that iron oxidation is not responsible for the change in the ( k cat/ K m) (AA)/( k cat/ K m) (LA) ratio. These results, coupled with the dependence of the 15-hLO-1 k cat/ K m kinetic isotope effect ( (D) k cat/ K m) on the presence of 12-HPETE and 12-HETE, indicate that the allosteric site, previously identified in 15-hLO-1 [Mogul, R., Johansen, E., and Holman, T. R. (1999) Biochemistry 39, 4801-4807], is responsible for the change in substrate specificity. The ability of LO products to regulate substrate specificity may be relevant with respect to cancer progression and warrants further investigation into the role of this product-feedback loop in the cell.

  4. Analysis of mammary specific gene locus regulation in differentiated cells derived by somatic cell fusion

    International Nuclear Information System (INIS)

    Robinson, Claire; Kolb, Andreas F.

    2009-01-01

    The transcriptional regulation of a gene is best analysed in the context of its normal chromatin surroundings. However, most somatic cells, in contrast to embryonic stem cells, are refractory to accurate modification by homologous recombination. We show here that it is possible to introduce precise genomic modifications in ES cells and to analyse the phenotypic consequences in differentiated cells by using a combination of gene targeting, site-specific recombination and somatic cell fusion. To provide a proof of principle, we have analysed the regulation of the casein gene locus in mammary gland cells derived from modified murine ES cells by somatic cell fusion. A β-galactosidase reporter gene was inserted in place of the β-casein gene and the modified ES cells, which do not express the reporter gene, were fused with the mouse mammary gland cell line HC11. The resulting cell clones expressed the β-galactosidase gene to a similar extent and with similar hormone responsiveness as the endogenous gene. However, a reporter gene under the control of a minimal β-casein promoter (encompassing the two consensus STAT5 binding sites which mediate the hormone response of the casein genes) was unable to replicate expression levels or hormone responsiveness of the endogenous gene when inserted into the same site of the casein locus. As expected, these results implicate sequences other than the STAT5 sites in the regulation of the β-casein gene

  5. Specific regulation of thermosensitive lipid droplet fusion by a nuclear hormone receptor pathway.

    Science.gov (United States)

    Li, Shiwei; Li, Qi; Kong, Yuanyuan; Wu, Shuang; Cui, Qingpo; Zhang, Mingming; Zhang, Shaobing O

    2017-08-15

    Nuclear receptors play important roles in regulating fat metabolism and energy production in humans. The regulatory functions and endogenous ligands of many nuclear receptors are still unidentified, however. Here, we report that CYP-37A1 (ortholog of human cytochrome P450 CYP4V2), EMB-8 (ortholog of human P450 oxidoreductase POR), and DAF-12 (homolog of human nuclear receptors VDR/LXR) constitute a hormone synthesis and nuclear receptor pathway in Caenorhabditis elegans This pathway specifically regulates the thermosensitive fusion of fat-storing lipid droplets. CYP-37A1, together with EMB-8, synthesizes a lipophilic hormone not identical to Δ7-dafachronic acid, which represses the fusion-promoting function of DAF-12. CYP-37A1 also negatively regulates thermotolerance and lifespan at high temperature in a DAF-12-dependent manner. Human CYP4V2 can substitute for CYP-37A1 in C. elegans This finding suggests the existence of a conserved CYP4V2-POR-nuclear receptor pathway that functions in converting multilocular lipid droplets to unilocular ones in human cells; misregulation of this pathway may lead to pathogenic fat storage.

  6. Age shall not weary us: deleterious effects of self-regulation depletion are specific to younger adults.

    Directory of Open Access Journals (Sweden)

    Theresa Dahm

    Full Text Available Self-regulation depletion (SRD, or ego-depletion, refers to decrements in self-regulation performance immediately following a different self-regulation-demanding activity. There are now over a hundred studies reporting SRD across a broad range of tasks and conditions. However, most studies have used young student samples. Because prefrontal brain regions thought to subserve self-regulation do not fully mature until 25 years of age, it is possible that SRD effects are confined to younger populations and are attenuated or disappear in older samples. We investigated this using the Stroop color task as an SRD induction and an autobiographical memory task as the outcome measure. We found that younger participants (<25 years were susceptible to depletion effects, but found no support for such effects in an older group (40-65 years. This suggests that the widely-reported phenomenon of SRD has important developmental boundary conditions casting doubt on claims that it represents a general feature of human cognition.

  7. Regulation of platelet activating factor receptor coupled phosphoinositide-specific phospholipase C activity

    International Nuclear Information System (INIS)

    Morrison, W.J.

    1988-01-01

    The major objectives of this study were two-fold. The first was to establish whether binding of platelet activating factor (PAF) to its receptor was integral to the stimulation of polyphosphoinositide-specific phospholipase C (PLC) in rabbit platelets. The second was to determine regulatory features of this receptor-coupled mechanism. [ 3 H]PAF binding demonstrated two binding sites, a high affinity site with a inhibitory constant (Ki) of 2.65 nM and a low affinity site with a Ki of 0.80 μM. PAF receptor coupled activation of phosphoinositide-specific PLC was studied in platelets which were made refractory, by short term pretreatments, to either PAF or thrombin. Saponin-permeabilized rabbit platelets continue to regulate the mechanism(s) coupling PAF receptors to PLC stimulation. However, TRPγS and GDPβS, which affect guanine nucleotide regulatory protein functions, were unable to modulate the PLC activity to any appreciable extent as compared to PAF. The possible involvement of protein kinase C (PKC) activation in regulating PAF-stimulated PLC activity was studied in rabbit platelets pretreated with staurosporine followed by pretreatments with PAF or phorbol 12-myristate 13-acetate (PMA)

  8. Identification of an elaborate NK-specific system regulating HLA-C expression.

    Directory of Open Access Journals (Sweden)

    Hongchuan Li

    2018-01-01

    Full Text Available The HLA-C gene appears to have evolved in higher primates to serve as a dominant source of ligands for the KIR2D family of inhibitory MHC class I receptors. The expression of NK cell-intrinsic MHC class I has been shown to regulate the murine Ly49 family of MHC class I receptors due to the interaction of these receptors with NK cell MHC in cis. However, cis interactions have not been demonstrated for the human KIR and HLA proteins. We report the discovery of an elaborate NK cell-specific system regulating HLA-C expression, indicating an important role for HLA-C in the development and function of NK cells. A large array of alternative transcripts with differences in intron/exon content are generated from an upstream NK-specific HLA-C promoter, and exon content varies between HLA-C alleles due to SNPs in splice donor/acceptor sites. Skipping of the first coding exon of HLA-C generates a subset of untranslatable mRNAs, and the proportion of untranslatable HLA-C mRNA decreases as NK cells mature, correlating with increased protein expression by mature NK cells. Polymorphism in a key Ets-binding site of the NK promoter has generated HLA-C alleles that lack significant promoter activity, resulting in reduced HLA-C expression and increased functional activity. The NK-intrinsic regulation of HLA-C thus represents a novel mechanism controlling the lytic activity of NK cells during development.

  9. Co-expression networks reveal the tissue-specific regulation of transcription and splicing.

    Science.gov (United States)

    Saha, Ashis; Kim, Yungil; Gewirtz, Ariel D H; Jo, Brian; Gao, Chuan; McDowell, Ian C; Engelhardt, Barbara E; Battle, Alexis

    2017-11-01

    Gene co-expression networks capture biologically important patterns in gene expression data, enabling functional analyses of genes, discovery of biomarkers, and interpretation of genetic variants. Most network analyses to date have been limited to assessing correlation between total gene expression levels in a single tissue or small sets of tissues. Here, we built networks that additionally capture the regulation of relative isoform abundance and splicing, along with tissue-specific connections unique to each of a diverse set of tissues. We used the Genotype-Tissue Expression (GTEx) project v6 RNA sequencing data across 50 tissues and 449 individuals. First, we developed a framework called Transcriptome-Wide Networks (TWNs) for combining total expression and relative isoform levels into a single sparse network, capturing the interplay between the regulation of splicing and transcription. We built TWNs for 16 tissues and found that hubs in these networks were strongly enriched for splicing and RNA binding genes, demonstrating their utility in unraveling regulation of splicing in the human transcriptome. Next, we used a Bayesian biclustering model that identifies network edges unique to a single tissue to reconstruct Tissue-Specific Networks (TSNs) for 26 distinct tissues and 10 groups of related tissues. Finally, we found genetic variants associated with pairs of adjacent nodes in our networks, supporting the estimated network structures and identifying 20 genetic variants with distant regulatory impact on transcription and splicing. Our networks provide an improved understanding of the complex relationships of the human transcriptome across tissues. © 2017 Saha et al.; Published by Cold Spring Harbor Laboratory Press.

  10. SNF1-related protein kinases 2 are negatively regulated by a plant-specific calcium sensor.

    Science.gov (United States)

    Bucholc, Maria; Ciesielski, Arkadiusz; Goch, Grażyna; Anielska-Mazur, Anna; Kulik, Anna; Krzywińska, Ewa; Dobrowolska, Grażyna

    2011-02-04

    SNF1-related protein kinases 2 (SnRK2s) are plant-specific enzymes involved in environmental stress signaling and abscisic acid-regulated plant development. Here, we report that SnRK2s interact with and are regulated by a plant-specific calcium-binding protein. We screened a Nicotiana plumbaginifolia Matchmaker cDNA library for proteins interacting with Nicotiana tabacum osmotic stress-activated protein kinase (NtOSAK), a member of the SnRK2 family. A putative EF-hand calcium-binding protein was identified as a molecular partner of NtOSAK. To determine whether the identified protein interacts only with NtOSAK or with other SnRK2s as well, we studied the interaction of an Arabidopsis thaliana orthologue of the calcium-binding protein with selected Arabidopsis SnRK2s using a two-hybrid system. All kinases studied interacted with the protein. The interactions were confirmed by bimolecular fluorescence complementation assay, indicating that the binding occurs in planta, exclusively in the cytoplasm. Calcium binding properties of the protein were analyzed by fluorescence spectroscopy using Tb(3+) as a spectroscopic probe. The calcium binding constant, determined by the protein fluorescence titration, was 2.5 ± 0.9 × 10(5) M(-1). The CD spectrum indicated that the secondary structure of the protein changes significantly in the presence of calcium, suggesting its possible function as a calcium sensor in plant cells. In vitro studies revealed that the activity of SnRK2 kinases analyzed is inhibited in a calcium-dependent manner by the identified calcium sensor, which we named SCS (SnRK2-interacting calcium sensor). Our results suggest that SCS is involved in response to abscisic acid during seed germination most probably by negative regulation of SnRK2s activity.

  11. Site-specific differences in the association between plantar tactile perception and mobility function in older adults

    Directory of Open Access Journals (Sweden)

    Yenisel eCruz-Almeida

    2014-04-01

    Full Text Available Introduction Impaired somatosensation is common in older adults and contributes to age-related loss of mobility function. However, little is known about whether somatosensation at different sites on the plantar surface of the foot are differentially related to mobility function. Such a finding may have important implications for clinical care of older adults and other at-risk populations, such as for optimizing interventions (e.g., footwear for augmenting somatosensory feedback and for improving the efficiency of clinical assessment. Materials and Methods Tactile perception was evaluated with a 10g monofilament at four sites on the plantar surface of each foot: great toe (GT, first metatarsal head (MT1, heel (H and fifth metatarsal head (MT5. Mobility function was assessed with the Berg Balance Scale and walking speed. Results Sixty-one older adults participated. Tactile perception was significantly positively associated with Berg Balance Score (adjusted R2 = 0.30 - 0.75; p = 0.03 - Discussion The present findings indicate that tactile perception at MT1 is more closely linked to mobility function than is tactile perception at GT, MT5 or H. These findings warrant further research to examine whether interventions (e.g., textured insoles and assessments that preferentially or exclusively focus on the site of MT1 may be more effective for optimizing clinical care.

  12. Arabidopsis ETO1 specifically interacts with and negatively regulates type 2 1-aminocyclopropane-1-carboxylate synthases

    Directory of Open Access Journals (Sweden)

    Saito Koji

    2005-08-01

    Full Text Available Abstract Background In Arabidopsis, ETO1 (ETHYLENE-OVERPRODUCER1 is a negative regulator of ethylene evolution by interacting with AtACS5, an isoform of the rate-limiting enzyme, 1-aminocyclopropane-1-carboxylate synthases (ACC synthase or ACS, in ethylene biosynthetic pathway. ETO1 directly inhibits the enzymatic activity of AtACS5. In addition, a specific interaction between ETO1 and AtCUL3, a constituent of a new type of E3 ubiquitin ligase complex, suggests the molecular mechanism in promoting AtACS5 degradation by the proteasome-dependent pathway. Because orthologous sequences to ETO1 are found in many plant species including tomato, we transformed tomato with Arabidopsis ETO1 to evaluate its ability to suppress ethylene production in tomato fruits. Results Transgenic tomato lines that overexpress Arabidopsis ETO1 (ETO1-OE did not show a significant delay of fruit ripening. So, we performed yeast two-hybrid assays to investigate potential heterologous interaction between ETO1 and three isozymes of ACC synthases from tomato. In the yeast two-hybrid system, ETO1 interacts with LE-ACS3 as well as AtACS5 but not with LE-ACS2 or LE-ACS4, two major isozymes whose gene expression is induced markedly in ripening fruits. According to the classification of ACC synthases, which is based on the C-terminal amino acid sequences, both LE-ACS3 and AtACS5 are categorized as type 2 isozymes and possess a consensus C-terminal sequence. In contrast, LE-ACS2 and LE-ACS4 are type 1 and type 3 isozymes, respectively, both of which do not possess this specific C-terminal sequence. Yeast two-hybrid analysis using chimeric constructs between LE-ACS2 and LE-ACS3 revealed that the type-2-ACS-specific C-terminal tail is required for interaction with ETO1. When treated with auxin to induce LE-ACS3, seedlings of ETO1-OE produced less ethylene than the wild type, despite comparable expression of the LE-ACS3 gene in the wild type. Conclusion These results suggest that ETO1

  13. Specificity determinants for autoproteolysis of LexA, a key regulator of bacterial SOS mutagenesis.

    Science.gov (United States)

    Mo, Charlie Y; Birdwell, L Dillon; Kohli, Rahul M

    2014-05-20

    Bacteria utilize the tightly regulated stress response (SOS) pathway to respond to a variety of genotoxic agents, including antimicrobials. Activation of the SOS response is regulated by a key repressor-protease, LexA, which undergoes autoproteolysis in the setting of stress, resulting in derepression of SOS genes. Remarkably, genetic inactivation of LexA's self-cleavage activity significantly decreases acquired antibiotic resistance in infection models and renders bacteria hypersensitive to traditional antibiotics, suggesting that a mechanistic study of LexA could help inform its viability as a novel target for combating acquired drug resistance. Despite structural insights into LexA, a detailed knowledge of the enzyme's protease specificity is lacking. Here, we employ saturation and positional scanning mutagenesis on LexA's internal cleavage region to analyze >140 mutants and generate a comprehensive specificity profile of LexA from the human pathogen Pseudomonas aeruginosa (LexAPa). We find that the LexAPa active site possesses a unique mode of substrate recognition. Positions P1-P3 prefer small hydrophobic residues that suggest specific contacts with the active site, while positions P5 and P1' show a preference for flexible glycine residues that may facilitate the conformational change that permits autoproteolysis. We further show that stabilizing the β-turn within the cleavage region enhances LexA autoproteolytic activity. Finally, we identify permissive positions flanking the scissile bond (P4 and P2') that are tolerant to extensive mutagenesis. Our studies shed light on the active site architecture of the LexA autoprotease and provide insights that may inform the design of probes of the SOS pathway.

  14. Genotype-Specific Regulation of Oral Innate Immunity by T2R38 Taste Receptor

    Science.gov (United States)

    Gil, Sucheol; Coldwell, Susan; Drury, Jeanie L.; Arroyo, Fabiola; Phi, Tran; Saadat, Sanaz; Kwong, Danny; Chung, Whasun Oh

    2015-01-01

    The bitter taste receptor T2R38 has been shown to regulate mucosal innate immune responses in the upper airway epithelium. Furthermore, SNPs in T2R38 influence the sensitivity to 6-n-propylthiouracil (PROP) and are associated with caries risk/protection. However, no study has been reported on the role of T2R38 in the innate immune responses to oral bacteria. We hypothesize that T2R38 regulates oral innate immunity and that this regulation is genotype-specific. Primary gingival epithelial cells carrying three common genotypes, PAV/PAV (PROP super-taster), AVI/PAV (intermediate) and AVI/AVI (non-taster) were stimulated with cariogenic bacteria Streptococcus mutans, periodontal pathogen Porphyromonas gingivalis or non-pathogen Fusobacterium nucleatum. QRT-PCR analyzed T2R38 mRNA, and T2R38-specific siRNA and ELISA were utilized to evaluate induction of hBD-2 (antimicrobial peptide), IL-1α and IL-8 in various donor-lines. Experiments were set up in duplicate and repeated three times. T2R38 mRNA induction in response to S. mutans was highest in PAV/PAV (4.3-fold above the unstimulated controls; p<0.05), while lowest in AVI/AVI (1.2-fold). In PAV/PAV, hBD-2 secretion in response to S. mutans was decreased by 77% when T2R38 was silenced. IL-1α secretion was higher in PAV/PAV compared to AVI/PAV or AVI/AVI with S. mutans stimulation, but it was reduced by half when T2R38 was silenced (p<0.05). In response to P. gingivalis, AVI/AVI showed 4.4-fold increase (p<0.05) in T2R38 expression, whereas the levels in PAV/PAV and AVI/PAV remained close to that of the controls. Secretion levels of IL-1α and IL-8 decreased in AVI/AVI in response to P. gingivalis when T2R38 was silenced (p<0.05), while the changes were not significant in PAV/PAV. Our data suggest that the regulation of gingival innate immunity by T2R38 is genotype-dependent and that the ability to induce a high level of hBD-2 by PAV/PAV carriers may be a reason for protection against caries in this group. PMID

  15. Impact of a brief intervention on self-regulation, self-efficacy and physical activity in older adults with type 2 diabetes

    Science.gov (United States)

    Olson, Erin A.; McAuley, Edward

    2015-01-01

    Despite evidence of the benefits of physical activity, most individuals with type 2 diabetes do not meet physical activity recommendations. The purpose of this study was to test the efficacy of a brief intervention targeting self-efficacy and self-regulation to increase physical activity in older adults with type 2 diabetes. Older adults (Mage = 61.8 ± 6.4) with type 2 diabetes or metabolic syndrome were randomized into a titrated physical activity intervention (n = 58) or an online health education course (n = 58). The intervention included walking exercise and theory-based group workshops. Self-efficacy, self-regulation and physical activity were assessed at baseline, post-intervention, and a follow-up. Results indicated a group by time effect for self-regulation [F(2,88) = 14.021, p self-efficacy [F(12,77) = 2.322, p self-efficacy and self-regulation. Future research warrants adjusting intervention strategies to increase long-term change. PMID:26162648

  16. Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment.

    LENUS (Irish Health Repository)

    Rogan, Mark P

    2012-02-01

    Recent advances in basic science have greatly expanded our understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the chloride and bicarbonate channel that is encoded by the gene, which is mutated in patients with CF. We review the structure, function, biosynthetic processing, and intracellular trafficking of CFTR and discuss the five classes of mutations and their impact on the CF phenotype. The therapeutic discussion is focused on the significant progress toward CFTR mutation-specific therapies. We review the results of encouraging clinical trials examining orally administered therapeutics, including agents that promote read-through of class I mutations (premature termination codons); correctors, which overcome the CFTR misfolding that characterizes the common class II mutation F508del; and potentiators, which enhance the function of class III or IV mutated CFTR at the plasma membrane. Long-term outcomes from successful mutation-specific treatments could finally answer the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease?

  17. Comparison of hand grip strength and upper limb pressure pain threshold between older adults with or without non-specific shoulder pain

    Directory of Open Access Journals (Sweden)

    Cesar Calvo Lobo

    2017-02-01

    Full Text Available Background There is a high prevalence of non-specific shoulder pain associated with upper limb functional limitations in older adults. The purpose of this study was to determine the minimal clinically important differences (MCID of grip strength and pressure pain threshold (PPT in the upper limb between older adults with or without non-specific shoulder pain. Methods A case-control study was carried out following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE criteria. A sample of 132 shoulders (mean ± SD years with (n = 66; 76.04 ± 7.58 and without (n = 66; 75.05 ± 6.26 non-specific pain were recruited. The grip strength and PPT of the anterior deltoid and extensor carpi radialis brevis (ECRB muscles were assessed. Results There were statistically significant differences (mean ± SD; P-value for anterior deltoid PPT (2.51 ± 0.69 vs 3.68 ± 0.65, kg/cm2; P < .001, ECRB PPT (2.20 ± 0.60 vs 3.35 ± 0.38 kg/cm2; P < .001 and grip strength (20.78 ± 10.94 vs 24.63 ± 9.38 kg; P = .032 between shoulders with and without non-specific pain, respectively. Discussion The MCID of 1.17 kg/cm2, 1.15 kg/cm2 and 3.84 kg were proposed for anterior deltoid PPT, ECRB PPT and grip strength, respectively, to assess the upper limb of older adults with non-specific shoulder pain after treatment. In addition, univariate and multivariate (linear regression and regression trees analyses may be used to consider age distribution, sex, pain intensity, grip strength and PPT in older adults including clinical and epidemiological studies with non-specific shoulder pain.

  18. Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle.

    Science.gov (United States)

    Vichaiwong, Kanokwan; Purohit, Suneet; An, Ding; Toyoda, Taro; Jessen, Niels; Hirshman, Michael F; Goodyear, Laurie J

    2010-10-15

    TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab-GAP (GTPase-activating protein) that is highly expressed in skeletal muscle, but little is known about TBC1D1 regulation and function. We studied TBC1D1 phosphorylation on three predicted AMPK (AMP-activated protein kinase) phosphorylation sites (Ser231, Ser660 and Ser700) and one predicted Akt phosphorylation site (Thr590) in control mice, AMPKα2 inactive transgenic mice (AMPKα2i TG) and Akt2-knockout mice (Akt2 KO). Muscle contraction significantly increased TBC1D1 phosphorylation on Ser231 and Ser660, tended to increase Ser700 phosphorylation, but had no effect on Thr590. AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside) also increased phosphorylation on Ser231, Ser660 and Ser700, but not Thr590, whereas insulin only increased Thr590 phosphorylation. Basal and contraction-stimulated TBC1D1 Ser231, Ser660 and Ser700 phosphorylation were greatly reduced in AMPKα2i TG mice, although contraction still elicited a small increase in phosphorylation. Akt2 KO mice had blunted insulin-stimulated TBC1D1 Thr590 phosphorylation. Contraction-stimulated TBC1D1 Ser231 and Ser660 phosphorylation were normal in high-fat-fed mice. Glucose uptake in vivo was significantly decreased in tibialis anterior muscles overexpressing TBC1D1 mutated on four predicted AMPK phosphorylation sites. In conclusion, contraction causes site-specific phosphorylation of TBC1D1 in skeletal muscle, and TBC1D1 phosphorylation on AMPK sites regulates contraction-stimulated glucose uptake. AMPK and Akt regulate TBC1D1 phosphorylation, but there must be additional upstream kinases that mediate TBC1D1 phosphorylation in skeletal muscle.

  19. Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling.

    Science.gov (United States)

    Brankatschk, Marko; Dunst, Sebastian; Nemetschke, Linda; Eaton, Suzanne

    2014-10-02

    The Insulin signaling pathway couples growth, development and lifespan to nutritional conditions. Here, we demonstrate a function for the Drosophila lipoprotein LTP in conveying information about dietary lipid composition to the brain to regulate Insulin signaling. When yeast lipids are present in the diet, free calcium levels rise in Blood Brain Barrier glial cells. This induces transport of LTP across the Blood Brain Barrier by two LDL receptor-related proteins: LRP1 and Megalin. LTP accumulates on specific neurons that connect to cells that produce Insulin-like peptides, and induces their release into the circulation. This increases systemic Insulin signaling and the rate of larval development on yeast-containing food compared with a plant-based food of similar nutritional content.

  20. Muscle specific microRNAs are regulated by endurance exercise in human skeletal muscle

    DEFF Research Database (Denmark)

    Nielsen, Søren; Scheele, Camilla; Yfanti, Christina

    2010-01-01

    Muscle specific miRNAs, myomiRs, have been shown to control muscle development in vitro and are differentially expressed at rest in diabetic skeletal muscle. Therefore, we investigated the expression of these myomiRs, including miR-1, miR-133a, miR-133b and miR-206 in muscle biopsies from vastus...... lateralis of healthy young males (n = 10) in relation to a hyperinsulinaemic–euglycaemic clamp as well as acute endurance exercise before and after 12 weeks of endurance training. The subjects increased their endurance capacity, VO2max (l min-1) by 17.4% (P improved insulin sensitivity by 19......, but their role in regulating human skeletal muscle adaptation remains unknown....

  1. Mitosis-specific phosphorylation of PML at T409 regulates spindle checkpoint.

    Science.gov (United States)

    Jin, J; Liu, J

    2016-08-31

    During mitosis, Promyelocytic leukemia nuclear bodies (PML NBs) change dramatically in morphology and composition, but little is known about function of PML in mitosis. Here, we show that PML is phosphorylated at T409 (PML p409) in a mitosis-specific manner. More importantly, PML p409 contributes to maintain the duration of pro-metaphase and regulates spindle checkpoint. Deficient PML p409 caused a shortening of pro-metaphase and challenged the nocodazole-triggered mitotic arrest. T409A mutation led to a higher frequency of misaligned chromosomes on metaphase plate, and subsequently death in late mitosis. In addition, inhibition of PML p409 repressed growth of tumor cells, suggesting that PML p409 is a potential target for cancer therapy. Collectively, our study demonstrated an important phosphorylated site of PML, which contributed to explore the role of PML in mitosis.

  2. Axial level-specific regulation of neuronal development: lessons from PITX2.

    Science.gov (United States)

    Waite, Mindy R; Martin, Donna M

    2015-02-01

    Transcriptional regulation of gene expression is vital for proper control of proliferation, migration, differentiation, and survival of developing neurons. Pitx2 encodes a homeodomain transcription factor that is highly expressed in the developing and adult mammalian brain. In humans, mutations in PITX2 result in Rieger syndrome, characterized by defects in the development of the eyes, umbilicus, and teeth and variable abnormalities in the brain, including hydrocephalus and cerebellar hypoplasia. Alternative splicing of Pitx2 in the mouse results in three isoforms, Pitx2a, Pitx2b, and Pitx2c, each of which is expressed symmetrically along the left-right axis of the brain throughout development. Here, we review recent evidence for axial and brain region-specific requirements for Pitx2 during neuronal migration and differentiation, highlighting known isoform contributions. © 2014 Wiley Periodicals, Inc.

  3. SPECIFIC REGULATIONS REGARDING THE SOLVING OF LABOR DISPUTES IN ROMANIAN LEGAL SYSTEM

    Directory of Open Access Journals (Sweden)

    Onica -Chipea Lavinia

    2012-01-01

    Full Text Available The paper aims to briefly review specific provisions of labor legislation for the solving of labor disputes. Those rules are found in matters of discrimination in the payment settlements, the public sector staff as well as some personnel status or disciplinary (work stops at Status of Teachers and established a derogationfrom the common law (Labor Code Law nr.62/2011 of Social Dialogue in resolving individual labor conflicts(former conflicts of rights. The role and importance of these regulations is that they give the parties the employment relationship, particularly employees, way, way more for rights enshrined in law. Appeals, complaints or expressions of individual grievances be settled outside the judicial system organ (the courts,authorizing officers, judicial administrative organs, which aim at restoring order violated.

  4. It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco

    Science.gov (United States)

    Hecht, Stephen S.

    2014-01-01

    The Family Smoking Prevention and Tobacco Control Act gives the Food and Drug Administration power to regulate tobacco products. This commentary calls for immediate regulation of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN) in cigarette tobacco as a logical path to cancer prevention. NNK and NNN, powerful carcinogens in laboratory animals, have been evaluated as “carcinogenic to humans” by the International Agency for Research on Cancer. NNK and NNN are present in the tobacco of virtually all marketed cigarettes; levels in cigarette smoke are directly proportional to the amounts in tobacco. The NNK metabolite NNAL, itself a strong carcinogen, is present in the urine of smokers and non-smokers exposed to secondhand smoke. Some of the highest levels of NNK and NNN are found in U.S. products. It is well established that factors such as choice of tobacco blend, agricultural conditions, and processing methods influence levels of NNK and NNN in cigarette tobacco and cigarette smoke. Therefore, it is time to control these factors and produce cigarettes with 100 ppb or less each of NNK and NNN in tobacco, which would result in an approximate 15-20 fold reduction of these carcinogens in the mainstream smoke of popular cigarettes sold in the United States. PMID:24806664

  5. RNAi Reveals Phase-Specific Global Regulators of Human Somatic Cell Reprogramming

    Directory of Open Access Journals (Sweden)

    Cheng-Xu Delon Toh

    2016-06-01

    Full Text Available Incomplete knowledge of the mechanisms at work continues to hamper efforts to maximize reprogramming efficiency. Here, we present a systematic genome-wide RNAi screen to determine the global regulators during the early stages of human reprogramming. Our screen identifies functional repressors and effectors that act to impede or promote the reprogramming process. Repressors and effectors form close interacting networks in pathways, including RNA processing, G protein signaling, protein ubiquitination, and chromatin modification. Combinatorial knockdown of five repressors (SMAD3, ZMYM2, SFRS11, SAE1, and ESET synergistically resulted in ∼85% TRA-1-60-positive cells. Removal of the novel splicing factor SFRS11 during reprogramming is accompanied by rapid acquisition of pluripotency-specific spliced forms. Mechanistically, SFRS11 regulates exon skipping and mutually exclusive splicing of transcripts in genes involved in cell differentiation, mRNA splicing, and chromatin modification. Our study provides insights into the reprogramming process, which comprises comprehensive and multi-layered transcriptional, splicing, and epigenetic machineries.

  6. Nuclear factor 1 regulates adipose tissue-specific expression in the mouse GLUT4 gene

    International Nuclear Information System (INIS)

    Miura, Shinji; Tsunoda, Nobuyo; Ikeda, Shinobu; Kai, Yuko; Cooke, David W.; Lane, M. Daniel; Ezaki, Osamu

    2004-01-01

    Previous studies demonstrated that an adipose tissue-specific element(s) (ASE) of the murine GLUT4 gene is located between -551 and -506 in the 5'-flanking sequence and that a high-fat responsive element(s) for down-regulation of the GLUT4 gene is located between bases -701 and -552. A binding site for nuclear factor 1 (NF1), that mediates insulin and cAMP-induced repression of GLUT4 in 3T3-L1 adipocytes is located between bases -700 and -688. To examine the role of NF1 in the regulation of GLUT4 gene expression in white adipose tissues (WAT) in vivo, we created two types of transgenic mice harboring mutated either 5' or 3' half-site of NF1-binding sites in GLUT4 minigene constructs. In both cases, the GLUT4 minigene was not expressed in WAT, while expression was maintained in brown adipose tissue, skeletal muscle, and heart. This was an unexpected finding, since a -551 GLUT4 minigene that did not have the NF1-binding site was expressed in WAT. We propose a model that explains the requirement for both the ASE and the NF1-binding site for expression of GLUT4 in WAT

  7. Genome specific PPARαB duplicates in salmonids and insights into estrogenic regulation in brown trout.

    Science.gov (United States)

    Madureira, Tânia Vieira; Pinheiro, Ivone; de Paula Freire, Rafaelle; Rocha, Eduardo; Castro, Luis Filipe; Urbatzka, Ralph

    2017-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of many processes in vertebrates, such as carbohydrate and lipid metabolism. PPARα, a member of the PPAR nuclear receptor gene subfamily (NR1C1), is involved in fatty acid metabolism, namely in peroxisomal β-oxidation. Two gene paralogues, pparαA and pparαB, were described in several teleost species with their origin dating back to the teleost-specific genome duplication (3R). Given the additional salmonid-specific genome duplication (4R), four genes could be theoretically anticipated for this gene subfamily. In this work, we examined the pparα gene repertoire in brown trout, Salmo trutta f. fario. Data disclosed two pparα-like sequences in brown trout. Phylogenetic analyses further revealed that the isolated genes are most likely genome pparαB duplicates, pparαBa and pparαBb, while pparαA is apparently absent in salmonids. Both genes showed a ubiquitous mRNA expression across a panel of 11 different organs. In vitro exposed primary brown trout hepatocytes strongly suggest that pparα gene paralogues are differently regulated by ethinylestradiol (EE2). PparαBb mRNA expression significantly decreased with dosage, reaching significance after exposure to 50μM EE2, while pparαBa mRNA increased, significant at 1μM EE2. The present data enhances the understanding of pparα function and evolution in teleost, and reinforces the evidence of a potential crosstalk between estrogenic and pparα signaling pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Neuron-specific specificity protein 4 bigenomically regulates the transcription of all mitochondria- and nucleus-encoded cytochrome c oxidase subunit genes in neurons.

    Science.gov (United States)

    Johar, Kaid; Priya, Anusha; Dhar, Shilpa; Liu, Qiuli; Wong-Riley, Margaret T T

    2013-11-01

    Neurons are highly dependent on oxidative metabolism for their energy supply, and cytochrome c oxidase (COX) is a key energy-generating enzyme in the mitochondria. A unique feature of COX is that it is one of only four proteins in mammalian cells that are bigenomically regulated. Of its thirteen subunits, three are encoded in the mitochondrial genome and ten are nuclear-encoded on nine different chromosomes. The mechanism of regulating this multisubunit, bigenomic enzyme poses a distinct challenge. In recent years, we found that nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2) mediate such bigenomic coordination. The latest candidate is the specificity factor (Sp) family of proteins. In N2a cells, we found that Sp1 regulates all 13 COX subunits. However, we discovered recently that in primary neurons, it is Sp4 and not Sp1 that regulates some of the key glutamatergic receptor subunit genes. The question naturally arises as to the role of Sp4 in regulating COX in primary neurons. The present study utilized multiple approaches, including chromatin immunoprecipitation, promoter mutational analysis, knockdown and over-expression of Sp4, as well as functional assays to document that Sp4 indeed functionally regulate all 13 subunits of COX as well as mitochondrial transcription factors A and B. The present study discovered that among the specificity family of transcription factors, it is the less known neuron-specific Sp4 that regulates the expression of all 13 subunits of mitochondrial cytochrome c oxidase (COX) enzyme in primary neurons. Sp4 also regulates the three mitochondrial transcription factors (TFAM, TFB1M, and TFB2M) and a COX assembly protein SURF-1 in primary neurons. © 2013 International Society for Neurochemistry.

  9. Astrocyte-specific regulation of hMeCP2 expression in Drosophila

    Directory of Open Access Journals (Sweden)

    David L. Hess-Homeier

    2014-10-01

    Full Text Available Alterations in the expression of Methyl-CpG-binding protein 2 (MeCP2 either by mutations or gene duplication leads to a wide spectrum of neurodevelopmental disorders including Rett Syndrome and MeCP2 duplication disorder. Common features of Rett Syndrome (RTT, MeCP2 duplication disorder, and neuropsychiatric disorders indicate that even moderate changes in MeCP2 protein levels result in functional and structural cell abnormalities. In this study, we investigated two areas of MeCP2 pathophysiology using Drosophila as a model system: the effects of MeCP2 glial gain-of-function activity on circuits controlling sleep behavior, and the cell-type specific regulation of MeCP2 expression. In this study, we first examined the effects of elevated MeCP2 levels on microcircuits by expressing human MeCP2 (hMeCP2 in astrocytes and distinct subsets of amine neurons including dopamine and octopamine (OA neurons. Depending on the cell-type, hMeCP2 expression reduced sleep levels, altered daytime/nighttime sleep patterns, and generated sleep maintenance deficits. Second, we identified a 498 base pair region of the MeCP2e2 isoform that is targeted for regulation in distinct subsets of astrocytes. Levels of the full-length hMeCP2e2 and mutant RTT R106W protein decreased in astrocytes in a temporally and spatially regulated manner. In contrast, expression of the deletion Δ166 hMeCP2 protein was not altered in the entire astrocyte population. qPCR experiments revealed a reduction in full-length hMeCP2e2 transcript levels suggesting transgenic hMeCP2 expression is regulated at the transcriptional level. Given the phenotypic complexities that are caused by alterations in MeCP2 levels, our results provide insight into distinct cellular mechanisms that control MeCP2 expression and link microcircuit abnormalities with defined behavioral deficits.

  10. Skeletal muscle gene expression in response to resistance exercise: sex specific regulation

    Directory of Open Access Journals (Sweden)

    Burant Charles F

    2010-11-01

    Full Text Available Abstract Background The molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting state and following anabolic stimuli, such as resistance exercise (RE, might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise or late recovery (24 h post-exercise time point. Muscle transcription profiles were compared in the resting state between men (n = 6 and women (n = 8, and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females. A logistic regression-based method (LRpath, following Bayesian moderated t-statistic (IMBT, was used to test gene functional groups and biological pathways enriched with differentially expressed genes. Results This investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females

  11. Determinants of user acceptance of a specific social platform for older adults: An empirical examination of user interface characteristics and behavioral intention.

    Science.gov (United States)

    Tsai, Tsai-Hsuan; Chang, Hsien-Tsung; Chen, Yan-Jiun; Chang, Yung-Sheng

    2017-01-01

    The use of the Internet and social applications has many benefits for the elderly, but numerous investigations have shown that the elderly do not perceive online social networks as a friendly social environment. Therefore, TreeIt, a social application specifically designed for the elderly, was developed for this study. In the TreeIt application, seven mechanisms promoting social interaction were designed to allow older adults to use social networking sites (SNSs) to increase social connection, maintain the intensity of social connections and strengthen social experience. This study's main objective was to investigate how user interface design affects older people's intention and attitude related to using SNSs. Fourteen user interface evaluation heuristics proposed by Zhang et al. were adopted as the criteria to assess user interface usability and further grouped into three categories: system support, user interface design and navigation. The technology acceptance model was adopted to assess older people's intention and attitude related to using SNSs. One hundred and one elderly persons were enrolled in this study as subjects, and the results showed that all of the hypotheses proposed in this study were valid: system support and perceived usefulness had a significant effect on behavioral intention; user interface design and perceived ease of use were positively correlated with perceived usefulness; and navigation exerted an influence on perceived ease of use. The results of this study are valuable for the future development of social applications for the elderly.

  12. Determinants of user acceptance of a specific social platform for older adults: An empirical examination of user interface characteristics and behavioral intention.

    Directory of Open Access Journals (Sweden)

    Tsai-Hsuan Tsai

    Full Text Available The use of the Internet and social applications has many benefits for the elderly, but numerous investigations have shown that the elderly do not perceive online social networks as a friendly social environment. Therefore, TreeIt, a social application specifically designed for the elderly, was developed for this study. In the TreeIt application, seven mechanisms promoting social interaction were designed to allow older adults to use social networking sites (SNSs to increase social connection, maintain the intensity of social connections and strengthen social experience. This study's main objective was to investigate how user interface design affects older people's intention and attitude related to using SNSs. Fourteen user interface evaluation heuristics proposed by Zhang et al. were adopted as the criteria to assess user interface usability and further grouped into three categories: system support, user interface design and navigation. The technology acceptance model was adopted to assess older people's intention and attitude related to using SNSs. One hundred and one elderly persons were enrolled in this study as subjects, and the results showed that all of the hypotheses proposed in this study were valid: system support and perceived usefulness had a significant effect on behavioral intention; user interface design and perceived ease of use were positively correlated with perceived usefulness; and navigation exerted an influence on perceived ease of use. The results of this study are valuable for the future development of social applications for the elderly.

  13. Determinants of user acceptance of a specific social platform for older adults: An empirical examination of user interface characteristics and behavioral intention

    Science.gov (United States)

    Chang, Hsien-Tsung; Chen, Yan-Jiun; Chang, Yung-Sheng

    2017-01-01

    The use of the Internet and social applications has many benefits for the elderly, but numerous investigations have shown that the elderly do not perceive online social networks as a friendly social environment. Therefore, TreeIt, a social application specifically designed for the elderly, was developed for this study. In the TreeIt application, seven mechanisms promoting social interaction were designed to allow older adults to use social networking sites (SNSs) to increase social connection, maintain the intensity of social connections and strengthen social experience. This study’s main objective was to investigate how user interface design affects older people’s intention and attitude related to using SNSs. Fourteen user interface evaluation heuristics proposed by Zhang et al. were adopted as the criteria to assess user interface usability and further grouped into three categories: system support, user interface design and navigation. The technology acceptance model was adopted to assess older people’s intention and attitude related to using SNSs. One hundred and one elderly persons were enrolled in this study as subjects, and the results showed that all of the hypotheses proposed in this study were valid: system support and perceived usefulness had a significant effect on behavioral intention; user interface design and perceived ease of use were positively correlated with perceived usefulness; and navigation exerted an influence on perceived ease of use. The results of this study are valuable for the future development of social applications for the elderly. PMID:28837566

  14. Structural Evidence for Regulation and Specificity of Flaviviral Proteases and Evolution of the Flaviviridae Fold

    Energy Technology Data Exchange (ETDEWEB)

    Aleshin,A.; Shiryaev, S.; Strongin, A.; Liddington, R.

    2007-01-01

    Pathogenic members of the flavivirus family, including West Nile Virus (WNV) and Dengue Virus (DV), are growing global threats for which there are no specific treatments. The two-component flaviviral enzyme NS2B-NS3 cleaves the viral polyprotein precursor within the host cell, a process that is required for viral replication. Here, we report the crystal structure of WNV NS2B-NS3pro both in a substrate-free form and in complex with the trypsin inhibitor aprotinin/BPTI. We show that aprotinin binds in a substrate-mimetic fashion in which the productive conformation of the protease is fully formed, providing evidence for an 'induced fit' mechanism of catalysis and allowing us to rationalize the distinct substrate specificities of WNV and DV proteases. We also show that the NS2B cofactor of WNV can adopt two very distinct conformations and that this is likely to be a general feature of flaviviral proteases, providing further opportunities for regulation. Finally, by comparing the flaviviral proteases with the more distantly related Hepatitis C virus, we provide insights into the evolution of the Flaviviridae fold. Our work should expedite the design of protease inhibitors to treat a range of flaviviral infections.

  15. Skin-specific regulation of SREBP processing and lipid biosynthesis by glycerol kinase 5

    Science.gov (United States)

    Zhang, Duanwu; Tomisato, Wataru; Su, Lijing; Sun, Lei; Choi, Jin Huk; Zhang, Zhao; Wang, Kuan-wen; Zhan, Xiaoming; Choi, Mihwa; Li, Xiaohong; Tang, Miao; Castro-Perez, Jose M.; Hildebrand, Sara; Murray, Anne R.; Moresco, Eva Marie Y.; Beutler, Bruce

    2017-01-01

    The recessive N-ethyl-N-nitrosourea–induced phenotype toku is characterized by delayed hair growth, progressive hair loss, and excessive accumulation of dermal cholesterol, triglycerides, and ceramides. The toku phenotype was attributed to a null allele of Gk5, encoding glycerol kinase 5 (GK5), a skin-specific kinase expressed predominantly in sebaceous glands. GK5 formed a complex with the sterol regulatory element-binding proteins (SREBPs) through their C-terminal regulatory domains, inhibiting SREBP processing and activation. In Gk5toku/toku mice, transcriptionally active SREBPs accumulated in the skin, but not in the liver; they were localized to the nucleus and led to elevated lipid synthesis and subsequent hair growth defects. Similar defective hair growth was observed in kinase-inactive GK5 mutant mice. Hair growth defects of homozygous toku mice were partially rescued by treatment with the HMG-CoA reductase inhibitor simvastatin. GK5 exists as part of a skin-specific regulatory mechanism for cholesterol biosynthesis, independent of cholesterol regulation elsewhere in the body. PMID:28607088

  16. Hypoxia promotes Mycobacterium tuberculosis-specific up-regulation of granulysin in human T cells.

    Science.gov (United States)

    Zenk, Sebastian F; Vollmer, Michael; Schercher, Esra; Kallert, Stephanie; Kubis, Jan; Stenger, Steffen

    2016-06-01

    Oxygen tension affects local immune responses in inflammation and infection. In tuberculosis mycobacteria avoid hypoxic areas and preferentially persist and reactivate in the oxygen-rich apex of the lung. Oxygen restriction activates antimicrobial effector mechanisms in macrophages and restricts growth of intracellular Mycobacterium tuberculosis (M.Tb). The effect of oxygen restriction on T cell-mediated antimicrobial effector mechanisms is unknown. Therefore we determined the influence of hypoxia on the expression of granulysin, an antimicrobial peptide of lymphocytes. Hypoxia increased the antigen-specific up-regulation of granulysin mRNA and protein in human CD4(+) and CD8(+) T lymphocytes. This observation was functionally relevant, because oxygen restriction supported the growth-limiting effect of antigen-specific T cells against virulent M.Tb residing in primary human macrophages. Our results provide evidence that oxygen restriction promotes the expression of granulysin and suggest that this effect-in conjunction with additional T cell-mediated immune responses-supports protection against mycobacteria. The therapeutic modulation of oxygen availability may offer a new strategy for the host-directed therapy of infectious diseases with intracellular pathogens.

  17. Region-specific proteolysis differentially regulates type 1 inositol 1,4,5-trisphosphate receptor activity.

    Science.gov (United States)

    Wang, Liwei; Wagner, Larry E; Alzayady, Kamil J; Yule, David I

    2017-07-14

    The inositol 1,4,5 trisphosphate receptor (IP 3 R) is an intracellular Ca 2+ release channel expressed predominately on the membranes of the endoplasmic reticulum. IP 3 R1 can be cleaved by caspase or calpain into at least two receptor fragments. However, the functional consequences of receptor fragmentation are poorly understood. Our previous work has demonstrated that IP 3 R1 channels, formed following either enzymatic fragmentation or expression of the corresponding complementary polypeptide chains, retain tetrameric architecture and are still activated by IP 3 binding despite the loss of peptide continuity. In this study, we demonstrate that region-specific receptor fragmentation modifies channel regulation. Specifically, the agonist-evoked temporal Ca 2+ release profile and protein kinase A modulation of Ca 2+ release are markedly altered. Moreover, we also demonstrate that activation of fragmented IP 3 R1 can result in a distinct functional outcome. Our work suggests that proteolysis of IP 3 R1 may represent a novel form of modulation of IP 3 R1 channel function and increases the repertoire of Ca 2+ signals achievable through this channel. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. A pollen-specific RALF from tomato that regulates pollen tube elongation.

    Science.gov (United States)

    Covey, Paul A; Subbaiah, Chalivendra C; Parsons, Ronald L; Pearce, Gregory; Lay, Fung T; Anderson, Marilyn A; Ryan, Clarence A; Bedinger, Patricia A

    2010-06-01

    Rapid Alkalinization Factors (RALFs) are plant peptides that rapidly increase the pH of plant suspension cell culture medium and inhibit root growth. A pollen-specific tomato (Solanum lycopersicum) RALF (SlPRALF) has been identified. The SlPRALF gene encodes a preproprotein that appears to be processed and released from the pollen tube as an active peptide. A synthetic SlPRALF peptide based on the putative active peptide did not affect pollen hydration or viability but inhibited the elongation of normal pollen tubes in an in vitro growth system. Inhibitory effects of SlPRALF were detectable at concentrations as low as 10 nm, and complete inhibition was observed at 1 mum peptide. At least 10-fold higher levels of alkSlPRALF, which lacks disulfide bonds, were required to see similar effects. A greater effect of peptide was observed in low-pH-buffered medium. Inhibition of pollen tube elongation was reversible if peptide was removed within 15 min of exposure. Addition of 100 nm SlPRALF to actively growing pollen tubes inhibited further elongation until tubes were 40 to 60 mum in length, after which pollen tubes became resistant to the peptide. The onset of resistance correlated with the timing of the exit of the male germ unit from the pollen grain into the tube. Thus, exogenous SlPRALF acts as a negative regulator of pollen tube elongation within a specific developmental window.

  19. Assessment of effects of differences in trunk posture during Fowler’s position on hemodynamics and cardiovascular regulation in older and younger subjects

    Directory of Open Access Journals (Sweden)

    Kubota S

    2017-03-01

    maintenance of SV and inhibited tachycardic response compared to an upright whole trunk regardless of age, although the autonomic mechanisms underlying tachycardic responses differed between younger and older adults. An upright upper trunk in Fowler’s position might help to reduce orthostatic stress and facilitate routine activities and conversation in frail patients. Keywords: aging, cardiovascular regulation, hemodynamics, Fowler’s position, stroke volume

  20. REGULATED VESICULAR TRAFFICKING OF SPECIFIC PCDH15 AND VLGR1 VARIANTS IN AUDITORY HAIR CELLS

    Science.gov (United States)

    Zallocchi, Marisa; Delimont, Duane; Meehan, Daniel T.; Cosgrove, Dominic

    2012-01-01

    Usher syndrome is a genetically heterogeneous disorder characterized by hearing and balance dysfunction and progressive retinitis pigmentosa. Mouse models carrying mutations for the nine Usher-associated genes have splayed stereocilia and some show delayed maturation of ribbon synapses suggesting these proteins may play different roles in terminal differentiation of auditory hair cells. The presence of the Usher proteins at the basal and apical aspects of the neurosensory epithelia suggests the existence of regulated trafficking through specific transport proteins and routes. Immature mouse cochleae and UB/OC-1 cells were used in this work to address whether specific variants of PCDH15 and VLGR1 are being selectively transported to opposite poles of the hair cells. Confocal co-localization studies between apical and basal vesicular markers and the different PCDH15 and VLGR1 variants along with sucrose density gradients and the use of vesicle trafficking inhibitors show the existence of Usher protein complexes in at least two vesicular sub-pools. The apically trafficked pool co-localized with the early endosomal vesicle marker, rab5, while the basally trafficked pool associates with membrane microdomains and SNAP25. Moreover, co-immunoprecipitation experiments between SNAP25 and VLGR1 show a physical interaction of these two proteins in organ of Corti and brain. Collectively, these findings establish the existence of a differential vesicular trafficking mechanism for specific Usher protein variants in mouse cochlear hair cells, with the apical variants playing a potential role in endosomal recycling and stereocilia development/maintenance and the basolateral variants involved in vesicle docking and/or fusion through SNAP25-mediated interactions. PMID:23035094

  1. Focused transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex modulates specific domains of self-regulation.

    Science.gov (United States)

    Pripfl, Jürgen; Lamm, Claus

    2015-02-01

    Recent neuroscience theories suggest that different kinds of self-regulation may share a common psychobiological mechanism. However, empirical evidence for a domain general self-regulation mechanism is scarce. The aim of this study was to investigate whether focused anodal transcranial direct current stimulation (tDCS), facilitating the activity of the dorsolateral prefrontal cortex (dlPFC), acts on a domain general self-regulation mechanism and thus modulates both affective and appetitive self-regulation. Twenty smokers participated in this within-subject sham controlled study. Effects of anodal left, anodal right and sham tDCS over the dlPFC on affective picture appraisal and nicotine craving-cue appraisal were assessed. Anodal right tDCS over the dlPFC reduced negative affect in emotion appraisal, but neither modulated regulation of positive emotion appraisal nor of craving appraisal. Anodal left stimulation did not induce any significant effects. The results of our study show that domain specific self-regulation networks are at work in the prefrontal cortex. Focused tDCS modulation of this specific self-regulation network could probably be used during the first phase of nicotine abstinence, during which negative affect might easily result in relapse. These findings have implications for neuroscience models of self-regulation and are of relevance for the development of brain stimulation based treatment methods for neuropsychiatric disorders associated with self-regulation deficits. Copyright © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  2. Nidogen-1 regulates laminin-1-dependent mammary-specific gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Pujuguet, Philippe; Simian, Marina; Liaw, Jane; Timpl, Rupert; Werb, Zena; Bissell, Mina J..

    2000-02-01

    Nidogen-1 (entactin) acts as a bridge between the extracellular matrix molecules laminin-1 and type IV collagen, and thus participates in the assembly of basement membranes. To investigate the role of nidogen-1 in regulating cell-type-specific gene expression in mammary epithelium, we designed a culture microecosystem in which each component, including epithelial cells, mesenchymal cells, lactogenic hormones and extracellular matrix, could be controlled. We found that primary and established mesenchymal and myoepithelial cells synthesized and secreted nidogen-1, whereas expression was absent in primary and established epithelial cells. In an epithelial cell line containing mesenchymal cells, nidogen-1 was produced by the mesenchymal cells but deposited between the epithelial cells. In this mixed culture, mammary epithelial cells express b-casein in the presence of lactogenic hormones. Addition of either laminin-1 plus nidogen-1, or laminin-1 alone to mammary epithelial cells induced b- casein production. We asked whether recombinant nidogen-1 alone could signal directly for b-casein. Nidogen-1 did not induce b-casein synthesis in epithelial cells, but it augmented the inductive capacity of laminin-1. These data suggest that nidogen-1 can cooperate with laminin-1 to regulate b-casein expression. Addition of full length nidogen-1 to the mixed cultures had no effect on b-casein gene expression; however, a nidogen-1 fragment containing the laminin-1 binding domain, but lacking the type IV collagen-binding domain, had a dominant negative effect on b-casein expression. These data point to a physiological role for nidogen-1 in the basement membrane-induced gene expression by epithelial cells.

  3. Differential Regulation of Strand-Specific Transcripts from Arabidopsis Centromeric Satellite Repeats.

    Directory of Open Access Journals (Sweden)

    2005-12-01

    Full Text Available Centromeres interact with the spindle apparatus to enable chromosome disjunction and typically contain thousands of tandemly arranged satellite repeats interspersed with retrotransposons. While their role has been obscure, centromeric repeats are epigenetically modified and centromere specification has a strong epigenetic component. In the yeast Schizosaccharomyces pombe, long heterochromatic repeats are transcribed and contribute to centromere function via RNA interference (RNAi. In the higher plant Arabidopsis thaliana, as in mammalian cells, centromeric satellite repeats are short (180 base pairs, are found in thousands of tandem copies, and are methylated. We have found transcripts from both strands of canonical, bulk Arabidopsis repeats. At least one subfamily of 180-base pair repeats is transcribed from only one strand and regulated by RNAi and histone modification. A second subfamily of repeats is also silenced, but silencing is lost on both strands in mutants in the CpG DNA methyltransferase MET1, the histone deacetylase HDA6/SIL1, or the chromatin remodeling ATPase DDM1. This regulation is due to transcription from Athila2 retrotransposons, which integrate in both orientations relative to the repeats, and differs between strains of Arabidopsis. Silencing lost in met1 or hda6 is reestablished in backcrosses to wild-type, but silencing lost in RNAi mutants and ddm1 is not. Twenty-four-nucleotide small interfering RNAs from centromeric repeats are retained in met1 and hda6, but not in ddm1, and may have a role in this epigenetic inheritance. Histone H3 lysine-9 dimethylation is associated with both classes of repeats. We propose roles for transcribed repeats in the epigenetic inheritance and evolution of centromeres.

  4. 50 CFR 32.3 - What are the procedures for publication of refuge-specific hunting regulations?

    Science.gov (United States)

    2010-10-01

    ... and publication of the opening of a wildlife refuge area to migratory game bird, upland game or big game hunting. (b) Refuge-specific hunting regulations may contain the following items: (1) Wildlife... FISHING General Provisions § 32.3 What are the procedures for publication of refuge-specific hunting...

  5. The Down regulated in Adenoma (dra) gene encodes an intestine-specific membrane sulfate transport protein.

    Science.gov (United States)

    Silberg, D G; Wang, W; Moseley, R H; Traber, P G

    1995-05-19

    A gene has been described, Down Regulated in Adenoma (dra), which is expressed in normal colon but is absent in the majority of colon adenomas and adenocarcinomas. However, the function of this protein is unknown. Because of sequence similarity to a recently cloned membrane sulfate transporter in rat liver, the transport function of Dra was examined. We established that dra encodes for a Na(+)-independent transporter for both sulfate and oxalate using microinjected Xenopus oocytes as an assay system. Sulfate transport was sensitive to the anion exchange inhibitor DIDS (4,4'-diisothiocyano-2,2' disulfonic acid stilbene). Using an RNase protection assay, we found that dra mRNA expression is limited to the small intestine and colon in mouse, therefore identifying Dra as an intestine-specific sulfate transporter. dra also had a unique pattern of expression during intestinal development. Northern blot analysis revealed a low level of expression in colon at birth with a marked increase in the first 2 postnatal weeks. In contrast, there was a lower, constant level of expression in small intestine in the postnatal period. Caco-2 cells, a colon carcinoma cell line that differentiates over time in culture, demonstrated a marked induction of dra mRNA as cells progressed from the preconfluent (undifferentiated) to the postconfluent (differentiated) state. These results show that Dra is an intestine-specific Na(+)-independent sulfate transporter that has differential expression during colonic development. This functional characterization provides the foundation for investigation of the role of Dra in intestinal sulfate transport and in the malignant phenotype.

  6. Sex-specific neural circuits of emotion regulation in the centromedial amygdala.

    Science.gov (United States)

    Wu, Yan; Li, Huandong; Zhou, Yuan; Yu, Jian; Zhang, Yuanchao; Song, Ming; Qin, Wen; Yu, Chunshui; Jiang, Tianzi

    2016-03-23

    Sex-related differences in emotion regulation (ER) in the frequency power distribution within the human amygdala, a brain region involved in emotion processing, have been reported. However, how sex differences in ER are manifested in the brain networks which are seeded on the amygdala subregions is unclear. The goal of this study was to investigate this issue from a brain network perspective. Utilizing resting-state functional connectivity (RSFC) analysis, we found that the sex-specific functional connectivity patterns associated with ER trait level were only seeded in the centromedial amygdala (CM). Women with a higher trait-level ER had a stronger negative RSFC between the right CM and the medial superior frontal gyrus (mSFG), and stronger positive RSFC between the right CM and the anterior insula (AI) and the superior temporal gyrus (STG). But men with a higher trait-level ER was associated with weaker negative RSFC of the right CM-mSFG and positive RSFCs of the right CM-left AI, right CM-right AI/STG, and right CM-left STG. These results provide evidence for the sex-related effects in ER based on CM and indicate that men and women may differ in the neural circuits associated with emotion representation and integration.

  7. Chronic medical conditions and mental health in older people : disability and psychosocial resources mediate specific mental health effects

    NARCIS (Netherlands)

    Ormel, J; Kempen, GIJM; Penninx, BWJH; Brilman, EI; Beekman, ATF; VanSonderen, E

    Background. This study describes the differences in psychological distress, disability and psychosocial resources between types of major medical conditions and sensory impairments (collectively denoted as CMCs); and tests whether disability and psychosocial resources mediate CMC-specific mental

  8. Macoilin, a conserved nervous system-specific ER membrane protein that regulates neuronal excitability.

    Directory of Open Access Journals (Sweden)

    Fausto Arellano-Carbajal

    2011-03-01

    Full Text Available Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O₂ responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca²(+ transients, at least in some neurons: in maco-1 mutants the O₂-sensing neuron PQR is unable to generate a Ca²(+ response to a rise in O₂. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O₂, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca²(+ channels, also fails to disrupt Ca²(+ responses in the PQR cell body to O₂ stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca²(+ channel α1 subunit, recapitulate the Ca²(+ response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or

  9. Regulation of Msx genes by a Bmp gradient is essential for neural crest specification.

    Science.gov (United States)

    Tribulo, Celeste; Aybar, Manuel J; Nguyen, Vu H; Mullins, Mary C; Mayor, Roberto

    2003-12-01

    There is evidence in Xenopus and zebrafish embryos that the neural crest/neural folds are specified at the border of the neural plate by a precise threshold concentration of a Bmp gradient. In order to understand the molecular mechanism by which a gradient of Bmp is able to specify the neural crest, we analyzed how the expression of Bmp targets, the Msx genes, is regulated and the role that Msx genes has in neural crest specification. As Msx genes are directly downstream of Bmp, we analyzed Msx gene expression after experimental modification in the level of Bmp activity by grafting a bead soaked with noggin into Xenopus embryos, by expressing in the ectoderm a dominant-negative Bmp4 or Bmp receptor in Xenopus and zebrafish embryos, and also through Bmp pathway component mutants in the zebrafish. All the results show that a reduction in the level of Bmp activity leads to an increase in the expression of Msx genes in the neural plate border. Interestingly, by reaching different levels of Bmp activity in animal cap ectoderm, we show that a specific concentration of Bmp induces msx1 expression to a level similar to that required to induce neural crest. Our results indicate that an intermediate level of Bmp activity specifies the expression of Msx genes in the neural fold region. In addition, we have analyzed the role that msx1 plays on neural crest specification. As msx1 has a role in dorsoventral pattering, we have carried out conditional gain- and loss-of-function experiments using different msx1 constructs fused to a glucocorticoid receptor element to avoid an early effect of this factor. We show that msx1 expression is able to induce all other early neural crest markers tested (snail, slug, foxd3) at the time of neural crest specification. Furthermore, the expression of a dominant negative of Msx genes leads to the inhibition of all the neural crest markers analyzed. It has been previously shown that snail is one of the earliest genes acting in the neural crest

  10. Tissue-specific down-regulation of RIPK 2 in Mycobacterium leprae-infected nu/nu mice

    Directory of Open Access Journals (Sweden)

    Gue-Tae Chae

    1992-01-01

    Full Text Available RIPK 2 is adapter molecule in the signal pathway involved in Toll-like receptors. However, there has been no reported association between receptor-interacting serine/threonine kinase 2 (RIPK 2 expression and the infectious diseases involving mycobacterial infection. This study found that its expression was down-regulated in the footpads and skin but was up-regulated in the liver of Mycobacterium leprae-infected nu/nu mice compared with those of the M. leprae non-infected nu/nu mice. It was observed that the interlukin-12p40 and interferon-γ genes involved in the susceptibility of M. leprae were down-regulated in the skin but were up-regulated in the liver. Overall, this suggests that regulation of RIPK 2 expression is tissue-specifically associated with M. leprae infection.

  11. Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide

    OpenAIRE

    Fomenko, Dmitri E.; Koc, Ahmet; Agisheva, Natalia; Jacobsen, Michael; Kaya, Alaattin; Malinouski, Mikalai; Rutherford, Julian C.; Siu, Kam-Leung; Jin, Dong-Yan; Winge, Dennis R.; Gladyshev, Vadim N.

    2011-01-01

    Hydrogen peroxide is thought to regulate cellular processes by direct oxidation of numerous cellular proteins, whereas antioxidants, most notably thiol peroxidases, are thought to reduce peroxides and inhibit H2O2 response. However, thiol peroxidases have also been implicated in activation of transcription factors and signaling. It remains unclear if these enzymes stimulate or inhibit redox regulation and whether this regulation is widespread or limited to a few cellular components. Herein, w...

  12. Skin-specific regulation of SREBP processing and lipid biosynthesis by glycerol kinase 5

    OpenAIRE

    Zhang, Duanwu; Tomisato, Wataru; Su, Lijing; Sun, Lei; Choi, Jin Huk; Zhang, Zhao; Wang, Kuan-wen; Zhan, Xiaoming; Choi, Mihwa; Li, Xiaohong; Tang, Miao; Castro-Perez, Jose M.; Hildebrand, Sara; Murray, Anne R.; Moresco, Eva Marie Y.

    2017-01-01

    We discovered a previously unrecognized regulator of cholesterol biosynthesis, glycerol kinase 5 (GK5), which functions exclusively in the skin independently of cholesterol regulation in other tissues. GK5 negatively regulates the processing and nuclear localization of sterol regulatory element binding proteins, transcription factors that control expression of virtually all cholesterol synthesis enzymes. Excessive amounts of cholesterol, triglycerides, and ceramides were found in the skin of ...

  13. Sex-specific relationships of physical activity, body composition, and muscle quality with lower-extremity physical function in older men and women.

    Science.gov (United States)

    Straight, Chad R; Brady, Anne O; Evans, Ellen

    2015-03-01

    This study aims to determine the sex-specific relationships of physical activity, body composition, and muscle quality with lower-extremity physical function in older men and women. Seventy-nine community-dwelling men (n = 39; mean [SD] age, 76.1 [6.2] y; mean [SD] body mass index, 27.3 [3.8] kg/m(2)) and women (n = 40; mean [SD] age, 75.8 [5.5] y; mean [SD] body mass index, 27.0 [3.8] kg/m(2)) were assessed for physical activity via questionnaire, body composition via dual-energy x-ray absorptiometry scanning, leg extension power using the Nottingham power rig, and muscle quality (W/kg; the ratio of leg extension power [W] to lower-body mineral-free lean mass [kg]). A composite measure of physical function was obtained by summing Z scores from the 6-minute walk, 8-ft up-and-go test, and 30-second chair-stand test. As expected, men had significantly greater levels of physical activity, lower adiposity, greater lean mass, higher leg extension power, and greater muscle quality compared with women (all P physical activity were the strongest predictors of lower-extremity physical function in men and independently explained 42% and 29% of the variance, respectively. In women, muscle quality (16%) and percent body fat (12%) were independent predictors after adjustment for covariates. Muscle quality is the strongest predictor of lower-extremity physical function in men and women, but sex impacts the importance of physical activity and adiposity. These findings suggest that older men and women may benefit from different intervention strategies for preventing physical disability and also highlight the importance of weight management for older women to preserve physical function.

  14. Practice specific model regulations: Radiation safety of non-medical irradiation facilities. Interim report for comment

    International Nuclear Information System (INIS)

    2003-08-01

    the infrastructure aimed at achieving its maximum efficiency, and extensively covers performance regulations. The BSS cover the application of ionizing radiation for all practices and interventions and are, therefore, basic and general in nature. Users must apply these basic requirements to their own particular practices. In this context, the preamble of the BSS states that: 'The Regulatory Authority may need to provide guidance on how certain regulatory requirements are to be fulfilled for various practices, for example in regulatory guideline documents.' There are certain requirements that, when applied to specific practices, can be fulfilled through virtually only one practical solution. In these cases, the regulatory authority would use a 'shall' statement for this solution. To meet other requirements, there may be more than one option. In these cases the regulatory authority would usually indicate the recommended option with a 'should' statement, which implies that licensees may choose another alternative provided that the level of safety is equivalent. This distinction has been maintained in this 'model regulations' for irradiation facilities in order to facilitate the decision of regulatory authorities on the degree of obligation

  15. Specific micro RNA-regulated TetR-KRAB transcriptional control of transgene expression in viral vector-transduced cells.

    Directory of Open Access Journals (Sweden)

    Virginie Pichard

    Full Text Available Precise control of transgene expression in a tissue-specific and temporally regulated manner is desirable for many basic and applied investigations gene therapy applications. This is important to regulate dose of transgene products and minimize unwanted effects. Previously described methods have employed tissue specific promoters, miRNA-based transgene silencing or tetR-KRAB-mediated suppression of transgene promoters. To improve on versatility of transgene expression control, we have developed expression systems that use combinations of a tetR-KRAB artificial transgene-repressor, endogenous miRNA silencing machinery and tissue specific promoters. Precise control of transgene expression was demonstrated in liver-, macrophage- and muscle-derived cells. Efficiency was also demonstrated in vivo in murine muscle. This multicomponent and modular regulatory system provides a robust and easily adaptable method for achieving regulated transgene expression in different tissue types. The improved precision of regulation will be useful for many gene therapy applications requiring specific spatiotemporal transgene regulation.

  16. Chl1 DNA helicase regulates Scc2 deposition specifically during DNA-replication in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Soumya Rudra

    Full Text Available The conserved family of cohesin proteins that mediate sister chromatid cohesion requires Scc2, Scc4 for chromatin-association and Eco1/Ctf7 for conversion to a tethering competent state. A popular model, based on the notion that cohesins form huge ring-like structures, is that Scc2, Scc4 function is essential only during G1 such that sister chromatid cohesion results simply from DNA replisome passage through pre-loaded cohesin rings. In such a scenario, cohesin deposition during G1 is temporally uncoupled from Eco1-dependent establishment reactions that occur during S-phase. Chl1 DNA helicase (homolog of human ChlR1/DDX11 and BACH1/BRIP1/FANCJ helicases implicated in Fanconi anemia, breast and ovarian cancer and Warsaw Breakage Syndrome plays a critical role in sister chromatid cohesion, however, the mechanism through which Chl1 promotes cohesion remains poorly understood. Here, we report that Chl1 promotes Scc2 loading unto DNA such that both Scc2 and cohesin enrichment to chromatin are defective in chl1 mutant cells. The results further show that both Chl1 expression and chromatin-recruitment are tightly regulated through the cell cycle, peaking during S-phase. Importantly, kinetic ChIP studies reveals that Chl1 is required for Scc2 chromatin-association specifically during S-phase, but not during G1. Despite normal chromatin enrichment of both Scc2 and cohesin during G1, chl1 mutant cells exhibit severe chromosome segregation and cohesion defects--revealing that G1-loaded cohesins is insufficient to promote cohesion. Based on these findings, we propose a new model wherein S-phase cohesin loading occurs during DNA replication and in concert with both cohesion establishment and chromatin assembly reactions--challenging the notion that DNA replication fork navigates through or around pre-loaded cohesin rings.

  17. BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation

    Directory of Open Access Journals (Sweden)

    Elizabeth E Manning

    2013-06-01

    Full Text Available Brain-derived neurotrophic factor (BDNF has been implicated in the pathophysiology of schizophrenia, yet its role in the development of specific symptoms is unclear. Methamphetamine (METH users have an increased risk of psychosis and schizophrenia, and METH-treated animals have been used extensively as a model to study the positive symptoms of schizophrenia. We investigated whether METH treatment in BDNF heterozygous mutant mice (HET has cumulative effects on sensorimotor gating, including the disruptive effects of psychotropic drugs. BDNF HETs and WT littermates were treated during young-adulthood with METH and, following a two-week break, prepulse inhibition (PPI was examined. At baseline, BDNF HETs showed reduced PPI compared to WT mice irrespective of METH pre-treatment. An acute challenge with amphetamine (AMPH disrupted PPI but male BDNF HETs were more sensitive to this effect, irrespective of METH pre-treatment. In contrast, female mice treated with METH were less sensitive to the disruptive effects of AMPH, and there were no effects of BDNF genotype. Similar changes were not observed in the response to an acute apomorphine or MK-801 challenge. These results show that genetically-induced reduction of BDNF caused changes in a behavioural endophenotype relevant to the positive symptoms of schizophrenia. However, major sex differences were observed in the effects of a psychotropic drug challenge on this behaviour. These findings suggest sex differences in the effects of BDNF depletion and METH treatment on the monoamine signaling pathways that regulate PPI. Given that these same pathways are thought to contribute to the expression of positive symptoms in schizophrenia, this work suggests that there may be significant sex differences in the pathophysiology underlying these symptoms. Elucidating these sex differences may be important for our understanding of the neurobiology of schizophrenia and developing better treatments strategies for the

  18. IGFBP-4 regulates adult skeletal growth in a sex-specific manner.

    Science.gov (United States)

    Maridas, David E; DeMambro, Victoria E; Le, Phuong T; Nagano, Kenichi; Baron, Roland; Mohan, Subburaman; Rosen, Clifford J

    2017-04-01

    Insulin-like growth factor-1 (IGF-1) and its binding proteins are critical mediators of skeletal growth. Insulin-like growth factor-binding protein 4 (IGFBP-4) is highly expressed in osteoblasts and inhibits IGF-1 actions in vitro Yet, in vivo studies suggest that it could potentiate IGF-1 and IGF-2 actions. In this study, we hypothesized that IGFBP-4 might potentiate the actions of IGF-1 on the skeleton. To test this, we comprehensively studied 8- and 16-week-old Igfbp4 -/- mice. Both male and female adult Igfbp4 -/- mice had marked growth retardation with reductions in body weight, body and femur lengths, fat proportion and lean mass at 8 and 16 weeks. Marked reductions in aBMD and aBMC were observed in 16-week-old Igfbp4 -/- females, but not in males. Femoral trabecular BV/TV and thickness, cortical fraction and thickness in 16-week-old Igfbp4 -/- females were significantly reduced. However, surprisingly, males had significantly more trabeculae with higher connectivity density than controls. Concordantly, histomorphometry revealed higher bone resorption and lower bone formation in Igfbp4 -/- females. In contrast, Igfbp4 -/- males had lower mineralized surface/bone surface. Femoral expression of Sost and circulating levels of sclerostin were reduced but only in Igfbp4 -/- males. Bone marrow stromal cultures from mutants showed increased osteogenesis, whereas osteoclastogenesis was markedly increased in cells from Igfbp4 -/- females but decreased in males. In sum, our results indicate that loss of Igfbp4 affects mesenchymal stromal cell differentiation, regulates osteoclastogenesis and influences both skeletal development and adult bone maintenance. Thus, IGFBP-4 modulates the skeleton in a gender-specific manner, acting as both a cell autonomous and cell non-autonomous factor. © 2017 The authors.

  19. Targeting Complex Sentences in Older School Children with Specific Language Impairment: Results from an Early-Phase Treatment Study

    Science.gov (United States)

    Balthazar, Catherine H.; Scott, Cheryl M.

    2018-01-01

    Purpose: This study investigated the effects of a complex sentence treatment at 2 dosage levels on language performance of 30 school-age children ages 10-14 years with specific language impairment. Method: Three types of complex sentences (adverbial, object complement, relative) were taught in sequence in once or twice weekly dosage conditions.…

  20. How balance task-specific training contributes to improving physical function in older subjects undergoing rehabilitation following hip fracture: a randomized controlled trial.

    Science.gov (United States)

    Monticone, Marco; Ambrosini, Emilia; Brunati, Roberto; Capone, Antonio; Pagliari, Giulia; Secci, Claudio; Zatti, Giovanni; Ferrante, Simona

    2018-03-01

    To evaluate the efficacy of a rehabilitation programme including balance task-specific training in improving physical function, pain, activities of daily living (ADL), balance and quality of life in subjects after a hip fracture. Randomized controlled trial. A total of 52 older subjects selected for internal fixation due to extra-capsular hip fracture were randomized to be included in an experimental ( n = 26) and control group ( n = 26). The experimental group underwent a rehabilitation programme based on balance task-specific training. The control group underwent general physiotherapy, including open kinetic chain exercises and walking training. Both groups individually followed programmes of 90-minute sessions five times/week for three weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a Pain Numerical Rating Scale, the Berg Balance Scale, the Functional Independence Measure and the 36-item Short-Form Health Survey. The participants were evaluated before and after training, and after 12 months. Significant effects of time, group and time × group were found for all outcome measures in favour of the experimental group. A clinically important between-group difference of 25 points was achieved after training and at follow-up in terms of the primary outcome (WOMAC function before treatment, after treatment and at follow-up was 84.8 (3.7), 39.8 (4.9) and 35.7 (6.2) for the experimental group and 80.9 (5.7), 65.2 (7.1) and 61.0 (11.1) for the control group). An inpatient rehabilitation programme based on balance task-specific training is useful in improving physical function, pain, ADL and quality of life in older patients after hip fracture.

  1. Impact of metacognition and motivation on the efficacy of strategic memory training in older adults: analysis of specific, transfer and maintenance effects.

    Science.gov (United States)

    Carretti, Barbara; Borella, Erika; Zavagnin, Michela; De Beni, Rossana

    2011-01-01

    The current study examines the contribution of a number of metacognitive and motivational variables in explaining specific, transfer and maintenance effects of a strategic memory training program, based on the use of mental imagery, in older adults. Participants were assessed before and after the training (immediately post-test, and at 3- and 6-month follow-up) on list recall (criterion) and working memory (transfer) tasks. At the pre-test, metacognition (use of strategies, belief about memory, control on memory) and motivational measures (cognitive engagement, self-efficacy) were also collected. The training produced a benefit in both the criterion and transfer tasks, which was maintained at follow-up. Some of the metacognitive and motivational measures, over and above the level of performance obtained at pre-test, predicted the gains in the objective memory measures. The findings confirmed the importance of considering the role of metacognitive attitudes of older adults in memory training activities. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  2. Wnt signaling positively regulates endothelial cell fate specification in the Fli1a-positive progenitor population via Lef1.

    Science.gov (United States)

    Hübner, Kathleen; Grassme, Kathrin S; Rao, Jyoti; Wenke, Nina K; Zimmer, Cordula L; Korte, Laura; Mu Ller, Katja; Sumanas, Saulius; Greber, Boris; Herzog, Wiebke

    2017-10-01

    During vertebrate embryogenesis, vascular endothelial cells (ECs) and primitive erythrocytes become specified within close proximity in the posterior lateral plate mesoderm (LPM) from a common progenitor. However, the signaling cascades regulating the specification into either lineage remain largely elusive. Here, we analyze the contribution of β-catenin dependent Wnt signaling to EC and erythrocyte specification during zebrafish embryogenesis. We generated novel β-catenin dependent Wnt signaling reporters which, by using destabilized fluorophores (Venus-Pest, dGFP), specifically allow us to detect Wnt signaling responses in narrow time windows as well as in spatially restricted domains, defined by Cre recombinase expression (Tg(axin2 BAC :Venus-Pest) mu288 ; Tg(14TCF:loxP-STOP-loxP-dGFP) mu202 ). We therefore can detect β-catenin dependent Wnt signaling activity in a subset of the Fli1a-positive progenitor population. Additionally, we show that mesodermal Wnt3a-mediated signaling via the transcription factor Lef1 positively regulates EC specification (defined by kdrl expression) at the expense of primitive erythrocyte specification (defined by gata1 expression) in zebrafish embryos. Using mesoderm derived from human embryonic stem cells, we identified the same principle of Wnt signaling dependent EC specification in conjunction with auto-upregulation of LEF1. Our data indicate a novel role of β-catenin dependent Wnt signaling in regulating EC specification during vasculogenesis. Copyright © 2017. Published by Elsevier Inc.

  3. 75 FR 18413 - 2009-2010 Refuge-Specific Hunting and Sport Fishing Regulations-Additions

    Science.gov (United States)

    2010-04-12

    ... industry (such as hotels, gas stations, taxidermy shops, bait and tackle shops, etc.) may be impacted from... near the time of acquisition. These regulations ensure that we make the determinations required by...

  4. GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters.

    Science.gov (United States)

    Ramesh, Sunita A; Tyerman, Stephen D; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A; Ryan, Peter R; Gilliham, Matthew; Gillham, Matthew

    2015-07-29

    The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms.

  5. What's the FOX Got to Do with the KITten? Regulating the Lineage-Specific Transcriptional Landscape in GIST.

    Science.gov (United States)

    Lee, Donna M; Duensing, Anette

    2018-02-01

    Transcriptional regulation of the KIT receptor tyrosine kinase, a master regulator in gastrointestinal stromal tumors (GIST) and their precursors, the interstitial cells of Cajal (ICC), is part of a positive feedback loop involving the transcription factor ETV1. A new study now shows that the forkhead box (FOX) family transcription factor FOXF1 not only is an upstream regulator of ETV1 and hence ICC/GIST lineage-specific gene transcription, but also functions as lineage-specific pioneer factor with an active role in chromatin rearrangement to facilitate ETV1 binding and transcriptional activity. Cancer Discov; 8(2); 146-9. ©2018 AACR See related article by Ran et al., p. 234 . ©2018 American Association for Cancer Research.

  6. Specificity Protein (Sp) Transcription Factors and Metformin Regulate Expression of the Long Non-coding RNA HULC

    Science.gov (United States)

    There is evidence that specificity protein 1 (Sp1) transcription factor (TF) regulates expression of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) cells. RNA interference (RNAi) studies showed that among several lncRNAs expressed in HepG2, SNU-449 and SK-Hep-1...

  7. MicroRNA-regulated non-viral vectors with improved tumor specificity in an orthotopic rat model of hepatocellular carcinoma

    DEFF Research Database (Denmark)

    Ronald, J A; Katzenberg, R; Nielsen, Carsten Haagen

    2013-01-01

    In hepatocellular carcinoma (HCC), tumor specificity of gene therapy is of utmost importance to preserve liver function. MicroRNAs (miRNAs) are powerful negative regulators of gene expression and many are downregulated in human HCC. We identified seven miRNAs that are also downregulated in tumors...

  8. The Ubiquitin-Specific Protease 14 (USP14) Is a Critical Regulator of Long-Term Memory Formation

    Science.gov (United States)

    Jarome, Timothy J.; Kwapis, Janine L.; Hallengren, Jada J.; Wilson, Scott M.; Helmstetter, Fred J.

    2014-01-01

    Numerous studies have suggested a role for ubiquitin-proteasome-mediated protein degradation in learning-dependent synaptic plasticity; however, very little is known about how protein degradation is regulated at the level of the proteasome during memory formation. The ubiquitin-specific protease 14 (USP14) is a proteasomal deubiquitinating enzyme…

  9. Substrate Specificity, Membrane Topology, and Activity Regulation of Human Alkaline Ceramidase 2 (ACER2)*

    OpenAIRE

    Sun, Wei; Jin, Junfei; Xu, Ruijuan; Hu, Wei; Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui

    2010-01-01

    Human alkaline ceramidase 2 (ACER2) plays an important role in cellular responses by regulating the hydrolysis of ceramides in cells. Here we report its biochemical characterization, membrane topology, and activity regulation. Recombinant ACER2 was expressed in yeast mutant cells (Δypc1Δydc1) that lack endogenous ceramidase activity, and microsomes from ACER2-expressiong yeast cells were used to biochemically characterize ACER2. ACER2 catalyzed the hydrolysis of various ceramides and followed...

  10. Recent Progress in Understanding Subtype Specific Regulation of NMDA Receptors by G Protein Coupled Receptors (GPCRs

    Directory of Open Access Journals (Sweden)

    Kai Yang

    2014-02-01

    Full Text Available G Protein Coupled Receptors (GPCRs are the largest family of receptors whose ligands constitute nearly a third of prescription drugs in the market. They are widely involved in diverse physiological functions including learning and memory. NMDA receptors (NMDARs, which belong to the ionotropic glutamate receptor family, are likewise ubiquitously expressed in the central nervous system (CNS and play a pivotal role in learning and memory. Despite its critical contribution to physiological and pathophysiological processes, few pharmacological interventions aimed directly at regulating NMDAR function have been developed to date. However, it is well established that NMDAR function is precisely regulated by cellular signalling cascades recruited downstream of G protein coupled receptor (GPCR stimulation. Accordingly, the downstream regulation of NMDARs likely represents an important determinant of outcome following treatment with neuropsychiatric agents that target selected GPCRs. Importantly, the functional consequence of such regulation on NMDAR function varies, based not only on the identity of the GPCR, but also on the cell type in which relevant receptors are expressed. Indeed, the mechanisms responsible for regulating NMDARs by GPCRs involve numerous intracellular signalling molecules and regulatory proteins that vary from one cell type to another. In the present article, we highlight recent findings from studies that have uncovered novel mechanisms by which selected GPCRs regulate NMDAR function and consequently NMDAR-dependent plasticity.

  11. Socioeconomic Factors and All Cause and Cause-Specific Mortality among Older People in Latin America, India, and China: A Population-Based Cohort Study

    OpenAIRE

    Ferri, Cleusa P.; Acosta, Daisy; Guerra, Mariella; Huang, Yueqin; Llibre-Rodriguez, Juan J.; Salas, Aquiles; Sosa, Ana Luisa; Williams, Joseph D.; Gaona, Ciro; Liu, Zhaorui; Noriega-Fernandez, Lisseth; Jotheeswaran, A. T.; Prince, Martin J.

    2012-01-01

    Editors' Summary Background Worldwide, half of all deaths occur in people aged 60 or older. Yet mortality among older people is a neglected topic in global health. In high income countries, where 84% of people do not die until they are aged 65 years or older, the causes of death among older people and the factors (determinants) that affect their risk of dying are well documented. In Europe, for example, the leading causes of death among older people are heart disease, stroke, and other chroni...

  12. Methodological Aspects of Subjective Life Expectancy: Effects of Culture-Specific Reporting Heterogeneity Among Older Adults in the United States.

    Science.gov (United States)

    Lee, Sunghee; Smith, Jacqui

    2016-05-01

    Subjective life expectancy (SLE) has been suggested as a predictor of mortality and mortality-related behaviors. Although critical for culturally diverse societies, these findings do not consider cross-cultural methodological comparability. Culture-specific reporting heterogeneity is a well-known phenomenon introducing biases, and research on this issue with SLE is not established. Using data from the Health and Retirement Study, we examined reporting heterogeneity in SLE focusing on item nonresponse, focal points, and reports over time for five ethnic-cultural groups: non-Hispanic Whites, non-Hispanic Blacks, non-Hispanic other races, English-interviewed Hispanics, and Spanish-interviewed Hispanics. On item nonresponse, Spanish-interviewed Hispanics said, "I don't know," to SLE significantly more than any other groups. Nearly half of the respondents chose 0, 50, or 100, making them focal points. However, the focal points differed: 50 for Whites, 100 for Blacks, and 0 for Spanish-interviewed Hispanics. The relationship of SLE measured at two time points was higher for Whites than minorities. Moreover, those who said "I don't know" to SLE showed higher subsequent mortality than those who gave an answer. SLE was not a significant mortality predictor for Hispanics. Overall, SLE is not free from culture-specific reporting heterogeneity. This warrants further research about its culture-relevant measurement mechanisms. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Extensions of the Rosner-Colditz breast cancer prediction model to include older women and type-specific predicted risk.

    Science.gov (United States)

    Glynn, Robert J; Colditz, Graham A; Tamimi, Rulla M; Chen, Wendy Y; Hankinson, Susan E; Willett, Walter W; Rosner, Bernard

    2017-08-01

    A breast cancer risk prediction rule previously developed by Rosner and Colditz has reasonable predictive ability. We developed a re-fitted version of this model, based on more than twice as many cases now including women up to age 85, and further extended it to a model that distinguished risk factor prediction of tumors with different estrogen/progesterone receptor status. We compared the calibration and discriminatory ability of the original, the re-fitted, and the type-specific models. Evaluation used data from the Nurses' Health Study during the period 1980-2008, when 4384 incident invasive breast cancers occurred over 1.5 million person-years. Model development used two-thirds of study subjects and validation used one-third. Predicted risks in the validation sample from the original and re-fitted models were highly correlated (ρ = 0.93), but several parameters, notably those related to use of menopausal hormone therapy and age, had different estimates. The re-fitted model was well-calibrated and had an overall C-statistic of 0.65. The extended, type-specific model identified several risk factors with varying associations with occurrence of tumors of different receptor status. However, this extended model relative to the prediction of any breast cancer did not meaningfully reclassify women who developed breast cancer to higher risk categories, nor women remaining cancer free to lower risk categories. The re-fitted Rosner-Colditz model has applicability to risk prediction in women up to age 85, and its discrimination is not improved by consideration of varying associations across tumor subtypes.

  14. Associations among workplace environment, self-regulation, and domain-specific physical activities among white-collar workers: a multilevel longitudinal study.

    Science.gov (United States)

    Watanabe, Kazuhiro; Kawakami, Norito; Otsuka, Yasumasa; Inoue, Shigeru

    2018-05-31

    Psychological and environmental determinants have been discussed for promoting physical activity among workers. However, few studies have investigated effects of both workplace environment and psychological determinants on physical activity. It is also unknown which domains of physical activities are promoted by these determinants. This study aimed to investigate main and interaction effects of workplace environment and individual self-regulation for physical activity on domain-specific physical activities among white-collar workers. A multi-site longitudinal study was conducted at baseline and about 5-month follow-up. A total of 49 worksites and employees within the worksites were recruited. Inclusion criteria for the worksites (a) were located in the Kanto area, Japan and (b) employed two or more employees. Employee inclusion criteria were (a) employed by the worksites, (b) aged 18 years or older, and (c) white-collar workers. For outcomes, three domain-specific physical activities (occupational, transport-related, and leisure-time) at baseline and follow-up were measured. For independent variables, self-regulation for physical activity, workplace environments (parking/bike, signs/bulletin boards/advertisements, stairs/elevators, physical activity/fitness facilities, work rules, written policies, and health promotion programs), and covariates at baseline were measured. Hierarchical Linear Modeling was conducted to investigate multilevel associations. Of the recruited worksites, 23 worksites and 562 employees, and 22 worksites and 459 employees completed the baseline and the follow-up surveys. As results of Hierarchical Linear Modeling, stairs/elevator (γ=3.80 [SE=1.80], ppsychological approaches to increase effect sizes to promote overall physical activity.

  15. Considering an Affect Regulation Framework for Examining the Association Between Body Dissatisfaction and Positive Body Image in Black Older Adolescent Females: Does Body Mass Index Matter?

    Science.gov (United States)

    Butler-Ajibade, Phoebe; Robinson, Seronda A.

    2014-01-01

    The present study provided an initial evaluation of an affect regulation model describing the association between body dissatisfaction and two contemporary measures of positive body image among 247 Black college-bound older adolescent females. We further tested whether possessing a higher body mass index (BMI) would strengthen these associations. Self-reported height and weight were used to calculate BMI. Respondents also completed a culturally-sensitive figure rating scale along with assessments of body appreciation and body image flexibility. Results indicated a robust positive association between the two measures of positive body image; BMI was the strongest predictor of both body appreciation and body image flexibility with body size discrepancy (current minus ideal) contributing incremental variance to both models tested. Implications for improving our understanding of the association between positive and negative body image and bolstering positive body image to promote health-protective behaviors among Black young women at this developmental juncture are discussed. PMID:25079011

  16. Characterization of upstream sequences of the LIM2 gene that bind developmentally regulated and lens-specific proteins

    Institute of Scientific and Technical Information of China (English)

    HSU Heng; Robert L. CHURCH

    2004-01-01

    During lens development, lens epithelial cells differentiate into fiber cells. To date, four major lens fiber cell intrinsic membrane proteins (MIP) ranging in size from 70 kD to 19 kD have been characterized. The second most abundant lens fiber cell intrinsic membrane protein is MP19. This protein probably is involved with lens cell communication and relates with cataractogenesis. The aim of this research is to characterize upstream sequences of the MP19 (also called LIM2) gene that bind developmentally regulated and lens-specific proteins. We have used the gel mobility assays and corresponding competition experiments to identify and characterize cis elements within approximately 500 bases of LIM2 upstream sequences. Our studies locate the positions of some cis elements, including a "CA" repeat, a methylation Hha I island, an FnuD II site, an Ap1 and an Ap2 consensus sequences, and identify some specific cis elements which relate to lens-specific transcription of LIM2. Our experiments also preliminarily identify trans factors which bind to specific cis elements of the LIM2 promoter and/or regulate transcription of LIM2. We conclude that developmental regulation and coordination of the MP 19 gene in ocular lens fiber cells is controlled by the presence of specific cis elements that bind regulatory trans factors that affect LIM2 gene expression. DNA methylation is one mechanism of controlling LIM2 gene expression during lens development.

  17. Sex-specific predictors of hearing-aid use in older persons: The age, gene/environment susceptibility - Reykjavik study

    Science.gov (United States)

    Fisher, Diana E.; Li, Chuan-Ming; Hoffman, Howard J.; Chiu, May S.; Themann, Christa L.; Petersen, Hannes; Jonsson, Palmi V.; Jonsson, Helgi; Jonasson, Fridbert; Sverrisdottir, Johanna Eyrun; Launer, Lenore J.; Eiriksdottir, Gudny; Gudnason, Vilmundur; Cotch, Mary Frances

    2015-01-01

    Objective We estimate the prevalence of hearing-aid use in Iceland and identify sex-specific factors associated with use. Design Population-based cohort study. Study sample A total of 5172 age, gene/environment susceptibility - Reykjavik study (AGES-RS) participants, aged 67 to 96 years (mean age 76.5 years), who completed air-conduction and pure-tone audiometry. Results Hearing-aid use was reported by 23.0% of men and 15.9% of women in the cohort, although among participants with at least moderate hearing loss in the better ear (pure-tone average [PTA] of thresholds at 0.5, 1, 2, and 4 kHz ≥ 35 dB hearing level [HL]) it was 49.9% and did not differ by sex. Self-reported hearing loss was the strongest predictor of hearing-aid use in men [OR: 2.68 (95% CI: 1.77, 4.08)] and women [OR: 3.07 (95% CI: 1.94, 4.86)], followed by hearing loss severity based on audiometry. Having diabetes or osteoarthritis were significant positive predictors of use in men, whereas greater physical activity and unimpaired cognitive status were important in women. Conclusions Hearing-aid use was comparable in Icelandic men and women with moderate or greater hearing loss. Self-recognition of hearing loss was the factor most predictive of hearing-aid use; other influential factors differed for men and women. PMID:25816699

  18. Thiol peroxidases mediate specific genome-wide regulation of gene expression in response to hydrogen peroxide

    Science.gov (United States)

    Fomenko, Dmitri E.; Koc, Ahmet; Agisheva, Natalia; Jacobsen, Michael; Kaya, Alaattin; Malinouski, Mikalai; Rutherford, Julian C.; Siu, Kam-Leung; Jin, Dong-Yan; Winge, Dennis R.; Gladyshev, Vadim N.

    2011-01-01

    Hydrogen peroxide is thought to regulate cellular processes by direct oxidation of numerous cellular proteins, whereas antioxidants, most notably thiol peroxidases, are thought to reduce peroxides and inhibit H2O2 response. However, thiol peroxidases have also been implicated in activation of transcription factors and signaling. It remains unclear if these enzymes stimulate or inhibit redox regulation and whether this regulation is widespread or limited to a few cellular components. Herein, we found that Saccharomyces cerevisiae cells lacking all eight thiol peroxidases were viable and withstood redox stresses. They transcriptionally responded to various redox treatments, but were unable to activate and repress gene expression in response to H2O2. Further studies involving redox transcription factors suggested that thiol peroxidases are major regulators of global gene expression in response to H2O2. The data suggest that thiol peroxidases sense and transfer oxidative signals to the signaling proteins and regulate transcription, whereas a direct interaction between H2O2 and other cellular proteins plays a secondary role. PMID:21282621

  19. Implications of environmental regulations on refinery product specification, operation and investment

    International Nuclear Information System (INIS)

    Amin, M.M.

    1992-01-01

    During the 1980s, refiners mainly in OECD countries were occupied with improving their refinery configurations for producing high-value light products which would not only satisfy the product demand slate but also meet the increasingly restrictive environmental regulations. In the 1990s refiners will continue to be challenged to improve the world's air quality not only by producing products that minimize emissions of toxic and hazardous hydrocarbons, but also through the refinery operation itself by investment in upgrading the industry and products to cope with the constant flow of new regulations. These investments will not only be limited to consuming centres but will also be extended to cover exporting refineries as well due to competition of acquiring market shares for product exports. The additional cost will be directly related to product quality and site regulations and will vary from one country to the other. This paper deals mainly with the air pollution and the impact of related environmental issues on the refining industry. Environmental regulations for refinery products in the USA and Europe are examined and international regulations for the tanker industry are noted. (author)

  20. Fuz regulates craniofacial development through tissue specific responses to signaling factors.

    Directory of Open Access Journals (Sweden)

    Zichao Zhang

    Full Text Available The planar cell polarity effector gene Fuz regulates ciliogenesis and Fuz loss of function studies reveal an array of embryonic phenotypes. However, cilia defects can affect many signaling pathways and, in humans, cilia defects underlie several craniofacial anomalies. To address this, we analyzed the craniofacial phenotype and signaling responses of the Fuz(-/- mice. We demonstrate a unique role for Fuz in regulating both Hedgehog (Hh and Wnt/β-catenin signaling during craniofacial development. Fuz expression first appears in the dorsal tissues and later in ventral tissues and craniofacial regions during embryonic development coincident with cilia development. The Fuz(-/- mice exhibit severe craniofacial deformities including anophthalmia, agenesis of the tongue and incisors, a hypoplastic mandible, cleft palate, ossification/skeletal defects and hyperplastic malformed Meckel's cartilage. Hh signaling is down-regulated in the Fuz null mice, while canonical Wnt signaling is up-regulated revealing the antagonistic relationship of these two pathways. Meckel's cartilage is expanded in the Fuz(-/- mice due to increased cell proliferation associated with the up-regulation of Wnt canonical target genes and decreased non-canonical pathway genes. Interestingly, cilia development was decreased in the mandible mesenchyme of Fuz null mice, suggesting that cilia may antagonize Wnt signaling in this tissue. Furthermore, expression of Fuz decreased expression of Wnt pathway genes as well as a Wnt-dependent reporter. Finally, chromatin IP experiments demonstrate that β-catenin/TCF-binding directly regulates Fuz expression. These data demonstrate a new model for coordination of Hh and Wnt signaling and reveal a Fuz-dependent negative feedback loop controlling Wnt/β-catenin signaling.

  1. Tissue-specific and pathogen-induced regulation of a Nicotiana plumbaginifolia beta-1,3-glucanase gene.

    Science.gov (United States)

    Castresana, C; de Carvalho, F; Gheysen, G; Habets, M; Inzé, D; Van Montagu, M

    1990-01-01

    The Nicotiana plumbaginifolia gn1 gene encoding a beta-1,3-glucanase isoform has been characterized. The gn1 product represents an isoform distinct from the previously identified tobacco beta-1,3-glucanases. By expressing gn1 in Escherichia coli, we have determined directly that the encoded protein does, indeed, correspond to a beta-1,3-glucanase. In N. plumbaginifolia, gn1 was found to be expressed in roots and older leaves. Transgenic tobacco plants containing the 5'-noncoding region of gn1 fused to the beta-glucuronidase (GUS) reporter gene also showed maximum levels of GUS activity in roots and older leaves. No detectable activity was present in the upper part of the transgenic plants with the exception of stem cells at the bases of emerging shoots. The expression conferred by the gn1 promoter was differentially induced in response to specific plant stress treatments. Studies of three plant-bacteria interactions showed high levels of GUS activity when infection resulted in a hypersensitive reaction. Increased gene expression was confined to cells surrounding the necrotic lesions. The observed expression pattern suggests that the characterized beta-1,3-glucanase plays a role both in plant development and in the defense response against pathogen infection. PMID:2152158

  2. Specific cognitive domains and symptoms of depression as predictors of activities of daily living in older adults with heterogeneous cognitive backgrounds

    Directory of Open Access Journals (Sweden)

    Jonas Jardim de Paula

    2015-07-01

    Full Text Available Cognitive functioning play an important role in the performance of activities of daily living (ADL. Although and association between this two measures are usually reported in neuropsychological studies, the results are inconsistent, especially in what aspects cognitive functioning are more or less related to each functional aspect. In addition, only a few studies investigated if depressive symptoms are associated with worse functional performance in older adults. Our objective is to investigate the role of different cognitive functions and the depressive symptoms in the performance of different groups of ADL and each activity individually. We assessed 264 older adults (96 normal aging controls, 85 patients diagnosed with mild cognitive impairment and 93 with mild probable Alzheimer’s disease dementia with low formal education (about 4 years. We used measures of ADL with different levels of complexity: Selfcare, Instrumental-Domestic and Instrumental Complex, along with composite factors of cognitive functions and the score of the Geriatric Depression Scale. Multiple linear regression analysis showed significant predictors of Instrumental-Domestic ADL (executive functions and episodic memory and Instrumental-Complex ADL (executive functions, episodic memory and language/semantic memory, with large effect sizes (22 and 28% of explained variance. Individual analysis of each Instrumental ADL shows a heterogeneous pattern of association with different cognitive factors and depressive symptoms, with effect sizes ranging from 22 to 38% of explained variance. Our results suggest that specific measures of ADL have different cognitive predictors and that depressive symptoms are associated with activities more dependent on social contact.

  3. Socioeconomic factors and all cause and cause-specific mortality among older people in Latin America, India, and China: a population-based cohort study.

    Directory of Open Access Journals (Sweden)

    Cleusa P Ferri

    2012-02-01

    Full Text Available Even in low and middle income countries most deaths occur in older adults. In Europe, the effects of better education and home ownership upon mortality seem to persist into old age, but these effects may not generalise to LMICs. Reliable data on causes and determinants of mortality are lacking.The vital status of 12,373 people aged 65 y and over was determined 3-5 y after baseline survey in sites in Latin America, India, and China. We report crude and standardised mortality rates, standardized mortality ratios comparing mortality experience with that in the United States, and estimated associations with socioeconomic factors using Cox's proportional hazards regression. Cause-specific mortality fractions were estimated using the InterVA algorithm. Crude mortality rates varied from 27.3 to 70.0 per 1,000 person-years, a 3-fold variation persisting after standardisation for demographic and economic factors. Compared with the US, mortality was much higher in urban India and rural China, much lower in Peru, Venezuela, and urban Mexico, and similar in other sites. Mortality rates were higher among men, and increased with age. Adjusting for these effects, it was found that education, occupational attainment, assets, and pension receipt were all inversely associated with mortality, and food insecurity positively associated. Mutually adjusted, only education remained protective (pooled hazard ratio 0.93, 95% CI 0.89-0.98. Most deaths occurred at home, but, except in India, most individuals received medical attention during their final illness. Chronic diseases were the main causes of death, together with tuberculosis and liver disease, with stroke the leading cause in nearly all sites.Education seems to have an important latent effect on mortality into late life. However, compositional differences in socioeconomic position do not explain differences in mortality between sites. Social protection for older people, and the effectiveness of health systems in

  4. Socioeconomic factors and all cause and cause-specific mortality among older people in Latin America, India, and China: a population-based cohort study.

    Science.gov (United States)

    Ferri, Cleusa P; Acosta, Daisy; Guerra, Mariella; Huang, Yueqin; Llibre-Rodriguez, Juan J; Salas, Aquiles; Sosa, Ana Luisa; Williams, Joseph D; Gaona, Ciro; Liu, Zhaorui; Noriega-Fernandez, Lisseth; Jotheeswaran, A T; Prince, Martin J

    2012-02-01

    Even in low and middle income countries most deaths occur in older adults. In Europe, the effects of better education and home ownership upon mortality seem to persist into old age, but these effects may not generalise to LMICs. Reliable data on causes and determinants of mortality are lacking. The vital status of 12,373 people aged 65 y and over was determined 3-5 y after baseline survey in sites in Latin America, India, and China. We report crude and standardised mortality rates, standardized mortality ratios comparing mortality experience with that in the United States, and estimated associations with socioeconomic factors using Cox's proportional hazards regression. Cause-specific mortality fractions were estimated using the InterVA algorithm. Crude mortality rates varied from 27.3 to 70.0 per 1,000 person-years, a 3-fold variation persisting after standardisation for demographic and economic factors. Compared with the US, mortality was much higher in urban India and rural China, much lower in Peru, Venezuela, and urban Mexico, and similar in other sites. Mortality rates were higher among men, and increased with age. Adjusting for these effects, it was found that education, occupational attainment, assets, and pension receipt were all inversely associated with mortality, and food insecurity positively associated. Mutually adjusted, only education remained protective (pooled hazard ratio 0.93, 95% CI 0.89-0.98). Most deaths occurred at home, but, except in India, most individuals received medical attention during their final illness. Chronic diseases were the main causes of death, together with tuberculosis and liver disease, with stroke the leading cause in nearly all sites. Education seems to have an important latent effect on mortality into late life. However, compositional differences in socioeconomic position do not explain differences in mortality between sites. Social protection for older people, and the effectiveness of health systems in preventing and

  5. GATA-2 and GATA-3 regulate trophoblast-specific gene expression in vivo.

    NARCIS (Netherlands)

    G.T. Ma (Grace); M.E. Roth (Matthew); J.C. Groskopf (John); F.G. Grosveld (Frank); J.D. Engel (Douglas); D.I.H. Linzer (Daniel); F.Y. Tsai (Fong-Ying); S.H. Orkin (Stuart)

    1997-01-01

    textabstractWe previously demonstrated that the zinc finger transcription factors GATA-2 and GATA-3 are expressed in trophoblast giant cells and that they regulate transcription from the mouse placental lactogen I gene promoter in a transfected trophoblast cell line. We present evidence here that

  6. Rapid male-specific regulatory divergence and down regulation of spermatogenesis genes in Drosophila species hybrids.

    Directory of Open Access Journals (Sweden)

    Jennifer Ferguson

    Full Text Available In most crosses between closely related species of Drosophila, the male hybrids are sterile and show postmeiotic abnormalities. A series of gene expression studies using genomic approaches have found significant down regulation of postmeiotic spermatogenesis genes in sterile male hybrids. These results have led some to suggest a direct relationship between down regulation in gene expression and hybrid sterility. An alternative explanation to a cause-and-effect relationship between misregulation of gene expression and male sterility is rapid divergence of male sex regulatory elements leading to incompatible interactions in an interspecies hybrid genome. To test the effect of regulatory divergence in spermatogenesis gene expression, we isolated 35 fertile D. simulans strains with D. mauritiana introgressions in either the X, second or third chromosome. We analyzed gene expression in these fertile hybrid strains for a subset of spermatogenesis genes previously reported as significantly under expressed in sterile hybrids relative to D. simulans. We found that fertile autosomal introgressions can cause levels of gene down regulation similar to that of sterile hybrids. We also found that X chromosome heterospecific introgressions cause significantly less gene down regulation than autosomal introgressions. Our results provide evidence that rapid male sex gene regulatory divergence can explain misexpression of spermatogenesis genes in hybrids.

  7. Astrocytic connexin hemichannels are regulated by PKC phosphorylation in an isoform-specific manner

    DEFF Research Database (Denmark)

    MacAulay, N.; Alstrom, J. S.; Hansen, D. B.

    2017-01-01

    /activation of PKC and by mutational disruption of the proposed PKC-phosphorylation sites. Cx30 hemichannel activity, in contrast, was down-regulated by PKC activation, in a manner suggesting PKC-mediated channel closure. No single PKC consensus site could be assigned to this regulatory property by mutational...

  8. Peroxisome proliferator activated receptor alpha regulates a male-specific cytochrome P450 in mouse liver.

    Science.gov (United States)

    Jeffery, Brett; Choudhury, Agharul I; Horley, Neill; Bruce, Mary; Tomlinson, Simon R; Roberts, Ruth A; Gray, Tim J B; Barrett, David A; Shaw, P Nicholas; Kendall, David; Bell, David R

    2004-09-15

    We set out to find if the strain-specific, male-specific hepatic expression of Cyp4a protein in mouse was due to expression of Cyp4a12 and to understand the genetic basis for reported differences in expression. 12-Lauric acid hydroxylase (LAH) activity was found to show higher levels in male ddY, but not C57Bl/6, mouse liver microsomes. The expression of Cyp4a12 mRNA was studied using RNAase protection assays in male and female liver and kidney of nine mouse strains. Cyp4a12 was found to be highly expressed in male liver and kidney, but at much lower levels in female liver and kidney, in all strains studied. Western blotting with an antibody specific for Cyp4a12 confirmed that Cyp4a12 was expressed in a male specific fashion in C57Bl/6 mouse liver. RNAase protection analysis for Cyp4a10 and 14 in ddY mice revealed that neither of these genes showed male-specific expression. To further investigate genetic factors that control male-specific Cyp4a12 expression, PPARalpha+/+ and -/- mice were studied, showing that total P450 and 12-LAH activity was male-specific in +/+, but not -/- mice. RNAase protection assays were used to confirm that Cyp4a12 was lower in -/- mice. However, the male-specific Slp and MUP-1 genes retained hepatic male-specific levels of expression in +/+ and -/- mice, showing that the decrease in Cyp4a12 was not a general effect on male-specific expression. Thus, PPARalpha has a specific effect on constitutive expression of Cyp4a12.

  9. Regulation of cuticle-degrading subtilisin proteases from the entomopathogenic fungi, Lecanicillium spp: implications for host specificity.

    Science.gov (United States)

    Bye, Natasha J; Charnley, A Keith

    2008-01-01

    The ability to produce cuticle-degrading proteases to facilitate host penetration does not distinguish per se entomopathogenic fungi from saprophytes. However, adapted pathogens may produce host-protein specific enzymes in response to cues. This possibility prompted an investigation of the regulation of isoforms of the subtilisin Pr1-like proteases from five aphid-pathogenic isolates of Lecanicillium spp. Significant differences were found in substrate specificity and regulation of Pr1-like proteases between isoforms of the same isolate and between different isolates. For example, the pI 8.6 isoform from KV71 was considerably more active against aphid than locust cuticle and was induced specifically by N-acetylglucosamine (NAG). Isoform pI 9.1 from the same isolate was only produced on insect cuticle while most other isoforms were more prominent on chitin containing substrates but not induced by NAG. The ability to regulate isoforms independently may allow production at critical points in host penetration. Appearance of proteases (not subtilisins) with pI 4.2 and 4.4 only on aphid cuticle was a possible link with host specificity of KV71. The absence of C or N metabolite repression in subtilisins from KV42 is unusual for pathogen proteases and may help to account for differences in virulence strategy between aphid-pathogenic isolates of Lecanicillium longisporum (unpublished data).

  10. An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration.

    Science.gov (United States)

    Kutys, Matthew L; Yamada, Kenneth M

    2014-09-01

    Rho-family GTPases govern distinct types of cell migration on different extracellular matrix proteins in tissue culture or three-dimensional (3D) matrices. We searched for mechanisms selectively regulating 3D cell migration in different matrix environments and discovered a form of Cdc42-RhoA crosstalk governing cell migration through a specific pair of GTPase activator and inhibitor molecules. We first identified βPix, a guanine nucleotide exchange factor (GEF), as a specific regulator of migration in 3D collagen using an affinity-precipitation-based GEF screen. Knockdown of βPix specifically blocks cell migration in fibrillar collagen microenvironments, leading to hyperactive cellular protrusion accompanied by increased collagen matrix contraction. Live FRET imaging and RNAi knockdown linked this βPix knockdown phenotype to loss of polarized Cdc42 but not Rac1 activity, accompanied by enhanced, de-localized RhoA activity. Mechanistically, collagen phospho-regulates βPix, leading to its association with srGAP1, a GTPase-activating protein (GAP), needed to suppress RhoA activity. Our results reveal a matrix-specific pathway controlling migration involving a GEF-GAP interaction of βPix with srGAP1 that is critical for maintaining suppressive crosstalk between Cdc42 and RhoA during 3D collagen migration.

  11. Ubiquitin-specific protease 14 regulates cell proliferation and apoptosis in oral squamous cell carcinoma.

    Science.gov (United States)

    Chen, Xiangyun; Wu, Jingjing; Chen, Yitian; Ye, Dongxia; Lei, Hu; Xu, Hanzhang; Yang, Li; Wu, Yingli; Gu, Wenli

    2016-10-01

    Ubiquitin-specific protease 14, a deubiquitinating enzyme, has been implicated in the tumorigenesis and progression of several cancers, but its role in oral squamous cell carcinoma remains to be elucidated. The aim of this study was to explore the expression pattern and roles of Ubiquitin-specific protease 14 in the occurrence and development of oral squamous cell carcinoma. Interestingly, Ubiquitin-specific protease 14 was overexpressed in oral cancer tissues and cell lines at both mRNA and protein levels. b-AP15, a specific inhibitor of Ubiquitin-specific protease 14, significantly inhibited the growth of cancer cells and increased cell apoptosis in a dose-dependent manner. Moreover, knockdown of Ubiquitin-specific protease 14 by shRNA significantly inhibited the proliferation and migration of cancer cells in vitro. Finally, using a xenograft mouse model of oral squamous cell carcinoma, knockdown of Ubiquitin-specific protease 14 markedly inhibited tumor growth and triggered the cancer cell apoptosis in vivo, supporting previous results. In conclusion, for the first time we have demonstrated the expression pattern of Ubiquitin-specific protease 14 in oral squamous cell carcinoma and verified a relationship with tumor growth and metastasis. These results may highlight new therapeutic strategies for tumor treatment, application of Ubiquitin-specific protease 14 selective inhibitor, such as b-AP15, or knockdown by shRNA. Collectively, Ubiquitin-specific protease 14 could be a potential therapeutic target for oral squamous cell carcinoma patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Structural correlation method for model reduction and practical estimation of patient specific parameters illustrated on heart rate regulation

    DEFF Research Database (Denmark)

    Ottesen, Johnny T.; Mehlsen, Jesper; Olufsen, Mette

    2014-01-01

    We consider the inverse and patient specific problem of short term (seconds to minutes) heart rate regulation specified by a system of nonlinear ODEs and corresponding data. We show how a recent method termed the structural correlation method (SCM) can be used for model reduction and for obtaining...... a set of practically identifiable parameters. The structural correlation method includes two steps: sensitivity and correlation analysis. When combined with an optimization step, it is possible to estimate model parameters, enabling the model to fit dynamics observed in data. This method is illustrated...... in detail on a model predicting baroreflex regulation of heart rate and applied to analysis of data from a rat and healthy humans. Numerous mathematical models have been proposed for prediction of baroreflex regulation of heart rate, yet most of these have been designed to provide qualitative predictions...

  13. Emotion Regulation and Emotion Coherence: Evidence for Strategy-Specific Effects

    Science.gov (United States)

    Dan-Glauser, Elise S.; Gross, James J.

    2014-01-01

    One of the central tenets of emotion theory is that emotions involve coordinated changes across experiential, behavioral, and physiological response domains. Surprisingly little is known, however, on how the strength of this emotion coherence is altered when people try to regulate their emotions. To address this issue, we recorded experiential, behavioral, and physiological responses while participants watched negative and positive pictures. Cross-correlations were used to quantify emotion coherence. Study 1 tested how two types of suppression (expressive and physiological) influence coherence. Results showed that both strategies decreased the response coherence measured in negative and positive contexts. Study 2 tested how multi-channel suppression (simultaneously targeting expressive and physiological responses) and acceptance influence emotion coherence. Results again showed that suppression decreased coherence. By contrast, acceptance was not significantly different from the unregulated condition. These findings help to clarify the nature of emotion response coherence by showing how different forms of emotion regulation may differentially affect it. PMID:23731438

  14. Emotion regulation and emotion coherence: evidence for strategy-specific effects.

    Science.gov (United States)

    Dan-Glauser, Elise S; Gross, James J

    2013-10-01

    One of the central tenets of emotion theory is that emotions involve coordinated changes across experiential, behavioral, and physiological response domains. Surprisingly little is known, however, about how the strength of this emotion coherence is altered when people try to regulate their emotions. To address this issue, we recorded experiential, behavioral, and physiological responses while participants watched negative and positive pictures. Cross-correlations were used to quantify emotion coherence. Study 1 tested how two types of suppression (expressive and physiological) influence coherence. Results showed that both strategies decreased the response coherence measured in negative and positive contexts. Study 2 tested how multichannel suppression (simultaneously targeting expressive and physiological responses) and acceptance influence emotion coherence. Results again showed that suppression decreased coherence. By contrast, acceptance was not significantly different from the unregulated condition. These findings help to clarify the nature of emotion response coherence by showing how different forms of emotion regulation may differentially affect it.

  15. Churchill regulates cell movement and mesoderm specification by repressing Nodal signaling

    Directory of Open Access Journals (Sweden)

    Mentzer Laura

    2007-11-01

    Full Text Available Abstract Background Cell movements are essential to the determination of cell fates during development. The zinc-finger transcription factor, Churchill (ChCh has been proposed to regulate cell fate by regulating cell movements during gastrulation in the chick. However, the mechanism of action of ChCh is not understood. Results We demonstrate that ChCh acts to repress the response to Nodal-related signals in zebrafish. When ChCh function is abrogated the expression of mesodermal markers is enhanced while ectodermal markers are expressed at decreased levels. In cell transplant assays, we observed that ChCh-deficient cells are more motile than wild-type cells. When placed in wild-type hosts, ChCh-deficient cells often leave the epiblast, migrate to the germ ring and are later found in mesodermal structures. We demonstrate that both movement of ChCh-compromised cells to the germ ring and acquisition of mesodermal character depend on the ability of the donor cells to respond to Nodal signals. Blocking Nodal signaling in the donor cells at the levels of Oep, Alk receptors or Fast1 inhibited migration to the germ ring and mesodermal fate change in the donor cells. We also detect additional unusual movements of transplanted ChCh-deficient cells which suggests that movement and acquisition of mesodermal character can be uncoupled. Finally, we demonstrate that ChCh is required to limit the transcriptional response to Nodal. Conclusion These data establish a broad role for ChCh in regulating both cell movement and Nodal signaling during early zebrafish development. We show that chch is required to limit mesodermal gene expression, inhibit Nodal-dependant movement of presumptive ectodermal cells and repress the transcriptional response to Nodal signaling. These findings reveal a dynamic role for chch in regulating cell movement and fate during early development.

  16. Gene Regulation in Primates Evolves under Tissue-Specific Selection Pressures

    OpenAIRE

    Blekhman, Ran; Oshlack, Alicia; Chabot, Adrien E.; Smyth, Gordon K.; Gilad, Yoav

    2008-01-01

    Author Summary It has long been hypothesized that in addition to structural changes to proteins, changes in gene regulation might underlie many of the anatomic and behavioral differences between humans and other primates. However, to date, there are only a handful of examples of regulatory adaptations in humans. In this work, we present a genome-wide study of gene expression levels in livers, kidneys, and hearts from three species: humans, chimpanzees, and rhesus macaques. These data allowed ...

  17. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    Science.gov (United States)

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Proteomic analysis of astrocytic secretion that regulates neurogenesis using quantitative amine-specific isobaric tagging

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Hu; Zhou, Wenhao [Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Wei, Liming; Zhong, Fan [Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Roda, Shanghai 200032 (China); Yang, Yi, E-mail: yyang@shmu.edu.cn [Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China)

    2010-01-08

    Astrocytes are essential components of neurogenic niches that affect neurogenesis through membrane association and/or the release of soluble factors. To identify factors released from astrocytes that could regulate neural stem cell differentiation and proliferation, we used mild oxygen-glucose deprivation (OGD) to inhibit the secretory capacity of astrocytes. Using the Transwell co-culture system, we found that OGD-treated astrocytes could not promote neural stem cell differentiation and proliferation. Next, isobaric tagging for the relative and absolute quantitation (iTRAQ) proteomics techniques was performed to identify the proteins in the supernatants of astrocytes (with or without OGD). Through a multi-step analysis and gene ontology classification, 130 extracellular proteins were identified, most of which were involved in neuronal development, the inflammatory response, extracellular matrix composition and supportive functions. Of these proteins, 44 had never been reported to be produced by astrocytes. Using ProteinPilot software analysis, we found that 60 extracellular proteins were significantly altered (27 upregulated and 33 downregulated) in the supernatant of OGD-treated astrocytes. Among these proteins, 7 have been reported to be able to regulate neurogenesis, while others may have the potential to regulate neurogenesis. This study profiles the major proteins released by astrocytes, which play important roles in the modulation of neurogenesis.

  19. RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes

    Directory of Open Access Journals (Sweden)

    Johanna Meier-Soelch

    2018-04-01

    Full Text Available The potent proinflammatory cytokine interleukin (IL-1 triggers gene expression through the NF-κB signaling pathway. Here, we investigated the cofactor requirements of strongly regulated IL-1 target genes whose expression is impaired in p65 NF-κB-deficient murine embryonic fibroblasts. By two independent small-hairpin (shRNA screens, we examined 170 genes annotated to encode nuclear cofactors for their role in Cxcl2 mRNA expression and identified 22 factors that modulated basal or IL-1-inducible Cxcl2 levels. The functions of 16 of these factors were validated for Cxcl2 and further analyzed for their role in regulation of 10 additional IL-1 target genes by RT-qPCR. These data reveal that each inducible gene has its own (quantitative requirement of cofactors to maintain basal levels and to respond to IL-1. Twelve factors (Epc1, H2afz, Kdm2b, Kdm6a, Mbd3, Mta2, Phf21a, Ruvbl1, Sin3b, Suv420h1, Taf1, and Ube3a have not been previously implicated in inflammatory cytokine functions. Bioinformatics analysis indicates that they are components of complex nuclear protein networks that regulate chromatin functions and gene transcription. Collectively, these data suggest that downstream from the essential NF-κB signal each cytokine-inducible target gene has further subtle requirements for individual sets of nuclear cofactors that shape its transcriptional activation profile.

  20. Proteomic analysis of astrocytic secretion that regulates neurogenesis using quantitative amine-specific isobaric tagging

    International Nuclear Information System (INIS)

    Yan, Hu; Zhou, Wenhao; Wei, Liming; Zhong, Fan; Yang, Yi

    2010-01-01

    Astrocytes are essential components of neurogenic niches that affect neurogenesis through membrane association and/or the release of soluble factors. To identify factors released from astrocytes that could regulate neural stem cell differentiation and proliferation, we used mild oxygen-glucose deprivation (OGD) to inhibit the secretory capacity of astrocytes. Using the Transwell co-culture system, we found that OGD-treated astrocytes could not promote neural stem cell differentiation and proliferation. Next, isobaric tagging for the relative and absolute quantitation (iTRAQ) proteomics techniques was performed to identify the proteins in the supernatants of astrocytes (with or without OGD). Through a multi-step analysis and gene ontology classification, 130 extracellular proteins were identified, most of which were involved in neuronal development, the inflammatory response, extracellular matrix composition and supportive functions. Of these proteins, 44 had never been reported to be produced by astrocytes. Using ProteinPilot software analysis, we found that 60 extracellular proteins were significantly altered (27 upregulated and 33 downregulated) in the supernatant of OGD-treated astrocytes. Among these proteins, 7 have been reported to be able to regulate neurogenesis, while others may have the potential to regulate neurogenesis. This study profiles the major proteins released by astrocytes, which play important roles in the modulation of neurogenesis.

  1. Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8+ T Cell-Lineage-Specific Function

    Directory of Open Access Journals (Sweden)

    Brendan E. Russ

    2017-12-01

    Full Text Available Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs, we mapped the dynamics of ∼25,000 putative CD8+ T cell transcriptional enhancers (TEs differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3+ chromatin signature upon differentiation. This unique TE subset exhibited characteristics of poised enhancers in the naive CD8+ T cell subset and demonstrated enrichment for transcription factor binding motifs known to be important for virus-specific CD8+ T cell differentiation. These data provide insights into the establishment and maintenance of the gene transcription profiles that define each stage of virus-specific T cell differentiation.

  2. Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1

    Directory of Open Access Journals (Sweden)

    Cornelia Kilchert

    2015-12-01

    Full Text Available In eukaryotic cells, inefficient splicing is surprisingly common and leads to the degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here, we uncover a mechanism by which specific intron-containing transcripts are targeted for nuclear degradation in fission yeast. Sequence elements within these “decay-promoting” introns co-transcriptionally recruit the exosome specificity factor Mmi1, which induces degradation of the unspliced precursor and leads to a reduction in the levels of the spliced mRNA. This mechanism negatively regulates levels of the RNA helicase DDX5/Dbp2 to promote cell survival in response to stress. In contrast, fast removal of decay-promoting introns by co-transcriptional splicing precludes Mmi1 recruitment and relieves negative expression regulation. We propose that decay-promoting introns facilitate the regulation of gene expression. Based on the identification of multiple additional Mmi1 targets, including mRNAs, long non-coding RNAs, and sn/snoRNAs, we suggest a general role in RNA regulation for Mmi1 through transcript degradation.

  3. PTSD, food addiction, and disordered eating in a sample of primarily older veterans: The mediating role of emotion regulation.

    Science.gov (United States)

    Mitchell, Karen S; Wolf, Erika J

    2016-09-30

    Posttraumatic stress disorder (PTSD) has been associated with eating disorders (EDs) and addictive behaviors, including the relatively new construct food addiction. However, few studies have investigated mechanisms that account for these associations, and men are underrepresented in studies of EDs and food addiction. We examined whether lifetime PTSD symptoms were associated with current food addiction and ED symptoms, and whether emotion regulation (expressive suppression and cognitive reappraisal), which has been associated with both PTSD and EDs, mediated these relations, in a sample of trauma-exposed, male (n=642) and female (n=55) veterans. Participants were recruited from the Knowledge Networks-GfK Research Panel and completed an online questionnaire. Structural equation modeling revealed that PTSD was directly associated with ED symptoms, food addiction, expressive suppression, and cognitive reappraisal in the full sample and with all constructs except cognitive reappraisal in the male subsample. Expressive suppression was significantly associated with ED symptoms and mediated the PTSD-ED relation. These results highlight the importance of investigating PTSD as a risk factor for food addiction and ED symptoms and the potential mediating role of emotion regulation in the development of PTSD and EDs in order to identify targets for treatments. Published by Elsevier Ireland Ltd.

  4. Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

    Science.gov (United States)

    Dumais, Kelly M; Veenema, Alexa H

    2016-01-01

    The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Vasopressin and oxytocin receptor systems in the brain: sex differences and sex-specific regulation of social behavior

    Science.gov (United States)

    Dumais, Kelly M.; Veenema, Alexa H.

    2015-01-01

    The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species- specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans. PMID:25951955

  6. Germline-specific MATH-BTB substrate adaptor MAB1 regulates spindle length and nuclei identity in maize.

    Science.gov (United States)

    Juranič, Martina; Srilunchang, Kanok-orn; Krohn, Nádia Graciele; Leljak-Levanic, Dunja; Sprunck, Stefanie; Dresselhaus, Thomas

    2012-12-01

    Germline and early embryo development constitute ideal model systems to study the establishment of polarity, cell identity, and asymmetric cell divisions (ACDs) in plants. We describe here the function of the MATH-BTB domain protein MAB1 that is exclusively expressed in the germ lineages and the zygote of maize (Zea mays). mab1 (RNA interference [RNAi]) mutant plants display chromosome segregation defects and short spindles during meiosis that cause insufficient separation and migration of nuclei. After the meiosis-to-mitosis transition, two attached nuclei of similar identity are formed in mab1 (RNAi) mutants leading to an arrest of further germline development. Transient expression studies of MAB1 in tobacco (Nicotiana tabacum) Bright Yellow-2 cells revealed a cell cycle-dependent nuclear localization pattern but no direct colocalization with the spindle apparatus. MAB1 is able to form homodimers and interacts with the E3 ubiquitin ligase component Cullin 3a (CUL3a) in the cytoplasm, likely as a substrate-specific adapter protein. The microtubule-severing subunit p60 of katanin was identified as a candidate substrate for MAB1, suggesting that MAB1 resembles the animal key ACD regulator Maternal Effect Lethal 26 (MEL-26). In summary, our findings provide further evidence for the importance of posttranslational regulation for asymmetric divisions and germline progression in plants and identified an unstable key protein that seems to be involved in regulating the stability of a spindle apparatus regulator(s).

  7. Germline-Specific MATH-BTB Substrate Adaptor MAB1 Regulates Spindle Length and Nuclei Identity in Maize[W

    Science.gov (United States)

    Juranić, Martina; Srilunchang, Kanok-orn; Krohn, Nádia Graciele; Leljak-Levanić, Dunja; Sprunck, Stefanie; Dresselhaus, Thomas

    2012-01-01

    Germline and early embryo development constitute ideal model systems to study the establishment of polarity, cell identity, and asymmetric cell divisions (ACDs) in plants. We describe here the function of the MATH-BTB domain protein MAB1 that is exclusively expressed in the germ lineages and the zygote of maize (Zea mays). mab1 (RNA interference [RNAi]) mutant plants display chromosome segregation defects and short spindles during meiosis that cause insufficient separation and migration of nuclei. After the meiosis-to-mitosis transition, two attached nuclei of similar identity are formed in mab1 (RNAi) mutants leading to an arrest of further germline development. Transient expression studies of MAB1 in tobacco (Nicotiana tabacum) Bright Yellow-2 cells revealed a cell cycle–dependent nuclear localization pattern but no direct colocalization with the spindle apparatus. MAB1 is able to form homodimers and interacts with the E3 ubiquitin ligase component Cullin 3a (CUL3a) in the cytoplasm, likely as a substrate-specific adapter protein. The microtubule-severing subunit p60 of katanin was identified as a candidate substrate for MAB1, suggesting that MAB1 resembles the animal key ACD regulator Maternal Effect Lethal 26 (MEL-26). In summary, our findings provide further evidence for the importance of posttranslational regulation for asymmetric divisions and germline progression in plants and identified an unstable key protein that seems to be involved in regulating the stability of a spindle apparatus regulator(s). PMID:23250449

  8. Insulation and wiring specificity of BceR-like response regulators and their target promoters in Bacillus subtilis.

    Science.gov (United States)

    Fang, Chong; Nagy-Staroń, Anna; Grafe, Martin; Heermann, Ralf; Jung, Kirsten; Gebhard, Susanne; Mascher, Thorsten

    2017-04-01

    BceRS and PsdRS are paralogous two-component systems in Bacillus subtilis controlling the response to antimicrobial peptides. In the presence of extracellular bacitracin and nisin, respectively, the two response regulators (RRs) bind their target promoters, P bceA or P psdA , resulting in a strong up-regulation of target gene expression and ultimately antibiotic resistance. Despite high sequence similarity between the RRs BceR and PsdR and their known binding sites, no cross-regulation has been observed between them. We therefore investigated the specificity determinants of P bceA and P psdA that ensure the insulation of these two paralogous pathways at the RR-promoter interface. In vivo and in vitro analyses demonstrate that the regulatory regions within these two promoters contain three important elements: in addition to the known (main) binding site, we identified a linker region and a secondary binding site that are crucial for functionality. Initial binding to the high-affinity, low-specificity main binding site is a prerequisite for the subsequent highly specific binding of a second RR dimer to the low-affinity secondary binding site. In addition to this hierarchical cooperative binding, discrimination requires a competition of the two RRs for their respective binding site mediated by only slight differences in binding affinities. © 2016 John Wiley & Sons Ltd.

  9. Coordinated Regulation of the EIIMan and fruRKI Operons of Streptococcus mutans by Global and Fructose-Specific Pathways.

    Science.gov (United States)

    Zeng, Lin; Chakraborty, Brinta; Farivar, Tanaz; Burne, Robert A

    2017-11-01

    The glucose/mannose-phosphotransferase system (PTS) permease EII Man encoded by manLMN in the dental caries pathogen Streptococcus mutans has a dominant influence on sugar-specific, CcpA-independent catabolite repression (CR). Mutations in manL affect energy metabolism and virulence-associated traits, including biofilm formation, acid tolerance, and competence. Using promoter::reporter fusions, expression of the manLMN and the fruRKI operons, encoding a transcriptional regulator, a fructose-1-phosphate kinase and a fructose-PTS permease EII Fru , respectively, was monitored in response to carbohydrate source and in mutants lacking CcpA, FruR, and components of EII Man Expression of genes for EII Man and EII Fru was directly regulated by CcpA and CR, as evinced by in vivo and in vitro methods. Unexpectedly, not only was the fruRKI operon negatively regulated by FruR, but also so was manLMN Carbohydrate transport by EII Man had a negative influence on expression of manLMN but not fruRKI In agreement with the proposed role of FruR in regulating these PTS operons, loss of fruR or fruK substantially altered growth on a number of carbohydrates, including fructose. RNA deep sequencing revealed profound changes in gene regulation caused by deletion of fruK or fruR Collectively, these findings demonstrate intimate interconnection of the regulation of two major PTS permeases in S. mutans and reveal novel and important contributions of fructose metabolism to global regulation of gene expression. IMPORTANCE The ability of Streptococcus mutans and other streptococcal pathogens to survive and cause human diseases is directly dependent upon their capacity to metabolize a variety of carbohydrates, including glucose and fructose. Our research reveals that metabolism of fructose has broad influences on the regulation of utilization of glucose and other sugars, and mutants with changes in certain genes involved in fructose metabolism display profoundly different abilities to grow and

  10. Inspection Regulation between General Procedural Codification and Field Specifics – a Case Study of Slovenia

    Directory of Open Access Journals (Sweden)

    Kovač Polonca

    2016-03-01

    Full Text Available Inspection, as the authoritative supervision of private liable persons to comply their activities with sector-specific laws, should ensure the full implementation of public policies. Slovenia adopted the Inspection Act (IA in 2002, in order to conduct efficient inspection, and simultaneously guarantee the defence rights of the supervised parties pursuant to the fundamental principles of the EU, the national Constitution, and general Administrative Procedure Act. This article addresses the search for a balance between general codification and sector-related specifics as stipulated by the IA, applying normative, constitutional case law and comparative methods. Special attention is dedicated to the IA rules regarding participants, their legal protection and stages of respective proceedings. It has been concluded that the most of the IA specifics are justified in order to efficiently serve the public interest. This study reveals that the Slovene IA can represent a role model for efficient yet democratic supervision in other MS as well.

  11. Tissue-specific regulation of mouse MicroRNA genes in endoderm-derived tissues

    OpenAIRE

    Gao, Yan; Schug, Jonathan; McKenna, Lindsay B.; Le Lay, John; Kaestner, Klaus H.; Greenbaum, Linda E.

    2010-01-01

    MicroRNAs fine-tune the activity of hundreds of protein-coding genes. The identification of tissue-specific microRNAs and their promoters has been constrained by the limited sensitivity of prior microRNA quantification methods. Here, we determine the entire microRNAome of three endoderm-derived tissues, liver, jejunum and pancreas, using ultra-high throughput sequencing. Although many microRNA genes are expressed at comparable levels, 162 microRNAs exhibited striking tissue-specificity. After...

  12. Modelling air quality according to INSPIRE data specifications, ISO standards and national regulations

    Directory of Open Access Journals (Sweden)

    Pachelski Wojciech

    2017-12-01

    Full Text Available Protection of the environment is an activity of many institutions, organizations and communities from global to regional and local scales. Any activity in this area needs structured database records, using advanced methodology, given, among others, in INSPIRE documents, ISO standards of 19100 series, and national regulations. The goal of this paper is to analyse both the legal provisions related to the air quality and also data sources associated with the prevention of air pollution. Furthermore, the UML application schema of the spatial data related to the air protection is proposed, for the use by urban planners. Also, the overview of the methodology of geographic information is given, including the Unified Modelling Language (UML, as well as the basic concepts of conceptual models within the INSPIRE project. The study is based on the relevant literature and documents, as well as on the expert knowledge gained through urban planning practice, as well as on the analysis of the spatial planning regulations. The UML application schema for different aspects related to the air protection, as presented in this paper, is an example of how to use the methodology also in other fields of the environment protection. Spatial planners know how to improve the air quality, but in the present state of law they often suffer from the lack of planning tools for real actions. In the spatial planners work an important issue are data that allow a thorough analysis of the area.

  13. The specification and testing of radioactive sources designated as ''special form'' under the IAEA transport regulations

    International Nuclear Information System (INIS)

    Aston, D.; Bodimeade, A.H.; Hall, E.G.; Taylor, C.B.G.

    1982-01-01

    The object of this study is to remove some of the uncertainties associated with the application of the IAEA Regulations insofar as they apply to Special Form materials. The first part of this project involved a comparison of the ISO and IAEA Regulations. An analysis of the physical tests has been carried out. The second and most important part of the project involved an assessment of the leakage tests used to evaluate the capsules after each of the physical tests. The work has defined and confirmed by experiment the relationship between the IAEA and ISO impact and percussion tests. The practical application of the tests particularly with regard to specimen orientation will be aided by the data now available. The work has established the sensitivities of the primary volumetric leak test methods and practical procedures are outlined. Volumetric leak test methods, with sentivities approximately 10 - 5 mbar l/s, are considered to be more reliable in detecting leakage paths in capsules than methods using solid leachable or non-leachable radioactive contents. The work reported should assist in the updating and clarification and harmonisation of IAEA Safety Series Nos 6 and 37 and ISO 4919 and ISO TR 4826

  14. ICK is essential for cell type-specific ciliogenesis and the regulation of ciliary transport.

    Science.gov (United States)

    Chaya, Taro; Omori, Yoshihiro; Kuwahara, Ryusuke; Furukawa, Takahisa

    2014-06-02

    Cilia and flagella are formed and maintained by intraflagellar transport (IFT) and play important roles in sensing and moving across species. At the distal tip of the cilia/flagella, IFT complexes turn around to switch from anterograde to retrograde transport; however, the underlying regulatory mechanism is unclear. Here, we identified ICK localization at the tip of cilia as a regulator of ciliary transport. In ICK-deficient mice, we found ciliary defects in neuronal progenitor cells with Hedgehog signal defects. ICK-deficient cells formed cilia with mislocalized Hedgehog signaling components. Loss of ICK caused the accumulation of IFT-A, IFT-B, and BBSome components at the ciliary tips. In contrast, overexpression of ICK induced the strong accumulation of IFT-B, but not IFT-A or BBSome components at ciliary tips. In addition, ICK directly phosphorylated Kif3a, while inhibition of this Kif3a phosphorylation affected ciliary formation. Our results suggest that ICK is a Kif3a kinase and essential for proper ciliogenesis in development by regulating ciliary transport at the tip of cilia. © 2014 The Authors.

  15. Differences in Site-Specific Fracture Risk Among Older Women with Discordant Results for Osteoporosis at Hip and Spine: the Study of Osteoporotic Fractures

    Science.gov (United States)

    Fink, Howard A.; Harrison, Stephanie L.; Taylor, Brent C.; Cummings, Steven R.; Schousboe, John T.; Kuskowski, Michael A.; Stone, Katie L.; Ensrud, Kristine E.

    2009-01-01

    To examine the fracture pattern in older women whose bone mineral density (BMD) T-score criteria for osteoporosis at hip and spine disagree, hip and spine BMD were measured in Study of Osteoporotic Fractures participants using dual energy x-ray absorptiometry (DXA). Hip osteoporosis was defined as T-score ≤-2.5 at femoral neck or total hip, and spine osteoporosis as T-score ≤-2.5 at lumbar spine. Incident clinical fractures were self-reported and centrally adjudicated. Incident radiographic spine fractures were defined morphometrically. Compared to women with osteoporosis at neither hip nor spine, those osteoporotic only at hip had a 3.0-fold age and weight-adjusted increased risk for hip fracture (95%CI 2.4-3.6), and smaller increases in risk of nonhip nonspine (HR=1.6), clinical spine (OR=2.2), and radiographic spine fractures (OR=1.5). Women osteoporotic only at spine had a 2.8-fold increased odds of radiographic spine fracture (95%CI 2.1-3.8), and smaller increases in risk of clinical spine (OR=1.4), nonhip nonspine (HR=1.6), and hip fractures (HR=1.2). Discordant BMD results predict different fracture patterns. DXA fracture risk estimation in these patients should be site-specific. Women osteoporotic only at spine would not have been identified from hip BMD measurement alone, and may have a sufficiently high fracture risk to warrant preventive treatment. PMID:18296090

  16. 78 FR 58753 - 2013-2014 Refuge-Specific Hunting and Sport Fishing Regulations

    Science.gov (United States)

    2013-09-24

    ... Information for Specific Refuges'' under SUPPLEMENTARY INFORMATION. FOR FURTHER INFORMATION CONTACT: Paul F... Slough NWR (1) Oregon A closed closed closed. Cherry Valley NWR (5) Pennsylvania........ A A A closed... Balcones Canyonlands NWR 93 4.3 Bandon Marsh NWR 108 5.0 Baskett Slough NWR 140 6.5 Cherry Valley NWR 315...

  17. DNA methylation of specific CpG sites in the promoter region regulates the transcription of the mouse oxytocin receptor.

    Directory of Open Access Journals (Sweden)

    Shimrat Mamrut

    Full Text Available Oxytocin is a peptide hormone, well known for its role in labor and suckling, and most recently for its involvement in mammalian social behavior. All central and peripheral actions of oxytocin are mediated through the oxytocin receptor, which is the product of a single gene. Transcription of the oxytocin receptor is subject to regulation by gonadal steroid hormones, and is profoundly elevated in the uterus and mammary glands during parturition. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression of the oxytocin receptor in individuals with autism. Here, we hypothesized that transcription of the mouse oxytocin receptor is regulated by DNA methylation of specific sites in its promoter, in a tissue-specific manner. Hypothalamus-derived GT1-7, and mammary-derived 4T1 murine cell lines displayed negative correlations between oxytocin receptor transcription and methylation of the gene promoter, and demethylation caused a significant enhancement of oxytocin receptor transcription in 4T1 cells. Using a reporter gene assay, we showed that methylation of specific sites in the gene promoter, including an estrogen response element, significantly inhibits transcription. Furthermore, methylation of the oxytocin receptor promoter was found to be differentially correlated with oxytocin receptor expression in mammary glands and the uterus of virgin and post-partum mice, suggesting that it plays a distinct role in oxytocin receptor transcription among tissues and under different physiological conditions. Together, these results support the hypothesis that the expression of the mouse oxytocin receptor gene is epigenetically regulated by DNA methylation of its promoter.

  18. Older Age Predicts Decreased Metastasis and Prostate Cancer-Specific Death for Men Treated With Radiation Therapy: Meta-Analysis of Radiation Therapy Oncology Group Trials

    Energy Technology Data Exchange (ETDEWEB)

    Hamstra, Daniel A., E-mail: dhamm@umich.edu [University of Michigan, Ann Arbor, Michigan (United States); Bae, Kyounghwa [Radiation Therapy Oncology Group, Philadelphia, Pennsylvania (United States); Pilepich, Miljenko V. [UCLA Medical Center, Los Angeles, California (United States); Hanks, Gerald E. [Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Grignon, David J. [Indiana University-Purdue University Indianapolis, Indiana (United States); McGowan, David G. [Cross Cancer Institute, Edmonton, Alberta (Canada); Roach, Mack [UCSF, San Francisco, California (United States); Lawton, Colleen [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Lee, R. Jeffrey [Intermountain Medical Center, Salt Lake City, Utah (United States); Sandler, Howard [Cedars-Sinai Medical Center, Los Angeles, California (United States)

    2011-12-01

    Purpose: The impact of age on prostate cancer (PCa) outcome has been controversial; therefore, we analyzed the effect of age on overall survival (OS), distant metastasis, prostate cancer-specific death (PCSD), and nonprostate cancer death (NPCD) on patients with locally advanced PCa. Methods and Materials: Patients who participated in four Radiation Therapy Oncology Group (RTOG) phase III trials, 8531, 8610, 9202, and 9413, were studied. Cox proportional hazards regression was used for OS analysis, and cumulative events analysis with Fine and Gray's regression was used for analyses of metastasis, PCSD, and NPCD. Results: Median follow-up of 4,128 patients with median age of 70 (range, 43-88 years) was 7.3 years. Most patients had high-risk disease: cT3 to cT4 (54%) and Gleason scores (GS) of 7 (45%) and 8 to 10 (27%). Older age ({<=}70 vs. >70 years) predicted for decreased OS (10-year rate, 55% vs. 41%, respectively; p < 0.0001) and increased NPCD (10-year rate, 28% vs. 46%, respectively; p < 0.0001) but decreased metastasis (10-year rate, 27% vs. 20%, respectively; p < 0.0001) and PCSD (10-year rate, 18% vs. 14%, respectively; p < 0.0001). To account for competing risks, outcomes were analyzed in 2-year intervals, and age-dependent differences in metastasis and PCSD persisted, even in the earliest time periods. When adjusted for other covariates, an age of >70 years remained associated with decreased OS (hazard ratio [HR], 1.56 [95% confidence interval [CI], 1.43-1.70] p < 0.0001) but with decreased metastasis (HR, 0.72 [95% CI, 0.63-0.83] p < 0.0001) and PCSD (HR, 0.78 [95% CI, 0.66-0.92] p < 0.0001). Finally, the impact of the duration of androgen deprivation therapy as a function of age was evaluated. Conclusions: These data support less aggressive PCa in older men, independent of other clinical features. While the biological underpinning of this finding remains unknown, stratification by age in future trials appears to be warranted.

  19. Regulation of angiogenesis in human skeletal muscle with specific focus on pro- angiogenic and angiostatic factors

    DEFF Research Database (Denmark)

    Høier, Birgitte

    It is well established that acute exercise promotes an angiogenic response and that a period of exercise training results in capillary growth. Skeletal muscle angiogenesis is a complex process that requires a coordinated interplay of multiple factors and compounds to ensure proper vascular function....... The angiogenic process is initiated through changes in mechanical and/or metabolic factors during exercise and when exercise is repeated these stimuli may result in capillary growth if needed. The present PhD thesis is based on six studies in which the regulation of angiogenesis in skeletal muscle...... was studied in peripheral arterial disease. Vascular endothelial growth factor (VEGF) is the most important factor in exercise-induced angiogenesis and is located primarily in muscle cells but also in endothelial cells, pericytes, and in the extracellular matrix. VEGF protein secretion to the interstitium...

  20. Nitrogen assimilation system in maize is regulated by developmental and tissue-specific mechanisms

    KAUST Repository

    Plett, Darren

    2016-08-10

    Key message: We found metabolites, enzyme activities and enzyme transcript abundances vary significantly across the maize lifecycle, but weak correlation exists between the three groups. We identified putative genes regulating nitrate assimilation. Abstract: Progress in improving nitrogen (N) use efficiency (NUE) of crop plants has been hampered by the complexity of the N uptake and utilisation systems. To understand this complexity we measured the activities of seven enzymes and ten metabolites related to N metabolism in the leaf and root tissues of Gaspe Flint maize plants grown in 0.5 or 2.5 mM NO3 − throughout the lifecycle. The amino acids had remarkably similar profiles across the lifecycle except for transient responses, which only appeared in the leaves for aspartate or in the roots for asparagine, serine and glycine. The activities of the enzymes for N assimilation were also coordinated to a certain degree, most noticeably with a peak in root activity late in the lifecycle, but with wide variation in the activity levels over the course of development. We analysed the transcriptional data for gene sets encoding the measured enzymes and found that, unlike the enzyme activities, transcript levels of the corresponding genes did not exhibit the same coordination across the lifecycle and were only weakly correlated with the levels of various amino acids or individual enzyme activities. We identified gene sets which were correlated with the enzyme activity profiles, including seven genes located within previously known quantitative trait loci for enzyme activities and hypothesise that these genes are important for the regulation of enzyme activities. This work provides insights into the complexity of the N assimilation system throughout development and identifies candidate regulatory genes, which warrant further investigation in efforts to improve NUE in crop plants. © 2016, Springer Science+Business Media Dordrecht.

  1. Nitrogen assimilation system in maize is regulated by developmental and tissue-specific mechanisms

    KAUST Repository

    Plett, Darren; Holtham, Luke; Baumann, Ute; Kalashyan, Elena; Francis, Karen; Enju, Akiko; Toubia, John; Roessner, Ute; Bacic, Antony; Rafalski, Antoni; Dhugga, Kanwarpal S.; Tester, Mark A.; Garnett, Trevor; Kaiser, Brent N.

    2016-01-01

    Key message: We found metabolites, enzyme activities and enzyme transcript abundances vary significantly across the maize lifecycle, but weak correlation exists between the three groups. We identified putative genes regulating nitrate assimilation. Abstract: Progress in improving nitrogen (N) use efficiency (NUE) of crop plants has been hampered by the complexity of the N uptake and utilisation systems. To understand this complexity we measured the activities of seven enzymes and ten metabolites related to N metabolism in the leaf and root tissues of Gaspe Flint maize plants grown in 0.5 or 2.5 mM NO3 − throughout the lifecycle. The amino acids had remarkably similar profiles across the lifecycle except for transient responses, which only appeared in the leaves for aspartate or in the roots for asparagine, serine and glycine. The activities of the enzymes for N assimilation were also coordinated to a certain degree, most noticeably with a peak in root activity late in the lifecycle, but with wide variation in the activity levels over the course of development. We analysed the transcriptional data for gene sets encoding the measured enzymes and found that, unlike the enzyme activities, transcript levels of the corresponding genes did not exhibit the same coordination across the lifecycle and were only weakly correlated with the levels of various amino acids or individual enzyme activities. We identified gene sets which were correlated with the enzyme activity profiles, including seven genes located within previously known quantitative trait loci for enzyme activities and hypothesise that these genes are important for the regulation of enzyme activities. This work provides insights into the complexity of the N assimilation system throughout development and identifies candidate regulatory genes, which warrant further investigation in efforts to improve NUE in crop plants. © 2016, Springer Science+Business Media Dordrecht.

  2. Patterns of hybrid loss of imprinting reveal tissue- and cluster-specific regulation.

    Directory of Open Access Journals (Sweden)

    Christopher D Wiley

    Full Text Available Crosses between natural populations of two species of deer mice, Peromyscus maniculatus (BW, and P. polionotus (PO, produce parent-of-origin effects on growth and development. BW females mated to PO males (bwxpo produce growth-retarded but otherwise healthy offspring. In contrast, PO females mated to BW males (POxBW produce overgrown and severely defective offspring. The hybrid phenotypes are pronounced in the placenta and include POxBW conceptuses which lack embryonic structures. Evidence to date links variation in control of genomic imprinting with the hybrid defects, particularly in the POxBW offspring. Establishment of genomic imprinting is typically mediated by gametic DNA methylation at sites known as gDMRs. However, imprinted gene clusters vary in their regulation by gDMR sequences.Here we further assess imprinted gene expression and DNA methylation at different cluster types in order to discern patterns. These data reveal POxBW misexpression at the Kcnq1ot1 and Peg3 clusters, both of which lose ICR methylation in placental tissues. In contrast, some embryonic transcripts (Peg10, Kcnq1ot1 reactivated the silenced allele with little or no loss of DNA methylation. Hybrid brains also display different patterns of imprinting perturbations. Several cluster pairs thought to use analogous regulatory mechanisms are differentially affected in the hybrids.These data reinforce the hypothesis that placental and somatic gene regulation differs significantly, as does that between imprinted gene clusters and between species. That such epigenetic regulatory variation exists in recently diverged species suggests a role in reproductive isolation, and that this variation is likely to be adaptive.

  3. Developmental wiring of specific neurons is regulated by RET-1/Nogo-A in Caenorhabditis elegans

    DEFF Research Database (Denmark)

    Torpe, Nanna; Nørgaard, Steffen; Høye, Anette M.

    2017-01-01

    Nogo-A is a membrane-bound protein that functions to inhibit neuronal migration, adhesion, and neurite outgrowth during development. In the mature nervous system, Nogo-A stabilizes neuronal wiring to inhibit neuronal plasticity and regeneration after injury. Here, we show that RET-1, the sole Nog...... present a previously unidentified function for RET-1 in the nervous system of C. elegans.......-A homolog in Caenorhabditis elegans, is required to control developmental wiring of a specific subset of neurons. In ret-1 deletion mutant animals, specific ventral nerve cord axons are misguided where they fail to respect the ventral midline boundary. We found that ret-1 is expressed in multiple neurons...

  4. Nitric oxide regulates input specificity of long-term depression and context dependence of cerebellar learning.

    Directory of Open Access Journals (Sweden)

    Hideaki Ogasawara

    2007-01-01

    Full Text Available Recent studies have shown that multiple internal models are acquired in the cerebellum and that these can be switched under a given context of behavior. It has been proposed that long-term depression (LTD of parallel fiber (PF-Purkinje cell (PC synapses forms the cellular basis of cerebellar learning, and that the presynaptically synthesized messenger nitric oxide (NO is a crucial "gatekeeper" for LTD. Because NO diffuses freely to neighboring synapses, this volume learning is not input-specific and brings into question the biological significance of LTD as the basic mechanism for efficient supervised learning. To better characterize the role of NO in cerebellar learning, we simulated the sequence of electrophysiological and biochemical events in PF-PC LTD by combining established simulation models of the electrophysiology, calcium dynamics, and signaling pathways of the PC. The results demonstrate that the local NO concentration is critical for induction of LTD and for its input specificity. Pre- and postsynaptic coincident firing is not sufficient for a PF-PC synapse to undergo LTD, and LTD is induced only when a sufficient amount of NO is provided by activation of the surrounding PFs. On the other hand, above-adequate levels of activity in nearby PFs cause accumulation of NO, which also allows LTD in neighboring synapses that were not directly stimulated, ruining input specificity. These findings lead us to propose the hypothesis that NO represents the relevance of a given context and enables context-dependent selection of internal models to be updated. We also predict sparse PF activity in vivo because, otherwise, input specificity would be lost.

  5. Area-specific development of distinct projection neuron subclasses is regulated by postnatal epigenetic modifications

    Science.gov (United States)

    Harb, Kawssar; Magrinelli, Elia; Nicolas, Céline S; Lukianets, Nikita; Frangeul, Laura; Pietri, Mariel; Sun, Tao; Sandoz, Guillaume; Grammont, Franck; Jabaudon, Denis; Studer, Michèle; Alfano, Christian

    2016-01-01

    During cortical development, the identity of major classes of long-distance projection neurons is established by the expression of molecular determinants, which become gradually restricted and mutually exclusive. However, the mechanisms by which projection neurons acquire their final properties during postnatal stages are still poorly understood. In this study, we show that the number of neurons co-expressing Ctip2 and Satb2, respectively involved in the early specification of subcerebral and callosal projection neurons, progressively increases after birth in the somatosensory cortex. Ctip2/Satb2 postnatal co-localization defines two distinct neuronal subclasses projecting either to the contralateral cortex or to the brainstem suggesting that Ctip2/Satb2 co-expression may refine their properties rather than determine their identity. Gain- and loss-of-function approaches reveal that the transcriptional adaptor Lmo4 drives this maturation program through modulation of epigenetic mechanisms in a time- and area-specific manner, thereby indicating that a previously unknown genetic program postnatally promotes the acquisition of final subtype-specific features. DOI: http://dx.doi.org/10.7554/eLife.09531.001 PMID:26814051

  6. SATB1 regulates SPARC expression in K562 cell line through binding to a specific sequence in the third intron

    International Nuclear Information System (INIS)

    Li, K.; Cai, R.; Dai, B.B.; Zhang, X.Q.; Wang, H.J.; Ge, S.F.; Xu, W.R.; Lu, J.

    2007-01-01

    Special AT-rich binding protein 1 (SATB1), a cell type-specific nuclear matrix attachment region (MAR) DNA-binding protein, tethers to a specific DNA sequence and regulates gene expression through chromatin remodeling and HDAC (histone deacetylase complex) recruitment. In this study, a SATB1 eukaryotic expression plasmid was transfected into the human erythroleukemia K562 cell line and individual clones that stably over-expressed the SATB1 protein were isolated. Microarray analysis revealed that hundreds of genes were either up- or down-regulated in the SATB1 over-expressing K562 cell lines. One of these was the extra-cellular matrix glycoprotein, SPARC (human secreted protein acidic and rich in cysteine). siRNA knock-down of SATB1 also reduced SPARC expression, which was consistent with elevated SPARC levels in the SATB1 over-expressing cell line. Bioinformatics software Mat-inspector showed that a 17 bp DNA sequence in the third intron of SPARC possessed a high potential for SATB1 binding; a finding confirmed by Chromatin immunoprecipitation (ChIP) with anti-SATB1 antibody. Our results show for the first time that forced-expression of SATB1 in K562 cells triggers SPARC up-regulation by binding to a 17 bp DNA sequence in the third intron

  7. Proteasome-associated deubiquitinase ubiquitin-specific protease 14 regulates prostate cancer proliferation by deubiquitinating and stabilizing androgen receptor.

    Science.gov (United States)

    Liao, Yuning; Liu, Ningning; Hua, Xianliang; Cai, Jianyu; Xia, Xiaohong; Wang, Xuejun; Huang, Hongbiao; Liu, Jinbao

    2017-02-02

    Androgen receptor (AR) is frequently over-expressed and plays a critical role in the growth and progression of human prostate cancer. The therapy attempting to target AR signalling was established in decades ago but the treatment of prostate cancer is far from being satisfactory. The assignable cause is that our understanding of the mechanism of AR regulation and re-activation remains incomplete. Increasing evidence suggests that deubiquitinases are involved in the regulation of cancer development and progression but the specific underlying mechanism often is not elucidated. In the current study, we have identified ubiquitin-specific protease 14 (USP14) as a novel regulator of AR, inhibiting the degradation of AR via deubiquitinating this oncoprotein in the androgen-responsive prostate cancer cells. We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells. Hence, we conclude that USP14 promotes prostate cancer progression likely through stabilization of AR, suggesting that USP14 could be a promising therapeutic target for prostate cancer.

  8. Global Transcriptome Analysis of Primary Cerebrocortical Cells: Identification of Genes Regulated by Triiodothyronine in Specific Cell Types.

    Science.gov (United States)

    Gil-Ibañez, Pilar; García-García, Francisco; Dopazo, Joaquín; Bernal, Juan; Morte, Beatriz

    2017-01-01

    Thyroid hormones, thyroxine, and triiodothyronine (T3) are crucial for cerebral cortex development acting through regulation of gene expression. To define the transcriptional program under T3 regulation, we have performed RNA-Seq of T3-treated and untreated primary mouse cerebrocortical cells. The expression of 1145 genes or 7.7% of expressed genes was changed upon T3 addition, of which 371 responded to T3 in the presence of cycloheximide indicating direct transcriptional regulation. The results were compared with available transcriptomic datasets of defined cellular types. In this way, we could identify targets of T3 within genes enriched in astrocytes and neurons, in specific layers including the subplate, and in specific neurons such as prepronociceptin, cholecystokinin, or cortistatin neurons. The subplate and the prepronociceptin neurons appear as potentially major targets of T3 action. T3 upregulates mostly genes related to cell membrane events, such as G-protein signaling, neurotransmission, and ion transport and downregulates genes involved in nuclear events associated with the M phase of cell cycle, such as chromosome organization and segregation. Remarkably, the transcriptomic changes induced by T3 sustain the transition from fetal to adult patterns of gene expression. The results allow defining in molecular terms the elusive role of thyroid hormones on neocortical development. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration.

    Science.gov (United States)

    Fearnley, Gareth W; Bruns, Alexander F; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

    2015-04-24

    Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform-specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cγ1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response. © 2015. Published by The Company of Biologists Ltd.

  10. VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration

    Directory of Open Access Journals (Sweden)

    Gareth W. Fearnley

    2015-07-01

    Full Text Available Vascular endothelial growth factor A (VEGF-A regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform-specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cγ1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response.

  11. Plant-specific Histone Deacetylases HDT½ Regulate GIBBERELLIN 2-OXIDASE 2 Expression to Control Arabidopsis Root Meristem Cell Number

    KAUST Repository

    Li, Huchen

    2017-08-31

    Root growth is modulated by environmental factors and depends on cell production in the root meristem (RM). New cells in the meristem are generated by stem cells and transit-amplifying cells, which together determine RM cell number. Transcription factors and chromatin-remodelling factors have been implicated in regulating the switch from stem cells to transit-amplifying cells. Here we show that two Arabidopsis thaliana paralogs encoding plant-specific histone deacetylases, HDT1 and HDT2, regulate a second switch from transit-amplifying cells to expanding cells. Knockdown of HDT½ (hdt1,2i) results in an earlier switch and causes a reduced RM cell number. Our data show that HDT½ negatively regulate the acetylation level of the C19-GIBBERELLIN 2-OXIDASE 2 (GA2ox2) locus and repress the expression of GA2ox2 in the RM and elongation zone. Overexpression of GA2ox2 in the RM phenocopies the hdt1,2i phenotype. Conversely, knockout of GA2ox2 partially rescues the root growth defect of hdt1,2i. These results suggest that by repressing the expression of GA2ox2, HDT½ likely fine-tune gibberellin metabolism and they are crucial for regulating the switch from cell division to expansion to determine RM cell number. We propose that HDT½ function as part of a mechanism that modulates root growth in response to environmental factors.

  12. "I'll stop procrastinating now!" Fostering specific processes of self-regulated learning to reduce academic procrastination.

    Science.gov (United States)

    Grunschel, Carola; Patrzek, Justine; Klingsieck, Katrin B; Fries, Stefan

    2018-01-01

    Academic procrastination is considered to be a result of self-regulation failure having detrimental effects on students' well-being and academic performance. In the present study, we developed and evaluated a group training that aimed to reduce academic procrastination. We based the training on a cyclical process model of self-regulated learning, thus, focusing on improving deficient processes of self-regulated learning among academic procrastinators (e.g., time management, dealing with distractions). The training comprised five sessions and took place once a week for 90 min in groups of no more than 10 students. Overall, 106 students completed the training. We evaluated the training using a comprehensive control group design with repeated measures (three points of measurement); the control group was trained after the intervention group's training. The results showed that our training was successful. The trained intervention group significantly reduced academic procrastination and improved specific processes of self-regulated learning (e.g., time management, concentration), whereas the untrained control group showed no change regarding these variables. After the control group had also been trained, the control group also showed the expected favorable changes. The students rated the training overall as good and found it recommendable for procrastinating friends. Hence, fostering self-regulatory processes in our intervention was a successful attempt to support students in reducing academic procrastination. The evaluation of the training encourages us to adapt the training for different groups of procrastinators.

  13. Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination.

    Science.gov (United States)

    Johnson, Laura E; Olson, Brian M; McNeel, Douglas G

    2017-07-18

    Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers. Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model. The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016). While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.

  14. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements (Arabic Edition)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-07-01

    The IAEA's Statute authorizes the Agency to 'establish or adopt' standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the conventions

  15. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements (Chinese Edition)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-03-01

    The IAEA's Statute authorizes the Agency to 'establish or adopt' standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the conventions

  16. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-10-15

    The IAEA's Statute authorizes the Agency to 'establish or adopt... standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the

  17. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements

    International Nuclear Information System (INIS)

    2012-01-01

    The IAEA's Statute authorizes the Agency to 'establish or adopt... standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the

  18. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements (French Edition)

    International Nuclear Information System (INIS)

    2013-01-01

    The IAEA's Statute authorizes the Agency to ''establish or adopt standards of safety for protection of health and minimization of danger to life and property'' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the

  19. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements (Chinese Edition)

    International Nuclear Information System (INIS)

    2013-01-01

    The IAEA's Statute authorizes the Agency to 'establish or adopt' standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the conventions

  20. Regulations for the Safe Transport of Radioactive Material. 2012 Edition. Specific Safety Requirements (Arabic Edition)

    International Nuclear Information System (INIS)

    2012-01-01

    The IAEA's Statute authorizes the Agency to 'establish or adopt' standards of safety for protection of health and minimization of danger to life and property' - standards that the IAEA must use in its own operations, and which States can apply by means of their regulatory provisions for nuclear and radiation safety. The IAEA does this in consultation with the competent organs of the United Nations and with the specialized agencies concerned. A comprehensive set of high quality standards under regular review is a key element of a stable and sustainable global safety regime, as is the IAEA's assistance in their application. The IAEA commenced its safety standards programme in 1958. The emphasis placed on quality, fitness for purpose and continuous improvement has led to the widespread use of the IAEA standards throughout the world. The Safety Standards Series now includes unified Fundamental Safety Principles, which represent an international consensus on what must constitute a high level of protection and safety. With the strong support of the Commission on Safety Standards, the IAEA is working to promote the global acceptance and use of its standards. Standards are only effective if they are properly applied in practice. The IAEA's safety services encompass design, siting and engineering safety, operational safety, radiation safety, safe transport of radioactive material and safe management of radioactive waste, as well as governmental organization, regulatory matters and safety culture in organizations. These safety services assist Member States in the application of the standards and enable valuable experience and insights to be shared. Regulating safety is a national responsibility, and many States have decided to adopt the IAEA's standards for use in their national regulations. For parties to the various international safety conventions, IAEA standards provide a consistent, reliable means of ensuring the effective fulfilment of obligations under the conventions

  1. Automatic design of basin-specific drought indexes for highly regulated water systems

    Science.gov (United States)

    Zaniolo, Marta; Giuliani, Matteo; Castelletti, Andrea Francesco; Pulido-Velazquez, Manuel

    2018-04-01

    Socio-economic costs of drought are progressively increasing worldwide due to undergoing alterations of hydro-meteorological regimes induced by climate change. Although drought management is largely studied in the literature, traditional drought indexes often fail at detecting critical events in highly regulated systems, where natural water availability is conditioned by the operation of water infrastructures such as dams, diversions, and pumping wells. Here, ad hoc index formulations are usually adopted based on empirical combinations of several, supposed-to-be significant, hydro-meteorological variables. These customized formulations, however, while effective in the design basin, can hardly be generalized and transferred to different contexts. In this study, we contribute FRIDA (FRamework for Index-based Drought Analysis), a novel framework for the automatic design of basin-customized drought indexes. In contrast to ad hoc empirical approaches, FRIDA is fully automated, generalizable, and portable across different basins. FRIDA builds an index representing a surrogate of the drought conditions of the basin, computed by combining all the relevant available information about the water circulating in the system identified by means of a feature extraction algorithm. We used the Wrapper for Quasi-Equally Informative Subset Selection (W-QEISS), which features a multi-objective evolutionary algorithm to find Pareto-efficient subsets of variables by maximizing the wrapper accuracy, minimizing the number of selected variables, and optimizing relevance and redundancy of the subset. The preferred variable subset is selected among the efficient solutions and used to formulate the final index according to alternative model structures. We apply FRIDA to the case study of the Jucar river basin (Spain), a drought-prone and highly regulated Mediterranean water resource system, where an advanced drought management plan relying on the formulation of an ad hoc state index is used

  2. EST analysis in Ginkgo biloba: an assessment of conserved developmental regulators and gymnosperm specific genes

    Directory of Open Access Journals (Sweden)

    Runko Suzan J

    2005-10-01

    Full Text Available Abstract Background Ginkgo biloba L. is the only surviving member of one of the oldest living seed plant groups with medicinal, spiritual and horticultural importance worldwide. As an evolutionary relic, it displays many characters found in the early, extinct seed plants and extant cycads. To establish a molecular base to understand the evolution of seeds and pollen, we created a cDNA library and EST dataset from the reproductive structures of male (microsporangiate, female (megasporangiate, and vegetative organs (leaves of Ginkgo biloba. Results RNA from newly emerged male and female reproductive organs and immature leaves was used to create three distinct cDNA libraries from which 6,434 ESTs were generated. These 6,434 ESTs from Ginkgo biloba were clustered into 3,830 unigenes. A comparison of our Ginkgo unigene set against the fully annotated genomes of rice and Arabidopsis, and all available ESTs in Genbank revealed that 256 Ginkgo unigenes match only genes among the gymnosperms and non-seed plants – many with multiple matches to genes in non-angiosperm plants. Conversely, another group of unigenes in Gingko had highly significant homology to transcription factors in angiosperms involved in development, including MADS box genes as well as post-transcriptional regulators. Several of the conserved developmental genes found in Ginkgo had top BLAST homology to cycad genes. We also note here the presence of ESTs in G. biloba similar to genes that to date have only been found in gymnosperms and an additional 22 Ginkgo genes common only to genes from cycads. Conclusion Our analysis of an EST dataset from G. biloba revealed genes potentially unique to gymnosperms. Many of these genes showed homology to fully sequenced clones from our cycad EST dataset found in common only with gymnosperms. Other Ginkgo ESTs are similar to developmental regulators in higher plants. This work sets the stage for future studies on Ginkgo to better understand seed and

  3. Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy

    Science.gov (United States)

    Reyes, Nicholas L.; Banks, Glen B.; Tsang, Mark; Margineantu, Daciana; Gu, Haiwei; Djukovic, Danijel; Chan, Jacky; Torres, Michelle; Liggitt, H. Denny; Hirenallur-S, Dinesh K.; Hockenbery, David M.; Raftery, Daniel; Iritani, Brian M.

    2015-01-01

    Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I “red” slow twitch and type II “white” fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. PMID:25548157

  4. Isomer-specific regulation of metabolism and PPARgamma signaling by CLA in human preadipocytes

    DEFF Research Database (Denmark)

    Brown, J Mark; Boysen, Maria Sandberg; Jensen, Søren Skov

    2003-01-01

    Trans-10,cis-12 conjugated linoleic acid (CLA) has previously been shown to be the CLA isomer responsible for CLA-induced reductions in body fat in animal models, and we have shown that this isomer, but not the cis-9,trans-11 CLA isomer, specifically decreased triglyceride (TG) accumulation...... transporter 4 gene expression. Furthermore, trans-10,cis-12 CLA reduced oleic acid uptake and oxidation when compared with all other treatments. In parallel to CLA's effects on metabolism, trans-10,cis-12 CLA decreased, whereas cis-9,trans-11 CLA increased, the expression of peroxisome proliferator...

  5. The Active Jasmonate JA-Ile Regulates a Specific Subset of Plant Jasmonate-Mediated Resistance to Herbivores in Nature

    Directory of Open Access Journals (Sweden)

    Meredith C. Schuman

    2018-06-01

    Full Text Available The jasmonate hormones are essential regulators of plant defense against herbivores and include several dozen derivatives of the oxylipin jasmonic acid (JA. Among these, the conjugate jasmonoyl isoleucine (JA-Ile has been shown to interact directly with the jasmonate co-receptor complex to regulate responses to jasmonate signaling. However, functional studies indicate that some aspects of jasmonate-mediated defense are not regulated by JA-Ile. Thus, it is not clear whether JA-Ile is best characterized as the master jasmonate regulator of defense, or if it regulates more specific aspects. We investigated possible functions of JA-Ile in anti-herbivore resistance of the wild tobacco Nicotiana attenuata, a model system for plant-herbivore interactions. We first analyzed the soluble and volatile secondary metabolomes of irJAR4xirJAR6, asLOX3, and WT plants, as well as an RNAi line targeting the jasmonate co-receptor CORONATINE INSENSITIVE 1 (irCOI1, following a standardized herbivory treatment. irJAR4xirJAR6 were the most similar to WT plants, having a ca. 60% overlap in differentially regulated metabolites with either asLOX3 or irCOI1. In contrast, while at least 25 volatiles differed between irCOI1 or asLOX3 and WT plants, there were few or no differences in herbivore-induced volatile emission between irJAR4xirJAR6 and WT plants, in glasshouse- or field-collected samples. We then measured the susceptibility of jasmonate-deficient vs. JA-Ile-deficient plants in nature, in comparison to wild-type (WT controls, and found that JA-Ile-deficient plants (irJAR4xirJAR6 are much better defended even than a mildly jasmonate-deficient line (asLOX3. The differences among lines could be attributed to differences in damage from specific herbivores, which appeared to prefer either one or the other jasmonate-deficient phenotype. We further investigated the elicitation of one herbivore-induced volatile known to be jasmonate-regulated and to mediate resistance to

  6. TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells.

    Science.gov (United States)

    Tsagaratou, Ageliki; González-Avalos, Edahí; Rautio, Sini; Scott-Browne, James P; Togher, Susan; Pastor, William A; Rothenberg, Ellen V; Chavez, Lukas; Lähdesmäki, Harri; Rao, Anjana

    2017-01-01

    TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4 + CD8 + double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).

  7. Cerebrovascular regulation in men and women: stimulus-specific role of cyclooxygenase.

    Science.gov (United States)

    Peltonen, Garrett L; Harrell, John W; Rousseau, Cameron L; Ernst, Brady S; Marino, Mariah L; Crain, Meghan K; Schrage, William G

    2015-07-01

    Greater cerebral artery vasodilation mediated by cyclooxygenase (COX) in female animals is unexplored in humans. We hypothesized that young, healthy women would exhibit greater basal cerebral blood flow (CBF) and greater vasodilation during hypoxia or hypercapnia compared to men, mediated by a larger contribution of COX. We measured middle cerebral artery velocity (MCAv, transcranial Doppler ultrasound) in 42 adults (24 women, 18 men; 24 ± 1 years) during two visits, in a double-blind, placebo-controlled design (COX inhibition, 100 mg oral indomethacin, Indo). Women were studied early in the follicular phase of the menstrual cycle (days 1-5). Two levels of isocapnic hypoxia (SPO2 = 90% and 80%) were induced for 5-min each. Separately, hypercapnia was induced by increasing end-tidal carbon dioxide (PETCO 2) 10 mmHg above baseline. A positive change in MCAv (ΔMCAv) reflected vasodilation. Basal MCAv was greater in women compared to men (P women exhibit greater basal CBF than men, but similar vasodilatory responses to hypoxia and hypercapnia. Moreover, COX is not obligatory for hypoxic vasodilation, but plays a vital and similar role in the regulation of basal CBF (~30%) and hypercapnic response (~55%) between sexes. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  8. Myostatin genotype regulates muscle-specific miRNA expression in mouse pectoralis muscle

    Directory of Open Access Journals (Sweden)

    Cheng Ye

    2010-11-01

    Full Text Available Abstract Background Loss of functional Myostatin results in a dramatic increase in skeletal muscle mass. It is unknown what role miRNAs play in Myostatin mediated repression of skeletal muscle mass. We hypothesized that Myostatin genotype would be associated with the differential expression of miRNAs in skeletal muscle. Findings Loss of functional Myostatin resulted in a significant increase (p .2 on miR-24 expression level. Myostatin genotype did not affect the expression level of MyoD or Myogenin (P > 0.5. Conclusions Myostatin may regulates the expression of miRNAs such as miR-133a, miR-133b, miR-1, and miR-206 in skeletal muscle as it has been observed that the expression of those miRNAs are significantly higher in myostatin null mice compared to wild type and heterozygous mice. In contrast, expression of myogenic factors such as MyoD or Myogenin has not been affected by myostatin in the muscle tissue.

  9. Regulation of notochord-specific expression of Ci-Bra downstream genes in Ciona intestinalis embryos.

    Science.gov (United States)

    Takahashi, Hiroki; Hotta, Kohji; Takagi, Chiyo; Ueno, Naoto; Satoh, Nori; Shoguchi, Eiichi

    2010-02-01

    Brachyury, a T-box transcription factor, is expressed in ascidian embryos exclusively in primordial notochord cells and plays a pivotal role in differentiation of notochord cells. Previously, we identified approximately 450 genes downstream of Ciona intestinalis Brachyury (Ci-Bra), and characterized the expression profiles of 45 of these in differentiating notochord cells. In this study, we looked for cisregulatory sequences in minimal enhancers of 20 Ci-Bra downstream genes by electroporating region within approximately 3 kb upstream of each gene fused with lacZ. Eight of the 20 reporters were expressed in notochord cells. The minimal enchancer for each of these eight genes was narrowed to a region approximately 0.5-1.0-kb long. We also explored the genome-wide and coordinate regulation of 43 Ci-Bra-downstream genes. When we determined their chromosomal localization, it became evident that they are not clustered in a given region of the genome, but rather distributed evenly over 13 of the 14 pairs of chromosomes, suggesting that gene clustering does not contribute to coordinate control of the Ci-Bra downstream gene expression. Our results might provide Insights Into the molecular mechanisms underlying notochord formation in chordates.

  10. Spatial distance regulates sex-specific feelings to suspected sexual and emotional infidelity.

    Science.gov (United States)

    Schützwohl, Achim; Morjaria, Sheena; Alvis, Shahin

    2011-09-15

    The present study investigates the hitherto neglected influence of the spatial distance between the jealous person, the partner, and a potential rival as a proximate contextual factor regulating emotion intensity. The study tested four predictions. (1) The jealousy mechanism responds with mild negative feelings at most as long as the partner is close to the jealous person. (2) The negative feelings increase when the partner is far from the jealous person but the rival is close. (3) The most uncomfortable feelings result when the partner and the rival are close together and both far from the jealous person. (4) Based on the evolutionary psychological considerations, men report stronger negative feelings than women when suspecting sexual infidelity. Conversely, women report stronger negative feelings than men when suspecting emotional infidelity. The results confirmed predictions 1 and 4. Reversing predictions 2 and 3, the close rival consistently elicited the most uncomfortable feelings. Implications and limitations of the present study are discussed and suggestions for future research are provided.

  11. Spatial Distance Regulates Sex-Specific Feelings to Suspected Sexual and Emotional Infidelity

    Directory of Open Access Journals (Sweden)

    Achim Schützwohl

    2011-07-01

    Full Text Available The present study investigates the hitherto neglected influence of the spatial distance between the jealous person, the partner, and a potential rival as a proximate contextual factor regulating emotion intensity. The study tested four predictions. (1 The jealousy mechanism responds with mild negative feelings at most as long as the partner is close to the jealous person. (2 The negative feelings increase when the partner is far from the jealous person but the rival is close. (3 The most uncomfortable feelings result when the partner and the rival are close together and both far from the jealous person. (4 Based on the evolutionary psychological considerations, men report stronger negative feelings than women when suspecting sexual infidelity. Conversely, women report stronger negative feelings than men when suspecting emotional infidelity. The results confirmed predictions 1 and 4. Reversing predictions 2 and 3, the close rival consistently elicited the most uncomfortable feelings. Implications and limitations of the present study are discussed and suggestions for future research are provided.

  12. The impact of policies regulating alcohol trading hours and days on specific alcohol-related harms: a systematic review.

    Science.gov (United States)

    Sanchez-Ramirez, Diana C; Voaklander, Donald

    2018-02-01

    Evidence supports the expectation that changes in time of alcohol sales associate with changes in alcohol-related harm in both directions. However, to the best of our knowledge, no comprehensive systematic reviews had examined the effect of policies restricting time of alcohol trading on specific alcohol-related harms. To compile existing evidence related to the impact of policies regulating alcohol trading hours/days of on specific harm outcomes such as: assault/violence, motor vehicle crashes/fatalities, injury, visits to the emergency department/hospital, murder/homicides and crime. Systematic review of literature studying the impact of policies regulation alcohol trading times in alcohol-related harm, published between January 2000 and October 2016 in English language. Results support the premise that policies regulating times of alcohol trading and consumption can contribute to reduce injuries, alcohol-related hospitalisations/emergency department visits, homicides and crime. Although the impact of alcohol trading policies in assault/violence and motor vehicle crashes/fatalities is also positive, these associations seem to be more complex and require further study. Evidence suggests a potential direct effect of policies that regulate alcohol trading times in the prevention of injuries, alcohol-related hospitalisations, homicides and crime. The impact of these alcohol trading policies in assault/violence and motor vehicle crashes/fatalities is less compelling. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  13. Specific regulation of point-mutated K-ras-immortalized cell proliferation by a photodynamic antisense strategy.

    Science.gov (United States)

    Higuchi, Maiko; Yamayoshi, Asako; Kato, Kiyoko; Kobori, Akio; Wake, Norio; Murakami, Akira

    2010-02-01

    It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.

  14. Sex chromosome-specific regulation in the Drosophila male germline but little evidence for chromosomal dosage compensation or meiotic inactivation.

    Directory of Open Access Journals (Sweden)

    Colin D Meiklejohn

    2011-08-01

    Full Text Available The evolution of heteromorphic sex chromosomes (e.g., XY in males or ZW in females has repeatedly elicited the evolution of two kinds of chromosome-specific regulation: dosage compensation--the equalization of X chromosome gene expression in males and females--and meiotic sex chromosome inactivation (MSCI--the transcriptional silencing and heterochromatinization of the X during meiosis in the male (or Z in the female germline. How the X chromosome is regulated in the Drosophila melanogaster male germline is unclear. Here we report three new findings concerning gene expression from the X in Drosophila testes. First, X chromosome-wide dosage compensation appears to be absent from most of the Drosophila male germline. Second, microarray analysis provides no evidence for X chromosome-specific inactivation during meiosis. Third, we confirm the previous discovery that the expression of transgene reporters driven by autosomal spermatogenesis-specific promoters is strongly reduced when inserted on the X chromosome versus the autosomes; but we show that this chromosomal difference in expression is established in premeiotic cells and persists in meiotic cells. The magnitude of the X-autosome difference in transgene expression cannot be explained by the absence of dosage compensation, suggesting that a previously unrecognized mechanism limits expression from the X during spermatogenesis in Drosophila. These findings help to resolve several previously conflicting reports and have implications for patterns of genome evolution and speciation in Drosophila.

  15. Considering an affect regulation framework for examining the association between body dissatisfaction and positive body image in Black older adolescent females: does body mass index matter?

    Science.gov (United States)

    Webb, Jennifer B; Butler-Ajibade, Phoebe; Robinson, Seronda A

    2014-09-01

    The present study provided an initial evaluation of an affect regulation model describing the association between body dissatisfaction and two contemporary measures of positive body image among 247 Black college-bound older adolescent females. We further tested whether possessing a higher body mass index (BMI) would strengthen these associations. Self-reported height and weight were used to calculate BMI. Respondents also completed a culturally-sensitive figure rating scale along with assessments of body appreciation and body image flexibility. Results indicated a robust positive association between the two measures of positive body image; BMI was the strongest predictor of both body appreciation and body image flexibility with body size discrepancy (current minus ideal) contributing incremental variance to both models tested. Implications for improving our understanding of the association between positive and negative body image and bolstering positive body image to promote health-protective behaviors among Black young women at this developmental juncture are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. The short version of the Activities-specific Balance Confidence (ABC) scale: Its validity, reliability, and relationship to balance impairment and falls in older adults

    OpenAIRE

    Schepens, Stacey; Goldberg, Allon; Wallace, Melissa

    2009-01-01

    A shortened version of the ABC 16-item scale (ABC-16), the ABC-6, has been proposed as an alternative balance confidence measure. We investigated whether the ABC-6 is a valid and reliable measure of balance confidence and examined its relationship to balance impairment and falls in older adults. Thirty-five community-dwelling older adults completed the ABC-16, including the six questions of the ABC-6. They also completed the following clinical balance tests: unipedal stance time (UST), functi...

  17. Specifications and Quality of Technetium99m Produced diopharmaceuticals According to Good Manufacturing Practice Regulations

    International Nuclear Information System (INIS)

    Abudaia, Jamal; Ben Othman, Monji H.; Maatoug, Maatoug A.; Maatoug, M. Omar

    2003-01-01

    A Technological revolution has occurred in the last two decades of this century in field of Cold Kits preparations processed by Lyophilization technique (A drying process while frozen) which are labeled afterwards with Technetium-99m radionuclide. Such materials are intended to be used as Radiopharmaceutical probes in nuclear medicine for the diagnosis of dynamic and static conditions of organs, and therefore; uncovering of diseases and syndromes targeting humans. Preferability and the advantages of such kits labeled with Technetium-99m radionuclide over other types of radiopharmaceuticals is attributed to the unique physical properties of the radionuclide including its short half life of 6.02 hours, low photon energy of 140 keV, lacking of alpha and beta particles which are usually exposing patients to have additional exposed doses. Moreover, simplicity in obtaining such radionuclide in form portable generators containing the mother radionuclide Molybdenum - 99 (i.e. solvent extraction generators or adsorption column chromatographic generators) for-on-the- spot-labeling, and the ability of formulating the cold kits as chemical complexes located at different organs of human body. Those lyophilized kits intended for radiopharmaceutical preparations labeled with Technetium - 99m radionuclide must stand for quality assurance standards and assessments for the sake of safety, efficiency, apyrogenecity, radiochemical purity, in- vivo stability and suitability for the endeavor planed for. Therefore, in order to control and optimize those considerations, implementations of the so-called GOOD MANUFACTURING PRACTICE composed of regulations and constitutional laws related to the process of preparation and final produced preparation must take place.(author)

  18. Isoform-specific regulation of osteogenic factors by polypeptide N-Acetylgalactosaminyltransferases 1 and 4

    International Nuclear Information System (INIS)

    Tang, Juan; Zheng, Hanxi; Chen, Ling; Gao, Shangshang; Shi, Xiaorui; Liu, Jingjing; Xu, Lan

    2017-01-01

    The family of UDP-GalNAc polypeptide: N-Acetylgalactosaminlytransfersases (ppGalNAcTs) catalyzes the initial step of O-linked protein glycosylation. Mucin-type O-glycoproteins are abundant in the bone and may play an important role in osteogenesis. Herein, we examined the effects of ppGalNAc-T isoforms on osteogenesis of MC3T3-E1 pre-osteoblasts. We found that ppGalNAc-T1 and -T4 isoforms were highly expressed during osteogenesis of MC3T3-E1 and their knockdown by short hairpin RNA (shRNA) decreased osteoblast formation and bone mineralization. Knockdown of ppGalNAc-T1 or -T4 decreased mRNA and protein levels of bone sialoprotein (BSP). Knockdown of ppGalNAc-T1decreased mRNA levels of osteocalcin (OC), osteoprotegerin (OPG). Knockdown ofppGalNAc-T4 isoform decreased mRNA levels of OC, OPG and vitamin D receptor (VDR). While knockdown of T1 or T4 isoforms did not change the expression of osteopontin (OPN), COLLI, receptor activator for nuclear factor-κB ligand (RANKL) and transforming growth factor-β (TGF-β). Our results demonstrated that the ppGalNAc-T4 was highly expressed in MC3T3-E1 cells during osteogenesis for the first time. We also found that ppGalNAc-T1 and -T4 affected the expression of different osteogenic factors, suggesting distinct roles ppGalNAc-T isoformsplay in regulating osteogenesis in vitro. - Highlights: • ppGalNAc-T1 and T4 are highly expressed during MC3T3 cell osteogenesis. • Knockdown of ppGalNAc-T1 and -T4 decreases osteogenic differentiation and mineralization. • Expression of osteogenic factors are differentially affected by decreased ppGalNAc-T1 and -T4 expression.

  19. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.

    Directory of Open Access Journals (Sweden)

    Carolina N Perdigoto

    2016-07-01

    Full Text Available An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2 in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

  20. Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development.

    Science.gov (United States)

    Perdigoto, Carolina N; Dauber, Katherine L; Bar, Carmit; Tsai, Pai-Chi; Valdes, Victor J; Cohen, Idan; Santoriello, Francis J; Zhao, Dejian; Zheng, Deyou; Hsu, Ya-Chieh; Ezhkova, Elena

    2016-07-01

    An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.

  1. Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing

    DEFF Research Database (Denmark)

    Fedorov, Oleg; Huber, Kilian; Eisenreich, Andreas

    2011-01-01

    There is a growing recognition of the importance of protein kinases in the control of alternative splicing. To define the underlying regulatory mechanisms, highly selective inhibitors are needed. Here, we report the discovery and characterization of the dichloroindolyl enaminonitrile KH-CB19......, a potent and highly specific inhibitor of the CDC2-like kinase isoforms 1 and 4 (CLK1/CLK4). Cocrystal structures of KH-CB19 with CLK1 and CLK3 revealed a non-ATP mimetic binding mode, conformational changes in helix aC and the phosphate binding loop and halogen bonding to the kinase hinge region. KH-CB19...... effectively suppressed phosphorylation of SR (serine/arginine) proteins in cells, consistent with its expected mechanism of action. Chemical inhibition of CLK1/CLK4 generated a unique pattern of splicing factor dephosphorylation and had at low nM concentration a profound effect on splicing of the two tissue...

  2. An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull.

    Science.gov (United States)

    McCarthy, Neil; Sidik, Alfire; Bertrand, Julien Y; Eberhart, Johann K

    2016-07-15

    The neurocranium generates most of the craniofacial skeleton and consists of prechordal and postchordal regions. Although development of the prechordal is well studied, little is known of the postchordal region. Here we characterize a signaling hierarchy necessary for postchordal neurocranial development involving Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells. The expression of hyaluron synthetase 2 (has2) in the cephalic mesoderm requires Fgf signaling and Has2 function, in turn, is required for postchordal neurocranial development. While Hedgehog (Hh)-deficient embryos also lack a postchordal neurocranium, this appears primarily due to a later defect in chondrocyte differentiation. Inhibitor studies demonstrate that postchordal neurocranial development requires early Fgf and later Hh signaling. Collectively, our results provide a mechanistic understanding of early postchordal neurocranial development and demonstrate a hierarchy of signaling between Fgf and Hh in the development of this structure. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

    DEFF Research Database (Denmark)

    Bokoch, Michael P; Zou, Yaozhong; Rasmussen, Søren Gøgsig Faarup

    2010-01-01

    extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known...... conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive...... about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the beta(2) adrenergic...

  4. Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice

    Directory of Open Access Journals (Sweden)

    Carlos R. Dostal

    2017-12-01

    Full Text Available Stressors activate the hypothalamic-pituitary-adrenal (HPA axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2. Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway. Keywords: Stress, Ido, Tdo, Kynurenine, Astrocyte, Liver

  5. Reliability and validity of the German short version of the Activities specific Balance Confidence (ABC-D6) scale in older adults.

    Science.gov (United States)

    Schott, Nadja

    2014-01-01

    The Activities specific Balance Confidence (ABC) is a questionnaire which was developed to assess falls-associated self-efficacy. The aim of this study was to evaluate reliability and validity of the German abbreviated 6-item version of the ABC scores in community-dwelling older people. The study sample included 384 subjects (age 71.1 ± 9.7). In order to determine the psychometric properties, reliability and validity were assessed through administration of the German adaptation of the ABC-D16 to participants twice, 10 days apart, and comparison of the ABC-D16 and the ABC-D6 with functional measures of balance and mobility (one-leg stance; 10 m walk; TUG; Fullerton Advanced Balance Scale (FAB)), physical activity (Physical Activity Scale for the Elderly (PASE)), physical fitness (30s arm curl, 30s chair stand, 6 min walk), cognition (Trail-Making-Test (TMT)), falls status, and quality of life (SF36). Factor analyses suggested a 1-factor solution for the ABC-D6 scale (explained variance 79.8%). Internal consistency (.95) and test-retest reliability (.98) for the ABC-D6 scores were excellent. Scores on the ABC-D6 were significantly lower than on the ABC-D16, but ABC-D16 and ABC-D6 scores were highly correlated (.94). There was an increasing difference in the ABC-scores between men and women with increasing age. Fallers reported lower balance confidence than non-fallers. The ABC-D6 score significantly correlated with functional measures of balance and mobility, physical activity, physical fitness, cognition, and quality of life (-.698valid instrument to asses falls-associated self-efficacy and may be used in future research projects and clinical trials. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Clone-specific expression, transcriptional regulation, and action of interleukin-6 in human colon carcinoma cells

    International Nuclear Information System (INIS)

    Brozek, Wolfgang; Bises, Giovanna; Fabjani, Gerhild; Cross, Heide S; Peterlik, Meinrad

    2008-01-01

    Many cancer cells produce interleukin-6 (IL-6), a cytokine that plays a role in growth stimulation, metastasis, and angiogenesis of secondary tumours in a variety of malignancies, including colorectal cancer. Effectiveness of IL-6 in this respect may depend on the quantity of basal and inducible IL-6 expressed as the tumour progresses through stages of malignancy. We therefore have evaluated the effect of IL-6 modulators, i.e. IL-1β, prostaglandin E 2 , 17β-estradiol, and 1,25-dihydroxyvitamin D 3 , on expression and synthesis of the cytokine at different stages of tumour progression. We utilized cultures of the human colon carcinoma cell clones Caco-2/AQ, COGA-1A and COGA-13, all of which expressed differentiation and proliferation markers typical of distinct stages of tumour progression. IL-6 mRNA and protein levels were assayed by RT-PCR and ELISA, respectively. DNA sequencing was utilized to detect polymorphisms in the IL-6 gene promoter. IL-6 mRNA and protein concentrations were low in well and moderately differentiated Caco-2/AQ and COGA-1A cells, but were high in poorly differentiated COGA-13 cells. Addition of IL-1β (5 ng/ml) to a COGA-13 culture raised IL-6 production approximately thousandfold via a prostaglandin-independent mechanism. Addition of 17β-estradiol (10 -7 M) reduced basal IL-6 production by one-third, but IL-1β-inducible IL-6 was unaffected. Search for polymorphisms in the IL-6 promoter revealed the presence of a single haplotype, i.e., -597A/-572G/-174C, in COGA-13 cells, which is associated with a high degree of transcriptional activity of the IL-6 gene. IL-6 blocked differentiation only in Caco-2/AQ cells and stimulated mitosis through up-regulation of c-myc proto-oncogene expression. These effects were inhibited by 10 -8 M 1,25-dihydroxyvitamin D 3 . In human colon carcinoma cells derived from well and moderately differentiated tumours, IL-6 expression is low and only marginally affected, if at all, by PGE 2 , 1,25-dihydroxyvitamin D

  7. IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

    Science.gov (United States)

    Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

    2016-02-01

    Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data

  8. Biosynthesis and regulation of coronatine, a non-host-specific phytotoxin produced by Pseudomonas syringae.

    Science.gov (United States)

    Bender, C L; Palmer, D A; Peñaloza-Vázquez, A; Rangaswamy, V; Ullrich, M

    1998-01-01

    Many P. syringae pathovars are known to produce low-molecular-weight, diffusible toxins in infected host plants. These phytotoxins reproduce some of the symptoms of the relevant bacterial disease and are effective at very low concentrations. Phytotoxins generally enhance the virulence of the P. syringae pathovar which produces them, but are not required for pathogenesis. Genes encoding phytotoxin production have been identified and cloned from several P. syringae pathovars. With the exception of coronatine, toxin biosynthetic gene clusters are generally chromosomally encoded. In several pathovars, the toxin biosynthetic gene cluster also contains a resistance gene which functions to protect the producing strain from the biocidal effects of the toxin. In the case of phaseolotoxin, a resistance gene (argK) has been utilized to engineer phaseolotoxin-resistant tobacco plants. Although P. syringae phytotoxins can induce very similar effects in plants (chlorosis and necrosis), their biosynthesis and mode of action can be quite different. Knowledge of the biosynthetic pathways to these toxins and the cloning of the structural genes for their biosynthesis has relevance to the development of new bioactive compounds with altered specificity. For example, polyketides constitute a huge family of structurally diverse natural products including antibiotics, chemotherapeutic compounds, and antiparasitics. Most of the research on polyketide synthesis in bacteria has focused on compounds synthesized by Streptomyces or other actinomycetes. It is also important to note that it is now possible to utilize a genetic rather than synthetic approach to biosynthesize novel polyketides with altered biological properties (Hutchinson and Fujii, 1995; Kao et al., 1994; Donadio et al., 1993; Katz and Donadio, 1993). Most of the reprogramming or engineering of novel polyketides has been done using actinomycete PKSs, but much of this technology could also be applied to polyketides synthesized by

  9. Genetic regulation by amino acids of specific membrane protein biosynthesis in isolated rat hepatocytes

    International Nuclear Information System (INIS)

    Chiles, T.C.; Handlogten, M.E.; Kilberg, M.S.

    1986-01-01

    Rat Hepatocytes in primary culture were incubated in amino acid-free (AAF) medium or amino acid-supplemented (AAS) medium for 2-6 hr. The effect of amino acid starvation on the synthesis of specific membrane proteins was monitored by including 3 H-leucine during the incubation. A crude plasma membrane fraction was prepared and then analyzed by 2-D gel electrophoresis followed by fluorography. Amino acid deprivation caused an induction of the synthesis of 5 of the 30 proteins studied. The ratio (AAF/-AAS) of cpm incorporated into the remaining 25 proteins was 0.8 +/- 0.2, whereas the ratio for the 5 proteins that showed amino acid-dependent synthesis ranged from 1.5 to 2.5. The presence of 4 μM actinomycin in the AAF medium completely blocked the starvation-induced synthesis of the 5 proteins tested, but did not alter significantly the ratio of cpm incorporated into the other 25 proteins. Binding studies involving ConA suggested a plasma membrane location for the 5 proteins. The molecular weight values of the starvation-induced proteins are 70, 66, 66, 67, and 45kD. Surface-labelling of intact cells and preparation of antibodies against the 5 proteins will be used to establish the subcellular location and to describe the amino acid-dependent synthesis of each in more detail

  10. Segment-specific terminal sequences of Bunyamwera bunyavirus regulate genome replication

    International Nuclear Information System (INIS)

    Barr, John N.; Elliott, Richard M.; Dunn, Ewan F.; Wertz, Gail W.

    2003-01-01

    Bunyamwera virus (BUNV) is the prototype of both the Orthobunyavirus genus and the Bunyaviridae family of segmented negative sense RNA viruses. The tripartite BUNV genome consists of small (S), medium (M), and large (L) segments that are transcribed to give a single mRNA and replicated to generate an antigenome that is the template for synthesis of further genomic RNA strands. We modified an existing cDNA-derived RNA synthesis system to allow identification of BUNV RNA replication and transcription products by direct metabolic labeling. Direct RNA analysis allowed us to distinguish between template activities that affected either RNA replication or mRNA transcription, an ability that was not possible using previous reporter gene expression assays. We generated genome analogs containing the entire nontranslated terminal sequences of the S, M, and L BUNV segments surrounding a common sequence. Analysis of RNAs synthesized from these templates revealed that the relative abilities of BUNV segments to perform RNA replication was M > L > S. Exchange of segment-specific terminal nucleotides identified a 12-nt region located within both the 3' and 5' termini of the M segment that correlated with its high replication ability

  11. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

    Energy Technology Data Exchange (ETDEWEB)

    Bokoch, Michael P.; Zou, Yaozhong; Rasmussen, Søren G.F.; Liu, Corey W.; Nygaard, Rie; Rosenbaum, Daniel M.; Fung, Juan José; Choi, Hee-Jung; Thian, Foon Sun; Kobilka, Tong Sun; Puglisi, Joseph D.; Weis, William I.; Pardo, Leonardo; Prosser, R. Scott; Mueller, Luciano; Kobilka, Brian K. (Stanford-MED); (Toronto); (BMS); (UAB, Spain)

    2010-01-14

    G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the {beta}{sub 2} adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.

  12. MyoD undergoes a distinct G2/M-specific regulation in muscle cells

    International Nuclear Information System (INIS)

    Batonnet-Pichon, Sabrina; Tintignac, Lionel J.; Castro, Anna; Sirri, Valentina; Leibovitch, Marie Pierre; Lorca, Thierry; Leibovitch, Serge A.

    2006-01-01

    The transcription factors MyoD and Myf5 present distinct patterns of expression during cell cycle progression and development. In contrast to the mitosis-specific disappearance of Myf5, which requires a D-box-like motif overlapping the basic domain, here we describe a stable and inactive mitotic form of MyoD phosphorylated on its serine 5 and serine 200 residues by cyclin B-cdc2. In mitosis, these modifications are required for releasing MyoD from condensed chromosomes and inhibiting its DNA-binding and transcriptional activation ability. Then, nuclear MyoD regains instability in the beginning of G1 phase due to rapid dephosphorylation events. Moreover, a non-phosphorylable MyoD S5A/S200A is not excluded from condensed chromatin and alters mitotic progression with apparent abnormalities. Thus, the drop of MyoD below a threshold level and its displacement from the mitotic chromatin could present another window in the cell cycle for resetting the myogenic transcriptional program and to maintain the myogenic determination of the proliferating cells

  13. MyoD undergoes a distinct G2/M-specific regulation in muscle cells.

    Science.gov (United States)

    Batonnet-Pichon, Sabrina; Tintignac, Lionel J; Castro, Anna; Sirri, Valentina; Leibovitch, Marie Pierre; Lorca, Thierry; Leibovitch, Serge A

    2006-12-10

    The transcription factors MyoD and Myf5 present distinct patterns of expression during cell cycle progression and development. In contrast to the mitosis-specific disappearance of Myf5, which requires a D-box-like motif overlapping the basic domain, here we describe a stable and inactive mitotic form of MyoD phosphorylated on its serine 5 and serine 200 residues by cyclin B-cdc2. In mitosis, these modifications are required for releasing MyoD from condensed chromosomes and inhibiting its DNA-binding and transcriptional activation ability. Then, nuclear MyoD regains instability in the beginning of G1 phase due to rapid dephosphorylation events. Moreover, a non-phosphorylable MyoD S5A/S200A is not excluded from condensed chromatin and alters mitotic progression with apparent abnormalities. Thus, the drop of MyoD below a threshold level and its displacement from the mitotic chromatin could present another window in the cell cycle for resetting the myogenic transcriptional program and to maintain the myogenic determination of the proliferating cells.

  14. Angiomodulin is a specific marker of vasculature and regulates VEGF-A dependent neo-angiogenesis

    Science.gov (United States)

    Hooper, Andrea T.; Shmelkov, Sergey V.; Gupta, Sunny; Milde, Till; Bambino, Kathryn; Gillen, Kelly; Goetz, Mollie; Chavala, Sai; Baljevic, Muhamed; Murphy, Andrew J.; Valenzuela, David M.; Gale, Nicholas W.; Thurston, Gavin; Yancopoulos, George D.; Vahdat, Linda; Evans, Todd; Rafii, Shahin

    2010-01-01

    Blood vessel formation is controlled by the balance between pro- and anti-angiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a VEGF-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGMlacZ/+) wherein we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17-22 hpf. Blockade of AGM activity with morpholino oligomers (MO) results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR-2/flk-1, is blocked by the simultaneous injection of AGM MO. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the pro-angiogenic effects of VEGF-A. PMID:19542015

  15. Inhibition of Rho kinase regulates specification of early differentiation events in P19 embryonal carcinoma stem cells.

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    Roman J Krawetz

    Full Text Available The Rho kinase pathway plays a key role in many early cell/tissue determination events that take place in embryogenesis. Rho and its downstream effector Rho kinase (ROCK play pivotal roles in cell migration, apoptosis (membrane blebbing, cell proliferation/cell cycle, cell-cell adhesion and gene regulation. We and others have previously demonstrated that inhibition of ROCK blocks endoderm differentiation in embryonal carcinoma stem cells, however, the effect of ROCK inhibition on mesoderm and ectoderm specification has not been fully examined. In this study, the role of ROCK within the specification and differentiation of all three germ layers was examined.P19 cells were treated with the specific ROCK inhibitor Y-27623, and increase in differentiation efficiency into neuro-ectodermal and mesodermal lineages was observed. However, as expected a dramatic decrease in early endodermal markers was observed when ROCK was inhibited. Interestingly, within these ROCK-inhibited RA treated cultures, increased levels of mesodermal or ectodermal markers were not observed, instead it was found that the pluripotent markers SSEA-1 and Oct-4 remained up-regulated similar to that seen in undifferentiated cultures. Using standard and widely accepted methods for reproducible P19 differentiation into all three germ layers, an enhancement of mesoderm and ectoderm differentiation with a concurrent loss of endoderm lineage specification was observed with Y-27632 treatment. Evidence would suggest that this effect is in part mediated through TGF-β and SMAD signaling as ROCK-inhibited cells displayed aberrant SMAD activation and did not return to a 'ground' state after the inhibition had been removed.Given this data and the fact that only a partial rescue of normal differentiation capacity occurred when ROCK inhibition was alleviated, the effect of ROCK inhibition on the differentiation capacity of pluripotent cell populations should be further examined to elucidate the

  16. Mammary gland-specific nuclear factor activity is positively regulated by lactogenic hormones and negatively by milk stasis.

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    Schmitt-Ney, M; Happ, B; Hofer, P; Hynes, N E; Groner, B

    1992-12-01

    The mammary gland-specific nuclear factor (MGF) is a crucial contributor to the regulation of transcription from the beta-casein gene promoter. The beta-casein gene encodes a major milk protein, which is expressed in mammary epithelial cells during lactation and can be induced by lactogenic hormones in the clonal mammary epithelial cell line HC11. We have investigated the specific DNA-binding activity of MGF in mammary epithelial cells in vivo and in vitro. Comparison of MGF in HC11 cells and mammary gland cells from lactating mice revealed molecules with identical DNA-binding properties. Bandshift and UV cross-linking experiments indicated that MGF in HC11 cells has a higher mol wt than MGF found in mice. Little MGF activity was detected in nuclear extracts from HC11 cells cultured in the absence of lactogenic hormones. Lactogenic hormone treatment of HC11 cells led to a strong induction of MGF activity. The induction of MGF activity as well as utilization of the beta-casein promoter were suppressed when epidermal growth factor was present in the tissue culture medium simultaneously with the lactogenic hormones. In lactating animals, MGF activity is regulated by suckling, milk stasis, and systemic hormone signals. The mammary glands from maximally lactating animals, 16 days postpartum, contain drastically reduced MGF activity after removal of the pups for only 8 h. The down-regulation of MGF by pup withdrawal was slower in early lactation, 6 days postpartum. We also investigated the relative contributions of local signals, generated by milk stasis, and systemic hormone signals to the regulation of MGF activity. The access to one row of mammary glands of lactating mothers was denied to the pups for 24 h. High levels of MGF were found in the accessible mammary glands, and intermediate levels of MGF were found in the inaccessible glands of the same mouse. Very low MGF levels were detected when the pups were removed from the dams for 24 h. We conclude that systemic as

  17. Ubiquitin-Specific Protease 2 Regulates Hepatic Gluconeogenesis and Diurnal Glucose Metabolism Through 11β-Hydroxysteroid Dehydrogenase 1

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    Molusky, Matthew M.; Li, Siming; Ma, Di; Yu, Lei; Lin, Jiandie D.

    2012-01-01

    Hepatic gluconeogenesis is important for maintaining steady blood glucose levels during starvation and through light/dark cycles. The regulatory network that transduces hormonal and circadian signals serves to integrate these physiological cues and adjust glucose synthesis and secretion by the liver. In this study, we identified ubiquitin-specific protease 2 (USP2) as an inducible regulator of hepatic gluconeogenesis that responds to nutritional status and clock. Adenoviral-mediated expression of USP2 in the liver promotes hepatic glucose production and exacerbates glucose intolerance in diet-induced obese mice. In contrast, in vivo RNA interference (RNAi) knockdown of this factor improves systemic glycemic control. USP2 is a target gene of peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α), a coactivator that integrates clock and energy metabolism, and is required for maintaining diurnal glucose homeostasis during restricted feeding. At the mechanistic level, USP2 regulates hepatic glucose metabolism through its induction of 11β-hydroxysteroid dehydrogenase 1 (HSD1) and glucocorticoid signaling in the liver. Pharmacological inhibition and liver-specific RNAi knockdown of HSD1 significantly impair the stimulation of hepatic gluconeogenesis by USP2. Together, these studies delineate a novel pathway that links hormonal and circadian signals to gluconeogenesis and glucose homeostasis. PMID:22447855

  18. Uncovering iron regulation with species-specific transcriptome patterns in Atlantic and coho salmon during a Caligus rogercresseyi infestation.

    Science.gov (United States)

    Valenzuela-Muñoz, V; Boltaña, S; Gallardo-Escárate, C

    2017-09-01

    Salmon species cultured in Chile evidence different levels of susceptibility to the sea louse Caligus rogercresseyi. These differences have mainly been associated with specific immune responses. Moreover, iron regulation seems to be an important mechanism to confer immunity during the host infestation. This response called nutritional immunity has been described in bacterial infections, despite that no comprehensive studies involving in marine ectoparasites infestation have been reported. With this aim, we analysed the transcriptome profiles of Atlantic and coho salmon infected with C. rogercresseyi to evidence modulation of the iron metabolism as a proxy of nutritional immune responses. Whole transcriptome sequencing was performed in samples of skin and head kidney from Atlantic and coho salmon infected with sea lice. RNA-seq analyses revealed significant upregulation of transcripts in both salmon species at 7 and 14 dpi in skin and head kidney, respectively. However, iron regulation transcripts were differentially modulated, evidencing species-specific expression profiles. Genes related to heme degradation and iron transport such as hepcidin, transferrin and haptoglobin were primary upregulated in Atlantic salmon; meanwhile, in coho salmon, genes associated with heme biosynthesis were strongly transcribed. In summary, Atlantic salmon, which are more susceptible to infestation, presented molecular mechanisms to deplete cellular iron availability, suggesting putative mechanisms of nutritional immunity. In contrast, resistant coho salmon were less affected by sea lice, mainly activating pro-inflammatory mechanisms to cope with infestation. © 2017 John Wiley & Sons Ltd.

  19. Location-specific epigenetic regulation of the metallothionein 3 gene in esophageal adenocarcinomas.

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    Dunfa Peng

    Full Text Available Metallothionein 3 (MT3 maintains intracellular metal homeostasis and protects against reactive oxygen species (ROS-induced DNA damage. In this study, we investigated the epigenetic alterations and gene expression of the MT3 gene in esophageal adenocarcinomas (EACs.Using quantitative bisulfite pyrosequencing, we detected unique DNA methylation profiles in the MT3 promoter region. The CpG nucleotides from -372 to -306 from the transcription start site (TSS were highly methylated in tumor (n = 64 and normal samples (n = 51, whereas CpG nucleotides closest to the TSS (-4 and +3 remained unmethylated in all normal and most tumor samples. Conversely, CpG nucleotides in two regions (from -139 to -49 and +296 to +344 were significantly hypermethylated in EACs as compared to normal samples [FDR3.0]. The DNA methylation levels from -127 to -8 CpG sites showed the strongest correlation with MT3 gene expression (r = -0.4, P<0.0001. Moreover, the DNA hypermethylation from -127 to -8 CpG sites significantly correlated with advanced tumor stages and lymph node metastasis (P = 0.005 and P = 0.0313, respectively. The ChIP analysis demonstrated a more repressive histone modification (H3K9me2 and less active histone modifications (H3K4me2, H3K9ace in OE33 cells than in FLO-1 cells; concordant with the presence of higher DNA methylation levels and silencing of MT3 expression in OE33 as compared to FLO-1 cells. Treatment of OE33 cells with 5-Aza-deoxycitidine restored MT3 expression with demethylation of its promoter region and reversal of the histone modifications towards active histone marks.In summary, EACs are characterized by frequent epigenetic silencing of MT3. The choice of specific regions in the CpG island is a critical step in determining the functional role and prognostic value of DNA methylation in cancer cells.

  20. Adiponectin receptor 2 is regulated by nutritional status, leptin and pregnancy in a tissue-specific manner.

    Science.gov (United States)

    González, Carmen Ruth; Caminos, Jorge Eduardo; Gallego, Rosalía; Tovar, Sulay; Vázquez, María Jesús; Garcés, María Fernanda; Lopez, Miguel; García-Caballero, Tomás; Tena-Sempere, Manuel; Nogueiras, Rubén; Diéguez, Carlos

    2010-01-12

    The aim of the present work was to study the regulation of circulating adiponectin levels and the expression of adiponectin receptor 2 (Adipo-R2) in several rat tissues in relation to fasting, leptin challenge, pregnancy, and chronic undernutrition. Using real-time PCR, we found Adipo-R2 mRNA expression in the liver, stomach, white and brown adipose tissues (WAT and BAT) of adult rats. Immunohistochemical studies confirmed protein expression in the same tissues. Adipo-R2 mRNA levels were decreased in liver after fasting, with no changes in the other tissues. Leptin decreased Adipo-R2 expression in liver and stomach, but increased its expression in WAT and BAT. Chronic caloric restriction in normal rats increased Adipo-R2 gene expression in stomach, while it decreased hepatic Adipo-R2 levels in pregnant rats. Using radioimmunoassay, we found that plasma adiponectin levels were diminished by fasting and leptin. Conversely, circulating adiponectin was increased in food-restricted rats, whereas its levels decreased in food-restricted pregnant rats by the end of gestation. In conclusion our findings provide the first evidence that (a) Adipo-R2 mRNA is regulated in a tissue-specific manner by fasting, but leptin is not responsible for those changes; (b) chronic caloric restriction in normal and pregnant rats also regulate Adipo-R2 mRNA in a tissue-specific manner; and (c) Adipo-R2 mRNA does not show a clear correlation with plasma adiponectin levels.

  1. Gender-specific roles for the melanocortin-3 receptor in the regulation of the mesolimbic dopamine system in mice.

    Science.gov (United States)

    Lippert, Rachel N; Ellacott, Kate L J; Cone, Roger D

    2014-05-01

    The melanocortin-3 receptor (MC3R) and MC4R are known to play critical roles in energy homeostasis. However, the physiological functions of the MC3R remain poorly understood. Earlier reports indicated that the ventral tegmental area (VTA) is one of the highest sites of MC3R expression, and we sought to determine the function of the receptor in this brain region. A MC3R-green-fluorescent protein transgenic mouse and a MC3R knockout mouse strain were used to characterize the neurochemical identity of the MC3R neurons in the VTA and to determine the effects of global MC3R deletion on VTA dopamine (DA) homeostasis. We demonstrate that the MC3R, but not MC4R, is expressed in up to a third of dopaminergic neurons of the VTA. Global deletion of the MC3R increases total dopamine by 42% in the VTA and decreases sucrose intake and preference in female but not male mice. Ovariectomy restores dopamine levels to normal, but aberrant decreased VTA dopamine levels are also observed in prepubertal female mice. Because arcuate Agouti-related peptide/neuropeptide Y neurons are known to innervate and regulate VTA signaling, the MC3R in dopaminergic neurons provides a specific input for communication of nutritional state within the mesolimbic dopamine system. Data provided here suggest that this input may be highly sexually dimorphic, functioning as a specific circuit regulating effects of estrogen on VTA dopamine levels and on sucrose preference. Overall, this data support a sexually dimorphic function of MC3R in regulation of the mesolimbic dopaminergic system and reward.

  2. The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4(+) T cells

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    Munir, Shamaila; Andersen, Gitte Holmen; Svane, Inge Marie

    2013-01-01

    Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8(+) T cells. In the present study, we develop these findings and report that CD4(+) helper T cells...... spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201-restricted PD-L1-epitope for the presence of possible CD4(+) T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4(+) T cells among the peripheral blood lymphocytes of cancer patients...... and - to lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4(+) T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4(+) T cells released interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-17 (IL-17) in response...

  3. Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation.

    Science.gov (United States)

    Dorado, Beatriz; Area, Estela; Akman, Hasan O; Hirano, Michio

    2011-01-01

    Deficiency of thymidine kinase 2 (TK2) is a frequent cause of isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases of disease onset, organ specificity and severity of TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2-/-). Although normal until postnatal day 8, Tk2-/- mice rapidly develop fatal encephalomyopathy between postnatal days 10 and 13. We have observed that wild-type Tk2 activity is constant in the second week of life, while Tk1 activity decreases significantly between postnatal days 8 and 13. The down-regulation of Tk1 activity unmasks Tk2 deficiency in Tk2-/- mice and correlates with the onset of mtDNA depletion in the brain and the heart. Resistance to pathology in Tk2 mutant organs depends on compensatory mechanisms to the reduced mtDNA level. Our analyses at postnatal day 13 have revealed that Tk2-/- heart significantly increases mitochondrial transcript levels relative to the mtDNA content. This transcriptional compensation allows the heart to maintain normal levels of mtDNA-encoded proteins. The up-regulation in mitochondrial transcripts is not due to increased expression of the master mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and nuclear respiratory factors 1 and 2, or to enhanced expression of the mitochondrial transcription factors A, B1 or B2. Instead, Tk2-/- heart compensates for mtDNA depletion by down-regulating the expression of the mitochondrial transcriptional terminator transcription factor 3 (MTERF3). Understanding the molecular mechanisms that allow Tk2 mutant organs to be spared may help design therapies for Tk2 deficiency.

  4. Pathogen-Specific Binding Soluble Down Syndrome Cell Adhesion Molecule (Dscam Regulates Phagocytosis via Membrane-Bound Dscam in Crab

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    Xue-Jie Li

    2018-04-01

    Full Text Available The Down syndrome cell adhesion molecule (Dscam gene is an extraordinary example of diversity that can produce thousands of isoforms and has so far been found only in insects and crustaceans. Cumulative evidence indicates that Dscam may contribute to the mechanistic foundations of specific immune responses in insects. However, the mechanism and functions of Dscam in relation to pathogens and immunity remain largely unknown. In this study, we identified the genome organization and alternative Dscam exons from Chinese mitten crab, Eriocheir sinensis. These variants, designated EsDscam, potentially produce 30,600 isoforms due to three alternatively spliced immunoglobulin (Ig domains and a transmembrane domain. EsDscam was significantly upregulated after bacterial challenge at both mRNA and protein levels. Moreover, bacterial specific EsDscam isoforms were found to bind specifically with the original bacteria to facilitate efficient clearance. Furthermore, bacteria-specific binding of soluble EsDscam via the complete Ig1–Ig4 domain significantly enhanced elimination of the original bacteria via phagocytosis by hemocytes; this function was abolished by partial Ig1–Ig4 domain truncation. Further studies showed that knockdown of membrane-bound EsDscam inhibited the ability of EsDscam with the same extracellular region to promote bacterial phagocytosis. Immunocytochemistry indicated colocalization of the soluble and membrane-bound forms of EsDscam at the hemocyte surface. Far-Western and coimmunoprecipitation assays demonstrated homotypic interactions between EsDscam isoforms. This study provides insights into a mechanism by which soluble Dscam regulates hemocyte phagocytosis via bacteria-specific binding and specific interactions with membrane-bound Dscam as a phagocytic receptor.

  5. Features of CRISPR-Cas Regulation Key to Highly Efficient and Temporally-Specific crRNA Production

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    Andjela Rodic

    2017-11-01

    Full Text Available Bacterial immune systems, such as CRISPR-Cas or restriction-modification (R-M systems, affect bacterial pathogenicity and antibiotic resistance by modulating horizontal gene flow. A model system for CRISPR-Cas regulation, the Type I-E system from Escherichia coli, is silent under standard laboratory conditions and experimentally observing the dynamics of CRISPR-Cas activation is challenging. Two characteristic features of CRISPR-Cas regulation in E. coli are cooperative transcription repression of cas gene and CRISPR array promoters, and fast non-specific degradation of full length CRISPR transcripts (pre-crRNA. In this work, we use computational modeling to understand how these features affect the system expression dynamics. Signaling which leads to CRISPR-Cas activation is currently unknown, so to bypass this step, we here propose a conceptual setup for cas expression activation, where cas genes are put under transcription control typical for a restriction-modification (R-M system and then introduced into a cell. Known transcription regulation of an R-M system is used as a proxy for currently unknown CRISPR-Cas transcription control, as both systems are characterized by high cooperativity, which is likely related to similar dynamical constraints of their function. We find that the two characteristic CRISPR-Cas control features are responsible for its temporally-specific dynamical response, so that the system makes a steep (switch-like transition from OFF to ON state with a time-delay controlled by pre-crRNA degradation rate. We furthermore find that cooperative transcription regulation qualitatively leads to a cross-over to a regime where, at higher pre-crRNA processing rates, crRNA generation approaches the limit of an infinitely abrupt system induction. We propose that these dynamical properties are associated with rapid expression of CRISPR-Cas components and efficient protection of bacterial cells against foreign DNA. In terms of synthetic

  6. Glycaemic response after intake of a high energy, high protein, diabetes-specific formula in older malnourished or at risk of malnutrition type 2 diabetes patients.

    Science.gov (United States)

    Laksir, Hamid; Lansink, Mirian; Regueme, Sophie C; de Vogel-van den Bosch, Johan; Pfeiffer, Andreas F H; Bourdel-Marchasson, Isabelle

    2017-10-06

    Several studies with diabetes-specific formulas (DSFs) for hyperglycaemic patients in need of nutritional support have been conducted in non-malnourished patients, mainly comparing products with varying macronutrient compositions. Here, the effect of a high energy, high protein DSF on postprandial responses was compared to a product with a similar macronutrient composition in malnourished or at risk of malnutrition patients with type 2 diabetes. In this randomised, double-blind cross-over study, 20 patients were included. After overnight fasting, patients consumed 200 mL of a DSF or standard supplement (control) (19.6 g protein, 31.2 g carbohydrates and 10.6 g fat), while continuing their anti-diabetic medication. The formulas differed in type of carbohydrates and presence of fibre. The postprandial glucose, insulin and glucagon responses were monitored over 4 h. Data were analysed with a Linear Mixed Model, and results of the modified ITT population (n = 19) are shown. Postprandial glucose response as incremental area under the curve (iAUC), was lower after consumption of DSF compared with control (489.7 ± 268.5 (mean ± SD) vs 581.3 ± 273.9 mmol/L min, respectively; p = 0.008). Also, the incremental maximum concentration of glucose (iCmax) was lower for DSF vs control (3.5 ± 1.4 vs 4.0 ± 1.4 mmol/L; p = 0.007). Postprandial insulin and glucagon levels, expressed as iAUC or iCmax, were not significantly different between groups. Consumption of a high energy, high protein DSF by older malnourished or at risk of malnutrition type 2 diabetes patients resulted in a significantly lower glucose response compared to control. These data suggest that the use of a DSF is preferred for patients with diabetes in need of nutritional support. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders

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    Paterson, Clare; Wang, Yanhong; Hyde, Thomas M.; Weinberger, Daniel R.; Kleinman, Joel E.; Law, Amanda J.

    2018-01-01

    Objective Genes implicated in schizophrenia are enriched in networks differentially regulated during human CNS development. Neuregulin 3 (NRG3), a brain-enriched neurotrophin, undergoes alternative splicing and is implicated in several neurological disorders with developmental origins. Isoform-specific increases in NRG3 are observed in schizophrenia and associated with rs10748842, a NRG3 risk polymorphism, suggesting NRG3 transcriptional dysregulation as a molecular mechanism of risk. The authors quantitatively mapped the temporal trajectories of NRG3 isoforms (classes I–IV) in the neocortex throughout the human lifespan, examined whether tissue-specific regulation of NRG3 occurs in humans, and determined if abnormalities in NRG3 transcriptomics occur in mood disorders and are genetically determined. Method NRG3 isoform classes I–IV were quantified using quantitative real-time polymerase chain reaction in human postmortem dorsolateral prefrontal cortex from 286 nonpsychiatric control individuals, from gestational week 14 to 85 years old, and individuals diagnosed with either bipolar disorder (N=34) or major depressive disorder (N=69). Tissue-specific mapping was investigated in several human tissues. rs10748842 was genotyped in individuals with mood disorders, and association with NRG3 isoform expression examined. Results NRG3 classes displayed individually specific expression trajectories across human neocortical development and aging; classes I, II, and IV were significantly associated with developmental stage. NRG3 class I was increased in bipolar and major depressive disorder, consistent with observations in schizophrenia. NRG3 class II was increased in bipolar disorder, and class III was increased in major depression. The rs10748842 risk genotype predicted elevated class II and III expression, consistent with previous reports in the brain, with tissue-specific analyses suggesting that classes II and III are brain-specific isoforms of NRG3. Conclusions

  8. Specific and Novel microRNAs Are Regulated as Response to Fungal Infection in Human Dendritic Cells

    Science.gov (United States)

    Dix, Andreas; Czakai, Kristin; Leonhardt, Ines; Schäferhoff, Karin; Bonin, Michael; Guthke, Reinhard; Einsele, Hermann; Kurzai, Oliver; Löffler, Jürgen; Linde, Jörg

    2017-01-01

    Within the last two decades, the incidence of invasive fungal infections has been significantly increased. They are characterized by high mortality rates and are often caused by Candida albicans and Aspergillus fumigatus. The increasing number of infections underlines the necessity for additional anti-fungal therapies, which require extended knowledge of gene regulations during fungal infection. MicroRNAs are regulators of important cellular processes, including the immune response. By analyzing their regulation and impact on target genes, novel therapeutic and diagnostic approaches may be developed. Here, we examine the role of microRNAs in human dendritic cells during fungal infection. Dendritic cells represent the bridge between the innate and the adaptive immune systems. Therefore, analysis of gene regulation of dendritic cells is of particular significance. By applying next-generation sequencing of small RNAs, we quantify microRNA expression in monocyte-derived dendritic cells after 6 and 12 h of infection with C. albicans and A. fumigatus as well as treatment with lipopolysaccharides (LPS). We identified 26 microRNAs that are differentially regulated after infection by the fungi or LPS. Three and five of them are specific for fungal infections after 6 and 12 h, respectively. We further validated interactions of miR-132-5p and miR-212-5p with immunological relevant target genes, such as FKBP1B, KLF4, and SPN, on both RNA and protein level. Our results indicate that these microRNAs fine-tune the expression of immune-related target genes during fungal infection. Beyond that, we identified previously undiscovered microRNAs. We validated three novel microRNAs via qRT-PCR. A comparison with known microRNAs revealed possible relations with the miR-378 family and miR-1260a/b for two of them, while the third one features a unique sequence with no resemblance to known microRNAs. In summary, this study analyzes the effect of known microRNAs in dendritic cells during

  9. Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.

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    Sreenivasan Paruthiyil

    2009-07-01

    Full Text Available Estrogens produce biological effects by interacting with two estrogen receptors, ERalpha and ERbeta. Drugs that selectively target ERalpha or ERbeta might be safer for conditions that have been traditionally treated with non-selective estrogens. Several synthetic and natural ERbeta-selective compounds have been identified. One class of ERbeta-selective agonists is represented by ERB-041 (WAY-202041 which binds to ERbeta much greater than ERalpha. A second class of ERbeta-selective agonists derived from plants include MF101, nyasol and liquiritigenin that bind similarly to both ERs, but only activate transcription with ERbeta. Diarylpropionitrile represents a third class of ERbeta-selective compounds because its selectivity is due to a combination of greater binding to ERbeta and transcriptional activity. However, it is unclear if these three classes of ERbeta-selective compounds produce similar biological activities. The goals of these studies were to determine the relative ERbeta selectivity and pattern of gene expression of these three classes of ERbeta-selective compounds compared to estradiol (E(2, which is a non-selective ER agonist. U2OS cells stably transfected with ERalpha or ERbeta were treated with E(2 or the ERbeta-selective compounds for 6 h. Microarray data demonstrated that ERB-041, MF101 and liquiritigenin were the most ERbeta-selective agonists compared to estradiol, followed by nyasol and then diarylpropionitrile. FRET analysis showed that all compounds induced a similar conformation of ERbeta, which is consistent with the finding that most genes regulated by the ERbeta-selective compounds were similar to each other and E(2. However, there were some classes of genes differentially regulated by the ERbeta agonists and E(2. Two ERbeta-selective compounds, MF101 and liquiritigenin had cell type-specific effects as they regulated different genes in HeLa, Caco-2 and Ishikawa cell lines expressing ERbeta. Our gene profiling studies

  10. Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic mice.

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    Eren, M; Painter, C A; Gleaves, L A; Schoenhard, J A; Atkinson, J B; Brown, N J; Vaughan, D E

    2003-11-01

    Numerous studies have described regulatory factors and sequences that control transcriptional responses in vitro. However, there is a paucity of information on the qualitative and quantitative regulation of heterologous promoters using transgenic strategies. In order to investigate the physiological regulation of human plasminogen activator inhibitor type-1 (hPAI-1) expression in vivo compared to murine PAI-1 (mPAI-1) and to test the physiological relevance of regulatory mechanisms described in vitro, we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) driven by the proximal -2.9 kb of the hPAI-1 promoter. Transgenic animals were treated with Ang II, TGF-beta1 and lipopolysaccharide (LPS) to compare the relative activation of the human and murine PAI-1 promoters. Ang II increased EGFP expression most effectively in brain, kidney and spleen, while mPAI-1 expression was quantitatively enhanced most prominently in heart and spleen. TGF-beta1 failed to induce activation of the hPAI-1 promoter but potently stimulated mPAI-1 in kidney and spleen. LPS administration triggered robust expression of mPAI-1 in liver, kidney, pancreas, spleen and lung, while EGFP was induced only modestly in heart and kidney. These results indicate that the transcriptional response of the endogenous mPAI-1 promoter varies widely in terms of location and magnitude of response to specific stimuli. Moreover, the physiological regulation of PAI-1 expression likely involves a complex interaction of transcription factors and DNA sequences that are not adequately replicated by in vitro functional studies focused on the proximal -2.9 kb promoter.

  11. The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels

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    Anne-Cécile eBoulay

    2015-02-01

    Full Text Available Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein Connexin 43 and 30 (Cx43 and Cx30 allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30Δ/Δ, we showed that absence of Cx30 does not affect blood-brain barrier (BBB organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding γ-Sarcoglycan (SG, a member of the Dystrophin-associated protein complex (DAPC connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC molecules in the cerebrovascular system and showed the presence of α-, β-, δ-, γ-, ε- and ζ- SG, as well as Sarcospan. Their expression was however not modified in Cx30Δ/Δ. These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, γ-Sarcoglycan, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions.

  12. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling

    DEFF Research Database (Denmark)

    Ungureanu, Daniela; Wu, Jinhua; Pekkala, Tuija

    2011-01-01

    Human JAK2 tyrosine kinase mediates signaling through numerous cytokine receptors. The JAK2 JH2 domain functions as a negative regulator and is presumed to be a catalytically inactive pseudokinase, but the mechanism(s) for its inhibition of JAK2 remains unknown. Mutations in JH2 lead to increased...... JAK2 activity, contributing to myeloproliferative neoplasms (MPNs). Here we show that JH2 is a dual-specificity protein kinase that phosphorylates two negative regulatory sites in JAK2: Ser523 and Tyr570. Inactivation of JH2 catalytic activity increased JAK2 basal activity and downstream signaling....... Notably, different MPN mutations abrogated JH2 activity in cells, and in MPN (V617F) patient cells phosphorylation of Tyr570 was reduced, suggesting that loss of JH2 activity contributes to the pathogenesis of MPNs. These results identify the catalytic activity of JH2 as a previously unrecognized...

  13. Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses.

    Science.gov (United States)

    Jeans, Alexander F; van Heusden, Fran C; Al-Mubarak, Bashayer; Padamsey, Zahid; Emptage, Nigel J

    2017-10-10

    Voltage-dependent Ca 2+ channels (VGCC) represent the principal source of Ca 2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca 2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca 2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  14. Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

    Directory of Open Access Journals (Sweden)

    Alexander F. Jeans

    2017-10-01

    Full Text Available Voltage-dependent Ca2+ channels (VGCC represent the principal source of Ca2+ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca2+ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca2+ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

  15. Toward epigenetic and gene regulation models of specific language impairment: looking for links among growth, genes, and impairments

    Directory of Open Access Journals (Sweden)

    Rice Mabel L

    2012-11-01

    Full Text Available Abstract Children with specific language impairment (SLI are thought to have an inherited form of language impairment that spares other developmental domains. SLI shows strong heritability and recent linkage and association studies have replicated results for candidate genes. Regulatory regions of the genes may be involved. Behavioral growth models of language development of children with SLI reveal that the onset of language is delayed, and the growth trajectories of children with SLI parallel those of younger children without SLI. The rate of language acquisition decelerates in the pre-adolescent period, resulting in immature language levels for the children with SLI that persist into adolescence and beyond. Recent genetic and epigenetic discoveries and models relevant to language impairment are reviewed. T cell regulation of onset, acceleration, and deceleration signaling are described as potential conceptual parallels to the growth timing elements of language acquisition and impairment. A growth signaling disruption (GSD hypothesis is proposed for SLI, which posits that faulty timing mechanisms at the cellular level, intrinsic to neurocortical functioning essential for language onset and growth regulation, are at the core of the growth outcomes of SLI. The GSD highlights the need to document and account for growth patterns over childhood and suggests needed directions for future investigation.

  16. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs.

    Science.gov (United States)

    Spiegel, Ivo; Mardinly, Alan R; Gabel, Harrison W; Bazinet, Jeremy E; Couch, Cameron H; Tzeng, Christopher P; Harmin, David A; Greenberg, Michael E

    2014-05-22

    The nervous system adapts to experience by inducing a transcriptional program that controls important aspects of synaptic plasticity. Although the molecular mechanisms of experience-dependent plasticity are well characterized in excitatory neurons, the mechanisms that regulate this process in inhibitory neurons are only poorly understood. Here, we describe a transcriptional program that is induced by neuronal activity in inhibitory neurons. We find that, while neuronal activity induces expression of early-response transcription factors such as Npas4 in both excitatory and inhibitory neurons, Npas4 activates distinct programs of late-response genes in inhibitory and excitatory neurons. These late-response genes differentially regulate synaptic input to these two types of neurons, promoting inhibition onto excitatory neurons while inducing excitation onto inhibitory neurons. These findings suggest that the functional outcomes of activity-induced transcriptional responses are adapted in a cell-type-specific manner to achieve a circuit-wide homeostatic response. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Cell-Type-Specific Regulation of the Retinoic Acid Receptor Mediated by the Orphan Nuclear Receptor TLX†

    Science.gov (United States)

    Kobayashi, Mime; Yu, Ruth T.; Yasuda, Kunio; Umesono, Kazuhiko

    2000-01-01

    Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor β (RARβ). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARβ2 promoter. The region surrounding the transcription start site of the avian RARβ2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARβ2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARβ gene in the eye. PMID:11073974

  18. Cell-type-specific regulation of the retinoic acid receptor mediated by the orphan nuclear receptor TLX.

    Science.gov (United States)

    Kobayashi, M; Yu, R T; Yasuda, K; Umesono, K

    2000-12-01

    Malformations in the eye can be caused by either an excess or deficiency of retinoids. An early target gene of the retinoid metabolite, retinoic acid (RA), is that encoding one of its own receptors, the retinoic acid receptor beta (RARbeta). To better understand the mechanisms underlying this autologous regulation, we characterized the chick RARbeta2 promoter. The region surrounding the transcription start site of the avian RARbeta2 promoter is over 90% conserved with the corresponding region in mammals and confers strong RA-dependent transactivation in primary cultured embryonic retina cells. This response is selective for RAR but not retinoid X receptor-specific agonists, demonstrating a principal role for RAR(s) in retina cells. Retina cells exhibit a far higher sensitivity to RA than do fibroblasts or osteoblasts, a property we found likely due to expression of the orphan nuclear receptor TLX. Ectopic expression of TLX in fibroblasts resulted in increased sensitivity to RA induction, an effect that is conserved between chick and mammals. We have identified a cis element, the silencing element relieved by TLX (SET), within the RARbeta2 promoter region which confers TLX- and RA-dependent transactivation. These results indicate an important role for TLX in autologous regulation of the RARbeta gene in the eye.

  19. Structural and functional conservation of CLEC-2 with the species-specific regulation of transcript expression in evolution.

    Science.gov (United States)

    Wang, Lan; Ren, Shifang; Zhu, Haiyan; Zhang, Dongmei; Hao, Yuqing; Ruan, Yuanyuan; Zhou, Lei; Lee, Chiayu; Qiu, Lin; Yun, Xiaojing; Xie, Jianhui

    2012-08-01

    CLEC-2 was first identified by sequence similarity to C-type lectin-like molecules with immune functions and has been reported as a receptor for the platelet-aggregating snake venom toxin rhodocytin and the endogenous sialoglycoprotein podoplanin. Recent researches indicate that CLEC-2-deficient mice were lethal at the embryonic stage associated with disorganized and blood-filled lymphatic vessels and severe edema. In view of a necessary role of CLEC-2 in the individual development, it is of interest to investigate its phylogenetic homology and highly conserved functional regions. In this work, we reported that CLEC-2 from different species holds with an extraordinary conservation by sequence alignment and phylogenetic tree analysis. The functional structures including N-linked oligosaccharide sites and ligand-binding domain implement a structural and functional conservation in a variety of species. The glycosylation sites (N120 and N134) are necessary for the surface expression CLEC-2. CLEC-2 from different species possesses the binding activity of mouse podoplanin. Nevertheless, the expression of CLEC-2 is regulated with a species-specific manner. The alternative splicing of pre-mRNA, a regulatory mechanism of gene expression, and the binding sites on promoter for several key transcription factors vary between different species. Therefore, CLEC-2 shares high sequence homology and functional identity. However the transcript expression might be tightly regulated by different mechanisms in evolution.

  20. dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats

    International Nuclear Information System (INIS)

    Baladron, Victoriano; Ruiz-Hidalgo, Maria Jose; Nueda, Maria Luisa; Diaz-Guerra, Maria Jose M.; Garcia-Ramirez, Jose Javier; Bonvini, Ezio; Gubina, Elena; Laborda, Jorge

    2005-01-01

    The protein dlk, encoded by the Dlk1 gene, belongs to the Notch epidermal growth factor (EGF)-like family of receptors and ligands, which participate in cell fate decisions during development. The molecular mechanisms by which dlk regulates cell differentiation remain unknown. By using the yeast two-hybrid system, we found that dlk interacts with Notch1 in a specific manner. Moreover, by using luciferase as a reporter gene under the control of a CSL/RBP-Jk/CBF-1-dependent promoter in the dlk-negative, Notch1-positive Balb/c 14 cell line, we found that addition of synthetic dlk EGF-like peptides to the culture medium or forced expression of dlk decreases endogenous Notch activity. Furthermore, the expression of the gene Hes-1, a target for Notch1 activation, diminishes in confluent Balb/c14 cells transfected with an expression construct encoding for the extracellular EGF-like region of dlk. The expression of Dlk1 and Notch1 increases in 3T3-L1 cells maintained in a confluent state for several days, which is associated with a concomitant decrease in Hes-1 expression. On the other hand, the decrease of Dlk1 expression in 3T3-L1 cells by antisense cDNA transfection is associated with an increase in Hes-1 expression. These results suggest that dlk functionally interacts in vivo with Notch1, which may lead to the regulation of differentiation processes modulated by Notch1 activation and signaling, including adipogenesis

  1. Species-Specific Antimonial Sensitivity in Leishmania Is Driven by Post-Transcriptional Regulation of AQP1

    Science.gov (United States)

    Mandal, Goutam; Mandal, Srotoswati; Sharma, Mansi; Charret, Karen Santos; Papadopoulou, Barbara; Bhattacharjee, Hiranmoy; Mukhopadhyay, Rita

    2015-01-01

    Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3’-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species. PMID:25714343

  2. Structural basis for different phosphoinositide specificities of the PX domains of sorting nexins regulating G-protein signaling.

    Science.gov (United States)

    Mas, Caroline; Norwood, Suzanne J; Bugarcic, Andrea; Kinna, Genevieve; Leneva, Natalya; Kovtun, Oleksiy; Ghai, Rajesh; Ona Yanez, Lorena E; Davis, Jasmine L; Teasdale, Rohan D; Collins, Brett M

    2014-10-10

    Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signaling. A subfamily of PX domain proteins possesses two unique PX-associated domains, as well as a regulator of G protein-coupled receptor signaling (RGS) domain that attenuates Gαs-coupled G protein-coupled receptor signaling. Here we delineate the structural organization of these RGS-PX proteins, revealing a protein family with a modular architecture that is conserved in all eukaryotes. The one exception to this is mammalian SNX19, which lacks the typical RGS structure but preserves all other domains. The PX domain is a sensor of membrane phosphoinositide lipids and we find that specific sequence alterations in the PX domains of the mammalian RGS-PX proteins, SNX13, SNX14, SNX19, and SNX25, confer differential phosphoinositide binding preferences. Although SNX13 and SNX19 PX domains bind the early endosomal lipid phosphatidylinositol 3-phosphate, SNX14 shows no membrane binding at all. Crystal structures of the SNX19 and SNX14 PX domains reveal key differences, with alterations in SNX14 leading to closure of the binding pocket to prevent phosphoinositide association. Our findings suggest a role for alternative membrane interactions in spatial control of RGS-PX proteins in cell signaling and trafficking. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. TCR Signal Strength Regulates Akt Substrate Specificity To Induce Alternate Murine Th and T Regulatory Cell Differentiation Programs.

    Science.gov (United States)

    Hawse, William F; Boggess, William C; Morel, Penelope A

    2017-07-15

    The Akt/mTOR pathway is a key driver of murine CD4 + T cell differentiation, and induction of regulatory T (Treg) cells results from low TCR signal strength and low Akt/mTOR signaling. However, strong TCR signals induce high Akt activity that promotes Th cell induction. Yet, it is unclear how Akt controls alternate T cell fate decisions. We find that the strength of the TCR signal results in differential Akt enzymatic activity. Surprisingly, the Akt substrate networks associated with T cell fate decisions are qualitatively different. Proteomic profiling of Akt signaling networks during Treg versus Th induction demonstrates that Akt differentially regulates RNA processing and splicing factors to drive T cell differentiation. Interestingly, heterogeneous nuclear ribonucleoprotein (hnRNP) L or hnRNP A1 are Akt substrates during Treg induction and have known roles in regulating the stability and splicing of key mRNAs that code for proteins in the canonical TCR signaling pathway, including CD3ζ and CD45. Functionally, inhibition of Akt enzymatic activity results in the dysregulation of splicing during T cell differentiation, and knockdown of hnRNP L or hnRNP A1 results in the lower induction of Treg cells. Together, this work suggests that a switch in substrate specificity coupled to the phosphorylation status of Akt may lead to alternative cell fates and demonstrates that proteins involved with alternative splicing are important factors in T cell fate decisions. Copyright © 2017 by The American Association of Immunologists, Inc.

  4. Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 Correlates with Poor Prognosis in Colorectal Cancer.

    Directory of Open Access Journals (Sweden)

    Haiyan Yan

    Full Text Available Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2 is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023, advanced clinical stages (P = 0.006 and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P < 0.001. Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer.

  5. Regulation of the number of cell division rounds by tissue-specific transcription factors and Cdk inhibitor during ascidian embryogenesis.

    Directory of Open Access Journals (Sweden)

    Mami Kuwajima

    Full Text Available Mechanisms that regulate the number of cell division rounds during embryogenesis have remained largely elusive. To investigate this issue, we used the ascidian, which develops into a tadpole larva with a small number of cells. The embryonic cells divide 11.45 times on average from fertilization to hatching. The number of cell division rounds varies depending on embryonic lineages. Notochord and muscle consist of large postmitotic cells and stop dividing early in developing embryos. Here we show that conversion of mesenchyme to muscle cell fates by inhibition of inductive FGF signaling or mis-expression of a muscle-specific key transcription factor for muscle differentiation, Tbx6, changed the number of cell divisions in accordance with the altered fate. Tbx6 likely activates a putative mechanism to halt cell division at a specific stage. However, precocious expression of Tbx6 has no effect on progression of the developmental clock itself. Zygotic expression of a cyclin-dependent kinase inhibitor, CKI-b, is initiated in muscle and then in notochord precursors. CKI-b is possibly downstream of tissue-specific key transcription factors of notochord and muscle. In the two distinct muscle lineages, postmitotic muscle cells are generated after 9 and 8 rounds of cell division depending on lineage, but the final cell divisions occur at a similar developmental stage. CKI-b gene expression starts simultaneously in both muscle lineages at the 110-cell stage, suggesting that CKI-b protein accumulation halts cell division at a similar stage. The difference in the number of cell divisions would be due to the cumulative difference in cell cycle length. These results suggest that muscle cells do not count the number of cell division rounds, and that accumulation of CKI-b protein triggered by tissue-specific key transcription factors after cell fate determination might act as a kind of timer that measures elapsed time before cell division termination.

  6. The regulation of cytoskeletal and liver-specific gene expression during liver regeneration and primary hepatocyte culture

    International Nuclear Information System (INIS)

    Robinson, G.S.

    1989-01-01

    The focus of this dissertation is to determine what role(s) the extracellular matrix and expression of certain cytoskeletal genes play in the regulation of hepatocyte growth and the maintenance of a differential state. The expression of several cytoskeletal and liver-specific genes was examined during liver regeneration and in hepatocyte cultures maintained in a hormonally-defined, serum-free medium and plated on two different matrices: rat tail collagen and the EHS matrix. During liver regeneration and in hepatocytes cultured on rat tail collagen, there was a dramatic increase in tubulin mRNA levels coincident with but not linked to DNA synthesis. The message levels for other cytoskeletal genes similarly increased, while a decrease was observed in the mRNA levels of the liver-specific genes, serum albumin and alpha 1 inhibitor III. Hepatocytes cultured on the EHS matrix resulted in the maintenance of low levels of cytoskeletal gene expression and high levels of liver-specific gene expression, similar to that observed in the normal liver. Results from subcellar fractionation and two-dimensional gel electrophoresis of 35 S-labelled proteins paralleled the results seen at the mRNA level. Preliminary work suggests that microtubule organization may play a role in the expression of the liver-specific genes which encode secreted proteins. These studies, which compare hepatocytes cultured on collagen or the EHS matrix gel, reveal that both cell-cell and cell-matrix interactions play a major role in the maintenance of the differential phenotype in hepatocytes

  7. Radiation protection technology. Specific course for authorized radiation protection representatives according the qualification guidelines technology for the radiation protection regulations (StrlSchV) and X-ray regulation (RoeV). 2. rev. ed.

    International Nuclear Information System (INIS)

    Rahn, Hans-Joachim

    2012-01-01

    The specific course for authorized radiation protection representatives according the qualification guidelines technology for the radiation protection regulations (StrlSchV) and X-ray regulation (RoeV). Covers the following issues: radiation protection - generally; licenses and notifications; scientific fundamentals; dosimetry, surveillance, control, documentation; technical radiation protection; radiation protection calculations.

  8. Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation

    Energy Technology Data Exchange (ETDEWEB)

    Kong, Chen; Lange, Jeffrey J.; Samovski, Dmitri [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Su, Xiong [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States); Liu, Jialiu [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Sundaresan, Sinju [Department of Internal Medicine, Center for Human Nutrition Washington University School of Medicine, St. Louis, MO 63110 (United States); Stahl, Philip D., E-mail: pstahl@wustl.edu [Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110 (United States)

    2013-05-03

    Highlights: •Hominoid-specific oncogene TBC1D3 is targeted to plasma membrane by palmitoylation. •TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. •TBC1D3 palmitoylation governs growth factors-induced TBC1D3 degradation. •Post-translational modifications may regulate oncogenic properties of TBC1D3. -- Abstract: Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.

  9. Prostate-Specific G-Protein Coupled Receptor, an Emerging Biomarker Regulating Inflammation and Prostate Cancer Invasion.

    Science.gov (United States)

    Rodriguez, M; Siwko, S; Liu, M

    2016-01-01

    Prostate cancer is highly prevalent among men in developed countries, but a significant proportion of detected cancers remain indolent, never progressing into aggressive carcinomas. This highlights the need to develop refined biomarkers that can distinguish between indolent and potentially dangerous cases. The prostate-specific G-protein coupled receptor (PSGR, or OR51E2) is an olfactory receptor family member with highly specific expression in human prostate epithelium that is highly overexpressed in PIN and prostate cancer. PSGR has been functionally implicated in prostate cancer cell invasiveness, suggesting a potential role in the transition to metastatic PCa. Recently, transgenic mice overexpressing PSGR in the prostate were reported to develop an acute inflammatory response followed by emergence of low grade PIN, whereas mice with compound PSGR overexpression and loss of PTEN exhibited accelerated formation of invasive prostate adenocarcinoma. This article will review recent PSGR findings with a focus on its role as a potential prostate cancer biomarker and regulator of prostate cancer invasion and inflammation.

  10. Sensitivity and specificity of the Geriatric Anxiety Inventory and the Hospital Anxiety and Depression Scale in the detection of anxiety disorders in older people with chronic obstructive pulmonary disease.

    Science.gov (United States)

    Cheung, Gary; Patrick, Colin; Sullivan, Glenda; Cooray, Manisha; Chang, Catherina L

    2012-01-01

    Anxiety and depression are prevalent in patients with chronic obstructive pulmonary disease (COPD). This study evaluates the sensitivity and specificity of two self-administered anxiety rating scales in older people with COPD. The Geriatric Anxiety Inventory (GAI) and the Hospital Anxiety and Depression Scale (HADS) are established useful screening tools but they have not been previously validated in this population. Older people with COPD completed the GAI and the HADS along with a structured diagnostic psychiatric interview, the Mini International Neuropsychiatric Interview (MINI). The outcomes of both rating scales were compared against the diagnosis of anxiety disorders based on the MINI. Receiver operating characteristic (ROC) curves were used to identify the optimal diagnostic cut points for each scale. Fourteen (25.5%) of the 55 participants, were diagnosed with an anxiety disorder. Mean GAI and HADS-anxiety subscale scores were significantly higher in subjects with an anxiety disorder than those without the diagnosis (p = 0.002 and 0.005 respectively). Both scales demonstrated moderate diagnostic value (area under the ROC curve was 0.83 for GAI and 0.79 for HADS). Optimal cut points were ≥3 (GAI) and ≥4 (HADS-anxiety subscale). At these cut-points, the GAI had a sensitivity of 85.7%, specificity of 78.0% and the HADS had a sensitivity of 78.6%, specificity 70.7%. Our results support the use of the GAI and HADS as screening instruments for anxiety disorders in older people with COPD. The optimal cut points in this population were lower than previously recommended for both rating scales. The results of this study should be replicated before these cut points can be recommended for general use in older people with COPD.

  11. Anodal Transcranial Direct Current Stimulation Shows Minimal, Measure-Specific Effects on Dynamic Postural Control in Young and Older Adults: A Double Blind, Sham-Controlled Study.

    Science.gov (United States)

    Craig, Chesney E; Doumas, Michail

    2017-01-01

    We investigated whether stimulating the cerebellum and primary motor cortex (M1) using transcranial direct current stimulation (tDCS) could affect postural control in young and older adults. tDCS was employed using a double-blind, sham-controlled design, in which young (aged 18-35) and older adults (aged 65+) were assessed over three sessions, one for each stimulatory condition-M1, cerebellar and sham. The effect of tDCS on postural control was assessed using a sway-referencing paradigm, which induced platform rotations in proportion to the participant's body sway, thus assessing sensory reweighting processes. Task difficulty was manipulated so that young adults experienced a support surface that was twice as compliant as that of older adults, in order to minimise baseline age differences in postural sway. Effects of tDCS on postural control were assessed during, immediately after and 30 minutes after tDCS. Additionally, the effect of tDCS on corticospinal excitability was measured by evaluating motor evoked potentials using transcranial magnetic stimulation immediately after and 30 minutes after tDCS. Minimal effects of tDCS on postural control were found in the eyes open condition only, and this was dependent on the measure assessed and age group. For young adults, stimulation had only offline effects, as cerebellar stimulation showed higher mean power frequency (MPF) of sway 30 minutes after stimulation. For older adults, both stimulation conditions delayed the increase in sway amplitude witnessed between blocks one and two until stimulation was no longer active. In conclusion, despite tDCS' growing popularity, we would caution researchers to consider carefully the type of measures assessed and the groups targeted in tDCS studies of postural control.

  12. The short version of the Activities-specific Balance Confidence (ABC) scale: its validity, reliability, and relationship to balance impairment and falls in older adults.

    Science.gov (United States)

    Schepens, Stacey; Goldberg, Allon; Wallace, Melissa

    2010-01-01

    A shortened version of the ABC 16-item scale (ABC-16), the ABC-6, has been proposed as an alternative balance confidence measure. We investigated whether the ABC-6 is a valid and reliable measure of balance confidence and examined its relationship to balance impairment and falls in older adults. Thirty-five community-dwelling older adults completed the ABC-16, including the 6 questions of the ABC-6. They also completed the following clinical balance tests: unipedal stance time (UST), functional reach (FR), Timed Up and Go (TUG), and maximum step length (MSL). Participants reported 12-month falls history. Balance confidence on the ABC-6 was significantly lower than on the ABC-16, however scores were highly correlated. Fallers reported lower balance confidence than non-fallers as measured by the ABC-6 scale, but confidence did not differ between the groups with the ABC-16. The ABC-6 significantly correlated with all balance tests assessed and number of falls. The ABC-16 significantly correlated with all balance tests assessed, but not with number of falls. Test-retest reliability for the ABC-16 and ABC-6 was good to excellent. The ABC-6 is a valid and reliable measure of balance confidence in community-dwelling older adults, and shows stronger relationships to falls than does the ABC-16. The ABC-6 may be a more useful balance confidence assessment tool than the ABC-16. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  13. Population-specific regulation of Chmp2b by Lbx1 during onset of synaptogenesis in lateral association interneurons.

    Directory of Open Access Journals (Sweden)

    Jun Xu

    Full Text Available Chmp2b is closely related to Vps2, a key component of the yeast protein complex that creates the intralumenal vesicles of multivesicular bodies. Dominant negative mutations in Chmp2b cause autophagosome accumulation and neurodegenerative disease. Loss of Chmp2b causes failure of dendritic spine maturation in cultured neurons. The homeobox gene Lbx1 plays an essential role in specifying postmitotic dorsal interneuron populations during late pattern formation in the neural tube. We have discovered that Chmp2b is one of the most highly regulated cell-autonomous targets of Lbx1 in the embryonic mouse neural tube. Chmp2b was expressed and depended on Lbx1 in only two of the five nascent, Lbx1-expressing, postmitotic, dorsal interneuron populations. It was also expressed in neural tube cell populations that lacked Lbx1 protein. The observed population-specific expression of Chmp2b indicated that only certain population-specific combinations of sequence specific transcription factors allow Chmp2b expression. The cell populations that expressed Chmp2b corresponded, in time and location, to neurons that make the first synapses of the spinal cord. Chmp2b protein was transported into neurites within the motor- and association-neuropils, where the first synapses are known to form between E11.5 and E12.5 in mouse neural tubes. Selective, developmentally-specified gene expression of Chmp2b may therefore be used to endow particular neuronal populations with the ability to mature dendritic spines. Such a mechanism could explain how mammalian embryos reproducibly establish the disynaptic cutaneous reflex only between particular cell populations.

  14. Specific phosphopeptide binding regulates a conformational change in the PI 3-kinase SH2 domain associated with enzyme activation.

    Science.gov (United States)

    Shoelson, S E; Sivaraja, M; Williams, K P; Hu, P; Schlessinger, J; Weiss, M A

    1993-01-01

    SH2 (src-homology 2) domains define a newly recognized binding motif that mediates the physical association of target phosphotyrosyl proteins with downstream effector enzymes. An example of such phosphoprotein-effector coupling is provided by the association of phosphatidylinositol 3-kinase (PI 3-kinase) with specific phosphorylation sites within the PDGF receptor, the c-Src/polyoma virus middle T antigen complex and the insulin receptor substrate IRS-1. Notably, phosphoprotein association with the SH2 domains of p85 also stimulates an increase in catalytic activity of the PI 3-kinase p110 subunit, which can be mimicked by phosphopeptides corresponding to targeted phosphoprotein phosphorylation sites. To investigate how phosphoprotein binding to the p85 SH2 domain stimulates p110 catalytic activation, we have examined the differential effects of phosphotyrosine and PDGF receptor-, IRS-1- and c-Src-derived phosphopeptides on the conformation of an isolated SH2 domain of PI 3-kinase. Although phosphotyrosine and both activating and non-activating phosphopeptides bind to the SH2 domain, activating phosphopeptides bind with higher affinity and induce a qualitatively distinct conformational change as monitored by CD and NMR spectroscopy. Amide proton exchange and protease protection assays further show that high affinity, specific phosphopeptide binding induces non-local dynamic SH2 domain stabilization. Based on these findings we propose that specific phosphoprotein binding to the p85 subunit induces a change in SH2 domain structure which is transmitted to the p110 subunit and regulates enzymatic activity by an allosteric mechanism. Images PMID:8382612

  15. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  16. Assessment of effects of differences in trunk posture during Fowler’s position on hemodynamics and cardiovascular regulation in older and younger subjects

    Science.gov (United States)

    Kubota, Satoshi; Endo, Yutaka; Kubota, Mitsue; Shigemasa, Tomohiko

    2017-01-01

    Background Downward shifts in blood volume with changing position generally cause tachycardic responses. Age-related decreases in vagal nerve activity could contribute to orthostatic hypotension in older individuals. Fowler’s position is a reclined position with the back between 30° and 60°, used to facilitate breathing, eating, and other routine daily activities in frail and elderly patients. Objective This study examined whether stroke volume (SV) was higher and heart rate (HR) lower in Fowler’s position with an upright upper trunk than in Fowler’s position with the whole trunk upright in both older and younger subjects, based on the assumption that lower HR would result from reduced sympathetic activation in older individuals. Methods We assessed hemodynamics and HR variability from electrocardiography, noninvasive arterial pressure and impedance cardiography in 11 younger male subjects (age range, 20–22 years) and 11 older male subjects (age range, 64–79 years), using three positions: supine, or Fowler’s positions with either 30° of lower trunk inclination and 60° of upper trunk inclination (UT60) or 60° of whole trunk inclination (WT60). Comparisons were then made between age groups and between positions. Results Reductions in SV and tachycardic response were smaller with UT60 than with WT60, in both younger and older subjects. In addition, reduced tachycardic response with upright upper trunk appeared attributable to decreased vagal withdrawal in younger subjects and to reduced sympathetic activation in older subjects. Conclusion Our findings indicate that an upright upper trunk during Fowler’s position allowed maintenance of SV and inhibited tachycardic response compared to an upright whole trunk regardless of age, although the autonomic mechanisms underlying tachycardic responses differed between younger and older adults. An upright upper trunk in Fowler’s position might help to reduce orthostatic stress and facilitate routine

  17. Distinct Roles for Intestinal Epithelial Cell-Specific Hdac1 and Hdac2 in the Regulation of Murine Intestinal Homeostasis.

    Science.gov (United States)

    Gonneaud, Alexis; Turgeon, Naomie; Boudreau, François; Perreault, Nathalie; Rivard, Nathalie; Asselin, Claude

    2016-02-01

    The intestinal epithelium responds to and transmits signals from the microbiota and the mucosal immune system to insure intestinal homeostasis. These interactions are in part conveyed by epigenetic modifications, which respond to environmental changes. Protein acetylation is an epigenetic signal regulated by histone deacetylases, including Hdac1 and Hdac2. We have previously shown that villin-Cre-inducible intestinal epithelial cell (IEC)-specific Hdac1 and Hdac2 deletions disturb intestinal homeostasis. To determine the role of Hdac1 and Hdac2 in the regulation of IEC function and the establishment of the dual knockout phenotype, we have generated villin-Cre murine models expressing one Hdac1 allele without Hdac2, or one Hdac2 allele without Hdac1. We have also investigated the effect of short-term deletion of both genes in naphtoflavone-inducible Ah-Cre and tamoxifen-inducible villin-Cre(ER) mice. Mice with one Hdac1 allele displayed normal tissue architecture, but increased sensitivity to DSS-induced colitis. In contrast, mice with one Hdac2 allele displayed intestinal architecture defects, increased proliferation, decreased goblet cell numbers as opposed to Paneth cells, increased immune cell infiltration associated with fibrosis, and increased sensitivity to DSS-induced colitis. In comparison to dual knockout mice, intermediary activation of Notch, mTOR, and Stat3 signaling pathways was observed. While villin-Cre(ER) Hdac1 and Hdac2 deletions led to an impaired epithelium and differentiation defects, Ah-Cre-mediated deletion resulted in blunted proliferation associated with the induction of a DNA damage response. Our results suggest that IEC determination and intestinal homeostasis are highly dependent on Hdac1 and Hdac2 activity levels, and that changes in the IEC acetylome may alter the mucosal environment. © 2015 Wiley Periodicals, Inc.

  18. Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity.

    Science.gov (United States)

    Hutterer, Corina; Milbradt, Jens; Hamilton, Stuart; Zaja, Mirko; Leban, Johann; Henry, Christophe; Vitt, Daniel; Steingruber, Mirjam; Sonntag, Eric; Zeitträger, Isabel; Bahsi, Hanife; Stamminger, Thomas; Rawlinson, William; Strobl, Stefan; Marschall, Manfred

    2017-07-01

    Infection with human cytomegalovirus (HCMV) is a serious medical problem, particularly in immunocompromised individuals and neonates. The success of (val)ganciclovir therapy is hampered by low drug compatibility and induction of viral resistance. A novel strategy of antiviral treatment is based on the exploitation of cell-directed signaling, e. g. pathways with a known relevance for carcinogenesis and tumor drug development. Here we describe a principle for putative antiviral drugs based on targeting dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs). DYRKs constitute an evolutionarily conserved family of protein kinases with key roles in the control of cell proliferation and differentiation. Members of the DYRK family are capable of phosphorylating a number of substrate proteins, including regulators of the cell cycle, e.g. DYRK1B can induce cell cycle arrest, a critical step for the regulation of HCMV replication. Here we provide first evidence for a critical role of DYRKs during viral replication and the high antiviral potential of DYRK inhibitors (SC84227, SC97202 and SC97208, Harmine and AZ-191). Using established replication assays for laboratory and clinically relevant strains of HCMV, concentration-dependent profiles of inhibition were obtained. Mean inhibitory concentrations (EC50) of 0.98 ± 0.08 μM/SC84227, 0.60 ± 0.02 μM/SC97202, 6.26 ± 1.64 μM/SC97208, 0.71 ± 0.019 μM/Harmine and 0.63 ± 0.23 μM/AZ-191 were determined with HCMV strain AD169-GFP for the infection of primary human fibroblasts. A first analysis of the mode of antiviral action suggested a block of viral replication at the early-late stage of HCMV gene expression. Moreover, rhesus macaque cytomegalovirus (RhCMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV-1) showed a similarly high sensitivity to these compounds. Thus, we conclude that DYRK signaling represents a promising target pathway for the development of novel anti

  19. Promoting Preservice Teachers' Dual Self-Regulation Roles as Learners and as Teachers: Effects of Generic vs. Specific Prompts

    Science.gov (United States)

    Kramarski, Bracha; Kohen, Zehavit

    2017-01-01

    Researchers have recently suggested that teachers must undertake important dual self-regulation roles if they want to become effective at improving their students' self-regulation. First, teachers need to become proficient at self-regulated learning (SRL) themselves, and then teachers need to learn explicitly how to proactively teach SRL -- termed…

  20. Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner

    Science.gov (United States)

    Dickens, M.J.; Balthazart, J.; Cornil, C. A.

    2012-01-01

    Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with stressed or non-stressed partners. We measured nuclei-specific AA changes, corresponding behavioural output, fertilisation rates and corticosterone (CORT) concentrations. In males, sexual interaction rapidly reversed stress-induced increases of AA in the medial preoptic nucleus (POM). This time scale (behaviour suggesting that the input from the sexual stimuli on POM AA may actively preserve sexual behaviour despite stress exposure. We also found distinct sex differences in contextual physiological responses: while males did not show any effect of partner status, females responded to both their stress exposure and the male partner’s stress exposure at the level of circulating CORT and AA. In addition, fertilisation rates and female CORT correlated with the male partner’s exhibition of sexually aggressive behaviour suggesting that female perception of the male can affect their physiology as much as direct stress. Overall, male reproduction appears relatively simple – sexual stimuli, irrespective of stress, drives major neural changes including rapid reversal of stress-induced changes of AA. In contrast, female reproduction appears more nuanced and context specific, with subjects responding physiologically and behaviourally to stress, the male partner’s stress exposure, and female-directed male behaviour. PMID:22612582

  1. miR-146a modulates autoreactive Th17 cell differentiation and regulates organ-specific autoimmunity.

    Science.gov (United States)

    Li, Bo; Wang, Xi; Choi, In Young; Wang, Yu-Chen; Liu, Siyuan; Pham, Alexander T; Moon, Heesung; Smith, Drake J; Rao, Dinesh S; Boldin, Mark P; Yang, Lili

    2017-10-02

    Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a-deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a-deficient mice with 2D2 T cell receptor-Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a-deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6- and IL-21-induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6- and IL-21-induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.

  2. Correlation of six-minute walking performance with quality of life is domain- and gender-specific in healthy older adults.

    Directory of Open Access Journals (Sweden)

    Andrey Jorge Serra

    Full Text Available We analyzed the relationship between performance on the 6-min walk test (6MWT and health-related quality of life (HRQoL in older subjects. Our secondary aim was to determine the distance to be completed on the 6MWT for the subject to achieve a score of 50 on the Short Form (36 Health Survey (SF-36. Associations were tested using linear correlation and multivariate linear regression. Participants were 130 healthy older individuals. The predictive performance of the 6MWT based on an SF-36 score of 50 was assessed using a receiver operating characteristic curve and its area under curve (AUC. Associations were observed between physical functioning, role-emotional, social functioning, vitality, general health score, and 6MWT performance in women, after adjusting for confounding variables (coefficients: 0.57, 0.38, 0.40, and 0.46, respectively; p < 0.05. No association was found for men. The distance for the 6MWT to predict an SF-36 score of 50 was 481 m for men in the physical functioning (AUC: 0.79 and role-physical (AUC: 0.84 domains, and 420 m for women in role-emotional (AUC: 0.75, role-physical (AUC: 0.80, and general health (AUC: 0.80 domains. Our results indicate that superior 6MWT performance may be associated with better HRQoL in several domains in only healthy older women. No association between 6MWT performance and role-emotional, mental health, or vitality domains was found. We suggest that a score of 50 is represented by a 6MWT distance of 481 m for men and 420 m for women, at least in the role-physical domain.

  3. The regulation of growth and metabolism of kidney stem cells with regional specificity using extracellular matrix derived from kidney.

    Science.gov (United States)

    O'Neill, John D; Freytes, Donald O; Anandappa, Annabelle J; Oliver, Juan A; Vunjak-Novakovic, Gordana V

    2013-12-01

    Native extracellular matrix (ECM) that is secreted and maintained by resident cells is of great interest for cell culture and cell delivery. We hypothesized that specialized bioengineered niches for stem cells can be established using ECM-derived scaffolding materials. Kidney was selected as a model system because of the high regional diversification of renal tissue matrix. By preparing the ECM from three specialized regions of the kidney (cortex, medulla, and papilla; whole kidney, heart, and bladder as controls) in three forms: (i) intact sheets of decellularized ECM, (ii) ECM hydrogels, and (iii) solubilized ECM, we investigated how the structure and composition of ECM affect the function of kidney stem cells (with mesenchymal stem cells, MSCs, as controls). All three forms of the ECM regulated KSC function, with differential structural and compositional effects. KSCs cultured on papilla ECM consistently displayed lower proliferation, higher metabolic activity, and differences in cell morphology, alignment, and structure formation as compared to KSCs on cortex and medulla ECM, effects not observed in corresponding MSC cultures. These data suggest that tissue- and region-specific ECM can provide an effective substrate for in vitro studies of therapeutic stem cells. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Neuron-specific regulation of class I PI3K catalytic subunits and their dysfunction in brain disorders

    Directory of Open Access Journals (Sweden)

    Christina eGross

    2014-02-01

    Full Text Available The PI3K complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ and p110δ, have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. While in non-neuronal cells these catalytic subunits may have partially redundant functions, there is increasing evidence that in neurons their roles are more specialized, and confined to distinct receptor-dependent pathways. This review will summarize the emerging role of class I PI3K catalytic subunits in neurotransmitter-regulated neuronal signaling, and their dysfunction in a variety of neurological diseases, including fragile X syndrome, schizophrenia and epilepsy. We will discuss recent literature describing the use of PI3K subunit-selective inhibitors to rescue brain disease-associated phenotypes in in vitro and animal models. These studies give rise to the exciting prospect that these drugs, originally designed for cancer treatment, may be repurposed as therapeutic drugs for brain disorders in the future.

  5. Microvillus-Specific Protein Tyrosine Phosphatase SAP-1 Plays a Role in Regulating the Intestinal Paracellular Transport of Macromolecules.

    Science.gov (United States)

    Mori, Shingo; Kamei, Noriyasu; Murata, Yoji; Takayama, Kozo; Matozaki, Takashi; Takeda-Morishita, Mariko

    2017-09-01

    The stomach cancer-associated protein tyrosine phosphatase 1 (SAP-1) is a receptor-type protein tyrosine phosphatase that is specifically expressed on the apical membrane of the intestinal epithelium. SAP-1 is known to maintain the balance of phosphorylation of proteins together with protein kinases; however, its biological function and impact on pharmacokinetics in the intestine remain unclear. The present study, therefore, aimed at clarifying the relationship between SAP-1 and the intestinal absorption behaviors of typical transporter substrates and macromolecules. The endogenous levels of glucose and total cholesterol in the blood were similar between wild-type and SAP-1-deficient mice (Sap1 -/- ), suggesting no contribution of SAP-1 to biogenic influx. Moreover, in vitro transport study with everted ileal sacs demonstrated that there was no difference in the absorption of breast cancer resistance protein, P-glycoprotein, and peptide transporter substrates between both mice. However, absorptive clearance of macromolecular model dextrans (FD-4 and FD-10) in Sap1 -/- mice was significantly higher than that in wild-type mice, and this was confirmed by the trend of increased FD-4 absorption from colonic loops of Sap1 -/- mice. Therefore, the results of this study suggest the partial contribution of SAP-1 to the regulated transport of hydrophilic macromolecules through paracellular tight junctions. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  6. Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome

    Directory of Open Access Journals (Sweden)

    Susan J. Harrison

    2012-05-01

    Progenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5. These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.

  7. The G1/S Specific Cyclin D2 Is a Regulator of HIV-1 Restriction in Non-proliferating Cells

    Science.gov (United States)

    Badia, Roger; Pujantell, Maria; Riveira-Muñoz, Eva; Puig, Teresa; Torres-Torronteras, Javier; Martí, Ramón; Clotet, Bonaventura; Ampudia, Rosa M.; Ballana, Ester

    2016-01-01

    Macrophages are a heterogeneous cell population strongly influenced by differentiation stimuli that become susceptible to HIV-1 infection after inactivation of the restriction factor SAMHD1 by cyclin-dependent kinases (CDK). Here, we have used primary human monocyte-derived macrophages differentiated through different stimuli to evaluate macrophage heterogeneity on cell activation and proliferation and susceptibility to HIV-1 infection. Stimulation of monocytes with GM-CSF induces a non-proliferating macrophage population highly restrictive to HIV-1 infection, characterized by the upregulation of the G1/S-specific cyclin D2, known to control early steps of cell cycle progression. Knockdown of cyclin D2, enhances HIV-1 replication in GM-CSF macrophages through inactivation of SAMHD1 restriction factor by phosphorylation. Co-immunoprecipitation experiments show that cyclin D2 forms a complex with CDK4 and p21, a factor known to restrict HIV-1 replication by affecting the function of the downstream cascade that leads to SAMHD1 deactivation. Thus, we demonstrate that cyclin D2 acts as regulator of cell cycle proteins affecting SAMHD1-mediated HIV-1 restriction in non-proliferating macrophages. PMID:27541004

  8. Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition

    Science.gov (United States)

    Dumais, Kelly M.; Alonso, Andrea G.; Immormino, Marisa A.; Bredewold, Remco; Veenema, Alexa H.

    2015-01-01

    Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. PMID:26630388

  9. Memory and Comprehension for Health Information among Older Adults: Distinguishing the Effects of Domain-General and Domain-Specific Knowledge

    Science.gov (United States)

    Chin, Jessie; Payne, Brennan; Gao, Xuefei; Conner-Garcia, Thembi; Graumlich, James F.; Murray, Michael D.; Morrow, Daniel G.; Stine-Morrow, Elizabeth A.L.

    2014-01-01

    While there is evidence that knowledge influences understanding of health information, less is known about the processing mechanisms underlying this effect and its impact on memory. We used the moving window paradigm to examine how older adults varying in domain-general crystallized ability (verbal ability) and health knowledge allocate attention to understand health and domain-general texts. Participants (n=107, aged 60 to 88 yrs) read and recalled single sentences about hypertension and about non-health topics. Mixed-effects modeling of word-by-word reading times suggested that domain-general crystallized ability increased conceptual integration regardless of text domain, while health knowledge selectively increased resource allocation to conceptual integration at clause boundaries in health texts. These patterns of attentional allocation were related to subsequent recall performance. Although older adults with lower levels of crystallized ability were less likely to engage in integrative processing, when they did, this strategy had a compensatory effect in improving recall. These findings suggest that semantic integration during reading is an important comprehension process that supports the construction of the memory representation and is engendered by knowledge. Implications of the findings for theories of text processing and memory as well as for designing patient education materials are discussed. PMID:24787361

  10. Lifestyle factors and site-specific risk of hip fracture in community dwelling older women – a 13-year prospective population-based cohort study

    Directory of Open Access Journals (Sweden)

    Määttä Mikko

    2012-09-01

    Full Text Available Abstract Background Several risk factors are associated to hip fractures. It seems that different hip fracture types have different etiologies. In this study, we evaluated the lifestyle-related risk factors for cervical and trochanteric hip fractures in older women over a 13-year follow-up period. Methods The study design was a prospective, population-based study consisting of 1681 women (mean age 72 years. Seventy-three percent (n = 1222 participated in the baseline measurements, including medical history, leisure-time physical activity, smoking, and nutrition, along with body anthropometrics and functional mobility. Cox regression was used to identify the independent predictors of cervical and trochanteric hip fractures. Results During the follow-up, 49 cervical and 31 trochanteric fractures were recorded. The women with hip fractures were older, taller, and thinner than the women with no fractures (p  Conclusions Impaired functional mobility, physical inactivity, and low body mass may increase the risk for hip fractures with different effects at the cervical and trochanteric levels.

  11. Memory and comprehension for health information among older adults: distinguishing the effects of domain-general and domain-specific knowledge.

    Science.gov (United States)

    Chin, Jessie; Payne, Brennan; Gao, Xuefei; Conner-Garcia, Thembi; Graumlich, James F; Murray, Michael D; Morrow, Daniel G; Stine-Morrow, Elizabeth A L

    2015-01-01

    While there is evidence that knowledge influences understanding of health information, less is known about the processing mechanisms underlying this effect and its impact on memory. We used the moving window paradigm to examine how older adults varying in domain-general crystallised ability (verbal ability) and health knowledge allocate attention to understand health and domain-general texts. Participants (n = 107, age: 60-88 years) read and recalled single sentences about hypertension and about non-health topics. Mixed-effects modelling of word-by-word reading times suggested that domain-general crystallised ability increased conceptual integration regardless of text domain, while health knowledge selectively increased resource allocation to conceptual integration at clause boundaries in health texts. These patterns of attentional allocation were related to subsequent recall performance. Although older adults with lower levels of crystallised ability were less likely to engage in integrative processing, when they did, this strategy had a compensatory effect in improving recall. These findings suggest that semantic integration during reading is an important comprehension process that supports the construction of the memory representation and is engendered by knowledge. Implications of the findings for theories of text processing and memory as well as for designing patient education materials are discussed.

  12. Clinical Interviewing with Older Adults

    Science.gov (United States)

    Mohlman, Jan; Sirota, Karen Gainer; Papp, Laszlo A.; Staples, Alison M.; King, Arlene; Gorenstein, Ethan E.

    2012-01-01

    Over the next few decades the older adult population will increase dramatically, and prevalence rates of psychiatric disorders are also expected to increase in the elderly cohort. These demographic projections highlight the need for diagnostic instruments and methods that are specifically tailored to older adults. The current paper discusses the…

  13. Chronic Restraint Stress Induces an Isoform-Specific Regulation on the Neural Cell Adhesion Molecule in the Hippocampus

    Science.gov (United States)

    Touyarot, K.; Sandi, C.

    2002-01-01

    Existing evidence indicates that 21-days exposure of rats to restraint stress induces dendritic atrophy in pyramidal cells of the hippocampus. This phenomenon has been related to altered performance in hippocampal-dependent learning tasks. Prior studies have shown that hippocampal expression of cell adhesion molecules is modified by such stress treatment, with the neural cell adhesion molecule (NCAM) decreasing and L1 increasing, their expression, at both the mRNA and protein levels. Given that NCAM comprises several isoforms, we investigated here whether chronic stress might differentially affect the expression of the three major isoforms (NCAM-120, NCAM-140, NCAM-180) in the hippocampus. In addition, as glucocorticoids have been implicated in the deleterious effects induced by chronic stress, we also evaluated plasma corticosterone levels and the hippocampal expression of the corticosteroid mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The results showed that the protein concentration of the NCAM-140 isoform decreased in the hippoampus of stressed rats. This effect was isoform-specific, because NCAM-120 and NCAM-180 levels were not significantly modified. In addition, whereas basal levels of plasma corticosterone tended to be increased, MR and GR concentrations were not significantly altered. Although possible changes in NCAM-120, NCAM-180 and corticosteroid receptors at earlier time points of the stress period cannot be ignored; this study suggests that a down-regulation of NCAM-140 might be implicated in the structural alterations consistently shown to be induced in the hippocampus by chronic stress exposure. As NCAM-140 is involved in cell-cell adhesion and neurite outgrowth, these findings suggest that this molecule might be one of the molecular mechanisms involved in the complex interactions among neurodegeneration-related events. PMID:12757368

  14. Lifestyle factors and site-specific risk of hip fracture in community dwelling older women – a 13-year prospective population-based cohort study

    Science.gov (United States)

    2012-01-01

    Background Several risk factors are associated to hip fractures. It seems that different hip fracture types have different etiologies. In this study, we evaluated the lifestyle-related risk factors for cervical and trochanteric hip fractures in older women over a 13-year follow-up period. Methods The study design was a prospective, population-based study consisting of 1681 women (mean age 72 years). Seventy-three percent (n = 1222) participated in the baseline measurements, including medical history, leisure-time physical activity, smoking, and nutrition, along with body anthropometrics and functional mobility. Cox regression was used to identify the independent predictors of cervical and trochanteric hip fractures. Results During the follow-up, 49 cervical and 31 trochanteric fractures were recorded. The women with hip fractures were older, taller, and thinner than the women with no fractures (p trochanteric fractures (HR = 3.4, 95% CI 1.8-6.6, and HR = 5.3, 95% CI 2.5-11.4, respectively). Low baseline physical activity was associated with an increased risk of hip fracture, especially in the cervical region (HR = 2.5, 95% CI 1.3-4.9). A decrease in cervical fracture risk (p = 0.002) was observed with physically active individuals compared to their less active peers (categories: very low or low, moderate, and high). Moderate coffee consumption and hypertension decreased the risk of cervical fractures (HR = 0.4, 95% CI 0.2-0.8, for both), while smoking was a predisposing factor for trochanteric fractures (HR = 3.2, 95% CI 1.1-9.3). Conclusions Impaired functional mobility, physical inactivity, and low body mass may increase the risk for hip fractures with different effects at the cervical and trochanteric levels. PMID:22978821

  15. 'It was like I had to fit into a category': Care-seekers' experiences of gender regulation in the Swedish trans-specific healthcare.

    Science.gov (United States)

    Linander, Ida; Alm, Erika; Goicolea, Isabel; Harryson, Lisa

    2017-05-01

    The few previous studies investigating regulation of gender in trans-specific healthcare are mainly based on text material and interviews with care-providers or consist solely of theoretical analyses. There is a lack of studies analysing how the regulation of gender is expressed in the care-seeker's own experiences, especially in a Nordic context. The aim of this study is to analyse narratives of individuals with trans experiences (sometimes called transgender people) to examine how gender performances can be regulated in trans-specific care in Sweden. The conceptual framework is inspired by trans studies, a Foucauldian analysis of power, queer phenomenology and the concept of cisnormativity. Fourteen interviews with people with trans experiences are analysed with constructivist grounded theory. The participants' experiences indicate that gender is constructed as norm-conforming, binary and stable in trans-specific healthcare. This gendered position is resisted, negotiated and embraced by the care-seekers. Norms and discourses both inside and outside trans-specific care contribute to the regulation and limit the room for action for care-users. We conclude that a trans-specific care that has a confirming approach to its care-users, instead of the current focus on gender norm conformity, has the potential to increase the self-determination of gender performance and increase the quality of care.

  16. Chiropractic treatment including instrument-assisted manipulation for non-specific dizziness and neck pain in community-dwelling older people: a feasibility randomised sham-controlled trial.

    Science.gov (United States)

    Kendall, Julie C; French, Simon D; Hartvigsen, Jan; Azari, Michael F

    2018-01-01

    Dizziness in older people is a risk factor for falls. Neck pain is associated with dizziness and responds favourably to neck manipulation. However, it is unknown if chiropractic intervention including instrument-assisted manipulation of the neck in older people with neck pain can also improve dizziness. This parallel two-arm pilot trial was conducted in Melbourne, Australia over nine months (October 2015 to June 2016). Participants aged 65-85 years, with self-reported chronic neck pain and dizziness, were recruited from the general public through advertisements in local community newspapers and via Facebook. Participants were randomised using a permuted block method to one of two groups: 1) Activator II™-instrument-assisted cervical and thoracic spine manipulation plus a combination of: light massage; mobilisation; range of motion exercises; and home advice about the application of heat, or 2) Sham-Activator II™-instrument-assisted manipulation (set to zero impulse) plus gentle touch of cervical and thoracic spinal regions. Participants were blinded to group allocation. The interventions were delivered weekly for four weeks. Assessments were conducted one week pre- and post-intervention. Clinical outcomes were assessed blindly and included: dizziness (dizziness handicap inventory [DHI]); neck pain (neck disability index [NDI]); self-reported concerns of falling; mood; physical function; and treatment satisfaction. Feasibility outcomes included recruitment rates, compliance with intervention and outcome assessment, study location, success of blinding, costs and harms. Out of 162 enquiries, 24 participants were screened as eligible and randomised to either the chiropractic ( n  = 13) or sham ( n  = 11) intervention group. Compliance was satisfactory with only two participants lost to follow up; thus, post-intervention data for 12 chiropractic intervention and 10 sham intervention participants were analysed. Blinding was similar between groups. Mild harms

  17. Brain-specific transcriptional regulator T-brain-1 controls brain wiring and neuronal activity in autism spectrum disorders

    Directory of Open Access Journals (Sweden)

    Tzyy-Nan eHuang

    2015-11-01

    Full Text Available T-brain-1 (TBR1 is a brain-specific T-box transcription factor. In 1995, Tbr1 was first identified from a subtractive hybridization that compared mouse embryonic and adult telencephalons. Previous studies of Tbr1–/– mice have indicated critical roles for TBR1 in the development of the cerebral cortex, amygdala and olfactory bulb. Neuronal migration and axonal projection are two important developmental features controlled by TBR1. Recently, recurrent de novo disruptive mutations in the TBR1 gene have been found in patients with autism spectrum disorders (ASDs. Human genetic studies have identified TBR1 as a high-confidence risk factor for ASDs. Because only one allele of the TBR1 gene is mutated in these patients, Tbr1+/– mice serve as a good genetic mouse model to explore the mechanism by which de novo TBR1 mutation leads to ASDs. Although neuronal migration and axonal projection defects of cerebral cortex are the most prominent phenotypes in Tbr1–/– mice, these features are not found in Tbr1+/– mice. Instead, inter- and intra-amygdalar axonal projections and NMDAR expression and activity in amygdala are particularly susceptible to Tbr1 haploinsufficiency. The studies indicated that both abnormal brain wiring (abnormal amygdalar connections and excitation/inhibition imbalance (NMDAR hypoactivity, two prominent models for ASD etiology, are present in Tbr1+/– mice. Moreover, calcium/calmodulin-dependent serine protein kinase (CASK was found to interact with TBR1. The CASK-TBR1 complex had been shown to directly bind the promoter of the Grin2b gene, which is also known as Nmdar2b, and upregulate Grin2b expression. This molecular function of TBR1 provides an explanation for NMDAR hypoactivity in Tbr1+/– mice. In addition to Grin2b, cell adhesion molecules-including Ntng1, Cdh8 and Cntn2-are also regulated by TBR1 to control axonal projections of amygdala. Taken together, the studies of Tbr1 provide an integrated picture of ASD

  18. Exclusions, exemptions and low specific activity material in the 1996 edition of the IAEA regulations for the safe transport of radioactive material

    International Nuclear Information System (INIS)

    Baekelandt, L.

    1997-01-01

    Exclusions and exemptions, total as well as partial, have always been part of the IAEA transport regulations, but these provisions were dispersed over various sections. In the 1996 edition of these regulations, some of these exclusions and exemptions have been kept unchanged, others have been changed and also, new ones have been added. This paper gives an overview of the exclusions and exemptions in the 1996 edition, the most important change with respect to the previous edition being the departure from the single exemption value of 70 Bq/g for all radionuclides to the radionuclide specific exemption values as specified in the IAEA Basic Safety Standards. As a consequence of this change, a new category of Low Specific Activity (LSA) material has been introduced. This paper also discusses the rationale of these changes to the regulations. (author)

  19. Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation.

    Science.gov (United States)

    Cho, Seong-Jun; Kang, Hana; Kim, Min Young; Lee, Jung Eun; Kim, Sung Jin; Nam, Seon Young; Kim, Ji Young; Kim, Hee Sun; Pyo, Suhkneung; Yang, Kwang Hee

    2016-04-01

    To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Splenocytes and IM-9 cells were uniformly irradiated with various doses of a (137)Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation

    International Nuclear Information System (INIS)

    Cho, Seong-Jun; Kang, Hana; Kim, Min Young; Lee, Jung Eun; Kim, Sung Jin; Nam, Seon Young; Kim, Ji Young; Kim, Hee Sun; Pyo, Suhkneung; Yang, Kwang Hee

    2016-01-01

    Purpose: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Methods and Materials: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a "1"3"7Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. Results: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Conclusion: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.

  1. Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation

    DEFF Research Database (Denmark)

    Milani, Lili; Lundmark, Anders; Nordlund, Jessica

    2008-01-01

    To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood...

  2. Site-Specific Phosphorylation of Ikaros Induced by Low-Dose Ionizing Radiation Regulates Cell Cycle Progression of B Lymphoblast Through CK2 and AKT Activation

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Seong-Jun; Kang, Hana [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of); Kim, Min Young [Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan (Korea, Republic of); Lee, Jung Eun; Kim, Sung Jin; Nam, Seon Young; Kim, Ji Young; Kim, Hee Sun [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of); Pyo, Suhkneung [College of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do (Korea, Republic of); Yang, Kwang Hee, E-mail: kwangheey@khnp.co.kr [KHNP Radiation Health Institute, Korea Hydro & Nuclear Power Co, Seoul (Korea, Republic of)

    2016-04-01

    Purpose: To determine how low-dose ionizing radiation (LDIR) regulates B lympho-proliferation and its molecular mechanism related with Ikaros, transcription factor. Methods and Materials: Splenocytes and IM-9 cells were uniformly irradiated with various doses of a {sup 137}Cs γ-source, and cell proliferation was analyzed. To determine the LDIR-specific phosphorylation of Ikaros, immunoprecipitation and Western blot analysis were performed. To investigate the physiologic function of LDIR-mediatied Ikaros phosphorylation, Ikaros mutants at phosphorylation sites were generated, and cell cycle analysis was performed. Results: First, we found that LDIR enhances B lymphoblast proliferation in an Ikaros-dependent manner. Moreover, we found that LDIR elevates the phosphorylation level of Ikaros protein. Interestingly, we showed that CK2 and AKT are involved in LDIR-induced Ikaros phosphorylation and capable of regulating DNA binding activity of Ikaros via specific phosphorylation. Finally, we identified LDIR-specific Ikaros phosphorylation sites at S391/S393 and showed that the Ikaros phosphorylations at these sites control Ikaros's ability to regulate G1/S cell cycle progression. Conclusion: Low-dose ionizing radiation specifically phosphorylates Ikaros protein at Ser 391/393 residues to regulate cell cycle progression in B lymphoblast.

  3. The Specific Roles of Vitamins in the Regulation of Immunosurveillance and Maintenance of Immunologic Homeostasis in the Gut

    OpenAIRE

    Hosomi, Koji; Kunisawa, Jun

    2017-01-01

    Vitamins are micronutrients which are essential for the maintenance of biological responses including immune system. Hence, vitamin deficiency increases a risk of infectious, allergic, and inflammatory diseases. Accumulating evidence has recently revealed the molecular and cellular mechanisms of vitamin-mediated regulation in the active and quiescent immune responses. In this review, we focus on the immunologic roles of vitamins in the regulation of homeostasis and surveillance in the gut.

  4. CELF family RNA-binding protein UNC-75 regulates two sets of mutually exclusive exons of the unc-32 gene in neuron-specific manners in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Hidehito Kuroyanagi

    Full Text Available An enormous number of alternative pre-mRNA splicing patterns in multicellular organisms are coordinately defined by a limited number of regulatory proteins and cis elements. Mutually exclusive alternative splicing should be strictly regulated and is a challenging model for elucidating regulation mechanisms. Here we provide models of the regulation of two sets of mutually exclusive exons, 4a-4c and 7a-7b, of the Caenorhabditis elegans uncoordinated (unc-32 gene, encoding the a subunit of V0 complex of vacuolar-type H(+-ATPases. We visualize selection patterns of exon 4 and exon 7 in vivo by utilizing a trio and a pair of symmetric fluorescence splicing reporter minigenes, respectively, to demonstrate that they are regulated in tissue-specific manners. Genetic analyses reveal that RBFOX family RNA-binding proteins ASD-1 and FOX-1 and a UGCAUG stretch in intron 7b are involved in the neuron-specific selection of exon 7a. Through further forward genetic screening, we identify UNC-75, a neuron-specific CELF family RNA-binding protein of unknown function, as an essential regulator for the exon 7a selection. Electrophoretic mobility shift assays specify a short fragment in intron 7a as the recognition site for UNC-75 and demonstrate that UNC-75 specifically binds via its three RNA recognition motifs to the element including a UUGUUGUGUUGU stretch. The UUGUUGUGUUGU stretch in the reporter minigenes is actually required for the selection of exon 7a in the nervous system. We compare the amounts of partially spliced RNAs in the wild-type and unc-75 mutant backgrounds and raise a model for the mutually exclusive selection of unc-32 exon 7 by the RBFOX family and UNC-75. The neuron-specific selection of unc-32 exon 4b is also regulated by UNC-75 and the unc-75 mutation suppresses the Unc phenotype of the exon-4b-specific allele of unc-32 mutants. Taken together, UNC-75 is the neuron-specific splicing factor and regulates both sets of the mutually exclusive

  5. Older workers

    NARCIS (Netherlands)

    Ybema,J.F.; Giesen, F.

    2014-01-01

    Due to an ageing population and global economic competition, there is a societal need for people to extend their working lives while maintaining high work productivity. This article presents an overview of the labour participation, job performance, and job characteristics of older workers in the

  6. Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition.

    Science.gov (United States)

    Dumais, Kelly M; Alonso, Andrea G; Immormino, Marisa A; Bredewold, Remco; Veenema, Alexa H

    2016-02-01

    Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Association of Cognitive Function With Cause-Specific Mortality in Middle and Older Age: Follow-up of Participants in the English Longitudinal Study of Ageing.

    Science.gov (United States)

    Batty, G David; Deary, Ian J; Zaninotto, Paola

    2016-02-01

    We examined the little-tested associations between general cognitive function in middle and older age and later risk of death from chronic diseases. In the English Longitudinal Study of Ageing (2002-2012), 11,391 study participants who were 50-100 years of age at study induction underwent a battery of cognitive tests and provided a range of collateral data. In an analytical sample of 9,204 people (4,982 women), there were 1,488 deaths during follow-up (mean duration, 9.0 years). When we combined scores from 4 cognition tests that represented 3 acknowledged key domains of cognitive functioning (memory, executive function, and processing speed), cognition was inversely associated with deaths from cancer (per each 1-standard-deviation decrease in general cognitive function score, hazard ratio = 1.21, 95% CI: 1.10, 1.33), cardiovascular disease (hazard ratio = 1.71, 95% CI: 1.55, 1.89), other causes (hazard ratio = 2.07, 95% CI: 1.79, 2.40), and respiratory illness (hazard ratio = 2.48, 95% CI: 2.12, 2.90). Controlling for a range of covariates, such as health behaviors and socioeconomic status, and left-censoring to explore reverse causality had very little impact on the strength of these relationships. These findings indicate that cognitive test scores can provide relatively simple indicators of the risk of death from an array of chronic diseases and that these associations appear to be independent of other commonly assessed risk factors. © The Author 2016. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Factors affecting self-regulatory driving practices among older adults.

    Science.gov (United States)

    Molnar, Lisa J; Charlton, Judith L; Eby, David W; Langford, Jim; Koppel, Sjaan; Kolenic, Giselle E; Marshall, Shawn

    2014-01-01

    The primary objective of this study was to better understand how self-regulatory driving practices at multiple levels of driver decision making are influenced by various factors. Specifically, the study investigated patterns of tactical and strategic self-regulation among a sample of 246 Australian older drivers. Of special interest was the relative influence of several variables on the adoption of self-regulation, including self-perceptions of health, functioning, and abilities for safe driving and driving confidence and comfort. The research was carried out at the Monash University Accident Research Centre, as part of its Ozcandrive study, a partnership with the Canadian Driving Research Initiative for Vehicular Safety in the Elderly (Candrive), and in conjunction with the University of Michigan Transportation Research Institute (UMTRI). Candrive/Ozcandrive represents the first study to follow a large group of older drivers over several years and collect comprehensive self-reported and objectively derived data on health, functioning, and driving. This study used a subset of data from the Candrive/Ozcandrive study. Upon enrolling in the study, participants underwent a comprehensive clinical assessment during which data on visual, cognitive, and psychomotor functioning were collected. Approximately 4 months after study enrollment, participants completed the Advanced Driving Decisions and Patterns of Travel (ADDAPT) questionnaire, a computer-based self-regulation instrument developed and pilot-tested at UMTRI. Self-regulation among older adults was found to be a multidimensional concept. Rates of self-regulation were tied closely to specific driving situations, as well as level of decision making. In addition, self-regulatory practices at the strategic and tactical levels of decision making were influenced by different sets of factors. Continuing efforts to better understand the self-regulatory practices of older drivers at multiple levels of driver performance and

  9. Quality regulation will make the goals of asset management specific; Zielkonkretisierung des Asset Managements durch die Qualitaetsregulierung

    Energy Technology Data Exchange (ETDEWEB)

    Fritz, Wolfgang [Consentec Consulting fuer Energiewirtschaft und -technik GmbH, Aachen (Germany); Vennegeerts, Hendrik [Forschungsgemeinschaft fuer Elektrische Anlagen und Stromwirtschaft e.V. (FGH), Aachen (Germany)

    2009-12-15

    The asset management of a network operator is responsible for decisions concerning the design, upkeep, modernisation and operation of networks. These decisions have an impact on costs and various quality aspects. Due to the absence of stringent instructions in some of its areas, asset management holds a substantial optimisation potential for network operators. Creative leeway exists in particular with regard to network reliability. Nowadays the level of reliability of a network has no immediate impact on the operator's turnover. However, this will change with the introduction of quality regulation through the Incentive Regulation Ordinance. This article discusses basic models for the resulting concretisation of goals and outlines the current debate as to how quality regulation should be framed.

  10. Nuclear movement regulated by non-Smad Nodal signaling via JNK is associated with Smad signaling during zebrafish endoderm specification.

    Science.gov (United States)

    Hozumi, Shunya; Aoki, Shun; Kikuchi, Yutaka

    2017-11-01

    Asymmetric nuclear positioning is observed during animal development, but its regulation and significance in cell differentiation remain poorly understood. Using zebrafish blastulae, we provide evidence that nuclear movement towards the yolk syncytial layer, which comprises extraembryonic tissue, occurs in the first cells fated to differentiate into the endoderm. Nodal signaling is essential for nuclear movement, whereas nuclear envelope proteins are involved in movement through microtubule formation. Positioning of the microtubule-organizing center, which is proposed to be crucial for nuclear movement, is regulated by Nodal signaling and nuclear envelope proteins. The non-Smad JNK signaling pathway, which is downstream of Nodal signaling, regulates nuclear movement independently of the Smad pathway, and this nuclear movement is associated with Smad signal transduction toward the nucleus. Our study provides insight into the function of nuclear movement in Smad signaling toward the nucleus, and could be applied to the control of TGFβ signaling. © 2017. Published by The Company of Biologists Ltd.

  11. Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids.

    Science.gov (United States)

    Ayyar, Vivaswath S; Almon, Richard R; Jusko, William J; DuBois, Debra C

    2015-06-01

    Glucocorticoids (GC) are steroid hormones, which regulate metabolism and immune function. Synthetic GCs, or corticosteroids (CS), have appreciable clinical utility via their ability to suppress inflammation in immune-mediated diseases like asthma and rheumatoid arthritis. Recent work has provided insight to novel GC-induced genes that mediate their anti-inflammatory effects, including glucocorticoid-induced leucine zipper (GILZ). Since GILZ comprises an important part of GC action, its regulation by both drug and hormone will influence CS therapy. In addition, GILZ expression is often employed as a biomarker of GC action, which requires judicious selection of sampling time. Understanding the in vivo regulation of GILZ mRNA expression over time will provide insight into both the physiological regulation of GILZ by endogenous GC and the dynamics of its enhancement by CS. A highly quantitative qRT-PCR assay was developed for measuring GILZ mRNA expression in tissues obtained from normal and CS-treated rats. This assay was applied to measure GILZ mRNA expression in eight tissues; to determine its endogenous regulation over time; and to characterize its dynamics in adipose tissue, muscle, and liver following treatment with CS. We demonstrate that GILZ mRNA is expressed in several tissues. GILZ mRNA expression in adipose tissue displayed a robust circadian rhythm that was entrained with the circadian oscillation of endogenous corticosterone; and is strongly enhanced by acute and chronic dosing. Single dosing also enhanced GILZ mRNA in muscle and liver, but the dynamics varied. In conclusion, GILZ is widely expressed in the rat and highly regulated by endogenous and exogenous GCs. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  12. Educational inequalities in cause-specific mortality in middle-aged and older men and women in eight western European populations

    NARCIS (Netherlands)

    Huisman, Martijn; Kunst, Anton E.; Bopp, Matthias; Borgan, Jens-Kristian; Borrell, Carme; Costa, Giuseppe; Deboosere, Patrick; Gadeyne, Sylvie; Glickman, Myer; Marinacci, Chiara; Minder, Christoph; Regidor, Enrique; Valkonen, Tapani; Mackenbach, Johan P.

    2005-01-01

    BACKGROUND: Studies of socioeconomic disparities in patterns of cause of death have been limited to single countries, middle-aged people, men, or broad cause of death groups. We assessed contribution of specific causes of death to disparities in mortality between groups with different levels of

  13. Russian Language Testing and Integrated Examination for Foreign Citizens in Russia: Legislation Background and Legal Regulation Specific Features

    Science.gov (United States)

    Dolzhikova, Anzhela

    2015-01-01

    The Russian Federation faces active law-making and legislative activities aimed at providing legal grounds for qualifying educational level of foreign nationals entering the country with the purpose to work and apply for citizenship. The article deals with the current legislation and regulations in their relationship with each other, their impact…

  14. Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes : evidence for specific and redundant patterns during ovulation

    NARCIS (Netherlands)

    Richards, JoAnne S; Hernandez-Gonzalez, Immaculada; Gonzalez-Robayna, Ignacio; Teuling, Eva; Lo, Yuet; Boerboom, Derek; Falender, Allison E; Doyle, Kari H; LeBaron, Richard G; Thompson, Vivian; Sandy, John D

    Protease cascades are essential for many biological events, including the LH-induced process of ovulation. ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin-like repeats-1) is expressed and hormonally regulated in the ovary by LH and the progesterone receptor. To determine whether

  15. Site-Specific Phosphorylation of PSD-95 PDZ Domains Reveals Fine-Tuned Regulation of Protein-Protein Interactions

    DEFF Research Database (Denmark)

    Pedersen, Søren W; Albertsen, Louise; Moran, Griffin E

    2017-01-01

    The postsynaptic density protein of 95 kDa (PSD-95) is a key scaffolding protein that controls signaling at synapses in the brain through interactions of its PDZ domains with the C-termini of receptors, ion channels, and enzymes. PSD-95 is highly regulated by phosphorylation. To explore the effec...

  16. Peptide microarray analysis of substrate specificity of the transmembrane Ser/Thr kinase KPI-2 reveals reactivity with cystic fibrosis transmembrane conductance regulator and phosphorylase.

    Science.gov (United States)

    Wang, Hong; Brautigan, David L

    2006-11-01

    Human lemur (Lmr) kinases are predicted to be Tyr kinases based on sequences and are related to neurotrophin receptor Trk kinases. This study used homogeneous recombinant KPI-2 (Lmr2, LMTK2, Cprk, brain-enriched protein kinase) kinase domain and a library of 1,154 peptides on a microarray to analyze substrate specificity. We found that KPI-2 is strictly a Ser/Thr kinase that reacts with Ser either preceded by or followed by Pro residues but unlike other Pro-directed kinases does not strictly require an adjacent Pro residue. The most reactive peptide in the library corresponds to Ser-737 of cystic fibrosis transmembrane conductance regulator, and the recombinant R domain of cystic fibrosis transmembrane conductance regulator was a preferred substrate. Furthermore the KPI-2 kinase phosphorylated peptides corresponding to the single site in phosphorylase and purified phosphorylase b, making this only the second known phosphorylase b kinase. Phosphorylase was used as a specific substrate to show that KPI-2 is inhibited in living cells by addition of nerve growth factor or serum. The results demonstrate the utility of the peptide library to probe specificity and discover kinase substrates and offer a specific assay that reveals hormonal regulation of the activity of this unusual transmembrane kinase.

  17. Assessing Self-Regulation as a Cyclical, Context-Specific Phenomenon: Overview and Analysis of SRL Microanalytic Protocols

    Directory of Open Access Journals (Sweden)

    Timothy J. Cleary

    2012-01-01

    Full Text Available The primary purpose of this paper is to review relevant research related to the use of an assessment technique, called Self-Regulated Learning (SRL Microanalysis. This structured interview is grounded in social-cognitive theory and research and thus seeks to evaluate students' regulatory processes as they engage in well-defined academic or nonacademic tasks and activities. We illustrate the essential features of this contextualized assessment approach and detail a simple five-step process that researchers can use to apply this approach to their work. Example questions and administration procedures for five key self-regulation subprocesses (i.e., including goal-setting, strategic planning, monitoring, self-evaluation, and attributions are highlighted, with particular emphasis placed on causal attributions. The psychometric properties of SRL microanalytic assessment protocols and potential areas of future research are presented.

  18. Regulation of somatic embryo development in Norway spruce (Picea abies). A molecular approach to the characterization of specific developmental stages

    Energy Technology Data Exchange (ETDEWEB)

    Sabala, I. [Swedish Univ. of Agricultural Sciences, Uppsala (Sweden). Dept. of Forest Genetics

    1998-12-31

    Embryo development is a complex process involving a set of strictly regulated events. The regulation of these events is poorly understood especially during the early stages of embryo development. Somatic embryos go through the same developmental stages as zygotic embryos making them an ideal model system for studying the regulation of embryo development. We have used embryogenic cultures of Picea abies to study some aspects of the regulation of embryo development in gymnosperms. The bottle neck during somatic embryogenesis is the switch from the proliferation stage to the maturation stage. This switch is initiated by giving somatic embryos a maturation treatment i.e. the embryos are treated with abscisic acid (ABA). Somatic embryos which respond to ABA by forming mature somatic embryos were stimulated to secret a 70 kDa protein, AF70. The af70 gene was isolated and characterised. The expression of the af70 gene was constitutive in embryos but was highly ABA-induced in seedlings. Moreover, expression of this gene was stimulated during cold acclimation of Picea abies seedlings. A full length Picea abies cDNA clone Pa18, encoding a protein with the characteristics of plant lipid transfer proteins (LTPs), was isolated and characterised. The Pa18 gene is constitutively expressed in embryogenic cultures of Picea abies representing different stages of development as well as in nonembryogenic callus and seedlings. In situ hybridization showed that Pa18 gene is expressed in all embryonic cells of proliferating somatic embryos but the expression of the gene in mature somatic and zygotic embryos is restricted to the outer cell layer. Southern blot analysis at different stringencies was consistent with a single gene. An alteration in expression of Pa18 causes disturbance in the formation of the proper outer cell layer in the maturing somatic embryos. In addition to its influence on embryo development the Pa18 gene product also inhibits growth of Agrobacterium tumefaciens 195

  19. CTCF-mediated transcriptional regulation through cell type-specific chromosome organization in the β-globin locus

    OpenAIRE

    Junier, Ivan; Dale, Ryan K.; Hou, Chunhui; Képès, François; Dean, Ann

    2012-01-01

    International audience; The principles underlying the architectural landscape of chromatin beyond the nucleosome level in living cells remains largely unknown despite its potential to play a role in mammalian gene regulation. We investigated the three-dimensional folding of a 1 Mbp region of human chromosome 11 containing the β-globin genes by integrating looping interactions of the CCCTC-binding insulator protein CTCF determined comprehensively by chromosome conformation capture (3C) into a ...

  20. CTCF Mediates the Cell-Type Specific Spatial Organization of the Kcnq5 Locus and the Local Gene Regulation

    OpenAIRE

    Ren, Licheng; Wang, Yang; Shi, Minglei; Wang, Xiaoning; Yang, Zhong; Zhao, Zhihu

    2012-01-01

    Chromatin loops play important roles in the dynamic spatial organization of genes in the nucleus. Growing evidence has revealed that the multivalent functional zinc finger protein CCCTC-binding factor (CTCF) is a master regulator of genome spatial organization, and mediates the ubiquitous chromatin loops within the genome. Using circular chromosome conformation capture (4C) methodology, we discovered that CTCF may be a master organizer in mediating the spatial organization of the kcnq5 gene l...

  1. Specific interaction between hnRNP H and HPV16 L1 proteins: Implications for late gene auto-regulation enabling rapid viral capsid protein production

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Zi-Zheng; Sun, Yuan-Yuan; Zhao, Min; Huang, Hui [National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian 361005 (China); School of Life Sciences, Xiamen University, Xiamen, Fujian 361005 (China); Zhang, Jun; Xia, Ning-Shao [National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian 361005 (China); School of Life Sciences, Xiamen University, Xiamen, Fujian 361005 (China); School of Public Health, Xiamen University, Xiamen, Fujian 361005 (China); Miao, Ji, E-mail: jmiao@xmu.edu.cn [National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian 361005 (China); School of Life Sciences, Xiamen University, Xiamen, Fujian 361005 (China); Zhao, Qinjian, E-mail: qinjian_zhao@xmu.edu.cn [National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, Fujian 361005 (China); School of Public Health, Xiamen University, Xiamen, Fujian 361005 (China)

    2013-01-18

    Highlights: ► The RNA-binding hnRNP H regulates late viral gene expression. ► hnRNP H activity was inhibited by a late viral protein. ► Specific interaction between HPV L1 and hnRNP H was demonstrated. ► Co-localization of HPV L1 and hnRNP H inside cells was observed. ► Viral capsid protein production, enabling rapid capsid assembly, was implicated. -- Abstract: Heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP H, are RNA-binding proteins that function as splicing factors and are involved in downstream gene regulation. hnRNP H, which binds to G triplet regions in RNA, has been shown to play an important role in regulating the staged expression of late proteins in viral systems. Here, we report that the specific association between hnRNP H and a late viral capsid protein, human papillomavirus (HPV) L1 protein, leads to the suppressed function of hnRNP H in the presence of the L1 protein. The direct interaction between the L1 protein and hnRNP H was demonstrated by complex formation in solution and intracellularly using a variety of biochemical and immunochemical methods, including peptide mapping, specific co-immunoprecipitation and confocal fluorescence microscopy. These results support a working hypothesis that a late viral protein HPV16 L1, which is down regulated by hnRNP H early in the viral life cycle may provide an auto-regulatory positive feedback loop that allows the rapid production of HPV capsid proteins through suppression of the function of hnRNP H at the late stage of the viral life cycle. In this positive feedback loop, the late viral gene products that were down regulated earlier themselves disable their suppressors, and this feedback mechanism could facilitate the rapid production of capsid proteins, allowing staged and efficient viral capsid assembly.

  2. CEP genes regulate root and shoot development in response to environmental cues and are specific to seed plants.

    Science.gov (United States)

    Delay, Christina; Imin, Nijat; Djordjevic, Michael A

    2013-12-01

    The manifestation of repetitive developmental programmes during plant growth can be adjusted in response to various environmental cues. During root development, this means being able to precisely control root growth and lateral root development. Small signalling peptides have been found to play roles in many aspects of root development. One member of the CEP (C-TERMINALLY ENCODED PEPTIDE) gene family has been shown to arrest root growth. Here we report that CEP genes are widespread among seed plants but are not present in land plants that lack true branching roots or root vasculature. We have identified 10 additional CEP genes in Arabidopsis. Expression analysis revealed that CEP genes are regulated by environmental cues such as nitrogen limitation, increased salt levels, increased osmotic strength, and increased CO2 levels in both roots and shoots. Analysis of synthetic CEP variants showed that both peptide sequence and modifications of key amino acids affect CEP biological activity. Analysis of several CEP over-expression lines revealed distinct roles for CEP genes in root and shoot development. A cep3 knockout mutant showed increased root and shoot growth under a range of abiotic stress, nutrient, and light conditions. We demonstrate that CEPs are negative regulators of root development, slowing primary root growth and reducing lateral root formation. We propose that CEPs are negative regulators that mediate environmental influences on plant development.

  3. Energy efficiency of housing for older citizens: Does it matter?

    International Nuclear Information System (INIS)

    Miller, Wendy; Vine, Desley; Amin, Zakaria

    2017-01-01

    Global population ageing has significant implications for public policy in areas such as health, housing and economic security. The notion of housing as a public health issue is not new, yet very little research has examined the links between housing specifically built for older people, energy performance and occupant health and economic security. Utilising a case study approach, this research examined the interplay between the energy efficiency of housing explicitly designed for this demographic, the thermal efficiency of their dwellings, and the impact on internal temperatures and monthly energy costs. The study shows that the thermal efficiency of the dwellings is not the same across all dwellings, impacting the internal temperatures experienced by the elderly occupants and their finances. This has implications for energy efficiency policy, policy governing the energy performance of buildings specifically designed for older people, as well as the mandatory disclosure of building performance. The study highlights in particular the need for energy policy to be further refined to link the thermal performance requirements of buildings to the broader health care plan and specific needs of older people. - Highlights: • Housing quality impacts on the health and economic wellbeing of older people. • This demographic can have limited capacity to manage and pay for thermal comfort. • Building thermal performance is not disclosed or linked to occupants' health care. • Energy and health policies need to be much more closely aligned. • This can be through building regulations, mandatory disclosure and heat wave plans.

  4. Health-Care Costs, Glycemic Control and Nutritional Status in Malnourished Older Diabetics Treated with a Hypercaloric Diabetes-Specific Enteral Nutritional Formula.

    Science.gov (United States)

    Sanz-Paris, Alejandro; Boj-Carceller, Diana; Lardies-Sanchez, Beatriz; Perez-Fernandez, Leticia; Cruz-Jentoft, Alfonso J

    2016-03-09

    Diabetes-specific formulas are an effective alternative for providing nutrients and maintaining glycemic control. This study assesses the effect of treatment with an oral enteral nutrition with a hypercaloric diabetes-specific formula (HDSF) for one year, on health-care resources use, health-care costs, glucose control and nutritional status, in 93 type-2 diabetes mellitus (T2DM) malnourished patients. Changes in health-care resources use and health-care costs were collected the year before and during the year of intervention. Glucose status and nutritional laboratory parameters were analyzed at baseline and one-year after the administration of HDSF. The administration of HDSF was significantly associated with a reduced use of health-care resources, fewer hospital admissions (54.7%; p Health-care costs were reduced by 65.6% (p nutritional parameters were improved at one year (albumin: +10.6%, p nutritional parameters. The use of health-care resources and costs were significantly reduced during the nutritional intervention.

  5. Self-regulation following prostatectomy : Phase-specific self-efficacy beliefs in implementing pelvic-floor exercise

    OpenAIRE

    Burkert, Silke; Knoll, Nina; Scholz, Urte; Roigas, Jan; Gralla, Oliver

    2012-01-01

    Beliefs in one's ability to perform a task or behaviour successfully are described as self-efficacy beliefs (Bandura, 1977). Since individuals have to deal with differing demands during a behaviour-change process, they form phase-specific self-efficacy beliefs directed at these respective challenges. The present study, based on the Health Action Process Approach (Schwarzer, 2001), examines the theoretical differentiation, relative importance, and differential effects of four phase-specific se...

  6. SIRT1 Regulates Thyroid-Stimulating Hormone Release by Enhancing PIP5Kgamma Activity through Deacetylation of Specific Lysine Residues in Mammals.

    Directory of Open Access Journals (Sweden)

    Sayaka Akieda-Asai

    Full Text Available BACKGROUND: SIRT1, a NAD-dependent deacetylase, has diverse roles in a variety of organs such as regulation of endocrine function and metabolism. However, it remains to be addressed how it regulates hormone release there. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that SIRT1 is abundantly expressed in pituitary thyrotropes and regulates thyroid hormone secretion. Manipulation of SIRT1 level revealed that SIRT1 positively regulated the exocytosis of TSH-containing granules. Using LC/MS-based interactomics, phosphatidylinositol-4-phosphate 5-kinase (PIP5Kgamma was identified as a SIRT1 binding partner and deacetylation substrate. SIRT1 deacetylated two specific lysine residues (K265/K268 in PIP5Kgamma and enhanced PIP5Kgamma enzyme activity. SIRT1-mediated TSH secretion was abolished by PIP5Kgamma knockdown. SIRT1 knockdown decreased the levels of deacetylated PIP5Kgamma, PI(4,5P(2, and reduced the secretion of TSH from pituitary cells. These results were also observed in SIRT1-knockout mice. CONCLUSIONS/SIGNIFICANCE: Our findings indicated that the control of TSH release by the SIRT1-PIP5Kgamma pathway is important for regulating the metabolism of the whole body.

  7. The Arabidopsis TOR Kinase Specifically Regulates the Expression of Nuclear Genes Coding for Plastidic Ribosomal Proteins and the Phosphorylation of the Cytosolic Ribosomal Protein S6.

    Science.gov (United States)

    Dobrenel, Thomas; Mancera-Martínez, Eder; Forzani, Céline; Azzopardi, Marianne; Davanture, Marlène; Moreau, Manon; Schepetilnikov, Mikhail; Chicher, Johana; Langella, Olivier; Zivy, Michel; Robaglia, Christophe; Ryabova, Lyubov A; Hanson, Johannes; Meyer, Christian

    2016-01-01

    Protein translation is an energy consuming process that has to be fine-tuned at both the cell and organism levels to match the availability of resources. The target of rapamycin kinase (TOR) is a key regulator of a large range of biological processes in response to environmental cues. In this study, we have investigated the effects of TOR inactivation on the expression and regulation of Arabidopsis ribosomal proteins at different levels of analysis, namely from transcriptomic to phosphoproteomic. TOR inactivation resulted in a coordinated down-regulation of the transcription and translation of nuclear-encoded mRNAs coding for plastidic ribosomal proteins, which could explain the chlorotic phenotype of the TOR silenced plants. We have identified in the 5' untranslated regions (UTRs) of this set of genes a conserved sequence related to the 5' terminal oligopyrimidine motif, which is known to confer translational regulation by the TOR kinase in other eukaryotes. Furthermore, the phosphoproteomic analysis of the ribosomal fraction following TOR inactivation revealed a lower phosphorylation of the conserved Ser240 residue in the C-terminal region of the 40S ribosomal protein S6 (RPS6). These results were confirmed by Western blot analysis using an antibody that specifically recognizes phosphorylated Ser240 in RPS6. Finally, this antibody was used to follow TOR activity in plants. Our results thus uncover a multi-level regulation of plant ribosomal genes and proteins by the TOR kinase.

  8. The C. elegans tailless/Tlx homolog nhr-67 regulates a stage-specific program of linker cell migration in male gonadogenesis.

    Science.gov (United States)

    Kato, Mihoko; Sternberg, Paul W

    2009-12-01

    Cell migration is a common event during organogenesis, yet little is known about how migration is temporally coordinated with organ development. We are investigating stage-specific programs of cell migration using the linker cell (LC), a migratory cell crucial for male gonadogenesis of C. elegans. During the L3 and L4 larval stages of wild-type males, the LC undergoes changes in its position along the migratory route, in transcriptional regulation of the unc-5 netrin receptor and zmp-1 zinc matrix metalloprotease, and in cell morphology. We have identified the tailless homolog nhr-67 as a cell-autonomous, stage-specific regulator of timing in LC migration programs. In nhr-67-deficient animals, each of the L3 and L4 stage changes is either severely delayed or never occurs, yet LC development before the early L3 stage or after the mid-L4 stage occurs with normal timing. We propose that there is a basal migration program utilized throughout LC migration that is modified by stage-specific regulators such as nhr-67.

  9. Advisory Material for the IAEA Regulations for the Safe Transport of Radioactive Material (2012 Ed.). Specific Safety Guide

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2014-06-15

    This Safety Guide provides recommendations and guidance on achieving and demonstrating compliance with IAEA Safety Standards Series No. SSR-6, Regulations for the Safe Transport of Radioactive Material (2012 Edition), which establishes the requirements to be applied to the national and international transport of radioactive material. Transport is deemed to comprise all operations and conditions associated with and involved in the movement of radioactive material, including the design, fabrication and maintenance of packaging, and the preparation, consigning, handling, carriage, storage in transit and receipt at the final destination of packages. This publication supersedes IAEA Safety Standards Series No. TS-G-1.1 Rev. 1, which was issued in 2008.

  10. Co-expression of the transcription factors CEH-14 and TTX-1 regulates AFD neuron-specific genes gcy-8 and gcy-18 in C. elegans.

    Science.gov (United States)

    Kagoshima, Hiroshi; Kohara, Yuji

    2015-03-15

    A wide variety of cells are generated by the expression of characteristic sets of genes, primarily those regulated by cell-specific transcription. To elucidate the mechanism regulating cell-specific gene expression in a highly specialized cell, AFD thermosensory neuron in Caenorhabditis elegans, we analyzed the promoter sequences of guanylyl cyclase genes, gcy-8 and gcy-18, exclusively expressed in AFD. In this study, we showed that AFD-specific expression of gcy-8 and gcy-18 requires the co-expression of homeodomain proteins, CEH-14/LHX3 and TTX-1/OTX1. We observed that mutation of ttx-1 or ceh-14 caused a reduction in the expression of gcy-8 and gcy-18 and that the expression was completely lost in double mutants. This synergy effect was also observed with other AFD marker genes, such as ntc-1, nlp-21and cng-3. Electrophoretic mobility shift assays revealed direct interaction of CEH-14 and TTX-1 proteins with gcy-8 and gcy-18 promoters in vitro. The binding sites of CEH-14 and TTX-1 proteins were confirmed to be essential for AFD-specific expression of gcy-8 and gcy-18 in vivo. We also demonstrated that forced expression of CEH-14 and TTX-1 in AWB chemosensory neurons induced ectopic expression of gcy-8 and gcy-18 reporters in this neuron. Finally, we showed that the regulation of gcy-8 and gcy-18 expression by ceh-14 and ttx-1 is evolutionally conserved in five Caenorhabditis species. Taken together, ceh-14 and ttx-1 expression determines the fate of AFD as terminal selector genes at the final step of cell specification. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Two genes with similarity to bacterial response regulators are rapidly and specifically induced by cytokinin in Arabidopsis

    Science.gov (United States)

    Brandstatter, I.; Kieber, J. J.; Evans, M. L. (Principal Investigator)

    1998-01-01

    Cytokinins are central regulators of plant growth and development, but little is known about their mode of action. By using differential display, we identified a gene, IBC6 (for induced by cytokinin), from etiolated Arabidopsis seedlings, that is induced rapidly by cytokinin. The steady state level of IBC6 mRNA was elevated within 10 min by the exogenous application of cytokinin, and this induction did not require de novo protein synthesis. IBC6 was not induced by other plant hormones or by light. A second Arabidopsis gene with a sequence highly similar to IBC6 was identified. This IBC7 gene also was induced by cytokinin, although with somewhat slower kinetics and to a lesser extent. The pattern of expression of the two genes was similar, with higher expression in leaves, rachises, and flowers and lower transcript levels in roots and siliques. Sequence analysis revealed that IBC6 and IBC7 are similar to the receiver domain of bacterial two-component response regulators. This homology, coupled with previously published work on the CKI1 histidine kinase homolog, suggests that these proteins may play a role in early cytokinin signaling.

  12. Clustering of Tissue-Specific Sub-TADs Accompanies the Regulation of HoxA Genes in Developing Limbs

    Science.gov (United States)

    Berlivet, Soizik; Paquette, Denis; Dumouchel, Annie; Langlais, David; Dostie, Josée; Kmita, Marie

    2013-01-01

    HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet “DNA loops”. Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in vertebrates. PMID:24385922

  13. Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs.

    Directory of Open Access Journals (Sweden)

    Soizik Berlivet

    Full Text Available HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs. We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet "DNA loops". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in vertebrates.

  14. Specific down-regulation of spermatogenesis genes targeted by 22G RNAs in hybrid sterile males associated with an X-Chromosome introgression.

    Science.gov (United States)

    Li, Runsheng; Ren, Xiaoliang; Bi, Yu; Ho, Vincy Wing Sze; Hsieh, Chia-Ling; Young, Amanda; Zhang, Zhihong; Lin, Tingting; Zhao, Yanmei; Miao, Long; Sarkies, Peter; Zhao, Zhongying

    2016-09-01

    Hybrid incompatibility (HI) prevents gene flow between species, thus lying at the heart of speciation genetics. One of the most common HIs is male sterility. Two superficially contradictory observations exist for hybrid male sterility. First, an introgression on the X Chromosome is more likely to produce male sterility than on autosome (so-called large-X theory); second, spermatogenesis genes are enriched on the autosomes but depleted on the X Chromosome (demasculinization of X Chromosome). Analysis of gene expression in Drosophila hybrids suggests a genetic interaction between the X Chromosome and autosomes that is essential for male fertility. However, the prevalence of such an interaction and its underlying mechanism remain largely unknown. Here we examine the interaction in nematode species by contrasting the expression of both coding genes and transposable elements (TEs) between hybrid sterile males and its parental nematode males. We use two lines of hybrid sterile males, each carrying an independent introgression fragment from Caenorhabditis briggsae X Chromosome in an otherwise Caenorhabditis nigoni background, which demonstrate similar defects in spermatogenesis. We observe a similar pattern of down-regulated genes that are specific for spermatogenesis between the two hybrids. Importantly, the down-regulated genes caused by the X Chromosome introgressions show a significant enrichment on the autosomes, supporting an epistatic interaction between the X Chromosome and autosomes. We investigate the underlying mechanism of the interaction by measuring small RNAs and find that a subset of 22G RNAs specifically targeting the down-regulated spermatogenesis genes is significantly up-regulated in hybrids, suggesting that perturbation of small RNA-mediated regulation may contribute to the X-autosome interaction. © 2016 Li et al.; Published by Cold Spring Harbor Laboratory Press.

  15. Fitness-Specific Epistemic Beliefs, Effort Regulation, Outcomes, and Indices of Motivation in High School Physical Education

    Science.gov (United States)

    Lodewyk, Ken R.; Gao, Zan

    2013-01-01

    Epistemic beliefs are deeply held convictions about the nature of knowledge, knowing, and learning. In this study, approximately 500 ninth and tenth-grade physical education (PE) students completed fitness-specific measures assessing their epistemic beliefs in the simplicity and stability of knowledge and the speed of its acquisition along with…

  16. Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain.

    Science.gov (United States)

    Lindefors, N; Brene, S; Herrera-Marschitz, M; Persson, H

    1989-01-01

    In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudate-putamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.

  17. Dexamethasone up-regulates skeletal muscle maximal Na+,K+ pump activity by muscle group specific mechanisms in humans

    DEFF Research Database (Denmark)

    Nordsborg, Nikolai; Goodmann, Craig; McKenna, Michael J.

    2005-01-01

    Dexamethasone, a widely clinically used glucocorticoid, increases human skeletal muscle Na+,K+ pump content, but the effects on maximal Na+,K+ pump activity and subunit specific mRNA are unknown. Ten healthy male subjects ingested dexamethasone for 5 days and the effects on Na+,K+ pump content......, maximal activity and subunit specific mRNA level (a1, a2, ß1, ß2, ß3) in deltoid and vastus lateralis muscle were investigated. Before treatment, maximal Na+,K+ pump activity, as well as a1, a2, ß1 and ß2 mRNA levels were higher (P ... increased Na+,K+ pump maximal activity in vastus lateralis and deltoid by 14 ± 7% (P Na+,K+ pump content by 18 ± 9% (P

  18. Interaction of hepatocyte nuclear factors in transcriptional regulation of tissue specific hormonal expression of human multidrug resistance-associated protein 2 (abcc2)

    International Nuclear Information System (INIS)

    Qadri, Ishtiaq; Hu, L.-J.; Iwahashi, Mieko; Al-Zuabi, Subhi; Quattrochi, Linda C.; Simon, Francis R.

    2009-01-01

    Multidrug resistance-associated protein 2 (MRP2) (ABCC2) is an ATP-binding cassette membrane protein located primarily on apical surface of hepatocytes that mediates transport of conjugated xenobiotics and endogenous compounds into bile. MRP2 is highly expressed in hepatocytes, and at lower levels in small intestines, stomach and kidney. Previous reports have characterized mammalian MRP2 promoters, but none have established the molecular mechanism(s) involved in liver enriched expression. This study aims to investigate the mechanism of hepatic MRP2 regulation. A 2130 bp of MRP2 promoter was cloned from PAC-1 clone P108G1-7, to identify putative liver specific/hormone responsive functional DNA binding sites. Using deletion analysis, site specific mutagenesis and co-transfection studies, liver specific expression was determined. MRP2 promoter-LUC constructs were highly expressed in liver cell lines compared to non-liver cells. The region extending from - 3 to+ 458 bp of MRP2 promoter starting from AUG contained the potential binding sites for CAAATT box enhancer binding protein (C/EBP), hepatocytes nuclear factor 1, 3 and 4 (HNF1, HNF3, and HNF4. Only HNF1 and HNF4 co-transfection with MRP2 luciferase increased expression. Site specific mutational analysis of HNF1 binding site indicated an important role for HNF1α. HNF4α induction of MRP2 was independent of HNF1 binding site. C/EBP, HNF3, and HNF6 inhibited HNF1α while HNF4α induced MRP2 luciferase expression and glucocorticoids stimulated MRP2 expression. This study emphasizes the complex regulation of MRP2 with HNF1α and HNF4α playing a central role. The coordinated regulation of xenobiotic transporters and oxidative conjugation may determine the adaptive responses to cellular detoxification processes

  19. A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.

    Science.gov (United States)

    Chen, Wei; Zhang, Xiaoting; Birsoy, Kivanc; Roeder, Robert G

    2010-06-01

    As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.

  20. Mechanisms of dietary response in mice and primates: a role for EGR1 in regulating the reaction to human-specific nutritional content.

    Directory of Open Access Journals (Sweden)

    Kai Weng

    Full Text Available Humans have a widely different diet from other primate species, and are dependent on its high nutritional content. The molecular mechanisms responsible for adaptation to the human diet are currently unknown. Here, we addressed this question by investigating whether the gene expression response observed in mice fed human and chimpanzee diets involves the same regulatory mechanisms as expression differences between humans and chimpanzees.Using mouse and primate transcriptomic data, we identified the transcription factor EGR1 (early growth response 1 as a putative regulator of diet-related differential gene expression between human and chimpanzee livers. Specifically, we predict that EGR1 regulates the response to the high caloric content of human diets. However, we also show that close to 90% of the dietary response to the primate diet found in mice, is not observed in primates. This might be explained by changes in tissue-specific gene expression between taxa.Our results suggest that the gene expression response to the nutritionally rich human diet is partially mediated by the transcription factor EGR1. While this EGR1-driven response is conserved between mice and primates, the bulk of the mouse response to human and chimpanzee dietary differences is not observed in primates. This result highlights the rapid evolution of diet-related expression regulation and underscores potential limitations of mouse models in dietary studies.

  1. Stage-specific regulation of four HD-ZIP III transcription factors during polar pattern formation in Larix leptolepis somatic embryos.

    Science.gov (United States)

    Li, Shui-gen; Li, Wan-feng; Han, Su-ying; Yang, Wen-hua; Qi, Li-wang

    2013-06-15

    Polar auxin transport provides a developmental signal for cell fate specification during somatic embryogenesis. Some members of the HD-ZIP III transcription factors participate in regulation of auxin transport, but little is known about this regulation in somatic embryogenesis. Here, four HD-ZIP III homologues from Larix leptolepis were identified and designated LaHDZ31, 32, 33 and 34. The occurrence of a miR165/166 target sequence in all four cDNA sequences indicated that they might be targets of miR165/166. Identification of the cleavage products of LaHDZ31 and LaHDZ32 in vivo confirmed that they were regulated by miRNA. Their mRNA accumulation patterns during somatic embryogenesis and the effects of 1-N-naphthylphthalamic acid (NPA) on their transcript levels and somatic embryo maturation were investigated. The results showed that the four genes had higher transcript levels at mature stages than at the proliferation stage, and that NPA treatment down-regulated the mRNA abundance of LaHDZ31, 32 and 33 at cotyledonary embryo stages, but had no effect on the mRNA abundance of LaHDZ34. We concluded that these four members of Larix HD-ZIP III family might participate in polar auxin transport and the development of somatic embryos, providing new insights into the regulatory mechanisms of somatic embryogenesis. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation

    OpenAIRE

    Dorado, Beatriz; Area, Estela; Akman, Hasan O.; Hirano, Michio

    2010-01-01

    Deficiency of thymidine kinase 2 (TK2) is a frequent cause of isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases of disease onset, organ specificity and severity of TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2−/−). Although normal until postnatal day 8, Tk2−/− mice rapidly develop fatal encephalomyopathy between postnatal days 10 and 13. We have observed that wild-type Tk2 activity is constant in t...

  3. The NKG2D ligand ULBP2 is specifically regulated through an invariant chain-dependent endosomal pathway

    DEFF Research Database (Denmark)

    Uhlenbrock, Franziska Katharina; Hagemann-Jensen, Michael Henrik; Kehlet, Stephanie

    2014-01-01

    by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties....... The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest...

  4. TGF-b and a specific TGF-b inhibitor regulate pericentrin B and MYH9 in glioma cell lines

    Directory of Open Access Journals (Sweden)

    Óscar Álzate

    2006-01-01

    Full Text Available Malignant gliomas are heterogeneous, highly invasive vascular tumours. The multifunctional cytokine, transforming growth factor-beta (TGF-P, is expressed by grade III/IV gliomas and promotes tumour angiogenesis, invasión and immune escape. It has been shown previously that a small TGF-P receptor type I (TGF-(3-RI molecule inhibitor (SB-431542 blocks TGF-(3-mediated signal transduction, induction of angiogenic factor expression and cellular motility. As glioma cell lines display differential sensitivity to TGF-P, it was expected that they would also be differentially impacted by disruption of TGF-P signalling. Differential in gel expression (DIGE analysis and mass spectrometry was used in this work for determining protein regulation effects of both TGF-P and SB-431542 on human glioma cell lines. It was found that pericentrin B and non muscle myosin were differentially expressed in fragments which likely resulted from protease activation by the tumour growth mechanism. These results suggest that both pericentrin B and non-muscle myosin might be potential glioma biomarkers. Key words: DIGE, proteomics, glioma, TGF-P, mass spectrometry, non muscle myosin, pericentrin B.

  5. Effects of chronic exposure to tributyltin on tissue-specific cytochrome P450 1 regulation in juvenile common carp.

    Science.gov (United States)

    Li, Zhi-Hua; Zhong, Li-Qiao; Mu, Wei-Na; Wu, Yan-Hua

    2016-01-01

    1. The purpose of this study was to compare tributyltin (TBT)-induced cytochrome P450 1 (CYP450 1) regulation in liver, gills and muscle of juvenile common carp (Cyprinus carpio). 2. Fish were exposed to sublethal concentrations of TBT (75, 0.75 and 7.5 μg/L) for 60 days. CYP450 1A was measured at the enzyme activity level as 7-ethoxyresorufin-O-deethylase (EROD) activity, as well as the mRNA expression of CYP450 1 family genes (CYP1A, CYP1B, CYP1C1 and CYP1C2) in fish tissues. 3. Based on the results, the liver displayed the highest absolute levels of EROD activity, both under nonexposed and exposed conditions. Additional, EROD activities and CYP1A gene levels showed a good correlation in all three organs. According to the mRNA expression of CYP450 1 family genes, it suggested that CYP1A was to accommodate most EROD activity in fish, but other CYP450 forms also involved in this proceeding. 4. Overall, the study revealed both similarities and differences in the concentration-dependent CYP450 1 responses of the three target organs, which could provide useful information to better understand the mechanisms of TBT-induced bio-toxicity.

  6. NHE10, a novel osteoclast-specific member of the Na+/H+ exchanger family, regulates osteoclast differentiation and survival

    International Nuclear Information System (INIS)

    Lee, Seoung Hoon; Kim, Taesoo; Park, Eui-Soon; Yang, Sujeong; Jeong, Daewon; Choi, Yongwon; Rho, Jaerang

    2008-01-01

    Bone homeostasis is tightly regulated by the balanced actions of osteoblasts (OBs) and osteoclasts (OCs). We previously analyzed the gene expression profile of OC differentiation using a cDNA microarray, and identified a novel osteoclastogenic gene candidate, clone OCL-1-E7 [J. Rho, C.R. Altmann, N.D. Socci, L. Merkov, N. Kim, H. So, O. Lee, M. Takami, A.H. Brivanlou, Y. Choi, Gene expression profiling of osteoclast differentiation by combined suppression subtractive hybridization (SSH) and cDNA microarray analysis, DNA Cell Biol. 21 (2002) 541-549]. In this study, we have isolated full-length cDNAs corresponding to this clone from mice and humans to determine the functional roles of this gene in osteoclastogenesis. The full-length cDNA of OCL-1-E7 encodes 12 membrane-spanning domains that are typical of isoforms of the Na + /H + exchangers (NHEs), indicating that this clone is a novel member of the NHE family (hereafter referred to as NHE10). Here, we show that NHE10 is highly expressed in OCs in response to receptor activator of nuclear factor-κB ligand signaling and is required for OC differentiation and survival

  7. Insights into inner ear-specific gene regulation: epigenetics and non-coding RNAs in inner ear development and regeneration

    Science.gov (United States)

    Avraham, Karen B.

    2016-01-01

    The vertebrate inner ear houses highly specialized sensory organs, tuned to detect and encode sound, head motion and gravity. Gene expression programs under the control of transcription factors orchestrate the formation and specialization of the non-sensory inner ear labyrinth and its sensory constituents. More recently, epigenetic factors and non-coding RNAs emerged as an additional layer of gene regulation, both in inner ear development and disease. In this review, we provide an overview on how epigenetic modifications and non-coding RNAs, in particular microRNAs (miRNAs), influence gene expression and summarize recent discoveries that highlight their critical role in the proper formation of the inner ear labyrinth and its sensory organs. In contrast to non-mammalian vertebrates, adult mammals lack the ability to regenerate inner ear mechano-sensory hair cells. Finally, we discuss recent insights into how epigenetic factors and miRNAs may facilitate, or in the case of mammals, restrict sensory hair cell regeneration. PMID:27836639

  8. Monorail/Foxa2 regulates floorplate differentiation and specification of oligodendrocytes, serotonergic raphé neurones and cranial motoneurones.

    Science.gov (United States)

    Norton, Will H; Mangoli, Maryam; Lele, Zsolt; Pogoda, Hans-Martin; Diamond, Brianne; Mercurio, Sara; Russell, Claire; Teraoka, Hiroki; Stickney, Heather L; Rauch, Gerd-Jörg; Heisenberg, Carl-Philipp; Houart, Corinne; Schilling, Thomas F; Frohnhoefer, Hans-Georg; Rastegar, Sepand; Neumann, Carl J; Gardiner, R Mark; Strähle, Uwe; Geisler, Robert; Rees, Michelle; Talbot, William S; Wilson, Stephen W

    2005-02-01

    In this study, we elucidate the roles of the winged-helix transcription factor Foxa2 in ventral CNS development in zebrafish. Through cloning of monorail (mol), which we find encodes the transcription factor Foxa2, and phenotypic analysis of mol-/- embryos, we show that floorplate is induced in the absence of Foxa2 function but fails to further differentiate. In mol-/- mutants, expression of Foxa and Hh family genes is not maintained in floorplate cells and lateral expansion of the floorplate fails to occur. Our results suggest that this is due to defects both in the regulation of Hh activity in medial floorplate cells as well as cell-autonomous requirements for Foxa2 in the prospective laterally positioned floorplate cells themselves. Foxa2 is also required for induction and/or patterning of several distinct cell types in the ventral CNS. Serotonergic neurones of the raphenucleus and the trochlear motor nucleus are absent in mol-/- embryos, and oculomotor and facial motoneurones ectopically occupy ventral CNS midline positions in the midbrain and hindbrain. There is also a severe reduction of prospective oligodendrocytes in the midbrain and hindbrain. Finally, in the absence of Foxa2, at least two likely Hh pathway target genes are ectopically expressed in more dorsal regions of the midbrain and hindbrain ventricular neuroepithelium, raising the possibility that Foxa2 activity may normally be required to limit the range of action of secreted Hh proteins.

  9. Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation

    Science.gov (United States)

    Tokunaga, Fuminori; Nishimasu, Hiroshi; Ishitani, Ryuichiro; Goto, Eiji; Noguchi, Takuya; Mio, Kazuhiro; Kamei, Kiyoko; Ma, Averil; Iwai, Kazuhiro; Nureki, Osamu

    2012-01-01

    LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-κB pathway through linear polyubiquitination of NEMO (NF-κB essential modulator, also known as IKKγ) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-κB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70–1.98 Å resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IκB kinase (IKK), which results in NF-κB suppression. These findings provide new insight into the regulation of immune and inflammatory responses. PMID:23032187

  10. Taxon-specific metagenomics of Trichoderma reveals a narrow community of opportunistic species that regulate each other’s development

    Science.gov (United States)

    Friedl, Martina A.

    2012-01-01

    In this paper, we report on the in situ diversity of the mycotrophic fungus Trichoderma (teleomorph Hypocrea, Ascomycota, Dikarya) revealed by a taxon-specific metagenomic approach. We designed a set of genus-specific internal transcribed spacer (ITS)1 and ITS2 rRNA primers and constructed a clone library containing 411 molecular operational taxonomic units (MOTUs). The overall species composition in the soil of the two distinct ecosystems in the Danube floodplain consisted of 15 known species and two potentially novel taxa. The latter taxa accounted for only 1.5 % of all MOTUs, suggesting that almost no hidden or uncultivable Hypocrea/Trichoderma species are present at least in these temperate forest soils. The species were unevenly distributed in vertical soil profiles although no universal factors controlling the distribution of all of them (chemical soil properties, vegetation type and affinity to rhizosphere) were revealed. In vitro experiments simulating infrageneric interactions between the pairs of species that were detected in the same soil horizon showed a broad spectrum of reactions from very strong competition over neutral coexistence to the pronounced synergism. Our data suggest that only a relatively small portion of Hypocrea/Trichoderma species is adapted to soil as a habitat and that the interaction between these species should be considered in a screening for Hypocrea/Trichoderma as an agent(s) of biological control of pests. PMID:22075025

  11. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Carl Owen

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B, a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B(-/- were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B(-/- mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD-fed adip-crePTP1B(-/- mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.

  12. DYRK1A (Dual-Specificity Tyrosine-Phosphorylated and -Regulated Kinase 1A: A Gene with Dosage Effect During Development and Neurogenesis

    Directory of Open Access Journals (Sweden)

    M. Dierssen

    2006-01-01

    Full Text Available DYRKs (dual-specificity tyrosine-regulated kinases are an emerging family of evolutionarily conserved dual-specificity kinases that play key roles in cell proliferation, survival, and development. The research in the last years suggests a relevant conserved function during neuronal development, related to proliferation and/or differentiation for DYRK1A. It is expressed in neural progenitor cells and has been proposed to participate in the signaling mechanisms that regulate dendrite differentiation. In Drosophila, disruption of the homolog minibrain gene results in flies with reduced neuroblast proliferation, decreased numbers of central brain neurons, and learning/memory deficits. Knockout DYRK1A mice are embryonic lethal, and heterozygotes show decreased viability and region-specific reductions in brain size. In humans, DYRK1A has been proposed to be involved in the neurodevelopmental alterations associated with Down syndrome. The large number of protein interaction and putative substrates described for DYRK1A suggest multiple pathways and functions to be involved in its developmental function. This review focuses on the functional role that DYRK1A plays in brain development.

  13. The translation initiation factor eIF4E regulates the sex-specific expression of the master switch gene Sxl in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Patricia L Graham

    2011-07-01

    Full Text Available In female fruit flies, Sex-lethal (Sxl turns off the X chromosome dosage compensation system by a mechanism involving a combination of alternative splicing and translational repression of the male specific lethal-2 (msl-2 mRNA. A genetic screen identified the translation initiation factor eif4e as a gene that acts together with Sxl to repress expression of the Msl-2 protein. However, eif4e is not required for Sxl mediated repression of msl-2 mRNA translation. Instead, eif4e functions as a co-factor in Sxl-dependent female-specific alternative splicing of msl-2 and also Sxl pre-mRNAs. Like other factors required for Sxl regulation of splicing, eif4e shows maternal-effect female-lethal interactions with Sxl. This female lethality can be enhanced by mutations in other co-factors that promote female-specific splicing and is caused by a failure to properly activate the Sxl-positive autoregulatory feedback loop in early embryos. In this feedback loop Sxl proteins promote their own synthesis by directing the female-specific alternative splicing of Sxl-Pm pre-mRNAs. Analysis of pre-mRNA splicing when eif4e activity is compromised demonstrates that Sxl-dependent female-specific splicing of both Sxl-Pm and msl-2 pre-mRNAs requires eif4e activity. Consistent with a direct involvement in Sxl-dependent alternative splicing, eIF4E is associated with unspliced Sxl-Pm pre-mRNAs and is found in complexes that contain early acting splicing factors--the U1/U2 snRNP protein Sans-fils (Snf, the U1 snRNP protein U1-70k, U2AF38, U2AF50, and the Wilms' Tumor 1 Associated Protein Fl(2d--that have been directly implicated in Sxl splicing regulation.

  14. Regulation of Alcohol Extinction and Cue-Induced Reinstatement by Specific Projections among Medial Prefrontal Cortex, Nucleus Accumbens, and Basolateral Amygdala.

    Science.gov (United States)

    Keistler, Colby R; Hammarlund, Emma; Barker, Jacqueline M; Bond, Colin W; DiLeone, Ralph J; Pittenger, Christopher; Taylor, Jane R

    2017-04-26

    The ability to inhibit drinking is a significant challenge for recovering alcoholics, especially in the presence of alcohol-associated cues. Previous studies have demonstrated that the regulation of cue-guided alcohol seeking is mediated by the basolateral amygdala (BLA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC). However, given the high interconnectivity between these structures, it is unclear how mPFC projections to each subcortical structure, as well as projections between BLA and NAc, mediate alcohol-seeking behaviors. Here, we evaluate how cortico-striatal, cortico-amygdalar, and amygdalo-striatal projections control extinction and relapse in a rat model of alcohol seeking. Specifically, we used a combinatorial viral technique to express diphtheria toxin receptors in specific neuron populations based on their projection targets. We then used this strategy to create directionally selective ablations of three distinct pathways after acquisition of ethanol self-administration but before extinction and reinstatement. We demonstrate that ablation of mPFC neurons projecting to NAc, but not BLA, blocks cue-induced reinstatement of alcohol seeking and neither pathway is necessary for extinction of responding. Further, we show that ablating BLA neurons that project to NAc disrupts extinction of alcohol approach behaviors and attenuates reinstatement. Together, these data provide evidence that the mPFC→NAc pathway is necessary for cue-induced reinstatement of alcohol seeking, expand our understanding of how the BLA→NAc pathway regulates alcohol behavior, and introduce a new methodology for the manipulation of target-specific neural projections. SIGNIFICANCE STATEMENT The vast majority of recovering alcoholics will relapse at least once and understanding how the brain regulates relapse will be key to developing more effective behavior and pharmacological therapies for alcoholism. Given the high interconnectivity of cortical, striatal, and limbic

  15. Mechanisms of isoform-specific Na/K pump regulation by short- and long-term adrenergic activation in rat ventricular myocytes.

    Science.gov (United States)

    Yin, Jian; Guo, Hui-Cai; Yu, Ding; Wang, Hui-Ci; Li, Jun-Xia; Wang, Yong-Li

    2014-01-01

    Many stressful conditions, including cardiovascular diseases, induce long-term elevations in circulating catecholamines, thereby leading to changes of the Na/K pump and thus affecting myocardial functions. However, only short-term adrenergic regulation of the Na/K pump has been reported. The present study is the first investigation of long-term adrenergic regulation of the Na/K pump and the potential mechanism. After acutely isolated Sprague-Dawley rat myocytes were incubated with noradrenaline or isoprenaline for 24 h, Na/K pump high- (IPH) and low-affinity current (IPL), α-isoform mRNA, and α-isoform protein were examined using patch-clamp, RT-PCR, and Western blotting techniques, respectively. After the short-term incubation, isoprenaline reduced the IPL through a PKA-dependent pathway that involves α1-isoform translocation from the membrane to early endosomes, and noradrenaline increased the IPH through a PKC-dependent pathway that involves α2-isoform translocation from late endosomes to the membrane. After long-term incubation, isoprenaline increased the IPL, α1-isoform mRNA, and α1-isoform protein, and noradrenaline reduced the IPH, α2-isoform mRNA, and α1-isoform protein through a PKA-or PKC-dependent pathway, respectively. These results suggest that long-term adrenergic Na/K pump regulation is isoform-specific and negatively feeds back on the short-term response. Furthermore, long-term regulation involves transcription and translation of the respective α-isoform, whereas short-term regulation involves the translocation of the available α-isoform to the plasma membrane. © 2014 S. Karger AG, Basel.

  16. Mechanisms of Isoform-Specific Na/K Pump Regulation by Short- and Long-Term Adrenergic Activation in Rat Ventricular Myocytes

    Directory of Open Access Journals (Sweden)

    Jian Yin

    2014-05-01

    Full Text Available Background: Many stressful conditions, including cardiovascular diseases, induce long-term elevations in circulating catecholamines, thereby leading to changes of the Na/K pump and thus affecting myocardial functions. However, only short-term adrenergic regulation of the Na/K pump has been reported. The present study is the first investigation of long-term adrenergic regulation of the Na/K pump and the potential mechanism. Methods: After acutely isolated Sprague-Dawley rat myocytes were incubated with noradrenaline or isoprenaline for 24 h, Na/K pump high- (IPH and low-affinity current (IPL, α-isoform mRNA, and α-isoform protein were examined using patch-clamp, RT-PCR, and Western blotting techniques, respectively. Results: After the short-term incubation, isoprenaline reduced the IPL through a PKA-dependent pathway that involves α1-isoform translocation from the membrane to early endosomes, and noradrenaline increased the IPH through a PKC-dependent pathway that involves α2-isoform translocation from late endosomes to the membrane. After long-term incubation, isoprenaline increased the IPL, α1-isoform mRNA, and α1-isoform protein, and noradrenaline reduced the IPH, α2-isoform mRNA, and α1-isoform protein through a PKA-or PKC-dependent pathway, respectively. Conclusions: These results suggest that long-term adrenergic Na/K pump regulation is isoform-specific and negatively feeds back on the short-term response. Furthermore, long-term regulation involves transcription and translation of the respective α-isoform, whereas short-term regulation involves the translocation of the available α-isoform to the plasma membrane.

  17. Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

    Science.gov (United States)

    Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

    2015-04-01

    Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Triptolide inhibits transcription of hTERT through down-regulation of transcription factor specificity protein 1 in primary effusion lymphoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Long, Cong; Wang, Jingchao [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 (China); Guo, Wei [Department of Pathology and Physiology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 (China); Wang, Huan; Wang, Chao; Liu, Yu [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 (China); Sun, Xiaoping, E-mail: xsun6@whu.edu.cn [Department of Pathogen Biology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071 (China); State Key Laboratory of Virology, Wuhan University, Wuhan, 430072 (China)

    2016-01-01

    Primary effusion lymphoma (PEL) is a rare and aggressive non-Hodgkin's lymphoma. Human telomerase reverse transcriptase (hTERT), a key component responsible for the regulation of telomerase activity, plays important roles in cellular immortalization and cancer development. Triptolide purified from Tripterygium extracts displays a broad-spectrum bioactivity profile, including immunosuppressive, anti-inflammatory, and anti-tumor. In this study, it is investigated whether triptolide reduces hTERT expression and suppresses its activity in PEL cells. The mRNA and protein levels of hTERT were examined by real time-PCR and Western blotting, respectively. The activity of hTERT promoter was determined by Dual luciferase reporter assay. Our results demonstrated that triptolide decreased expression of hTERT at both mRNA and protein levels. Further gene sequence analysis indicated that the activity of hTERT promoter was suppressed by triptolide. Triptolide also reduced the half-time of hTERT. Additionally, triptolide inhibited the expression of transcription factor specificity protein 1(Sp1) in PEL cells. Furthermore, knock-down of Sp1 by using specific shRNAs resulted in down-regulation of hTERT transcription and protein expression levels. Inhibition of Sp1 by specific shRNAs enhanced triptolide-induced cell growth inhibition and apoptosis. Collectively, our results demonstrate that the inhibitory effect of triptolide on hTERT transcription is possibly mediated by inhibition of transcription factor Sp1 in PEL cells. - Highlights: • Triptolide reduces expression of hTERT by decreasing its transcription level. • Triptolide reduces promoter activity and stability of hTERT. • Triptolide down-regulates expression of Sp1. • Special Sp1 shRNAs inhibit transcription and protein expression of hTERT. • Triptolide and Sp1 shRNA2 induce cell proliferation inhibition and apoptosis.

  19. Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation

    Directory of Open Access Journals (Sweden)

    Kamola Saydaminova

    Full Text Available Genome editing with site-specific endonucleases has implications for basic biomedical research as well as for gene therapy. We generated helper-dependent, capsid-modified adenovirus (HD-Ad5/35 vectors for zinc-finger nuclease (ZFN– or transcription activator-like effector nuclease (TALEN–mediated genome editing in human CD34+ hematopoietic stem cells (HSCs from mobilized adult donors. The production of these vectors required that ZFN and TALEN expression in HD-Ad5/35 producer 293-Cre cells was suppressed. To do this, we developed a microRNA (miRNA-based system for regulation of gene expression based on miRNA expression profiling of 293-Cre and CD34+ cells. Using miR-183-5p and miR-218-5p based regulation of transgene gene expression, we first produced an HD-Ad5/35 vector expressing a ZFN specific to the HIV coreceptor gene ccr5. We demonstrated that HD-Ad5/35.ZFNmiR vector conferred ccr5 knock out in primitive HSC (i.e., long-term culture initiating cells and NOD/SCID repopulating cells. The ccr5 gene disruption frequency achieved in engrafted HSCs found in the bone marrow of transplanted mice is clinically relevant for HIV therapy considering that these cells can give rise to multiple lineages, including all the lineages that represent targets and reservoirs for HIV. We produced a second HD-Ad5/35 vector expressing a TALEN targeting the DNase hypersensitivity region 2 (HS2 within the globin locus control region. This vector has potential for targeted gene correction in hemoglobinopathies. The miRNA regulated HD-Ad5/35 vector platform for expression of site-specific endonucleases has numerous advantages over currently used vectors as a tool for genome engineering of HSCs for therapeutic purposes.

  20. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

    DEFF Research Database (Denmark)

    Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb

    2016-01-01

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined...... with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell...... lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic...

  1. Sexuality in Older Adults (65+)

    DEFF Research Database (Denmark)

    Træen, Bente; Carvalheira, Ana; Kvalem, Ingela Lundin

    2017-01-01

    with their bodies than men, particularly in sexual contexts, older women appear to be less vulnerable to body-related dissatisfaction than younger women. Despite the age-specific dynamics of sexual satisfaction and sexual well-being, which parallel age-related decrease in the frequency of sexual activity, research...... findings from different countries show that substantial proportions of aging men and women are satisfied with their sex life. There is some limited evidence that this proportion may be increasing across cohorts. Gender differences in factors that influence sexual satisfaction among older adults appear...... marginal. Conclusion: Older age can affect sexual satisfaction on individual, interpersonal, and culture-related levels. Future research in older adults' sexuality should focus on sexual well-being in women who are without partners, sexual satisfaction among aging lesbian, gay, bisexual, and transgender...

  2. Older women, work and health.

    Science.gov (United States)

    Payne, S; Doyal, L

    2010-05-01

    Older women make up an increasingly important sector in the labour market. However, we know little about their health-the various influences on their health and the ways in which paid and unpaid work impact on both physical and mental well being. This paper reviews the available literature on older women's health in the workplace, focussing on work-specific and more general risks for older women, including stress, discrimination, physical hazards and the 'double burden' of paid work and caring responsibilities. Databases searched included Web of Science, CAS, CINAHL, Medline and ASSIA, together with UK and European statistical sources. We conclude with a three-point research agenda, calling for more empirical work on the risks faced by older women, studies that take a life-course perspective of women's occupational health and work that explores the interactions between unpaid and paid work in later life.

  3. Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)

    International Nuclear Information System (INIS)

    Oi, Ami; Katayama, Syouichi; Hatano, Naoya; Sugiyama, Yasunori; Kameshita, Isamu; Sueyoshi, Noriyuki

    2017-01-01

    Cyclin-dependent kinase-like 5 (CDKL5) is a Ser/Thr protein kinase primarily expressed in the central nervous system and is known to cause X-linked neurodevelopmental disorders such as Rett syndrome. However, the mechanisms regulating CDKL5 have not yet been fully clarified. Therefore, in this study, we investigated the protein kinase that directly phosphorylates CDKL5, identifying it as dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), an enzyme binding to and phosphorylating CDKL5. We showed that subcellular distribution of CDKL5 was regulated by its phosphorylation by DYRK1A. In mouse neuroblastoma Neuro2a cells, CDKL5 was localized in both the cytosol and nucleus, whereas DYRK1A showed a typical nuclear localization. When CDKL5 and DYRK1A were co-expressed, the cytosolic localization of CDKL5 was significantly increased. Results of site-directed mutagenesis revealed that the phosphorylation site was Ser-308, in the vicinity of the nuclear localization signal. A mutation mimicking the phosphorylated serine residue by aspartate substitution (S308D) changed CDKL5 localization to the cytosol, whereas the corresponding alanine-substituted analog, CDKL5(S308A), was primarily localized to the nucleus. Taken together, these results strongly suggested that DYRK1A bound to CDKL5 and phosphorylated it on Ser-308, thus interfering with its nuclear localization. - Highlights: • We investigated the mechanism regulating subcellular localization of CDKL5. • DYRK1A was identified as an enzyme that bound to and phosphorylated CDKL5. • The phosphorylation site of CDKL5 was Ser-308, in the vicinity of the NLS. • When DYRK1A was co-expressed, the cytosolic CDKL5 was significantly increased. • In conclusion, DYRK1A regulates CDKL5 localization via phosphorylation on Ser-308.

  4. Depression in Older Adults

    Science.gov (United States)

    ... here Home » Depression In Older Adults: More Facts Depression In Older Adults: More Facts Depression affects more ... combination of both. [8] Older Adult Attitudes Toward Depression: According to a Mental Health America survey [9] ...

  5. Cancer in Older Adults

    Science.gov (United States)

    ... Home > Navigating Cancer Care > For Older Adults For Older Adults A full-text transcript is available. More than ... Advanced Cancer For Children For Teens For Young Adults For Older Adults Aging and Cancer Cancer Care Decisions for ...

  6. Older Adults and Alcohol

    Science.gov (United States)

    ... Other Psychiatric Disorders Other Substance Abuse HIV/AIDS Older Adults A national 2008 survey found that about 40 ... of adults ages 65 and older drink alcohol. Older adults can experience a variety of problems from drinking ...

  7. Are treatment effects of neurofeedback training in children with ADHD related to the successful regulation of brain activity? A review on the learning of regulation of brain activity and a contribution to the discussion on specificity.

    Directory of Open Access Journals (Sweden)

    Agnieszka eZuberer

    2015-03-01

    Full Text Available While issues of efficacy and specificity are crucial for the future of neurofeedback training, there may be alternative designs and control analyses to circumvent the methodological and ethical problems associated with double-blind placebo studies. Surprisingly, most NF studies do not report the most immediate result of their NF training, i.e. whether or not children with ADHD gain control over their brain activity during the training sessions. For the investigation of specificity, however, it seems essential to analyze the learning and adaptation processes that take place in the course of the training and to relate improvements in self-regulated brain activity across training sessions to behavioral, neuropsychological and electrophysiological outcomes. To this aim, a review of studies on neurofeedback training with ADHD patients, which include the analysis of learning across training sessions or relate training performance to outcome, is presented. Methods on how to evaluate and quantify learning of EEG regulation over time are discussed. Non-learning has been reported in a small number of ADHD-studies, but has not been a focus of general methodological discussion so far. For this reason, selected results from the brain-computer interface (BCI research on the so-called brain-computer illiteracy, the inability to gain control over one’s brain activity, are also included. It is concluded that in the discussion on specificity, more attention should be devoted to the analysis of EEG regulation performance in the course of the training and its impact on clinical outcome. It is necessary to improve the knowledge on characteristic cross-session and within-session learning trajectories in ADHD and to provide the best conditions for learning.

  8. Scientific opinion on the safety of proline-specific oligopeptidase as a novel food pursuant to Regulation (EC) No 258/97

    DEFF Research Database (Denmark)

    Poulsen, Morten

    2017-01-01

    and of the Council, taking into account the comments and objections of a scientific nature raised by Member States. The novel food is an enzyme preparation of prolyl-oligopeptidase produced with a genetically modified Aspergillus niger self clone strain. The target population is the general adult population......Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on proline-specific oligopeptidase (Tolerase® G) as a novel food ingredient submitted pursuant to Regulation (EC) No 258/97 of the European Parliament...

  9. Relationships between serum Omentin-1 levels and bone mineral density in older men with osteoporosis

    Institute of Scientific and Technical Information of China (English)

    Li Yang; Xin-Lan Zhao; Bin Liao; Ai-Ping Qin

    2016-01-01

    Objective: To investigate the correlation between serum Omentin-1 levels and the presence of osteoporosis in older men. Methods: Serum Omentin-1, bone turnover biochemical markers, and bone mineral density (BMD) were determined in 45 older men with osteoporosis or 45 older men without osteoporosis (65e70 years old). Results: Omentin-1 levels were increased in older men with osteoporosis, and the differences remained significant after con-trolling for fat mass. Omentin-1 was negatively correlated with BMD. In a multiple linear stepwise regression analysis, Omentin-1, lean mass, but not fat mass, were independent predictors of BMD for the combined group. Significant negative correlations between Omentin-1 and bone-specific alkaline phosphatase (BAP) and bone cross-linked N-telopeptides of typeⅠcollagen (NTX) were found. Omentin-1 was also independently associated with BMD and bone turnover markers in older men with osteoporosis and control groups that were considered separately. Conclusions: Omentin-1 is an independent predictor of BMD in older men with osteoporosis, and it is negatively correlated with bone turnover biochemical markers. It is suggested that Omentin-1 may exert a negative effect on bone mass through the regulation of the osteoblast differentiation in the older men with osteoporosis.

  10. GAS REGULATION OF GALAXIES: THE EVOLUTION OF THE COSMIC SPECIFIC STAR FORMATION RATE, THE METALLICITY-MASS-STAR-FORMATION RATE RELATION, AND THE STELLAR CONTENT OF HALOS

    Energy Technology Data Exchange (ETDEWEB)

    Lilly, Simon J.; Carollo, C. Marcella; Pipino, Antonio; Peng Yingjie [Institute for Astronomy, Department of Physics, ETH Zurich, CH-8093 Zurich (Switzerland); Renzini, Alvio [Department of Physics and Astronomy Galileo Galilei, Universita degli Studi di Padova, via Marzolo 8, I-35131 Padova (Italy)

    2013-08-01

    A very simple physical model of galaxies is one in which the formation of stars is instantaneously regulated by the mass of gas in a reservoir with mass loss scaling with the star-formation rate (SFR). This model links together three different aspects of the evolving galaxy population: (1) the cosmic time evolution of the specific star-formation rate (sSFR) relative to the growth of halos, (2) the gas-phase metallicities across the galaxy population and over cosmic time, and (3) the ratio of the stellar to dark matter mass of halos. The gas regulator is defined by the gas consumption timescale ({epsilon}{sup -1}) and the mass loading {lambda} of the wind outflow {lambda}{center_dot}SFR. The simplest regulator, in which {epsilon} and {lambda} are constant, sets the sSFR equal to exactly the specific accretion rate of the galaxy; more realistic situations lead to an sSFR that is perturbed from this precise relation. Because the gas consumption timescale is shorter than the timescale on which the system evolves, the metallicity Z is set primarily by the instantaneous operation of the regulator system rather than by the past history of the system. The metallicity of the gas reservoir depends on {epsilon}, {lambda}, and sSFR, and the regulator system therefore naturally produces a Z(m{sub star}, SFR) relation if {epsilon} and {lambda} depend on the stellar mass m{sub star}. Furthermore, this relation will be the same at all epochs unless the parameters {epsilon} and {lambda} themselves change with time. A so-called fundamental metallicity relation is naturally produced by these conditions. The overall mass-metallicity relation Z(m{sub star}) directly provides the fraction f{sub star}(m{sub star}) of incoming baryons that are being transformed into stars. The observed Z(m{sub star}) relation of Sloan Digital Sky Survey (SDSS) galaxies implies a strong dependence of stellar mass on halo mass that reconciles the different faint-end slopes of the stellar and halo mass

  11. Immune-Specific Expression and Estrogenic Regulation of the Four Estrogen Receptor Isoforms in Female Rainbow Trout (Oncorhynchus mykiss

    Directory of Open Access Journals (Sweden)

    Ayako Casanova-Nakayama

    2018-03-01

    Full Text Available Genomic actions of estrogens in vertebrates are exerted via two intracellular estrogen receptor (ER subtypes, ERα and ERβ, which show cell- and tissue-specific expression profiles. Mammalian immune cells express ERs and are responsive to estrogens. More recently, evidence became available that ERs are also present in the immune organs and cells of teleost fish, suggesting that the immunomodulatory function of estrogens has been conserved throughout vertebrate evolution. For a better understanding of the sensitivity and the responsiveness of the fish immune system to estrogens, more insight is needed on the abundance of ERs in the fish immune system, the cellular ratios of the ER subtypes, and their autoregulation by estrogens. Consequently, the aims of the present study were (i to determine the absolute mRNA copy numbers of the four ER isoforms in the immune organs and cells of rainbow trout, Oncorhynchus mykiss, and to compare them to the hepatic ER numbers; (ii to analyse the ER mRNA isoform ratios in the immune system; and, (iii finally, to examine the alterations of immune ER mRNA expression levels in sexually immature trout exposed to 17β-estradiol (E2, as well as the alterations of immune ER mRNA expression levels in sexually mature trout during the reproductive cycle. All four ER isoforms were present in immune organs—head kidney, spleen-and immune cells from head kidney and blood of rainbow trout, but their mRNA levels were substantially lower than in the liver. The ER isoform ratios were tissue- and cell-specific, both within the immune system, but also between the immune system and the liver. Short-term administration of E2 to juvenile female trout altered the ER mRNA levels in the liver, but the ERs of the immune organs and cells were not responsive. Changes of ER gene transcript numbers in immune organs and cells occurred during the reproductive cycle of mature female trout, but the changes in the immune ER profiles differed

  12. Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways.

    Science.gov (United States)

    Veenema, A H; Bredewold, R; De Vries, G J

    2012-01-01

    In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males. These findings demonstrate that activation of V1a receptors in the lateral septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Regulators of Long-Term Memory Revealed by Mushroom Body-Specific Gene Expression Profiling in Drosophila melanogaster.

    Science.gov (United States)

    Widmer, Yves F; Bilican, Adem; Bruggmann, Rémy; Sprecher, Simon G

    2018-06-20

    Memory formation is achieved by genetically tightly controlled molecular pathways that result in a change of synaptic strength and synapse organization. While for short-term memory traces rapidly acting biochemical pathways are in place, the formation of long-lasting memories requires changes in the transcriptional program of a cell. Although many genes involved in learning and memory formation have been identified, little is known about the genetic mechanisms required for changing the transcriptional program during different phases of long-term memory formation. With Drosophila melanogaster as a model system we profiled transcriptomic changes in the mushroom body, a memory center in the fly brain, at distinct time intervals during appetitive olfactory long-term memory formation using the targeted DamID technique. We describe the gene expression profiles during these phases and tested 33 selected candidate genes for deficits in long-term memory formation using RNAi knockdown. We identified 10 genes that enhance or decrease memory when knocked-down in the mushroom body. For vajk-1 and hacd1 , the two strongest hits, we gained further support for their crucial role in appetitive learning and forgetting. These findings show that profiling gene expression changes in specific cell-types harboring memory traces provides a powerful entry point to identify new genes involved in learning and memory. The presented transcriptomic data may further be used as resource to study genes acting at different memory phases. Copyright © 2018, Genetics.

  14. On vitamin D-dependent regulation of local mechanisms of non-specific defense in children with connective tissue dysplasia

    Directory of Open Access Journals (Sweden)

    L.I. Omelchenko

    2017-11-01

    concentrations of vitamin D and lysozyme (r = 0.65. Conclusions. The obtained results indicated vitamin D-dependent regulation of the antimicrobial peptide production in the epitheliocytes of the intestinal mucosa in connective tissue dysplasia. The severity of HBD-2 and lysozyme production disorders in children with CTD and VDD determines the appropriateness of correcting vitamin D in this category of patients.

  15. Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

    Science.gov (United States)

    Ito, Daisuke; Yogosawa, Satomi; Mimoto, Rei; Hirooka, Shinichi; Horiuchi, Takashi; Eto, Ken; Yanaga, Katsuhiko; Yoshida, Kiyotsugu

    2017-08-01

    Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Hsp90 interacts specifically with viral RNA and differentially regulates replication initiation of Bamboo mosaic virus and associated satellite RNA.

    Directory of Open Access Journals (Sweden)

    Ying Wen Huang

    Full Text Available Host factors play crucial roles in the replication of plus-strand RNA viruses. In this report, a heat shock protein 90 homologue of Nicotiana benthamiana, NbHsp90, was identified in association with partially purified replicase complexes from BaMV-infected tissue, and shown to specifically interact with the 3' untranslated region (3' UTR of BaMV genomic RNA, but not with the 3' UTR of BaMV-associated satellite RNA (satBaMV RNA or that of genomic RNA of other viruses, such as Potato virus X (PVX or Cucumber mosaic virus (CMV. Mutational analyses revealed that the interaction occurs between the middle domain of NbHsp90 and domain E of the BaMV 3' UTR. The knockdown or inhibition of NbHsp90 suppressed BaMV infectivity, but not that of satBaMV RNA, PVX, or CMV in N. benthamiana. Time-course analysis further revealed that the inhibitory effect of 17-AAG is significant only during the immediate early stages of BaMV replication. Moreover, yeast two-hybrid and GST pull-down assays demonstrated the existence of an interaction between NbHsp90 and the BaMV RNA-dependent RNA polymerase. These results reveal a novel role for NbHsp90 in the selective enhancement of BaMV replication, most likely through direct interaction with the 3' UTR of BaMV RNA during the initiation of BaMV RNA replication.

  17. Brn3a regulates neuronal subtype specification in the trigeminal ganglion by promoting Runx expression during sensory differentiation

    Directory of Open Access Journals (Sweden)

    Raisa Eng S

    2010-01-01

    Full Text Available Abstract The transcription factor Brn3a, product of the pou4f1 gene, is expressed in most sensory neurons throughout embryogenesis. Prior work has demonstrated a role for Brn3a in the repression of early neurogenic genes; here we describe a second major role for Brn3a in the specification of sensory subtypes in the trigeminal ganglion (TG. Sensory neurons initially co-express multiple Trk-family neurotrophin receptors, but are later marked by the unique expression of TrkA, TrkB or TrkC. Maturation of these sensory subtypes is known to depend on the expression of Runx transcription factors. Newborn Brn3a knockout mice fail to express TrkC, which is associated in the TG with mechanoreceptors, plus a set of functional genes associated with nociceptor subtypes. In embryonic Brn3a-/- ganglia, the normal expression of Runx3 is never initiated in TrkC+ neurons, and Runx1 expression is greatly attenuated in TrkA+ nociceptors. These changes are accompanied by expanded expression of TrkB in neurons that abnormally express multiple Trks, followed by the loss of TrkC and TrkA expression. In transgenic embryos expressing a Brn3a-VP16 dominant transactivator, Runx3 mRNA expression is increased, suggesting that it is a direct regulatory target of Brn3a. Chromatin immunoprecipitation confirms that Brn3a binds in vivo to a conserved upstream enhancer element within histone H3-acetylated chromatin in the Runx3 locus. Together these data show that Brn3a acts upstream of the Runx factors, which then repress TrkB expression to allow establishment of the non-overlapping Trk receptor profiles and correct terminally differentiated phenotypes.

  18. A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.

    Science.gov (United States)

    Law, Bernard M H; Spain, Victoria A; Leinster, Veronica H L; Chia, Ruth; Beilina, Alexandra; Cho, Hyun J; Taymans, Jean-Marc; Urban, Mary K; Sancho, Rosa M; Blanca Ramírez, Marian; Biskup, Saskia; Baekelandt, Veerle; Cai, Huaibin; Cookson, Mark R; Berwick, Daniel C; Harvey, Kirsten

    2014-01-10

    Mutations in LRRK2, encoding the multifunctional protein leucine-rich repeat kinase 2 (LRRK2), are a common cause of Parkinson disease. LRRK2 has been suggested to influence the cytoskeleton as LRRK2 mutants reduce neurite outgrowth and cause an accumulation of hyperphosphorylated Tau. This might cause alterations in the dynamic instability of microtubules suggested to contribute to the pathogenesis of Parkinson disease. Here, we describe a direct interaction between LRRK2 and β-tubulin. This interaction is conferred by the LRRK2 Roc domain and is disrupted by the familial R1441G mutation and artificial Roc domain mutations that mimic autophosphorylation. LRRK2 selectively interacts with three β-tubulin isoforms: TUBB, TUBB4, and TUBB6, one of which (TUBB4) is mutated in the movement disorder dystonia type 4 (DYT4). Binding specificity is determined by lysine 362 and alanine 364 of β-tubulin. Molecular modeling was used to map the interaction surface to the luminal face of microtubule protofibrils in close proximity to the lysine 40 acetylation site in α-tubulin. This location is predicted to be poorly accessible within mature stabilized microtubules, but exposed in dynamic microtubule populations. Consistent with this finding, endogenous LRRK2 displays a preferential localization to dynamic microtubules within growth cones, rather than adjacent axonal microtubule bundles. This interaction is functionally relevant to microtubule dynamics, as mouse embryonic fibroblasts derived from LRRK2 knock-out mice display increased microtubule acetylation. Taken together, our data shed light on the nature of the LRRK2-tubulin interaction, and indicate that alterations in microtubule stability caused by changes in LRRK2 might contribute to the pathogenesis of Parkinson disease.

  19. Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease.

    Directory of Open Access Journals (Sweden)

    Alison Marshall

    Full Text Available The IFN-γ-inducible chemokines CXCL9, CXCL10, and CXCL11 play a key role in many inflammatory conditions, particularly those mediated by T cells. Therefore, the production of these chemokines in peripheral tissues could be instrumental in the pathophysiology of tissue-specific immunological diseases such as oral lichen planus (OLP. In the present study, we assessed the production of keratinocyte-derived CXCL9/10/11 under basal and inflammatory conditions and investigated whether these chemokines were involved in the pathogenesis of OLP. We used semi-quantitative PCR, ELISA, chemotaxis assays, and fluorescence-activated cell sorting (FACS to assess the expression and functional role of CXCL9/10/11 in oral keratinocytes (three strains of normal human oral keratinocytes (NHOK, and the H357 oral cancer cell line in the presence or absence of IFN-γ. CXCL9/10/11 were also assessed in tissues from normal patients and those with oral lichen planus (OLP. The time course study in oral keratinocytes treated with IFN-γ showed that expression of CXCL9/10/11 chemokines was significantly enhanced by IFN-γ in a time-dependent manner. In particular, CXCL10, a prominent chemokine that was overexpressed by IFN-γ-stimulated NHOK, was able to effectively recruit CD4 lymphocytes, mainly CD4+CD45RA- cell