Dissociation mediates the relationship between peer victimization and hallucinatory experiences among early adolescents.

PubMed

Yamasaki, Syudo; Ando, Shuntaro; Koike, Shinsuke; Usami, Satoshi; Endo, Kaori; French, Paul; Sasaki, Tsukasa; Furukawa, Toshi A; Hasegawa-Hiraiwa, Mariko; Kasai, Kiyoto; Nishida, Atsushi

2016-06-01

Peer victimization increases the risk of experiencing psychotic symptoms among clinical and general populations, but the mechanism underlying this association remains unclear. Dissociation, which is related to peer victimization and hallucinatory experiences, has been demonstrated as a significant mediator in the relation between childhood victimization and hallucinatory experience among adult patients with psychosis. However, no studies have examined the mediating effect of dissociation in a general early adolescent population. We examined whether dissociation mediates the relationship between peer victimization and hallucinatory experiences among 10-year-old adolescents using a population-based cross-sectional survey of early adolescents and their main parent (Tokyo Early Adolescence Survey; N  = 4478). We examined the mediating effect of dissociation, as well as external locus of control and depressive symptoms, on the relationship between peer victimization and hallucinatory experiences using path analysis. The model assuming mediation effects indicated good model fit (comparative fit index = .999; root mean square error of approximation = .015). The mediation effect between peer victimization and hallucination via dissociation (standardized indirect effect = .038, p  < .001) was statistically significant, whereas the mediation effects of depressive symptoms (standardized indirect effect = -.0066, p  = 0.318) and external locus of control (standardized indirect effect = .0024, p  = 0.321) were not significant. These results suggest that dissociation is a mediator in the relation between peer victimization and hallucinatory experiences in early adolescence. For appropriate intervention strategies, assessing dissociation and peer victimization as they affect hallucinatory experiences is necessary.

Pharmacogenomics in early-phase clinical development

PubMed Central

Burt, Tal; Dhillon, Savita

2015-01-01

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs. PMID:23837482

Endothelial gaps and adherent leukocytes in allergen-induced early- and late-phase plasma leakage in rat airways.

PubMed Central

Baluk, P.; Bolton, P.; Hirata, A.; Thurston, G.; McDonald, D. M.

1998-01-01

Exposure of sensitized individuals to antigen can induce allergic responses in the respiratory tract, manifested by early and late phases of vasodilatation, plasma leakage, leukocyte influx, and bronchoconstriction. Similar responses can occur in the skin, eye, and gastrointestinal tract. The early-phase response involves mast cell mediators and the late-phase response is leukocyte dependent, but the mechanism of leakage is not understood. We sought to identify the leaky blood vessels, to determine whether these vessels contained endothelial gaps, and to analyze the relationship of the gaps to adherent leukocytes, using biotinylated lectins or silver nitrate to stain the cells in situ and Monastral blue as a tracer to quantify plasma leakage. Most of the leakage occurred in postcapillary venules (< 40-microns diameter), whereas most of the leukocyte migration (predominantly neutrophils) occurred in collecting venules. Capillaries and arterioles did not leak. Endothelial gaps were found in the leaky venules, both by silver nitrate staining and by scanning electron microscopy, and 94% of the gaps were distinct from sites of leukocyte adhesion or migration. We conclude that endothelial gaps contribute to both early and late phases of plasma leakage induced by antigen, but most leakage occurs upstream to sites of leukocyte adhesion. Images Figure 3 Figure 5 Figure 6 Figure 7 PMID:9626051

Early-life conditions and health at older ages: The mediating role of educational attainment, family and employment trajectories.

PubMed

Arpino, Bruno; Gumà, Jordi; Julià, Albert

2018-01-01

We examine to what extent the effect of early-life conditions (health and socioeconomic status) on health in later life is mediated by educational attainment and life-course trajectories (fertility, partnership, employment). Using data from the Survey of Health, Ageing and Retirement in Europe (N = 12,034), we apply, separately by gender, multichannel sequence analysis and cluster analysis to obtain groups of similar family and employment histories. The KHB method is used to disentangle direct and indirect effects of early-life conditions on health. Early-life-conditions indirectly impact on health in later life as result of their influence on education and family and employment trajectories. For example, between 22% and 42% of the effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Even higher percentages are found for men (35% - 57%). On the contrary, the positive effect of poor health at childhood on poor health at older ages is not significantly mediated by education and life-course trajectories. Education captures most of the mediating effect of parental socio-economic status. More specifically, between 66% and 75% of the indirect effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Again, higher percentages are found for men (86% - 93%). Early-life conditions, especially socioeconomic status, influence family and employment trajectories indirectly through their impact on education. We also find a persistent direct impact of early-life conditions on health at older ages. Our findings demonstrate that early-life experiences influence education and life-course trajectories and health in later life, suggesting that public investments in children are expected to produce long lasting effects on people's lives throughout the different phases of their

Attenuation of p38-mediated miR-1/133 expression facilitates myoblast proliferation during the early stage of muscle regeneration.

PubMed

Zhang, Duo; Li, Xihua; Chen, Chuchu; Li, Yuyin; Zhao, Lei; Jing, Yanyan; Liu, Wei; Wang, Xiaoyun; Zhang, Ying; Xia, Hongfeng; Chang, Yaning; Gao, Xiang; Yan, Jun; Ying, Hao

2012-01-01

Myoblast proliferation following myotrauma is regulated by multiple factors including growth factors, signal pathways, transcription factors, and miRNAs. However, the molecular mechanisms underlying the orchestration of these regulatory factors remain unclear. Here we show that p38 signaling is required for miR-1/133a clusters transcription and both p38 activity and miR-1/133 expression are attenuated during the early stage of muscle regeneration in various animal models. Additionally, we show that both miR-1 and miR-133 reduce Cyclin D1 expression and repress myoblast proliferation by inducing G1 phase arrest. Furthermore, we demonstrate that miR-133 inhibits mitotic progression by targeting Sp1, which mediates Cyclin D1 transcription, while miR-1 suppresses G1/S phase transition by targeting Cyclin D1. Finally, we reveal that proproliferative FGF2, which is elevated during muscle regeneration, attenuates p38 signaling and miR-1/133 expression. Taken together, our results suggest that downregulation of p38-mediated miR-1/133 expression by FGF2 and subsequent upregulation of Sp1/Cyclin D1 contribute to the increased myoblast proliferation during the early stage of muscle regeneration.

Attenuation of p38-Mediated miR-1/133 Expression Facilitates Myoblast Proliferation during the Early Stage of Muscle Regeneration

PubMed Central

Zhang, Duo; Li, Xihua; Chen, Chuchu; Li, Yuyin; Zhao, Lei; Jing, Yanyan; Liu, Wei; Wang, Xiaoyun; Zhang, Ying; Xia, Hongfeng; Chang, Yaning; Gao, Xiang; Yan, Jun; Ying, Hao

2012-01-01

Myoblast proliferation following myotrauma is regulated by multiple factors including growth factors, signal pathways, transcription factors, and miRNAs. However, the molecular mechanisms underlying the orchestration of these regulatory factors remain unclear. Here we show that p38 signaling is required for miR-1/133a clusters transcription and both p38 activity and miR-1/133 expression are attenuated during the early stage of muscle regeneration in various animal models. Additionally, we show that both miR-1 and miR-133 reduce Cyclin D1 expression and repress myoblast proliferation by inducing G1 phase arrest. Furthermore, we demonstrate that miR-133 inhibits mitotic progression by targeting Sp1, which mediates Cyclin D1 transcription, while miR-1 suppresses G1/S phase transition by targeting Cyclin D1. Finally, we reveal that proproliferative FGF2, which is elevated during muscle regeneration, attenuates p38 signaling and miR-1/133 expression. Taken together, our results suggest that downregulation of p38-mediated miR-1/133 expression by FGF2 and subsequent upregulation of Sp1/Cyclin D1 contribute to the increased myoblast proliferation during the early stage of muscle regeneration. PMID:22911796

Early Intervention Services for Early-Phase Psychosis - Centre for integrative psychiatry in Psychiatric Hospital "Sveti Ivan", Croatia.

PubMed

Matić, Katarina; Gereš, Natko; Gerlach, Josefina; Prskalo-Čule, Diana; Zadravec Vrbanc, Tihana; Lovretić, Vanja; Librenjak, Dina; Vuk Pisk, Sandra; Ivezić, Ena; Šimunović Filipčić, Ivona; Jeleč, Vjekoslav; Filipčić, Igor

2018-06-01

There is a growing body of evidence suggesting that early and effective management in the critical early years of schizophrenia can improve long-term outcomes. The objective of this study was to evaluate time to relapse of the patients with early-phase psychosis treated in the Centre for integrative psychiatry (CIP). We performed a retrospective cohort study on the sample of 373 early-phase psychosis patients admitted to Psychiatric Hospital "Sveti Ivan", Zagreb Croatia: from January 1, 2015 to December 31, 2017. The primary outcome was time to relapse. Patients who were admitted to group psychotherapeutic program after the end of acute treatment had 70% lower hazard for relapse (HR=0.30; 95% CI 0.16-0.58). Patients who were included first in the psychotherapeutic program and then treated and controlled in the daily hospital had 74% lower hazard for relapse (HR=0.26; 95% CI 0.10-0.67). In early-phase psychosis, integrative early intervention service has relevant beneficial effects compare to treatment as usual. These results justified the implementation of multimodal early intervention services in treatment of patients with early-phase psychosis.

Early-life conditions and health at older ages: The mediating role of educational attainment, family and employment trajectories

PubMed Central

2018-01-01

Objectives We examine to what extent the effect of early-life conditions (health and socioeconomic status) on health in later life is mediated by educational attainment and life-course trajectories (fertility, partnership, employment). Methods Using data from the Survey of Health, Ageing and Retirement in Europe (N = 12,034), we apply, separately by gender, multichannel sequence analysis and cluster analysis to obtain groups of similar family and employment histories. The KHB method is used to disentangle direct and indirect effects of early-life conditions on health. Results Early-life-conditions indirectly impact on health in later life as result of their influence on education and family and employment trajectories. For example, between 22% and 42% of the effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Even higher percentages are found for men (35% - 57%). On the contrary, the positive effect of poor health at childhood on poor health at older ages is not significantly mediated by education and life-course trajectories. Education captures most of the mediating effect of parental socio-economic status. More specifically, between 66% and 75% of the indirect effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Again, higher percentages are found for men (86% - 93%). Early-life conditions, especially socioeconomic status, influence family and employment trajectories indirectly through their impact on education. We also find a persistent direct impact of early-life conditions on health at older ages. Conclusions Our findings demonstrate that early-life experiences influence education and life-course trajectories and health in later life, suggesting that public investments in children are expected to produce long lasting effects on people’s lives

Intergenerational neural mediators of early-life anxious temperament.

PubMed

Fox, Andrew S; Oler, Jonathan A; Shackman, Alexander J; Shelton, Steven E; Raveendran, Muthuswamy; McKay, D Reese; Converse, Alexander K; Alexander, Andrew; Davidson, Richard J; Blangero, John; Rogers, Jeffrey; Kalin, Ned H

2015-07-21

Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism-not brain structure-that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.

An early history of T cell-mediated cytotoxicity.

PubMed

Golstein, Pierre; Griffiths, Gillian M

2018-04-16

After 60 years of intense fundamental research into T cell-mediated cytotoxicity, we have gained a detailed knowledge of the cells involved, specific recognition mechanisms and post-recognition perforin-granzyme-based and FAS-based molecular mechanisms. What could not be anticipated at the outset was how discovery of the mechanisms regulating the activation and function of cytotoxic T cells would lead to new developments in cancer immunotherapy. Given the profound recent interest in therapeutic manipulation of cytotoxic T cell responses, it is an opportune time to look back on the early history of the field. This Timeline describes how the early findings occurred and eventually led to current therapeutic applications.

Relationship between ADAMTS13 activity, von Willebrand factor antigen levels and platelet function in the early and late phases after TIA or ischaemic stroke.

PubMed

McCabe, Dominick J H; Murphy, Stephen J X; Starke, Richard; Harrison, Paul; Brown, Martin M; Sidhu, Paul S; Mackie, Ian J; Scully, Marie; Machin, Samuel J

2015-01-15

Reduced ADAMTS13 activity is seen in thrombotic thrombocytopenic purpura (TTP), and may lead to accumulation of prothrombotic ultra-large von Willebrand factor (ULVWF) multimers in vivo. ADAMTS13 activity and its relationship with VWF antigen (VWF:Ag) levels and platelet function in 'non-TTP related' TIA or ischaemic stroke has not been comprehensively studied. In this prospective pilot observational analytical case-control study, ADAMTS13 activity and VWF:Ag levels were quantified in platelet poor plasma in 53 patients in the early phase (≤ 4 weeks) and 34 of these patients in the late phase (≥ 3 months) after TIA or ischaemic stroke on aspirin. Data were compared with those from 22 controls not on aspirin. The impact of ADAMTS13 on platelet function in whole blood was quantified by measuring Collagen-ADP (C-ADP) and Collagen-Epinephrine closure times on a platelet function analyser (PFA-100(®)). Median ADAMTS13 activity was significantly reduced in the early phase (71.96% vs. 95.5%, P <0.01) but not in the late phase after TIA or stroke compared with controls (86.3% vs. 95.5%, P=0.19). There was a significant inverse relationship between ADAMTS13 activity and VWF:Ag levels in the early phase (r=-0.31; P=0.024), but not in the late phase after TIA or stroke (P=0.74). There was a positive correlation between ADAMTS13 activity and C-ADP closure times in early phase patients only, likely mediated via VWF:Ag levels. ADAMTS13 activity is reduced and VWF:Ag expression is increased within 4 weeks of TIA or ischaemic stroke onset, and can promote enhanced platelet adhesion and aggregation in response to stimulation with collagen and ADP via VWF-mediated pathways. These data improve our understanding of the dynamic haemostatic and thrombotic profiles of ischaemic cerebrovascular disease (CVD) patients, and are important in view of the potential future role that ADAMTS13 may have to play as an anti-thrombotic agent in CVD. Copyright © 2014 Elsevier B.V. All rights

ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle.

PubMed

Ray, Alo; Blevins, Chessica; Wani, Gulzar; Wani, Altaf A

2016-01-01

Cell cycle checkpoint is mediated by ATR and ATM kinases, as a prompt early response to a variety of DNA insults, and culminates in a highly orchestrated signal transduction cascade. Previously, we defined the regulatory role of nucleotide excision repair (NER) factors, DDB2 and XPC, in checkpoint and ATR/ATM-dependent repair pathway via ATR and ATM phosphorylation and recruitment to ultraviolet radiation (UVR)-induced damage sites. Here, we have dissected the molecular mechanisms of DDB2- and XPC- mediated regulation of ATR and ATM recruitment and activation upon UVR exposures. We show that the ATR and ATM activation and accumulation to UVR-induced damage not only depends on DDB2 and XPC, but also on the NER protein XPA, suggesting that the assembly of an active NER complex is essential for ATR and ATM recruitment. ATR and ATM localization and H2AX phosphorylation at the lesion sites occur as early as ten minutes in asynchronous as well as G1 arrested cells, showing that repair and checkpoint-mediated by ATR and ATM starts early upon UV irradiation. Moreover, our results demonstrated that ATR and ATM recruitment and H2AX phosphorylation are dependent on NER proteins in G1 phase, but not in S phase. We reasoned that in G1 the UVR-induced ssDNA gaps or processed ssDNA, and the bound NER complex promote ATR and ATM recruitment. In S phase, when the UV lesions result in stalled replication forks with long single-stranded DNA, ATR and ATM recruitment to these sites is regulated by different sets of proteins. Taken together, these results provide evidence that UVR-induced ATR and ATM recruitment and activation differ in G1 and S phases due to the existence of distinct types of DNA lesions, which promote assembly of different proteins involved in the process of DNA repair and checkpoint activation.

Does early communication mediate the relationship between motor ability and social function in children with cerebral palsy?

PubMed

Lipscombe, Belinda; Boyd, Roslyn N; Coleman, Andrea; Fahey, Michael; Rawicki, Barry; Whittingham, Koa

2016-01-01

Children diagnosed with neurodevelopmental conditions such as cerebral palsy (CP) are at risk of experiencing restrictions in social activities negatively impacting their subsequent social functioning. Research has identified motor and communication ability as being unique determinants of social function capabilities in children with CP, to date, no research has investigated whether communication is a mediator of the relationship between motor ability and social functioning. To investigate whether early communication ability at 24 months corrected age (ca.) mediates the relationship between early motor ability at 24 months ca. and later social development at 60 months ca. in a cohort of children diagnosed with cerebral palsy (CP). A cohort of 71 children (43 male) diagnosed with CP (GMFCS I=24, 33.8%, II=9, 12.7%, III=12, 16.9%, IV=10, 14.1%, V=16, 22.5%) were assessed at 24 and 60 months ca. Assessments included the Gross Motor Function Measure (GMFM), the Communication and Symbolic Behaviour Scales-Developmental Profile (CSBS-DP) Infant-Toddler Checklist and the Paediatric Evaluation of Disability Inventory (PEDI). A mediation model was examined using bootstrapping. Early communication skills mediated the relationship between early motor abilities and later social functioning, b=0.24 (95% CI=0.08-0.43 and the mediation model was significant, F (2, 68)=32.77, p<0.001, R(2)=0.49. Early communication ability partially mediates the relationship between early motor ability and later social function in children with CP. This demonstrates the important role of early communication in ongoing social development. Early identification of communication delay and enriched language exposure is crucial in this population. Copyright © 2016 Elsevier Ltd. All rights reserved.

IL-6, a central acute-phase mediator, as an early biomarker for exposure to zinc-based metal fumes.

PubMed

Baumann, R; Joraslafsky, S; Markert, A; Rack, I; Davatgarbenam, S; Kossack, V; Gerhards, B; Kraus, T; Brand, P; Gube, M

2016-12-12

-γ), cell counts] and the lung function parameters did not show any significant changes after exposure. Consistent with its role of the mediation of the acute-phase response, systemic increases of IL-6 after welding fume exposure peak at 10h before the increases of the acute-phase reactants CRP and SAA at 29h. IL-6 may represent a highly sensitive and early biomarker for the exposure to metal fumes containing zinc and copper. As IL-6, CRP and SAA are independent, strong risk markers for future cardiovascular diseases, these data may particularly be important for long-term welders with respect to their cardiovascular health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Complexion-mediated martensitic phase transformation in Titanium.

PubMed

Zhang, J; Tasan, C C; Lai, M J; Dippel, A-C; Raabe, D

2017-02-01

The most efficient way to tune microstructures and mechanical properties of metallic alloys lies in designing and using athermal phase transformations. Examples are shape memory alloys and high strength steels, which together stand for 1,500 million tons annual production. In these materials, martensite formation and mechanical twinning are tuned via composition adjustment for realizing complex microstructures and beneficial mechanical properties. Here we report a new phase transformation that has the potential to widen the application window of Ti alloys, the most important structural material in aerospace design, by nanostructuring them via complexion-mediated transformation. This is a reversible martensitic transformation mechanism that leads to a final nanolaminate structure of α″ (orthorhombic) martensite bounded with planar complexions of athermal ω (a-ω, hexagonal). Both phases are crystallographically related to the parent β (BCC) matrix. As expected from a planar complexion, the a-ω is stable only at the hetero-interface.

Poverty and Behavior Problems during Early Childhood: The Mediating Role of Maternal Depression Symptoms and Parenting

ERIC Educational Resources Information Center

Mazza, Julia Rachel; Pingault, Jean-Baptiste; Booij, Linda; Boivin, Michel; Tremblay, Richard; Lambert, Jean; Zunzunegui, Maria Victoria; Côté, Sylvana

2017-01-01

Poverty is a well-established risk factor for behavior problems, yet our understanding of putative family mediators during early childhood (i.e., before age 5 years) is limited. The present study investigated whether the association between poverty and behavior problems during early childhood is mediated simultaneously by perceived parenting,…

Phase III Early Restoration Meeting | NOAA Gulf Spill Restoration

Science.gov Websites

Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News Publications Press Releases Story programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Phase III Early Restoration Meeting - Pensacola, FL (rescheduled) | NOAA

Science.gov Websites

Restoration Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Early Childhood Maltreatment and Girls' Sexual Behavior: The Mediating Role of Pubertal Timing.

PubMed

Ryan, Rebecca M; Mendle, Jane; Markowitz, Anna J

2015-09-01

Although links between early childhood maltreatment and girls' sexual behavior in adolescence have been well established, it is unclear whether different forms of maltreatment are differentially associated with sexual outcomes and whether distinct mechanisms explain associations across maltreatment types. Using data from National Longitudinal Study of Adolescent Health (Add Health), the present study examines whether physical abuse, sexual abuse, and physical neglect in early childhood differentially predict girls' age at first intercourse and number of sexual partners in early adulthood. The study also tests whether early pubertal timing mediates the link between early maltreatment and sexual behavior (N = 6,364). Findings indicate that early sexual and physical abuse were equally predictive of earlier age at first intercourse and a greater number of sexual partners, but that only the sexual abuse-age at first intercourse link was mediated by early puberty. These results suggest that sexual abuse and physical abuse are associated with earlier and riskier sexual behavior in girls relative to no maltreatment and to similar degrees. However, only the link between sexual abuse and sexual behavior involves a biological mechanism manifested in early pubertal timing. Copyright © 2015 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

Metacognition in Early Phase Psychosis: Toward Understanding Neural Substrates

PubMed Central

Vohs, Jenifer L.; Hummer, Tom A.; Yung, Matthew G.; Francis, Michael M.; Lysaker, Paul H.; Breier, Alan

2015-01-01

Individuals in the early phases of psychotic illness have disturbed metacognitive capacity, which has been linked to a number of poor outcomes. Little is known, however, about the neural systems associated with metacognition in this population. The purpose of this study was to elucidate the neuroanatomical correlates of metacognition. We anticipated that higher levels of metacognition may be dependent upon gray matter density (GMD) of regions within the prefrontal cortex. Examining whole-brain structure in 25 individuals with early phase psychosis, we found positive correlations between increased medial prefrontal cortex and ventral striatum GMD and higher metacognition. These findings represent an important step in understanding the path through which the biological correlates of psychotic illness may culminate into poor metacognition and, ultimately, disrupted functioning. Such a path will serve to validate and promote metacognition as a viable treatment target in early phase psychosis. PMID:26132568

Complexion-mediated martensitic phase transformation in Titanium

PubMed Central

Zhang, J.; Tasan, C. C.; Lai, M. J.; Dippel, A. -C.; Raabe, D.

2017-01-01

The most efficient way to tune microstructures and mechanical properties of metallic alloys lies in designing and using athermal phase transformations. Examples are shape memory alloys and high strength steels, which together stand for 1,500 million tons annual production. In these materials, martensite formation and mechanical twinning are tuned via composition adjustment for realizing complex microstructures and beneficial mechanical properties. Here we report a new phase transformation that has the potential to widen the application window of Ti alloys, the most important structural material in aerospace design, by nanostructuring them via complexion-mediated transformation. This is a reversible martensitic transformation mechanism that leads to a final nanolaminate structure of α″ (orthorhombic) martensite bounded with planar complexions of athermal ω (a–ω, hexagonal). Both phases are crystallographically related to the parent β (BCC) matrix. As expected from a planar complexion, the a–ω is stable only at the hetero-interface. PMID:28145484

The Early Risers Preventive Intervention: Testing for Six-year Outcomes and Mediational Processes

ERIC Educational Resources Information Center

Bernat, Debra H.; August, Gerald J.; Hektner, Joel M.; Bloomquist, Michael L.

2007-01-01

We examined effects of the Early Risers "Skills for Success" early-age-targeted prevention program on serious conduct problems following 5 years of continuous intervention and one year of follow-up. We also examined if intervention effects on proximally-targeted variables found after 3 years mediated intervention effects on conduct…

Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury.

PubMed

Shah, Dilip; Romero, Freddy; Stafstrom, William; Duong, Michelle; Summer, Ross

2014-01-01

Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5'-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI.

Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury

PubMed Central

Shah, Dilip; Romero, Freddy; Stafstrom, William; Duong, Michelle

2013-01-01

Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5′-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI. PMID:24285266

Auto-inhibitory regulation of angiotensin II functionality in hamster aorta during the early phases of dyslipidemia.

PubMed

Pereira, Priscila Cristina; Pernomian, Larissa; Côco, Hariane; Gomes, Mayara Santos; Franco, João José; Marchi, Kátia Colombo; Hipólito, Ulisses Vilela; Uyemura, Sergio Akira; Tirapelli, Carlos Renato; de Oliveira, Ana Maria

2016-06-15

Emerging data point the crosstalk between dyslipidemia and renin-angiotensin system (RAS). Advanced dyslipidemia is described to induce RAS activation in the vasculature. However, the interplay between early dyslipidemia and the RAS remains unexplored. Knowing that hamsters and humans have a similar lipid profile, we investigated the effects of early and advanced dyslipidemia on angiotensin II-induced contraction. Cumulative concentration-response curves for angiotensin II (1.0pmol/l to 1.0µmol/l) were obtained in the hamster thoracic aorta. We also investigated the modulatory action of NAD(P)H oxidase on angiotensin II-induced contraction using ML171 (Nox-1 inhibitor, 0.5µmol/l) and VAS2870 (Nox-4 inhibitor, 5µmol/l). Early dyslipidemia was detected in hamsters treated with a cholesterol-rich diet for 15 days. Early dyslipidemia decreased the contraction induced by angiotensin II and the concentration of Nox-4-derived hydrogen peroxide. Advanced dyslipidemia, observed in hamsters treated with cholesterol-rich diet for 30 days, restored the contractile response induced by angiotensin II by compensatory mechanism that involves Nox-4-mediated oxidative stress. The hyporresponsiveness to angiotensin II may be an auto-inhibitory regulation of the angiotensinergic function during early dyslipidemia in an attempt to reduce the effects of the upregulation of the vascular RAS during the advanced stages of atherogenesis. The recovery of vascular angiotensin II functionality during the advanced phases of dyslipidemia is the result of the upregulation of redox-pro-inflammatory pathway that might be most likely involved in atherogenesis progression rather than in the recovery of vascular function. Taken together, our findings show the early phase of dyslipidemia may be the most favorable moment for effective atheroprotective therapeutic interventions. Copyright © 2016 Elsevier B.V. All rights reserved.

Postpartum Circulating Markers of Inflammation and the Systemic Acute-Phase Response After Early-Onset Preeclampsia.

PubMed

van Rijn, Bas B; Bruinse, Hein W; Veerbeek, Jan H; Post Uiterweer, Emiel D; Koenen, Steven V; van der Bom, Johanna G; Rijkers, Ger T; Roest, Mark; Franx, Arie

2016-02-01

Preeclampsia is an inflammatory-mediated hypertensive disorder of pregnancy and seems to be an early indicator of increased cardiovascular risk, but mechanisms underlying this association are unclear. In this study, we identified levels of circulating inflammatory markers and dynamic changes in the systemic acute-phase response in 44 women with a history of severe early-onset preeclampsia, compared with 29 controls with only uneventful pregnancies at 1.5 to 3.5 years postpartum. Models used were in vivo seasonal influenza vaccination and in vitro whole-blood culture with T-cell stimulants and the toll-like receptor-4 ligand lipopolysaccharide. Outcome measures were C-reactive protein, interleukin-6 (IL-6), IL-18, fibrinogen, myeloperoxidase, and a panel of 13 cytokines representative of the innate and adaptive inflammatory response, in addition to established cardiovascular markers. The in vivo acute-phase response was higher for women with previous preeclampsia than that for controls without such a history, although only significant for C-reactive protein (P=0.04). Preeclampsia was associated with higher IL-1β (P<0.05) and IL-8 (P<0.01) responses to T-cell activation. Hierarchical clustering revealed 2 distinct inflammatory clusters associated with previous preeclampsia: an adaptive response cluster associated with increased C-reactive protein and IL-6 before and after vaccination, increased weight, and low high-density lipoprotein cholesterol; and a toll-like receptor-4 mediated the cluster associated with increased IL-18 before and after vaccination but not associated with other cardiovascular markers. Furthermore, we found interactions between previous preeclampsia, common TLR4 gene variants, and the IL-18 response to vaccination. In conclusion, preeclampsia is associated with alterations in the inflammatory response postpartum mostly independent of other established cardiovascular risk markers. © 2015 American Heart Association, Inc.

Maternal depressive symptoms and early childhood cognitive development: a review of putative environmental mediators.

PubMed

Ahun, Marilyn N; Côté, Sylvana M

2018-06-06

Despite the abundance of research investigating the associations between maternal depressive symptoms (MDS) and children's cognitive development, little is known about the putative mechanisms through which depressive symptoms are associated with children's cognitive development. The aim of this review was to summarize the literature on family mediators (i.e., maternal parenting behaviors, mother-child interactions, and family stress) involved in this association in early childhood. The review includes seven studies, five longitudinal and two cross-sectional, which tested putative mediators of the association between MDS and children's cognitive development. Studies were selected from online databases (PubMed, PsycNet) and manual searches. Only studies which quantitatively assessed associations between MDS in the postnatal period and child cognitive development in early childhood (i.e., 0-5 years) and included mediator variables were included in the review. Six out of seven studies identified mediating variables. The mediators included maternal responsiveness, parenting style, family dysfunction, the quality of the home environment, and maternal caregiving practices. Different mediators were identified across the reviewed studies. Maternal depressive symptoms are partly associated with child cognitive development via family processes and parenting practices. Various mediating processes are at play. Further research is needed on the role of maternal and paternal mental health and gene-environment correlations in this association. A better understanding of the mediating pathways is needed for the design of preventative intervention targeting specific family processes.

Fluctuation-driven electroweak phase transition. [in early universe

NASA Technical Reports Server (NTRS)

Gleiser, Marcelo; Kolb, Edward W.

1992-01-01

We examine the dynamics of the electroweak phase transition in the early Universe. For Higgs masses in the range 46 less than or = M sub H less than or = 150 GeV and top quark masses less than 200 GeV, regions of symmetric and asymmetric vacuum coexist to below the critical temperature, with thermal equilibrium between the two phases maintained by fluctuations of both phases. We propose that the transition to the asymmetric vacuum is completed by percolation of these subcritical fluctuations. Our results are relevant to scenarios of baryogenesis that invoke a weakly first-order phase transition at the electroweak scale.

Effects of Prenatal Cocaine Exposure on Early Sexual Behavior: Gender Difference in Externalizing Behavior as a Mediator

PubMed Central

Min, Meeyoung O.; Minnes, Sonia; Lang, Adelaide; Yoon, Susan; Singer, Lynn T.

2015-01-01

Background Prenatal cocaine exposure (PCE) is associated with increased risk for externalizing behavior problems; childhood externalizing behavior problems are linked with subsequent early sexual behavior. The present study examined the effects of PCE on early sexual initiation (sexual intercourse prior to age 15) and whether externalizing behavior in preadolescence mediated the relationship. Methods Three hundred fifty-four (180 PCE and 174 non-cocaine exposed; 192 girls, 142 boys), primarily African-American, low socioeconomic status, 15-year old adolescents participated in a prospective longitudinal study. Adolescents’ sexual behavior was assessed at 15 years using the Youth Risk Behavior Surveillance System. Externalizing behavior was assessed at 12 years using the Youth Self-Report. Results Logistic regression models indicated that adolescents with PCE (n=69, 38%) were 2.2 times more likely (95% CI= 1.2 – 4.1, p < .01) to engage in early sexual intercourse than non-exposed peers (n=49, 28%) controlling for covariates. This relationship was fully mediated by self-reported externalizing behavior in girls but not in boys, suggesting childhood externalizing behavior as a gender moderated mediator. Blood lead level during preschool years was also related to a greater likelihood of early sexual intercourse (OR=2.6, 95% CI=1.4 – 4.7, p < .002). Greater parental monitoring decreased the likelihood of early sexual intercourse, while violence exposure increased the risk. Conclusions PCE is related to early sexual intercourse, and externalizing behavior problems mediate PCE effects in female adolescents. Interventions targeting externalizing behavior may reduce early sexual initiation and thereby reduce HIV risk behaviors and early, unplanned pregnancy in girls with PCE. PMID:26088698

Effects of prenatal cocaine exposure on early sexual behavior: Gender difference in externalizing behavior as a mediator.

PubMed

Min, Meeyoung O; Minnes, Sonia; Lang, Adelaide; Yoon, Susan; Singer, Lynn T

2015-08-01

Prenatal cocaine exposure (PCE) is associated with increased risk for externalizing behavior problems; childhood externalizing behavior problems are linked with subsequent early sexual behavior. The present study examined the effects of PCE on early sexual initiation (sexual intercourse prior to age 15) and whether externalizing behavior in preadolescence mediated the relationship. Three hundred fifty-four (180 PCE and 174 non-cocaine exposed; 192 girls, 142 boys), primarily African-American, low socioeconomic status, 15-year-old adolescents participated in a prospective longitudinal study. Adolescents' sexual behavior was assessed at 15 years using the Youth Risk Behavior Surveillance System. Externalizing behavior was assessed at 12 years using the Youth Self-Report. Logistic regression models indicated that adolescents with PCE (n=69, 38%) were 2.2 times more likely (95% CI=1.2-4.1, p<.01) to engage in early sexual intercourse than non-exposed peers (n=49, 28%) controlling for covariates. This relationship was fully mediated by self-reported externalizing behavior in girls but not in boys, suggesting childhood externalizing behavior as a gender moderated mediator. Blood lead level during preschool years was also related to a greater likelihood of early sexual intercourse (OR=2.6, 95% CI=1.4-4.7, p<.002). Greater parental monitoring decreased the likelihood of early sexual intercourse, while violence exposure increased the risk. PCE is related to early sexual intercourse, and externalizing behavior problems mediate PCE effects in female adolescents. Interventions targeting externalizing behavior may reduce early sexual initiation and thereby reduce HIV risk behaviors and early, unplanned pregnancy in girls with PCE. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The progamic phase of an early-divergent angiosperm, Annona cherimola (Annonaceae)

PubMed Central

Lora, J.; Hormaza, J. I.; Herrero, M.

2010-01-01

Background and Aims Recent studies of reproductive biology in ancient angiosperm lineages are beginning to shed light on the early evolution of flowering plants, but comparative studies are restricted by fragmented and meagre species representation in these angiosperm clades. In the present study, the progamic phase, from pollination to fertilization, is characterized in Annona cherimola, which is a member of the Annonaceae, the largest extant family among early-divergent angiosperms. Beside interest due to its phylogenetic position, this species is also an ancient crop with a clear niche for expansion in subtropical climates. Methods The kinetics of the reproductive process was established following controlled pollinations and sequential fixation. Gynoecium anatomy, pollen tube pathway, embryo sac and early post-fertilization events were characterized histochemically. Key Results A plesiomorphic gynoecium with a semi-open carpel shows a continuous secretory papillar surface along the carpel margins, which run from the stigma down to the obturator in the ovary. The pollen grains germinate in the stigma and compete in the stigma-style interface to reach the narrow secretory area that lines the margins of the semi-open stylar canal and is able to host just one to three pollen tubes. The embryo sac has eight nuclei and is well provisioned with large starch grains that are used during early cellular endosperm development. Conclusions A plesiomorphic simple gynoecium hosts a simple pollen–pistil interaction, based on a support–control system of pollen tube growth. Support is provided through basipetal secretory activity in the cells that line the pollen tube pathway. Spatial constraints, favouring pollen tube competition, are mediated by a dramatic reduction in the secretory surface available for pollen tube growth at the stigma–style interface. This extramural pollen tube competition contrasts with the intrastylar competition predominant in more recently derived

Defect-mediated spatial complexity and chaos in a phase-conjugate resonator

NASA Technical Reports Server (NTRS)

Indebetouw, Guy; Liu, Siuying R.

1992-01-01

We have studied the spatiotemporal dynamics of a phase-conjugate resonator. The cavity Fresnel number is used to vary the degree of transverse confinement of the system. The generation and subsequent motion of the phase defects in the wave front are seen to mediate the system's dynamics. The number of defects and the complexity of their motion increases as the confinement is relaxed, leading the system through a sequence of bifurcations and eventually to chaos.

Volunteering for early phase gene transfer research in Parkinson disease.

PubMed

Kim, S Y H; Holloway, R G; Frank, S; Beck, C A; Zimmerman, C; Wilson, R; Kieburtz, K

2006-04-11

For early phase trials of novel interventions-such as gene transfer for Parkinson disease (PD)--whose focus is primarily on safety and tolerability, it is important that participants have a realistic understanding of the goals of such research. Recently, some have expressed concern that patients with PD may have unrealistic expectations. The authors examined why patients with PD might volunteer for invasive early phase research by interviewing 92 patients with PD and comparing those who would (n = 46) and those who would not (n = 46) participate in a hypothetical phase I gene-transfer study. The two groups' demographic, clinical, functional, and quality of life measures, as well as their understanding of the research protocol, were similar. The groups did not differ on their perception of potential for personal benefit nor on the level of likelihood of benefit they saw as a precondition for volunteering. However, those willing to participate tended to perceive lower probability of risk, were tolerant of greater probability of risk, and were more optimistic about the phase I study's potential benefits to society. They also appeared more decisive and action-oriented than the unwilling group. It is likely that the decision whether to participate in early phase PD gene transfer studies will depend mostly on patients' attitudes regarding risk, optimism about science, and an action orientation, rather than on their clinical, functional, or demographic characteristics.

Implementing Effective Mission Systems Engineering Practices During Early Project Formulation Phases

NASA Technical Reports Server (NTRS)

Moton, Tryshanda

2016-01-01

Developing and implementing a plan for a NASA space mission can be a complicated process. The needs, goals, and objectives of any proposed mission or technology must be assessed early in the Project Life Cycle. The key to successful development of a space mission or flight project is the inclusion of systems engineering in early project formulation, namely during Pre-phase A, Phase A, and Phase B of the NASA Project Life Cycle. When a space mission or new technology is in pre-development, or "pre-Formulation", feasibility must be determined based on cost, schedule, and risk. Inclusion of system engineering during project formulation is key because in addition to assessing feasibility, design concepts are developed and alternatives to design concepts are evaluated. Lack of systems engineering involvement early in the project formulation can result in increased risks later in the implementation and operations phases of the project. One proven method for effective systems engineering practice during the pre-Formulation Phase is the use of a mission conceptual design or technology development laboratory, such as the Mission Design Lab (MDL) at NASA's Goddard Space Flight Center (GSFC). This paper will review the engineering process practiced routinely in the MDL for successful mission or project development during the pre-Formulation Phase.

Moderation and Mediation in Structural Equation Modeling: Applications for Early Intervention Research

ERIC Educational Resources Information Center

Hopwood, Christopher J.

2007-01-01

Second-generation early intervention research typically involves the specification of multivariate relations between interventions, outcomes, and other variables. Moderation and mediation involve variables or sets of variables that influence relations between interventions and outcomes. Following the framework of Baron and Kenny's (1986) seminal…

Contingency management for college student smokers: The role of drinking as a moderator and mediator of smoking abstinence during treatment.

PubMed

Cassidy, Rachel N; Jackson, Kristina M; Rohsenow, Damaris J; Tidey, Jennifer W; Tevyaw, Tracy O' L; Barnett, Nancy P; Monti, Peter M; Miller, Mollie E; Colby, Suzanne M

2018-05-01

Contingency management (CM) is effective for promoting smoking abstinence; however, moderators and mediators of CM treatment efficacy in young adult populations are under-explored. We leveraged fine-grained data from a large randomized controlled trial: 1) to determine whether early attainment of sustained abstinence mediated the effect of treatment on abstinence; 2) to test whether heavy drinking moderated the effect of treatment on abstinence; and 3) to test a serial mediation model of the effects of drinking during early treatment on sustained smoking abstinence. College student smokers (N=110) were randomized to receive either CM treatment or noncontingent reinforcement (NR) over a 21-day treatment period. All participants received $5 for providing twice-daily breath carbon monoxide (CO) samples. In CM, additional money was provided for samples that indicated smoking reduction (Initial Phase; first 7days), and for samples ≤5ppm (Abstinence Phase; following 14days). CM treatment led to greater sustained abstinence relative to NR. Longer sustained abstinence in the Initial Phase partially mediated the effect of treatment on sustained abstinence in the Abstinence Phase. Heavier pretreatment drinkers had shorter periods of sustained abstinence in the Abstinence Phase; this effect was greater in CM. A serial mediation model determined that increased drinking during the Initial Phase led to decreased sustained abstinence, which then led to decreased sustained abstinence in the Abstinence Phase. These data provide a greater understanding of how heavy drinking and early sustained abstinence may affect success during treatment in young adults undergoing contingency management treatment for smoking. Copyright © 2018. Published by Elsevier Ltd.

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2010 CFR

2010-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2014 CFR

2014-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2011 CFR

2011-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2012 CFR

2012-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

40 CFR 76.8 - Early election for Group 1, Phase II boilers.

Code of Federal Regulations, 2013 CFR

2013-07-01

... PROGRAMS (CONTINUED) ACID RAIN NITROGEN OXIDES EMISSION REDUCTION PROGRAM § 76.8 Early election for Group 1... plan and: (i) If a Phase I Acid Rain permit governing the source at which the unit is located has been... chapter to include the early election plan; or (ii) If a Phase I Acid Rain permit governing the source at...

Phase III Early Restoration Meeting - Corpus Christi, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News programmatic approach to early restoration planning for Phase III and future early restoration plans. Open

Early Adolescent Sexual Debut: The Mediating Role of Working Memory Ability, Sensation Seeking, and Impulsivity

PubMed Central

Khurana, Atika; Romer, Daniel; Betancourt, Laura M.; Brodsky, Nancy L.; Giannetta, Joan M.; Hurt, Hallam

2013-01-01

Although deficits in working memory ability have been implicated in suboptimal decision making and risk taking among adolescents, its influence on early sexual initiation has so far not been examined. Analyzing 2 waves of panel data from a community sample of adolescents (N = 347; Mean age[baseline] = 13.4 years), assessed 1 year apart, the present study tested the hypothesis that weak working memory ability predicts early sexual initiation and explored whether this relationship is mediated by sensation seeking and 2 forms of impulsivity, namely acting-without-thinking and temporal discounting. The 2 forms of impulsivity were expected to be positively associated with early sexual initiation, whereas sensation seeking was hypothesized to be unrelated or to have a protective influence, due to its positive association with working memory. Results obtained from structural equation modeling procedures supported these predictions and in addition showed that the effects of 3 prominent risk factors (Black racial identity, low socioeconomic background, and early pubertal maturation) on early sexual initiation were entirely mediated by working memory and impulsivity. The findings are discussed in regard to their implications for preventing early sexual onset among adolescents. PMID:22369334

The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

PubMed Central

Houlihan, Shauna L; Feng, Yuanyi

2014-01-01

Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 PMID:25245017

Recovering from Early Deprivation: Attachment Mediates Effects of Caregiving on Psychopathology

PubMed Central

McGoron, Lucy; Gleason, Mary Margaret; Smyke, Anna T.; Drury, Stacy S.; Nelson, Charles A.; Gregas, Mathew C.; Fox, Nathan A.; Zeanah, Charles H.

2014-01-01

Objective Children exposed to early institutional rearing are at risk for developing psychopathology. The present investigation examines caregiving quality and the role of attachment security as they relate to symptoms of psychopathology in young children exposed to early institutionalization. Methods Participants were enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal intervention study of children abandoned and placed in institutions at or shortly after birth. Measures included observed caregiving when children were 30 months of age, observed attachment security at 42 months and caregiver reports of children’s psychopathology at 54 months. At 54 months, some children remained in institutions, others were in foster care, others had been adopted domestically, and still others had been returned to their biological families. Thus, the children had experienced varying amounts of institutional rearing. Results After controlling for gender, quality of caregiving when children were 30 months old was associated with symptoms of multiple domains of psychopathology at 54 months of age. Ratings of security of attachment at 42 months mediated the associations between quality caregiving at 30 months and fewer symptoms of psychopathology at 54 months. Conclusions Among deprived young children, high quality caregiving at 30 months predicted reduced psychopathology and functional impairment at 54 months. Security of attachment mediated this relationship. Interventions for young children who have experienced deprivation may benefit from explicitly targeting caregiver-child attachment relationships. PMID:22721591

Does Emotion Dysregulation Mediate the Relationship between Early Maltreatment and Later Substance Dependence? Findings of the CANSAS Study.

PubMed

Wolff, Sebastian; Holl, Julia; Stopsack, Malte; Arens, Elisabeth A; Höcker, Anja; Staben, Katharina A; Hiller, Philipp; Klein, Michael; Schäfer, Ingo; Barnow, Sven

2016-01-01

Maltreatment in childhood and adolescence is a risk factor for substance use disorders (SUDs) in adulthood. This association has rarely been investigated in the light of emotion dysregulation. To fill this gap, this study examines emotion dysregulation and SUDs among adults with a history of early maltreatment. Comparison of emotion dysregulation in adults with a history of early abuse and neglect who developed either an SUD (n = 105) or no mental disorder (n = 54). Further, a mediation model for the association between the severity of early maltreatment and SUDs was tested. Participants completed research diagnostic interviews for psychopathology, the Difficulties in Emotion Regulation Scale, and the Childhood Trauma Questionnaire. By using hierarchical regression techniques and mediational analyses controlling for age and gender, it was possible to provide evidence for the mediating role of emotion dysregulation between early emotional and physical maltreatment and later SUDs. Emotion dysregulation is a potential mechanism underlying the relationship between early emotional and physical maltreatment and the development of SUDs. In light of these findings, focusing on the early training of adaptive emotion regulation strategies after childhood maltreatment might be of considerable relevance to prevent the development of SUDs. © 2016 S. Karger AG, Basel.

Delinquency, parental involvement, early adult criminality, and sex: Evidence of moderated mediation.

PubMed

Walters, Glenn D

2013-08-01

One purpose of this study was to determine whether parental involvement, measured in late adolescence, mediates the relationship between delinquency in mid-adolescence and crime in early adulthood. This study's second purpose was to ascertain whether this relationship is moderated by sex, such that late adolescent parental involvement mediates the delinquency-crime relationship in females but not in males. A secondary analysis of data provided by 579 (272 males, 307 females) members of the National Longitudinal Survey of Youth-Child (NLSYC) was conducted in an effort to evaluate the possibility of moderated mediation in the relationship between delinquency at age 16, parental involvement at age 18, and criminality at age 24. Moderated mediation analysis, path analysis, and causal mediation analysis revealed the presence of a conditional indirect relationship between delinquency, parental involvement, and adult crime moderated by sex. These results are consistent with views on cumulative disadvantage and gendered pathways to crime. Copyright © 2013 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Phase III Early Restoration Meeting - Lake Charles, LA | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News early restoration planning for Phase III and future early restoration plans. Open House: 5:30pm Public

Does Aggregate School-Wide Achievement Mediate Fifth Grade Outcomes for Former Early Childhood Education Participants?

ERIC Educational Resources Information Center

Curenton, Stephanie M.; Dong, Nianbo; Shen, Xiangjin

2015-01-01

This study used a multilevel mediation model to test the theory that former early childhood education (ECE) attendees' 5th grade achievement is mediated by the aggregate school-wide achievement of their elementary school. Aggregate school-wide achievement was defined as the percentage of 5th graders in a school who were at/above academic…

Attention and Language as Mediators of Academic Outcomes Following Early Psychosocial Deprivation

ERIC Educational Resources Information Center

Merz, Emily C.; McCall, Robert B.; Wright, Amanda J.

2013-01-01

Children adopted from institutions at older ages are at increased risk of persistent attention problems, lower cognition, and academic difficulties. This study examined cognitive and behavior problems as mediators of the association between early psychosocial deprivation and academic functioning. Participants were 8-17-year-old children adopted…

Peer substance use as a mediator between early pubertal timing and adolescent substance use: longitudinal associations and moderating effect of maltreatment.

PubMed

Negriff, Sonya; Trickett, Penelope K

2012-11-01

Early pubertal timing has received considerable empirical support as a risk for adolescent substance use. However, few studies have examined the mediators linking these variables. Therefore, the aims of this study were (1) to examine peer substance use as a mediator between pubertal timing and adolescent substance use longitudinally and (2) to test gender and maltreatment experience as moderators of the mediational model. Data were obtained from time 1, 2, and 3 of a longitudinal study of maltreatment and development. At time 1 the sample was comprised of 303 maltreated and 151 comparison children aged 9-13 years (213 females and 241 males). Longitudinal mediation was tested using structural equation modeling and moderating effects were tested using multiple group analysis. Peer substance use mediated the relationship between early pubertal timing and later adolescent substance use for the total sample. Moderation analyses indicated this significant indirect effect did not differ for males and females. However, it did differ for maltreated versus comparison adolescents with the mediational effect only remaining significant for the comparison group. This is one of the first studies to examine peer substance use as a mediator of pubertal timing and adolescent substance use using a longitudinal design. Early maturing males are at equal risk to early maturing females for interacting with peers that may draw them into substance use. Additionally, the findings indicate that while peers are mediators for comparison adolescents a different mechanism may link early puberty to substance use for maltreated adolescents. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Gas-phase water-mediated equilibrium between methylglyoxal and its geminal diol

PubMed Central

Axson, Jessica L.; Takahashi, Kaito; De Haan, David O.; Vaida, Veronica

2010-01-01

In aqueous solution, aldehydes, and to a lesser extent ketones, hydrate to form geminal diols. We investigate the hydration of methylglyoxal (MG) in the gas phase, a process not previously considered to occur in water-restricted environments. In this study, we spectroscopically identified methylglyoxal diol (MGD) and obtained the gas-phase partial pressures of MG and MGD. These results, in conjunction with the relative humidity, were used to obtain the equilibrium constant, KP, for the water-mediated hydration of MG in the gas phase. The Gibbs free energy for this process, ΔG°, obtained as a result, suggests a larger than expected gas-phase diol concentration. This may have significant implications for understanding the role of organics in atmospheric chemistry. PMID:20142510

Improvements in maternal depression as a mediator of intervention effects on early childhood problem behavior

PubMed Central

Shaw, Daniel S.; Connell, Arin; Dishion, Thomas J.; Wilson, Melvin N.; Gardner, Frances

2009-01-01

Maternal depression has been consistently linked to the development of child problem behavior, particularly in early childhood, but few studies have examined whether reductions in maternal depression serve as a mediator in relation to changes associated with a family-based intervention. The current study addressed this issue with a sample of 731 families receiving services from a national food supplement and nutrition program. Families with toddlers between ages 2 and 3 were sereened and then randomized to a brief family intervention, the Family Check-Up, which included linked interventions that were tailored and adapted to the families needs. Follow-up intervention services were provided at age 3 and follow-up of child outcomes oecurred at ages 3 and 4. Latent growth models revealed intervention effects for early externalizing and internalizing problems from 2 to 4, and reductions in maternal depression from ages 2 to 3. In addition, reductions in maternal depression mediated improvements in both child externalizing and internalizing problem behavior after accounting for the potential mediating effects of improvements in positive parenting. The results are discussed with respect to targeting maternal depression in future intervention studies aimed at improving early child problem behavior. PMID:19338691

Early visual processing is enhanced in the midluteal phase of the menstrual cycle.

PubMed

Lusk, Bethany R; Carr, Andrea R; Ranson, Valerie A; Bryant, Richard A; Felmingham, Kim L

2015-12-01

Event-related potential (ERP) studies have revealed an early attentional bias in processing unpleasant emotional images in women. Recent neuroimaging data suggests there are significant differences in cortical emotional processing according to menstrual phase. This study examined the impact of menstrual phase on visual emotional processing in women compared to men. ERPs were recorded from 28 early follicular women, 29 midluteal women, and 27 men while they completed a passive viewing task of neutral and low- and high- arousing pleasant and unpleasant images. There was a significant effect of menstrual phase in early visual processing, as midluteal women displayed significantly greater P1 amplitude at occipital regions to all visual images compared to men. Both midluteal and early follicular women displayed larger N1 amplitudes than men (although this only reached significance for the midluteal group) to the visual images. No sex or menstrual phase differences were apparent in later N2, P3, or LPP. A condition effect demonstrated greater P3 and LPP amplitude to highly-arousing unpleasant images relative to all other stimuli conditions. These results indicate that women have greater early automatic visual processing compared to men, and suggests that this effect is particularly strong in women in the midluteal phase at the earliest stage of visual attention processing. Our findings highlight the importance of considering menstrual phase when examining sex differences in the cortical processing of visual stimuli. Copyright © 2015 Elsevier Ltd. All rights reserved.

Statistical controversies in clinical research: early-phase adaptive design for combination immunotherapies.

PubMed

Wages, N A; Slingluff, C L; Petroni, G R

2017-04-01

In recent years, investigators have asserted that the 3 + 3 design lacks flexibility, making its use in modern early-phase trial settings, such as combinations and/or biological agents, inefficient. More innovative approaches are required to address contemporary research questions, such as those posed in trials involving immunotherapies. We describe the implementation of an adaptive design for identifying an optimal treatment regimen, defined by low toxicity and high immune response, in an early-phase trial of a melanoma helper peptide vaccine plus novel adjuvant combinations. Operating characteristics demonstrate the ability of the method to effectively recommend optimal regimens in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined immunotherapy regimens. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of two small molecule inhibitors in relapsed/refractory mantle cell lymphoma. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The curvilinear relationship of early-life adversity and successful aging: the mediating role of mental health.

PubMed

Höltge, Jan; Mc Gee, Shauna L; Thoma, Myriam V

2018-02-15

The steeling effect suggests that early-life adversity can have a beneficial impact later in life. However, little is known about its underlying mechanisms and long-term outcomes . The study aimed to examine the role of early-life adversity (ELA) on successful aging, and whether this relationship can be explained by mental and physical health. Socio-demographics, early-life adversity (ELA), individual quality of life (iQoL), and mental and physical health of 270 individuals (M age = 66.82 years, 71.5% female) were assessed. Polynomial regressions and mediation analyses were conducted. Significant inverse U-shaped associations were found between ELA and iQoL (β = -.59, p = .005) and between ELA and mental health (β = -.64, p = .002), but not between ELA and physical health. Furthermore, mental health significantly mediated the relationship between ELA and iQoL (b = -.84, BCa CI [-1.66, -.27]). Highest level of individual quality of life (i.e. successful aging) was related to a moderate amount of ELA. Additionally, mental health significantly mediated this relationship. These findings suggest that some amount of ELA could be beneficial for successful aging. Resource-focused interventions are needed to improve health and promote successful aging for an underdetected, at-risk subgroup with low early-life adversity.

Early language mediates the relations between preschool inattention and school-age reading achievement.

PubMed

O'Neill, Sarah; Thornton, Veronica; Marks, David J; Rajendran, Khushmand; Halperin, Jeffrey M

2016-05-01

Early inattention is associated with later reading problems in children, but the mechanism by which this occurs is unclear. We investigated whether the negative relation between preschoolers' ADHD symptoms and 8-year-old reading achievement is directly related to the severity of inattention or is mediated by early language skills. Children (n = 150; 76% boys) were evaluated at 3 time points: preschool (T1), mean (SD) age = 4.24 (.49) years; 1 year later (T2), mean (SD) age = 5.28 (.50) years; and during school age (T3), mean (SD) age = 8.61 (.31) years. At T1, parents' Kiddie-SADS responses were dimensionalized to reflect ADHD severity. Children completed the Language domain of the NEPSY (i.e., A Developmental Neuropsychological Assessment) at T1 and again at T2. At T3, children completed the Wechsler Individual Achievement Test, Second Edition Word Reading, Pseudoword Decoding, Reading Comprehension, and Spelling subtests, and their teachers completed ratings of Reading and Written Expression performance in school. The mediating effect of T2 Language on the relation between preschool Inattention and age 8 Reading was examined using the nonparametric bootstrapping procedure, while controlling for T1 Language. Language ability at T2 mediated the path from preschool inattention (but not hyperactivity/impulsivity) to 8-year-old reading achievement (both test scores and ratings) after controlling for preschoolers' language ability. Early attentional deficits may negatively impact school-age reading outcomes by compromising the development of language skills, which in turn imperils later reading achievement. Screening children with attentional problems for language impairment, as well as implementing early intervention for both attentional and language problems may be critical to promote reading achievement during school years. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Serum Metabolomics Reveals Serotonin as a Predictor of Severe Dengue in the Early Phase of Dengue Fever

PubMed Central

Thein, Tun Linn; Fang, Jinling; Pang, Junxiong; Ooi, Eng Eong; Leo, Yee Sin; Ong, Choon Nam; Tannenbaum, Steven R.

2016-01-01

Effective triage of dengue patients early in the disease course for in- or out-patient management would be useful for optimal healthcare resource utilization while minimizing poor clinical outcome due to delayed intervention. Yet, early prognosis of severe dengue is hampered by the heterogeneity in clinical presentation and routine hematological and biochemical measurements in dengue patients that collectively correlates poorly with eventual clinical outcome. Herein, untargeted liquid-chromatography mass spectrometry metabolomics of serum from patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) in the febrile phase (<96 h) was used to globally probe the serum metabolome to uncover early prognostic biomarkers of DHF. We identified 20 metabolites that are differentially enriched (p<0.05, fold change >1.5) in the serum, among which are two products of tryptophan metabolism–serotonin and kynurenine. Serotonin, involved in platelet aggregation and activation decreased significantly, whereas kynurenine, an immunomodulator, increased significantly in patients with DHF, consistent with thrombocytopenia and immunopathology in severe dengue. To sensitively and accurately evaluate serotonin levels as prognostic biomarkers, we implemented stable-isotope dilution mass spectrometry and used convalescence samples as their own controls. DHF serotonin was significantly 1.98 fold lower in febrile compared to convalescence phase, and significantly 1.76 fold lower compared to DF in the febrile phase of illness. Thus, serotonin alone provided good prognostic utility (Area Under Curve, AUC of serotonin = 0.8). Additionally, immune mediators associated with DHF may further increase the predictive ability than just serotonin alone. Nine cytokines, including IFN-γ, IL-1β, IL-4, IL-8, G-CSF, MIP-1β, FGF basic, TNFα and RANTES were significantly different between DF and DHF, among which IFN-γ ranked top by multivariate statistics. Combining serotonin and IFN-γ improved

Paternal malparenting and offspring personality disorders: Mediating effect of early maladaptive schemas.

PubMed

Batool, Naila; Shehzadi, Humaira; Riaz, Muhammad Naveed; Riaz, Muhammad Akram

2017-04-01

To examine the mediating role of maladaptive schemas between permissive/authoritarian parenting by fathers and personality disorders, including histrionic, antisocial, narcissistic and depressive attitudes among adults. This cross-sectional study was conducted at the University of Sargodha, Sargodha, Pakistan, and comprised university students. Data was collected by administering the parental authority questionnaire, the young schema questionnaire and the personality diagnostic questionnaire. SPSS 23 was used for data analysis. The study was completed in one year. It was started from June 2014 and ended in June 2015. Of the 200 participants who were handed the questionnaires, 100(50%) returned it fully filled up. Of them, 87(87%) were women and 13(13%) were men. All scales had greater than 0.70 alpha reliability coefficients. The values of skewness for all scales ranged from 0.10 to 0.86.Permissive parenting style had positive correlation with histrionic (p<0.05), narcissistic (p<0.05) and antisocial personality disorders (p<0.01). Authoritarian parenting had positive correlation with early maladaptive schemas (p<0.01) and depressive personality disorder (p<0.05). Both permissive and authoritarian parenting styles led to personality disorders among offspring in the adult phase of their lives.

Exploring the victimization‒early substance misuse relationship: In search of moderating and mediating effects.

PubMed

Walters, Glenn D; Espelage, Dorothy L

2018-07-01

This study was designed to address two research questions. The first research question asked whether physical abuse victimization at the hands of parents/guardians, bullying victimization at the hands of peers, and the abuse x bullying interaction encouraged early involvement in substance misuse. The second research question inquired as to whether the victimization‒substance misuse relationship was mediated by variables proposed by various theories and research studies-specifically, cognitive impulsivity, negative affect, and low self-esteem. A moderated mediation hypothesis was tested in a group of 865 (417 boys, 448 girls) schoolchildren from the Illinois Study of Bullying and Sexual Violence who were 10 to 15 years of age at the time of initial contact. A path analysis performed with three waves of data revealed that physical abuse and bullying victimization predicted substance misuse with mediation by cognitive impulsivity, but there was no evidence of moderation. On the basis of these results, it was concluded that victimization, whether through parental physical abuse or peer bullying, increases cognitive impulsivity, and that cognitive impulsivity, in turn, encourages early involvement in substance misuse. The practical implications of these results are that interventions designed to counter cognitive impulsivity and encourage cognitive control may be effective in preventing children traumatized by physical abuse and bullying from entering the early stages of a drug or substance using lifestyle. Copyright © 2018 Elsevier Ltd. All rights reserved.

Recovering from early deprivation: attachment mediates effects of caregiving on psychopathology.

PubMed

McGoron, Lucy; Gleason, Mary Margaret; Smyke, Anna T; Drury, Stacy S; Nelson, Charles A; Gregas, Matthew C; Fox, Nathan A; Zeanah, Charles H

2012-07-01

Children exposed to early institutional rearing are at risk for developing psychopathology. The present investigation examines caregiving quality and the role of attachment security as they relate to symptoms of psychopathology in young children exposed to early institutionalization. Participants were enrolled in the Bucharest Early Intervention Project (BEIP), a longitudinal intervention study of children abandoned and placed in institutions at or shortly after birth. Measures included observed caregiving when children were 30 months of age, observed attachment security at 42 months, and caregiver reports of children's psychopathology at 54 months. At 54 months, some children remained in institutions, others were in foster care, others had been adopted domestically, and still others had been returned to their biological families. Thus, the children had experienced varying amounts of institutional rearing. After controlling for gender, quality of caregiving when children were 30 months old was associated with symptoms of multiple domains of psychopathology at 54 months of age. Ratings of security of attachment at 42 months mediated the associations between quality caregiving at 30 months and fewer symptoms of psychopathology at 54 months. Among deprived young children, high-quality caregiving at 30 months predicted reduced psychopathology and functional impairment at 54 months. Security of attachment mediated this relationship. Interventions for young children who have experienced deprivation may benefit from explicitly targeting caregiver-child attachment relationships. Copyright © 2012 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Integrating Crystallography into Early Metabolism Studies

NASA Astrophysics Data System (ADS)

Cruciani, Gabriele; Aristei, Yasmin; Goracci, Laura; Carosati, Emanuele

Since bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information to be produced early in the discovery phase. Once obtained, researchers can judge whether or not a potential candidate should be eliminated from the pipeline, or modified to improve chemical stability or safety. The use of in silico methods to predict the site of metabolism in Phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, which provides the site of metabolism for any CYP-mediated reaction acting on unknown substrates. The methodology can be applied automatically to all the cytochromes whose Xray 3D structure is known, but can be also applied to homology model 3D structures. The fully automated procedure can be used to detect positions that should be protected in order to avoid metabolic degradation, or to check the suitability of a new scaffold or pro-drug. Therefore the procedure is also a valuable new tool in early ADME-Tox, where drug-safety and metabolic profile patterns must be evaluated as soon, and as early, as possible.

Paternal involvement and early infant neurodevelopment: the mediation role of maternal parenting stress.

PubMed

Kim, Minjeong; Kang, Su-Kyoung; Yee, Bangsil; Shim, So-Yeon; Chung, Mira

2016-12-12

Father-child interactions are associated with improved developmental outcomes among infants. However, to the best of our knowledge, no study has addressed the effects of paternal involvement on the neurodevelopment of infants who are less than 6 months of age, and no study has reported how maternal parenting stress mediates the relationship between paternal involvement and infant neurodevelopment during early infancy. This study investigates the direct and indirect relationship between paternal involvement and infant neurodevelopment at 3-4 months of age. The indirect relationship was assessed through the mediating factor of maternal parenting stress. The participants were recruited through the Sesalmaul Research Center's website from April to June 2014. The final data included 255 mothers and their healthy infants, who were aged 3-4 months. The mothers reported paternal involvement and maternal parenting stress by using Korean Parenting Alliance Inventory (K-PAI) and Parenting Stress Index (PSI), respectively. Experts visited the participants' homes to observe infant neurodevelopment, and completed a developmental examination using Korean version of the Ages and Stages Questionnaire II (K-ASQ II). A hierarchical multiple regression analysis was used for data analysis. Infants' mean ages were 106 days and girls accounted for 46.3%. The mean total scores (reference range) of the K-PAI, PSI, and the K-ASQ II were 55.5 (17-68), 45.8 (25-100), and 243.2 (0-300), respectively. Paternal involvement had a positive relationship with K-ASQ II scores (β = 0.29, p < 0.001) at 3-4 months of age, whereas maternal parenting stress was negatively related with K-ASQ II scores (β = -0.32, p < 0.001). Maternal parenting stress mediated the relationship between paternal involvement and early infant neurodevelopment (Z = 3.24, p < 0.001). A hierarchical multiple regression analysis showed that paternal involvement reduced maternal parenting stress (�

Childhood abuse and late-life depression: Mediating effects of psychosocial factors for early- and late-onset depression.

PubMed

Wielaard, Ilse; Hoyer, Mathijs; Rhebergen, Didi; Stek, Max L; Comijs, Hannie C

2018-03-01

Childhood abuse makes people vulnerable to developing depression, even in late life. Psychosocial factors that are common in late life, such as loneliness or lack of a partner, may explain this association. Our aim was to investigate whether the association between childhood abuse and depression in older adults can be explained by psychosocial factors. Cross-sectional data were derived from the Netherlands Study of Depression in Older Persons (aged 60-93), including 132 without lifetime depression, 242 persons with an early-onset depression (<60 years), and 125 with a late-onset (≥60 years) depression. Childhood abuse (yes/no) and a frequency-based childhood abuse index were included. Multinomial regression and multivariable mediation analyses were used to examine the association between childhood abuse and the onset of depression, and the influence of loneliness, social network, and partner status. Multinomial regression analyses showed a significant association between childhood abuse and the childhood abuse index with early- and late-onset depression. Multivariable mediation analyses showed that the association between childhood abuse and early-onset depression was partly mediated by social network size and loneliness. This was particularly present for emotional neglect and psychological abuse, but not for physical and sexual abuse. No psychosocial mediators were found for the association between childhood abuse and late-onset depression. A smaller social network and feelings of loneliness mediate the association between childhood abuse and early-onset depression in older adults. Our findings show the importance of detecting childhood abuse as well as the age at depression onset and mapping of relevant psychosocial factors in the treatment of late-life depression. Copyright © 2018 John Wiley & Sons, Ltd.

Glucocorticoid-mediated Period2 induction delays the phase of circadian rhythm

PubMed Central

Cheon, Solmi; Park, Noheon; Cho, Sehyung; Kim, Kyungjin

2013-01-01

Glucocorticoid (GC) signaling synchronizes the circadian rhythm of individual peripheral cells and induces the expression of circadian genes, including Period1 (Per1) and Period2 (Per2). However, no GC response element (GRE) has been reported in the Per2 promoter region. Here we report the molecular mechanisms of Per2 induction by GC signaling and its relevance to the regulation of circadian timing. We found that GC prominently induced Per2 expression and delayed the circadian phase. The overlapping GRE and E-box (GE2) region in the proximal Per2 promoter was responsible for GC-mediated Per2 induction. The GRE in the Per2 promoter was unique in that brain and muscle ARNT-like protein-1 (BMAL1) was essential for GC-induced Per2 expression, whereas other GRE-containing promoters, such as Per1 and mouse mammary tumor virus, responded to dexamethasone in the absence of BMAL1. This specialized regulatory mechanism was mediated by BMAL1-dependent binding of the GC receptor to GRE in Per2 promoter. When Per2 induction was abrogated by the mutation of the GRE or E-box, the circadian oscillation phase failed to be delayed compared with that of the wild-type. Therefore, the current study demonstrates that the rapid Per2 induction mediated by GC is crucial for delaying the circadian rhythm. PMID:23620290

Remembering Parents in Parent-Mediated Early Intervention: An Approach to Examining Impact on Parents and Families

ERIC Educational Resources Information Center

Wainer, Allison L.; Hepburn, Susan; McMahon Griffith, Elizabeth

2017-01-01

The goal of this review is to advance the discussion regarding meaningful outcomes of early intervention for children with autism spectrum disorder. The rapid growth in the development and evaluation of early intervention approaches for autism spectrum disorder includes both therapist-driven and parent-mediated interventions. The majority of…

Discovery of a vezatin-like protein for dynein-mediated early endosome transport

PubMed Central

Yao, Xuanli; Arst, Herbert N.; Wang, Xiangfeng; Xiang, Xin

2015-01-01

Early endosomes are transported bidirectionally by cytoplasmic dynein and kinesin-3, but how the movements are regulated in vivo remains unclear. Here our forward genetic study led to the discovery of VezA, a vezatin-like protein in Aspergillus nidulans, as a factor critical for early endosome distribution. Loss of vezA causes an abnormal accumulation of early endosomes at the hyphal tip, where microtubule plus ends are located. This abnormal accumulation depends on kinesin-3 and is due to a decrease in the frequency but not the speed of dynein-mediated early endosome movement. VezA-GFP signals are enriched at the hypha tip in an actin-dependent manner but are not obviously associated with early endosomes, thus differing from the early endosome association of the cargo adapter HookA (Hook in A. nidulans). On loss of VezA, HookA associates normally with early endosomes, but the interaction between dynein-dynactin and the early-endosome-bound HookA is significantly decreased. However, VezA is not required for linking dynein-dynactin to the cytosolic ∆C-HookA, lacking the cargo-binding C-terminus. These results identify VezA as a novel regulator required for the interaction between dynein and the Hook-bound early endosomes in vivo. PMID:26378255

Proteomic analysis of early phase of conidia germination in Aspergillus nidulans.

PubMed

Oh, Young Taek; Ahn, Chun-Seob; Kim, Jeong Geun; Ro, Hyeon-Su; Lee, Chang-Won; Kim, Jae Won

2010-03-01

In order to investigate proteins involved in early phase of conidia germination, proteomic analysis was performed using two-dimensional gel electrophoresis (2D-GE) in conjunction with MALDI-TOF mass spectrometry (MS). The expression levels of 241 proteins varied quantitatively with statistical significance (P<0.05) at the early phase of the germination stage. Out of these 57 were identified by MALDI-TOF MS. Through classification of physiological functions from Conserved Domain Database analysis, among the identified proteins, 21, 13, and 6 proteins were associated with energy metabolism, protein synthesis, and protein folding process, respectively. Interestingly, eight proteins, which are involved in detoxification of reactive oxygen species (ROS) including catalase A, thioredoxin reductase, and mitochondrial peroxiredoxin, were also identified. The expression levels of the genes were further confirmed using Northern blot and reverse transcriptase (RT)-PCR analyses. This study represents the first proteomic analysis of early phase of conidia germination and will contribute to a better understanding of the molecular events involved in conidia germination process. Copyright (c) 2009 Elsevier Inc. All rights reserved.

A Systematic Review of Fidelity of Implementation in Parent-Mediated Early Communication Intervention

ERIC Educational Resources Information Center

Lieberman-Betz, Rebecca G.

2015-01-01

This article examined the reporting of four elements of fidelity of implementation (FOI) in parent-mediated early communication treatment studies. Thirty-five studies were reviewed to extract information regarding reporting of dosage, adherence, quality, and participant responsiveness for both practitioners and parents involved in parent-delivered…

Cortisol Reactivity to Social Stress as a Mediator of Early Adversity on Risk and Adaptive Outcomes

ERIC Educational Resources Information Center

Conradt, Elisabeth; Abar, Beau; Lester, Barry M.; LaGasse, Linda L.; Shankaran, Seetha; Bada, Henrietta; Bauer, Charles R.; Whitaker, Toni M.; Hammond, Jane A.

2014-01-01

Children chronically exposed to stress early in life are at increased risk for maladaptive outcomes, though the physiological mechanisms driving these effects are unknown. Cortisol reactivity was tested as a mediator of the relation between prenatal substance exposure and/or early adversity on adaptive and maladaptive outcomes. Data were drawn…

Technology-Mediated Writing Instruction in the Early Literacy Program: Perils, Procedures, and Possibilities

ERIC Educational Resources Information Center

Beam, Sandra; Williams, Cheri

2015-01-01

The purpose of this qualitative case study was to examine one kindergarten teacher's use of digital and multimodal technologies to mediate early writing instruction and explore the students' appropriation of that instruction to support their independent writing. Data sources included observations of writing instruction, as well as students'…

Promoting Early Literacy via Practicing Invented Spelling: A Comparison of Different Mediation Routines

ERIC Educational Resources Information Center

Levin, Iris; Aram, Dorit

2013-01-01

The present study compared the effects of different mediation routines provided to kindergartners from families of low socioeconomic status on the students' invented spelling attempts and on their gains obtained on spelling and other early literacy skills (letter naming, sounds of letters, word segmentation, and word decoding). The effects of the…

Challenges and perspective of drug repurposing strategies in early phase clinical trials.

PubMed

Kato, Shumei; Moulder, Stacy L; Ueno, Naoto T; Wheler, Jennifer J; Meric-Bernstam, Funda; Kurzrock, Razelle; Janku, Filip

2015-01-01

Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies.

Critical roles of myeloid differentiation factor 88-dependent proinflammatory cytokine release in early phase clearance of Listeria monocytogenes in mice.

PubMed

Seki, Ekihiro; Tsutsui, Hiroko; Tsuji, Noriko M; Hayashi, Nobuki; Adachi, Keishi; Nakano, Hiroki; Futatsugi-Yumikura, Shizue; Takeuchi, Osamu; Hoshino, Katsuaki; Akira, Shizuo; Fujimoto, Jiro; Nakanishi, Kenji

2002-10-01

Listeria monocytogenes (LM), a facultative intracellular Gram-positive bacterium, often causes lethal infection of the host. In this study we investigated the molecular mechanism underlying LM eradication in the early phase of infection. Upon infection with LM, both IL-12 and IL-18 were produced, and then they synergistically induced IFN-gamma production, leading to normal LM clearance in the host. IFN-gamma knockout (KO) mice were highly susceptible to LM infection. IL-12/IL-18 double knockout mice were also highly susceptible. Their susceptibility was less than that of IFN-gamma KO mice, but more than that of single IL-12 or IL-18 KO mice. Mice deficient in myeloid differentiation factor 88 (MyD88), an essential adaptor molecule used by signal transduction pathways of all members of the Toll-like receptor (TLR) family, showed an inability to produce IL-12 and IFN-gamma following LM infection and were most susceptible to LM. Furthermore, MyD88-deficient, but not IFN-gamma-deficient, Kupffer cells could not produce TNF-alpha in response to LM in vitro, indicating the importance of MyD88-dependent TNF-alpha production for host defense. As TLR2 KO, but not TLR4 KO, mice showed partial impairment in their capacity to produce IL-12, IFN-gamma, and TNF-alpha, TLR2 activation partly contributed to the induction of IL-12-mediated IFN-gamma production. These results indicated a critical role for TLRs/MyD88-dependent IL-12/TNF-alpha production and for IL-12- and IL-18-mediated IFN-gamma production in early phase clearance of LM.

Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage.

PubMed

Liu, Jie; Jin, Xinchun; Liu, Ke J; Liu, Wenlan

2012-02-29

Blood-brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here, we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran and promoted the secretion of metalloproteinase-2 and -9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT (2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane) or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity, and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2 h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis.

Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood brain barrier damage in early ischemic stroke stage

PubMed Central

Liu, Jie; Jin, Xinchun; Liu, Ke J.; Liu, Wenlan

2012-01-01

Blood brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran, and promoted the secretion of metalloproteinase-2 and 9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2-h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis. PMID:22378877

Phase III Early Restoration Meeting - Galveston, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Impact of incretin on early-phase insulin secretion and glucose excursion.

PubMed

Shen, Jie; Chen, Zhi; Chen, Chaofeng; Zhu, Xiao; Han, Yajuan

2013-10-01

This study investigated the impact of incretin on early-phase insulin secretion and glucose excursion. The normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) groups included 16, 8, and 19 subjects, respectively. Subjects underwent continuous glucose monitoring for 3 days, followed by an oral glucose tolerance test. Plasma glucose, insulin, glucagon, total glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-l (GLP-1) levels were measured at 30-min increments for 2 h after glucose intake. Differences with P < 0.05 were considered statistically significant. The area under the curve (AUC) of total GIP (120-min GIP-AUC) of the T2DM group was significantly lower than those of the NGT and IGT groups. The 120-min GLP-1-AUC of the NGT group was significantly larger than those of the T2DM and IGT groups. The early-phase insulin secretion index (ΔI30/ΔG30) of the T2DM group was significantly lower than those of the NGT and IGT groups. Mean amplitudes of glycemic excursions (MAGEs) went in the order of NGT < IGT < T2DM (P < 0.01, IGT vs. NGT; P < 0.001, T2DM vs. IGT). The 120-min GIP-AUC was negatively correlated with MAGE (r = -0.464), but uncorrelated with ΔI30/ΔG30. The 120-min GLP-1-AUC was positively correlated with ΔI30/ΔG30 (r = 0.580), but negatively correlated with MAGE (r = -0.606). Incretin may ameliorate glucose excursions, and GLP-1 may exert them by promoting early-phase insulin secretion. No correlation was observed between GIP secretion and early-phase insulin secretion.

The Potential Link between Gut Microbiota and IgE-Mediated Food Allergy in Early Life

PubMed Central

Molloy, John; Allen, Katrina; Collier, Fiona; Tang, Mimi L. K.; Ward, Alister C.; Vuillermin, Peter

2013-01-01

There has been a dramatic rise in the prevalence of IgE-mediated food allergy over recent decades, particularly among infants and young children. The cause of this increase is unknown but one putative factor is a change in the composition, richness and balance of the microbiota that colonize the human gut during early infancy. The coevolution of the human gastrointestinal tract and commensal microbiota has resulted in a symbiotic relationship in which gut microbiota play a vital role in early life immune development and function, as well as maintenance of gut wall epithelial integrity. Since IgE mediated food allergy is associated with immune dysregulation and impaired gut epithelial integrity there is substantial interest in the potential link between gut microbiota and food allergy. Although the exact link between gut microbiota and food allergy is yet to be established in humans, recent experimental evidence suggests that specific patterns of gut microbiota colonization may influence the risk and manifestations of food allergy. An understanding of the relationship between gut microbiota and food allergy has the potential to inform both the prevention and treatment of food allergy. In this paper we review the theory and evidence linking gut microbiota and IgE-mediated food allergy in early life. We then consider the implications and challenges for future research, including the techniques of measuring and analyzing gut microbiota, and the types of studies required to advance knowledge in the field. PMID:24351744

Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

PubMed Central

Aigbirhio, Franklin I.; Fryer, Tim D.; Menon, David K.; Warburton, Elizabeth A.; Baron, Jean-Claude

2015-01-01

Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1–6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD. PMID:26439113

Receptor-Mediated and Fluid-Phase Transcytosis of Horseradish Peroxidase across Rat Hepatocytes

PubMed Central

Ellinger, Isabella; Fuchs, Renate

2010-01-01

Horseradish peroxidase (HRP) is often used as a fluid-phase marker to characterize endocytic and transcytotic processes. Likewise, it has been applied to investigate the mechanisms of biliary secretion of fluid in rat liver hepatocytes. However, HRP contains mannose residues and thus binds to mannose receptors (MRs) on liver cells, including hepatocytes. To study the role of MR-mediated endocytosis of HRP transport in hepatocytes, we determined the influence of the oligosaccharid mannan on HRP biliary secretion in the isolated perfused rat liver. A 1-minute pulse of HRP was applied followed by marker-free perfusion. HRP appeared in bile with biphasic kinetics: a first peak at 7 minutes and a second peak at 15 minutes after labeling. Perfusion with 0.8 mg/mL HRP in the presence of a twofold excess of mannan reduced the first peak by 41% without effect on the second one. Together with recently published data on MR expression in rat hepatocytes this demonstrates two different mechanisms for HRP transcytosis: a rapid, receptor-mediated transport and a slower fluid-phase transport. PMID:20168981

From CNTNAP2 to Early Expressive Language in Infancy: The Mediation Role of Rapid Auditory Processing.

PubMed

Riva, Valentina; Cantiani, Chiara; Benasich, April A; Molteni, Massimo; Piazza, Caterina; Giorda, Roberto; Dionne, Ginette; Marino, Cecilia

2018-06-01

Although it is clear that early language acquisition can be a target of CNTNAP2, the pathway between gene and language is still largely unknown. This research focused on the mediation role of rapid auditory processing (RAP). We tested RAP at 6 months of age by the use of event-related potentials, as a mediator between common variants of the CNTNAP2 gene (rs7794745 and rs2710102) and 20-month-old language outcome in a prospective longitudinal study of 96 Italian infants. The mediation model examines the hypothesis that language outcome is explained by a sequence of effects involving RAP and CNTNAP2. The ability to discriminate spectrotemporally complex auditory frequency changes at 6 months of age mediates the contribution of rs2710102 to expressive vocabulary at 20 months. The indirect effect revealed that rs2710102 C/C was associated with lower P3 amplitude in the right hemisphere, which, in turn, predicted poorer expressive vocabulary at 20 months of age. These findings add to a growing body of literature implicating RAP as a viable marker in genetic studies of language development. The results demonstrate a potential developmental cascade of effects, whereby CNTNAP2 drives RAP functioning that, in turn, contributes to early expressive outcome.

Early Risk Reduction Phase 1 FLIR/Laser Designator Window. Revision

DTIC Science & Technology

1991-12-31

Sandwich-Type FLIR Windows," Air Force AFWAL-TR-83- 4122, Nov 1983. 4-1 Hughes Danbury Optical Systems Final Report, "ATA Window Technology Program," PRBll...Risk Reduction -- Phase I, Optical Properties Measurement Techniques of Three Wide Band Window Materials," 22 August 1991. xii I i 86PR0869 30... Optical Systems, Lexington, MA, 02173, 1 Feb 1991. 5-7 McDonnell Aircraft Company Technical Memorandum TM 256.91.0056.01, "Early Risk Reduction -- Phase

Mediation of early maladaptive schemas between perceptions of parental rearing style and personality disorder symptoms.

PubMed

Thimm, Jens C

2010-03-01

In schema therapy (ST), early maladaptive schemas (EMS) are proposed to be the defining core of personality disorders. Adverse relational experiences in childhood are assumed to be the main cause for the development of EMS. The present study explored the links between perceived parental rearing behaviours, EMS, and personality disorder symptoms in a clinical sample (N=108). Results from mediation analyses suggest that EMS mediate the relationships between recalled parenting rearing behaviours and personality disorder symptoms. Findings give support to the theoretical model ST is based on.

Maternal Warmth and Early Adolescents' Internalizing Symptoms and Externalizing Behavior: Mediation via Emotional Insecurity

ERIC Educational Resources Information Center

Alegre, Albert; Benson, Mark J.; Pérez-Escoda, Núria

2014-01-01

This study examines the relation between maternal warmth and the internalizing and externalizing problems of early adolescents, and the potential mediation of this relation by emotional insecurity. The hypotheses for the study derive from Cummings and Davies' theory of emotional security. The current study extends the theory to security processes…

Rab7 Associates with Early Endosomes to Mediate Sorting and Transport of Semliki Forest Virus to Late Endosomes

PubMed Central

Vonderheit, Andreas

2005-01-01

Semliki forest virus (SFV) is internalized by clathrin-mediated endocytosis, and transported via early endosomes to late endosomes and lysosomes. The intracellular pathway taken by individual fluorescently labeled SFV particles was followed using immunofluorescence in untransfected cells, and by video-enhanced, triple-color fluorescence microscopy in live cells transfected with GFP- and RFP-tagged Rab5, Rab7, Rab4, and Arf1. The viruses progressed from Rab5-positive early endosomes to a population of early endosomes (about 10% of total) that contained both Rab5 and Rab7. SFV were sequestered in the Rab7 domains, and they were sorted away from the early endosomes when these domains detached as separate transport carriers devoid of Rab5, Rab4, EEA1, Arf1, and transferrin. The process was independent of Arf1 and the acidic pH in early endosomes. Nocodazole treatment showed that the release of transport carriers was assisted by microtubules. Expression of constitutively inactive Rab7T22N resulted in accumulation of SFV in early endosomes. We concluded that Rab7 is recruited to early endosomes, where it forms distinct domains that mediate cargo sorting as well as the formation of late-endosome-targeted transport vesicles. PMID:15954801

Delinquent-oriented attitudes mediate the relation between parental inconsistent discipline and early adolescent behavior.

PubMed

Halgunseth, Linda C; Perkins, Daniel F; Lippold, Melissa A; Nix, Robert L

2013-04-01

Although substantial research supports the association between parental inconsistent discipline and early adolescent behaviors, less is understood on mechanisms underlying this relation. This study examined the mediating influence of delinquent-oriented attitudes in early adolescence. Using a longitudinal sample of 324 rural adolescents and their parents, findings revealed that inconsistent discipline in sixth grade predicted an increase in adolescent delinquent-oriented attitudes by seventh grade which, in turn, predicted both an increase in early adolescent antisocial behaviors and a decrease in socially competent behaviors by eighth grade. Therefore, it appears that accepting attitudes toward delinquency may in part develop from experiencing inconsistent discipline at home and may offer a possible explanation as to why early adolescents later engage in more antisocial and less socially competent behaviors. Findings may inform family-based preventive intervention programs that seek to decrease behavior problems and promote social competence in early adolescents. (PsycINFO Database Record (c) 2013 APA, all rights reserved).

Delinquent-Oriented Attitudes Mediate the Relation Between Parental Inconsistent Discipline and Early Adolescent Behavior

PubMed Central

Halgunseth, Linda C.; Perkins, Daniel F.; Lippold, Melissa A.; Nix, Robert L.

2013-01-01

Although substantial research supports the association between parental inconsistent discipline and early adolescent behaviors, less is understood on mechanisms underlying this relation. This study examined the mediating influence of delinquent-oriented attitudes in early adolescence. Using a longitudinal sample of 324 rural adolescents and their parents, findings revealed that inconsistent discipline in 6th grade predicted an increase in adolescent delinquent-oriented attitudes by 7th grade which, in turn, predicted both an increase in early adolescent antisocial behaviors and a decrease in socially competent behaviors by 8th grade. Therefore, it appears that accepting attitudes toward delinquency may in part develop from experiencing inconsistent discipline at home and may offer a possible explanation as to why early adolescents later engage in more antisocial and less socially competent behaviors. Findings may inform family-based preventive intervention programs that seek to decrease behavior problems and promote social competence in early adolescents. PMID:23544924

Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT

DTIC Science & Technology

2016-08-01

AWARD NUMBER: W81XWH-12-1-0138 TITLE: Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT PRINCIPAL INVESTIGATOR...NUMBER W81XWH-12-1-0138 Early Detection of Amyloid Plaque in Alzheimer’s Disease via X-ray Phase CT 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6...method for early detection of amyloid plaque in Alzheimer’s disease , with three Specific Aims: #1 Develop and optimize an x-ray PCCT to explore the

Complementary Gli activity mediates early patterning of the mouse visual system.

PubMed

Furimsky, Marosh; Wallace, Valerie A

2006-03-01

The Sonic hedgehog (Shh) signaling pathway plays a key role in the development of the vertebrate central nervous system, including the eye. This pathway is mediated by the Gli transcription factors (Gli1, Gli2, and Gli3) that differentially activate and repress the expression of specific downstream target genes. In this study, we investigated the roles of the three vertebrate Glis in mediating midline Shh signaling in early ocular development. We examined the ocular phenotypes of Shh and Gli combination mutant mouse embryos and monitored proximodistal and dorsoventral patterning by the expression of specific eye development regulatory genes using in situ hybridization. We show that midline Shh signaling relieves the repressor activity of Gli3 adjacent to the midline and then promotes eye pattern formation through the nonredundant activities of all three Gli proteins. Gli3, in particular, is required to specify the dorsal optic stalk and to define the boundary between the optic stalk and the optic cup.

Chemical phase analysis of seed mediated synthesized anisotropic silver nanoparticles

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

Bharti, Amardeep, E-mail: abharti@pu.ac.in; Goyal, Navdeep; Singh, Suman

Noble-metal nanoparticles are of great interest because of its broad applications almost in every stream (i.e. biology, chemistry and engineering) due to their unique size/shape dependant properties. In this paper, chemical phase of seed mediated synthesized anisotropic silver nanoparticle (AgNPs) has been investigated via fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA). These nanaoparticles were synthesized by seed-growth method controlled by urea and dextrose results to highly stable 12-20 nm particle size revealed by zeta potential and transmission electron microscopy (TEM)

Neighborhood Deprivation during Early Childhood and Conduct Problems in Middle Childhood: Mediation by Aggressive Response Generation.

PubMed

Galán, Chardée A; Shaw, Daniel S; Dishion, Thomas J; Wilson, Melvin N

2017-07-01

The tremendous negative impact of conduct problems to the individual and society has provided the impetus for identifying risk factors, particularly in early childhood. Exposure to neighborhood deprivation in early childhood is a robust predictor of conduct problems in middle childhood. Efforts to identify and test mediating mechanisms by which neighborhood deprivation confers increased risk for behavioral problems have predominantly focused on peer relationships and community-level social processes. Less attention has been dedicated to potential cognitive mediators of this relationship, such as aggressive response generation, which refers to the tendency to generate aggressive solutions to ambiguous social stimuli with negative outcomes. In this study, we examined aggressive response generation, a salient component of social information processing, as a mediating process linking neighborhood deprivation to later conduct problems at age 10.5. Participants (N = 731; 50.5 % male) were drawn from a multisite randomized prevention trial that includes an ethnically diverse and low-income sample of male and female children and their primary caregivers followed prospectively from toddlerhood to middle childhood. Results indicated that aggressive response generation partially mediated the relationship between neighborhood deprivation and parent- and teacher-report of conduct problems, but not youth-report. Results suggest that the detrimental effects of neighborhood deprivation on youth adjustment may occur by altering the manner in which children process social information.

Neighborhood Deprivation during Early Childhood and Conduct Problems in Middle Childhood: Mediation by Aggressive Response Generation

PubMed Central

Shaw, Daniel S.; Dishion, Thomas J.; Wilson, Melvin N.

2018-01-01

The tremendous negative impact of conduct problems to the individual and society has provided the impetus for identifying risk factors, particularly in early childhood. Exposure to neighborhood deprivation in early childhood is a robust predictor of conduct problems in middle childhood. Efforts to identify and test mediating mechanisms by which neighborhood deprivation confers increased risk for behavioral problems have predominantly focused on peer relationships and community-level social processes. Less attention has been dedicated to potential cognitive mediators of this relationship, such as aggressive response generation, which refers to the tendency to generate aggressive solutions to ambiguous social stimuli with negative outcomes. In this study, we examined aggressive response generation, a salient component of social information processing, as a mediating process linking neighborhood deprivation to later conduct problems at age 10.5. Participants (N = 731; 50.5 % male) were drawn from a multisite randomized prevention trial that includes an ethnically diverse and low-income sample of male and female children and their primary caregivers followed prospectively from toddlerhood to middle childhood. Results indicated that aggressive response generation partially mediated the relationship between neighborhood deprivation and parent- and teacher-report of conduct problems, but not youth-report. Results suggest that the detrimental effects of neighborhood deprivation on youth adjustment may occur by altering the manner in which children process social information. PMID:27696324

Parenting, Marital Conflict and Adjustment from Early- To Mid-Adolescence: Mediated by Adolescent Attachment Style?

ERIC Educational Resources Information Center

Doyle, Anna Beth; Markiewicz, Dorothy

2005-01-01

Contributions of 3 dimensions of parenting (psychological control, warmth, and behavioural control), marital conflict, and attachment style (anxiety and avoidance) to adjustment from early to middle adolescence were assessed. Mediation of marital conflict effects by parenting, and of parenting effects by attachment were examined. Adolescents (n =…

Wide-field phase imaging for the endoscopic detection of dysplasia and early-stage esophageal cancer

NASA Astrophysics Data System (ADS)

Fitzpatrick, C. R. M.; Gordon, G. S. D.; Sawyer, T. W.; Wilkinson, T. D.; Bohndiek, S. E.

2018-02-01

Esophageal cancer has a 5-year survival rate below 20%, but can be curatively resected if it is detected early. At present, poor contrast for early lesions in white light imaging leads to a high miss rate in standard-of- care endoscopic surveillance. Early lesions in the esophagus, referred to as dysplasia, are characterized by an abundance of abnormal cells with enlarged nuclei. This tissue has a different refractive index profile to healthy tissue, which results in different light scattering properties and provides a source of endogenous contrast that can be exploited for advanced endoscopic imaging. For example, point measurements of such contrast can be made with scattering spectroscopy, while optical coherence tomography generates volumetric data. However, both require specialist interpretation for diagnostic decision making. We propose combining wide-field phase imaging with existing white light endoscopy in order to provide enhanced contrast for dysplasia and early-stage cancer in an image format that is familiar to endoscopists. Wide-field phase imaging in endoscopy can be achieved using coherent illumination combined with phase retrieval algorithms. Here, we present the design and simulation of a benchtop phase imaging system that is compatible with capsule endoscopy. We have undertaken preliminary optical modelling of the phase imaging setup, including aberration correction simulations and an investigation into distinguishing between different tissue phantom scattering coefficients. As our approach is based on phase retrieval rather than interferometry, it is feasible to realize a device with low-cost components for future clinical implementation.

Nucleation and Epitaxy-Mediated Phase Transformation of a Precursor Cadmium Carbonate Phase at the Calcite/Water Interface

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

Riechers, Shawn L.; Rosso, Kevin M.; Kerisit, Sebastien N.

Mineral nucleation can be catalyzed by the presence of mineral substrates; however, the mechanisms of heterogeneous nucleation remain poorly understood. A combination of in situ time-sequenced measurements and nano-manipulation experiments were performed using atomic force microscopy (AFM) to probe the mechanisms of heteroepitaxial nucleation of otavite (CdCO3) on calcite (CaCO3) single crystals that exposed the (10-14) surface. Otavite and calcite are isostructural carbonates that display a 4% lattice mismatch, based on their (10-14) surface areas. AFM observations revealed a two-stage process in the nucleation of cadmium carbonate surface precipitates. As evidenced by changes in height, shape, growth behavior, and frictionmore » signal of the precipitates, a precursor phase was observed to initially form on the surface and subsequently undergo an epitaxy-mediated phase transformation to otavite, which then grew epitaxially. Nano-manipulation experiments, in which the applied force was increased progressively until precipitates were removed from the surface, showed that adhesion of the precursor phase to the substrate was distinctively weaker than that of the epitaxial phase, consistent with that of an amorphous phase. These findings demonstrate for the first time that heterogeneous mineral nucleation can follow a non-classical pathway like that found in homogenous aqueous conditions.« less

Accumulation of unsaturated lipids in monocytes during early phase pyrogen tolerance.

PubMed

Szewczenko-Pawlikowski, M; Kozak, W

2000-04-12

This paper presents data that inspired a new explanation for the mechanism of early phase endotoxin tolerance. Rabbits injected intravenously with LPS from Salmonella abortus developed a two-phase fever (6 h) and monophasic hyperlipidemia of very low density lipoproteins (two consecutive days). If during these days rabbits were injected with the same dose of LPS at 24-h intervals, the second phase of fever disappeared, i.e. early phase pyrogenic tolerance was obtained. This was correlated with a decrease of lipoprotein hyperlipidemia (measured 1.5 h after LPS injection) and an accumulation of lipids rich in double bonds in monocytes (measured 3.5 h after LPS injection). Results showed that the degree of unsaturation of acyl chains (AC) in monocytes (AC/DB, DB=double bonds) is negatively correlated (r=-0.72) with fever response (fever index). The authors maintain that a gradual increase in monocyte membrane fluidity is an adaptation to repeated exposure of monocytes to lipid A and is responsible for the progressive desensitization of monocytes to endotoxin. It is suggested that disorders of this mechanism lead to an accumulation of abnormal quantities of saturated lipids and cholesterol within macrophages, which, as foam cells, are the starting point for atherosclerosis pathology.

Phase III Early Restoration Meeting - Port Arthur, TX | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Phase III Early Restoration Meeting - Panama City, FL | NOAA Gulf Spill

Science.gov Websites

Areas Alabama Florida Louisiana Mississippi Texas Region-wide Open Ocean Data Media & News planning for Phase III and future early restoration plans. Open House: 6:00pm Public Meeting: 6:30pm

Beryllium and boron constraints on an early Galactic bright phase

NASA Technical Reports Server (NTRS)

Fields, Brian D.; Schramm, David N.; Truran, James W.

1993-01-01

The recent observations of Be and B in metal-deficient halo dwarfs are used to constrain a 'bright phase' of enhanced cosmic-ray flux in the early Galaxy. Assuming that this Be and B arises from cosmic-ray spallation in the early Galaxy, limits are placed on the intensity of the early (Population II) cosmic-ray flux relative to the present (Population I) flux. A simple estimate of bounds on the flux ratio is 1 - 40. This upper bound would restrict galaxies like our own from producing neutrino fluxes that would be detectable in any currently proposed detectors. It is found that the relative enhancement of the early flux varies inversely with the relative time of enhancement. It is noted that associated gamma-ray production via pp - pi sup 0 pp may be a significant contribution to the gamma-ray background above 100 MeV.

Early Childhood Technology Integrated Instructional System (EC-TIIS) Phase 1: A Final Report

ERIC Educational Resources Information Center

Hutinger, Patricia; Robinson, Linda; Schneider, Carol

2004-01-01

The Early Childhood Technology Integrated Instructional System (EC-TIIS), a Steppingstones of Technology Innovation Phase 1--Development project, was developed by the Center for Best Practices in Early Childhood (the Center) at Western Illinois University as an online instructional system. EC-TIIS' ultimate goal was to improve technology services…

Dispositional Optimism and Therapeutic Expectations in Early Phase Oncology Trials

PubMed Central

Jansen, Lynn A.; Mahadevan, Daruka; Appelbaum, Paul S.; Klein, William MP; Weinstein, Neil D.; Mori, Motomi; Daffé, Racky; Sulmasy, Daniel P.

2016-01-01

Purpose Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early phase oncology trials. Optimism, however, is not a unitary construct – it can also be defined as a general disposition, or what is called dispositional optimism. We assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. We also assessed how dispositional optimism related to unrealistic optimism. Methods Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Results Dispositional optimism was significantly associated with higher expectations for personal therapeutic benefit (Spearman r=0.333, p<0.0001), but was not associated with the therapeutic misconception. (Spearman r=−0.075, p=0.329). Dispositional optimism was weakly associated with unrealistic optimism (Spearman r=0.215, p=0.005). In multivariate analysis, both dispositional optimism (p=0.02) and unrealistic optimism (p<0.0001) were independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (p=.0001), but not dispositional optimism, was independently associated with the therapeutic misconception. Conclusion High expectations for therapeutic benefit among patient-subjects in early phase oncology trials should not be assumed to result from misunderstanding of specific information about the trials. Our data reveal that these expectations are associated with either a dispositionally positive outlook on life or biased expectations about specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have different consequences for informed consent in early phase oncology research. PMID:26882017

Self-esteem in Early Adolescence as Predictor of Depressive Symptoms in Late Adolescence and Early Adulthood: The Mediating Role of Motivational and Social Factors.

PubMed

Masselink, M; Van Roekel, E; Oldehinkel, A J

2018-05-01

Ample research has shown that low self-esteem increases the risk to develop depressive symptoms during adolescence. However, the mechanism underlying this association remains largely unknown, as well as how long adolescents with low self-esteem remain vulnerable to developing depressive symptoms. Insight into this mechanism may not only result in a better theoretical understanding but also provide directions for possible interventions. To address these gaps in knowledge, we investigated whether self-esteem in early adolescence predicted depressive symptoms in late adolescence and early adulthood. Moreover, we investigated a cascading mediational model, in which we focused on factors that are inherently related to self-esteem and the adolescent developmental period: approach and avoidance motivation and the social factors social contact, social problems, and social support. We used data from four waves of the TRAILS study (N = 2228, 51% girls): early adolescence (mean age 11 years), middle adolescence (mean age 14 years), late adolescence (mean age 16 years), and early adulthood (mean age 22 years). Path-analyses showed that low self-esteem is an enduring vulnerability for developing depressive symptoms. Self-esteem in early adolescence predicted depressive symptoms in late adolescence as well as early adulthood. This association was independently mediated by avoidance motivation and social problems, but not by approach motivation. The effect sizes were relatively small, indicating that having low self-esteem is a vulnerability factor, but does not necessarily predispose adolescents to developing depressive symptoms on their way to adulthood. Our study contributes to the understanding of the mechanisms underlying the association between self-esteem and depressive symptoms, and has identified avoidance motivation and social problems as possible targets for intervention.

The Association of Birth Complications and Externalizing Behavior in Early Adolescents: Direct and Mediating Effects

PubMed Central

Liu, Jianghong; Raine, Adrian; Wuerker, Anne; Venables, Peter H.; Mednick, Sarnoff

2012-01-01

Prior studies have shown that birth complications interact with psychosocial risk factors in predisposing to increased externalizing behavior in childhood and criminal behavior in adulthood. However, little is known about the direct relationship between birth complications and externalizing behavior. Furthermore, the mechanism by which the birth complications predispose to externalizing behavior is not well explored. This study aims to assess whether birth complications predispose to early adolescent externalizing behavior and to test whether Intelligence Quotient (IQ) mediates relationships between predictor and outcome variables. We used data from a prospective, longitudinal birth cohort of 1,795 3-year-old boys and girls from Mauritius to test hypotheses. Birth complications were assessed from hospital record data, malnutrition from a pediatric exam at age 3 years, psychosocial adversity from parental interviews at age 3 years, and externalizing behavior problems from parental ratings at age 11 years. We found that babies with birth complications are more likely to develop externalizing behavior problems at age 11. Low IQ was associated with birth complications and was found to mediate the link between early predictors and later externalizing behavior. These prospective, longitudinal findings have potential clinical implications for the identification of early adolescent externalizing behavior and for public health attempts to prevent the occurrence of child externalizing behavior problems. PMID:22485069

Developmental trajectories and longitudinal mediation effects of self-esteem, peer attachment, child maltreatment and depression on early adolescents.

PubMed

Ju, Soyoung; Lee, Yanghee

2018-02-01

The purpose of this study is to identify the developmental trajectories of peer attachment, self-esteem, depression, and child maltreatment, and to understand the longitudinal mediation effects that peer attachment and self-esteem have on the influence of perceived abuse on early adolescent depression. This study uses Year 1 to Year 5 data of the 4th grader panel of the Korea Youth Panel Survey (KYPS) and utilizes a multivariate latent growth model to analyze the main variables in the applicable data between 5th (i.e., Year 2) and 8th (i.e., Year 5) grades. The results indicate that from the 5th to the 8th grade, the degree of abuse and depression increases while self-esteem gradually decreases with slowly lowering peer attachment. A significant distribution of the initial values and the rate of change were present for all main variables of the study, confirming individual differences in time wise changes. Further, more exposure to abuse correlated with a decrease in self-esteem, while an increase in self-esteem greatly reduced depression. The initial value of self-esteem showed a partial mediation effect, whereas the rate of change indicated a full mediation effect with a significant longitudinal mediation effect. More experience of abuse during early adolescence indicated a lower degree of peer attachment, and a higher peer attachment was related to decreased depression. A significant partial mediation effect was present for both the initial value and the rate of change of peer attachment, and a longitudinal mediation effect was present. This study confirmed that self-esteem in early adolescents is an important protective factor that can greatly reduce the degree of depression, and suggests continuous interventions conducted to increase self-esteem in adolescence. Furthermore, by determining that peer attachment decreases the degree of depression in children at risk, the study emphasizes the healing aspect of adolescent peer attachment. Copyright © 2017 Elsevier

78 FR 39736 - Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-02

..., choosing a study population, using a control group and blinding, dose selection, treatment plans...] Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular... document entitled ``Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of...

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide-a for early-stage cancer of the larynx: Phase Ib study.

PubMed

Shafirstein, Gal; Rigual, Nestor R; Arshad, Hassan; Cooper, Michele T; Bellnier, David A; Wilding, Gregory; Tan, Wei; Merzianu, Mihai; Henderson, Barbara W

2016-04-01

The purpose of this study was for us to report results regarding the safety of 3-(1'-hexyloxyethyl) pyropheophorbide-a (HPPH) mediated photodynamic therapy (PDT) in early laryngeal disease, and offer preliminary information on treatment responses. A single-institution, phase Ib, open label, noncomparative study of HPPH-PDT in patients with high-risk dysplasia, carcinoma in situ, and T1 squamous cell carcinoma (SCC) of the larynx. The primary outcomes were safety and maximum tolerated dose (MTD), and the secondary outcome was response. Twenty-nine patients and 30 lesions were treated. The most common adverse event (AE) was transient hoarseness of voice. Severe edema, requiring tracheostomy, was the most serious AE, which occurred in 2 patients within several hours of therapy. The MTD was 100 J/cm(2) . Patients with T1 SCC seemed to have good complete response rate (82%) to HPPH-PDT at MTD. HPPH-PDT can be safely used to treat early-stage laryngeal cancer, with potential efficacy. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E377-E383, 2016. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc.

Longitudinal pathways from early maternal depression to children's dysregulated representations: a moderated mediation analysis of harsh parenting and gender.

PubMed

Martoccio, Tiffany L; Brophy-Herb, Holly E; Maupin, Angela N; Robinson, Joann L

2016-01-01

There is some evidence linking maternal depression, harsh parenting, and children's internal representations of attachment, yet, longitudinal examinations of these relationships and differences in the developmental pathways between boys and girls are lacking. Moderated mediation growth curves were employed to examine harsh parenting as a mechanism underlying the link between maternal depression and children's dysregulated representations using a nationally-representative, economically-vulnerable sample of mothers and their children (n = 575; 49% boys, 51% girls). Dysregulation representations were measured using the MacArthur Story Stem Battery at five years of age (M = 5.14, SD = 0.29). Harsh parenting mediated the association between early maternal depression and dysregulated representations for girls. Though initial harsh parenting was a significant mediator for boys, a stronger direct effect of maternal depression to dysregulated representations emerged over time. Results are discussed in terms of their implications for intervention efforts aimed at promoting early supportive parenting.

SMC1-Mediated Intra-S-Phase Arrest Facilitates Bocavirus DNA Replication

PubMed Central

Luo, Yong; Deng, Xuefeng; Cheng, Fang; Li, Yi

2013-01-01

Activation of a host DNA damage response (DDR) is essential for DNA replication of minute virus of canines (MVC), a member of the genus Bocavirus of the Parvoviridae family; however, the mechanism by which DDR contributes to viral DNA replication is unknown. In the current study, we demonstrate that MVC infection triggers the intra-S-phase arrest to slow down host cellular DNA replication and to recruit cellular DNA replication factors for viral DNA replication. The intra-S-phase arrest is regulated by ATM (ataxia telangiectasia-mutated kinase) signaling in a p53-independent manner. Moreover, we demonstrate that SMC1 (structural maintenance of chromosomes 1) is the key regulator of the intra-S-phase arrest induced during infection. Either knockdown of SMC1 or complementation with a dominant negative SMC1 mutant blocks both the intra-S-phase arrest and viral DNA replication. Finally, we show that the intra-S-phase arrest induced during MVC infection was caused neither by damaged host cellular DNA nor by viral proteins but by replicating viral genomes physically associated with the DNA damage sensor, the Mre11-Rad50-Nbs1 (MRN) complex. In conclusion, the feedback loop between MVC DNA replication and the intra-S-phase arrest is mediated by ATM-SMC1 signaling and plays a critical role in MVC DNA replication. Thus, our findings unravel the mechanism underlying DDR signaling-facilitated MVC DNA replication and demonstrate a novel strategy of DNA virus-host interaction. PMID:23365434

Numerical investigation of the early flight phase in ski-jumping.

PubMed

Gardan, N; Schneider, A; Polidori, G; Trenchard, H; Seigneur, J M; Beaumont, F; Fourchet, F; Taiar, R

2017-07-05

The purpose of this study is to develop a numerical methodology based on real data from wind tunnel experiments to investigate the effect of the ski jumper's posture and speed on aerodynamic forces in a wide range of angles of attack. To improve our knowledge of the aerodynamic behavior of the ski jumper and his equipment during the early flight phase of the ski jump, we applied CFD methodology to evaluate the influence of angle of attack (α=14°, 21.5°, 29°, 36.5° and 44°) and speed (u=23, 26 and 29m/s) on aerodynamic forces in the situation of stable attitude of the ski jumper's body and skis. The standard k-ω turbulence model was used to investigate both the influence of the ski jumper's posture and speed on aerodynamic performance during the early flight phase. Numerical results show that the ski jumper's speed has very little impact on the lift and drag coefficients. Conversely, the lift and drag forces acting on the ski jumper's body during the early flight phase of the jump are strongly influenced by the variations of the angle of attack. The present results suggest that the greater the ski jumper's angle of inclination, with respect to the relative flow, the greater the pressure difference between the lower and upper parts of the skier. Further studies will focus on the dependency of the parameters with both the angle of attack α and the body-ski angle β as control variables. It will be possible to test and optimize different ski jumping styles in different ski jumping hills and investigate different environmental conditions such as temperature, altitude or crosswinds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dispositional optimism and therapeutic expectations in early-phase oncology trials.

PubMed

Jansen, Lynn A; Mahadevan, Daruka; Appelbaum, Paul S; Klein, William M P; Weinstein, Neil D; Mori, Motomi; Daffé, Racky; Sulmasy, Daniel P

2016-04-15

Prior research has identified unrealistic optimism as a bias that might impair informed consent among patient-subjects in early-phase oncology trials. However, optimism is not a unitary construct; it also can be defined as a general disposition, or what is called dispositional optimism. The authors assessed whether dispositional optimism would be related to high expectations for personal therapeutic benefit reported by patient-subjects in these trials but not to the therapeutic misconception. The authors also assessed how dispositional optimism related to unrealistic optimism. Patient-subjects completed questionnaires designed to measure expectations for therapeutic benefit, dispositional optimism, unrealistic optimism, and the therapeutic misconception. Dispositional optimism was found to be significantly associated with higher expectations for personal therapeutic benefit (Spearman rank correlation coefficient [r], 0.333; P<.0001), but was not associated with the therapeutic misconception (Spearman r, -0.075; P = .329). Dispositional optimism was found to be weakly associated with unrealistic optimism (Spearman r, 0.215; P = .005). On multivariate analysis, both dispositional optimism (P = .02) and unrealistic optimism (P<.0001) were found to be independently associated with high expectations for personal therapeutic benefit. Unrealistic optimism (P = .0001), but not dispositional optimism, was found to be independently associated with the therapeutic misconception. High expectations for therapeutic benefit among patient-subjects in early-phase oncology trials should not be assumed to result from misunderstanding of specific information regarding the trials. The data from the current study indicate that these expectations are associated with either a dispositionally positive outlook on life or biased expectations concerning specific aspects of trial participation. Not all manifestations of optimism are the same, and different types of optimism likely have

Development of Environmental Load Estimation Model for Road Drainage Systems in the Early Design Phase

NASA Astrophysics Data System (ADS)

Park, Jin-Young; Lee, Dong-Eun; Kim, Byung-Soo

2017-10-01

Due to the increasing concern about climate change, efforts to reduce environmental load are continuously being made in construction industry, and LCA (life cycle assessment) is being presented as an effective method to assess environmental load. Since LCA requires information on construction quantity used for environmental load estimation, however, it is not being utilized in the environmental review in the early design phase where it is difficult to obtain such information. In this study, computation system for construction quantity based on standard cross section of road drainage facilities was developed to compute construction quantity required for LCA using only information available in the early design phase to develop and verify the effectiveness of a model that can perform environmental load estimation. The result showed that it is an effective model that can be used in the early design phase as it revealed a 13.39% mean absolute error rate.

Adolescent, but not adult, rats exhibit ethanol-mediated appetitive second-order conditioning

PubMed Central

Pautassi, Ricardo Marcos; Myers, Mallory; Spear, Linda Patia; Molina, Juan Carlos; Spear, Norman E.

2008-01-01

Background Adolescent rats are less sensitive to the sedative effects of ethanol than older animals. They also seem to perceive the reinforcing properties of ethanol. However, unlike neonates or infants, ethanol-mediated appetitive behavior has yet to be clearly shown in adolescents. Appetitive ethanol reinforcement was assessed in adolescent (postnatal day 33, P33) and adult rats (P71) through second-order conditioning (SOC). Methods On P32 or P70 animals were intragastrically administered ethanol (0.5 or 2.0 g/kg) paired with intraoral pulses of sucrose (CS1, first-order conditioning phase). CS1 delivery took place either 5-20 (Early pairing) or 30-45 (Late pairing) min following ethanol. CS1 exposure and ethanol administration were separated by 240 min in unpaired controls. On P33 or P71, animals were presented the CS1 (second-order conditioning phase) while in a distinctive chamber (CS2). Then, they were tested for CS2 preference. Results Early and late paired adolescents, but not adults, had greater preference for the CS2 than controls, a result indicative of ontogenetic variation in ethanol-mediated reinforcement. During the CS1 - CS2 associative phase, paired adolescents given 2.0 g/kg ethanol wall-climbed more than controls. Blood and brain ethanol levels associated with the 0.5 and 2.0 g/kg doses at the onset of each conditioning phase did not differ substantially across age, with mean BECs of 38 and 112 mg %. Conclusions These data indicate age-related differences between adolescent and adult rats in terms of sensitivity to ethanol’s motivational effects. Adolescents exhibit high sensitivity for ethanol’s appetitive effects. These animals also showed EtOH-mediated behavioral activation during the second-order conditioning phase. The SOC preparation provides a valuable conditioning model for assessing ethanol’s motivational effects across ontogeny. PMID:18782343

Imaging of early acceleration phase of the 2013-2014 Boso slow slip event

NASA Astrophysics Data System (ADS)

Fukuda, J.; Kato, A.; Obara, K.; Miura, S.; Kato, T.

2014-12-01

Based on GPS and seismic data, we examine the spatiotemporal evolution of a slow slip event (SSE) and associated seismic activity that occurred off the Boso peninsula, central Japan, from December 2013 to January 2014. We use GPS data from 71 stations of the GEONET and 6 stations operated by Earthquake Research Institute of the University of Tokyo and Tohoku University around the Boso peninsula. We apply a modified version of the Network Inversion Filter to the GPS time series at the 77 stations to estimate the spatiotemporal evolution of daily cumulative slip and slip rate on the subducting Philippine Sea plate. In addition, we create an improved earthquake catalog by applying a matched filter technique to continuous seismograms and examine the spatiotemporal relations between slow slip and seismicity. We find that the SSE started in early December 2013. The spatiotemporal evolution of slow slip and seismicity is divided into two distinct phases, an earlier slow phase from early to 30 December 2013 (Phase I) and a subsequent faster phase from 30 December 2013 to 9 January 2014 (Phase II). During Phase I, slip accelerated slowly up to a maximum rate of 1.6 m/yr with potentially accelerating　along-strike propagation at speeds on the order of 1 km/day or less and no accompanying seismicity. On the other hand, during Phase II, slip accelerated rapidly up to a maximum rate of 4.5 m/yr and then rapidly decelerated. The slip front propagated along strike at a constant speed of ~10 km/day. During the Phase II, slow slip was accompanied by seismic swarm activity that was highly correlated in space and time with slip rate, suggesting that the swarm activity was triggered by stress loading due to slow slip. Early slow acceleration of slip has not been identified in the past Boso SSEs in 1996, 2002, 2007, and 2011. It is not clear at this point whether the past Boso SSEs started with slow acceleration similarly to the 2013-2014 SSE. The transition from the slow to the

Does aggregate school-wide achievement mediate fifth grade outcomes for former early childhood education participants?

PubMed

Curenton, Stephanie M; Dong, Nianbo; Shen, Xiangjin

2015-07-01

This study used a multilevel mediation model to test the theory that former early childhood education (ECE) attendees' 5th grade achievement is mediated by the aggregate school-wide achievement of their elementary school. Aggregate school-wide achievement was defined as the percentage of 5th graders in a school who were at/above academic proficiency in reading or math. Research questions were: (a) Do ECE program participants have better achievement at 5th grade compared with their matched peers who did not participate in an ECE program?; and (b) Is the association between ECE attendance and 5th grade academic performance mediated by school-wide achievement? Results indicated that children who attended prekindergarten (pre-K) and child care outperformed their matched peers who had not attended ECE programs; conversely, those children who did not attend ECE actually outperformed their Head Start counterparts. Mediation analyses indicated that aggregate school-wide achievement at 5th grade partially mediated the association between former ECE attendance and 5th grade performance; however, these mediated effects were small. Overall, the size of the total effects of ECE and the 5th grade academic outcomes were consistent with prior studies. This research confirms the long-term effects of pre-K and child care until 5th grade. (c) 2015 APA, all rights reserved).

Perspectives and Open Problems in the Early Phases of Left-Right Patterning

PubMed Central

Vandenberg, Laura N.; Levin, Michael

2009-01-01

Summary Embryonic left-right (LR) patterning is a fascinating aspect of embryogenesis. The field currently faces important questions about the origin of LR asymmetry, the mechanisms by which consistent asymmetry is imposed on the scale of the whole embryo, and the degree of conservation of early phases of LR patterning among model systems. Recent progress on planar cell polarity and cellular asymmetry in a variety of tissues and species provides a new perspective on the early phases of LR patterning. Despite the huge diversity in body-plans over which consistent LR asymmetry is imposed, and the apparent divergence in molecular pathways that underlie laterality, the data reveal conservation of physiological modules among phyla and a basic scheme of cellular chirality amplified by a planar cell polarity-like pathway over large cell fields. PMID:19084609

Mitotic wavefronts mediated by mechanical signaling in early Drosophila embryos

NASA Astrophysics Data System (ADS)

Kang, Louis; Idema, Timon; Liu, Andrea; Lubensky, Tom

2013-03-01

Mitosis in the early Drosophila embryo demonstrates spatial and temporal correlations in the form of wavefronts that travel across the embryo in each cell cycle. This coordinated phenomenon requires a signaling mechanism, which we suggest is mechanical in origin. We have constructed a theoretical model that supports nonlinear wavefront propagation in a mechanically-excitable medium. Previously, we have shown that this model captures quantitatively the wavefront speed as it varies with cell cycle number, for reasonable values of the elastic moduli and damping coefficient of the medium. Now we show that our model also captures the displacements of cell nuclei in the embryo in response to the traveling wavefront. This new result further supports that mechanical signaling may play an important role in mediating mitotic wavefronts.

Dynamic range of Nef-mediated evasion of HLA class II-restricted immune responses in early HIV-1 infection.

PubMed

Mahiti, Macdonald; Brumme, Zabrina L; Jessen, Heiko; Brockman, Mark A; Ueno, Takamasa

2015-07-31

HLA class II-restricted CD4(+) T lymphocytes play an important role in controlling HIV-1 replication, especially in the acute/early infection stage. But, HIV-1 Nef counteracts this immune response by down-regulating HLA-DR and up-regulating the invariant chain associated with immature HLA-II (Ii). Although functional heterogeneity of various Nef activities, including down-regulation of HLA class I (HLA-I), is well documented, our understanding of Nef-mediated evasion of HLA-II-restricted immune responses during acute/early infection remains limited. Here, we examined the ability of Nef clones from 47 subjects with acute/early progressive infection and 46 subjects with chronic progressive infection to up-regulate Ii and down-regulate HLA-DR and HLA-I from the surface of HIV-infected cells. HLA-I down-regulation function was preserved among acute/early Nef clones, whereas both HLA-DR down-regulation and Ii up-regulation functions displayed relatively broad dynamic ranges. Nef's ability to down-regulate HLA-DR and up-regulate Ii correlated positively at this stage, suggesting they are functionally linked in vivo. Acute/early Nef clones also exhibited higher HLA-DR down-regulation and lower Ii up-regulation functions compared to chronic Nef clones. Taken together, our results support enhanced Nef-mediated HLA class II immune evasion activities in acute/early compared to chronic infection, highlighting the potential importance of these functions following transmission. Copyright © 2015 Elsevier Inc. All rights reserved.

Ultra-Early Phase pathologies of Alzheimer's disease and other neurodegenerative diseases.

PubMed

Okazawa, Hitoshi

2017-01-01

The concept of neurodegenerative diseases and the therapeutics targeting these intractable diseases are changing rapidly. Protein aggregation as the top of pathological cascade is now challenged, and many alternative ideas are proposed. Early molecular pathologies before microscopic detection of diseases protein aggregates, which I propose to call "Ultra-Early Phase pathologies or phase 0 pathologies", are the focus of research that might explain the failures of clinical trials with anti-Aβ antibodies against Alzheimer's disease. In this review article, I summarize the critical issues that should be successfully and consistently answered by a new concept of neurodegeneration. For reevaluating old concepts and reconstructing a new concept of neurodegeneration that will replace the old ones, non-biased comprehensive approaches including proteome combined with systems biology analyses will be a powerful tool. I introduce our recent efforts in this orientation that have reached to the stage of non-clinical proof of concept applicable to clinical trials.

Bullying Mediates Between Attention-Deficit/Hyperactivity Disorder in Childhood and Psychotic Experiences in Early Adolescence.

PubMed

Hennig, Timo; Jaya, Edo S; Lincoln, Tania M

2017-09-01

Although a childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) is known to be linked to psychotic experiences and psychotic disorders in later life, the developmental trajectories that could explain this association are unknown. Using a sample from the prospective population-based Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 8247), we hypothesized that the previously reported association of ADHD combined subtype in childhood and psychotic experiences in early adolescence is mediated by traumatic events and by involvement in bullying. Moreover, we expected this mediation to be specific to ADHD and tested this by comparison with specific phobia. Children with ADHD combined subtype at age 7 were more often involved in bullying at age 10 (OR 3.635, 95% CI 1.973-6.697) and had more psychotic experiences at age 12 (OR 3.362, 95% CI 1.781-6.348). Moreover, children who were involved in bullying had more psychotic experiences (2.005, 95% CI 1.684-2.388). Bullying was a significant mediator between ADHD and psychotic experiences accounting for 41%-50% of the effect. Traumatic events from birth to age 11 were also significantly associated with ADHD combined subtype and psychotic experiences; however, there was no evidence of mediation. Specific phobia was significantly associated with psychotic experiences, but not with bullying. To conclude, bullying is a relevant translating mechanism from ADHD in childhood to psychotic experiences in early adolescence. Interventions that eliminate bullying in children with ADHD could potentially reduce the risk of having psychotic experiences in later life by up to 50%. Clinicians should thus screen for bullying in routine assessments of children with ADHD. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma.

PubMed

Friedberg, Joseph S; Mick, Rosemarie; Stevenson, James; Metz, James; Zhu, Timothy; Buyske, Jo; Sterman, Daniel H; Pass, Harvey I; Glatstein, Eli; Hahn, Stephen M

2003-03-01

Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Relationship between Duration of Untreated Psychosis and Intrinsic Corticostriatal Connectivity in Patients with Early Phase Schizophrenia.

PubMed

Sarpal, Deepak K; Robinson, Delbert G; Fales, Christina; Lencz, Todd; Argyelan, Miklos; Karlsgodt, Katherine H; Gallego, Juan A; John, Majnu; Kane, John M; Szeszko, Philip R; Malhotra, Anil K

2017-10-01

Patients with first-episode psychosis experience psychotic symptoms for a mean of up to 2 years prior to initiation of treatment, and long duration of untreated psychosis (DUP) is associated with poor clinical outcomes. Meanwhile, evidence compiled from numerous studies suggests that longer DUP is not associated with structural brain abnormalities. To date, few studies have examined the relationship between DUP and functional neuroimaging measures. In the present study, we used seed-based resting-state functional connectivity to examine the impact of DUP on corticostriatal circuitry. We included 83 patients with early phase schizophrenia and minimal exposure to antipsychotic drugs (<2 years), who underwent resting state scanning while entering 12 weeks of prospective treatment with second-generation antipsychotic drugs. Functional connectivity maps of the striatum were generated and examined in relation to DUP as a covariate. Mediation analyses were performed on a composite measure of corticostriatal connectivity derived from the significant results of our DUP analysis. We found that longer DUP correlated with worse response to treatment as well as overall decreased functional connectivity between striatal nodes and specific regions within frontal and parietal cortices. Moreover, the relationship between DUP and treatment response was significantly mediated by corticostriatal connectivity. Our results indicate that variation in corticostriatal circuitry may play a role in the relationship between longer DUP and worsened response to treatment. Future prospective studies are necessary to further characterize potential causal links between DUP, striatal circuitry and clinical outcomes.

Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms.

PubMed

Fekri, Farnaz; Delos Santos, Ralph Christian; Karshafian, Raffi; Antonescu, Costin N

2016-01-01

Drug delivery to tumors is limited by several factors, including drug permeability of the target cell plasma membrane. Ultrasound in combination with microbubbles (USMB) is a promising strategy to overcome these limitations. USMB treatment elicits enhanced cellular uptake of materials such as drugs, in part as a result of sheer stress and formation of transient membrane pores. Pores formed upon USMB treatment are rapidly resealed, suggesting that other processes such as enhanced endocytosis may contribute to the enhanced material uptake by cells upon USMB treatment. How USMB regulates endocytic processes remains incompletely understood. Cells constitutively utilize several distinct mechanisms of endocytosis, including clathrin-mediated endocytosis (CME) for the internalization of receptor-bound macromolecules such as Transferrin Receptor (TfR), and distinct mechanism(s) that mediate the majority of fluid-phase endocytosis. Tracking the abundance of TfR on the cell surface and the internalization of its ligand transferrin revealed that USMB acutely enhances the rate of CME. Total internal reflection fluorescence microscopy experiments revealed that USMB treatment altered the assembly of clathrin-coated pits, the basic structural units of CME. In addition, the rate of fluid-phase endocytosis was enhanced, but with delayed onset upon USMB treatment relative to the enhancement of CME, suggesting that the two processes are distinctly regulated by USMB. Indeed, vacuolin-1 or desipramine treatment prevented the enhancement of CME but not of fluid phase endocytosis upon USMB, suggesting that lysosome exocytosis and acid sphingomyelinase, respectively, are required for the regulation of CME but not fluid phase endocytosis upon USMB treatment. These results indicate that USMB enhances both CME and fluid phase endocytosis through distinct signaling mechanisms, and suggest that strategies for potentiating the enhancement of endocytosis upon USMB treatment may improve targeted

Early follicular phase hormone levels in relation to patterns of alcohol, tobacco, and coffee use.

PubMed

Lucero, J; Harlow, B L; Barbieri, R L; Sluss, P; Cramer, D W

2001-10-01

To examine the effects of alcohol, caffeine, and tobacco use on early follicular phase FSH, LH, E2, and sex hormone-binding globulin (SHBG). Cross-sectional study. Academic medical center. Four hundred ninety-eight women selected from the general population, ages 36-45, who were not currently pregnant, breast feeding, or using exogenous hormones. A general questionnaire assessing demography, anthropometry, and smoking habits and a standardized dietary questionnaire assessing food and beverage frequencies, including sources of alcohol and caffeine. FSH, LH, E2, and SHBG levels measured during the early follicular phase of the menstrual cycle. Significant associations observed in a univariate analysis included age > or =40 and current smoking associated with higher FSH; higher body mass index (BMI) associated with lower SHBG levels; and daily alcohol use, cholesterol consumption greater than the median, and coffee use >1 cup/d associated with higher E2 levels. In a multivariate model, total caffeine use was significantly associated with E2 levels after adjustment for age, BMI, total calories, current smoking, alcohol, cholesterol consumption, and day of sampling. Early follicular phase E2 increased from 28.2 pg/mL for women consuming < or =100 mg of caffeine to 45.2 pg/mL for women consuming > or =500 mg of caffeine per day, about a 70% increase. Coffee consumption and total caffeine use may increase early follicular phase E2 levels independent of related habits of alcohol or tobacco use.

Do alcohol expectancy outcomes and valuations mediate peer influences and lifetime alcohol use among early adolescents?

PubMed

Zamboanga, Byron L; Schwartz, Seth J; Ham, Lindsay S; Jarvis, Lorna Hernandez; Olthuis, Janine V

2009-12-01

Building on the theory of reasoned action (I. Ajzen & M. Fishbein, 1973, 1980; M. Fishbein & I. Ajzen, 1975) and expectancy theory, the authors examined the mediating role of alcohol expectancies in adolescent drinking behaviors by testing whether alcohol expectancy outcomes and valuations (the extent to which these outcomes are perceived as good or bad) mediate the association between peer influences and lifetime alcohol use. Early adolescents (N = 904) from 2 public middle schools in western Michigan completed a battery of questionnaires. Overall, results showed that alcohol expectancies and valuations partially mediated the relations between peer influences (peer use and peer approval) and lifetime alcohol use. The findings suggest that associating with peers who are perceived as using alcohol and approving of drinking may influence adolescents' alcohol expectancies. The authors briefly discuss future research directions and implications for prevention.

Early life stress stimulates hippocampal reelin gene expression in a sex-specific manner: evidence for corticosterone-mediated action.

PubMed

Gross, Claus M; Flubacher, Armin; Tinnes, Stefanie; Heyer, Andrea; Scheller, Marie; Herpfer, Inga; Berger, Mathias; Frotscher, Michael; Lieb, Klaus; Haas, Carola A

2012-03-01

Early life stress predisposes to the development of psychiatric disorders. In this context the hippocampal formation is of particular interest, because it is affected by stress on the structural and cognitive level. Since little is known how early life stress is translated on the molecular level, we mimicked early life stress in mouse models and analyzed the expression of the glycoprotein Reelin, a master molecule for development and differentiation of the hippocampus. From postnatal day 1 (P1) to P14, mouse pups were subjected to one of the following treatments: nonhandling (NH), handling (H), maternal separation (MS), and early deprivation (ED) followed by immediate (P15) or delayed (P70) real time RT-PCR analysis of reelin mRNA expression. We show that at P15, reelin mRNA levels were significantly increased in male H and ED groups when compared with the NH group. In contrast, no stress-induced alterations of reelin mRNA expression were found in female animals. This sex difference in stress-mediated stimulation of reelin expression was maintained into adulthood, since at P70 intergroup differences were still found in male, but not in female mice. On the cellular level, however, we did not find any significant differences in cell densities of Reelin-immunolabeled neurons between treatment groups or sexes, but an overall reduction of Reelin-expressing neurons in the adult hippocampus when compared to P15. To address the question whether corticosterone mediates the stress-induced up-regulation of reelin gene expression, we used age-matched hippocampal slice cultures derived from male and female mouse pups. Quantitative determination of mRNA levels revealed that corticosterone treatment significantly up-regulated reelin mRNA expression in male, but not in female hippocampi. Taken together, these results show a sex-specific regulation of reelin gene expression by early life experience, most likely mediated by corticosterone. Copyright © 2010 Wiley Periodicals, Inc.

34 CFR 303.431 - Mediation.

Code of Federal Regulations, 2012 CFR

2012-07-01

... REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION EARLY INTERVENTION PROGRAM FOR INFANTS AND TODDLERS WITH... who are qualified mediators and knowledgeable in laws and regulations relating to the provision of early intervention services. (ii) The lead agency must select mediators on a random, rotational, or...

34 CFR 303.431 - Mediation.

Code of Federal Regulations, 2013 CFR

2013-07-01

... REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION EARLY INTERVENTION PROGRAM FOR INFANTS AND TODDLERS WITH... who are qualified mediators and knowledgeable in laws and regulations relating to the provision of early intervention services. (ii) The lead agency must select mediators on a random, rotational, or...

34 CFR 303.431 - Mediation.

Code of Federal Regulations, 2014 CFR

2014-07-01

... REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION EARLY INTERVENTION PROGRAM FOR INFANTS AND TODDLERS WITH... who are qualified mediators and knowledgeable in laws and regulations relating to the provision of early intervention services. (ii) The lead agency must select mediators on a random, rotational, or...

Testosterone reactivity to provocation mediates the effect of early intervention on aggressive behavior.

PubMed

Carré, Justin M; Iselin, Anne-Marie R; Welker, Keith M; Hariri, Ahmad R; Dodge, Kenneth A

2014-05-01

We tested the hypotheses that the Fast Track intervention program for high-risk children would reduce adult aggressive behavior and that this effect would be mediated by decreased testosterone responses to social provocation. Participants were a subsample of males from the full trial sample, who during kindergarten had been randomly assigned to the 10-year Fast Track intervention or to a control group. The Fast Track program attempted to develop children's social competencies through child social-cognitive and emotional-coping skills training, peer-relations coaching, academic tutoring, and classroom management, as well as training for parents to manage their child's behavior. At a mean age of 26 years, participants responded to laboratory provocations. Results indicated that, relative to control participants, men assigned to the intervention demonstrated reduced aggression and testosterone reactivity to social provocations. Moreover, reduced testosterone reactivity mediated the effect of intervention on aggressive behavior, which provides evidence for an enduring biological mechanism underlying the effect of early psychosocial intervention on aggressive behavior in adulthood.

Nucleation of Iron Oxide Nanoparticles Mediated by Mms6 Protein in Situ

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

Kashyap, Sanjay; Woehl, Taylor J; Liu, Xunpei

2014-09-23

Biomineralization proteins are widely used as templating agents in biomimetic synthesis of a variety of organic–inorganic nanostructures. However, the role of the protein in controlling the nucleation and growth of biomimetic particles is not well understood, because the mechanism of the bioinspired reaction is often deduced from ex situ analysis of the resultant nanoscale mineral phase. Here we report the direct visualization of biomimetic iron oxide nanoparticle nucleation mediated by an acidic bacterial recombinant protein, Mms6, during an in situ reaction induced by the controlled addition of sodium hydroxide to solution-phase Mms6 protein micelles incubated with ferric chloride. Using inmore » situ liquid cell scanning transmission electron microscopy we observe the liquid iron prenucleation phase and nascent amorphous nanoparticles forming preferentially on the surface of protein micelles. Our results provide insight into the early steps of protein-mediated biomimetic nucleation of iron oxide and point to the importance of an extended protein surface during nanoparticle formation.« less

PDF neuron firing phase-shifts key circadian activity neurons in Drosophila.

PubMed

Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

2014-06-17

Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY.

Root colonization dynamics of two ectomycorrhizal fungi of contrasting life history strategies are mediated by

Treesearch

Erik A. Lilleskov; Thomas D. Bruns

2003-01-01

-Here we investigated whether root colonization dynamics of ectomycorrhizal fungi (EMF) of contrasting life history strategies (i.e. early vs late successional dominants) were affected by resource availability, as mediated either directly via the soil, or indirectly via host nutrition. -In a two phase experiment, Pinusm muricata seedlings were co-...

78 FR 5816 - Guidance for Industry on Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-28

.... The guidance provides recommendations on when and how genomic principles should be considered and... recommendations on when and how genomic principles should be considered and applied in early-phase clinical... the larger, later adequate, and well-controlled trials (phase 3) that are needed to support marketing...

Early Attachment-Figure Separation and Increased Risk for Later Depression: Potential Mediation by Proinflammatory Processes

PubMed Central

Hennessy, Michael B.; Deak, Terrence; Schiml-Webb, Patricia A.

2009-01-01

Early maternal separation and other disruptions of attachment relations are known to increase risk for the later onset of depressive illness in vulnerable individuals. It is suggested here that sensitization involving proinflammatory processes may contribute to this effect. This argument is based on: (1) current notions of the role of proinflammatory cytokines in depressive illness; (2) evidence that proinflammatory cytokines mediate depressive-like behavior during separation in a rodent model of infant attachment; and (3) comparisons of the effects of early proinflammatory activation versus maternal separation on later proinflammatory activity and biobehavioral processes related to depression. The possible interaction of proinflammatory processes and corticotropin-releasing factor in the sensitization process is discussed. PMID:20359585

SGLT2 mediates glucose reabsorption in the early proximal tubule.

PubMed

Vallon, Volker; Platt, Kenneth A; Cunard, Robyn; Schroth, Jana; Whaley, Jean; Thomson, Scott C; Koepsell, Hermann; Rieg, Timo

2011-01-01

Mutations in the gene encoding for the Na(+)-glucose co-transporter SGLT2 (SLC5A2) associate with familial renal glucosuria, but the role of SGLT2 in the kidney is incompletely understood. Here, we determined the localization of SGLT2 in the mouse kidney and generated and characterized SGLT2-deficient mice. In wild-type (WT) mice, immunohistochemistry localized SGLT2 to the brush border membrane of the early proximal tubule. Sglt2(-/-) mice had glucosuria, polyuria, and increased food and fluid intake without differences in plasma glucose concentrations, GFR, or urinary excretion of other proximal tubular substrates (including amino acids) compared with WT mice. SGLT2 deficiency did not associate with volume depletion, suggested by similar body weight, BP, and hematocrit; however, plasma renin concentrations were modestly higher and plasma aldosterone levels were lower in Sglt2(-/-) mice. Whole-kidney clearance studies showed that fractional glucose reabsorption was significantly lower in Sglt2(-/-) mice compared with WT mice and varied in Sglt2(-/-) mice between 10 and 60%, inversely with the amount of filtered glucose. Free-flow micropuncture revealed that for early proximal collections, 78 ± 6% of the filtered glucose was reabsorbed in WT mice compared with no reabsorption in Sglt2(-/-) mice. For late proximal collections, fractional glucose reabsorption was 93 ± 1% in WT and 21 ± 6% in Sglt2(-/-) mice, respectively. These results demonstrate that SGLT2 mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. This mouse model mimics and explains the glucosuric phenotype of individuals carrying SLC5A2 mutations.

DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression

PubMed Central

Barr, Alexis R.; Cooper, Samuel; Heldt, Frank S.; Butera, Francesca; Stoy, Henriette; Mansfeld, Jörg; Novák, Béla; Bakal, Chris

2017-01-01

Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability. PMID:28317845

Geoeffectiveness during the early phase of Solar Cycle 24

NASA Astrophysics Data System (ADS)

Pande, Bimal

Geoeffectiveness during the early phase of Solar Cycle 24 \\underline{} Abstract\\underline{} It is very important and interesting to understand the solar eruptions because it produces the geoeffectiveness in our Earth environment. In the rise phase of the solar cycle, geoeffective events are less frequent, thus this provide us better opportunity to study these events including the detection of their source regions. Keeping this in mind, we have analysed the data of rise phase of current solar cycle 24 ( 2009-2012). During above time period, we have selected 59 geoeffective events having Disturbance Storm Time (Dst) index < -50 nT. Based on the Dst index, we divided the events into two categories i.e. moderate (< -50 nT > -100 nT ) and intense ( <-100 nT). To locate the solar source regions of geoeffective and SEPs associated events, we have used available images, movies and Solar Geophysical data (SGD) list: for example movies from SOHO/EIT, images and movies from the Solar Dynamic Observatory (SDO). In this study, we will discuss and compare the different properties of associated CMEs, flares and their relation with geoeffectiveness.

Working Memory Ability Predicts Trajectories of Early Alcohol Use in Adolescents: The Mediational Role of Impulsivity

PubMed Central

Khurana, Atika; Romer, Dan; Betancourt, Laura M.; Brodsky, Nancy L.; Giannetta, Joan M.; Hurt, Hallam

2012-01-01

Aims 1) To evaluate the role of pre-existing weakness in working memory ability (WM) as a risk factor for early alcohol use as mediated by different forms of impulsivity. 2) To assess the adverse effects of progressive alcohol use on variations in WM over time. Design, Setting and Participants A community sample of 358 adolescents [48% males, Meanage(baseline) = 11.4± 0.87 years] from a longitudinal cohort design, assessed annually over four consecutive years with less than 6% attrition. Measurements Repeated assessments were conducted for the following key variables: WM (based on performance on four separate tasks), frequency of alcohol use (AU), and three forms of impulsivity, namely sensation seeking (SS), acting-without-thinking (AWT) and delay discounting (DD). Latent growth curve modeling procedures were used to identify individual trajectories of change for all key variables. Findings Weakness in WM (at baseline) significantly predicted both concurrent alcohol use and increased frequency of use over the four waves (p <.05). This effect was entirely mediated by two forms of impulsivity, AWT and DD, both of which were characterized by underlying weakness in WM. No individual variation was observed in the slopes of WM, which suggests that individual variations in alcohol use were not associated with changes in WM in our early adolescent sample. Conclusions Early adolescent alcohol use may be a consequence of (pre-existing) weaknesses in working memory (WM) rather than a cause of it. Efforts to reduce early alcohol use should consider the distinct roles of different impulsivity dimensions, in addition to WM, as potential targets of intervention. PMID:23033972

Synergistic suppression of early phase of adipogenesis by microsomal PGE synthase-1 (PTGES1)-produced PGE2 and aldo-keto reductase 1B3-produced PGF2α.

PubMed

Fujimori, Ko; Yano, Mutsumi; Ueno, Toshiyuki

2012-01-01

We recently reported that aldo-keto reductase 1B3-produced prostaglandin (PG) F(2α) suppressed the early phase of adipogenesis. PGE(2) is also known to suppress adipogenesis. In this study, we found that microsomal PGE(2) synthase (PGES)-1 (mPGES-1; PTGES1) acted as the PGES in adipocytes and that PGE(2) and PGF(2α) synergistically suppressed the early phase of adipogenesis. PGE(2) production was detected in preadipocytes and transiently enhanced at 3 h after the initiation of adipogenesis of mouse adipocytic 3T3-L1 cells, followed by a quick decrease; and its production profile was similar to the expression of the cyclooxygenase-2 (PTGS2) gene. When 3T3-L1 cells were transfected with siRNAs for any one of the three major PTGESs, i.e., PTGES1, PTGES2 (mPGES-2), and PTGES3 (cytosolic PGES), only PTGES1 siRNA suppressed PGE(2) production and enhanced the expression of adipogenic genes. AE1-329, a PTGER4 (EP4) receptor agonist, increased the expression of the Ptgs2 gene with a peak at 1 h after the initiation of adipogenesis. PGE(2)-mediated enhancement of the PTGS2 expression was suppressed by the co-treatment with L-161982, a PTGER4 receptor antagonist. Moreover, AE1-329 enhanced the expression of the Ptgs2 gene by binding of the cyclic AMP response element (CRE)-binding protein to the CRE of the Ptgs2 promoter; and its binding was suppressed by co-treatment with L-161982, which was demonstrated by promoter luciferase and chromatin immunoprecipitation assays. Furthermore, when 3T3-L1 cells were caused to differentiate into adipocytes in medium containing both PGE(2) and PGF(2α), the expression of the adipogenic genes and the intracellular triglyceride level were decreased to a greater extent than in medium containing either of them, revealing that PGE(2) and PGF(2α) independently suppressed adipogenesis. These results indicate that PGE(2) was synthesized by PTGES1 in adipocytes and synergistically suppressed the early phase of adipogenesis of 3T3-L1 cells in

Synergistic Suppression of Early Phase of Adipogenesis by Microsomal PGE Synthase-1 (PTGES1)-Produced PGE2 and Aldo-Keto Reductase 1B3-Produced PGF2α

PubMed Central

Fujimori, Ko; Yano, Mutsumi; Ueno, Toshiyuki

2012-01-01

We recently reported that aldo-keto reductase 1B3-produced prostaglandin (PG) F2α suppressed the early phase of adipogenesis. PGE2 is also known to suppress adipogenesis. In this study, we found that microsomal PGE2 synthase (PGES)-1 (mPGES-1; PTGES1) acted as the PGES in adipocytes and that PGE2 and PGF2α synergistically suppressed the early phase of adipogenesis. PGE2 production was detected in preadipocytes and transiently enhanced at 3 h after the initiation of adipogenesis of mouse adipocytic 3T3-L1 cells, followed by a quick decrease; and its production profile was similar to the expression of the cyclooxygenase-2 (PTGS2) gene. When 3T3-L1 cells were transfected with siRNAs for any one of the three major PTGESs, i.e., PTGES1, PTGES2 (mPGES-2), and PTGES3 (cytosolic PGES), only PTGES1 siRNA suppressed PGE2 production and enhanced the expression of adipogenic genes. AE1-329, a PTGER4 (EP4) receptor agonist, increased the expression of the Ptgs2 gene with a peak at 1 h after the initiation of adipogenesis. PGE2-mediated enhancement of the PTGS2 expression was suppressed by the co-treatment with L-161982, a PTGER4 receptor antagonist. Moreover, AE1-329 enhanced the expression of the Ptgs2 gene by binding of the cyclic AMP response element (CRE)-binding protein to the CRE of the Ptgs2 promoter; and its binding was suppressed by co-treatment with L-161982, which was demonstrated by promoter luciferase and chromatin immunoprecipitation assays. Furthermore, when 3T3-L1 cells were caused to differentiate into adipocytes in medium containing both PGE2 and PGF2α, the expression of the adipogenic genes and the intracellular triglyceride level were decreased to a greater extent than in medium containing either of them, revealing that PGE2 and PGF2α independently suppressed adipogenesis. These results indicate that PGE2 was synthesized by PTGES1 in adipocytes and synergistically suppressed the early phase of adipogenesis of 3T3-L1 cells in cooperation with PGF2�

Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity

PubMed Central

Soloski, Mark J.; Crowder, Lauren A.; Lahey, Lauren J.; Wagner, Catriona A.

2014-01-01

Chemokines and cytokines are key signaling molecules that orchestrate the trafficking of immune cells, direct them to sites of tissue injury and inflammation and modulate their states of activation and effector cell function. We have measured, using a multiplex-based approach, the levels of 58 immune mediators and 7 acute phase markers in sera derived from of a cohort of patients diagnosed with acute Lyme disease and matched controls. This analysis identified a cytokine signature associated with the early stages of infection and allowed us to identify two subsets (mediator-high and mediator-low) of acute Lyme patients with distinct cytokine signatures that also differed significantly (p<0.0005) in symptom presentation. In particular, the T cell chemokines CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) were coordinately increased in the mediator-high group and levels of these chemokines could be associated with seroconversion status and elevated liver function tests (p = 0.027 and p = 0.021 respectively). There was also upregulation of acute phase proteins including CRP and serum amyloid A. Consistent with the role of CXCL9/CXCL10 in attracting immune cells to the site of infection, CXCR3+ CD4 T cells are reduced in the blood of early acute Lyme disease (p = 0.01) and the decrease correlates with chemokine levels (p = 0.0375). The levels of CXCL9/10 did not relate to the size or number of skin lesions but elevated levels of serum CXCL9/CXCL10 were associated with elevated liver enzymes levels. Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations. PMID:24740099

Pathways to fraction learning: Numerical abilities mediate the relation between early cognitive competencies and later fraction knowledge.

PubMed

Ye, Ai; Resnick, Ilyse; Hansen, Nicole; Rodrigues, Jessica; Rinne, Luke; Jordan, Nancy C

2016-12-01

The current study investigated the mediating role of number-related skills in the developmental relationship between early cognitive competencies and later fraction knowledge using structural equation modeling. Fifth-grade numerical skills (i.e., whole number line estimation, non-symbolic proportional reasoning, multiplication, and long division skills) mapped onto two distinct factors: magnitude reasoning and calculation. Controlling for participants' (N=536) demographic characteristics, these two factors fully mediated relationships between third-grade general cognitive competencies (attentive behavior, verbal and nonverbal intellectual abilities, and working memory) and sixth-grade fraction knowledge (concepts and procedures combined). However, specific developmental pathways differed by type of fraction knowledge. Magnitude reasoning ability fully mediated paths from all four cognitive competencies to knowledge of fraction concepts, whereas calculation ability fully mediated paths from attentive behavior and verbal ability to knowledge of fraction procedures (all with medium to large effect sizes). These findings suggest that there are partly overlapping, yet distinct, developmental pathways from cognitive competencies to general fraction knowledge, fraction concepts, and fraction procedures. Copyright © 2016 Elsevier Inc. All rights reserved.

Proinflammatory adipokine leptin mediates disinfection byproduct bromodichloromethane-induced early steatohepatitic injury in obesity

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

Das, Suvarthi; Kumar, Ashutosh; Seth, Ratanesh Kumar

Today's developed world faces a major public health challenge in the rise in the obese population and the increased incidence in fatty liver disease. There is a strong association among diet induced obesity, fatty liver disease and development of nonalcoholic steatohepatitis but the environmental link to disease progression remains unclear. Here we demonstrate that in obesity, early steatohepatitic lesions induced by the water disinfection byproduct bromodichloromethane are mediated by increased oxidative stress and leptin which act in synchrony to potentiate disease progression. Low acute exposure to bromodichloromethane (BDCM), in diet-induced obesity produced oxidative stress as shown by increased lipid peroxidation,more » protein free radical and nitrotyrosine formation and elevated leptin levels. Exposed obese mice showed histopathological signs of early steatohepatitic injury and necrosis. Spontaneous knockout mice for leptin or systemic leptin receptor knockout mice had significantly decreased oxidative stress and TNF-α levels. Co-incubation of leptin and BDCM caused Kupffer cell activation as shown by increased MCP-1 release and NADPH oxidase membrane assembly, a phenomenon that was decreased in Kupffer cells isolated from leptin receptor knockout mice. In obese mice that were BDCM-exposed, livers showed a significant increase in Kupffer cell activation marker CD68 and, increased necrosis as assessed by levels of isocitrate dehydrogenase, events that were decreased in the absence of leptin or its receptor. In conclusion, our results show that exposure to the disinfection byproduct BDCM in diet-induced obesity augments steatohepatitic injury by potentiating the effects of leptin on oxidative stress, Kupffer cell activation and cell death in the liver. - Highlights: ► BDCM acute exposure sensitizes liver to increased free radical stress in obesity. ► BDCM-induced higher leptin contributes to early steatohepatitic lesions. ► Increased leptin mediates

Somatostatin protects human retinal pericytes from inflammation mediated by microglia.

PubMed

Mazzeo, Aurora; Arroba, Ana I; Beltramo, Elena; Valverde, Angela M; Porta, Massimo

2017-11-01

Diabetic retinopathy (DR) is usually considered a microvascular disease. However, involvement of the neuroretina in the early stages of DR has recently gained major credit. Inflammatory processes, leading to glial activation and neuronal apoptosis, develop early in the retina of diabetic subjects. Pericytes constitute a link between the vascular and the neural retina, play a central role in blood-retinal barrier maintenance, and may influence neuroinflammation. Somatostatin (SST) is a potent neuroprotective factor, which is down-regulated during early DR. In this paper, we have investigated the effects of the inflammatory signals triggered by the activation of microglia on inflammation and apoptosis/survival pathways in pericytes. Microglia cells (Bv-2) were stimulated with lipopolysaccharide (LPS) and/or SST. Human retinal pericytes (HRP) were exposed to conditioned media (CM) collected from Bv-2 cells in physiological conditions and in the settings described above. A panel of inflammation, apoptosis and survival mediators was analyzed. HRP treated with LPS-CM showed a significant increase of pro-inflammatory (iNos and TNFα) and pro-apoptotic mediators (FasL, active caspase-8, tBid and Bax), and a concomitant decrease in pro-survival factors (BclxL and pAkt). SST added to LPS was able to counteract these effects in all conditions. In conclusion, SST is able to modulate apoptosis/survival pathways in HRP during microglia-mediated inflammation. These results demonstrate a crosstalk between microglia and retinal pericytes, evidencing a possible defensive role of microglia in the early phases of DR. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prediction of early and late preeclampsia by flow-mediated dilation of the brachial artery*

PubMed Central

Brandão, Augusto Henriques Fulgêncio; Evangelista, Aline Aarão; Martins, Raphaela Menin Franco; Leite, Henrique Vítor; Cabral, Antônio Carlos Vieira

2014-01-01

Objective To assess the accuracy in the prediction of both early and late preeclampsia by flow-mediated dilation of the brachial artery (FMD), a biophysical marker for endothelial dysfunction. Materials and Methods A total of 91 patients, considered at high risk for development of preeclampsia were submitted to brachial artery FMD between 24 and 28 weeks of gestation. Results Nineteen out of the selected patients developed preeclampsia, 8 in its early form and 11 in the late form. With a cut-off value of 6.5%, the FMD sensitivity for early preeclampsia prediction was 75.0%, with specificity of 73.3%, positive predictive value (PPV) of 32.4% and negative predictive value (NPV) of 91.9%. For the prediction of late preeclampsia, sensitivity = 83.3%, specificity = 73.2%, PPV = 34.4% and NPV = 96.2% were observed. And for the prediction of all associated forms of preeclampsia, sensitivity = 84.2%, specificity = 73.6%, PPV = 45.7% and NPV = 94.6% were observed. Conclusion FMD of the brachial artery is a test with good accuracy in the prediction of both early and late preeclampsia, which may represent a positive impact on the follow-up of pregnant women at high risk for developing this syndrome. PMID:25741086

Decreased endometrial vascularity and receptivity in unexplained recurrent miscarriage patients during midluteal and early pregnancy phases.

PubMed

Tan, Shu-Yin; Hang, Fu; Purvarshi, Gowreesunkur; Li, Min-Qing; Meng, Da-Hua; Huang, Ling-Ling

2015-10-01

To evaluate the predictive value of three-dimensional (3D)-power Doppler sonography on recurrent miscarriage. The study patients were divided into a recurrent miscarriage group (30 cases) and a normal pregnancy group (21 cases). Measurement of endometrial thickness was performed using two-dimensional transvaginal ultrasound in the midluteal phase. The endometrial volume, vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) in midluteal and placenta volume, as well as the VI, FI, and VFI of early pregnancy were measured using Virtual Organ Computer-aided Analysis of 3D-power Doppler ultrasound. Endometrial thickness, endometrial volume, endometrial vascular data, VI, FI, and VFI of the midluteal phase were lower in the recurrent miscarriage group compared with the normal pregnancy group (p < 0.05). Placental volume, VI, and VFI during early pregnancy were lower in the miscarriage group compared with the normal pregnancy group (p < 0.05). There was no significant change in FI between the recurrent miscarriage and control groups during early pregnancy (p > 0.05). The predictive accuracy of endometrial thickness, endometrial volume, VI, FI, and VFI in the midluteal phase, and placenta volume, VI, FI, and VFI in early pregnancy as measured by the receiver operating characteristic curve to predict miscarriage before 12 gestational weeks in participants was 0.681, 0.876, 0.770, 0.720, 0.879, 0.771, 0.907, 0.592, respectively. The 3D-power Doppler ultrasound is a more comprehensive and sensitive method for evaluating endometrial receptivity. Endometrial volume, VI, FI, and VFI in the midluteal phase, as well as VI in early pregnancy, can be considered as predictive factors for recurrent miscarriage. Copyright © 2015. Published by Elsevier B.V.

Effects of early comprehensive interventions on child neurodevelopment in poor rural areas of China: a moderated mediation analysis.

PubMed

Liu, S; Wang, Z; Zhao, C; Huang, X; Liang, X; Wang, X; Lu, S; Scherpbier, R W

2018-06-01

To examine the effects of early comprehensive interventions on home environment and child neurodevelopment among children younger than 3 years in poor rural areas of China, as well as the underlying mediating and moderating mechanisms. Non-randomized intervention study was conducted among 216 children aged 0-3 years in Shanxi province of China. Based on a 2 × 2 factor design, children in Lin and Fenxi County were assigned to an intervention group with duration less than 1 year (n = 26) or an intervention group with duration longer than 1 year (n = 82), while children in Fangshan County served as a control group with duration less than 1 year (n = 30) or a control group with duration longer than 1 year (n = 78). The control group received national public health services (NPHS), while the intervention group received NPHS plus comprehensive interventions covering health, nutrition, early psychosocial stimulation, and child protection. Home environment (Infant-Toddler Home Observation for Measurement of the Environment [HOME]) and child neurodevelopment (Ages and Stages Questionnaire [ASQ]) were measured by observation and interview with mothers after the intervention program. The intervention group showed significantly higher overall HOME, organization, learning materials, and involvement than the control group, only for a duration longer than 1 year. Children in the intervention group performed better in overall ASQ, fine motor, problem-solving, and personal-social than children in the control group. Moderated mediation analyses indicated that there were significantly indirect effects of treatment on overall ASQ through overall HOME, organization, and involvement only when the duration was longer than 1 year. Early comprehensive interventions longer than 1 year improve home environment and promote child neurodevelopment among children younger than 3 years in poor rural areas. What is more, effects of early comprehensive interventions longer than 1 year on

Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis.

PubMed

Mickiewicz, Beata; Thompson, Graham C; Blackwood, Jaime; Jenne, Craig N; Winston, Brent W; Vogel, Hans J; Joffe, Ari R

2015-09-09

The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis. Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence. In children ages 2-17 years, combining metabolomic and

Effects of temperature on early-phase transmission of Yersina pestis by the flea, Xenopsylla cheopis.

PubMed

Schotthoefer, Anna M; Bearden, Scott W; Vetter, Sara M; Holmes, Jennifer; Montenieri, John A; Graham, Christine B; Woods, Michael E; Eisen, Rebecca J; Gage, Kenneth L

2011-03-01

Sharp declines in human and animal cases of plague, caused by the bacterium Yersinia pestis (Yersin), have been observed when outbreaks coincide with hot weather. Failure of biofilm production, or blockage, to occur in the flea, as temperatures reach 30 degrees C has been suggested as an explanation for these declines. Recent work demonstrating efficient flea transmission during the first few days after fleas have taken an infectious blood meal, in the absence of blockage (e.g., early-phase transmission), however, has called this hypothesis into question. To explore the potential effects of temperature on early-phase transmission, we infected colony-reared Xenopsylla cheopis (Rothchild) fleas with a wild-type strain of plague bacteria using an artificial feeding system, and held groups of fleas at 10, 23, 27, and 30 degrees C. Naive Swiss Webster mice were exposed to fleas from each of these temperatures on days 1-4 postinfection, and monitored for signs of infection for 21 d. Temperature did not significantly influence the rates of transmission observed for fleas held at 23, 27, and 30 degrees C. Estimated per flea transmission efficiencies for these higher temperatures ranged from 2.32 to 4.96% (95% confidence interval [CI]: 0.96-8.74). In contrast, no transmission was observed in mice challenged by fleas held at 10 degrees C (per flea transmission efficiency estimates, 0-1.68%). These results suggest that declines in human and animal cases during hot weather are not related to changes in the abilities of X. cheopis fleas to transmit Y. pestis infections during the early-phase period. By contrast, transmission may be delayed or inhibited at low temperatures, indicating that epizootic spread of Y. pestis by X. cheopis via early-phase transmission is unlikely during colder periods of the year.

Carbohydrate-mediated responses during zygotic and early somatic embryogenesis in the endangered conifer, Araucaria angustifolia

PubMed Central

Elbl, Paula; De Souza, Amanda P.; Jardim, Vinicius; de Oliveira, Leandro F.; Macedo, Amanda F.; dos Santos, André L. W.; Buckeridge, Marcos S.; Floh, Eny I. S.

2017-01-01

Three zygotic developmental stages and two somatic Araucaria angustifolia cell lines with contrasting embryogenic potential were analyzed to identify the carbohydrate-mediated responses associated with embryo formation. Using a comparison between zygotic and somatic embryogenesis systems, the non-structural carbohydrate content, cell wall sugar composition and expression of genes involved in sugar sensing were analyzed, and a network analysis was used to identify coordinated features during embryogenesis. We observed that carbohydrate-mediated responses occur mainly during the early stages of zygotic embryo formation, and that during seed development there are coordinated changes that affect the development of the different structures (embryo and megagametophyte). Furthermore, sucrose and starch accumulation were associated with the responsiveness of the cell lines. This study sheds light on how carbohydrate metabolism is influenced during zygotic and somatic embryogenesis in the endangered conifer species, A. angustifolia. PMID:28678868

Early Educational Intervention, Early Cumulative Risk, and the Early Home Environment as Predictors of Young Adult Outcomes Within a High-Risk Sample

PubMed Central

Pungello, Elizabeth P.; Kainz, Kirsten; Burchinal, Margaret; Wasik, Barbara H.; Sparling, Joseph J.; Ramey, Craig T.; Campbell, Frances A.

2009-01-01

The extent to which early educational intervention, early cumulative risk, and the early home environment were associated with young adult outcomes was investigated in a sample of 139 young adults (age 21) from high-risk families enrolled in randomized trials of early intervention. Positive effects of treatment were found for education attainment, attending college, and skilled employment; negative effects of risk were found for education attainment, graduating high school, being employed and avoiding teen parenthood. The home mediated the effects of risk for graduating high school, but not being employed or teen parenthood. Evidence for moderated mediation was found for educational attainment; the home mediated the association between risk and educational attainment for the control group, but not the treated group. PMID:20331676

Early phase drugs and biologicals clinical trials on worldwide leading causes of death: a descriptive analysis.

PubMed

Dal-Ré, Rafael

2011-06-01

To describe the global effort targeting the major causes of mortality in terms of "open" early phase clinical trials with drugs and biologicals. Sixteen of the 20 leading causes of death were chosen; 9 of these were also amongst the top 10 causes of death in low-income countries. Studies were identified from the ClinicalTrials.gov database and included phase 1 and/or 2 "interventional" "open" trials, i.e. those recruiting or about to start recruitment. Trials were considered in terms of sponsorship [industry, universities and other organisations (UNO), and US federal agencies (NIH included)], genders and age groups included, and whether they were conducted with drugs and/or biologicals. The search was performed in March 2010. A total of 2,298 (824 phase 1; 1,474 phase 2) trials were retrieved. Of these, 67% were on trachea, bronchus, and lung cancers (25%); diabetes mellitus (15%); colon and rectum cancers (14%); and HIV/AIDS (12%). In contrast, only 4% were trials on diarrhoeal disease, nephrosis and nephritis, liver cirrhosis, and prematurity and low birth weight. UNO were the first source of funding. Fifty-two percent of phase 1 non-cancer trials were on healthy volunteers. Twenty-nine percent of all trials were co-funded. There were 4.6 times as many drug trials as those with biologicals. Only 7% were conducted with a combination of drugs and biologicals, the majority (78%) on cancers. Discrimination in terms of gender or age group was not observed. Four of the 16 diseases considered represented 2/3 of early phase trials. Cancers were a top priority for all sponsors. Increasing attention should be given to conditions with current and projected global high mortality rates that had few "open" early phase trials.

Increased AIF-1-mediated TNF-α expression during implantation phase in IVF cycles with GnRH antagonist protocol.

PubMed

Xu, Bufang; Zhou, Mingjuan; Wang, Jingwen; Zhang, Dan; Guo, Feng; Si, Chenchen; Leung, Peter C K; Zhang, Aijun

2018-06-12

Is allograft inflammatory factor-1 (AIF-1), a cytokine associated with inflammation and allograft rejection, aberrantly elevated in in vitro fertilization (IVF) cycles with gonadotropin-releasing hormone (GnRH) antagonist protocol with potential effects on endometrial receptivity? Our findings indicated AIF-1 is increased in IVF cycles with GnRH antagonist protocol and mediates greater TNF-α expression during implantation phase, which may be unfavorable for embryo implantation. Studies have shown that GnRH antagonist protocol cycles have lower implantation and clinical pregnancy rates than GnRH agonist long protocol cycles. Endometrial receptivity but not embryo quality is a key factor contributing to this phenomenon; however, the mechanism is still unknown. Implantation and pregnancy rates were studied in 238 patients undergoing their first cycle of IVF/ICSI between 2012 and 2014. Forty of these patients opted to have no fresh embryo replacement and were divided into two equal groups: (i) GnRH antagonist protocol and (ii) GnRH agonist long protocol, group 3 included 20 infertile women with a tubal factor in untreated cycles. During the same interval, endometrial tissues were taken from 18 infertile women with a tubal factor in the early proliferative phase, late proliferative phase, and mid-secretory phase of the menstrual cycle (n = 6/group). Microarray analysis, RT-qPCR, Western blot analysis, immunohistochemistry were used to investigate the expression levels of AIF-1 and the related cytokines (TNF-α, IL1β, IL1RA, IL6, IL12, IL15 and IL18). The effect of AIF-1 on uterine receptivity was modeled using in vitro adhesion experiments (coculture of JAR cells and Ishikawa cells). The expression of AIF-1 was the highest in early proliferative phase, decreasing thereafter in the late proliferative phase, and almost disappearing in the mid-secretory phase, indicating that low AIF-1 expression might be important for embryo implantation during implantation phase

Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

PubMed

Lin, Chieh-Hsin; Chen, Ping-Kun; Chang, Yue-Cune; Chuo, Liang-Jen; Chen, Yan-Syun; Tsai, Guochuan E; Lane, Hsien-Yuan

2014-05-01

N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD. We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint. Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects. Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Early marijuana initiation: The link between prenatal marijuana exposure, early childhood behavior, and negative adult roles.

PubMed

Goldschmidt, Lidush; Richardson, Gale A; Larkby, Cynthia; Day, Nancy L

We investigated the associations among gestational factors including prenatal marijuana exposure (PME), child behavior at age 3, early age of onset of marijuana use (EAOM, <15years), and adult roles at 22years. Participants were drawn from the Maternal Health Practices and Child Development (MHPCD) Project, a longitudinal study of prenatal substance exposure in offspring who have been studied for over 22years since the prenatal phase. Data from the prenatal, birth, 3-, and 22-year phases (N=608) were used in the present study. Age of onset of offspring substance use was determined based on data from the 14-, 16-, and 22-year phases. The subjects were of lower socioeconomic status, 43% were Caucasian and the remaining were African-American, and 48% were males. Early childhood behavior was significantly (p<0.05) related to EAOM after controlling for PME, birth and childhood environmental risk factors, and Conduct Disorder. EAOM was significantly associated with negative adult roles including increased risk of being arrested (p<0.001), lower educational attainment (p<0.001), having a child without being married (p<0.05), and unemployment at 22years (p<0.001). The correlations between PME and negative adult roles and between early childhood behavior and negative adult roles were also statistically significant. Pathway analysis demonstrated that EAOM significantly mediated the associations between PME and fulfillment of adult roles and between early childhood behavior and adult roles. There are a number of intervention points that could be targeted that would have a long-term impact on lowering the probability of EAOM and less success in adult roles. Copyright © 2016 Elsevier Inc. All rights reserved.

Peer Victimization and Related Mental Health Problems in Early Adolescence: The Mediating Role of Parental and Peer Support

ERIC Educational Resources Information Center

Rasalingam, Anurajee; Clench-Aas, Jocelyne; Raanaas, Ruth Kjaersti

2017-01-01

Peer victimization is a widespread phenomenon especially prevalent in early adolescence. This study investigates the prevalence of peer victimization and its association with mental health problems and impact on everyday life, and the possible mediating effect of parental and peer support. Data are based on a cross-sectional health survey (N =…

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

PubMed

Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

2017-04-01

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064. © 2016 AlphaMed Press.

PDF neuron firing phase-shifts key circadian activity neurons in Drosophila

PubMed Central

Guo, Fang; Cerullo, Isadora; Chen, Xiao; Rosbash, Michael

2014-01-01

Our experiments address two long-standing models for the function of the Drosophila brain circadian network: a dual oscillator model, which emphasizes the primacy of PDF-containing neurons, and a cell-autonomous model for circadian phase adjustment. We identify five different circadian (E) neurons that are a major source of rhythmicity and locomotor activity. Brief firing of PDF cells at different times of day generates a phase response curve (PRC), which mimics a light-mediated PRC and requires PDF receptor expression in the five E neurons. Firing also resembles light by causing TIM degradation in downstream neurons. Unlike light however, firing-mediated phase-shifting is CRY-independent and exploits the E3 ligase component CUL-3 in the early night to degrade TIM. Our results suggest that PDF neurons integrate light information and then modulate the phase of E cell oscillations and behavioral rhythms. The results also explain how fly brain rhythms persist in constant darkness and without CRY. DOI: http://dx.doi.org/10.7554/eLife.02780.001 PMID:24939987

Loneliness and Life Satisfaction in Turkish Early Adolescents: The Mediating Role of Self Esteem and Social Support

ERIC Educational Resources Information Center

Kapikiran, Sahin

2013-01-01

This study aimed to measure whether self-esteem and social support are mediators in the relationship between loneliness and life satisfaction. The study includes early teenagers from the 6th, 7th and 8th grades aged between 11 and 15 (M = 13.31, SD = 1.09). The study group consisted of 431 secondary school students from large and medium sized…

Mediating processes between stress and problematic marijuana use.

PubMed

Ketcherside, Ariel; Filbey, Francesca M

2015-06-01

The literature widely reports that stress is associated with marijuana use, yet, to date, the path from stress to marijuana-related problems has not been tested. In this study, we evaluated whether negative affect mediates the relationship between stress and marijuana use. To that end, we tested models to determine mediators between problems with marijuana use (via Marijuana Problem Scale), stress (via Early Life Stress Questionnaire, Perceived Stress Scale), and negative affect (via Beck Depression Inventory; Beck Anxiety Inventory) in 157 current heavy marijuana users. Mediation tests and bootstrap confidence intervals were carried out via the "Mediation" package in R. Depression and anxiety scores both significantly mediated the relationship between perceived stress and problematic marijuana use. Only depression significantly mediated the relationship between early life stress and problematic marijuana use. Early life stress, perceived stress and problematic marijuana use were significant only as independent variables and dependent variables. These findings demonstrate that (1) depression mediated both early life stress and perceived stress, and problematic marijuana use, and, (2) anxiety mediated perceived stress and problematic marijuana use. This mediation analysis represents a strong first step toward understanding the relationship between these variables; however, longitudinal studies are needed to determine causality between these variables. To conclude, addressing concomitant depression and anxiety in those who report either perceived stress or early life stress is important for the prevention of cannabis use disorders. Copyright © 2015. Published by Elsevier Ltd.

Six1 overexpression at early stages of HPV16-mediated transformation of human keratinocytes promotes differentiation resistance and EMT

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

Xu, Hanwen; Pirisi, Lucia; Creek, Kim E., E-mail: creekk@sccp.sc.edu

Previous studies in our laboratory discovered that SIX1 mRNA expression increased during in vitro progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. In this study, we explored the role of Six1 at early stages of HPV16-mediated transformation by overexpressing Six1 in HKc/HPV16. We found that Six1 overexpression in HKc/HPV16 increased cell proliferation and promoted cell migration and invasion by inducing epithelial–mesenchymal transition (EMT). Moreover, the overexpression of Six1 in HKc/HPV16 resulted in resistance to serum and calcium-induced differentiation, which is the hallmark of the HKc/DR phenotype. Activation of MAPK in HKc/HPV16 overexpressing Six1 is linked to resistancemore » to calcium-induced differentiation. In conclusion, this study determined that Six1 overexpression resulted in differentiation resistance and promoted EMT at early stages of HPV16-mediated transformation of human keratinocytes. - Highlights: • Six1 expression increases during HPV16-mediated transformation. • Six1 overexpression causes differentiation resistance in HPV16-immortalized cells. • Six1 overexpression in HPV16-immortalized keratinocytes activates MAPK. • Activation of MAPK promotes EMT and differentiation resistance. • Six1 overexpression reduces Smad-dependent TGF-β signaling.« less

Overweight during childhood and internalizing symptoms in early adolescence: The mediating role of peer victimization and the desire to be thinner.

PubMed

Pryor, Laura; Brendgen, Mara; Boivin, Michel; Dubois, Lise; Japel, Christa; Falissard, Bruno; Tremblay, Richard E; Côté, Sylvana M

2016-09-15

Overweight is associated with depression and anxiety among adults. It is unclear whether this association begins in childhood. Overweight among children is associated with a higher risk of peer victimization, and may mediate an association between overweight and internalizing symptoms. No study has tested this hypothesis in a longitudinal population-based sample using developmental trajectories of overweight in middle childhood. Data was drawn from the population-based Quebec Longitudinal Study of Child Development. A three-group trajectory model of overweight development (6-12 years) was previously identified using a semi-parametric group-based approach (n=1678): "early-onset" (11.0%), "late-onset" (16.6%) and "never overweight" (72.5%). Mediation models tested the link between overweight status and child-reported depression and anxiety at 13 years via peer victimization and body dissatisfaction. Children on an early-onset overweight trajectory were at increased risk for both depression (B=.318, 95% CI=.141;.496) and anxiety (B=.262, 95% CI=.09;.44) at 13 years. These direct associations were mediated by peer victimization and subsequent desire to be thinner. Children on a late-onset childhood overweight trajectory were at increased risk for both depression (B=.332, 95% CI=.187;.477) and anxiety (B=.215; 95% CI=.072;.358) at 13 years, mediated by the desire to be thinner. We were unable to control for previous levels of body dissatisfaction. Our measure of peer victimization was not specific to weight-based teasing. Overweight during middle childhood increases risk of early adolescence internalizing symptoms. Peer victimization and body dissatisfaction are partly responsible for this link. Copyright © 2016 Elsevier B.V. All rights reserved.

Worldwide isotope ratios of the Fukushima release and early-phase external dose reconstruction

PubMed Central

Chaisan, Kittisak; Smith, Jim T.; Bossew, Peter; Kirchner, Gerald; Laptev, Gennady V.

2013-01-01

Measurements of radionuclides (RNs) in air made worldwide following the Fukushima accident are quantitatively compared with air and soil measurements made in Japan. Isotopic ratios RN:137Cs of 131I, 132Te, 134,136Cs, are correlated with distance from release. It is shown, for the first time, that both within Japan and globally, ratios RN:137Cs in air were relatively constant for primarily particle associated radionuclides (134,136Cs; 132Te) but that 131I shows much lower local (<80 km) isotope ratios in soils relative to 137Cs. Derived isotope ratios are used to reconstruct external dose rate during the early phase post-accident. Model “blind” tests show more than 95% of predictions within a factor of two of measurements from 15 sites to the north, northwest and west of the power station. It is demonstrated that generic isotope ratios provide a sound basis for reconstruction of early-phase external dose rates in these most contaminated areas. PMID:24018776

The TIM Barrel Architecture Facilitated the Early Evolution of Protein-Mediated Metabolism.

PubMed

Goldman, Aaron David; Beatty, Joshua T; Landweber, Laura F

2016-01-01

The triosephosphate isomerase (TIM) barrel protein fold is a structurally repetitive architecture that is present in approximately 10% of all enzymes. It is generally assumed that this ubiquity in modern proteomes reflects an essential historical role in early protein-mediated metabolism. Here, we provide quantitative and comparative analyses to support several hypotheses about the early importance of the TIM barrel architecture. An information theoretical analysis of protein structures supports the hypothesis that the TIM barrel architecture could arise more easily by duplication and recombination compared to other mixed α/β structures. We show that TIM barrel enzymes corresponding to the most taxonomically broad superfamilies also have the broadest range of functions, often aided by metal and nucleotide-derived cofactors that are thought to reflect an earlier stage of metabolic evolution. By comparison to other putatively ancient protein architectures, we find that the functional diversity of TIM barrel proteins cannot be explained simply by their antiquity. Instead, the breadth of TIM barrel functions can be explained, in part, by the incorporation of a broad range of cofactors, a trend that does not appear to be shared by proteins in general. These results support the hypothesis that the simple and functionally general TIM barrel architecture may have arisen early in the evolution of protein biosynthesis and provided an ideal scaffold to facilitate the metabolic transition from ribozymes, peptides, and geochemical catalysts to modern protein enzymes.

Size-isolation of ultrasound-mediated phase change perfluorocarbon droplets using differential centrifugation.

PubMed

Mercado, Karla P; Radhakrishnan, Kirthi; Stewart, Kyle; Snider, Lindsay; Ryan, Devin; Haworth, Kevin J

2016-05-01

Perfluorocarbon droplets that are capable of an ultrasound-mediated phase transition have applications in diagnostic and therapeutic ultrasound. Techniques to modify the droplet size distribution are of interest because of the size-dependent acoustic response of the droplets. Differential centrifugation has been used to isolate specific sizes of microbubbles. In this work, differential centrifugation was employed to isolate droplets with diameters between 1 and 3 μm and 2 and 5 μm from an initially polydisperse distribution. Further, an empirical model was developed for predicting the droplet size distribution following differential centrifugation and to facilitate the selection of centrifugation parameters for obtaining desired size distributions.

Size-isolation of ultrasound-mediated phase change perfluorocarbon droplets using differential centrifugation

PubMed Central

Mercado, Karla P.; Radhakrishnan, Kirthi; Stewart, Kyle; Snider, Lindsay; Ryan, Devin; Haworth, Kevin J.

2016-01-01

Perfluorocarbon droplets that are capable of an ultrasound-mediated phase transition have applications in diagnostic and therapeutic ultrasound. Techniques to modify the droplet size distribution are of interest because of the size-dependent acoustic response of the droplets. Differential centrifugation has been used to isolate specific sizes of microbubbles. In this work, differential centrifugation was employed to isolate droplets with diameters between 1 and 3 μm and 2 and 5 μm from an initially polydisperse distribution. Further, an empirical model was developed for predicting the droplet size distribution following differential centrifugation and to facilitate the selection of centrifugation parameters for obtaining desired size distributions. PMID:27250199

Three steps to writing adaptive study protocols in the early phase clinical development of new medicines

PubMed Central

2014-01-01

This article attempts to define terminology and to describe a process for writing adaptive, early phase study protocols which are transparent, self-intuitive and uniform. It provides a step by step guide, giving templates from projects which received regulatory authorisation and were successfully performed in the UK. During adaptive studies evolving data is used to modify the trial design and conduct within the protocol-defined remit. Adaptations within that remit are documented using non-substantial protocol amendments which do not require regulatory or ethical review. This concept is efficient in gathering relevant data in exploratory early phase studies, ethical and time- and cost-effective. PMID:24980283

Cosmological QCD phase transition in steady non-equilibrium dissipative Hořava–Lifshitz early universe

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

Khodadi, M., E-mail: M.Khodadi@sbu.ac.ir; Sepangi, H.R., E-mail: hr-sepangi@sbu.ac.ir

We study the phase transition from quark–gluon plasma to hadrons in the early universe in the context of non-equilibrium thermodynamics. According to the standard model of cosmology, a phase transition associated with chiral symmetry breaking after the electro-weak transition has occurred when the universe was about 1–10 μs old. We focus attention on such a phase transition in the presence of a viscous relativistic cosmological background fluid in the framework of non-detailed balance Hořava–Lifshitz cosmology within an effective model of QCD. We consider a flat Friedmann–Robertson–Walker universe filled with a non-causal and a causal bulk viscous cosmological fluid respectively and investigatemore » the effects of the running coupling constants of Hořava–Lifshitz gravity, λ, on the evolution of the physical quantities relevant to a description of the early universe, namely, the temperature T, scale factor a, deceleration parameter q and dimensionless ratio of the bulk viscosity coefficient to entropy density (ξ)/s . We assume that the bulk viscosity cosmological background fluid obeys the evolution equation of the steady truncated (Eckart) and full version of the Israel–Stewart fluid, respectively. -- Highlights: •In this paper we have studied quark–hadron phase transition in the early universe in the context of the Hořava–Lifshitz model. •We use a flat FRW universe with the bulk viscosity cosmological background fluid obeying the evolution equation of the steady truncated (Eckart) and full version of the Israel–Stewart fluid, respectively.« less

Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

PubMed

Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

2017-02-01

Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes.

PubMed

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide- co -glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP-mediated PSDT on MH7A synoviocytes. The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP-mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP-mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP-mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N -acetylcysteine. Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP-mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase-transition nanoparticle-mediated PSDT in the future.

Oxygen and indocyanine green loaded phase-transition nanoparticle-mediated photo-sonodynamic cytotoxic effects on rheumatoid arthritis fibroblast-like synoviocytes

PubMed Central

Tang, Qin; Cui, Jianyu; Tian, Zhonghua; Sun, Jiangchuan; Wang, Zhigang; Chang, Shufang; Zhu, Shenyin

2017-01-01

Background Photodynamic therapy and sonodynamic therapy are developing, minimally invasive, and site-specific modalities for cancer therapy. A combined strategy PSDT (photodynamic therapy followed by sonodynamic therapy) has been proposed in this study. Here, we aimed to develop novel biodegradable poly(DL-lactide-co-glycolic acid) phase-transition nanoparticles simultaneously loaded with oxygen and indocyanine green (OI-NPs) and to investigate the cytotoxic effects and the potential mechanisms of OI-NP–mediated PSDT on MH7A synoviocytes. Methods The OI-NPs were prepared using a modified double emulsion method and the physicochemical properties were determined. The cellular uptake of OI-NPs was detected by confocal microscopy and flow cytometry. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide assay, flow cytometry, and Hoechst 33342/propidium iodide double staining were used to determine the cytotoxic effect of OI-NP–mediated PSDT on MH7A cells. Fluorescence microscope and fluorescence microplate reader were used to detect reactive oxygen species (ROS) generation. Results The OI-NPs were a stable and efficient carrier to deliver oxygen and indocyanine green, and enhanced cellular uptake was observed in MH7A cells with the nanoparticles. OI-NP–mediated PSDT caused more serious cell damage and more evident cell apoptosis, compared with other groups. Furthermore, increased generation of intracellular ROS was detected in MH7A cells treated with PSDT. Interestingly, the OI-NP–mediated PSDT-induced cell viability loss was effectively rescued by pretreatment with the ROS scavenger N-acetylcysteine. Conclusion Multifunctional OI-NPs were successfully developed and characterized for the combined delivery of oxygen and indocyanine green, and OI-NP–mediated PSDT would be a potential cytotoxic treatment for MH7A cells. This study may provide a novel strategy for the treatment of RA and develop a model of theranostic application through phase

Brain Regions Related to Impulsivity Mediate the Effects of Early Adversity on Antisocial Behavior.

PubMed

Mackey, Scott; Chaarani, Bader; Kan, Kees-Jan; Spechler, Philip A; Orr, Catherine; Banaschewski, Tobias; Barker, Gareth; Bokde, Arun L W; Bromberg, Uli; Büchel, Christian; Cattrell, Anna; Conrod, Patricia J; Desrivières, Sylvane; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Paillère Martinot, Marie-Laure; Artiges, Eric; Nees, Frauke; Papadopoulos-Orfanos, Dimitri; Poustka, Luise; Smolka, Michael N; Jurk, Sarah; Walter, Henrik; Whelan, Robert; Schumann, Gunter; Althoff, Robert R; Garavan, Hugh

2017-08-15

Individual differences in impulsivity and early adversity are known to be strong predictors of adolescent antisocial behavior. However, the neurobiological bases of impulsivity and their relation to antisocial behavior and adversity are poorly understood. Impulsivity was estimated with a temporal discounting task. Voxel-based morphometry was used to determine the brain structural correlates of temporal discounting in a large cohort (n = 1830) of 14- to 15-year-old children. Mediation analysis was then used to determine whether the volumes of brain regions associated with temporal discounting mediate the relation between adverse life events (e.g., family conflict, serious accidents) and antisocial behaviors (e.g., precocious sexual activity, bullying, illicit substance use). Greater temporal discounting (more impulsivity) was associated with 1) lower volume in frontomedial cortex and bilateral insula and 2) greater volume in a subcortical region encompassing the ventral striatum, hypothalamus and anterior thalamus. The volume ratio between these cortical and subcortical regions was found to partially mediate the relation between adverse life events and antisocial behavior. Temporal discounting is related to regions of the brain involved in reward processing and interoception. The results support a developmental imbalance model of impulsivity and are consistent with the idea that negative environmental factors can alter the developing brain in ways that promote antisocial behavior. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Contribution of economic evaluation to decision making in early phases of product development: a methodological and empirical review.

PubMed

Hartz, Susanne; John, Jürgen

2008-01-01

Economic evaluation as an integral part of health technology assessment is today mostly applied to established technologies. Evaluating healthcare innovations in their early states of development has recently attracted attention. Although it offers several benefits, it also holds methodological challenges. The aim of our study was to investigate the possible contributions of economic evaluation to industry's decision making early in product development and to confront the results with the actual use of early data in economic assessments. We conducted a literature research to detect methodological contributions as well as economic evaluations that used data from early phases of product development. Economic analysis can be beneficially used in early phases of product development for various purposes including early market assessment, R&D portfolio management, and first estimations of pricing and reimbursement scenarios. Analytical tools available for these purposes have been identified. Numerous empirical works were detected, but most do not disclose any concrete decision context and could not be directly matched with the suggested applications. Industry can benefit from starting economic evaluation early in product development in several ways. Empirical evidence suggests that there is still potential left unused.

Hemoglobin phase of oxygenation and deoxygenation in early brain development measured using fNIRS

PubMed Central

Watanabe, Hama; Shitara, Yoshihiko; Aoki, Yoshinori; Inoue, Takanobu; Tsuchida, Shinya; Takahashi, Naoto; Taga, Gentaro

2017-01-01

A crucial issue in neonatal medicine is the impact of preterm birth on the developmental trajectory of the brain. Although a growing number of studies have shown alterations in the structure and function of the brain in preterm-born infants, we propose a method to detect subtle differences in neurovascular and metabolic functions in neonates and infants. Functional near-infrared spectroscopy (fNIRS) was used to obtain time-averaged phase differences between spontaneous low-frequency (less than 0.1 Hz) oscillatory changes in oxygenated hemoglobin (oxy-Hb) and those in deoxygenated hemoglobin (deoxy-Hb). This phase difference was referred to as hemoglobin phase of oxygenation and deoxygenation (hPod) in the cerebral tissue of sleeping neonates and infants. We examined hPod in term, late preterm, and early preterm infants with no evidence of clinical issues and found that all groups of infants showed developmental changes in the values of hPod from an in-phase to an antiphase pattern. Comparison of hPod among the groups revealed that developmental changes in hPod in early preterm infants precede those in late preterm and term infants at term equivalent age but then, progress at a slower pace. This study suggests that hPod measured using fNIRS is sensitive to the developmental stage of the integration of circular, neurovascular, and metabolic functions in the brains of neonates and infants. PMID:28196885

[Electrophysiological characteristics of hippocampal postnatal early development mediated by AMPA receptors in rats].

PubMed

Chen, Xue-Yi; Zhang, Ai-Feng; Zhao, Wen; Gao, Yu-Dan; Duan, Hong-Mei; Hao, Peng; Yang, Zhao-Yang; Li, Xiao-Guang

2018-04-25

The present study was aimed to investigate the electrophysiological characteristics of hippocampal postnatal early development mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rats. Forty-eight Wistar rats were divided into postnatal 0.5-, 1-, 2- and 3-month groups (n = 12). Spontaneous excitatory postsynaptic currents (sEPSCs) and field excitatory postsynaptic potentials (fEPSPs) mediated by AMPA receptors were recorded to evaluate the changes in the intrinsic membrane properties of hippocampal CA1 pyramidal neurons by using patch-clamp and MED64 planar microelectrode array technique respectively. The results showed that, during the period of postnatal 0.5-3 months, some of the intrinsic membrane properties of hippocampal CA1 pyramidal neurons, such as the membrane capacitance (Cm) and the resting membrane potential (RMP), showed no significant changes, while the membrane input resistance (Rin) and the time constant (τ) of the cells were decreased significantly. The amplitude, frequency and kinetics (both rise and decay times) of sEPSCs were significantly increased during the period of postnatal 0.5-1 month, but they were all decreased during the period of postnatal 1-3 months. In addition, the range of evoked fEPSPs in hippocamal CA1 region was significantly expanded, but the fEPSP amplitudes were decreased significantly during the period of postnatal 0.5-3 months. Furthermore, the evoked fEPSPs could be significantly inhibited by extracellular application of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These results suggest that AMPA receptor may act as a major type of excitatory receptor to regulate synaptic transmission and connections during the early stage of hippocampal postnatal development, which promotes the development and functional maturation of hippocampus in rats.

Inside information: Financial conflicts of interest for research subjects in early phase clinical trials.

PubMed

Helft, Paul R; Ratain, Mark J; Epstein, Richard A; Siegler, Mark

2004-05-05

In recent years, several research subjects have told us that they had bought or intended to buy stock in the companies sponsoring the clinical trials in which they were enrolled. This situation has led us to ask what, if any, are physician-investigators' scientific, ethical, and legal responsibilities concerning research subjects who choose to buy stock in the companies sponsoring the clinical trials in which they are participating. Although the scope of this problem is unknown and is likely to be small, this commentary examines the scientific, ethical, and legal concerns raised by such activities on the part of research subjects enrolled in early phase clinical trials. In addition, this commentary also outlines the basis for our opinion that research subjects involved in an early phase clinical trial should avoid the financial conflicts of interest created by trading stock in the company sponsoring the clinical trial.

Enabling Parametric Optimal Ascent Trajectory Modeling During Early Phases of Design

NASA Technical Reports Server (NTRS)

Holt, James B.; Dees, Patrick D.; Diaz, Manuel J.

2015-01-01

During the early phases of engineering design, the costs committed are high, costs incurred are low, and the design freedom is high. It is well documented that decisions made in these early design phases drive the entire design's life cycle. In a traditional paradigm, key design decisions are made when little is known about the design. As the design matures, design changes become more difficult -- in both cost and schedule -- to enact. Indeed, the current capability-based paradigm that has emerged because of the constrained economic environment calls for the infusion of knowledge acquired during later design phases into earlier design phases, i.e. bring knowledge acquired during preliminary and detailed design into pre-conceptual and conceptual design. An area of critical importance to launch vehicle design is the optimization of its ascent trajectory, as the optimal trajectory will be able to take full advantage of the launch vehicle's capability to deliver a maximum amount of payload into orbit. Hence, the optimal ascent trajectory plays an important role in the vehicle's affordability posture as the need for more economically viable access to space solutions are needed in today's constrained economic environment. The problem of ascent trajectory optimization is not a new one. There are several programs that are widely used in industry that allows trajectory analysts to, based on detailed vehicle and insertion orbit parameters, determine the optimal ascent trajectory. Yet, little information is known about the launch vehicle early in the design phase - information that is required of many different disciplines in order to successfully optimize the ascent trajectory. Thus, the current paradigm of optimizing ascent trajectories involves generating point solutions for every change in a vehicle's design parameters. This is often a very tedious, manual, and time-consuming task for the analysts. Moreover, the trajectory design space is highly non-linear and multi

Divided attention can enhance early-phase memory encoding: the attentional boost effect and study trial duration.

PubMed

Mulligan, Neil W; Spataro, Pietro

2015-07-01

Divided attention during encoding typically produces marked reductions in later memory. The attentional boost effect (ABE) is a surprising variation on this phenomenon. In this paradigm, each study stimulus (e.g., a word) is presented along with a target or a distractor (e.g., different colored circles) in a detection task. Later memory is better for stimuli co-occurring with targets. The present experiments indicate that the ABE arises during an early phase of memory encoding that involves initial stimulus perception and comprehension rather than at a later phase entailing controlled, elaborative rehearsal. Experiment 1 demonstrated that the ABE was robust at a short study duration (700 ms) and did not increase with increasing study trial durations (1,500 ms and 4,000 ms). Furthermore, the target condition is boosted to the level of memory performance in a full-attention condition for the short duration but not the long duration. Both results followed from the early-phase account. This account also predicts that for very short study times (limiting the influence of late-phase controlled encoding and thus minimizing the usual negative effect of divided attention), the target condition will produce better memory than will the full-attention condition. Experiment 2 used a study time of 400 ms and found that words presented with targets lead to greater recognition accuracy than do either words presented with distractors or words in the full-attention condition. Consistent with the early-phase account, a divided attention condition actually produced superior memory than did the full-attention condition, a very unusual but theoretically predicted result. (c) 2015 APA, all rights reserved.

Early Childhood Settings in 15 Countries: What Are Their Structural Characteristics? The IEA Preprimary Project, Phase 2.

ERIC Educational Resources Information Center

Olmsted, Patricia P., Ed.; Montie, Jeanne, Ed.

This is the second of four monographs reporting the findings of Phase 2 of the International Association for the Evaluation of Educational Achievement (IEA) Preprimary Project, which presents data on the physical characteristics of children's early childhood settings. Early childhood settings were documented in the following 15 countries: (1)…

Efficient runner safety assessment during early design phase and root cause analysis

NASA Astrophysics Data System (ADS)

Liang, Q. W.; Lais, S.; Gentner, C.; Braun, O.

2012-11-01

Fatigue related problems in Francis turbines, especially high head Francis turbines, have been published several times in the last years. During operation the runner is exposed to various steady and unsteady hydraulic loads. Therefore the analysis of forced response of the runner structure requires a combined approach of fluid dynamics and structural dynamics. Due to the high complexity of the phenomena and due to the limitation of computer power, the numerical prediction was in the past too expensive and not feasible for the use as standard design tool. However, due to continuous improvement of the knowledge and the simulation tools such complex analysis has become part of the design procedure in ANDRITZ HYDRO. This article describes the application of most advanced analysis techniques in runner safety check (RSC), including steady state CFD analysis, transient CFD analysis considering rotor stator interaction (RSI), static FE analysis and modal analysis in water considering the added mass effect, in the early design phase. This procedure allows a very efficient interaction between the hydraulic designer and the mechanical designer during the design phase, such that a risk of failure can be detected and avoided in an early design stage.The RSC procedure can also be applied to a root cause analysis (RCA) both to find out the cause of failure and to quickly define a technical solution to meet the safety criteria. An efficient application to a RCA of cracks in a Francis runner is quoted in this article as an example. The results of the RCA are presented together with an efficient and inexpensive solution whose effectiveness could be proven again by applying the described RSC technics. It is shown that, with the RSC procedure developed and applied as standard procedure in ANDRITZ HYDRO such a failure is excluded in an early design phase. Moreover, the RSC procedure is compatible with different commercial and open source codes and can be easily adapted to apply for

The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

PubMed Central

Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder; Sabourin, David; Collas, Philippe; Bruus, Henrik; Dufva, Martin

2013-01-01

Introduction High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. Methods and results Adipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process. Conclusions Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process. PMID:23723991

Inhibition of Connexin 43 Hemichannel-Mediated ATP Release Attenuates Early Inflammation During the Foreign Body Response

PubMed Central

Calder, Bennett W.; Rhett, Joshua Matthew; Bainbridge, Heather; Fann, Stephen A.; Gourdie, Robert G.

2015-01-01

Background: In the last 50 years, the use of medical implants has increased dramatically. Failure of implanted devices and biomaterials is a significant source of morbidity and increasing healthcare expenditures. An important cause of implant failure is the host inflammatory response. Recent evidence implicates extracellular ATP as an important inflammatory signaling molecule. A major pathway for release of cytoplasmic ATP into the extracellular space is through connexin hemichannels, which are the unpaired constituents of gap junction intercellular channels. Blockade of hemichannels of the connexin 43 (Cx43) isoform has been shown to reduce inflammation and improve healing. We have developed a Cx43 mimetic peptide (JM2) that targets the microtubule-binding domain of Cx43. The following report investigates the role of the Cx43 microtubule-binding domain in extracellular ATP release by Cx43 hemichannels and how this impacts early inflammatory events of the foreign body reaction. Methods: In vitro Cx43 hemichannel-mediated ATP release by cultured human microvascular endothelial cells subjected to hypocalcemic and normocalcemic conditions was measured after application of JM2 and the known hemichannel blocker, flufenamic acid. A submuscular silicone implant model was used to investigate in vivo ATP signaling during the early foreign body response. Implants were coated with control pluronic vehicle or pluronic carrying JM2, ATP, JM2+ATP, or known hemichannel blockers and harvested at 24 h for analysis. Results: JM2 significantly inhibited connexin hemichannel-mediated ATP release from cultured endothelial cells. Importantly, the early inflammatory response to submuscular silicone implants was inhibited by JM2. The reduction in inflammation by JM2 was reversed by the addition of exogenous ATP to the pluronic vehicle. Conclusions: These data indicate that ATP released through Cx43 hemichannels into the vasculature is an important signal driving the early inflammatory

Inhibition of connexin 43 hemichannel-mediated ATP release attenuates early inflammation during the foreign body response.

PubMed

Calder, Bennett W; Matthew Rhett, Joshua; Bainbridge, Heather; Fann, Stephen A; Gourdie, Robert G; Yost, Michael J

2015-06-01

In the last 50 years, the use of medical implants has increased dramatically. Failure of implanted devices and biomaterials is a significant source of morbidity and increasing healthcare expenditures. An important cause of implant failure is the host inflammatory response. Recent evidence implicates extracellular ATP as an important inflammatory signaling molecule. A major pathway for release of cytoplasmic ATP into the extracellular space is through connexin hemichannels, which are the unpaired constituents of gap junction intercellular channels. Blockade of hemichannels of the connexin 43 (Cx43) isoform has been shown to reduce inflammation and improve healing. We have developed a Cx43 mimetic peptide (JM2) that targets the microtubule-binding domain of Cx43. The following report investigates the role of the Cx43 microtubule-binding domain in extracellular ATP release by Cx43 hemichannels and how this impacts early inflammatory events of the foreign body reaction. In vitro Cx43 hemichannel-mediated ATP release by cultured human microvascular endothelial cells subjected to hypocalcemic and normocalcemic conditions was measured after application of JM2 and the known hemichannel blocker, flufenamic acid. A submuscular silicone implant model was used to investigate in vivo ATP signaling during the early foreign body response. Implants were coated with control pluronic vehicle or pluronic carrying JM2, ATP, JM2+ATP, or known hemichannel blockers and harvested at 24 h for analysis. JM2 significantly inhibited connexin hemichannel-mediated ATP release from cultured endothelial cells. Importantly, the early inflammatory response to submuscular silicone implants was inhibited by JM2. The reduction in inflammation by JM2 was reversed by the addition of exogenous ATP to the pluronic vehicle. These data indicate that ATP released through Cx43 hemichannels into the vasculature is an important signal driving the early inflammatory response to implanted devices. A vital

PAH1-encoded Phosphatidate Phosphatase Plays a Role in the Growth Phase- and Inositol-mediated Regulation of Lipid Synthesis in Saccharomyces cerevisiae*

PubMed Central

Pascual, Florencia; Soto-Cardalda, Aníbal; Carman, George M.

2013-01-01

In the yeast Saccharomyces cerevisiae, the synthesis of phospholipids in the exponential phase of growth occurs at the expense of the storage lipid triacylglycerol. As exponential phase cells progress into the stationary phase, the synthesis of triacylglycerol occurs at the expense of phospholipids. Early work indicates a role of the phosphatidate phosphatase (PAP) in this metabolism; the enzyme produces the diacylglycerol needed for the synthesis of triacylglycerol and simultaneously controls the level of phosphatidate for the synthesis of phospholipids. Four genes (APP1, DPP1, LPP1, and PAH1) encode PAP activity in yeast, and it has been unclear which gene is responsible for the synthesis of triacylglycerol throughout growth. An analysis of lipid synthesis and composition, as well as PAP activity in various PAP mutant strains, showed the essential role of PAH1 in triacylglycerol synthesis throughout growth. Pah1p is a phosphorylated enzyme whose in vivo function is dependent on its dephosphorylation by the Nem1p-Spo7p protein phosphatase complex. nem1Δ mutant cells exhibited defects in triacylglycerol synthesis and lipid metabolism that mirrored those imparted by the pah1Δ mutation, substantiating the importance of Pah1p dephosphorylation throughout growth. An analysis of cells bearing PPAH1-lacZ and PPAH1-DPP1 reporter genes showed that PAH1 expression was induced throughout growth and that the induction in the stationary phase was stimulated by inositol supplementation. A mutant analysis indicated that the Ino2p/Ino4p/Opi1p regulatory circuit and transcription factors Gis1p and Rph1p mediated this regulation. PMID:24196957

Characterization of Early-Phase Neutrophil Extracellular Traps in Urinary Tract Infections

PubMed Central

Yu, Yanbao; Kwon, Keehwan; Tsitrin, Tamara; Sikorski, Patricia; Nelson, Karen E.; Pieper, Rembert

2017-01-01

Neutrophils have an important role in the antimicrobial defense and resolution of urinary tract infections (UTIs). Our research suggests that a mechanism known as neutrophil extracellular trap (NET) formation is a defense strategy to combat pathogens that have invaded the urinary tract. A set of human urine specimens with very high neutrophil counts had microscopic evidence of cellular aggregation and lysis. Deoxyribonuclease I (DNase) treatment resulted in disaggregation of such structures, release of DNA fragments and a proteome enriched in histones and azurophilic granule effectors whose quantitative composition was similar to that of previously described in vitro-formed NETs. The effector proteins were further enriched in DNA-protein complexes isolated in native PAGE gels. Immunofluorescence microscopy revealed a flattened morphology of neutrophils associated with decondensed chromatin, remnants of granules in the cell periphery, and myeloperoxidase co-localized with extracellular DNA, features consistent with early-phase NETs. Nuclear staining revealed that a considerable fraction of bacterial cells in these structures were dead. The proteomes of two pathogens, Staphylococcus aureus and Escherichia coli, were indicative of adaptive responses to early-phase NETs, specifically the release of virulence factors and arrest of ribosomal protein synthesis. Finally, we discovered patterns of proteolysis consistent with widespread cleavage of proteins by neutrophil elastase, proteinase 3 and cathepsin G and evidence of citrullination in many nuclear proteins. PMID:28129394

Fatigue-induced early onset of anticipatory postural adjustments in non-fatigued muscles: support for a centrally mediated adaptation.

PubMed

Strang, Adam J; Berg, William P; Hieronymus, Mathias

2009-08-01

Muscle fatigue has been shown to result in early onset of anticipatory postural adjustments (APAs) relative to those produced in a non-fatigued state. This adaptation is thought to reflect an attempt to preserve postural stability during a focal movement performed in a fatigued state. It remains unclear, however, whether this adaptation is of central (e.g., central nervous system motor command) or peripheral (e.g., muscle contractile properties), origin. One way to confirm that this adaptation is centrally driven is to identify fatigued-induced early APA onsets in non-fatigued muscles. In this study, APAs were obtained using a rapid bilateral reaching maneuver and recorded via surface electromyography before and after conditions of rest (n = 25) or fatigue (n = 25). Fatigue was generated using isokinetic exercise of the right leg. Results showed that fatigue-induced early APA onsets occurred in fatigued and non-fatigued muscles, confirming that fatigue-induced early APA onset is a centrally mediated adaptation.

Sustained attention is favored by progesterone during early luteal phase and visuo-spatial memory by estrogens during ovulatory phase in young women.

PubMed

Solís-Ortiz, S; Corsi-Cabrera, M

2008-08-01

Studies examining the influence of the menstrual cycle on cognitive function have been highly contradictory. The maintenance of attention is key to successful information processing, however how it co-vary with other cognitive functions and mood in function of phases of the menstrual cycle is not well know. Therefore, neuropsychological performance of nine healthy women with regular menstrual cycles was assessed during ovulation (OVU), early luteal (EL), late luteal (LL) and menstrual (MEN) phases. Neuropsychological test scores of sustained attention, executive functions, manual coordination, visuo-spatial memory, verbal fluency, spatial ability, anxiety and depression were obtained and submitted to a principal components analysis (PCA). Five eigenvectors that accounted the 68.31% of the total variance were identified. Performance of the sustained attention was grouped in an independent eigenvector (component 1), and the scores on verbal fluency and visuo-spatial memory were grouped together in an eigenvector (component 5), which explained 17.69% and 12.03% of the total variance, respectively. The component 1 (p<0.034) and the component 5 (p<0.003) showed significant variations during the menstrual cycle. Sustained attention showed an increase in the EL phase, when the progesterone is high. Visuo-spatial memory was increased, while that verbal fluency was decreased during the OVU phase, when the estrogens levels are high. These results indicate that sustained attention is favored by early luteal phase progesterone and do not covaried with any other neuropsychological variables studied. The influence of the estrogens on visuo-spatial memory was corroborated, and covaried inversely with verbal fluency.

CD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL

PubMed Central

Csányi, Gábor; Feck, Douglas M.; Ghoshal, Pushpankur; Singla, Bhupesh; Lin, Huiping; Nagarajan, Shanmugam; Meijles, Daniel N.; Al Ghouleh, Imad; Cantu-Medellin, Nadiezhda; Kelley, Eric E.; Mateuszuk, Lukasz; Isenberg, Jeffrey S.; Watkins, Simon

2017-01-01

Abstract Aims: Macropinocytosis has been implicated in cardiovascular and other disorders, yet physiological factors that initiate fluid-phase internalization and the signaling mechanisms involved remain poorly identified. The present study was designed to examine whether matrix protein thrombospondin-1 (TSP1) stimulates macrophage macropinocytosis and, if so, to investigate the potential signaling mechanism involved. Results: TSP1 treatment of human and murine macrophages stimulated membrane ruffle formation and pericellular solute internalization by macropinocytosis. Blockade of TSP1 cognate receptor CD47 and NADPH oxidase 1 (Nox1) signaling, inhibition of phosphoinositide 3-kinase, and transcriptional knockdown of myotubularin-related protein 6 abolished TSP1-induced macropinocytosis. Our results demonstrate that Nox1 signaling leads to dephosphorylation of actin-binding protein cofilin at Ser-3, actin remodeling, and macropinocytotic uptake of unmodified native low-density lipoprotein (nLDL), leading to foam cell formation. Finally, peritoneal chimera studies suggest the role of CD47 in macrophage lipid macropinocytosis in hypercholesterolemic ApoE−/− mice in vivo. Innovation: Activation of a previously unidentified TSP1-CD47 signaling pathway in macrophages stimulates direct receptor-independent internalization of nLDL, leading to significant lipid accumulation and foam cell formation. These findings reveal a new paradigm in which delimited Nox1-mediated redox signaling, independent of classical lipid oxidation, contributes to early propagation of vascular inflammatory disease. Conclusions: The findings of the present study demonstrate a new mechanism of solute uptake with implications for a wide array of cell types, including macrophages, dendritic cells, and cancer cells, and multiple pathological conditions in which matrix proteins are upregulated. Antioxid. Redox Signal. 26, 886–901. PMID:27958762

Monitoring of temperature-mediated phase transitions of adipose tissue by combined optical coherence tomography and Abbe refractometry.

PubMed

Yanina, Irina Y; Popov, Alexey P; Bykov, Alexander V; Meglinski, Igor V; Tuchin, Valery V

2018-01-01

Observation of temperature-mediated phase transitions between lipid components of the adipose tissues has been performed by combined use of the Abbe refractometry and optical coherence tomography. The phase transitions of the lipid components were clearly observed in the range of temperatures from 24°C to 60°C, and assessed by quantitatively monitoring the changes of the refractive index of 1- to 2-mm-thick porcine fat tissue slices. The developed approach has a great potential as an alternative method for obtaining accurate information on the processes occurring during thermal lipolysis. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

Early Human Testing Initiative Phase 1 Regenerative Life Support Systems

NASA Image and Video Library

1995-08-08

Early Human Testing (EHT) Initiative Phase 1 Regenerative Life Support Systems Laboratory (RLSSL). Nigel Packham activities in the Variable Pressure Growth Chamber which he lived inside for 15 days. A crowd of well-wishers outside the test chamber, at the console are John Lewis, Ed Mohr and Marybeth Edeen (15577). Packham exiting the chamber (15578-81). Packham is the focus of television cameras and reporters (15582-3). Don Henninger interviewed by reporters (15584). Packham is presented with a jacket after his stay in the chamber (15585). Packham inside the wheat growth chamber checking the condition of the plants (15586-7, 15597). Packham exercising on a recumbant bicycle (15588, 15592). Packham, through the window into the growth chamber, displays a handful of wheat plants to console monitor Dan Barta (15589-90). Group portrait of the team conducting the Early Human Testing Initiative Phase 1 Regenerative Life Support Systems test and include, front row, from left: Jeff Dominick and Don Overton and back row, from left, unidentified member, Marybeth Edeen, Nigel Packham, John Lewis, Ed Mohr, Dan Barta and Tim Monk (15591). Harry Halford prepares to send a package through the airlock to Packham (15593). Packham displays a handful of wheat plants (15594). Packham fixes himself a bowl of cereal (15595) and retrieves a carton of milk from the refrigerator (15596). Packham retrieves a package from the airlock (15598). Packham packs up trash in plastic bag (15599-600) and sends it back through the airlock (15601). Packham gets a cup of water (15602) and heats it in the microwave (15603).

[The correlation between serum uric acid level and early-phase insulin secretion in subjects with normal glucose regulation].

PubMed

Lu, L; Zheng, F P; Li, H

2016-05-01

To investigate the correlation between serum uric acid (SUA) level and early-phase insulin secretion in subjects with normal glucose regulation (NGR). Totally 367 community NGR residents confirmed by a 75g oral glucose tolerance test were enrolled. The insulin resistance index (HOMA-IR) and the early-phase insulin secretion index after a glucose load (ΔI30/ΔG30) were used to estimate the insulin sensitivity and the early-phase insulin secretion, respectively. The subjects were divided into 4 groups according to the SUA level quartiles. Differences in early-phase insulin levels, ΔI30/ΔG30, and HOMA-IR were compared among the 4 groups. Age, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, fasting insulin (FINS), 30 minutes postprandial insulin(30 minINS), 2 hours postprandial insulin(2hINS), HOMA-IR and TG levels increased across the rising categories of SUA levels, while the HDL-C was decreased across the SUA groups (P<0.01). The SUA level was positively correlated with age(r=0.157, P<0.01), BMI(r=0.262, P<0.01), waist circumference(r=0.372, P<0.01), systolic blood pressure(r=0.200, P<0.01), diastolic blood pressure(r=0.254, P<0.01), 30 minutes postprandial plasma glucose(r=0.118, P=0.023), FINS(r=0.249, P<0.01), 30minINS(r=0.189, P<0.01), 2hINS(r=0.206, P<0.01), glycosylated hemoglobin(HbA1c, r=0.106, P=0.042), HOMA-IR(r=0.244, P<0.01), TG(r=0.350, P<0.01), ΔI30/ΔG30(r=0.144, P<0.01), and negatively correlated with HDL-C level(r=-0.321, P<0.01). Multiple stepwise regression analysis showed that SUA(β=0.292, P<0.01) and HOMA-IR(β=29.821, P<0.01) were positively associated with ΔI30/ΔG30. SUA level is closely related with the early-phase insulin secretion in NGR subjects.

Early age alcohol use and later alcohol problems in adolescents: individual and peer mediators in a bi-national study.

PubMed

Mason, W Alex; Toumbourou, John W; Herrenkohl, Todd I; Hemphill, Sheryl A; Catalano, Richard F; Patton, George C

2011-12-01

This paper examines whether there is cross-national similarity in the longitudinal relationship between early age alcohol use and adolescent alcohol problems. Potential mechanisms underlying this relationship also are examined, testing adolescent alcohol use, low self-regulation, and peer deviance as possible mediators. Students (N = 1,945) participating in the International Youth Development Study, a longitudinal panel survey study, responded to questions on alcohol use and influencing factors, and were followed annually over a 3-year period from 2002 to 2004 (98% retention rate). State-representative, community student samples were recruited in grade 7 in Washington State, United States (US, n = 961, 78% of those eligible; Mage = 13.09, SD = .44) and Victoria, Australia (n = 984, 76% of those eligible; Mage = 12.93, SD = .41). Analyses were conducted using multiple-group structural equation modeling. In both states, early age alcohol use (age 13) had a small but statistically significant association with subsequent alcohol problems (age 15). Overall, there was little evidence for mediation of early alcohol effects. Low self-regulation prospectively predicted peer deviance, alcohol use, and alcohol problems in both states. Peer deviance was more positively related to alcohol use and low self-regulation among students in Victoria compared to students in Washington State. The small but persistent association of early age alcohol use with alcohol problems across both samples is consistent with efforts to delay alcohol initiation to help prevent problematic alcohol use. Self-regulation was an important influence, supporting the need to further investigate the developmental contribution of neurobehavioral disinhibition.

TGF-β mediates early angiogenesis and latent fibrosis in an Emilin1-deficient mouse model of aortic valve disease

PubMed Central

Munjal, Charu; Opoka, Amy M.; Osinska, Hanna; James, Jeanne F.; Bressan, Giorgio M.; Hinton, Robert B.

2014-01-01

Aortic valve disease (AVD) is characterized by elastic fiber fragmentation (EFF), fibrosis and aberrant angiogenesis. Emilin1 is an elastin-binding glycoprotein that regulates elastogenesis and inhibits TGF-β signaling, but the role of Emilin1 in valve tissue is unknown. We tested the hypothesis that Emilin1 deficiency results in AVD, mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β dysregulation. Using histology, immunohistochemistry, electron microscopy, quantitative gene expression analysis, immunoblotting and echocardiography, we examined the effects of Emilin1 deficiency (Emilin1−/−) in mouse aortic valve tissue. Emilin1 deficiency results in early postnatal cell-matrix defects in aortic valve tissue, including EFF, that progress to latent AVD and premature death. The Emilin1−/− aortic valve displays early aberrant provisional angiogenesis and late neovascularization. In addition, Emilin1−/− aortic valves are characterized by early valve interstitial cell activation and proliferation and late myofibroblast-like cell activation and fibrosis. Interestingly, canonical TGF-β signaling (phosphorylated Smad2 and Smad3) is upregulated constitutively from birth to senescence, whereas non-canonical TGF-β signaling (phosphorylated Erk1 and Erk2) progressively increases over time. Emilin1 deficiency recapitulates human fibrotic AVD, and advanced disease is mediated by non-canonical (MAPK/phosphorylated Erk1 and Erk2) TGF-β activation. The early manifestation of EFF and aberrant angiogenesis suggests that these processes are crucial intermediate factors involved in disease progression and therefore might provide new therapeutic targets for human AVD. PMID:25056700

Relationship between mediation analysis and the structured life course approach

PubMed Central

Howe, Laura D; Smith, Andrew D; Macdonald-Wallis, Corrie; Anderson, Emma L; Galobardes, Bruna; Lawlor, Debbie A; Ben-Shlomo, Yoav; Hardy, Rebecca; Cooper, Rachel; Tilling, Kate; Fraser, Abigail

2016-01-01

Abstract Many questions in life course epidemiology involve mediation and/or interaction because of the long latency period between exposures and outcomes. In this paper, we explore how mediation analysis (based on counterfactual theory and implemented using conventional regression approaches) links with a structured approach to selecting life course hypotheses. Using theory and simulated data, we show how the alternative life course hypotheses assessed in the structured life course approach correspond to different combinations of mediation and interaction parameters. For example, an early life critical period model corresponds to a direct effect of the early life exposure, but no indirect effect via the mediator and no interaction between the early life exposure and the mediator. We also compare these methods using an illustrative real-data example using data on parental occupational social class (early life exposure), own adult occupational social class (mediator) and physical capability (outcome). PMID:27681097

77 FR 36958 - Proposed Requirements-Race to the Top-Early Learning Challenge; Phase 2

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

... DEPARTMENT OF EDUCATION 34 CFR Chapter II DEPARTMENT OF HEALTH AND HUMAN SERVICES 45 CFR Subtitle... Requirements--Race to the Top--Early Learning Challenge; Phase 2 AGENCY: Department of Education and Department of Health and Human Services. ACTION: Proposed requirements. SUMMARY: The Secretary of Education and...

Mothers' early depressive symptoms and children's first-grade adjustment: a transactional analysis of child withdrawal as a mediator.

PubMed

Yan, Ni; Dix, Theodore

2014-05-01

The depression-inhibition hypothesis suggests that mothers' depressive symptoms undermine development because they lead children to withdraw from social contact. To test this, this study examined whether poor first-grade adjustment among children of mothers with depressive symptoms is mediated by the emergence of child withdrawal in early development. Based on 1,364 dyads, four waves of data spanning from 24 months to first grade (7 years) were used to examine paths by which children's withdrawal mediates relations between mothers' early depressive symptoms and three first-grade outcomes: social competence, academic performance, and externalizing behavior problems. Structural equation modeling revealed three principal paths. First, direct relations were observed: Mothers' depressive symptoms predicted early child withdrawal and increases in child withdrawal over time, which predicted poor first-grade adjustment. Second, reciprocal relations were observed: Mothers' depressive symptoms predicted child withdrawal, which predicted increases in depressive symptoms. Third, relations via mother-child mutual responsiveness were observed: Depression-related increases in child withdrawal predicted declines in mutual responsiveness, which predicted poor first-grade adjustment. The findings suggest that, due to its interdependence with maternal depression and low mother-child mutual responsiveness over time, child withdrawal may play an important role in the poor first-grade adjustment of children whose mothers are high in depressive symptoms. © 2013 The Authors. Journal of Child Psychology and Psychiatry. © 2013 Association for Child and Adolescent Mental Health.

The Effectiveness of a Cross-Setting Complementary Staff- and Parent-Mediated Early Intensive Behavioral Intervention for Young Children with ASD

ERIC Educational Resources Information Center

Fava, Leonardo; Strauss, Kristin; Valeri, Giovanni; D'Elia, Lidia; Arima, Serena; Vicari, Stefano

2011-01-01

We compared the effects of Early Intensive Behavioral Intervention (EIBI) and eclectic intervention in children with ASD on autism severity, developmental performance, adaptive behavior, language skills and challenging behaviors. Twelve children received cross-setting staff- and parent-mediated EIBI of centre-based one-to-one and play sessions as…

Antigravity treadmill training during the early rehabilitation phase following unicompartmental knee arthroplasty: A case series.

PubMed

Huang, Chun-Hao; Schroeder, E Todd; Powers, Christopher

2018-02-26

Patients who have undergone unicompartmental knee arthroplasty (UKA) have been reported to exhibit altered gait 19-25 months post-surgery. The most common gait impairment in this population is inadequate knee flexion and a corresponding decrease in the knee extensor moment during loading response (i.e., quadriceps avoidance). The purpose of this case series was to determine whether incorporation of antigravity treadmill training into a standard physical therapy program can eliminate quadriceps avoidance gait during the early rehabilitation phase following UKA. Four females who underwent UKA were recruited for this study. Participants completed antigravity treadmill training three times per week for 12 weeks in addition to their standard physical therapy program. Instrumented gait analysis was performed at baseline (pre-intervention), week 6 (mid-intervention), and week 12 (post-intervention). We found that peak knee flexion and the peak knee extensor moment during the weight acceptance phase of gait increased to normal values following the 12-week intervention period (14.1 ± 6.5° to 20.6 ± 1.5° and 0.4 ± 0.3 to 0.7 ± 0.2 Nm/kg respectively). The findings of this case series suggest that a standard physical therapy program that incorporates early gait training using an antigravity treadmill may be beneficial in eliminating "quadriceps avoidance" during the early rehabilitation phase following UKA.

The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings.

PubMed

Lorch, U; Berelowitz, K; Ozen, C; Naseem, A; Akuffo, E; Taubel, J

2012-05-01

The interest in adaptive study design is evident from the growing amount of clinical research employing this model in the mid to later stages of medicines development. Little has been published on the practical application and merits of adaptive study design in early phase clinical research. This paper describes a retrospective analysis performed on a sample of 29 industry lead adaptive early phase studies commencing between 1 January 2006 and 31 December 2010 in a clinical trials unit in London, England. All studies containing at least one adaptive feature in the original protocol were included in the analysis. The scope of the analysis was to assess whether the use of adaptive study designs provided tangible benefits over the use of conventional study designs using time savings as the main measure. We conclude that the use of adaptive study design saves time in early phase research programs. This is achieved by abolishing the need for substantial amendments or by mitigating their impact on timelines and by using adaptive scheduling efficiencies.

White matter changes in early phase schizophrenia and cannabis use: an update and systematic review of diffusion tensor imaging studies.

PubMed

Cookey, Jacob; Bernier, Denise; Tibbo, Philip G

2014-07-01

The impact of cannabis use on the brain tissue is still unclear, both in the healthy developing brain and in people with schizophrenia. The focus of this review is on white matter, the primary connective infrastructure of the brain. We systematically reviewed diffusion tensor imaging (DTI) studies of early phase schizophrenia (illness effect), of cannabis use in otherwise healthy brains (drug effect), and of early phase schizophrenia with cannabis use (combined effects). Studies had to include a healthy, non-cannabis using, control group as well as report on fractional anisotropy as it is the most commonly used DTI index. We excluded cohorts with heavy alcohol or illicit drug use and studies with a sample size of less than 20 in the clinical group. We retained 17 studies of early phase schizophrenia, which together indicate deficits in white matter integrity observed in all fiber tract families, but most frequently in association, callosal and projection fibers. In otherwise healthy cannabis users (2 studies), deficits in white matter tracts were reported mainly in callosal fibers, but also in projection and limbic fibers. In cannabis users with early phase schizophrenia (1 study), deficits in white matter integrity were also observed in all fiber tract families, except for limbic fibers. The current literature points to several families of white matter tracts being differentially affected in early phase schizophrenia. Further work is required to reveal the impact of cannabis use in otherwise healthy people as well as those with schizophrenia. Paucity of available studies as well as restricting analysis to FA values represent the main limitations of this review. Copyright © 2014 Elsevier B.V. All rights reserved.

Relationship between mediation analysis and the structured life course approach.

PubMed

Howe, Laura D; Smith, Andrew D; Macdonald-Wallis, Corrie; Anderson, Emma L; Galobardes, Bruna; Lawlor, Debbie A; Ben-Shlomo, Yoav; Hardy, Rebecca; Cooper, Rachel; Tilling, Kate; Fraser, Abigail

2016-08-01

Many questions in life course epidemiology involve mediation and/or interaction because of the long latency period between exposures and outcomes. In this paper, we explore how mediation analysis (based on counterfactual theory and implemented using conventional regression approaches) links with a structured approach to selecting life course hypotheses. Using theory and simulated data, we show how the alternative life course hypotheses assessed in the structured life course approach correspond to different combinations of mediation and interaction parameters. For example, an early life critical period model corresponds to a direct effect of the early life exposure, but no indirect effect via the mediator and no interaction between the early life exposure and the mediator. We also compare these methods using an illustrative real-data example using data on parental occupational social class (early life exposure), own adult occupational social class (mediator) and physical capability (outcome). © The Author 2016. Published by Oxford University Press on behalf of the International Epidemiological Association.

Anaphase-promoting complex/cyclosome-CDH1-mediated proteolysis of the forkhead box M1 transcription factor is critical for regulated entry into S phase.

PubMed

Park, Hyun Jung; Costa, Robert H; Lau, Lester F; Tyner, Angela L; Raychaudhuri, Pradip

2008-09-01

The forkhead box M1 (FoxM1) transcription factor is overexpressed in many cancers, and in mouse models it is required for tumor progression. FoxM1 activates expression of the cell cycle genes required for both S and M phase progression. Here we demonstrate that FoxM1 is degraded in late mitosis and early G(1) phase by the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. FoxM1 interacts with the APC/C complex and its adaptor, Cdh1. Expression of Cdh1 stimulated degradation of the FoxM1 protein, and depletion of Cdh1 resulted in stabilization of the FoxM1 protein in late mitosis and in early G(1) phase of the cell cycle. Cdh1 has been implicated in regulating S phase entry. We show that codepletion of FoxM1 inhibits early S phase entry observed in Cdh1-depleted cells. The N-terminal region of FoxM1 contains both destruction box (D box) and KEN box sequences that are required for targeting by Cdh1. Mutation of either the D box sequence or the KEN box sequence stabilized FoxM1 and blocked Cdh1-induced proteolysis. Cells expressing a nondegradable form of FoxM1 entered S phase rapidly following release from M phase arrest. Together, our observations show that FoxM1 is one of the targets of Cdh1 in late M or early G(1) phase and that its proteolysis is important for regulated entry into S phase.

The Role of Early-Phase Transmission in the Spread of Yersinia pestis

PubMed Central

EISEN, REBECCA J.; DENNIS, DAVID T.; GAGE, KENNETH L.

2015-01-01

Early-phase transmission (EPT) of Yersinia pestis by unblocked fleas is a well-documented, replicable phenomenon with poorly defined mechanisms. We review evidence demonstrating EPT and current knowledge on its biological and biomechanical processes. We discuss the importance of EPT in the epizootic spread of Y. pestis and its role in the maintenance of plague bacteria in nature. We further address the role of EPT in the epidemiology of plague. PMID:26336267

Associations of Early- and Later-Childhood Poverty With Child Cognitive Function in Indonesia: Effect Decomposition in the Presence of Exposure-Induced Mediator-Outcome Confounding.

PubMed

Maika, Amelia; Mittinty, Murthy N; Brinkman, Sally; Lynch, John

2017-05-15

The amount of family financial resources available in early life influences child health and development. Using data from the 2000 and 2007 waves of the Indonesian Family Life Survey, we estimated the associations of early-life poverty (at age <7 years) and poverty in later childhood (at age 7-14 years) with cognitive function at age 7-14 years. Our analysis provided little support for the idea that an early intervention to support household income has a larger effect than intervention later in childhood; both seemed equally important. We also decomposed the effect of poverty at age <7 years into direct and indirect effects mediated through poverty and schooling/home environment at age 7-14 years. For decomposing the effects, we used 3 approaches: 1) joint mediators, 2) path-specific, and 3) intervention analog. Being exposed to poverty before age 7 years had a larger direct effect (difference in cognitive function z score) on child cognitive function at age 7-14 years (i.e., joint mediators β = -0.07, 95% confidence interval: -0.12, -0.02) than the indirect effects mediated through later poverty at age 7-14 years (β = -0.01, 95% confidence interval: -0.04, 0.01) and school attendance/home environment at age 7-14 years. The effect of poverty on cognitive function was small; nevertheless, financial intervention may still benefit children's cognitive function. © The Author 2017. 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.

Early change in coping strategies in responsive treatments for borderline personality disorder: A mediation analysis.

PubMed

Kramer, Ueli; Keller, Sabine; Caspar, Franz; de Roten, Yves; Despland, Jean-Nicolas; Kolly, Stéphane

2017-05-01

Difficulty in emotion regulation is a hallmark feature of patients with borderline personality disorder (BPD). Therefore, change in the frequency of certain patients' coping strategies-aiming at emotion regulation-are among the most promising mechanisms of change in treatments for BPD. In parallel, it was highlighted that therapist responsiveness significantly contributed to outcome across treatment approaches (Stiles, 2009). Based on a randomized controlled trial (Kramer et al., 2014), the present process-outcome mediation analysis aims at examining the patient's early change in frequency of coping strategies-in particular the decrease in behavioral forms of coping-as potential mechanism of change in responsive treatments for BPD. A total of 57 patients with BPD were included in the present analysis, out of whom 27 were randomly assigned to a 10-session psychiatric treatment and 30 to a 10-session psychiatric treatment augmented with the responsive intervention of the motive-oriented therapeutic relationship (Caspar, 2007). The 1st, 5th, and 9th session of each therapy were transcribed and analyzed using the Coping Action Pattern Rating Scale (Perry et al., 2005; 171 sessions analyzed in total), a validated observer-rated method for assessing coping strategies in the therapy process. Psychological distress was assessed using the OQ-45 at intake, after Session 5, and after Session 10. The results confirmed a responsiveness effect associated with the motive-oriented therapeutic relationship and showed a significant decrease in frequency of behavioral forms of coping, F(1, 54) = 3.09, p = .05, d = .56, which was not different between the 2 conditions. In addition, we demonstrated that the early decrease in behavioral forms of coping between Sessions 1 and 5 partially mediated the link between the group assignment and the change in psychological distress between Sessions 5 and 10. These results shed light on the centrality of therapist responsiveness in treatments for

An early secretory pathway mediated by GNOM-LIKE 1 and GNOM is essential for basal polarity establishment in Arabidopsis thaliana

DOE PAGES

Doyle, Siamsa M.; Haeger, Ash; Vain, Thomas; ...

2015-02-02

Spatial regulation of the plant hormone indole-3-acetic acid (IAA, or auxin) is essential for plant development. Auxin gradient establishment is mediated by polarly localized auxin transporters, including PIN-FORMED (PIN) proteins. Their localization and abundance at the plasma membrane are tightly regulated by endomembrane machinery, especially the endocytic and recycling pathways mediated by the ADP ribosylation factor guanine nucleotide exchange factor (ARF-GEF) GNOM. We assessed the role of the early secretory pathway in establishing PIN1 polarity in Arabidopsis thaliana by pharmacological and genetic approaches. We identified the compound endosidin 8 (ES8), which selectively interferes with PIN1 basal polarity without altering themore » polarity of apical proteins. ES8 alters the auxin distribution pattern in the root and induces a strong developmental phenotype, including reduced root length. The ARF-GEF–defective mutants gnom-like 1 ( gnl1-1) and gnom ( van7) are significantly resistant to ES8. The compound does not affect recycling or vacuolar trafficking of PIN1 but leads to its intracellular accumulation, resulting in loss of PIN1 basal polarity at the plasma membrane. In conclusion, our data confirm a role for GNOM in endoplasmic reticulum (ER)–Golgi trafficking and reveal that a GNL1/GNOM-mediated early secretory pathway selectively regulates PIN1 basal polarity establishment in a manner essential for normal plant development.« less

Increasing the sensitivity of reverse phase protein arrays by antibody-mediated signal amplification

PubMed Central

2010-01-01

Background Reverse phase protein arrays (RPPA) emerged as a useful experimental platform to analyze biological samples in a high-throughput format. Different signal detection methods have been described to generate a quantitative readout on RPPA including the use of fluorescently labeled antibodies. Increasing the sensitivity of RPPA approaches is important since many signaling proteins or posttranslational modifications are present at a low level. Results A new antibody-mediated signal amplification (AMSA) strategy relying on sequential incubation steps with fluorescently-labeled secondary antibodies reactive against each other is introduced here. The signal quantification is performed in the near-infrared range. The RPPA-based analysis of 14 endogenous proteins in seven different cell lines demonstrated a strong correlation (r = 0.89) between AMSA and standard NIR detection. Probing serial dilutions of human cancer cell lines with different primary antibodies demonstrated that the new amplification approach improved the limit of detection especially for low abundant target proteins. Conclusions Antibody-mediated signal amplification is a convenient and cost-effective approach for the robust and specific quantification of low abundant proteins on RPPAs. Contrasting other amplification approaches it allows target protein detection over a large linear range. PMID:20569466

Improving quality-of-life outcomes for patients with cancer through mediating effects of depressive symptoms and functional status: a three-path mediation model.

PubMed

Hsu, Mei-Chi; Tu, Chun-Hsien

2014-09-01

To test a hypothetical three-path mediation model evaluating the effects of functional status and depressive symptoms on the relationship between fatigue and quality of life in patients with cancer on the basis of the Theory of Unpleasant Symptoms. Patients with cancer often experience two or more concurrent, interrelated, mutually influential symptoms. Multiple unpleasant symptoms that have been proposed as mediating variables affecting quality of life in a model proposed in recent cancer studies are scanty. This study was a cross-sectional, descriptive, correlational design. Three hundred and twenty-six patients with cancer from oncology clinics were recruited in Taiwan between 2010-2011. Mediation models were tested and confirmed by applying structural modelling using Analysis of Moment Structures and the joint significance test. Fatigue affects patient quality of life directly or indirectly through functional status and depressive symptoms. These two mediating variables exhibited direct effects on quality of life. A path analysis approach revealed that 47·28 and 67·70% of the total effects of functional status and depressive symptoms, respectively, on the quality-of-life mediation models are attributable to 29·6 and 44·7% of the total effects between fatigue and quality of life, which mediated through two mediators, respectively. Quality of life may be enhanced by simultaneously improving physiological and psychological factors. An understanding of mediating effects is valuable in nursing care of patients with cancer, particularly in the early phase of treatment or in newly diagnosed stages I-III or recently treated patients with cancer in different disease stages. © 2013 John Wiley & Sons Ltd.

Transcriptomic dose-and-time-course indicators of early key events in a cytotoxicity-mediated mode of action for rodent urinary bladder tumorigenesis

EPA Science Inventory

TRANSCRIPTOMIC DOSE- AND TIME-COURSE INDICATORS OF EARLY KEY EVENTS IN A CYTOTOXICITY-MEDIATED MODE OF ACTION FOR RODENT URINARY BLADDER TUMORIGENESISDiuron is a substituted urea compound used globally as an herbicide. Urinary bladder tumors were induced in rats after chronic die...

Webcam Delivery of the Lidcombe Program for Early Stuttering: A Phase I Clinical Trial

ERIC Educational Resources Information Center

O'Brian, Sue; Smith, Kylie; Onslow, Mark

2014-01-01

Purpose: The Lidcombe Program is an operant treatment for early stuttering shown with meta-analysis to have a favorable odds ratio. However, many clients are unable to access the treatment because of distance and lifestyle factors. In this Phase I trial, we explored the potential efficacy, practicality, and viability of an Internet webcam Lidcombe…

Single microfilaments mediate the early steps of microtubule bundling during preprophase band formation in onion cotyledon epidermal cells

PubMed Central

Takeuchi, Miyuki; Karahara, Ichirou; Kajimura, Naoko; Takaoka, Akio; Murata, Kazuyoshi; Misaki, Kazuyo; Yonemura, Shigenobu; Staehelin, L. Andrew; Mineyuki, Yoshinobu

2016-01-01

The preprophase band (PPB) is a cytokinetic apparatus that determines the site of cell division in plants. It originates as a broad band of microtubules (MTs) in G2 and narrows to demarcate the future division site during late prophase. Studies with fluorescent probes have shown that PPBs contain F-actin during early stages of their development but become actin depleted in late prophase. Although this suggests that actins contribute to the early stages of PPB formation, how actins contribute to PPB-MT organization remains unsolved. To address this question, we used electron tomography to investigate the spatial relationship between microfilaments (MFs) and MTs at different stages of PPB assembly in onion cotyledon epidermal cells. We demonstrate that the PPB actins observed by fluorescence microscopy correspond to short, single MFs. A majority of the MFs are bound to MTs, with a subset forming MT-MF-MT bridging structures. During the later stages of PPB assembly, the MF-mediated links between MTs are displaced by MT-MT linkers as the PPB MT arrays mature into tightly packed MT bundles. On the basis of these observations, we propose that the primary function of actins during PPB formation is to mediate the initial bundling of the PPB MTs. PMID:27053663

Anti-Nociceptive Effect of Resveratrol During Inflammatory Hyperalgesia via Differential Regulation of pro-Inflammatory Mediators.

PubMed

Singh, Ajeet Kumar; Vinayak, Manjula

2016-07-01

Sensitization of nociceptive neurons by inflammatory mediators leads to hypersensitivity for normal painful stimuli which is termed hyperalgesia. Oxidative stress is an essential factor in pathological pain; therefore, antioxidants qualify as potential anti-hyperalgesic agents. The present study examines the efficacy of the natural antioxidant resveratrol in complete Freund's adjuvant (CFA) induced hyperalgesic rats. Thermal hyperalgesia was measured at different time points by paw withdrawal latency test and confirmed by c-Fos expression in spinal dorsal horn. The impact of resveratrol treatment on inflammatory mediators at peripheral (paw skin) and central (spinal cord) sites was determined during early (6 h) as well as late phase (48 h) of hyperalgesia. Intraplanter injection of CFA increased the level of cytokines IL-1β, TNF-α and IL-6 as well as inflammatory enzymes COX-2 and iNOS in paw skin in both phases. In case of spinal cord, the level of COX-2 was found to be elevated in both phases, whereas iNOS could not be detected. The cytokines were found to be elevated only in late phase in spinal cord. Administration of resveratrol (20 mg/kg) shifted the level of all inflammatory mediators towards normal, except cytokines in paw skin. The present study suggests that the anti-nociceptive effect of resveratrol is implicated at both peripheral and central sites in a tissue specific manner. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Diffusion-weighted MR imaging findings of kidneys in patients with early phase of obstruction.

PubMed

Bozgeyik, Zulkif; Kocakoc, Ercan; Sonmezgoz, Fitnet

2009-04-01

Diffusion-weighted (DW) magnetic resonance (MR) imaging is an MR technique used to show molecular diffusion. The apparent diffusion coefficient (ADC), as a quantitative parameter calculated from the DW MR images. The purpose of this study is to evaluate the ability of DW MR imaging in early phase of obstruction due to urolithiasis. Twenty-six patients with acute dilatation of the pelvicalyceal system detected by intravenous urography were included in this study. MR imaging was performed using a 1.5 T whole-body superconducting MR scanner. DW imaging can be performed using single-shot spin-echo, echo-planar imaging (EPI) sequences with the following diffusion gradient b values: 100, 600, 1000 s/mm(2). Circular region of interest (ROI) was placed in the renal parenchyma for the measurement of ADC values in the normal and obstructed kidney. For statistical analyses, Paired t test were used. In spite of obstructed kidneys had the lower ADC values compared to normal kidneys, these alterations were statistically insignificant. We did not observe significantly different ADC values of early phase of obstructed kidneys compared to normal kidneys.

Solar Radiation as Driving Force In Early Evolution

NASA Technical Reports Server (NTRS)

Rothschild, Lynn J.; Peterson, David L. (Technical Monitor)

2002-01-01

Ultraviolet radiation (UVR) has provided an evolutionary challenge to life on Earth in that it is both an agent of mutation and as well as a selective force. Today surface fluxes of UVR vary diurnally, seasonally, etc. Still, the UVR flux was probably substantially higher during the early phases of evolution, suggesting that its role in evolution was even more prominent during this time. In this presentation, the creative role of UVR in evolution is discussed, specifically in connection with the role that UVR may have played in the evolution of early microbial ecosystems. The presentation will include discussions of the direct influence of UVR on such processes as photosynthesis and genetic damage, as well as the indirect influence of UVR as mediated through the production of reactive oxygen species. These biological effects of UVR will be viewed against the backdrop of the physical nature of the early Earth, surely a very different place then than now.

Loss of Intralipid®- but Not Sevoflurane-Mediated Cardioprotection in Early Type-2 Diabetic Hearts of Fructose-Fed Rats: Importance of ROS Signaling

PubMed Central

Zhang, Liyan; Affolter, Andreas; Gandhi, Manoj; Hersberger, Martin; Warren, Blair E.; Lemieux, Hélène; Sobhi, Hany F.; Clanachan, Alexander S.; Zaugg, Michael

2014-01-01

Background Insulin resistance and early type-2 diabetes are highly prevalent. However, it is unknown whether Intralipid® and sevoflurane protect the early diabetic heart against ischemia-reperfusion injury. Methods Early type-2 diabetic hearts from Sprague-Dawley rats fed for 6 weeks with fructose were exposed to 15 min of ischemia and 30 min of reperfusion. Intralipid® (1%) was administered at the onset of reperfusion. Peri-ischemic sevoflurane (2 vol.-%) served as alternative protection strategy. Recovery of left ventricular function was recorded and the activation of Akt and ERK 1/2 was monitored. Mitochondrial function was assessed by high-resolution respirometry and mitochondrial ROS production was measured by Amplex Red and aconitase activity assays. Acylcarnitine tissue content was measured and concentration-response curves of complex IV inhibition by palmitoylcarnitine were obtained. Results Intralipid® did not exert protection in early diabetic hearts, while sevoflurane improved functional recovery. Sevoflurane protection was abolished by concomitant administration of the ROS scavenger N-2-mercaptopropionyl glycine. Sevoflurane, but not Intralipid® produced protective ROS during reperfusion, which activated Akt. Intralipid® failed to inhibit respiratory complex IV, while sevoflurane inhibited complex I. Early diabetic hearts exhibited reduced carnitine-palmitoyl-transferase-1 activity, but palmitoylcarnitine could not rescue protection and enhance postischemic functional recovery. Cardiac mitochondria from early diabetic rats exhibited an increased content of subunit IV-2 of respiratory complex IV and of uncoupling protein-3. Conclusions Early type-2 diabetic hearts lose complex IV-mediated protection by Intralipid® potentially due to a switch in complex IV subunit expression and increased mitochondrial uncoupling, but are amenable to complex I-mediated sevoflurane protection. PMID:25127027

String mediated phase transitions

NASA Technical Reports Server (NTRS)

Copeland, ED; Haws, D.; Rivers, R.; Holbraad, S.

1988-01-01

It is demonstrated from first principles how the existence of string-like structures can cause a system to undergo a phase transition. In particular, the role of topologically stable cosmic string in the restoration of spontaneously broken symmetries is emphasized. How the thermodynamic properties of strings alter when stiffness and nearest neighbor string-string interactions are included is discussed.

Executive Function Mediates the Relations between Parental Behaviors and Children's Early Academic Ability

PubMed Central

Devine, Rory T.; Bignardi, Giacomo; Hughes, Claire

2016-01-01

The past decade has witnessed a growth of interest in parental influences on individual differences in children's executive function (EF) on the one hand and in the academic consequences of variation in children's EF on the other hand. The primary aim of this longitudinal study was to examine whether children's EF mediated the relation between three distinct aspects of parental behavior (i.e., parental scaffolding, negative parent-child interactions, and the provision of informal learning opportunities) and children's academic ability (as measured by standard tests of literacy and numeracy skills). Data were collected from 117 parent-child dyads (60 boys) at two time points ~1 year apart (M Age at Time 1 = 3.94 years, SD = 0.53; M Age at Time 2 = 5.11 years, SD = 0.54). At both time points children completed a battery of tasks designed to measure general cognitive ability (e.g., non-verbal reasoning) and EF (e.g., inhibition, cognitive flexibility, working memory). Our models revealed that children's EF (but not general cognitive ability) mediated the relations between parental scaffolding and negative parent-child interactions and children's early academic ability. In contrast, parental provision of opportunities for learning in the home environment was directly related to children's academic abilities. These results suggest that parental scaffolding and negative parent-child interactions influence children's academic ability by shaping children's emerging EF. PMID:28018253

Phase Transitions in the Early Universe: The Cosmology of Non-Minimal Scalar Sectors

NASA Astrophysics Data System (ADS)

Kost, Jeffrey D.

Light scalar fields such as axions and string moduli can play an important role in early-universe cosmology. However, many factors can significantly impact their late-time cosmological abundances. For example, in cases where the potentials for these fields are generated dynamically--such as during cosmological mass-generating phase transitions--the duration of the time interval required for these potentials to fully develop can have significant repercussions. Likewise, in scenarios with multiple scalars, mixing amongst the fields can also give rise to an effective timescale that modifies the resulting late-time abundances. Previous studies have focused on the effects of either the first or the second timescale in isolation. In this thesis, by contrast, we examine the new features that arise from the interplay between these two timescales when both mixing and time-dependent phase transitions are introduced together. First, we find that the effects of these timescales can conspire to alter not only the total late-time abundance of the system--often by many orders of magnitude--but also its distribution across the different fields. Second, we find that these effects can produce large parametric resonances which render the energy densities of the fields highly sensitive to the degree of mixing as well as the duration of the time interval over which the phase transition unfolds. Finally, we find that these effects can even give rise to a "re-overdamping" phenomenon which causes the total energy density of the system to behave in novel ways that differ from those exhibited by pure dark matter or vacuum energy. All of these features therefore give rise to new possibilities for early-universe phenomenology and cosmological evolution. They also highlight the importance of taking into account the time dependence associated with phase transitions in cosmological settings. In the second part of this thesis, we proceed to study the early-universe cosmology of a Kaluza-Klein (KK

Cognitive function in early clinical phase huntington disease after rivastigmine treatment.

PubMed

Sešok, Sanja; Bolle, Nika; Kobal, Jan; Bucik, Valentin; Vodušek, David B

2014-09-01

In Huntington disease (HD) patients receiving rivastigmine treatment improvement of behavioral symptoms and of cognitive function (assessed with screening diagnostic instruments) has been reported. The aim of the present study was to verify such improvement in cognitive function by cognitive function assessment with a detailed neuropsychological battery covering all relevant cognitive systems expected to be impaired in early phase HD. Eighteen (18) HD patients entered the study and were randomly allocated to the rivastigmine and placebo group. All subjects underwent neuropsychological assessment at baseline. Follow-up neuropsychological assessment was applied after 6 months of rivastigmine or placebo treatment. Eighteen (18) healthy controls entered the study to control for practice effect and underwent neuropsychological assessment at baseline and after 6 months, without treatment. The neuropsychological battery consisted of assessment tools that are sensitive to cognitive impairment seen in early phase HD: CTMT, SDMT, Stroop (attention and information control), RFFT, TOL, Verbal fluency (executive functioning), CVLT-II, RCFT (learning and memory). Effect of rivastigmine and possible effect of practice was assessed using the mixed ANOVA model. No statistically significant effect of rivastigmine treatment on cognitive function in HD patients was detected. There was no evidence for practice or placebo effect. Detailed neuropsychological assessment did not confirm previously reported effect of rivastigmine treatment on cognitive function in HD patients. The limitations of our study are, in particular, small sample size and the lack of a single measure of relevant cognitive functioning in HD patients. Instead of focusing solely on statistical significance, a clinical relevance study is proposed to clarify the issue of rivastigmine effects in HD.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual

PubMed Central

Massett, Holly A.; Mishkin, Grace; Rubinstein, Larry; Ivy, S. Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A.; Abrams, Jeffrey S.

2016-01-01

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAPs) received for slow-accruing Phase 1 and 2 trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for Phase 1 trials and 66 for Phase 2 trials. Primary reasons cited for slow accrual were safety/toxicity (Phase 1: 48%), design/protocol concerns (Phase 1: 42%, Phase 2: 33%), and eligibility criteria (Phase 1: 41%, Phase 2: 35%). The most commonly proposed corrective actions were adding institutions (Phase 1: 43%, Phase 2: 85%) and amending the trial to change eligibility or design (Phase 1: 55%, Phase 2: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (Phase 1=48; Phase 2=46). Of these, 67% of Phase 1 and 70% of Phase 2 trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial lifecycles, but it may be more beneficial to invest in earlier accrual planning. PMID:27401246

Trajectories of BMI from early childhood through early adolescence: SES and psychosocial predictors.

PubMed

Lane, Sean P; Bluestone, Cheryl; Burke, Christopher T

2013-02-01

This study examined the ways in which body mass index (BMI) percentile - an identified risk factor for overweight and cardiovascular disease in adulthood - develops from birth through early adolescence. In addition, we examined whether psychosocial factors, such as parenting style and maternal depression, mediated the link between socio-economic status (SES) and BMI growth. Design. Data were obtained from phases 1-3 of the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care and Youth Development (SECCYD) - a longitudinal study that followed children from 10 communities in the United States from birth to age 11. We applied growth mixture models to identify distinct subtypes of BMI development. Within these models, we performed between- and within-class mediation analyses to examine whether SES predicted class membership or differences in development within each class via maternal depression and parenting styles. Results identified three prototypic trajectories of BMI percentile growth, elevated, steady increase, and stable. We found evidence for both between- and within-class mediation, suggesting multiple pathways by which SES can affect BMI development. These findings add to the research that suggests that being in a family with a low SES is associated with falling into patterns of development characterized by early and lasting increases in BMI relative to one's peers, and that this association is partly accounted for by maternal depression and parenting styles. What is already known? Past research has found evidence that patterns of childhood overweight are impacted by socioeconomic status through psychosocial factors like parenting and depression. This evidence is often limited to individual points in time where neglectful, permissive, and authoritarian parenting and higher levels of maternal depression are associated with higher levels of overweight status among children from infancy to adolescence. However, little

Solution-mediated phase transformation of haloperidol mesylate in the presence of sodium lauryl sulfate.

PubMed

Greco, Kristyn; Bogner, Robin

2011-09-01

Forming a salt is a common way to increase the solubility of a poorly soluble compound. However, the solubility enhancement gained by salt formation may be lost due to solution-mediated phase transformation (SMPT) during dissolution. The SMPT of a salt can occur due to a supersaturated solution near the dissolving surface caused by pH or other solution conditions. In addition to changes in pH, surfactants are also known to affect SMPT. In this study, SMPT of a highly soluble salt, haloperidol mesylate, at pH 7 in the presence of a commonly used surfactant, sodium lauryl sulfate (SLS), was investigated. Dissolution experiments were performed using a flow-through dissolution apparatus with solutions containing various concentrations of SLS. Compacts of haloperidol mesylate were observed during dissolution in the flow-through apparatus using a stereomicroscope. Raman microscopy was used to characterize solids. The dissolution of haloperidol mesylate was significantly influenced by the addition of sodium lauryl sulfate. In conditions where SMPT was expected, the addition of SLS at low concentrations (0.1-0.2 mM) reduced the dissolution of haloperidol mesylate. In solutions containing concentrations of SLS above the critical micelle concentration (CMC) (10-15 mM), the dissolution of haloperidol mesylate increased compared to below the CMC. The solids recovered from solubility experiments of haloperidol mesylate indicated that haloperidol free base precipitated at all concentrations of SLS. Above 5 mM of SLS, Raman microscopy suggested a new form, perhaps the estolate salt. The addition of surfactant in solids that undergo solution-mediated phase transformation can add complexity to the dissolution profiles and conversion.

Inhibition of Reticulon-1A-Mediated Endoplasmic Reticulum Stress in Early AKI Attenuates Renal Fibrosis Development.

PubMed

Fan, Ying; Xiao, Wenzhen; Lee, Kyung; Salem, Fadi; Wen, Jiejun; He, Li; Zhang, Jing; Fei, Yang; Cheng, Dongsheng; Bao, Hongda; Liu, Yumei; Lin, Fujun; Jiang, Gengru; Guo, Zhiyong; Wang, Niansong; He, John Cijiang

2017-07-01

Several animal studies have shown an important role for endoplasmic reticulum (ER) stress in AKI, whereas human studies are lacking. We recently reported that Reticulon-1A (RTN1A) is a key mediator of ER stress and kidney cell injury. Here, we investigated whether modulation of RTN1A expression during AKI contributes to the progression to CKD. In a retrospective study of 51 patients with AKI, increased expression of RTN1A and other ER stress markers were associated with the severity of kidney injury and with progression to CKD. In an inducible tubular cell-specific RTN1A-knockdown mouse model subjected to folic acid nephropathy (FAN) or aristolochic acid nephropathy, reduction of RTN1A expression during the initial stage of AKI attenuated ER stress and kidney cell injury in early stages and renal fibrosis development in later stages. Treatment of wild-type mice with tauroursodeoxycholic acid, an inhibitor of ER stress, after the induction of kidney injury with FA facilitated renoprotection similar to that observed in RTN1A-knockdown mice. Conversely, in transgenic mice with inducible tubular cell-specific overexpression of RTN1A subjected to FAN, induction of RTN1A overexpression aggravated ER stress and renal injury at the early stage and renal fibrosis at the late stage of FAN. Together, our human and mouse data suggest that the RTN1A-mediated ER stress response may be an important determinant in the severity of AKI and maladaptive repair that may promote progression to CKD. Copyright © 2017 by the American Society of Nephrology.

Unknown loads affect force production capacity in early phases of bench press throws.

PubMed

Hernández Davó, J L; Sabido Solana, R; Sarabia Marínm, J M; Sánchez Martos, Á; Moya Ramón, M

2015-10-01

Explosive strength training aims to improve force generation in early phases of movement due to its importance in sport performance. The present study examined the influence of lack of knowledge about the load lifted in explosive parameters during bench press throws. Thirteen healthy young men (22.8±2.0 years) participated in the study. Participants performed bench press throws with three different loads (30, 50 and 70% of 1 repetition maximum) in two different conditions (known and unknown loads). In unknown condition, loads were changed within sets in each repetition and participants did not know the load, whereas in known condition the load did not change within sets and participants had knowledge about the load lifted. Results of repeated-measures ANOVA revealed that unknown conditions involves higher power in the first 30, 50, 100 and 150 ms with the three loads, higher values of ratio of force development in those first instants, and differences in time to reach maximal rate of force development with 50 and 70% of 1 repetition maximum. This study showed that unknown conditions elicit higher values of explosive parameters in early phases of bench press throws, thereby this kind of methodology could be considered in explosive strength training.

Analysis of Loss-of-Coolant Accidents in the NIST Research Reactor - Early Phase

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

Baek, Joo S.; Diamond, David

A study of the fuel temperature during the early phase of a loss-of-coolant accident (LOCA) in the NIST research reactor (NBSR) was completed. Previous studies had been reported in the preliminary safety analysis report for the conversion of the NBSR from high-enriched uranium (HEU) fuel to low-enriched (LEU) fuel. Those studies had focused on the most vulnerable LOCA situation, namely, a double-ended guillotine break in the time period after reactor trip when water is drained from either the coolant channels inside the fuel elements or the region outside the fuel elements. The current study fills in a gap in themore » analysis which is the early phase of the event when there may still be water present but the reactor is at power or immediately after reactor trip and pumps have tripped. The calculations were done, for both the current HEU-fueled core and the proposed LEU core, with the TRACE thermal-hydraulic systems code. Several break locations and different break sizes were considered. In all cases the increase in the clad (or fuel meat) temperature was relatively small so that a large margin to the temperature threshold for blistering (the Safety Limit for the NBSR) remained.« less

Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression.

PubMed

Nezu, Masahiro; Souma, Tomokazu; Yu, Lei; Suzuki, Takafumi; Saigusa, Daisuke; Ito, Sadayoshi; Suzuki, Norio; Yamamoto, Masayuki

2017-02-01

Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Extinct radioactivities - A three-phase mixing model. [for early solar system abundances

NASA Technical Reports Server (NTRS)

Clayton, D. D.

1983-01-01

A new class of models is advanced for interpreting the relationship of radioactive abundances in the early solar system to their average concentration in the interstellar medium. The model assumes that fresh radioactivities are ejected from supernovae into the hot interstellar medium, and that the time scales for changes of phase into molecular clouds determine how much survives for formation therein of the solar system. A more realistic and physically motivated understanding of the low observed concentrations of I-129, Pu-244, and Pd-107 may result.

Examination of a modified cell cycle synchronization method and bovine nuclear transfer using synchronized early G1 phase fibroblast cells.

PubMed

Urakawa, Manami; Ideta, Atsushi; Sawada, Tokihiko; Aoyagi, Yoshito

2004-08-01

Somatic cell nuclear transfer has a low success rate, due to a high incidence of fetal loss and increased perinatal morbidity/mortality. One factor that may affect the successful development of nuclear transfer embryos is the cell cycle stage of the donor cell. In order to establish a cell cycle synchronization method that can consistently produce cloned embryos and offspring, we examined the effects of different combinations of three cell treatments on the recovery rate of mitotic phase cells using bovine fetal fibroblasts. In the first experiment, we examined the recovery rate of mitotic phase cells by a combination of treatment with a metaphase arrestant (1 microM 2-methoxyestradiol), shaking the plate and selecting cells with a diameter of 20 microns. As a result, 99% of mitotic phase cells were recovered by repeating the combined treatment of metaphase arrestant and shaking, and collection of cells with a specific diameter. In the second experiment, nuclear transfer was carried out using early G1 phase cells by choosing pairs of bridged cells derived from mitotic phase cells recovered by the combined treatment of 1 microM 2-methoxyestradiol and shaking, and collection of cells with a diameter of 20 microns. The reconstructed embryos were transferred to recipient heifers to determine post-implantation development. Development of embryos reconstructed from early G1 phase cells from the >/=6 cells stage on Day 3 to the morula-blastocyst stage on Day 6 was 100%. Ten blastocysts constructed from two cell lines were transferred into 10 recipient heifers. Nine of the 10 recipients delivered single live calves. In conclusion, mitotic phase bovine fibroblast cells were easily recovered by the combined treatments of 1 microM 2-methoxyestradiol, shaking, and selecting cells of the appropriate diameter. Furthermore, nuclear transfer using cells in the early G1 phase as donor cells gave a high rate of offspring production.

Early cumulative risk predicts externalizing behavior at age 10: The mediating role of adverse parenting.

PubMed

Gach, Emily J; Ip, Ka I; Sameroff, Arnold J; Olson, Sheryl L

2018-02-01

Multiple environmental risk factors in early childhood predict a broad range of adverse developmental outcomes. However, most prior longitudinal research has not illuminated explanatory mechanisms. Our main goals were to examine predictive associations between cumulative ecological risk factors in early childhood and children's later externalizing problems and to determine whether these associations were explained by variations in parenting quality. Participants were 241 children (118 girls) at risk for school-age conduct problems and their parents and teachers. Children were approximately 3 years old at Time 1 (T1) and 10 years old at Time 2 (T2). Reports of contextual risk at T1 were used to develop a cumulative risk index consisting of 6 singular risk variables from 3 ecological levels: social resources (low income; social isolation), family resources (marital aggression; poor total family functioning), and maternal resources (single parent status; poor maternal mental health). At T1, parenting variables were measured (corporal punishment, warm responsiveness, maternal efficacy, and negative perceptions of child behavior). At T2, mothers, fathers, and teachers reported child externalizing problems. Johnson's relative weight analysis revealed that the cumulative risk index was a more powerful predictor of age 10 years externalizing behavior than any of the singular contextual risk variables. Adverse parenting mediated the effects of cumulative risk on later child externalizing problems. Our findings have significant implications for understanding long-term effects of multiple contextual risk factors present in early childhood and for the implementation of positive parenting interventions early on. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Nuclear Translocation of MEK1 Triggers a Complex T cell Response through the Co-repressor Silencing Mediator of Retinoid and Thyroid Hormone Receptor (SMRT)

PubMed Central

Guo, Lei; Chen, Chaoyu; Liang, Qiaoling; Karim, Md. Zunayet; Gorska, Magdalena M.; Alam, Rafeul

2012-01-01

MEK1 phosphorylates ERK1/2 and regulates T cell generation, differentiation and function. MEK1 has recently been shown to translocate to the nucleus. Its nuclear function is largely unknown. By studying human CD4 T cells we demonstrate that a low level of MEK1 is present in the nucleus of CD4 T cells under basal conditions. T cell activation further increases the nuclear translocation of MEK1. MEK1 interacts with the nuclear receptor co-repressor SMRT. MEK1 reduces the nuclear level of SMRT in an activation-dependent manner. MEK1 is recruited to the promoter of c-Fos upon TCR stimulation. Conversely, SMRT is bound to the c-Fos promoter under basal conditions and is removed upon TCR stimulation. We examined the role of SMRT in regulation of T cell function. siRNA-mediated knockdown of SMRT results in a biphasic effect on cytokine production. The production of the cytokines—IL2, IL4, IL10 and IFNγ increases in the early phase (8 hr) and then decreases in the late phase (48 hr). The late phase decrease is associated with inhibition of T cell proliferation. The late phase inhibition of T cell activation is, in part, mediated by IL10 that is produced in the early phase, and in part, by β-catenin signaling. Thus, we have identified a novel nuclear function of MEK1. MEK1 triggers a complex pattern of early T cell activation followed by a late inhibition through its interaction with SMRT. This biphasic dual effect likely reflects a homeostatic regulation of T cell function by MEK1. PMID:23225884

The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis.

PubMed

Scalfari, Antonio; Romualdi, Chiara; Nicholas, Richard S; Mattoscio, Miriam; Magliozzi, Roberta; Morra, Aldo; Monaco, Salvatore; Muraro, Paolo A; Calabrese, Massimiliano

2018-05-16

To investigate the relationship among cortical radiologic changes, the number of early relapses (ERs), and the long-term course of multiple sclerosis (MS). In this cohort study, we assessed the number of cortical lesions (CLs) and white matter (WM) lesions and the cortical thickness (Cth) at clinical onset and after 7.9 mean years among 219 patients with relapsing remitting (RR) MS with 1 (Low-ER), 2 (Mid-ER), and ≥3 (High-ER) ERs during the first 2 years. Kaplan-Meier and Cox regression analyses investigated early factors influencing the risk of secondary progressive (SP) MS. Fifty-nine patients (27%) converted to SPMS in 6.1 mean years. A larger number of CLs at onset predicted a higher risk of SPMS (hazard ratio [HR] 2.16, 4.79, and 12.3 for 2, 5, and 7 CLs, respectively, p < 0.001) and shorter latency to progression. The High-ER compared to the Low-ER and Mid-ER groups had a larger volume of WM lesions and CLs at onset, accrued more CLs, experienced more severe cortical atrophy over time, and entered the SP phase more rapidly. In the multivariate model, older age at onset (HR 1.97, p < 0.001), a larger baseline CL (HR 2.21, p = 0.005) and WM lesion (HR 1.32, p = 0.03) volume, early changes of global Cth (HR 1.36, p = 0.03), and ≥3 ERs (HR 6.08, p < 0.001) independently predicted a higher probability of SP. Extensive cortical damage at onset is associated with florid inflammatory clinical activity and predisposes to a rapid occurrence of the progressive phase. Age at onset, the number of early attacks, and the extent of baseline focal cortical damage can identify groups at high risk of progression who may benefit from more active therapy. © 2018 American Academy of Neurology.

Exposure to peer delinquency as a mediator between self-report pubertal timing and delinquency: A longitudinal study of mediation

PubMed Central

Negriff, Sonya; Ji, Juye; Trickett, Penelope K.

2013-01-01

This study examined exposure to peer delinquency as a mediator between pubertal timing and self-reported delinquency longitudinally and whether this mediational model was moderated by either gender or maltreatment experience. Data were obtained from Time 1, 2, and 3 of a longitudinal study of maltreatment and development. At Time 1 the sample comprised 454 children aged 9–13 years. Analyses via structural equation modeling supported full mediation. Gender did not moderate this mediational relationship, but maltreatment experience did. The results show that early maturing males and females are both at risk for being exposed to peers that may draw them into delinquent behavior. Additionally, the mechanism linking early pubertal timing to delinquency differs depending on maltreatment experience. PMID:21262055

Feasibility study for early removal of HEU from CPP-651-Phase II

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

Smith, C.V.; Henry, R.; Milligan, C.

1997-09-01

A two-phase feasibility study was initiated in late 1996 to identify a way to expedite the removal of SNM from the CPP-651 vault. The first phase of this study provided preliminary information that appeared promising, but needed additional detailed planning and evaluate to validate the concepts and conclusions. The focus of Phase 2 was to provide the validation via resource-loaded schedules and more detailed cost estimates. Section 1 describes the purpose and objectives of the Phase 2 tasks and the programmatic drivers that influence related CPP-651 high-enriched uranium (HEU) management issues. Section 2 identifies the evaluation criteria and methodology andmore » the transfer issues and barriers preventing shipment. Section 3 provides site-specific background information for the CPP-651 facility and the Idaho National Engineering and Environmental Laboratory (INEEL) and describes the development of the basic material removal schedule, the proposed base case plan for removal of SNM, and the proposed HEU material management/shipping issues and strategies. Section 4 identifies the proposed options for accelerated removal of SNM and how they were evaluated via detailed scheduling, resource histograms, and cost analysis. Section 5 summarizes principal tasks for implementing this plan and other related HEU CPP-651 management issues that require continued planning efforts to assure successful implementation of this proposed early removal strategy.« less

Exploring correlation between perceived parenting styles, early maladaptive schemas, and depression among women with depressive symptoms in iran and India- role of early maladaptive schemas as mediators and moderatos.

PubMed

Khajouei Nia, Maryam; Sovani, Anuradha; Sarami Forooshani, Gholam Reza

2014-12-01

Many studies have reported that inadequate parental styles can contribute to depressive symptoms through dysfunctional cognitive styles. This study aimed to investigate the association of dysfunctional schemas and parenting style with depression, as well as the role of maladaptive schemas such as moderators and mediators in Iran and India. The study sample was selected randomly and consisted of 200 (age group 16-60 y) depressed females (mild to moderate); 100 from Tehran (Iran) and another 100 from Pune (India). The type of the research was causal-comparative. The data collection took place in hospitals and clinics in the targeted cities. Descriptive statistic tests and hierarchical multiple regression were executed (for the purpose of analyzing data) by SPSS 17. It was demonstrated that the association between parenting and depression was not moderated by early maladaptive schemas. On the contrary, the results supported meditational models in which parenting styles are associated with the cognitive schemas, and these in turn are related to depressive symptoms. It was also found that abandonment mediates the impacts of maternal style on depression in Iran. On the other hand, abandonment and punitiveness schemas mediated the relation between paternal style and depression in India. These findings suggest that the correlation between childhood experiences and depression in adulthood are mediated by dysfunctional schemas.

Two Distinct Mechanisms Govern RpoS-Mediated Repression of Tick-Phase Genes during Mammalian Host Adaptation by Borrelia burgdorferi, the Lyme Disease Spirochete.

PubMed

Grove, Arianna P; Liveris, Dionysios; Iyer, Radha; Petzke, Mary; Rudman, Joseph; Caimano, Melissa J; Radolf, Justin D; Schwartz, Ira

2017-08-22

The alternative sigma factor RpoS plays a key role modulating gene expression in Borrelia burgdorferi , the Lyme disease spirochete, by transcribing mammalian host-phase genes and repressing σ 70 -dependent genes required within the arthropod vector. To identify cis regulatory elements involved in RpoS-dependent repression, we analyzed green fluorescent protein (GFP) transcriptional reporters containing portions of the upstream regions of the prototypical tick-phase genes ospAB , the glp operon, and bba74 As RpoS-mediated repression occurs only following mammalian host adaptation, strains containing the reporters were grown in dialysis membrane chambers (DMCs) implanted into the peritoneal cavities of rats. Wild-type spirochetes harboring ospAB - and glp-gfp constructs containing only the minimal (-35/-10) σ 70 promoter elements had significantly lower expression in DMCs relative to growth in vitro at 37°C; no reduction in expression occurred in a DMC-cultivated RpoS mutant harboring these constructs. In contrast, RpoS-mediated repression of bba74 required a stretch of DNA located between -165 and -82 relative to its transcriptional start site. Electrophoretic mobility shift assays employing extracts of DMC-cultivated B. burgdorferi produced a gel shift, whereas extracts from RpoS mutant spirochetes did not. Collectively, these data demonstrate that RpoS-mediated repression of tick-phase borrelial genes occurs by at least two distinct mechanisms. One (e.g., ospAB and the glp operon) involves primarily sequence elements near the core promoter, while the other (e.g., bba74 ) involves an RpoS-induced transacting repressor. Our results provide a genetic framework for further dissection of the essential "gatekeeper" role of RpoS throughout the B. burgdorferi enzootic cycle. IMPORTANCE Borrelia burgdorferi , the Lyme disease spirochete, modulates gene expression to adapt to the distinctive environments of its mammalian host and arthropod vector during its enzootic

Heavy Alcohol Use in Early Adulthood as a Function of Childhood ADHD: Developmentally-Specific Mediation by Social Impairment and Delinquency

PubMed Central

Molina, Brooke S.G.; Walther, Christine A. P.; Cheong, JeeWon; Pedersen, Sarah; Gnagy, Elizabeth M.; Pelham, William E.

2014-01-01

Frequent heavy drinking in early adulthood, particularly prior to age 21, is associated with multiple health and legal consequences including continued problems with drinking later into adulthood. Children with Attention-Deficit/Hyperactivity Disorder (ADHD) are at risk of alcohol use disorder in adulthood, but little is known about their frequency of underage drinking as young adults or about mediational pathways that might contribute to this risky outcome. The current study used data from the Pittsburgh ADHD Longitudinal Study (PALS) to test social impairment and delinquency pathways from childhood ADHD to heavy drinking in early adulthood for individuals with (n=148) and without (n=117) childhood ADHD. Although ADHD did not predict heavy drinking, indirect mediating effects in opposing directions were found. A delinquency pathway from childhood ADHD to increased heavy drinking included adolescent and subsequently adult delinquent behavior. A social impairment pathway from childhood ADHD to decreased heavy drinking included adolescent, but not adult, social impairment. These findings help to explain the heterogeneity of results for alcohol use among individuals with ADHD and suggest that common ADHD-related impairments may operate differently from each other and distinctly across developmental periods. PMID:24611838

The relationship between childhood conduct disorder and adult antisocial behavior is partially mediated by early-onset alcohol abuse.

PubMed

Khalifa, Najat; Duggan, Conor; Howard, Rick; Lumsden, John

2012-10-01

Early-onset alcohol abuse (EOAA) was previously found to both mediate and moderate the effect of childhood conduct disorder (CD) on adult antisocial behavior (ASB) in an American community sample of young adults (Howard, R., Finn, P. R., Gallagher, J., & Jose, P. (2011). Adolescent-onset alcohol abuse exacerbates the influence of childhood conduct disorder on late adolescent and early adult antisocial behavior. Journal of Forensic Psychiatry and Psychology. Advance online publication. doi:10.1080/14789949.2011.641996). This study tested whether this result would generalize to a British forensic sample comprising 100 male forensic patients with confirmed personality disorder. Results confirmed that those in whom EOAA co-occurred with CD showed the highest level of personality pathology, particularly Cluster B traits and antisocial/borderline comorbidity. Those with co-occurring CD with EOAA, compared with those showing only CD, showed more violence in their criminal history and greater recreational drug use. Regression analysis showed that both EOAA and CD predicted adult ASB when covariates were controlled. Further analysis showed that EOAA significantly mediated but did not moderate the effect of CD on ASB. The failure to demonstrate an exacerbating effect of EOAA on the relationship between CD and ASB likely reflects the high prevalence of CD in this forensic sample. Some implications of these findings are discussed. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

53BP1 promotes microhomology-mediated end-joining in G1-phase cells

PubMed Central

Xiong, Xiahui; Du, Zhanwen; Wang, Ying; Feng, Zhihui; Fan, Pan; Yan, Chunhong; Willers, Henning; Zhang, Junran

2015-01-01

Alternative non-homologous end joining (alt-NHEJ) was originally identified as a backup repair mechanism in the absence of classical NHEJ (c-NHEJ) factors but recent studies have demonstrated that alt-NHEJ is active even when c-NHEJ as well as homologous recombination is available. The functions of 53BP1 in NHEJ processes are not well understood. Here, we report that 53BP1 promotes DNA double-strand break (DSB) repair and genomic stability not only in c-NHEJ-proficient but also -deficient human G1-phase cells. Using an array of repair substrates we show that these effects of 53BP1 are correlated with a promotion of microhomology-mediated end-joining (MMEJ), a subtype of alt-NHEJ, in G1-phase. Consistent with a specific role in MMEJ we confirm that 53BP1 status does not affect c-NHEJ. 53BP1 supports sequence deletion during MMEJ consistent with a putative role in facilitating end-resection. Interestingly, promotion of MMEJ by 53BP1 in G1-phase cells is only observed in the presence of functional BRCA1. Depletion of both 53BP1 and BRCA1 increases repair needing microhomology usage and augments loss of DNA sequence, suggesting that MMEJ is a highly regulated DSB repair process. Together, these findings significantly expand our understanding of the cell-cycle-dependent roles of 53BP1 in DSB repair. PMID:25586219

Early Breastfeeding Problems Mediate the Negative Association between Maternal Obesity and Exclusive Breastfeeding at 1 and 2 Months Postpartum1–3

PubMed Central

O’Sullivan, Elizabeth J; Perrine, Cria G; Rasmussen, Kathleen M

2015-01-01

Background Compared with normal-weight women, women with obesity experience poorer breastfeeding outcomes. Successful breastfeeding among women with obesity is important for achieving national breastfeeding goals. Objectives The objectives were to determine whether the negative association between obesity and any or exclusive breastfeeding at 1 and 2 mo postpartum is mediated through breastfeeding problems that occur in the first 2 wk postpartum and if this association differs by parity. Methods Mothers (1151 normal-weight and 580 obese) in the Infant Feeding Practices Study II provided information on sociodemographic and psychosocial characteristics, body mass index, and breastfeeding outcomes. At 1 mo postpartum, participants reported the breastfeeding problems they experienced in the first 2 wk postpartum from a predefined list of 17 options. We used factor analysis to condense these problems into 4 explanatory variables; continuous factor scores were computed for use in further analyses. We used maximum likelihood logistic regression to assess mediation of the association between obesity and breastfeeding outcomes through early breastfeeding problems. Results No significant effect of obesity was found on any breastfeeding at 1 or 2 mo. At 1 mo postpartum, for both primiparous and multiparous women, there was a significant direct effect of obesity on exclusive breastfeeding and a significant indirect effect of obesity through early breastfeeding problems related to the explanatory mediating variable “Insufficient Milk” (throughout the remainder of the Abstract, this factor will be denoted by upper case notation). At 2 mo postpartum both the direct effect of obesity and the indirect effect through Insufficient Milk were significant in primiparous women but only the indirect effect remained significant in multiparous women. Conclusions Early problems related to Insufficient Milk may partially explain the association between obesity and poor exclusive

Early Induction of NRF2 Antioxidant Pathway by RHBDF2 Mediates Rapid Cutaneous Wound Healing

PubMed Central

Hosur, Vishnu; Burzenski, Lisa M.; Stearns, Timothy M.; Farley, Michelle L.; Sundberg, John P.; Wiles, Michael V.; Shultz, Leonard D.

2017-01-01

Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2cub/cub) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2cub/cub mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2cub/cub and Rhbdf2+/+ mice at 0h, 15 min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15 min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2cub/cub mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds. PMID:28268192

Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing.

PubMed

Hosur, Vishnu; Burzenski, Lisa M; Stearns, Timothy M; Farley, Michelle L; Sundberg, John P; Wiles, Michael V; Shultz, Leonard D

2017-04-01

Rhomboid family protein RHBDF2, an upstream regulator of the epidermal growth factor (EGF) receptor signaling, has been implicated in cutaneous wound healing. However, the underlying molecular mechanisms are still emerging. In humans, a gain-of-function mutation in the RHBDF2 gene accelerates cutaneous wound healing in an EGFR-dependent manner. Likewise, a gain-of-function mutation in the mouse Rhbdf2 gene (Rhbdf2 cub/cub ) shows a regenerative phenotype (rapid ear-hole closure) resulting from constitutive activation of the EGFR pathway. Because the RHBDF2-regulated EGFR pathway is relevant to cutaneous wound healing in humans, we used Rhbdf2 cub/cub mice to investigate the biological networks and pathways leading to accelerated ear-hole closure, with the goal of identifying therapeutic targets potentially effective in promoting wound healing in humans. Comparative transcriptome analysis of ear pinna tissue from Rhbdf2 cub/cub and Rhbdf2 +/+ mice at 0h, 15min, 2h, and 24h post-wounding revealed an early induction of the nuclear factor E2-related factor 2 (NRF2)-mediated anti-oxidative pathway (0h and 15min), followed by the integrin-receptor aggregation pathway (2h) as early-stage events immediately and shortly after wounding in Rhbdf2 cub/cub mice. Additionally, we observed genes enriched for the Fc fragment of the IgG receptor IIIa (FCGR3A)-mediated phagocytosis pathway 24h post-wounding. Although cutaneous wound repair in healthy individuals is generally non-problematic, it can be severely impaired due to aging, diabetes, and chronic inflammation. This study suggests that activation of the NRF2-antioxidant pathway by rhomboid protein RHBDF2 might be beneficial in treating chronic non-healing wounds. Copyright © 2017 Elsevier Inc. All rights reserved.

Early-phase prandial insulin secretion: its role in the pathogenesis of type 2 diabetes mellitus and its modulation by repaglinide.

PubMed

Owens, D R; Cozma, L S; Luzio, S D

2002-12-01

The major contributory factor to increasing hyperglycaemia in established Type 2 diabetes mellitus (T2DM) appears to be the progressive delay and attenuation of the prandial insulin response. An important consequence of this derangement is that hepatic glucose production is no longer suppressed during times of prandial glucose intake. Together with a relative impairment in the rate of peripheral glucose disposal, this leads to supra-physiological plasma glucose excursions, which may damage the vasculature. An obvious therapeutic strategy, therefore, would be to increase insulin availability when most needed--in the early prandial phase. In experiments with exogenous insulin interventions, peak post-prandial blood glucose increments were curtailed without undue increases in total insulin exposure. However, available evidence suggests that the sulphonylurea glibenclamide does not effectively alter early-phase prandial insulin release but predominately increases late-phase and basal insulin output, thus incurring the risk of hypoglycaemia. The novel insulin secretagogue repaglinide, by contrast, augments early-phase prandial insulin secretion when taken before meals, as shown by studies in non-diabetic people and patients with newly diagnosed, previously untreated T2DM. Repaglinide exerts its greatest effect on the insulin secretion rate during the first 30 min after a meal is started, thereby going some way to restoring the early insulin secretion curve seen after a meal in non-diabetic people. No residual secretagogue activity is seen 4 hr after taking a single dose of up to 2 mg. Prandial glucose regulation with repaglinide could be associated with lower post-prandial glucose excursions and less risk of post-prandial hypoglycaemia than glibenclamide.

Mechanisms of the early phases of plant gravitropism

NASA Technical Reports Server (NTRS)

Kiss, J. Z.

2000-01-01

Gravitropism is directed growth of a plant or plant organ in response to gravity and can be divided into the following temporal sequence: perception, transduction, and response. This article is a review of the research on the early events of gravitropism (i.e., phenomena associated with the perception and transduction phases). The two major hypotheses for graviperception are the protoplast-pressure and starch-statolith models. While most researchers support the concept of statoliths, there are suggestions that plants have multiple mechanisms of perception. Evidence supports the hypothesis that the actin cytoskeleton is involved in graviperception/transduction, but the details of these mechanisms remain elusive. A number of recent developments, such as increased use of the molecular genetic approach, magnetophoresis, and laser ablation, have facilitated research in graviperception and have allowed for refinement of the current models. In addition, the entire continuum of acceleration forces from hypo- to hyper-gravity have been useful in studying perception mechanisms. Future interdisciplinary molecular approaches and the availability of sophisticated laboratories on the International Space Station should help to develop new insights into mechanisms of gravitropism in plants.

Early Restoration | NOAA Gulf Spill Restoration

Science.gov Websites

Early Restoration Plan. On April 20, 2011 we reached an agreement with BP to start restoration planning draft plan for the third phase of early restoration in December 2013. We are considering your comments : All Phase III information and documents Phase II Useful Links: Phase II Early Restoration Plan &

A serial mediation model testing early adversity, self-concept clarity, and thin-ideal internalization as predictors of body dissatisfaction.

PubMed

Vartanian, Lenny R; Froreich, Franzisca V; Smyth, Joshua M

2016-12-01

This study examined the associations among early family adversity (e.g., family violence, neglect), self-concept clarity (i.e., having a clear and coherent sense of one's own personal identity), thin-ideal internalization, and body dissatisfaction. Female university students in Australia (n=323) and adult female community members in the United States (n=371) completed self-report measures of the relevant constructs. In both samples, serial mediation analysis revealed that early family adversity was negatively associated with self-concept clarity, self-concept clarity was negatively associated with thin-ideal internalization, and thin-ideal internalization was positively associated with body dissatisfaction. These findings suggest that early adverse experiences might impair individuals' self-concept clarity, and that low self-concept clarity might increase the risk of internalization of the thin ideal (as a means of defining the self) and consequently body dissatisfaction. These findings also suggest possible avenues for prevention and intervention efforts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Challenges Facing Early Phase Trials Sponsored by the National Cancer Institute: An Analysis of Corrective Action Plans to Improve Accrual.

PubMed

Massett, Holly A; Mishkin, Grace; Rubinstein, Larry; Ivy, S Percy; Denicoff, Andrea; Godwin, Elizabeth; DiPiazza, Kate; Bolognese, Jennifer; Zwiebel, James A; Abrams, Jeffrey S

2016-11-15

Accruing patients in a timely manner represents a significant challenge to early phase cancer clinical trials. The NCI Cancer Therapy Evaluation Program analyzed 19 months of corrective action plans (CAP) received for slow-accruing phase I and II trials to identify slow accrual reasons, evaluate whether proposed corrective actions matched these reasons, and assess the CAP impact on trial accrual, duration, and likelihood of meeting primary scientific objectives. Of the 135 CAPs analyzed, 69 were for phase I trials and 66 for phase II trials. Primary reasons cited for slow accrual were safety/toxicity (phase I: 48%), design/protocol concerns (phase I: 42%, phase II: 33%), and eligibility criteria (phase I: 41%, phase II: 35%). The most commonly proposed corrective actions were adding institutions (phase I: 43%, phase II: 85%) and amending the trial to change eligibility or design (phase I: 55%, phase II: 44%). Only 40% of CAPs provided proposed corrective actions that matched the reasons given for slow accrual. Seventy percent of trials were closed to accrual at time of analysis (phase I = 48; phase II = 46). Of these, 67% of phase I and 70% of phase II trials met their primary objectives, but they were active three times longer than projected. Among closed trials, 24% had an accrual rate increase associated with a greater likelihood of meeting their primary scientific objectives. Ultimately, trials receiving CAPs saw improved accrual rates. Future trials may benefit from implementing CAPs early in trial life cycles, but it may be more beneficial to invest in earlier accrual planning. Clin Cancer Res; 22(22); 5408-16. ©2016 AACRSee related commentary by Mileham and Kim, p. 5397. ©2016 American Association for Cancer Research.

Current status of amorphous formulation and other special dosage forms as formulations for early clinical phases.

PubMed

Kawakami, Kohsaku

2009-09-01

Although most chemists in the pharmaceutical industry have a good understanding on favorable physicochemical properties for drug candidates, formulators must still deal with many challenging candidates. On the other hand, formulators are not allowed to spend much time on formulation development for early phases of the clinical studies. Thus, it is basically difficult to apply special dosage form technologies to the candidates for the first-in-human formulations. Despite the availability of numerous reviews on oral special dosage forms, information on their applicability as the early phase formulation has been limited. This article describes quick review on the oral special dosage forms that may be applied to the early clinical formulations, followed by discussion focused on the amorphous formulations, which still has relatively many issues to be proved for the general use. The major problems that inhibit the use of the amorphous formulation are difficulty in the manufacturing and the poor chemical/physical stability. Notably, the poor physical stability can be critical, because of not the poor stability itself but the difficulty in the timely evaluation in the preclinical developmental timeframes. Research directions of the amorphous formulations are suggested to utilize this promising technology without disturbing the preclinical developmental timelines.

Conspecific Leaf Litter-Mediated Effect of Conspecific Adult Neighborhood on Early-Stage Seedling Survival in A Subtropical Forest.

PubMed

Liu, Heming; Shen, Guochun; Ma, Zunping; Yang, Qingsong; Xia, Jianyang; Fang, Xiaofeng; Wang, Xihua

2016-11-25

Conspecific adults have strong negative effect on the survival of nearby early-stage seedlings and thus can promote species coexistence by providing space for the regeneration of heterospecifics. The leaf litter fall from the conspecific adults, and it could mediate this conspecific negative adult effect. However, field evidence for such effect of conspecific leaf litter remains absent. In this study, we used generalized linear mixed models to assess the effects of conspecific leaf litter on the early-stage seedling survival of four dominant species (Machilus leptophylla, Litsea elongate, Acer pubinerve and Distylium myricoides) in early-stage seedlings in a subtropical evergreen broad-leaved forest in eastern China. Our results consistently showed that the conspecific leaf litter of three species negatively affected the seedling survival. Meanwhile, the traditional conspecific adult neighborhood indices failed to detect this negative conspecific adult effect. Our study revealed that the accumulation of conspecific leaf litter around adults can largely reduce the survival rate of nearby seedlings. Ignoring it could result in underestimation of the importance of negative density dependence and negative species interactions in the natural forest communities.

Men Managing, Not Teaching Foundation Phase: Teachers, Masculinity and the Early Years of Primary Schooling

ERIC Educational Resources Information Center

Moosa, Shaaista; Bhana, Deevia

2017-01-01

In this article we argue that eliminating the divisions of labour between men and women could work towards counteracting gender inequality within professions. Globally women are over-represented in the teaching of young children in the early years of primary school, or Foundation Phase (FP), as it is known in South Africa. We are concerned to go…

77 FR 58359 - Applications for New Awards; Race to the Top-Early Learning Challenge; Phase 2

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-20

... amended by section 1832(b) of Division B of Pub. L. 112-10, the Department of Defense and Full-Year... DEPARTMENT OF EDUCATION DEPARTMENT OF HEALTH AND HUMAN SERVICES Applications for New Awards; Race to the Top--Early Learning Challenge; Phase 2 AGENCY: Department of Education and Department of...

The Low-luminosity Type IIP Supernova 2016bkv with Early-phase Circumstellar Interaction

NASA Astrophysics Data System (ADS)

Nakaoka, Tatsuya; Kawabata, Koji S.; Maeda, Keiichi; Tanaka, Masaomi; Yamanaka, Masayuki; Moriya, Takashi J.; Tominaga, Nozomu; Morokuma, Tomoki; Takaki, Katsutoshi; Kawabata, Miho; Kawahara, Naoki; Itoh, Ryosuke; Shiki, Kensei; Mori, Hiroki; Hirochi, Jun; Abe, Taisei; Uemura, Makoto; Yoshida, Michitoshi; Akitaya, Hiroshi; Moritani, Yuki; Ueno, Issei; Urano, Takeshi; Isogai, Mizuki; Hanayama, Hidekazu; Nagayama, Takahiro

2018-06-01

We present optical and near-infrared observations of a low-luminosity (LL) Type IIP supernova (SN) 2016bkv from the initial rising phase to the plateau phase. Our observations show that the end of the plateau is extended to ≳140 days since the explosion, indicating that this SN takes one of the longest times to finish the plateau phase among Type IIP SNe (SNe IIP), including LL SNe IIP. The line velocities of various ions at the middle of the plateau phase are as low as 1000–1500 km s‑1, which is the lowest even among LL SNe IIP. These measurements imply that the ejecta mass in SN 2016bkv is larger than that of the well-studied LL IIP SN 2003Z. In the early phase, SN 2016bkv shows a strong bump in the light curve. In addition, the optical spectra in this bump phase exhibit a blue continuum accompanied by a narrow Hα emission line. These features indicate an interaction between the SN ejecta and the circumstellar matter (CSM) as in SNe IIn. Assuming the ejecta–CSM interaction scenario, the mass loss rate is estimated to be ∼ 1.7× {10}-2 {M}ȯ yr‑1 within a few years before the SN explosion. This is comparable to or even larger than the largest mass loss rate observed for the Galactic red supergiants (∼ {10}-3 {M}ȯ yr‑1 for VY CMa). We suggest that the progenitor star of SN 2016bkv experienced a violent mass loss just before the SN explosion.

Loop-mediated isothermal amplification (LAMP): early detection of Toxoplasma gondii infection in mice.

PubMed

Kong, Qing-Ming; Lu, Shao-Hong; Tong, Qun-Bo; Lou, Di; Chen, Rui; Zheng, Bin; Kumagai, Takashi; Wen, Li-Yong; Ohta, Nobuo; Zhou, Xiao-Nong

2012-01-03

Toxoplasmosis is a widespread zoonotic parasitic disease that occurs in both animals and humans. Traditional molecular assays are often difficult to perform, especially for the early diagnosis of Toxoplasma gondii infections. Here, we established a novel loop-mediated isothermal amplification targeting the 529 bp repeat element (529 bp-LAMP) to detect T. gondii DNA in blood samples of experimental mice infected with tachyzoites of the RH strain. The assay was performed with Bst DNA polymerase at 65°C for 1 h. The detection limit of the 529 bp-LAMP assay was as low as 0.6 fg of T. gondii DNA. The sensitivity of this assay was 100 and 1000 fold higher than that of the LAMP targeting B1 gene (B1-LAMP) and nested PCR targeting 529 bp repeat element (529 bp-nested PCR), respectively. The specificity of the 529 bp-LAMP assay was determined using the DNA samples of Trypanosoma evansi, Plasmodium falciparum, Paragonimus westermani, Schistosoma japonicum, Fasciola hepatica and Angiostrongylus cantonensis. No cross-reactivity with the DNA of any parasites was found. The assay was able to detect T. gondii DNA in all mouse blood samples at one day post infection (dpi). We report the following findings: (i) The detection limit of the 529 bp-LAMP assay is 0.6 fg of T. gondii DNA; (ii) The assay does not involve any cross-reactivity with the DNA of other parasites; (iii) This is the first report on the application of the LAMP assay for early diagnosis of toxoplasmosis in blood samples from experimentally infected mice. Due to its simplicity, sensitivity and cost-effectiveness for common use, we suggest that this assay should be used as an early diagnostic tool for health control of toxoplasmosis.

Nitrate reductase-mediated early nitric oxide burst alleviates oxidative damage induced by aluminum through enhancement of antioxidant defenses in roots of wheat (Triticum aestivum).

PubMed

Sun, Chengliang; Lu, Lingli; Liu, Lijuan; Liu, Wenjing; Yu, Yan; Liu, Xiaoxia; Hu, Yan; Jin, Chongwei; Lin, Xianyong

2014-03-01

• Nitric oxide (NO) is an important signaling molecule involved in the physiological processes of plants. The role of NO release in the tolerance strategies of roots of wheat (Triticum aestivum) under aluminum (Al) stress was investigated using two genotypes with different Al resistances. • An early NO burst at 3 h was observed in the root tips of the Al-tolerant genotype Jian-864, whereas the Al-sensitive genotype Yang-5 showed no NO accumulation at 3 h but an extremely high NO concentration after 12 h. Stimulating NO production at 3 h in the root tips of Yang-5 with the NO donor relieved Al-induced root inhibition and callose production, as well as oxidative damage and ROS accumulation, while elimination of the early NO burst by NO scavenger aggravated root inhibition in Jian-864. • Synthesis of early NO in roots of Jian-864 was mediated through nitrate reductase (NR) but not through NO synthase. Elevated antioxidant enzyme activities were induced by Al stress in both wheat genotypes and significantly enhanced by NO donor, but suppressed by NO scavenger or NR inhibitor. • These results suggest that an NR-mediated early NO burst plays an important role in Al resistance of wheat through modulating enhanced antioxidant defense to adapt to Al stress. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

The early phase of /see symbol/ production development in adult Japanese learners of English.

PubMed

Saito, Kazuya; Munro, Murray J

2014-12-01

Although previous research indicates that Japanese speakers' second language (L2) perception and production of English /see symbol/ may improve with increased L2 experience, relatively little is known about the fine phonetic details of their /see symbol/ productions, especially during the early phase of L2 speech learning. This cross-sectional study examined acoustic properties of word-initial /see symbol/ from 60 Japanese learners with a length of residence of between one month and one year in Canada. Their performance was compared to that of 15 native speakers of English and 15 low-proficiency Japanese learners of English. Formant frequencies (F2 and F3) and F1 transition durations were evaluated under three task conditions--word reading, sentence reading, and timed picture description. Learners with as little as two to three months of residence demonstrated target-like F2 frequencies. In addition, increased LOR was predictive of more target-like transition durations. Although the learners showed some improvement in F3 as a function of LOR, they did so mainly at a controlled level of speech production. The findings suggest that during the early phase of L2 segmental development, production accuracy is task-dependent and is influenced by the availability of L1 phonetic cues for redeployment in L2.

Restoration of energy level in the early phase of acute pediatric pancreatitis.

PubMed

Mosztbacher, Dóra; Farkas, Nelli; Solymár, Margit; Pár, Gabriella; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Márta, Katalin; Mikó, Alexandra; Rumbus, Zoltán; Varjú, Péter; Hegyi, Péter; Párniczky, Andrea

2017-02-14

Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatment of acute pediatric pancreatitis. The preferred reporting items for systematic review (PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (PubMed: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly (SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better

Restoration of energy level in the early phase of acute pediatric pancreatitis

PubMed Central

Mosztbacher, Dóra; Farkas, Nelli; Solymár, Margit; Pár, Gabriella; Bajor, Judit; Szűcs, Ákos; Czimmer, József; Márta, Katalin; Mikó, Alexandra; Rumbus, Zoltán; Varjú, Péter; Hegyi, Péter; Párniczky, Andrea

2017-01-01

Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatment of acute pediatric pancreatitis. The preferred reporting items for systematic review (PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (PubMed: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly (SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better

Welcome to the Twilight Zone: a forgotten early phase of human evolutionary studies.

PubMed

Delisle, Richard G

2012-06-01

The field of paleoanthropology arose out of a strange and unacknowledged early phase of development prior to about the 1930s. It is often assumed that a key pillar of the discipline, the unity of humankind--the notion that humans are clearly separated phylogenetically (genealogically) from other non-human primates--was widely accepted from the inception of paleoanthropology around 1860. However, a final consensus on this fundamental question only appeared later on in the 20th century. This paper will focus on two key areas of disagreement, which reveal the unsettled state of this question during this early period: the question of uncertainty with respect to the number, identity and boundary of primate species (including humans) which prevailed in the 18th, 19th and early 20th centuries; and the matter of uncertainty with respect to the nature of the phylogenetic relationships among the various human populations and the other primate species which prevailed between 1864 and 1931. Consideration of these matters reveals that the modern research structure that paleoanthropologists take for granted today is much more recent than believed. Copyright © 2012 Elsevier Ltd. All rights reserved.

Novel percutaneous suture-mediated patent foramen ovale closure technique. Early results of the NobleStitch EL Italian Registry.

PubMed

Gaspardone, Achille; De Marco, Federico; Sgueglia, Gregory A; De Santis, Antonella; Iamele, Maria; D'Ascoli, Emanuela; Tusa, Maurizio; Corciu, Anca; Mullen, Michael; Nobles, Anthony; Carminati, Mario; Bedogni, Francesco

2018-04-03

To assess the efficacy of a novel percutaneous "device-less" suture mediated patent foramen ovale (PFO) closure system. Between June 2016 and October 2017, a prospective registry aimed at assessing the safety and efficacy of the NobleStitch EL (HeartStitch, Fountain Valley, CA) suture-based PFO closure system was carried out at 12 sites in Italy. Among 200 consecutive evaluated patients, 192 were considered suitable for suture-mediated PFO closure (44±13 years, 114 women). Suture of the septum with the NobleStitch EL system was carried out successfully in 186 (96%) patients. Median fluoroscopy time was 16.1 (13.0-22.5) minutes and contrast volume 200 (150-270) ml. At 206±130 days follow-up, microbubbles transthoracic echocardiography with Valsalva maneuver revealed no RLS (grade 0) in 139 (75%) patients and RLS grade ≤1 in 166 (89%) patients. Significant RLS was present in 20 (11%) patients (grade 2 and 3 in 11 and 9 patients, respectively). There were no device-related complications. The early results of this first Italian Registry indicates that the suture mediated "deviceless" closure of PFO is feasible in the majority of septal anatomies, provides an effective closure of PFO comparable to traditional devices with an excellent safety profile at medium term follow-up.

Investigating the effect of child maltreatment on early adolescent peer-on-peer sexual aggression: testing a multiple mediator model in a non-incarcerated sample of Danish adolescents.

PubMed

Bramsen, Rikke Holm; Lasgaard, Mathias; Koss, Mary P; Elklit, Ask; Banner, Jytte

2014-01-01

The aim of the present study was to investigate the relationship between child maltreatment and severe early adolescent peer-on-peer sexual aggression, using a multiple mediator model. The study comprised 330 male Grade 9 students with a mean age of 14.9 years (SD=0.5). Estimates from the mediation model indicated significant indirect effects of child physical abuse on sexual aggression via peer influence and insecure-hostile masculinity. No significant total effect of child sexual abuse and child neglect on sexual aggression was found. Findings of the present study identify risk factors that are potentially changeable and therefore of value in informing the design of prevention programs aiming at early adolescent peer-on-peer sexual aggression in at-risk youth.

Early Parenting and the Development of Externalizing Behavior Problems: Longitudinal Mediation Through Children's Executive Function.

PubMed

Sulik, Michael J; Blair, Clancy; Mills-Koonce, Roger; Berry, Daniel; Greenberg, Mark

2015-01-01

Path analysis was used to investigate the longitudinal associations among parenting and children's executive function and externalizing behavior problems from 36 to 90 months of age in the Family Life Project (N = 1,115), a study of child development in the context of rural poverty. While controlling for stability in the constructs, semistructured observations of parenting prospectively predicted performance on a battery of executive function tasks and primary caregivers' reports of externalizing behavior. Furthermore, the association between early parenting and later externalizing behavior was longitudinally mediated by executive function, providing support for a process model in which sensitive parenting promotes children's self-regulation, which in turn reduces children's externalizing behavior. © 2015 The Authors. Child Development © 2015 Society for Research in Child Development, Inc.

Mediators and Moderators of the Relation Between Parental ADHD Symptomatology and the Early Development of Child ADHD and ODD Symptoms

PubMed Central

Breaux, Rosanna P.; Brown, Hallie R.; Harvey, Elizabeth A.

2016-01-01

The present study examined mediators and moderators of the relation between parental ADHD symptomatology and the development of child attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) symptoms across the preschool years. Participants included 258 (138 boys) 3-year-old children (M = 44.13 months, SD = 3.39) with and without behavior problems and their parents who took part in a 3-year longitudinal study. Maternal ADHD symptoms predicted later ADHD symptoms in children, controlling for early child symptomatology. Both family history of ADHD and paternal comorbid psychopathology predicted later child ADHD and ODD symptoms, but they did not account for the association between maternal and child ADHD symptoms. Although paternal ADHD symptoms were associated with age 3 child ADHD symptoms, they did not significantly predict later child ADHD symptoms controlling for early symptomatology. Family adversity moderated the relation between maternal ADHD and child ADHD symptoms, such that the relation between maternal and child ADHD symptoms was stronger for families with less adversity. Maternal overreactive parenting mediated the relation between maternal ADHD symptoms and later child ADHD and ODD symptoms. Our findings suggest that targeting paternal comorbid psychopathology and maternal parenting holds promise for attenuating the effects of parental ADHD on children’s ADHD. PMID:27752934

Muscle contributions to knee extension in the early stance phase in patients with knee osteoarthritis.

PubMed

Ogaya, Shinya; Kubota, Ryo; Chujo, Yuta; Hirooka, Eiko; Kwang-Ho, Kim; Hase, Kimitaka

2017-10-01

The aim of this study was to analyze individual muscle contributions to knee angular acceleration using a musculoskeletal simulation analysis and evaluate knee extension mechanics in the early stance phase in patients with knee osteoarthritis (OA). The subjects comprised 15 patients with medial knee OA and 14 healthy elderly individuals. All participants underwent gait performance test using 8 infrared cameras and two force plates to measure the kinetic and kinematic data. The simulation was driven by 92 Hill-type muscle-tendon units of the lower extremities and a trunk with 23° of freedom. We analyzed each muscle contribution to knee angular acceleration in the 5%-15% and 15%-25% periods of the stance phase (% SP) using an induced acceleration analysis. We compared accelerations by individual muscles between the two groups using an analysis of covariance for controlling gait speed. Patients with knee OA had a significantly lesser knee extension acceleration by the vasti muscles and higher knee acceleration by hip adductors than those in controls in 5-15% SP. In addition, knee OA resulted in significantly lesser knee extension acceleration by the vasti muscles in 15-25% SP. These results indicate that patients with knee OA have decreased dependency on the vasti muscles to control knee movements during early stance phase. Hip adductor muscles, which mainly control mediolateral motion, partly compensate for the weak knee extension by the vasti muscles in patients with knee OA. Copyright © 2017 Elsevier B.V. All rights reserved.

Developing models of how cognitive improvements change functioning: Mediation, moderation and moderated mediation

PubMed Central

Wykes, Til; Reeder, Clare; Huddy, Vyv; Taylor, Rumina; Wood, Helen; Ghirasim, Natalia; Kontis, Dimitrios; Landau, Sabine

2012-01-01

Background Cognitive remediation (CRT) affects functioning but the extent and type of cognitive improvements necessary are unknown. Aim To develop and test models of how cognitive improvement transfers to work behaviour using the data from a current service. Method Participants (N49) with a support worker and a paid or voluntary job were offered CRT in a Phase 2 single group design with three assessments: baseline, post therapy and follow-up. Working memory, cognitive flexibility, planning and work outcomes were assessed. Results Three models were tested (mediation — cognitive improvements drive functioning improvement; moderation — post treatment cognitive level affects the impact of CRT on functioning; moderated mediation — cognition drives functioning improvements only after a certain level is achieved). There was evidence of mediation (planning improvement associated with improved work quality). There was no evidence that cognitive flexibility (total Wisconsin Card Sorting Test errors) and working memory (Wechsler Adult Intelligence Scale III digit span) mediated work functioning despite significant effects. There was some evidence of moderated mediation for planning improvement if participants had poorer memory and/or made fewer WCST errors. The total CRT effect on work quality was d = 0.55, but the indirect (planning-mediated CRT effect) was d = 0.082 Conclusion Planning improvements led to better work quality but only accounted for a small proportion of the total effect on work outcome. Other specific and non-specific effects of CRT and the work programme are likely to account for some of the remaining effect. This is the first time complex models have been tested and future Phase 3 studies need to further test mediation and moderated mediation models. PMID:22503640

The effect of cerebral palsy on arithmetic accuracy is mediated by working memory, intelligence, early numeracy, and instruction time.

PubMed

Jenks, Kathleen M; de Moor, Jan; van Lieshout, Ernest C D M; Maathuis, Karel G B; Keus, Inge; Gorter, Jan Willem

2007-01-01

The development of addition and subtraction accuracy was assessed in first graders with cerebral palsy (CP) in both mainstream (16) and special education (41) and a control group of first graders in mainstream education (16). The control group out-performed the CP groups in addition and subtraction accuracy and this difference could not be fully explained by differences in intelligence. Both CP groups showed evidence of working memory deficits. The three groups exhibited different developmental patterns in the area of early numeracy skills. Children with CP in special education were found to receive less arithmetic instruction and instruction time was positively related to arithmetic accuracy. Structural equation modeling revealed that the effect of CP on arithmetic accuracy is mediated by intelligence, working memory, early numeracy, and instruction time.

Sex differences in acute hormonal and subjective response to naltrexone: the impact of menstrual cycle phase

PubMed Central

Roche, Daniel J.O.; King, Andrea C.

2015-01-01

Women often exhibit larger hormonal and subjective responses to opioid receptor antagonists than men, but the biological mechanisms mediating this effect remain unclear. Among women, fluctuations in estradiol (E2) and progesterone (P4) across the menstrual cycle (MC) affect the endogenous opioid system. Therefore, the goal of the current study was to compare acute naltrexone response between women in the early follicular phase of the MC (low E2 and P4), women in the luteal phase of the MC (high E2 and P4), and men. Seventy healthy controls (n = 46 women) participated in two morning sessions in which they received 50 mg naltrexone or placebo in a randomized, counterbalanced order. Women were randomized to complete both sessions in either the early follicular (n = 23) or luteal phase of the MC. Serum cortisol, prolactin, and luteinizing hormone (LH), salivary cortisol, and subjective response were assessed upon arrival to the laboratory and at regular intervals after pill administration. In luteal and early follicular women but not men, naltrexone (vs. placebo) increased serum cortisol and prolactin levels from baseline; however, the naltrexone-induced increases in these hormones were significantly greater in luteal women than early follicular women. Additionally, only luteal women demonstrated an increase from baseline in salivary cortisol levels and the severity of adverse drug effects in response to naltrexone. In sum, the results indicate that luteal phase women are more sensitive to acute hormonal and subjective effects of naltrexone than early follicular women and men. These findings may have important implications for the use of naltrexone in women. PMID:25459893

78 FR 69690 - Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-20

... and Gene Therapy Products; Extension of Comment Period AGENCY: Food and Drug Administration, HHS...: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products'' that... sponsors of Investigational New Drug Applications for cellular therapy (CT) and gene therapy (GT) products...

Ultrastructural Complexity of Nuclear Components During Early Apoptotic Phases in Breast Cancer Cells

PubMed Central

Castelli, Christian; Losa, Gabriele A.

2001-01-01

Fractal morphometry was used to investigate the ultrastructural features of the plasma membrane, perinuclear membrane and nuclear chromatin in SK‐BR‐3 human breast cancer cells undergoing apoptosis. Cells were incubated with 1 μM calcimycin (A23187) for 24 h. Cells in the early stage of apoptosis had fractal dimension (FD) values indicating that their plasma membranes were less rough (lower FD) than those of control cells, while their perinuclear membranes were unaffected. Changes of the chromatin texture within the entire nucleus and in selected nuclear domains were more pronounced in treated cells. This confirms that the morphological reorganization imputable to a loss of structural complexity (reduced FD) occurs in the early stage of apoptosis, is accompanied by the inhibition of distinct enzymatic events and precedes the onset of conventional cellular markers, which can only be detected during the active phases of the apoptotic process. PMID:11790854

The hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the evaluation of hepatic fibrosis and early liver cirrhosis in a rat model: an experimental study.

PubMed

Ma, Chunmei; Liu, Ailian; Wang, Yuanyuan; Geng, Xiaoling; Hao, Li; Song, Qingwei; Sun, Bo; Wang, Heqing; Zhao, Gang

2014-07-17

To evaluate the hepatocyte phase of Gd-EOB-DTPA-enhanced MRI in the early diagnosis of hepatic fibrosis and cirrhosis and assessment of liver function in a rat model. In 2 groups of SD rats, liver fibrosis was induced in experimental animals by repetitive carbon tetrachloride injections, while the control group received saline injections. Five experimental rats and 2 control rats were randomly selected at weeks 4, 8, 12. One week after carbon tetrachloride administration, MRI (FIRM T1WI) scan was performed. Gd-EOB-DTPA (0.08mL) was injected into the rat's tail vein and hepatocyte phase images were obtained after 20min. The pre-enhanced phase and hepatocyte phase signal intensities (SI) were measured, and the relative contrast enhancement index (RCEI) was calculated. ANOVA analysis (LSD) of RCEI values in controls (n=6), hepatic fibrosis (n=7), and histopathologically-determined early cirrhosis group (n=6) was performed. RECI values showed a decreasing trend in the control group, hepatic fibrosis and early cirrhosis groups (1.11±0.43, 0.96±0.22, and 0.57±0.33, respectively). While the difference between the control and early cirrhosis groups was statistically significant (p=0.013), there was no significant difference in the hepatic fibrosis group vs the control (p=0.416) and the hepatic fibrosis group vs the early cirrhosis group (p=0.054). Hepatocyte phase RCEI values obtained with Gd-EOB-DTPA-enhanced MRI scan indicate liver injury in hepatic fibrosis and early cirrhosis. RCEI values are helpful for early diagnosis of liver cirrhosis. Copyright © 2014 Elsevier Inc. All rights reserved.

Maintenance phase in psoralen-ultraviolet A phototherapy of early-stage mycosis fungoides. A critically appraised topic.

PubMed

Grandi, V; Delfino, C; Pileri, A; Pimpinelli, N

2017-08-01

A 65-year-old patient affected by mycosis fungoides (MF) stage IB achieved complete remission (CR) after a cycle of PUVA phototherapy. The U.S. Cutaneous Lymphoma Consortium (USCLC) guidelines suggest that the patient should be kept in the maintenance phase, defined as a 'period of gradual decrease of frequency of UVL [ultraviolet light] while in clinical remission before discontinuation of phototherapy' by slowly tapering the number of psoralen-ultraviolet A (PUVA) applications over time up to clinical relapse. The USCLC guidelines also suggest a standardized schedule for the maintenance phase. Alternatively, the patient could end PUVA therapy and go straight to follow-up. The aim of this critically appraised topic (CAT) was to determine if a maintenance phase gives a significant benefit in terms of relapse rate (RR) and RFI in patients affected by early-stage MF who had achieved CR under PUVA phototherapy. Embase, PubMed and TRIP databases were searched for 'mycosis fungoides' AND [('photochemotherapy' OR 'puva') OR 'psoralen'] in June 2016. Three articles matched our inclusion criteria and are discussed in this CAT. In this field of research the literature is poor and the reported level of evidence is low. Only one of the studies was conducted prospectively, and none were randomized. No significant difference in terms of reduction in relapse rate or increase in RFI in patients who underwent a PUVA maintenance phase emerged when compared with those who went for simple follow-up. Further randomized clinical trials (RCTs) are required in order to evaluate maintenance phase vs. no treatment before it can be favoured as the standard protocol of treatment in early-stage MF. At the time of writing this paper, we report an ongoing Austrian multicentre RCT (Clinical Trial.gov identifier: NCT01686594) that will hopefully give useful results in this topic. © 2017 British Association of Dermatologists.

Low expression of soluble human leukocyte antigen G in early gestation and subsequent placenta-mediated complications of pregnancy.

PubMed

Marozio, Luca; Garofalo, Anna; Berchialla, Paola; Tavella, Anna Maria; Salton, Loredana; Cavallo, Franco; Benedetto, Chiara

2017-09-01

Abnormal placentation is a common pathogenic mechanism of many placenta-mediated complications of late pregnancy, including pre-eclampsia, fetal growth restriction, stillbirth, and placental abruption. During successful placentation, the trophoblast (which is a semi-allograft) is not rejected by decidual immune cells because of maternal immune tolerance, mainly induced by human leukocyte antigen G (HLA-G). Deficient HLA-G expression seems to be associated with the development of complications of pregnancy. The aim of this study was to determine whether low soluble HLA-G (sHLA-G) levels in maternal blood at the beginning of pregnancy may be associated with subsequent placenta-mediated complications. For this retrospective case-control study, 117 cases of placenta-mediated complications of pregnancy and 234 controls with uneventful pregnancy were selected. Plasma sHLA-G levels were measured at 11-13 weeks' gestation by the enzyme-linked immunosorbent assay method in blood samples previously obtained at first-trimester prenatal screening for chromosomal fetal abnormalities. Women who subsequently developed placenta-mediated complications had significantly lower sHLA-G levels at the beginning of pregnancy (median, 43.08 IU/mL) than controls (median, 49.10 IU/mL; P = 0.008). An sHLA-G level lower than 43.50 IU/mL at the end of the first trimester was associated with a twofold increased risk of developing a pregnancy complication (odds ratio, 1.82; 95% confidence interval, 1.22-2.73). The strongest association, although only moderately strong, was observed with severe pre-eclampsia (odds ratio, 2.66; 95% confidence interval, 1.08-6.56). Placenta-mediated complications of pregnancy may be associated with low sHLA-G levels in the first trimester, suggesting a potential role of sHLA-G in the early stages of placentation. © 2017 Japan Society of Obstetrics and Gynecology.

Vulnerability to Peer Influence: A Moderated Mediation Study of Early Adolescent Alcohol Use Initiation

PubMed Central

Trucco, Elisa M.; Colder, Craig R.; Wieczorek, William F.

2011-01-01

Affiliation with deviant peers is a correlate of adolescent alcohol use; however, the mechanism accounting for this association remains unclear, particularly with respect to initiation of alcohol use in early adolescence. This prospective study examines perceived peer attitudes and use as a mediator between peer delinquency and initiation of alcohol use, and how parenting may moderate vulnerability to this risk pathway. Participants included 371 11–13 year-old adolescents (55.5% female, 83.0% Caucasian). Results suggested that high levels of peer delinquency prospectively predicted perceived peer approval and use of alcohol and that peer approval and use of alcohol prospectively predicted initiation of alcohol use. Thus, reinforcement and modeling alcohol use appear to be important mechanisms by which delinquent peers influence the initiation of drinking. There was no support for parental warmth or control as moderators of peer influence. PMID:21420241

Phase I Trial of Adenovirus-Mediated IL-12 Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following Therapy

DTIC Science & Technology

2005-10-01

salvage seed implant, cryotherapy ) or who have a rising PSA while on hormone therapy for locally advanced prostate cancer are as follows: a. A...Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following Therapy PRINCIPAL INVESTIGATOR: Simon J. Hall, MD...CONTRACT NUMBER Phase I Trial of Adenovirus-Mediated IL-12 Gene Transduction in Patients with Recurrent Locally Advanced Prostate Cancer Following

Methylene blue prevents surgery-induced peritoneal adhesions but impairs the early phase of anastomotic wound healing

PubMed Central

Dinc, Soykan; Ozaslan, Cihangir; Kuru, Bekir; Karaca, Sefa; Ustun, Huseyin; Alagol, Haluk; Renda, Nurten; Oz, Murat

2006-01-01

Objectives Adhesion formation continues to be an important problem in gastrointestinal surgery. In recent years, methylene blue (MB) has been reported to be an effective agent for preventing peritoneal adhesions. However, its effects on the wound healing process are unknown. In the present study, we investigated the effects of MB on the early and late phases of anastomotic wound healing and on adhesion formation. Methods We randomly categorized 92 rats into 2 groups in bursting pressure measurements and 50 rats into 3 groups in the adhesion model. We divided the animals into saline-treated (n = 46) or MB-treated (n = 46) groups. Bursting pressures of the anastomoses were measured on postoperative days 3 and 7. In biochemical studies, tissue hydroxyproline levels, total nitrite/nitrate levels and nitric oxide synthase activity were measured on postoperative days 3 and 7. In the adhesion model, we randomly categorized rats into sham (n = 10), saline-treated (n = 20) and MB-treated (n = 20) groups, and the formation of intraperitoneal adhesions was scored on postoperative day 14. We compared the measurement of bursting pressure and biochemical measurements of tissue hydroxyproline levels, total nitrite/nitrate levels and nitric oxide synthase activity. Histopathological findings of specimens were presented. Results During the early phase of wound healing (postoperative day 3), bursting pressures, tissue hydroxyproline, total nitrite/nitrate levels and nitric oxide synthase activity in the MB-treated group were significantly lower than those of the saline-treated group. On postoperative day 7, there was no significant difference in these parameters between MB and saline-treated groups. In the adhesion model, MB caused a significant reduction in the formation of peritoneal adhesions. Conclusion MB prevents peritoneal adhesions but causes a significant impairment of anastomotic bursting pressure during the early phase of the wound healing process by its transient

The Impacts of Organizational Justice on Early Childhood Educators' Intention to Participate in Professional Associations: The Mediator Role of Deliberative Beliefs.

PubMed

Lin, Chun-Wen

2018-01-01

Guided by the general incentives rational action model and deliberative participatory democracy framework, we investigated whether deliberative beliefs, including normative and personal aspects, mediate the relationship between distributive, procedural, and interactive organizational justice and intention to participate in professional associations. Self-report measures of organizational justice, deliberative belief, and intention of participation were obtained from 789 early childhood educators in Taiwan. Structural equation modeling was used to analyze the proposed model. According to the results of the study, there is a relationship between organizational justice and intention of professional association participation, and a fully significant mediation effect was found for deliberative beliefs between organizational justice and intention to participate. These findings are discussed with respect to improving professional association participation and applying deliberative pedagogy.

Teachers' Beliefs on Foreign Language Teaching Practices in Early Phases of Primary Education: A Case Study

ERIC Educational Resources Information Center

Caner, Mustafa; Subasi, Gonca; Kara, Selma

2010-01-01

The purpose of the study was to examine whether teacher beliefs would play a role in their actual practices while teaching target language in early phases of primary education, principally, in kindergarten and first grades in a state school. As it is a very broad research area, the researchers exclusively analyzed teaching practices and teaching…

A tale of two timescales: Mixing, mass generation, and phase transitions in the early universe

NASA Astrophysics Data System (ADS)

Dienes, Keith R.; Kost, Jeff; Thomas, Brooks

2016-02-01

Light scalar fields such as axions and string moduli can play an important role in early-universe cosmology. However, many factors can significantly impact their late-time cosmological abundances. For example, in cases where the potentials for these fields are generated dynamically—such as during cosmological mass-generating phase transitions—the duration of the time interval required for these potentials to fully develop can have significant repercussions. Likewise, in scenarios with multiple scalars, mixing amongst the fields can also give rise to an effective timescale that modifies the resulting late-time abundances. Previous studies have focused on the effects of either the first or the second timescale in isolation. In this paper, by contrast, we examine the new features that arise from the interplay between these two timescales when both mixing and time-dependent phase transitions are introduced together. First, we find that the effects of these timescales can conspire to alter not only the total late-time abundance of the system—often by many orders of magnitude—but also its distribution across the different fields. Second, we find that these effects can produce large parametric resonances which render the energy densities of the fields highly sensitive to the degree of mixing as well as the duration of the time interval over which the phase transition unfolds. Finally, we find that these effects can even give rise to a "reoverdamping" phenomenon which causes the total energy density of the system to behave in novel ways that differ from those exhibited by pure dark matter or vacuum energy. All of these features therefore give rise to new possibilities for early-universe phenomenology and cosmological evolution. They also highlight the importance of taking into account the time dependence associated with phase transitions in cosmological settings.

Socioeconomic status and executive function: developmental trajectories and mediation.

PubMed

Hackman, Daniel A; Gallop, Robert; Evans, Gary W; Farah, Martha J

2015-09-01

Childhood socioeconomic status (SES) predicts executive function (EF), but fundamental aspects of this relation remain unknown: the developmental course of the SES disparity, its continued sensitivity to SES changes during that course, and the features of childhood experience responsible for the SES-EF relation. Regarding course, early disparities would be expected to grow during development if caused by accumulating stressors at a given constant level of SES. Alternatively, they would narrow if schooling partly compensates for the effects of earlier deprivation, allowing lower-SES children to 'catch up'. The potential for later childhood SES change to affect EF is also unknown. Regarding mediating factors, previous analyses produced mixed answers, possibly due to correlation amongst candidate mediators. We address these issues with measures of SES, working memory and planning, along with multiple candidate mediators, from the NICHD Study of Early Childcare (n = 1009). Early family income-to-needs and maternal education predicted planning by first grade, and income-to-needs predicted working memory performance at 54 months. Effects of early SES remained consistent through middle childhood, indicating that the relation between early indicators of SES and EF emerges in childhood and persists without narrowing or widening across early and middle childhood. Changes in family income-to-needs were associated with significant changes in planning and trend-level changes in working memory. Mediation analyses supported the role of early childhood home characteristics in explaining the association between SES and EF, while early childhood maternal sensitivity was specifically implicated in the association between maternal education and planning. Early emerging and persistent SES-related differences in EF, partially explained by characteristics of the home and family environment, are thus a potential source of socioeconomic disparities in achievement and health across

Proteomics analysis identified peroxiredoxin 2 involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

PubMed

Kuzuya, Kentaro; Ichihara, Sahoko; Suzuki, Yuka; Inoue, Chisa; Ichihara, Gaku; Kurimoto, Syota; Oikawa, Shinji

2018-01-01

Given the hypothesis that inflammation plays a critical role in the progression of cardiovascular diseases, the aim of the present study was to identify new diagnostic and prognostic biomarkers of myocardial proteins involved in early-phase cardiac impairment, using proteomics analysis. Using the two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression of proteins in the whole left ventricles between control hamsters, dilated cardiomyopathic hamsters (TO-2), and hypertrophy cardiomyopathic hamsters (Bio14.6) at 6 weeks of age (n = 6, each group). Proteomic analysis identified 10 protein spots with significant alterations, with 7 up-regulated and 3 down-regulated proteins in the left ventricles of both TO-2 and Bio 14.6 hamsters, compared with control hamsters. Of the total alterations, peroxiredoxin 2 (PRDX2) showed significant upregulation in the left ventricles of TO-2 and Bio 14.6 hamsters. Our data suggest that PRDX2, a redox regulating molecule, is involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

Prefrontal gray matter morphology mediates the association between serum anticholinergicity and cognitive functioning in early course schizophrenia.

PubMed

Wojtalik, Jessica A; Eack, Shaun M; Pollock, Bruce G; Keshavan, Matcheri S

2012-11-30

Antipsychotic and other medications used in the treatment of schizophrenia place a burden on the cholinergic subsystems of the brain, which have been associated with increased cognitive impairment in the disorder. This study sought to examine the neurobiologic correlates of the association between serum anticholinergic activity (SAA) and cognitive impairments in early schizophrenia. Neurocognitive performance on measures of memory and executive function, structural magnetic resonance imaging (MRI) scans, and SAA assays were collected from 47 early course, stabilized outpatients with schizophrenia or schizoaffective disorder. Voxel-based morphometry analyses employing general linear models, adjusting for demographic and illness-related confounds, were used to investigate the associations between SAA, gray matter morphology, and neurocognitive impairment. SAA was related to working memory and executive function impairments. Higher SAA was significantly associated with lower gray matter density in broad regions of the frontal and medial-temporal lobes, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, and striatum. Lower gray matter volume in the left DLPFC was found to significantly mediate the association between SAA and working memory impairment. Disease- and/or medication-related cholinergic dysfunction may be associated with brain volume abnormalities in early course schizophrenia, which may account for the association between SAA and cognitive dysfunction in the disorder. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

The Mediator Role of Early Maladaptive Schemas Between Childhood Sexual Abuse and Impulsive Symptoms in Female Survivors of CSA.

PubMed

Estévez, Ana; Ozerinjauregi, Nagore; Herrero-Fernández, David; Jauregui, Paula

2016-04-24

Child abuse is a traumatic experience that may have psychological consequences such as dysfunctional beliefs. The aim of this study was to analyze the impulsive behaviors (alcohol abuse, gambling, drug abuse, eating disorders, Internet abuse, videogame abuse, shopping and sex addiction) in sexual abuse survivors and to study the mediating role of early maladaptive schemas in the appearance of impulsive behaviors in adult female victims. The sample consisted of 182 adult women who had suffered childhood sexual abuse (CSA), mostly referred by associations for the treatment of childhood abuse and maltreatment. Sexual abuse was found to be positively related to the domains of Disconnection/Rejection and Impaired Autonomy. Moreover, these domains were significantly related to impulsivity and impulsive behaviors. Finally, the Disconnection/Rejection domain was found to mediate between CSA and eating disorders and alcohol abuse. These results may provide important guidance for clinical intervention. © The Author(s) 2016.

Early Parenting and the Development of Externalizing Behavior Problems: Longitudinal Mediation through Children’s Executive Function

PubMed Central

Sulik, Michael J.; Blair, Clancy; Mills-Koonce, Roger; Berry, Daniel; Greenberg, Mark

2015-01-01

Path analysis was used to investigate the longitudinal associations among parenting and children’s executive function and externalizing behavior problems from 36 to 90 months of age in the Family Life Project (N = 1,115), a study of child development in the context of rural poverty. While controlling for stability in the constructs, semi-structured observations of parenting prospectively predicted performance on a battery of executive function tasks and primary caregivers’ reports of externalizing behavior. Furthermore, the association between early parenting and later externalizing behavior was longitudinally mediated by executive function, providing support for a process model in which sensitive parenting promotes children’s self-regulation, which in turn reduces children’s externalizing behavior. PMID:26082032

Conspecific Leaf Litter-Mediated Effect of Conspecific Adult Neighborhood on Early-Stage Seedling Survival in A Subtropical Forest

PubMed Central

Liu, Heming; Shen, Guochun; Ma, Zunping; Yang, Qingsong; Xia, Jianyang; Fang, Xiaofeng; Wang, Xihua

2016-01-01

Conspecific adults have strong negative effect on the survival of nearby early-stage seedlings and thus can promote species coexistence by providing space for the regeneration of heterospecifics. The leaf litter fall from the conspecific adults, and it could mediate this conspecific negative adult effect. However, field evidence for such effect of conspecific leaf litter remains absent. In this study, we used generalized linear mixed models to assess the effects of conspecific leaf litter on the early-stage seedling survival of four dominant species (Machilus leptophylla, Litsea elongate, Acer pubinerve and Distylium myricoides) in early-stage seedlings in a subtropical evergreen broad-leaved forest in eastern China. Our results consistently showed that the conspecific leaf litter of three species negatively affected the seedling survival. Meanwhile, the traditional conspecific adult neighborhood indices failed to detect this negative conspecific adult effect. Our study revealed that the accumulation of conspecific leaf litter around adults can largely reduce the survival rate of nearby seedlings. Ignoring it could result in underestimation of the importance of negative density dependence and negative species interactions in the natural forest communities. PMID:27886275

Extension of quality-by-design concept to the early development phase of pharmaceutical R&D processes.

PubMed

Csóka, Ildikó; Pallagi, Edina; Paál, Tamás L

2018-03-27

Here, we propose the extension of the quality-by-design (QbD) concept to also fit the early development phases of pharmaceuticals by adding elements that are currently widely applied, but not yet included in the QbD model in a structured way. These are the introduction of a 'zero' preformulation phase (i.e., selection of drug substance, possible dosage forms and administration routes based on the evaluated therapeutic need); building in stakeholders' (industry, patient, and regulatory) requirements into the quality target product profile (QTTP); and the use of modern quality management tools during the composition and process design phase [collecting critical quality attributes (CQAs) and selection of CPPs) for (still laboratory-scale) design space (DS) development. Moreover, during industrial scale-up, CQAs (as well as critical process parameters; CPPs) can be changed; however, we recommend that the existing QbD elements are reconsidered and updated after this phase. Copyright © 2018 Elsevier Ltd. All rights reserved.

Strontium ranelate causes osteophytes overgrowth in a model of early phase osteoarthritis.

PubMed

Chu, Jian-Guo; Dai, Mu-Wei; Wang, Yu; Tian, Fa-Ming; Song, Hui-Ping; Xiao, Ya-Ping; Shao, Li-Tao; Zhang, Ying-Ze; Zhang, Liu

2017-02-10

Osteoarthritis (OA) involves cartilage changes as well as modifications of subchondral bone and synovial tissues. Strontium ranelate (SR), an anti-osteoporosis compound, which is currently in phase III clinical trial for treatment of OA. Evidences suggest that SR preferably deposited in osteophyte, other than in subchondral bone in early phase of OA. This phenomenon raises concern about its utility for OA treatment as a disease-modifying drug. To evaluate the effect of SR on cartilage, subchondral bone mass and subchondral trabecular bone structure in medial meniscectomized (MNX) guinea pigs. Thirty-six 3-month-old male Dunkin Hartley albino guinea pigs received either sham or medial meniscectomy operations. One week after the procedure, meniscectomized animals began 12 weeks of SR (625 mg/kg, daily) treatment by oral gavage for MNX + SR group, or normal saline for MNX + V group. All animals were euthanized 12 weeks later, cartilage degeneration and subchondral bone micro-architecture was analyzed. Both OARSI scores (P = 0.523 for marcoscopic scores, P = 0.297 for histological scores) and Cartilage thickness (P = 0.335) in MNX + SR group were comparable to MNX + V group. However, osteophyte sizes were larger in MNX + SR group (P = 0.014), and collapsed osteophytes in MNX + SR group (7 by 12) were significantly more than in MNX + V group (1 by 12) (P = 0.027), while immunohistochemistry indicates catabolic changes in osteophyte/plateau junction. Micro-CT analysis showed bone mineral density (BMD) (P = 0.001), bone volume fraction (BV/TV) (P = 0.008), trabecular spacing (Tb.Sp) (P = 0.020), trabecular thickness (Tb.Th) (P = 0.012) and structure model index (SMI) (P = 0.005) levels to be significantly higher in the MNX + SR group than in the MNX + V group. SR (625 mg/kg/day) did not protect cartilage from degeneration in MNX guinea pigs but subchondral bone was significantly enhanced. In early

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8+ T-Cell Antiviral Activity and Correlates with Preservation of the CD4+ T-Cell Compartment

PubMed Central

Ghiglione, Yanina; Falivene, Juliana; Socias, María Eugenia; Laufer, Natalia; Coloccini, Romina Soledad; Rodriguez, Ana María; Ruiz, María Julia; Pando, María Ángeles; Giavedoni, Luis David; Cahn, Pedro; Sued, Omar; Salomon, Horacio; Gherardi, María Magdalena

2013-01-01

The important role of the CD8+ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8+ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8+ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4+ T-cell set points were observed in PHI subjects with higher HIV-specific CD8+ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-γ. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1β (MIP-1β). All together, this study underscores the importance of CD8+ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. PMID:23616666

Non-classical phase diagram for virus bacterial coevolution mediated by clustered regularly interspaced short palindromic repeats.

PubMed

Han, Pu; Deem, Michael W

2017-02-01

CRISPR is a newly discovered prokaryotic immune system. Bacteria and archaea with this system incorporate genetic material from invading viruses into their genomes, providing protection against future infection by similar viruses. The condition for coexistence of prokaryots and viruses is an interesting problem in evolutionary biology. In this work, we show an intriguing phase diagram of the virus extinction probability, which is more complex than that of the classical predator-prey model. As the CRISPR incorporates genetic material, viruses are under pressure to evolve to escape recognition by CRISPR. When bacteria have a small rate of deleting spacers, a new parameter region in which bacteria and viruses can coexist arises, and it leads to a more complex coexistence patten for bacteria and viruses. For example, when the virus mutation rate is low, the virus extinction probability changes non-montonically with the bacterial exposure rate. The virus and bacteria coevolution not only alters the virus extinction probability, but also changes the bacterial population structure. Additionally, we show that recombination is a successful strategy for viruses to escape from CRISPR recognition when viruses have multiple proto-spacers, providing support for a recombination-mediated escape mechanism suggested experimentally. Finally, we suggest that the re-entrant phase diagram, in which phages can progress through three phases of extinction and two phases of abundance at low spacer deletion rates as a function of exposure rate to bacteria, is an experimentally testable phenomenon. © 2017 The Author(s).

Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity.

PubMed

Li, Ying; You, Qiang-Long; Zhang, Sheng-Rong; Huang, Wei-Yuan; Zou, Wen-Jun; Jie, Wei; Li, Shu-Ji; Liu, Ji-Hong; Lv, Chuang-Ye; Cong, Jin; Hu, Yu-Ying; Gao, Tian-Ming; Li, Jian-Ming

2017-04-18

Special AT-rich sequence-binding protein 2 (Satb2) is a protein binding to the matrix attachment regions of DNA and important for gene regulation. Patients with SATB2 mutation usually suffer moderate to severe mental retardation. However, the mechanisms for the defects of intellectual activities in patients with SATB2 mutation are largely unclear. Here we established the heterozygous Satb2 mutant mice and Satb2 conditional knockout mice to mimic the patients with SATB2 mutation and figured out the role of Satb2 in mental activities. We found that the spatial memory and working memory were significantly damaged in the heterozygous Satb2 mutant mice, early postnatal Satb2-deficient mice (CaMKIIα-Cre + Satb2 fl/fl mice), and adult Satb2 ablation mice (Satb2 fl/fl mice injected with CaMKIIα-Cre virus). Functionally, late phase long-term potentiation (L-LTP) in these Satb2 mutant mice was greatly impaired. Morphologically, in CA1 neurons of CaMKIIα-Cre + Satb2 fl/fl mice, we found decreased spine density of the basal dendrites and less branches of apical dendrites that extended into lacunar molecular layer. Mechanistically, expression levels of immediate early genes (IEGs) including Fos, FosB, and Egr1 were significantly decreased after Satb2 deletion. And, Satb2 could regulate expression of FosB by binding to the promoter of FosB directly. In general, our study uncovers that Satb2 plays an important role in spatial memory and working memory by regulating IEGs-mediated hippocampal synaptic plasticity.

Early life traumatic stressors and the mediating role of PTSD in incident HIV infection among US men, comparisons by sexual orientation and race/ethnicity: results from the NESARC, 2004-2005.

PubMed

Reisner, Sari L; Falb, Kathryn L; Mimiaga, Matthew J

2011-08-01

Stressful life events in childhood during critical periods of development have long-term psychological and neurobiological sequelae, which may affect risk for HIV infection across the life course. Data were from a nationally representative sample of 13,274 US men (National Epidemiologic Survey on Alcohol and Related Conditions, 2004-2005). Weighted multivariable logistic regression models examined (1) the association of childhood violent events before age 18 on 12-month incident HIV infection and (2) whether posttraumatic stress disorder (PTSD) diagnosis (clinical interview) mediated the association between early life events and HIV. Overall, the 12-month HIV incidence was <1% (0.35%); 44% of new infections were among racial/ethnic minorities and 31% among men who have sex with men). One-third of the sample (33.5%) reported one or more early life stressors (physical abuse, sexual abuse, neglect, verbal violence, or witnessed violence). In a weighted multivariable logistic regression model adjusted for age, education, family's socioeconomic position, and sexual behaviors, each additional early life violent event was associated with an elevated odds of HIV infection [adjusted odds ratio (aOR) = 1.32; 95% confidence interval (CI): 1.16 to 1.50]. Adding PTSD to this adjusted model, PTSD was highly associated with incident HIV infection (aOR = 5.75; 95% CI: 4.76 to 6.95). There was evidence that PTSD partially mediated the relationship between early life events and HIV (aOR = 1.14; 95% CI: 1.02 to 1.28). Experiencing early life violent family stressors was associated with HIV infection among men. Early life events and HIV infection were mediated by PTSD, which has implications for understanding disparities in HIV infection. Interventions are urgently needed that address the long-term sequelae of childhood violence.

Glutamate-mediated excitotoxicity in schizophrenia: A review

PubMed Central

Plitman, Eric; Nakajima, Shinichiro; de la Fuente-Sandoval, Camilo; Gerretsen, Philip; Chakravarty, M. Mallar; Kobylianskii, Jane; Chung, Jun Ku; Caravaggio, Fernando; Iwata, Yusuke; Remington, Gary; Graff-Guerrero, Ariel

2015-01-01

Findings from neuroimaging studies in patients with schizophrenia suggest widespread structural changes although the mechanisms through which these changes occur are currently unknown. Glutamatergic activity appears to be increased in the early phases of schizophrenia and may contribute to these structural alterations through an excitotoxic effect. The primary aim of this review was to describe the possible role of glutamate-mediated excitotoxicity in explaining the presence of neuroanatomical changes within schizophrenia. A Medline® literature search was conducted, identifying English language studies on the topic of glutamate-mediated excitotoxicity in schizophrenia, using the terms “schizophreni*” and “glutam*” and ((“MRS” or “MRI” or “magnetic resonance”) or (“computed tomography” or “CT”)). Studies concomitantly investigating glutamatergic activity and brain structure in patients with schizophrenia were included. Results are discussed in the context of findings from preclinical studies. Seven studies were identified that met the inclusion criteria. These studies provide inconclusive support for the role of glutamate-mediated excitotoxicity in the occurrence of structural changes within schizophrenia, with the caveat that there is a paucity of human studies investigating this topic. Preclinical data suggest that an excitotoxic effect may occur as a result of a paradoxical increase in glutamatergic activity following N-methyl-D-aspartate receptor hypofunction. Based on animal literature, glutamate-mediated excitotoxicity may account for certain structural changes present in schizophrenia, but additional human studies are required to substantiate these findings. Future studies should adopt a longitudinal design and employ magnetic resonance imaging techniques to investigate whether an association between glutamatergic activity and structural changes exists in patients with schizophrenia. PMID:25159198

77 FR 7174 - Correction Notice for Deepwater Horizon Oil Spill; Draft Phase I Early Restoration Plan and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-10

... DEPARTMENT OF THE INTERIOR Fish and Wildlife Service [FWS-R4-FHC-2012-N030; FVHC98130406900Y4-XXX-FF04G01000] Correction Notice for Deepwater Horizon Oil Spill; Draft Phase I Early Restoration Plan and Environmental Assessment AGENCY: Fish and Wildlife Service, Interior. ACTION: Notice of availability and request...

Evaluation of measles-rubella vaccination for mothers in early puerperal phase.

PubMed

Hisano, Michi; Kato, Tatsuo; Inoue, Eisuke; Sago, Haruhiko; Yamaguchi, Koushi

2016-02-24

The postpartum period is an ideal opportunity to vaccinate mothers with inadequate immunity to vaccine-preventable diseases including measles and rubella. A prospective study of measles-rubella (MR) vaccination in the early puerperal phase was conducted in 171 mothers, who had insufficient antibody titers when screened for immunity to measles (≤ 1:4 on the neutralization test [NT]) or rubella (≤ 1:16 on the hemagglutination inhibition [HI] test) during pregnancy. To evaluate the efficacy of MR vaccination in the postpartum period, we determined their post-vaccination antibody titers and immune responses to vaccination, and investigated the association between these and their prolactin (PRL) levels and Th1/Th2 ratios at the time of vaccination. We also examined the passage of viral RNA and antigen into breast milk. Of the 169 participants who completed the study schedule, 117 and 101 had low antibody titers against measles and rubella, respectively. In the measles-seronegative group, the antibody-positive rate was 87% on the NT assay, and the NT geometric mean antibody titer was 11.4 (95% confidence interval [CI], 10.0-13.0). In the rubella-seronegative group, the antibody-positive rate was 88% on the HI test assay, and the HI geometric mean antibody titer was 64.0 (95% CI, 53.9-76.0). There was no association between the post-vaccination antibody titers and the PRL levels or Th1/Th2 ratios at the time of vaccination. In the rubella-seronegative group, subjects with higher Th1/Th2 ratios showed higher rates of responsiveness than those with lower ratios (P=0.045). Although measles virus RNA was isolated from the breast milk of two vaccinated mothers, breastfeeding was not associated with clinical disease in any infants. MR vaccination in the early puerperal phase is considered an effective way to prevent the diseases, regardless of the mother's immunological status and hormonal milieu. Copyright © 2016 Elsevier Ltd. All rights reserved.

Temporal regulation of expression of immediate early and second phase transcripts by endothelin-1 in cardiomyocytes

PubMed Central

Cullingford, Timothy E; Markou, Thomais; Fuller, Stephen J; Giraldo, Alejandro; Pikkarainen, Sampsa; Zoumpoulidou, Georgia; Alsafi, Ali; Ekere, Collins; Kemp, Timothy J; Dennis, Jayne L; Game, Laurence; Sugden, Peter H; Clerk, Angela

2008-01-01

Background Endothelin-1 stimulates Gq protein-coupled receptors to promote proliferation in dividing cells or hypertrophy in terminally differentiated cardiomyocytes. In cardiomyocytes, endothelin-1 rapidly (within minutes) stimulates protein kinase signaling, including extracellular-signal regulated kinases 1/2 (ERK1/2; though not ERK5), with phenotypic/physiological changes developing from approximately 12 h. Hypertrophy is associated with changes in mRNA/protein expression, presumably consequent to protein kinase signaling, but the connections between early, transient signaling events and developed hypertrophy are unknown. Results Using microarrays, we defined the early transcriptional responses of neonatal rat cardiomyocytes to endothelin-1 over 4 h, differentiating between immediate early gene (IEG) and second phase RNAs with cycloheximide. IEGs exhibited differential temporal and transient regulation, with expression of second phase RNAs within 1 h. Of transcripts upregulated at 30 minutes encoding established proteins, 28 were inhibited >50% by U0126 (which inhibits ERK1/2/5 signaling), with 9 inhibited 25-50%. Expression of only four transcripts was not inhibited. At 1 h, most RNAs (approximately 67%) were equally changed in total and polysomal RNA with approximately 17% of transcripts increased to a greater extent in polysomes. Thus, changes in expression of most protein-coding RNAs should be reflected in protein synthesis. However, approximately 16% of transcripts were essentially excluded from the polysomes, including some protein-coding mRNAs, presumably inefficiently translated. Conclusion The phasic, temporal regulation of early transcriptional responses induced by endothelin-1 in cardiomyocytes indicates that, even in terminally differentiated cells, signals are propagated beyond the primary signaling pathways through transcriptional networks leading to phenotypic changes (that is, hypertrophy). Furthermore, ERK1/2 signaling plays a major role in

In situ probing of doping- and stress-mediated phase transitions in a single-crystalline VO2 nanobeam by spatially resolved Raman spectroscopy

NASA Astrophysics Data System (ADS)

Chang, Sung-Jin; Park, Jong Bae; Lee, Gaehang; Kim, Hae Jin; Lee, Jin-Bae; Bae, Tae-Sung; Han, Young-Kyu; Park, Tae Jung; Huh, Yun Suk; Hong, Woong-Ki

2014-06-01

We demonstrate an experimental in situ observation of the temperature-dependent evolution of doping- and stress-mediated structural phase transitions in an individual single-crystalline VO2 nanobeam on a Au-coated substrate under exposure to hydrogen gas using spatially resolved Raman spectroscopy. The nucleation temperature of the rutile R structural phase in the VO2 nanobeam upon heating under hydrogen gas was lower than that under air. The spatial structural phase evolution behavior along the length of the VO2 nanobeam under hydrogen gas upon heating was much more inhomogeneous than that along the length of the same nanobeam under air. The triclinic T phase of the VO2 nanobeam upon heating under hydrogen gas transformed to the R phase and this R phase was stabilized even at room temperature in air after sample cooling. In particular, after the VO2 nanobeam with the R phase was annealed at approximately 250 °C in air, it exhibited the monoclinic M1 phase (not the T phase) at room temperature during heating and cooling cycles. These results were attributed to the interplay between hydrogen doping and stress associated with nanobeam-substrate interactions. Our study has important implications for engineering metal-insulator transition properties and developing functional devices based on VO2 nanostructures through doping and stress.We demonstrate an experimental in situ observation of the temperature-dependent evolution of doping- and stress-mediated structural phase transitions in an individual single-crystalline VO2 nanobeam on a Au-coated substrate under exposure to hydrogen gas using spatially resolved Raman spectroscopy. The nucleation temperature of the rutile R structural phase in the VO2 nanobeam upon heating under hydrogen gas was lower than that under air. The spatial structural phase evolution behavior along the length of the VO2 nanobeam under hydrogen gas upon heating was much more inhomogeneous than that along the length of the same nanobeam under

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

PubMed

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

2012-11-01

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

Cognitive effects of bilateral high frequency repetitive transcranial magnetic stimulation in early phase psychosis: a pilot study.

PubMed

Francis, Michael M; Hummer, Tom A; Vohs, Jenifer L; Yung, Matthew G; Visco, Andrew C; Mehdiyoun, Nikki F; Kulig, Teresa C; Um, Miji; Yang, Ziyi; Motamed, Mehrdad; Liffick, Emily; Zhang, Ying; Breier, Alan

2018-05-31

Cognitive dysfunction is a core facet of schizophrenia that is present early in the course of the illness and contributes to diminished functioning and outcomes. Repetitive transcranial magnetic stimulation (rTMS) is a relatively new neuropsychiatric intervention. Initially used in treatment resistant depression, investigators are now studying rTMS for other psychiatric diseases such as schizophrenia. In this study we examined the effect of high frequency rTMS on cognitive function in a group of individuals with early phase psychosis. Twenty subjects were randomized (1:1) in double-blind fashion to rTMS or sham condition. Over two weeks subjects underwent ten sessions of high frequency, bilateral, sequential rTMS targeting the dorsolateral prefrontal cortex (DLPFC). Prior to beginning and following completion of study treatment, subjects completed a cognitive assessment and magnetic resonance imaging. Subjects receiving rTMS, compared to sham treatment, displayed improvement on a standardized cognitive battery both immediately following the course of study treatment and at follow-up two weeks later. Imaging results revealed that left frontal cortical thickness at baseline was correlated with treatment response. The study treatment was found to be safe and well tolerated. These results suggest that rTMS may hold promise for the treatment of cognitive dysfunction in the early phase of psychosis, and that MRI may provide biomarkers predicting response to the treatment.

Que Es la Mediacion? (What Is Mediation?).

ERIC Educational Resources Information Center

Consortium for Appropriate Dispute Resolution in Special Education (CADRE), Eugene, OR.

This brief paper, in Spanish, discusses the use of mediation as a method for resolving disagreements between schools or early intervention programs and parents of children with disabilities. It identifies benefits of mediation such as maintenance of an ongoing and positive relationship between the school and family, simple resolution of conflicts…

Early age of e-cigarette use onset mediates the association between impulsivity and e-cigarette use frequency in youth.

PubMed

Bold, Krysten W; Morean, Meghan E; Kong, Grace; Simon, Patricia; Camenga, Deepa R; Cavallo, Dana A; Krishnan-Sarin, Suchitra

2017-12-01

Identifying risk factors for youth e-cigarette use is critical, given high rates of e-cigarette use and unknown health effects of long-term use. The current study examined whether an early age of onset of e-cigarette use mediates the association between impulsivity and e-cigarette frequency. Cross-sectional survey data of e-cigarette users (n=927) were collected from 8 high schools in southeastern Connecticut. The sample was 44.7% female (mean age 16.2 [SD=1.2], mean age of e-cigarette onset 14.7 [SD=1.6]). Two domains of self-reported, trait impulsivity were assessed using the abbreviated Barratt Impulsiveness Scale: impaired self-regulation (e.g., problems with concentration or self-control) and behavioral impulsivity (e.g., doing things without thinking). Mediation was tested with Mplus, and the model included school as a cluster variable and controlled for covariates related to e-cigarette use (i.e., sex, age, race, peer use, and other tobacco products ever tried). The hypothesized mediation was supported for both domains of impulsivity (impaired self-regulation a 1 b=0.09, SE=0.02, 95%CI [0.03-0.14], p=.002; behavioral impulsivity a 2 b=0.07, SE=0.03, 95%CI [.01-.14], p=0.03). Specifically, impaired self-regulation (B=-0.33, SE=0.06, p<0.001) and behavioral impulsivity (B=-0.26, SE=0.11, p=0.02) predicted trying e-cigarettes at an earlier age, and earlier initiation was associated with more days of e-cigarette use in the past month (B=-0.28, SE=0.08, p<0.001). Adolescents who endorse aspects of impulsivity, such as acting without thinking, are at greater risk for more frequent e-cigarette use through an early age of e-cigarette initiation. Further research is needed to evaluate these relationships longitudinally and to develop targeted e-cigarette interventions for impulsive youth. Copyright © 2017 Elsevier B.V. All rights reserved.

Decrease in early right alpha band phase synchronization and late gamma band oscillations in processing syntax in music.

PubMed

Ruiz, María Herrojo; Koelsch, Stefan; Bhattacharya, Joydeep

2009-04-01

The present study investigated the neural correlates associated with the processing of music-syntactical irregularities as compared with regular syntactic structures in music. Previous studies reported an early ( approximately 200 ms) right anterior negative component (ERAN) by traditional event-related-potential analysis during music-syntactical irregularities, yet little is known about the underlying oscillatory and synchronization properties of brain responses which are supposed to play a crucial role in general cognition including music perception. First we showed that the ERAN was primarily represented by low frequency (<8 Hz) brain oscillations. Further, we found that music-syntactical irregularities as compared with music-syntactical regularities, were associated with (i) an early decrease in the alpha band (9-10 Hz) phase synchronization between right fronto-central and left temporal brain regions, and (ii) a late ( approximately 500 ms) decrease in gamma band (38-50 Hz) oscillations over fronto-central brain regions. These results indicate a weaker degree of long-range integration when the musical expectancy is violated. In summary, our results reveal neural mechanisms of music-syntactic processing that operate at different levels of cortical integration, ranging from early decrease in long-range alpha phase synchronization to late local gamma oscillations. 2008 Wiley-Liss, Inc.

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis.

PubMed

Tarantini, Stefano; Giles, Cory B; Wren, Jonathan D; Ashpole, Nicole M; Valcarcel-Ares, M Noa; Wei, Jeanne Y; Sonntag, William E; Ungvari, Zoltan; Csiszar, Anna

2016-08-01

Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1 f/f mice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the

Computer mediated decision making : phase 2

DOT National Transportation Integrated Search

1999-02-01

The presentation of highly technical information during the public phases of complex design projects is often complicated by the participants' inability to understand the terminology and interpret the materials provided. The research was undertaken a...

Effect of leaf incubation temperature profiles on Agrobacterium tumefaciens-mediated transient expression.

PubMed

Jung, Sang-Kyu; McDonald, Karen A; Dandekar, Abhaya M

2015-01-01

Agrobacterium tumefaciens-mediated transient expression is known to be highly dependent on incubation temperature. Compared with early studies that were conducted at constant temperature, we examined the effect of variable leaf incubation temperature on transient expression. As a model system, synthetic endoglucanase (E1) and endoxylanase (Xyn10A) genes were transiently expressed in detached whole sunflower leaves via vacuum infiltration for biofuel applications. We found that the kinetics of transient expression strongly depended on timing of the temperature change as well as leaf incubation temperature. Surprisingly, we found that high incubation temperature (27-30 °C) which is suboptimal for T-DNA transfer, significantly enhanced transient expression if the high temperature was applied during the late phase (Day 3-6) of leaf incubation whereas incubation temperature in a range of 20-25 °C for an early phase (Day 0-2) resulted in higher production. On the basis of these results, we propose that transient expression is governed by both T-DNA transfer and protein synthesis in plant cells that have different temperature dependent kinetics. Because the phases were separated in time and had different optimal temperatures, we were then able to develop a novel two phase optimization strategy for leaf incubation temperature. Applying the time-varying temperature profile, we were able to increase the protein accumulation by fivefold compared with the control at a constant temperature of 20 °C. From our knowledge, this is the first report illustrating the effect of variable temperature profiling for improved transient expression. © 2015 American Institute of Chemical Engineers.

Internal Dose from Food and Drink Ingestion in the Early Phase after the Accident

NASA Astrophysics Data System (ADS)

Kawai, Masaki; Yoshizawa, Nobuaki; Hirakawa, Sachiko; Murakami, Kana; Takizawa, Mari; Sato, Osamu; Takagi, Shunji; Miyatake, Hirokazu; Takahashi, Tomoyuki; Suzuki, Gen

2017-09-01

Activity concentrations in food and drink, represented by water and vegetables, have been monitored continuously since the Fukushima Daiichi Nuclear Power Plant accident, with a focus on radioactive cesium. On the other hand, iodine-131 was not measured systematically in the early phase after the accident. The activity concentrations of iodine-131 in food and drink are important to estimate internal exposure due to ingestion pathway. When the internal dose from ingestion in the evacuation areas is estimated, water is considered as the main ingestion pathway. In this study, we estimated the values of activity concentrations in water in the early phase after the accident, using a compartment model as an estimation method. The model uses measurement values of activity concentration and deposition rate of iodine-131 onto the ground, which is calculated from an atmospheric dispersion simulation. The model considers how drinking water would be affected by radionuclides deposited into water. We estimated the activity concentrations of water on Kawamata town and Minamisouma city during March of 2011 and the committed effective doses were 0.08 mSv and 0.06 mSv. We calculated the transfer parameters in the model for estimating the activity concentrations in the areas with a small amount of measurement data. In addition, we estimated the committed effective doses from vegetables using atmospheric dispersion simulation and FARMLAND model in case of eating certain vegetables as option information.

Metacognitive beliefs mediate the effect of emotional abuse on depressive and psychotic symptoms in severe mental disorders.

PubMed

Østefjells, T; Lystad, J U; Berg, A O; Hagen, R; Loewy, R; Sandvik, L; Melle, I; Røssberg, J I

2017-10-01

Early trauma is linked to higher symptom levels in bipolar and psychotic disorders, but the translating mechanisms are not well understood. This study examines whether the relationship between early emotional abuse and depressive symptoms is mediated by metacognitive beliefs about thoughts being uncontrollable/dangerous, and whether this pathway extends to influence positive symptoms. Patients (N = 261) with psychotic or bipolar disorders were assessed for early trauma experiences, metacognitive beliefs, and current depression/anxiety and positive symptoms. Mediation path analyses using ordinary least-squares regressions tested if the effect of early emotional abuse on depression/anxiety was mediated by metacognitive beliefs, and if the effect of early emotional abuse on positive symptoms was mediated by metacognitive beliefs and depression/anxiety. Metacognitive beliefs about thoughts being uncontrollable/dangerous significantly mediated the relationship between early emotional abuse and depression/anxiety. Metacognitive beliefs and depression/anxiety significantly mediated the relationship between early emotional abuse and positive symptoms. The models explained a moderate amount of the variance in symptoms (R 2 = 0.21-0.29). Our results indicate that early emotional abuse is relevant to depression/anxiety and positive symptoms in bipolar and psychotic disorders, and suggest that metacognitive beliefs could play a role in an affective pathway to psychosis. Metacognitive beliefs could be relevant treatment targets with regards to depression/anxiety and positive symptoms in bipolar and psychotic disorders.

Masks as Self-Study. Challenging and Sustaining Teachers' Personal and Professional Personae in Early-Mid Career Life Phases

ERIC Educational Resources Information Center

Leitch, Ruth

2010-01-01

Drawing on previous research identifying how teachers' capacities to sustain their effectiveness in different phases of their professional lives are affected positively and/or negatively by their sense of identity, this paper illuminates three early-mid career teachers' self-study inquiries, centring on mask work. The creative development of…

Explaining Why Early-Maturing Girls Are More Exposed to Sexual Harassment in Early Adolescence

ERIC Educational Resources Information Center

Skoog, Therése; Bayram Özdemir, Sevgi

2016-01-01

In this study, we tested two competing explanations of the previously established link between early female puberty and sexual harassment in early adolescence. The sample included 680 seventh-grade Swedish girls (M[subscript age] = 13.40, SD = 0.53). Findings revealed that looking more sexually mature and being sexually active mediated the link…

Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension

PubMed Central

Foss, Jason D.; Fink, Gregory D.

2015-01-01

Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼170 mmHg. RDNX reduced MAP ∼10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves. PMID:26661098

The Impact of Early Design Phase Risk Identification Biases on Space System Project Performance

NASA Technical Reports Server (NTRS)

Reeves, John D., Jr.; Eveleigh, Tim; Holzer, Thomas; Sarkani, Shahryar

2012-01-01

Risk identification during the early design phases of complex systems is commonly implemented but often fails to result in the identification of events and circumstances that truly challenge project performance. Inefficiencies in cost and schedule estimation are usually held accountable for cost and schedule overruns, but the true root cause is often the realization of programmatic risks. A deeper understanding of frequent risk identification trends and biases pervasive during space system design and development is needed, for it would lead to improved execution of existing identification processes and methods.

Depression and resilience in women with HIV and early life stress: does trauma play a mediating role? A cross-sectional study.

PubMed

Spies, Georgina; Seedat, Soraya

2014-02-24

The present study sought to assess the relationship between depressive symptomatology and resilience among women infected with HIV and to investigate whether trauma exposure (childhood trauma, other discrete lifetime traumatic events) or the presence of post-traumatic stress symptomatology mediated this relationship. Cross-sectional study. Western Cape, South Africa. A convenience sample of 95 women infected with HIV in peri-urban communities in the Western Cape, South Africa. All women had exposure to moderate-to-severe childhood trauma as determined by the Childhood Trauma Questionnaire. We examined the relationship between depressive symptomatology and resilience (the Connor-Davidson Resilience Scale) and investigated whether trauma exposure or the presence of post-traumatic stress symptomatology mediated this relationship through the Sobel test for mediation and PLS path analysis. There was a significant negative correlation between depressive symptomatology and resilience (p=<0.01). PLS path analysis revealed a significant direct effect between depression and resilience. On the Sobel test for mediation, distal (childhood trauma) and proximal traumatic events did not significantly mediate this association (p=> 0.05). However, post-traumatic stress symptomatology significantly mediated the relationship between depression and resilience in trauma-exposed women living with HIV. In the present study, higher levels of resilience were associated with lower levels of self-reported depression. Although causal inferences are not possible, this suggests that in this sample, resilience may act as protective factor against the development of clinical depression. The results also indicate that post-traumatic stress symptoms (PTSS), which are highly prevalent in HIV-infected and trauma exposed individuals and often comorbid with depression, may further explain and account for this relationship. Further investigation is required to determine whether early identification

Depression and resilience in women with HIV and early life stress: does trauma play a mediating role? A cross-sectional study

PubMed Central

Spies, Georgina; Seedat, Soraya

2014-01-01

Objectives The present study sought to assess the relationship between depressive symptomatology and resilience among women infected with HIV and to investigate whether trauma exposure (childhood trauma, other discrete lifetime traumatic events) or the presence of post-traumatic stress symptomatology mediated this relationship. Design Cross-sectional study. Setting Western Cape, South Africa. Participants A convenience sample of 95 women infected with HIV in peri-urban communities in the Western Cape, South Africa. All women had exposure to moderate-to-severe childhood trauma as determined by the Childhood Trauma Questionnaire. Primary and secondary outcome measures We examined the relationship between depressive symptomatology and resilience (the Connor-Davidson Resilience Scale) and investigated whether trauma exposure or the presence of post-traumatic stress symptomatology mediated this relationship through the Sobel test for mediation and PLS path analysis. Results There was a significant negative correlation between depressive symptomatology and resilience (p=<0.01). PLS path analysis revealed a significant direct effect between depression and resilience. On the Sobel test for mediation, distal (childhood trauma) and proximal traumatic events did not significantly mediate this association (p=> 0.05). However, post-traumatic stress symptomatology significantly mediated the relationship between depression and resilience in trauma-exposed women living with HIV. Conclusions In the present study, higher levels of resilience were associated with lower levels of self-reported depression. Although causal inferences are not possible, this suggests that in this sample, resilience may act as protective factor against the development of clinical depression. The results also indicate that post-traumatic stress symptoms (PTSS), which are highly prevalent in HIV-infected and trauma exposed individuals and often comorbid with depression, may further explain and account for

[Spiral CT of the head-neck area: the advantages of the early arterial phase in the detection of squamous-cell carcinomas].

PubMed

Conrad, R; Pauleit, D; Layer, G; Kandyba, J; Kohlbecher, R; Hortling, N; Baselides, P; Schild, H

1999-07-01

To determine if scanning in the arterial phase improves detection of squamous cell carcinomas in the pharynx and larynx. In a prospective clinical study 20 patients with a pharyngeal or laryngeal carcinoma were examined with by spiral CT. 80 ml lopromid were intravenously injected as a bolus with a rate of 3 ml/sec. Two consecutive spiral CT scans were performed with start-delay times of 20 and 70 seconds respectively. Delineation and contrast enhancement of tumours, cervical lymph nodes and vessels were evaluated. The radiodensities (HU) of tumors, lymph nodes vessels, pharyngeal wall and muscle were measured. Comparing early and late start delay time scans tumor assessment in the early phase was better in 58%, less in 16% and equal in both scans in 26%. 82% of the pathologic lymph nodes had more peripheral enhancement than surrounding muscle tissue. During the arterial phase the measured radiodensities of the common carotid artery and jugular vein were significantly higher than in the second phase. Contrast-enhanced special CT permits accurate morphologic assessment (size, infiltration) of pharyngeal and supraglottic laryngeal squamous cell carcinoma, while pathologic lymph nodes already have a sufficient contrast enhancement for the detection.

Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia.

PubMed

Beretta, S; Pastori, C; Sala, G; Piazza, F; Ferrarese, C; Cattalini, A; de Curtis, M; Librizzi, L

2011-05-01

The acute effects of simvastatin lactone (lipophilic) and simvastatin acid (hydrophilic) on transient focal ischemia were assessed using the isolated guinea pig brain maintained in vitro by arterial perfusion. This new model of cerebral ischemia allows the assessment of the very early phase of the ischemic process, with the functional preservation of the vascular and neuronal compartments and the blood-brain barrier (bbb). The middle cerebral artery was transiently tied for 30 min followed by reperfusion for 60 min. Statins (nanomolar doses) were administered by intravascular continuous infusion starting 60 min before ischemia induction. Brain cortical activity and arterial vascular tone were continuously recorded. At the end of the experiment immunoreactivity for microtubule-associated protein 2 (MAP-2), expression of survival kinases (ERK and Akt) and total anti-oxidant capacity were assayed. Brains treated with simvastatin lactone showed i) reduced amplitude and delayed onset of ischemic depressions, ii) preservation of MAP-2 immunoreactivity, iii) activation of ERK signaling in the ischemic hemisphere and iv) increase in whole-brain anti-oxidant capacity. Treatment with the bbb-impermeable simvastatin acid was ineffective on the above-mentioned parameters. Vascular resistance recordings and Akt signaling were unchanged by any statin treatment. Our findings suggest that intravascular-delivered simvastatin exerts an acute lipophilicity-dependent protective effect in the early phase of cerebral ischemia. Copyright © 2011 Elsevier Ltd. All rights reserved.

Coping Expectancies, Not Enhancement Expectancies, Mediate Trauma Experience Effects on Problem Alcohol Use: A Prospective Study From Early Childhood to Adolescence.

PubMed

Jester, Jennifer M; Steinberg, Davia B; Heitzeg, Mary M; Zucker, Robert A

2015-09-01

The relationship between experiencing trauma and increased alcohol consumption has been well established. Exposure to childhood trauma has been linked to both early onset of drinking and problematic substance use. However, the mechanisms underlying this relationship remain unclear. The results of early work suggested that drinking to relieve negative affect (i.e., drinking to cope) was driving this connection. However, the findings of more recent work suggest that drinking might be used to enhance positive affect as a way of addressing the aftereffects of early trauma. The current study looked at these two drinking expectancies as indirect pathways between the experience in early childhood of living in a home with parental violence and peak alcohol use in emerging adulthood. Participants were 1,064 children and their parents involved in a longitudinal community study of children at high risk for the development of alcoholism and a community contrast group of those at lower risk. Baseline assessment was at age 3-5 years, self-reports of internalizing behavior and drinking expectancies were obtained at age 12-14, and drinking measures were assessed at age 18-20. Results indicated that coping expectancy was a mediator of the relationship between early childhood trauma and later peak alcohol use, whereas enhancement expectancy was not. Children living in homes with parental violence were more likely to develop ineffective coping strategies, such as using alcohol to decrease negative affect. These results support the self-medication theory. They also demonstrate the long-term effects of early life experience on drinking behavior in early adulthood.

Temperament, Executive Control, and ADHD across Early Development

PubMed Central

Rabinovitz, Beth B.; O’Neill, Sarah; Rajendran, Khushmand; Halperin, Jeffrey M.

2015-01-01

Research examining factors linking early temperament and later ADHD is limited by cross-sectional approaches and having the same informant rate both temperament and psychopathology. We used multi-informant/multi-method longitudinal data to test the hypothesis that negative emotionality during preschool is positively associated with ADHD symptom severity in middle childhood, but developing executive control mediates this relation. Children (N=161) with and without ADHD were evaluated three times: Parent and teacher temperament ratings and NEPSY Visual Attention at ages 3–4 years; WISC-IV Working Memory Index and NEPSY Response Set at age 6 years; and ADHD symptoms using the Kiddie-SADS at age 7 years. Parent and teacher ratings of preschoolers’ temperament were combined to form an Anger/Frustration composite. Similarly, an Executive Functioning composite was derived from age 6 measures. Bootstrapping was used to determine whether age 6 Executive Functioning mediated the relation between early Anger/Frustration and later ADHD symptom severity, while controlling for early executive functioning. Preschoolers’ Anger/Frustration was significantly associated with later ADHD symptoms, with this relation partially mediated by age 6 Executive Functioning. Developing executive control mediates the relation between early Anger/Frustration and later ADHD symptom severity, suggesting that Anger/Frustration influences ADHD symptom severity through its impact on developing executive control. Early interventions targeting the harmful influences of negative emotionality or enhancing executive functioning may diminish later ADHD severity. PMID:26854505

Nonstandard maternal work schedules during infancy: Implications for children's early behavior problems

PubMed Central

Daniel, Stephanie S.; Grzywacz, Joseph G.; Leerkes, Esther; Tucker, Jenna; Han, Wen-Jui

2009-01-01

This paper examines the associations between maternal nonstandard work schedules during infancy and children's early behavior problems, and the extent to which infant temperament may moderate these associations. Hypothesized associations were tested using data from the National Institute of Child Health and Human Development (NICHD) Study of Early Child Care (Phase I). Analyses focused on mothers who returned to work by the time the child was 6 months of age, and who worked an average of at least 35 h per week from 6 through 36 months. At 24 and 36 months, children whose mothers worked a nonstandard schedule had higher internalizing and externalizing behaviors. Modest, albeit inconsistent, evidence suggests that temperamentally reactive children may be more vulnerable to maternal work schedules. Maternal depressive symptoms partially mediated associations between nonstandard maternal work schedules and child behavior outcomes. PMID:19233479

Life stressors as mediators of the relation between socioeconomic position and mental health problems in early adolescence: the TRAILS study.

PubMed

Amone-P'Olak, Kennedy; Ormel, Johan; Huisman, Martijn; Verhulst, Frank C; Oldehinkel, Albertine J; Burger, Huibert

2009-10-01

Life stressors and family socioeconomic position have often been associated with mental health status. The aim of the present study is to contribute to the understanding of the pathways from low socioeconomic position and life stressors to mental problems. In a cross-sectional analysis using data from a longitudinal study of early adolescents (N = 2,149, 51% girls; mean age 13.6 years, SD 0.53, range 12-15), we assessed the extent of mediation of the association between family socioeconomic position and mental health problems by different types of life stressors in multiple regression models. Stressors were rated as environment related or person related. Information on socioeconomic position was obtained directly from parents, and internalizing and externalizing problem behaviors were assessed by reports from multiple informants (parents, self, and teachers). Low socioeconomic position was associated with more mental health problems and more life stressors. Both environment-related and person-related stressors predicted mental health problems independently of socioeconomic position. The associations between socioeconomic position and all mental health outcomes were partly mediated by environment-related life stressors. Mediation by environment-related and person-related stressors as assessed by linear regression amounted to 56% (95% confidence interval [CI] 35%-78%) and 7% (95% CI -25% to 38%) for internalizing problems and 13% (95% CI 7%-19%) and 5% (95% CI -2% to 13%) for externalizing problems, respectively. Environment-related, but not person-related, stressors partly mediated the association between socio economic position and adolescent mental problems. The extent of mediation was larger for internalizing than for externalizing problems. Because the effect sizes of the associations were relatively small, targeted interventions to prevent impaired mental health may have only modest benefits to adolescents from low socioeconomic background.

Early cytokine modulation after the rapid induction phase of sublingual immunotherapy with mite monomeric allergoids.

PubMed

Di Gioacchino, M; Perrone, A; Petrarca, C; Di Claudio, F; Mistrello, G; Falagiani, P; Dadorante, V; Verna, N; Braga, M; Ballone, E; Cavallucci, E

2008-01-01

The influence of different treatment schedules of sublingual immunotherapy (SLIT) in activating IL-10-producing T-cells, crucial in inducing allergen-specific tolerance, is not completely understood. The present work was designed to evaluate allergen driven interleukin release by mononuclear cells in the early phase of SLIT, after application of different induction schemes. Twenty mite-allergic patients were enrolled, 10 (group A) treated with a traditional 98 day induction scheme and 10 (group B) with a 16 day scheme with monomeric allergoid vaccine. At the end of the induction phase, the cumulative doses taken by group A and group B patients were equivalent to 50.5 and 50.3 microg of mite group 1 allergens, respectively. The release of Th1-, Th2- and Treg-related interleukins was assessed in culture supernatants of 5 microg/ml Der-p1-stimulated mononuclear cells, isolated before and after the induction phases. No relevant treatment-related side effects were observed. Interleukin release was similar in the two groups at the enrolment. Non-stimulated and Der p 1 stimulated release of studied cytokines was similar in the two groups at enrolment. Der p 1 stimulation significantly increased IL-10 release (p<0.0002) after treatment in group B patients, and this effect was higher (p=0.05) compared to group A patients. Furthermore, at the end of SLIT induction TNF-alpha, IL-4 and IFN-gamma production were reduced in group B patients (p<0.05, p=0.062 and p=0.060, respectively). The rapid induction scheme of sublingual immunotherapy induces an early immune suppression more effectively than the slower one. The rapid induction scheme should be the preferential way to start sublingual immunotherapy, particularly when monomeric allergoids are utilized.

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

PubMed Central

Sharma, Ricky A.

2012-01-01

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

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review.

PubMed

Lin, Yinzhi; Ukaji, Tamami; Koide, Naoki; Umezawa, Kazuo

2018-03-03

We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.

F247. INTERNALIZED STIGMA HAS A STRONGER RELATIONSHIP WITH INTRINSIC MOTIVATION COMPARED TO AMOTIVATION IN EARLY PHASE AND PROLONGED SCHIZOPHRENIA

PubMed Central

Firmin, Ruth; Luther, Lauren; Lysaker, Paul; Vohs, Jennifer

2018-01-01

Abstract Background Motivation deficits predict decreased functioning in schizophrenia. Recent work suggests deficits reflect challenges in separate domains: intrinsic motivation (one’s internal drive to engage in a behavior out of enjoyment or interest) and amotivation (one’s broader decrease in motivated behavior linked to avolition and anhedonia). Internalized stigma is another determinant of functioning for people with schizophrenia that may impact motivation. However, little is known about these relationships, including which aspects of motivation it may impact nor when these links emerge. Identifying the link between these constructs may help to identify whether internalized stigma may be a novel treatment target to facilitate improvements in motivation. Methods Forty adults with early phase schizophrenia and 66 adults with prolonged schizophrenia completed measures of internalized stigma, intrinsic motivation, and amotivation. Pearson’s correlations were examined followed by Fischer’s r-to-z transformations to compare differences in the magnitude of associations between internalized stigma and intrinsic motivation and internalized stigma and amotivation among the first episode and prolonged samples. Next, we conducted stepwise regressions to examine whether internalized stigma was associated with intrinsic motivation above and beyond associations with amotivation in each sample. Results In the early phase sample, the association between internalized stigma was greater with intrinsic motivation (r=-0.48, p=.00) compared to amotivation (r=0.27, p=0.10). Associations with internalized stigma in the prolonged sample were also greater with intrinsic motivation (r=-0.30, p=0.02) versus amotivation (r=0.19, p=0.12). The magnitude of the associations between internalized stigma and intrinsic motivation (z=1.03, p=0.15) and between internalized stigma and amotivation (z=0.41, p = 0.34) did not significantly differ when comparing phase of illness. Regression

Titanium(IV) isopropoxide mediated solution phase reductive amination on an automated platform: application in the generation of urea and amide libraries.

PubMed

Bhattacharyya, S; Fan, L; Vo, L; Labadie, J

2000-04-01

Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident(TM) library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and purity from 4 primary amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.

ROS mediated high anti-bacterial efficacy of strain tolerant layered phase pure nano-calcium hydroxide.

PubMed

Samanta, Aniruddha; Podder, Soumik; Ghosh, Chandan Kumar; Bhattacharya, Manjima; Ghosh, Jiten; Mallik, Awadesh Kumar; Dey, Arjun; Mukhopadhyay, Anoop Kumar

2017-08-01

The present work provides the first ever report on extraordinarily high antibacterial efficacy of phase pure micro-layered calcium hydroxide nanoparticles (LCHNPs) even under dark condition. The LCHNPs synthesized especially in aqueous medium by a simple, inexpensive method show adequate mechanical properties along with the presence of a unique strain tolerant behaviour. The LCHNPs are characterized by FTIR, Raman spectroscopy, XRD, Rietveld analysis, FE-SEM, TEM, TG-DTA, surface area, particle size distribution, zeta potential analysis and nanoindentation techniques. The LCHNPs have 98.1% phase pure hexagonal Ca(OH) 2 as the major phase having micro-layered architecture made up of about ~100-200nm thick individual nano-layers. The nanomechanical properties e.g., nanohardness (H) and Young's modulus (E) of the LCHNPs are found to have a unique load independent behavior. The dielectric responses (e.g., dielectric constant and dielectric loss) and antibacterial properties are evaluated for such LCHNPs. Further, the LCHNPs show much better antibacterial potency against both gram-positive e.g., Staphylococcus aureus (S. aureus) and gram-negative e.g., Pseudomonas putida (P. putida) bacteria even in dark especially, with the lowest ever reported MIC value (e.g., 1 μg ml -1 ) against the P. putida bacterial strain and exhibit ROS mediated antibacterial proficiency. Finally, such LCHNPs has almost ~8-16% inhibition efficacy towards the development of biofilm of these microorganisms quantified by colorimetric detection process. So, such LCHNPs may find potential applications in the areas of healthcare industry and environmental engineering. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early Adversity, Psychopathology, and Latent Class Profiles of Global Physical Health From Preschool Through Early Adolescence.

PubMed

Whalen, Diana J; Belden, Andy C; Tillman, Rebecca; Barch, Deanna M; Luby, Joan L

The purpose of the present report was to describe the longitudinal trajectories of physical health beginning during preschool and continuing into early adolescence; explore whether these trajectories were predicted by psychosocial adversity, family income-to-needs ratio, and psychiatric disorders occurring during the preschool period; and determine whether psychiatric disorders mediated these relations. Participants included 296 children participating in a longitudinal study of early-onset psychopathology spanning 10 years. Semistructured clinical interviews were conducted with caregivers to determine children's psychiatric diagnoses between ages 3 and 6 years. Caregivers also completed annual assessments of their child's physical health problems (ages 3-13) and reported on the family's income and indicators of psychosocial adversity. Growth mixture modeling revealed 2 trajectories of physical health problems: a stable, low group (n = 199) and a high, increasing group (n = 57) indicating linear increases in physical health problems from ages 3 to 13. Preschool psychiatric diagnoses (Estimate [Est] = 0.05, p < .001), family income-to-needs ratio (Est = -0.01, p = .012), and psychosocial adversity (Est = 0.02, p = .015) predicted membership in the high, increasing trajectory of physical health problems. Early-onset psychopathology mediated relations between psychosocial adversity and physical health problems (αβ = 0.31, p = .050) and between income-to-needs ratio and physical health problems (αβ = -0.29, p < .021). These findings indicate the importance of early indicators of risk: low income-to-needs ratios, high psychosocial adversity, and psychiatric disorders occurring during the preschool period for contributing to increasing physical health problems from preschool through early adolescence. Early-onset psychiatric disorders also mediated relations between psychosocial adversity, income-to-needs ratio, and physical health problems.

Studies of high temperature ternary phases in mixed-metal-rich early transition metal sulfide and phosphide systems

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

Marking, Gregory Allen

1994-01-04

Investigations of ternary mixed early transition metal-rich sulfide and phosphide systems resulted in the discovery of new structures and new phases. A new series of Zr and Hf - group V transition metal - sulfur K-phases was synthesized and crystallographically characterized. When the group V transition metal was Nb or Ta, the unit cell volume was larger than any previously reported K-phase. The presence of adventitious oxygen was determined in two K-phases through a combination of neutron scattering and X-ray diffraction experiments. A compound Hf 10Ta 3S 3 was found to crystallize in a new-structure type similar to the knownmore » gamma brasses. This structure is unique in that it is the only reported "stuffed" gamma-brass type structure. The metal components, Hf and Ta, are larger in size and more electropositive than the metals found in normal gamma brasses (e.g. Cu and Zn) and because of the larger metallic radii, sulfur can be incorporated into the structure where it plays an integral role in stabilizing this phase relative to others. X-ray single-crystal, X-ray powder and neutron powder refinements were performed on this structure. A new structure was found in the ternary Nb-Zr-P system which has characteristics in common with many known early transition metal-rich sulfides, selenides, and phosphides. This structure has the simplest known interconnection of the basic building blocks known for this structural class. Anomalous scattering was a powerful tool for differentiating between Zr and Nb when using Mo Kα X-radiation. The compounds ZrNbP and HfNbP formed in the space group Prima with the simple Co 2Si structure which is among the most common structures found for crystalline solid materials. Solid solution compounds in the Ta-Nb-P, Ta-Zr-P, Nb-Zr-P, Hf-Nb-P, and Hf-Zr-S systems were crystallographically characterized. The structural information corroborated ideas about bonding in metal-rich compounds.« less

Integrated electrokinetically driven microfluidic devices with pH-mediated solid-phase extraction coupled to microchip electrophoresis for preterm birth biomarkers.

PubMed

Sonker, Mukul; Knob, Radim; Sahore, Vishal; Woolley, Adam T

2017-07-01

Integration in microfluidics is important for achieving automation. Sample preconcentration integrated with separation in a microfluidic setup can have a substantial impact on rapid analysis of low-abundance disease biomarkers. Here, we have developed a microfluidic device that uses pH-mediated solid-phase extraction (SPE) for the enrichment and elution of preterm birth (PTB) biomarkers. Furthermore, this SPE module was integrated with microchip electrophoresis for combined enrichment and separation of multiple analytes, including a PTB peptide biomarker (P1). A reversed-phase octyl methacrylate monolith was polymerized as the SPE medium in polyethylene glycol diacrylate modified cyclic olefin copolymer microfluidic channels. Eluent for pH-mediated SPE of PTB biomarkers on the monolith was optimized using different pH values and ionic concentrations. Nearly 50-fold enrichment was observed in single channel SPE devices for a low nanomolar solution of P1, with great elution time reproducibility (<7% RSD). The monolith binding capacity was determined to be 400 pg (0.2 pmol). A mixture of a model peptide (FA) and a PTB biomarker (P1) was extracted, eluted, injected, and then separated by microchip electrophoresis in our integrated device with ∼15-fold enrichment. This device shows important progress towards an integrated electrokinetically operated platform for preconcentration and separation of biomarkers. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

7T T₂*-weighted magnetic resonance imaging reveals cortical phase differences between early- and late-onset Alzheimer's disease.

PubMed

van Rooden, Sanneke; Doan, Nhat Trung; Versluis, Maarten J; Goos, Jeroen D C; Webb, Andrew G; Oleksik, Ania M; van der Flier, Wiesje M; Scheltens, Philip; Barkhof, Frederik; Weverling-Rynsburger, Annelies W E; Blauw, Gerard Jan; Reiber, Johan H C; van Buchem, Mark A; Milles, Julien; van der Grond, Jeroen

2015-01-01

The aim of this study is to explore regional iron-related differences in the cerebral cortex, indicative of Alzheimer's disease pathology, between early- and late-onset Alzheimer's disease (EOAD, LOAD, respectively) patients using 7T magnetic resonance phase images. High-resolution T2(∗)-weighted scans were acquired in 12 EOAD patients and 17 LOAD patients with mild to moderate disease and 27 healthy elderly control subjects. Lobar peak-to-peak phase shifts and regional mean phase contrasts were computed. An increased peak-to-peak phase shift was found for all lobar regions in EOAD patients compared with LOAD patients (p < 0.05). Regional mean phase contrast in EOAD patients was higher than in LOAD patients in the superior medial and middle frontal gyrus, anterior and middle cingulate gyrus, postcentral gyrus, superior and inferior parietal gyrus, and precuneus (p ≤ 0.042). These data suggest that EOAD patients have an increased iron accumulation, possibly related to an increased amyloid deposition, in specific cortical regions as compared with LOAD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Causal Mediation in Educational Research: An Illustration Using International Assessment Data

ERIC Educational Resources Information Center

Caro, Daniel H.

2015-01-01

This paper applies the causal mediation framework proposed by Kosuke Imai and colleagues (Imai, Keele, & Tingley, 2010) to educational research by examining the causal mediating role of early literacy activities in parental education influences on reading performance. The paper argues that the study of causal mediation is particularly relevant…

The Timing of Middle-Childhood Peer Rejection and Friendship: Linking Early Behavior to Early-Adolescent Adjustment

ERIC Educational Resources Information Center

Pedersen, Sara; Vitaro, Frank; Barker, Edward D.; Borge, Anne I. H.

2007-01-01

This study used a sample of 551 children surveyed yearly from ages 6 to 13 to examine the longitudinal associations among early behavior, middle-childhood peer rejection and friendedness, and early-adolescent depressive symptoms, loneliness, and delinquency. The study tested a sequential mediation hypothesis in which (a) behavior problems in the…

Identifying mediating factors of moral reasoning in science education

NASA Astrophysics Data System (ADS)

Zeidler, Dana L.; Schafer, Larry E.

The purpose of this research was to examine how science content knowledge, moral reasoning ability, attitudes, and past experiences mediate the formation of moral judgments on environmental dilemmas. The study was conducted in two phases using environmental science majors and nonscience majors of college age. Phase One determined if environmental science majors exhibited higher levels of moral reasoning on nontechnical environmental social issues than on general social issues and examined the extent to which possible mediating factors accounted for differences in moral reasoning. Phase Two was qualitative in nature, the purpose of which was to observe and identify trends in conversations between subjects as to how certain mediating factors are revealed as people form moral judgments. The framework on which this study was constructed incorporates a progressive educational position; a position that views science education as being interdisciplinary, and a social means to a social end.

Curcumin Inhibits CD4+ T Cell Activation, but Augments CD69 Expression and TGF-β1-Mediated Generation of Regulatory T Cells at Late Phase

PubMed Central

Kim, Girak; Jang, Mi Seon; Son, Young Min; Seo, Min Ji; Ji, Sang Yun; Han, Seung Hyun; Jung, In Duk; Park, Yeong-Min; Jung, Hyun Jung; Yun, Cheol-Heui

2013-01-01

Background Curcumin is a promising candidate for a natural medicinal agent to treat chronic inflammatory diseases. Although CD4+ T cells have been implicated in the pathogenesis of chronic inflammation, whether curcumin directly regulates CD4+ T cells has not been definitively established. Here, we showed curcumin-mediated regulation of CD2/CD3/CD28-initiated CD4+ T cell activation in vitro. Methodology/Principal Findings Primary human CD4+ T cells were stimulated with anti-CD2/CD3/CD28 antibody-coated beads as an in vitro surrogate system for antigen presenting cell-T cell interaction and treated with curcumin. We found that curcumin suppresses CD2/CD3/CD28-initiated CD4+ T cell activation by inhibiting cell proliferation, differentiation and cytokine production. On the other hand, curcumin attenuated the spontaneous decline of CD69 expression and indirectly increased expression of CCR7, L-selectin and Transforming growth factor-β1 (TGF-β1) at the late phase of CD2/CD3/CD28-initiated T cell activation. Curcumin-mediated up-regulation of CD69 at late phase was associated with ERK1/2 signaling. Furthermore, TGF-β1 was involved in curcumin-mediated regulation of T cell activation and late-phase generation of regulatory T cells. Conclusions/Significance Curcumin not merely blocks, but regulates CD2/CD3/CD28-initiated CD4+ T cell activation by augmenting CD69, CCR7, L-selectin and TGF-β1 expression followed by regulatory T cell generation. These results suggest that curcumin could directly reduce T cell-dependent inflammatory stress by modulating CD4+ T cell activation at multiple levels. PMID:23658623

Early stages of styrene-isoprene copolymerization in gas phase clusters probed by resonance enhanced multiphoton ionization.

PubMed

Mahmoud, Hatem; Germanenko, Igor N; El-Shall, M Samy

2006-04-06

We present direct evidence for the formation of the covalent bonded styrene (isoprene)(2) oligomer and the isoprene dimer ions following resonance ionization of the gas phase styrene-isoprene binary clusters. The application of resonance ionization to study polymerization reactions in clusters provides new information on the structure and mechanism of formation of the early stages of polymerization and holds considerable promise for the discovery of new initiation mechanisms and for the development of novel materials with unique properties.

Cooperation between Epstein-Barr Virus Immune Evasion Proteins Spreads Protection from CD8+ T Cell Recognition across All Three Phases of the Lytic Cycle

PubMed Central

Quinn, Laura L.; Zuo, Jianmin; Abbott, Rachel J. M.; Shannon-Lowe, Claire; Tierney, Rosemary J.; Hislop, Andrew D.; Rowe, Martin

2014-01-01

CD8+ T cell responses to Epstein-Barr virus (EBV) lytic cycle expressed antigens display a hierarchy of immunodominance, in which responses to epitopes of immediate-early (IE) and some early (E) antigens are more frequently observed than responses to epitopes of late (L) expressed antigens. It has been proposed that this hierarchy, which correlates with the phase-specific efficiency of antigen presentation, may be due to the influence of viral immune-evasion genes. At least three EBV-encoded genes, BNLF2a, BGLF5 and BILF1, have the potential to inhibit processing and presentation of CD8+ T cell epitopes. Here we examined the relative contribution of these genes to modulation of CD8+ T cell recognition of EBV lytic antigens expressed at different phases of the replication cycle in EBV-transformed B-cells (LCLs) which spontaneously reactivate lytic cycle. Selective shRNA-mediated knockdown of BNLF2a expression led to more efficient recognition of immediate-early (IE)- and early (E)-derived epitopes by CD8+ T cells, while knock down of BILF1 increased recognition of epitopes from E and late (L)-expressed antigens. Contrary to what might have been predicted from previous ectopic expression studies in EBV-negative model cell lines, the shRNA-mediated inhibition of BGLF5 expression in LCLs showed only modest, if any, increase in recognition of epitopes expressed in any phase of lytic cycle. These data indicate that whilst BNLF2a interferes with antigen presentation with diminishing efficiency as lytic cycle progresses (IE>E>>L), interference by BILF1 increases with progression through lytic cycle (IEphase-specific effects that provide mechanistic insight

Early Origins of Child Obesity: Bridging Disciplines and Phases of Development - September 30–October 1, 2010

PubMed Central

Christoffel, Katherine Kaufer; Wang, Xiaobin; Binns, Helen J.

2012-01-01

This report summarizes a conference: “Early Origins of Child Obesity: Bridging Disciplines and Phases of Development”, held in Chicago on September 30–October 1, 2010. The conference was funded in part by the National Institutes of Health and the Williams Heart Foundation, to achieve the conference objective: forging a next-step research agenda related to the early origins of childhood obesity. This research agenda was to include working with an array of factors (from genetic determinants to societal ones) along a continuum from prenatal life to age 7, with an emphasis on how the developing child deals with the challenges presented by his/her environment (prenatal, parental, nutritional, etc.). The conference offered a unique opportunity to facilitate communication and planning of future work among a variety of researchers whose work separately addresses different periods in early life. Over the span of two days, speakers addressed existing, critical research topics within each of the most-studied age ranges. On the final day, workshops fostered the discussion needed to identify the highest priority research topics related to linking varied early factor domains. These are presented for use in planning future research and research funding. PMID:23443002

Marital conflict and early adolescents' self-evaluation: the role of parenting quality and early adolescents' appraisals.

PubMed

Siffert, Andrea; Schwarz, Beate; Stutz, Melanie

2012-06-01

Cognitive appraisals and family dynamics have been identified as mediators of the relationship between marital conflict and children's adjustment. Surprisingly little research has investigated both meditational processes in the same study. Guided by the cognitive-contextual framework and the spillover hypothesis, the present study integrated factors from both theories early adolescents' appraisals of threat and self-blame, as well as perceived parenting quality as mediators of the link between early adolescents' perception of marital conflict and their self-evaluations (self-esteem and scholastic competence). Analyses were based on the first two waves of an ongoing longitudinal study. Participants were 176 two-parent families, and their early adolescents (50.5% girls) whose mean age was 10.61 years at Time 1 (SD =0.40) and 11.63 years at Time 2 (SD=0.39). Structural equation modeling analyses indicated that parenting quality and early adolescents' perceived threat provided indirect pathways between marital conflict and early adolescents' self-esteem 1 year later when controlling for their initial level of self-esteem. With respect to scholastic competence, only fathers' parenting was an indirect link. Self-blame did not play a role. Implications for understanding the mechanisms by which exposure to marital conflict predicts early adolescents' maladjustment are discussed.

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

PubMed

London, Wendy B; Bagatell, Rochelle; Weigel, Brenda J; Fox, Elizabeth; Guo, Dongjing; Van Ryn, Collin; Naranjo, Arlene; Park, Julie R

2017-12-15

Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial

Review of hardware cost estimation methods, models and tools applied to early phases of space mission planning

NASA Astrophysics Data System (ADS)

Trivailo, O.; Sippel, M.; Şekercioğlu, Y. A.

2012-08-01

The primary purpose of this paper is to review currently existing cost estimation methods, models, tools and resources applicable to the space sector. While key space sector methods are outlined, a specific focus is placed on hardware cost estimation on a system level, particularly for early mission phases during which specifications and requirements are not yet crystallised, and information is limited. For the space industry, cost engineering within the systems engineering framework is an integral discipline. The cost of any space program now constitutes a stringent design criterion, which must be considered and carefully controlled during the entire program life cycle. A first step to any program budget is a representative cost estimate which usually hinges on a particular estimation approach, or methodology. Therefore appropriate selection of specific cost models, methods and tools is paramount, a difficult task given the highly variable nature, scope as well as scientific and technical requirements applicable to each program. Numerous methods, models and tools exist. However new ways are needed to address very early, pre-Phase 0 cost estimation during the initial program research and establishment phase when system specifications are limited, but the available research budget needs to be established and defined. Due to their specificity, for vehicles such as reusable launchers with a manned capability, a lack of historical data implies that using either the classic heuristic approach such as parametric cost estimation based on underlying CERs, or the analogy approach, is therefore, by definition, limited. This review identifies prominent cost estimation models applied to the space sector, and their underlying cost driving parameters and factors. Strengths, weaknesses, and suitability to specific mission types and classes are also highlighted. Current approaches which strategically amalgamate various cost estimation strategies both for formulation and validation

The Effector TepP Mediates Recruitment and Activation of Phosphoinositide 3-Kinase on Early Chlamydia trachomatis Vacuoles.

PubMed

Carpenter, Victoria; Chen, Yi-Shan; Dolat, Lee; Valdivia, Raphael H

2017-01-01

Chlamydia trachomatis delivers multiple type 3 secreted effector proteins to host epithelial cells to manipulate cytoskeletal functions, membrane dynamics, and signaling pathways. TepP is the most abundant effector protein secreted early in infection, but its molecular function is poorly understood. In this report, we provide evidence that TepP is important for bacterial replication in cervical epithelial cells, activation of type I IFN genes, and recruitment of class I phosphoinositide 3-kinases (PI3K) and signaling adaptor protein CrkL to nascent pathogen-containing vacuoles (inclusions). We also show that TepP is a target of tyrosine phosphorylation by Src kinases but that these modifications do not appear to influence the recruitment of PI3K or CrkL. The translocation of TepP correlated with an increase in the intracellular pools of phosphoinositide-(3,4,5)-triphosphate but not the activation of the prosurvival kinase Akt, suggesting that TepP-mediated activation of PI3K is spatially restricted to early inclusions. Furthermore, we linked PI3K activity to the dampening of transcription of type I interferon (IFN)-induced genes early in infection. Overall, these findings indicate that TepP can modulate cell signaling and, potentially, membrane trafficking events by spatially restricted activation of PI3K. IMPORTANCE This article shows that Chlamydia recruits PI3K, an enzyme important for host cell survival and internal membrane functions, to the pathogens inside cells by secreting a scaffolding protein called TepP. TepP enhances Chlamydia replication and dampens the activation of immune responses.

Cytotoxic Th1 and Th17 cells infiltrate the intestinal mucosa of Behcet patients and exhibit high levels of TNF-α in early phases of the disease

PubMed Central

Emmi, Giacomo; Silvestri, Elena; Bella, Chiara Della; Grassi, Alessia; Benagiano, Marisa; Cianchi, Fabio; Squatrito, Danilo; Cantarini, Luca; Emmi, Lorenzo; Selmi, Carlo; Prisco, Domenico; D’Elios, Mario Milco

2016-01-01

Abstract Background: Gastrointestinal involvement is one of the most serious in Behçet disease, potentially leading to severe complications. Aim of this study was to investigate at mucosal level the T-cell responses in Behçet patients with early intestinal involvement. Methods: We isolated T cells from intestinal mucosa of 8 patients with intestinal symptoms started within 6 months. T lymphocytes were cloned and analyzed for surface phenotype and cytokines production. Results: We obtained 382 T-cell clones: 324 were CD4+ and 58 were CD8+. Within the 324 CD4+ clones, 195 were able to secrete IFN-γ and TNF-α, but not IL-4, nor IL-17 thus showing a polarized Th1 profile, whereas CD4 clones producing both IFN-γ and IL-17 (Th1/Th17 profile) were 79. Likewise, the number of CD8 clones producing type 1 cytokines was higher than those of CD8 clones producing both type 1 and 2 cytokines. Almost all intestinal-derived T-cell clones expressed perforin-mediated cytotoxicity and Fas–Fas Ligand-mediated pro-apoptotic activity. Conclusions: Our results indicate that in the early stages of the disease, both Th1 and Th17 cells drive inflammation leading to mucosal damage via abnormal and long-lasting cytokines production as well as via both perforin- and Fas–Fas ligand-mediated cytotoxicity. Finally, all the T cells at mucosal level were able to produce large amount of TNF-α, suggesting that its production is a property of intestinal T cells of patients with early active intestinal disease. These results support the therapy with anti-TNF-α agents and suggest the use of anti-IL-17 monoclonal antibodies in Behçet patients with early intestinal involvement. PMID:27930541

Early adversity, psychopathology, and latent class profiles of global physical health from preschool through early adolescence

PubMed Central

Whalen, Diana J.; Belden, Andy C.; Tillman, Rebecca; Barch, Deanna M.; Luby, Joan L.

2016-01-01

Objective The purpose of the present report was to describe the longitudinal trajectories of physical health beginning during preschool and continuing into early adolescence, explore whether these trajectories were predicted by psychosocial adversity, family income-to-needs ratio, and psychiatric disorders occurring during the preschool period, and determine whether psychiatric disorders mediated these relations. Methods Participants included 296 children participating in a longitudinal study of early-onset psychopathology spanning ten years. Semi-structured clinical interviews were conducted with caregivers to determine children’s psychiatric diagnoses between ages 3–6. Caregivers also completed annual assessments of their child’s physical health problems (ages 3–13), as well as reported on the family’s income and indicators of psychosocial adversity. Results Growth mixture modeling revealed two trajectories of physical health problems: a stable, low group (n = 199) and a high, increasing group (n = 57) indicating linear increases in physical health problems from ages 3–13. Preschool psychiatric diagnoses (Est= 0.05, p<.001), family income-to-needs ratio (Est= −0.01, p=.012), and psychosocial adversity (Est=0.02, p=.015) predicted membership in the high, increasing trajectory of physical health problems. Early-onset psychopathology mediated relations between psychosocial adversity and physical health problems (αβ= 0.31, p=.050) and between income-to-needs ratio and physical health problems (αβ= −0.29, p<.021). Conclusions These findings indicate the importance of early indicators of risk: low income-to-needs ratios, high psychosocial adversity, and psychiatric disorders occurring during the preschool period for contributing to increasing physical health problems from preschool through early adolescence. Early-onset psychiatric disorders also mediated relations between psychosocial adversity, income-to-needs ratio, and physical health problems

Characteristics of Mononuclear Phagocytes Mediating Antilisterial Resistance in Splenectomized Mice

PubMed Central

Pietrangeli, Carolynn; Pang, King C.; Skamene, Emil; Kongshavn, Patricia A. L.

1983-01-01

The characteristics of mononuclear phagocytes mediating resistance to infection with Listeria monocytogenes during the early phase (up to 48 h) of the response were investigated in mice of the A strain that had undergone splenectomy. Although irradiation in the sham-operated host had no effect on its antilisterial response when administered immediately before infection, it markedly reduced the ability of the splenectomized host to resist listerial challenge. This effect of radiation was demonstrable in the high-dose range (600 r) and could not be reversed immediately by repopulation with 20 × 106 syngeneic nucleated bone marrow cells. Administration of silica 24 h before infection profoundly enhanced the growth of L. monocytogenes in the liver of splenectomized mice. Shielding of the liver, but not the bone marrow, protected the splenectomized host against the effects of radiation, indicating that the cell population responsible for mediating the enhanced antilisterial resistance resides in the liver. The enhanced antilisterial resistance of splenectomized mice was specifically because of the absence of the spleen and not merely because of the removal of a favorable replicating environment for listeria organisms. PMID:6299948

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

PubMed

Bektik, Emre; Dennis, Adrienne; Pawlowski, Gary; Zhou, Chen; Maleski, Danielle; Takahashi, Satoru; Laurita, Kenneth R; Deschênes, Isabelle; Fu, Ji-Dong

2018-05-04

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of 5-ethynyl-20-deoxyuridine (EdU)⁺/α-myosin heavy chain (αMHC)-GFP⁺ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFP high iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFP low cells. However, S-phase synchronization did not enhance the reprogramming with a polycistronic-viral vector, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit.

Carbachol improves secretion in the early phase after rabbit submandibular gland transplantation.

PubMed

Shi, L; Cong, X; Zhang, Y; Ding, C; Ding, Q W; Fu, F Y; Wu, L L; Yu, G Y

2010-05-01

To investigate the changes in the muscarinic receptor signaling pathway with submandibular gland (SMG) transplantation and whether carbachol improves secretion in transplanted SMGs. SMG autotransplantation was performed in a rabbit model. Carbachol (1 microM) was infused into the transplanted glands from postoperative day 1-7. The expression of the M1 and M3 muscarinic receptors, aquaporin-5 (AQP5), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by RT-PCR, immunoblotting or immunofluorescence. The content of inositol 1, 4, 5-trisphosphate (IP(3)) was measured by radioimmunoassay. Salivary flow of the transplanted SMGs was decreased after transplantation. As well, the expressions of M1 and M3 receptors and their downstream signaling molecules, IP(3), p-ERK1/2 and AQP5, were all reduced. Atrophy of acinar cells was shown in transplanted glands. However, all these alterations were reversed after carbachol treatment for 7 days. Furthermore, carbachol directly increased the mRNA expression of AQP5 and phosphorylation of ERK1/2 in cultured neonatal rabbit SMG cells. A lack of acetylcholine and downregulation of the muscarinic receptor signaling pathway is involved in the early hypofunction of transplanted SMGs. Carbachol treatment could be a new therapeutic strategy to improve secretion and prevent the obstruction of Wharton's duct in the early phase after SMG transplantation.

Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis.

PubMed

Sternak, Magdalena; Jakubowski, Andrzej; Czarnowska, Elzbieta; Slominska, Ewa M; Smolenski, Ryszard T; Szafarz, Malgorzata; Walczak, Maria; Sitek, Barbara; Wojcik, Tomasz; Jasztal, Agnieszka; Kaminski, Karol; Chlopicki, Stefan

2015-09-01

Exogenous 1-methylnicotinamide (MNA) displays anti-inflammatory activity. The aim of this work was to characterize the profile of release of endogenous MNA during the initiation and progression of murine hepatitis induced by Concanavalin A (ConA). In particular we aimed to clarify the role of interleukin-6 (IL-6) as well as the energy state of hepatocytes in MNA release in early and late phases of ConA-induced hepatitis in mice. Hepatitis was induced by ConA in IL-6(+/+) and IL-6(-/-) mice, and various parameters of liver inflammation and injury, as well as the energy state of hepatocytes, were analysed in relation to MNA release. The decrease in ATP/ADP and NADH/NAD ratios, cytokine release (IL-6, IFN-ɤ), acute phase response (e.g. haptoglobin) and liver injury (alanine aminotransaminase, ALT) were all blunted in ConA-induced hepatitis in IL-6(-/-) mice as compared to IL-6(+/+) mice. The release of MNA in response to Con A was also significantly blunted in IL-6(-/-) mice as compared to IL-6(+/+) mice in the early stage of ConA-induced hepatitis. In turn, nicotinamide N-methyltransferase (NNMT) and aldehyde oxidase (AO) activities were blunted in the liver and MNA plasma concentration was elevated to similar degree in the late stage after Concanavalin A in IL-6(+/+) and IL-6(-/-) mice. In conclusion, we demonstrated that in ConA-induced hepatitis, early, but not late MNA release was IL-6-dependent. Our results suggest that in the initiation and early hepatitis, MNA release is linked to the energy deficit/impaired redox status in hepatocytes, while in a later phase, MNA release is rather linked to the systemic inflammation. Copyright © 2015 Elsevier B.V. All rights reserved.

Stable 1T-phase MoS2 as an effective electron mediator promoting photocatalytic hydrogen production.

PubMed

Shi, Jian-Wen; Zou, Yajun; Ma, Dandan; Fan, Zhaoyang; Cheng, Linhao; Sun, Diankun; Wang, Zeyan; Niu, Chunming; Wang, Lianzhou

2018-05-17

Coupling two semiconductors together to construct a Z-scheme type photocatalytic system is an efficient strategy to solve the serious recombination challenge of photogenerated electrons and holes. In this work, we develop a novel composite photocatalyst by sandwiching metallic 1T-phase MoS2 nanosheets between MoO3 and g-C3N4 (MoO3/1T-MoS2/g-C3N4) for the first time. The metallic 1T-phase MoS2 acts as an efficient electron mediator between MoO3 and g-C3N4 to construct an all-solid-state Z-scheme photocatalytic system, resulting in a highly-efficient spatial charge separation and transfer process. Benefiting from this, the newly developed MoO3/1T-MoS2/g-C3N4 exhibits a drastically enhanced photocatalytic H2 evolution rate of 513.0 μmol h-1 g-1 under visible light irradiation (>420 nm), which is nearly 12 times higher than that of the pure g-C3N4 (39.5 μmol h-1 g-1), and 3.5 times higher than that of MoO3/g-C3N4 (145.7 μmol h-1 g-1). More importantly, the originally unstable 1T-phase MoS2 becomes very stable in MoO3/1T-MoS2/g-C3N4 because of the sandwich structure where 1T-phase MoS2 is protected by MoO3 and g-C3N4, which endows the photocatalyst with excellent photostability. It is believed that this study will provide new insights into the design of efficient and stable Z-scheme heterostructures for photocatalytic applications.

A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K+ channels in carbon monoxide–induced proarrhythmic early afterdepolarizations

PubMed Central

Al-Owais, Moza M.; Hettiarachchi, Nishani T.; Kirton, Hannah M.; Hardy, Matthew E.; Boyle, John P.; Scragg, Jason L.; Steele, Derek S.; Peers, Chris

2017-01-01

Exposure to CO causes early afterdepolarization arrhythmias. Previous studies in rats have indicated that arrhythmias arose as a result of augmentation of the late Na+ current. The purpose of the present study was to examine the basis for CO-induced arrhythmias in guinea pig myocytes in which action potentials (APs) more closely resemble those of human myocytes. Whole-cell current- and voltage-clamp recordings were made from isolated guinea pig myocytes as well as from human embryonic kidney 293 (HEK293) cells that express wild-type or a C723S mutant form of ether-a-go-go–related gene (ERG; Kv11.1). We also monitored the formation of peroxynitrite (ONOO−) in HEK293 cells fluorimetrically. CO—applied as the CO-releasing molecule, CORM-2—prolonged the APs and induced early afterdepolarizations in guinea pig myocytes. In HEK293 cells, CO inhibited wild-type, but not C723S mutant, Kv11.1 K+ currents. Inhibition was prevented by an antioxidant, mitochondrial inhibitors, or inhibition of NO formation. CO also raised ONOO− levels, an effect that was reversed by the ONOO− scavenger, FeTPPS [5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrinato-iron(III)], which also prevented the CO inhibition of Kv11.1 currents and abolished the effects of CO on Kv11.1 tail currents and APs in guinea pig myocytes. Our data suggest that CO induces arrhythmias in guinea pig cardiac myocytes via the ONOO−-mediated inhibition of Kv11.1 K+ channels.—Al-Owais, M. M., Hettiarachchi, N. T., Kirton, H. M., Hardy, M. E., Boyle, J. P., Scragg, J. L., Steele, D. S., Peers, C. A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K+ channels in carbon monoxide–induced proarrhythmic early afterdepolarizations. PMID:28743763

The impact of early parenting bonding on young adults' internet addiction, through the mediation effects of negative relating to others and sadness.

PubMed

Kalaitzaki, Argyroula E; Birtchnell, John

2014-03-01

The aim of the present study is the investigation of the potential role of negative relating to others, perceived loneliness, sadness, and anxiety, as mediators of the association between early parental bonding and adult Internet Addiction (IA). The factorial structure of the Internet Addiction Test (IAT) and the prevalence rates of it in a Greek sample will also be investigated. A total of 774 participants were recruited from a Technological Education Institute (mean age=20.2, SD=2.8) and from high school technical schools (mean age=19.9, SD=7.4). The IAT was used to measure the degree of problematic Internet use behaviors; the Parental Bonding Instrument was used to assess one's recalled parenting experiences during the first 16years of life; the shortened Person's Relating to Others Questionnaire was used to assess one's negative (i.e. maladaptive) relating to others (NRO). Both exploratory and confirmatory factor analyses confirmed the three-factor structure of the IAT. Only 1.0% of the sample was severely addicted to the Internet. The mediated effects of only the NRO and sadness were confirmed. Negative relating to others was found to fully mediate the effect of both the father's optimal parenting and affectionless control on IA, whereas sadness was found to fully mediate the effect of the mother's optimal parenting on IA. Overall, the results suggest that parenting style has an indirect impact on IA, through the mediating role of negative relating to others or sadness in later life. Both family-based and individual-based prevention and intervention efforts may reduce the incidence of IA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Development and application of a biorelevant dissolution method using USP apparatus 4 in early phase formulation development.

PubMed

Fang, Jiang B; Robertson, Vivian K; Rawat, Archana; Flick, Tawnya; Tang, Zhe J; Cauchon, Nina S; McElvain, James S

2010-10-04

Dissolution testing is frequently used to determine the rate and extent at which a drug is released from a dosage form, and it plays many important roles throughout drug product development. However, the traditional dissolution approach often emphasizes its application in quality control testing and usually strives to obtain 100% drug release. As a result, dissolution methods are not necessarily biorelevant and meaningful application of traditional dissolution methods in the early phases of drug product development can be very limited. This article will describe the development of a biorelevant in vitro dissolution method using USP apparatus 4, biorelevant media, and real-time online UV analysis. Several case studies in the areas of formulation selection, lot-to-lot variability, and food effect will be presented to demonstrate the application of this method in early phase formulation development. This biorelevant dissolution method using USP apparatus 4 provides a valuable tool to predict certain aspects of the in vivo drug release. It can be used to facilitate the formulation development/selection for pharmacokinetic (PK) and clinical studies. It may also potentially be used to minimize the number of PK studies, and to aid in the design of more efficient PK and clinical studies.

Humoral and cell-mediated immune responses in DNA immunized mink challenged with wild-type canine distemper virus.

PubMed

Nielsen, Line; Søgaard, Mette; Karlskov-Mortensen, Peter; Jensen, Trine Hammer; Jensen, Tove Dannemann; Aasted, Bent; Blixenkrone-Møller, Merete

2009-07-30

The aim of the study was to investigate the different phases of the immune response after DNA immunization with the hemagglutinin and nucleoprotein genes from canine distemper virus (CDV). Although attenuated live CDV vaccines have effectively reduced the incidence of disease, canine distemper is still a problem worldwide. The broad host range of CDV creates a constant viral reservoir among wildlife animals. Our results demonstrated early humoral and cell-mediated immune responses (IFN-gamma) in DNA vaccinated mink compared to mock-vaccinated mink after challenge with a Danish wild-type CDV. The DNA vaccine-induced immunity protected the natural host against disease development.

Exposure to socioeconomic adversity in early life and risk of depression at 18 years: The mediating role of locus of control.

PubMed

Culpin, Iryna; Stapinski, Lexine; Miles, Ömür Budanur; Araya, Ricardo; Joinson, Carol

2015-09-01

Previous studies have linked exposure to early socioeconomic adversity to depression, but the mechanisms of this association are not well understood. Locus of control (LoC), an individual's control-related beliefs, has been implicated as a possible mechanism, however, longitudinal evidence to support this is lacking. The study sample comprised 8803 participants from a UK cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Indicators of early socioeconomic adversity were collected from the antenatal period to 5 years and modelled as a latent factor. Depression was assessed using the Clinical Interview Schedule-Revised (CIS-R) at 18 years. LoC was assessed with the Nowicki-Strickland Internal-External (CNSIE) scale at 16 years. Using structural equation modelling, we found that 34% of the total estimated association between early socioeconomic adversity and depression at 18 years was explained by external LoC at 16 years. There was weak evidence of a direct pathway from early socioeconomic adversity to depression after accounting for the indirect effect via external locus of control. Socioeconomic adversity was associated with more external LoC, which, in turn, was associated with depression. Attrition may have led to an underestimation of the direct and indirect effect sizes in the complete case analysis. Results suggest that external LoC in adolescence is one of the factors mediating the link between early adversity and depression at 18 years. Cognitive interventions that seek to modify maladaptive control beliefs in adolescence may be effective in reducing risk of depression following early life adversity. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Absent 99mTc-MIBI Uptake in the Thyroid Gland during Early Phase of Parathyroid Scintigraphy in Patients with Primary and Secondary Hyperparathyroidism.

PubMed

Jovanovska, Anamarija; Stoilovska, Bojana; Mileva, Magdalena; Miladinova, Daniela; Majstorov, Venjamin; Ugrinska, Ana

2018-05-20

Thyroid uptake of technetium-99m methoxyisobutylisonitrile ( 99m Tc-MIBI) during parathyroid scintigraphy can be affected by various conditions. To evaluate the frequency of absent 99m Tc-MIBI uptake by the thyroid gland in the early phase of dual-phase parathyroid scintigraphy. The early planar images of dual phase Tc 99m MIBI parathyroid scintigraphy from 217 patients performed between 2014 and 2017 were retrospectively analysed. Patients were divided into two groups. The first group included 147 patients with primary hyperparathyroidism and the second group included 70 patients with chronic renal failure. Patient records, laboratory and ultrasonographic data were analysed in all patients. Descriptive statistic was used for data analysis. Out of all patients in the first group, 18 patients (12.24%) showed absent thyroid uptake. Thyroidectomy was performed in 44.4% of these patients, and the rest of them had some thyroid disease. Only one patient had no thyroid or another chronic disease. In the second group, 8 patients (11.42%) presented with absent thyroid uptake of MIBI. Among them, 5 patients had no history of thyroid disease and had been on hemodialysis programme, and 3 patients had hypothyroidism. Absent 99m Tc-MIBI uptake in the thyroid during the early phase of parathyroid scintigraphy is most frequently related to thyroid disease. A small proportion of patients with chronic renal failure can present with absent 99m Tc-MIBI uptake in the thyroid as well. The mechanism for this alteration is still unclear and needs further investigation.

The association between anomalous self-experience and suicidality in first-episode schizophrenia seems mediated by depression.

PubMed

Haug, Elisabeth; Melle, Ingrid; Andreassen, Ole A; Raballo, Andrea; Bratlien, Unni; Øie, Merete; Lien, Lars; Møller, Paul

2012-07-01

A recent hypothesis is that suicidality in schizophrenia may be linked to the patients' altered basic self-awareness or sense of self, termed self-disorders (SDs). The aim of the study was to investigate whether SDs in first-episode schizophrenia spectrum disorders are related to suicidality and whether this relationship is independent of or mediated by depression or other standard clinical measures. Self-disorders were assessed in 49 patients with first-episode schizophrenia by means of the Examination of Anomalous Self-Experience (EASE) instrument. Symptoms severity and functioning were assessed using the Structured Clinical Interview for the Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Global Assessment of Functioning-Split Version. Suicidality was measured by the Calgary Depression Scale for Schizophrenia item 8. Analyses detected a significant association between current suicidality, current depression, and SDs as measured by the EASE. The effect of SDs on suicidal ideation appeared to be mediated by depression. The interaction between anomalous self-experiences and depression could be a rational clinical target for the prevention of suicidality in the early phases of schizophrenia and supports the rationale for including assessment of SDs in early intervention efforts. Copyright © 2012 Elsevier Inc. All rights reserved.

Early Intervention in Bipolar Disorder.

PubMed

Vieta, Eduard; Salagre, Estela; Grande, Iria; Carvalho, André F; Fernandes, Brisa S; Berk, Michael; Birmaher, Boris; Tohen, Mauricio; Suppes, Trisha

2018-05-01

Bipolar disorder is a recurrent disorder that affects more than 1% of the world population and usually has its onset during youth. Its chronic course is associated with high rates of morbidity and mortality, making bipolar disorder one of the main causes of disability among young and working-age people. The implementation of early intervention strategies may help to change the outcome of the illness and avert potentially irreversible harm to patients with bipolar disorder, as early phases may be more responsive to treatment and may need less aggressive therapies. Early intervention in bipolar disorder is gaining momentum. Current evidence emerging from longitudinal studies indicates that parental early-onset bipolar disorder is the most consistent risk factor for bipolar disorder. Longitudinal studies also indicate that a full-blown manic episode is often preceded by a variety of prodromal symptoms, particularly subsyndromal manic symptoms, therefore supporting the existence of an at-risk state in bipolar disorder that could be targeted through early intervention. There are also identifiable risk factors that influence the course of bipolar disorder, some of them potentially modifiable. Valid biomarkers or diagnosis tools to help clinicians identify individuals at high risk of conversion to bipolar disorder are still lacking, although there are some promising early results. Pending more solid evidence on the best treatment strategy in early phases of bipolar disorder, physicians should carefully weigh the risks and benefits of each intervention. Further studies will provide the evidence needed to finish shaping the concept of early intervention. AJP AT 175 Remembering Our Past As We Envision Our Future April 1925: Interpretations of Manic-Depressive Phases Earl Bond and G.E. Partridge reviewed a number of patients with manic-depressive illness in search of a unifying endo-psychic conflict. They concluded that understanding either phase of illness was "elusive" and

Berni Alder and Phase Transitions in Two Dimensions

NASA Astrophysics Data System (ADS)

Kosterlitz, J. Michael

I do not know Berni Alder as a person, but I feel that I know him well through his seminal paper "Phase Transition in Elastic Disks𠇍 by B. J. Alder and T. E. Wainwright [1962], which was essential in motivating David Thouless and myself to think about phase transitions in two dimensional systems with a continuous symmetry. In the early 1970's, the conventional wisdom was that a crystalline solid could not exist in a two dimensional world because of the rigorous Mermin-Wagner theorem prohibiting true long range translational order at any non-zero temperature. This contradiction was settled by the theory of dislocation mediated melting to an intermediate hexatic phase followed by a second transition to the isotropic fluid at a higher temperature. This scenario, with its associated sophisticated theory, seemed to settle the controversy of two dimensional melting once and for all. However, in our elation at understanding the fundamental physics and the essential excitations of melting in 2D, we had all forgotten that the early work of Berni Alder also showed that this melting involved a weak first order transition while theory now predicted melting by two successive continuous transitions with no discontinuity in area at the critical pressure. This discrepancy could be hand waved away by arguing that Berni's system was far too small and his computers far too slow so that the areal discontinuity could be due to finite size effects or to failing to equilibrate the system. Experiments were not able to resolve the order of the transitions, but seemed to agree quantitatively with theory…

The Interplay between Inflammation, Coagulation and Endothelial Injury in the Early Phase of Acute Pancreatitis: Clinical Implications

PubMed Central

Dumnicka, Paulina; Maduzia, Dawid; Ceranowicz, Piotr; Olszanecki, Rafał; Drożdż, Ryszard; Kuśnierz-Cabala, Beata

2017-01-01

Acute pancreatitis (AP) is an inflammatory disease with varied severity, ranging from mild local inflammation to severe systemic involvement resulting in substantial mortality. Early pathologic events in AP, both local and systemic, are associated with vascular derangements, including endothelial activation and injury, dysregulation of vasomotor tone, increased vascular permeability, increased leukocyte migration to tissues, and activation of coagulation. The purpose of the review was to summarize current evidence regarding the interplay between inflammation, coagulation and endothelial dysfunction in the early phase of AP. Practical aspects were emphasized: (1) we summarized available data on diagnostic usefulness of the markers of endothelial dysfunction and activated coagulation in early prediction of severe AP; (2) we reviewed in detail the results of experimental studies and clinical trials targeting coagulation-inflammation interactions in severe AP. Among laboratory tests, d-dimer and angiopoietin-2 measurements seem the most useful in early prediction of severe AP. Although most clinical trials evaluating anticoagulants in treatment of severe AP did not show benefits, they also did not show significantly increased bleeding risk. Promising results of human trials were published for low molecular weight heparin treatment. Several anticoagulants that proved beneficial in animal experiments are thus worth testing in patients. PMID:28208708

P-TEFb, the Super Elongation Complex and Mediator Regulate a Subset of Non-paused Genes during Early Drosophila Embryo Development

PubMed Central

Dahlberg, Olle; Shilkova, Olga; Tang, Min; Holmqvist, Per-Henrik; Mannervik, Mattias

2015-01-01

Positive Transcription Elongation Factor b (P-TEFb) is a kinase consisting of Cdk9 and Cyclin T that releases RNA Polymerase II (Pol II) into active elongation. It can assemble into a larger Super Elongation Complex (SEC) consisting of additional elongation factors. Here, we use a miRNA-based approach to knock down the maternal contribution of P-TEFb and SEC components in early Drosophila embryos. P-TEFb or SEC depletion results in loss of cells from the embryo posterior and in cellularization defects. Interestingly, the expression of many patterning genes containing promoter-proximal paused Pol II is relatively normal in P-TEFb embryos. Instead, P-TEFb and SEC are required for expression of some non-paused, rapidly transcribed genes in pre-cellular embryos, including the cellularization gene Serendipity-α. We also demonstrate that another P-TEFb regulated gene, terminus, has an essential function in embryo development. Similar morphological and gene expression phenotypes were observed upon knock down of Mediator subunits, providing in vivo evidence that P-TEFb, the SEC and Mediator collaborate in transcription control. Surprisingly, P-TEFb depletion does not affect the ratio of Pol II at the promoter versus the 3’ end, despite affecting global Pol II Ser2 phosphorylation levels. Instead, Pol II occupancy is reduced at P-TEFb down-regulated genes. We conclude that a subset of non-paused, pre-cellular genes are among the most susceptible to reduced P-TEFb, SEC and Mediator levels in Drosophila embryos. PMID:25679530

Active and separate secretion of fiber and penton base during the early phase of Ad2 or Ad5 infection

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

Yan, Yuhua; Zhang, Bo; Hou, Weihong

Fiber and penton base overproduced in adenovirus (Ad) infected cells can be secreted prior to progeny release and thereby regulate progeny spread. We aimed to investigate the mechanisms of fiber and penton base secretion in Ad2- or Ad5-infected A549 cells. Our flow cytometry analyses detected abundant surface fiber molecules, but little penton base molecules at 12 h post infection. Immunogold staining combined with transmission electron microscopic analyses revealed separate, non-co-localized release of fiber and penton base in the proximity of the plasma membrane. Depolymerization of microtubule and actin cytoskeletons, and inhibition of Rock kinase and myosin II activity together demonstratedmore » cytoskeletal network-dependent fiber secretion. Inhibition of intracellular calcium [Ca{sup 2+}]{sub i} signaling caused diminished fiber secretion, which was associated with diminished progeny production. Thus, fiber and penton base are actively and separately secreted during the early stages of Ad2 or Ad5 infection, their secretion may play important role in Ad life cycle. - Highlights: •Excessive production of structural proteins is common to viral infection, which may regulate the host-virus equilibrium and the spreading of viruses. •The adenovirus (Ad) structural proteins, fiber and penton base, are respectively important for Ad binding to its receptor and subsequent internalization in host cells. In Ad infected cells, these two structural proteins are excessively produced. •The mechanisms underlying the release of fiber and penton base molecules at the early phase of Ad infection is yet poorly understood. •Our studies show that in Ad5 or Ad2 infected A549 cells, fiber and penton base molecules are actively and separately secreted. •Fiber secretion is dependent on cytoskeleton-mediated protein traffic. •Inhibition of myosin II motor and Ca{sup 2+} signaling activity significantly diminishes fiber secretion. •These findings could contribute to our

Childhood family disruption and adult height: is there a mediating role of puberty?

PubMed Central

Sheppard, Paula; Garcia, Justin R.; Sear, Rebecca

2015-01-01

Background and objectives: Childhood family background is known to be associated with child growth and development, including the onset of puberty, but less is known about the influence of childhood family disruption on outcomes in later life. Given the associations between early family disruption and childhood development, we predicted that there may be long-term health-relevant consequences of childhood disruption. Methodology: Using data from a large US interview sample (n = 16 207), we test if death or divorce of parents, at different childhood periods, was associated with adult stature, and whether age at puberty mediated this relationship, for men and women. Results: Men: parental death and divorce during early childhood was associated with shorter adult height, and later puberty. Later puberty was associated with shorter adult height. Path analyses demonstrated that the relationship between parental divorce and height was completely mediated by age at puberty; although parental death was only partially mediated by age at puberty. Women: the father’s death during early childhood was associated with earlier puberty, which was in turn associated with shorter adult stature. The relationship between paternal death and height is entirely mediated by age at puberty; no evidence of a direct relationship between childhood family disruption and adult height. Conclusions: Early childhood familial disruption is associated with shorter height for men, and is partially mediated by later puberty. For women, the relationship between father’s death, and height was completely mediated by earlier puberty. These findings indicate that disruption during childhood can have long-reaching health repercussions, particularly for boys. PMID:26609061

Ethnic Group Differences in Early Head Start Parents Parenting Beliefs and Practices and Links to Children's Early Cognitive Development

ERIC Educational Resources Information Center

Keels, Micere

2009-01-01

Data from the Early Head Start Research and Evaluation study were used to examine the extent to which several factors mediate between- and within-ethnic-group differences in parenting beliefs and behaviors, and children's early cognitive development (analysis sample of 1198 families). The findings indicate that Hispanic-, European-, and…

Screening for Partner Violence Among Family Mediation Clients: Differentiating Types of Abuse.

PubMed

Cleak, Helen; Schofield, Margot J; Axelsen, Lauren; Bickerdike, Andrew

2018-04-01

Family mediation is mandated in Australia for couples in dispute over separation and parenting as a first step in dispute resolution, except where there is a history of intimate partner violence. However, validation of effective well-differentiated partner violence screening instruments suitable for mediation settings is at an early phase of development. This study contributes to calls for better violence screening instruments in the mediation context to detect a differentiated range of abusive behaviors by examining the reliability and validity of both established scales, and newly developed scales that measured intimate partner violence by partner and by self. The study also aimed to examine relationships between types of abuse, and between gender and types of abuse. A third aim was to examine associations between types of abuse and other relationship indicators such as acrimony and parenting alliance. The data reported here are part of a larger mixed method, naturalistic longitudinal study of clients attending nine family mediation centers in Victoria, Australia. The current analyses on baseline cross-sectional screening data confirmed the reliability of three subscales of the Conflict Tactics Scale (CTS2), and the reliability and validity of three new scales measuring intimidation, controlling and jealous behavior, and financial control. Most clients disclosed a history of at least one type of violence by partner: 95% reported psychological aggression, 72% controlling and jealous behavior, 50% financial control, and 35% physical assault. Higher rates of abuse perpetration were reported by partner versus by self, and gender differences were identified. There were strong associations between certain patterns of psychologically abusive behavior and both acrimony and parenting alliance. The implications for family mediation services and future research are discussed.

Socioeconomic status, infant feeding practices and early childhood obesity.

PubMed

Gibbs, B G; Forste, R

2014-04-01

Children from low socioeconomic households are at greater risk of obesity. As breastfeeding can protect against child obesity, disadvantaged infants are less likely to breastfeed relative to more advantaged children. Whether infant feeding patterns, as well as other maternal characteristics mediate the association between social class and obesity has not been established in available research. Examine the impact of infant feeding practices on child obesity and identify the mechanisms that link socioeconomic status (SES) with child obesity. Based on a nationally representative longitudinal survey (ECLS-B) of early childhood (n = 8030), we examine how breastfeeding practices, the early introduction of solid foods and putting an infant to bed with a bottle mediate the relationship between social class and early childhood obesity relative to the mediating influence of other maternal characteristics (BMI, age at birth, smoking, depression and daycare use). Infants predominantly fed formula for the first 6 months were about 2.5 times more likely to be obese at 24 months of age relative to infants predominantly fed breast milk. The early introduction of solid foods (< 4 months) and putting the child to bed with a bottle also increased the likelihood of obesity. Unhealthy infant feeding practices were the primary mechanism mediating the relationship between SES and early childhood obesity. Results are consistent across measures of child obesity although the effect size of infant feeding practices varies. The encouragement and support of breastfeeding and other healthy feeding practices are especially important for low socioeconomic children who are at increased risk of early childhood obesity. Targeting socioeconomically disadvantaged mothers for breastfeeding support and for infant-led feeding strategies may reduce the negative association between SES and child obesity. The implications are discussed in terms of policy and practice. © 2013 The Authors. Pediatric

Maternal sensitivity and effortful control in early childhood as predictors of adolescents' adjustment: The mediating roles of peer group affiliation and social behaviors.

PubMed

Laible, Deborah; Carlo, Gustavo; Davis, Alexandra N; Karahuta, Erin

2016-06-01

Longitudinal links between early childhood temperament, maternal sensitivity, and adolescents' adjustment have been proposed and found in several longitudinal studies, but the mechanisms of influence have not been explored. The authors examined the paths from maternal sensitivity and temperament in early childhood to adolescents' prosocial, aggressive, and delinquent behaviors via childhood social behaviors and peer group affiliation. Data at 54 months, Grade 3 (M age = 9.03, SD = .31), Grade 6 (M age = 11.95, SD = .34), and Grade 9 (M age = 15.57, SD = .78) from the NICHD SECCYD longitudinal investigation of 1,364 participants (52% boys) was analyzed. Overall, results yielded evidence that maternal sensitivity and child temperament at 54 months of age predicted prosocial, aggressive, and delinquent outcomes at age 15. Affiliation with peer groups (especially with prosocial peers) and social behaviors in childhood mediated the aforementioned paths for effortful control, but not for maternal sensitivity. Discussion focuses on the implications for understanding the long-term effects of early childhood predictors on behavioral outcomes in adolescence. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Migration as a turning point in food habits: the early phase of dietary acculturation among women from South Asian, African, and Middle Eastern Countries living in Norway.

PubMed

Terragni, Laura; Garnweidner, Lisa M; Pettersen, Kjell Sverre; Mosdøl, Annhild

2014-01-01

This article explores the early phase of dietary acculturation after migration. South Asian, African and Middle Eastern women (N = 21) living in Norway were interviewed about their early experiences with food in a new context. The findings pointed to abrupt changes in food habits in the first period after migration. To various degrees, women reported unfamiliarity with foods in shops, uncertainty about meal formats and food preparation and fear of eating food prohibited by their religion. Their food consumption tended to be restricted to food items perceived as familiar or safe. Our findings indicate that the first period after migration represents a specific phase in the process of dietary acculturation. Early initiatives aimed at enhancing confidence in food and familiarity with the new food culture are recommended.

Endosome-Associated CRT1 Functions Early in Resistance Gene–Mediated Defense Signaling in Arabidopsis and Tobacco[W

PubMed Central

Kang, Hong-Gu; Oh, Chang-Sik; Sato, Masanao; Katagiri, Fumiaki; Glazebrook, Jane; Takahashi, Hideki; Kachroo, Pradeep; Martin, Gregory B.; Klessig, Daniel F.

2010-01-01

Resistance gene–mediated immunity confers protection against pathogen infection in a wide range of plants. A genetic screen for Arabidopsis thaliana mutants compromised for recognition of turnip crinkle virus previously identified CRT1, a member of the GHKL ATPase/kinase superfamily. Here, we demonstrate that CRT1 interacts with various resistance proteins from different structural classes, and this interaction is disrupted when these resistance proteins are activated. The Arabidopsis mutant crt1-2 crh1-1, which lacks CRT1 and its closest homolog, displayed compromised resistance to avirulent Pseudomonas syringae and Hyaloperonospora arabidopsidis. Additionally, resistance-associated hypersensitive cell death was suppressed in Nicotiana benthamiana silenced for expression of CRT1 homolog(s). Thus, CRT1 appears to be a general factor for resistance gene–mediated immunity. Since elevation of cytosolic calcium triggered by avirulent P. syringae was compromised in crt1-2 crh1-1 plants, but cell death triggered by Nt MEK2DD was unaffected in CRT1-silenced N. benthamiana, CRT1 likely functions at an early step in this pathway. Genome-wide transcriptome analysis led to identification of CRT1-Associated genes, many of which are associated with transport processes, responses to (a)biotic stress, and the endomembrane system. Confocal microscopy and subcellular fractionation revealed that CRT1 localizes to endosome-like vesicles, suggesting a key process in resistance protein activation/signaling occurs in this subcellular compartment. PMID:20332379

Parenting Stress as a Mediator Between Childhood ADHD and Early Adult Female Outcomes.

PubMed

Gordon, Chanelle T; Hinshaw, Stephen P

2017-01-01

The purpose of this study is to examine the mediating role of parenting stress (both parental distress and stress due to dysfunctional interactions in the mother-daughter relationship [PSDI]) in the link between childhood attention-deficit/hyperactivity disorder (ADHD) status and several important young adult outcomes. The diverse sample comprised 140 girls with ADHD and 88 age- and ethnicity-matched comparisons, evaluated at ages 6-12 years and followed prospectively for five years (M age = 14.2) and 10 years (M age = 19.6). The PSDI experienced by a mother during her daughter's adolescence mediated the link between her daughter's childhood ADHD status and adult externalizing and internalizing symptoms. PSDI also mediated the link between ADHD status and young adult nonsuicidal self-injury and had an indirect effect in the relation between childhood ADHD and young adult depressive symptoms. The mediating role of PSDI with respect to internalizing symptoms and depressive symptoms remained in place even when covarying adolescent internalizing/depressive symptoms. Parenting stress, particularly related to maternal perceptions of dysfunctional interactions with adolescent daughters, serves as a key mediator in the association between childhood ADHD status and important domains of young adult functioning. Minimizing parenting stress and dysfunctional mother-daughter interactions during adolescence might reduce the risk of adverse adult outcomes for girls with ADHD.

Maladaptive Schemas as Mediators in the Relationship Between Child Sexual Abuse and Displaced Aggression.

PubMed

Estévez, Ana; Ozerinjauregi, Nagore; Herrero-Fernández, David

2016-01-01

Child sexual abuse is one of the most serious forms of abuse due to the psychological consequences that persist even into adulthood. Expressions of anger among child sexual abuse survivors remain common even years after the event. While child sexual abuse has been extensively studied, the expression of displaced aggression has been studied less. Some factors, such as the maladaptive early schemas, might account for this deficiency. The objective of this study was to analyze the relationships between child sexual abuse, displaced aggression, and these schemas according to gender and determine if these early schemas mediate the relationship between child sexual abuse and displaced aggression. A total of 168 Spanish subjects who were victims of child sexual abuse completed measures of childhood trauma, displaced aggression, and early maladaptive schemas. The results depict the relationship between child sexual abuse, displaced aggression, and early maladaptive schemas. Women scored higher than men in child sexual abuse, emotional abuse, disconnection or rejection and impaired autonomy. Mediational analysis found a significant mediation effect of disconnection or rejection on the relationship between child sexual abuse and displaced aggression; however, impaired autonomy did not mediate significantly.

The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition.

PubMed

Kino, T; Rice, K C; Chrousos, G P

2007-05-01

Interleukin-6 and downstream liver effectors acute phase reactants are implicated in the systemic inflammatory reaction. Peroxisome proliferator-activated receptor delta (PPARdelta), which binds to and is activated by a variety of fatty acids, was recently shown to have anti-inflammatory actions. We examined the ability of the synthetic PPARdelta agonist GW501516 to suppress interleukin-6-induced expression of acute phase proteins in human hepatoma HepG2 cells and rat primary hepatocytes. Results GW501516 dose-dependently suppressed interleukin-6-induced mRNA expression of the acute phase protein alpha1-antichymotrypsin in HepG2 cells. The compound also suppressed interleukin-6-induced mRNA expression of alpha2-acid glycoprotein, beta-fibrinogen and alpha2-macroglobulin in and the secretion of C-reactive protein by rat primary hepatocytes. Depletion of the PPARdelta receptor, but not of PPARalpha or gamma, attenuated the suppressive effect of GW501516 on interleukin-6-induced alpha1-antichymotrypsin mRNA expression, indicating that PPARdelta specifically mediated this effect. Since interleukin-6 stimulates the transcriptional activity of the alpha1-antichymotrypsin promoter by activating the signal transducer and activator of transcription (STAT) 3, we examined functional interaction of this transcription factor and PPARdelta on this promoter. Overexpression of PPARdelta enhanced the suppressive effect of GW501516 on STAT3-activated transcriptional activity of the alpha1-antichymotrypsin promoter, while GW501516 suppressed interleukin-6-induced binding of this transcription factor to this promoter. These findings indicate that agonist-activated PPARdelta interferes with interleukin-6-induced acute phase reaction in the liver by inhibiting the transcriptional activity of STAT3. PPARdelta agonists might be useful for the suppression of systemic inflammatory reactions in which IL-6 plays a central role.

2,3-diphosphoglycerate, nucleotide phosophate, and organic and inorganic phosphate levels during the early phases of diabetic ketoacidosis.

PubMed

Kanter, Y; Gerson, J R; Bessman, A N

1977-05-01

The relation between serum and red blood cell (RBC) inorganic phosphate levels, RBC 2,3-diphosphoglycerate (2,3-DPG) levels, RBC nucleotide phosphate (Pn), and RBC total phosphate (Pt) levels were studied during the early phases of treatment and recovery from diabetic ketoacidosis (DKA). A steady drop in serum inorganic phosphate was found during the first 24 hours of insulin treatment and was most profound at 24 hours. No statistically significant changes (P less than 0.05) were found in red cell inorganic phosphate or nucleotide phosphate levels during the 24-hour study period. The levels of total red cell phosphate were lower in this group of patients than in nonacidotic diabetic subjects and decreased slightly after 24 hours of treatment. The red cell 2,3-DPG levels were low at the initiation of therapy and remained low during the 24-hour study period. Glucose, bicarbonate, lactate, and ketone levels fell in linear patterns with treatment. In view of the current evidence for the effects of low 2,3-DPG on oxygen delivery and the relation of low serum phosphate levels to RBC glycolysis and 2,3-DPG formation, this study reemphasizes the need for phosphate replacement during the early phases of treatment of DKA.

Dietary Soy Supplement on Fibromyalgia Symptoms: A Randomized, Double-Blind, Placebo-Controlled, Early Phase Trial

PubMed Central

Wahner-Roedler, Dietlind L.; Thompson, Jeffrey M.; Luedtke, Connie A.; King, Susan M.; Cha, Stephen S.; Elkin, Peter L.; Bruce, Barbara K.; Townsend, Cynthia O.; Bergeson, Jody R.; Eickhoff, Andrea L.; Loehrer, Laura L.; Sood, Amit; Bauer, Brent A.

2011-01-01

Most patients with fibromyalgia use complementary and alternative medicine (CAM). Properly designed controlled trials are necessary to assess the effectiveness of these practices. This study was a randomized, double-blind, placebo-controlled, early phase trial. Fifty patients seen at a fibromyalgia outpatient treatment program were randomly assigned to a daily soy or placebo (casein) shake. Outcome measures were scores of the Fibromyalgia Impact Questionnaire (FIQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and after 6 weeks of intervention. Analysis was with standard statistics based on the null hypothesis, and separation test for early phase CAM comparative trials. Twenty-eight patients completed the study. Use of standard statistics with intent-to-treat analysis showed that total FIQ scores decreased by 14% in the soy group (P = .02) and by 18% in the placebo group (P < .001). The difference in change in scores between the groups was not significant (P = .16). With the same analysis, CES-D scores decreased in the soy group by 16% (P = .004) and in the placebo group by 15% (P = .05). The change in scores was similar in the groups (P = .83). Results of statistical analysis using the separation test and intent-to-treat analysis revealed no benefit of soy compared with placebo. Shakes that contain soy and shakes that contain casein, when combined with a multidisciplinary fibromyalgia treatment program, provide a decrease in fibromyalgia symptoms. Separation between the effects of soy and casein (control) shakes did not favor the intervention. Therefore, large-sample studies using soy for patients with fibromyalgia are probably not indicated. PMID:18990724

Long-term potentiation decay and memory loss are mediated by AMPAR endocytosis.

PubMed

Dong, Zhifang; Han, Huili; Li, Hongjie; Bai, Yanrui; Wang, Wei; Tu, Man; Peng, Yan; Zhou, Limin; He, Wenting; Wu, Xiaobin; Tan, Tao; Liu, Mingjing; Wu, Xiaoyan; Zhou, Weihui; Jin, Wuyang; Zhang, Shu; Sacktor, Todd Charlton; Li, Tingyu; Song, Weihong; Wang, Yu Tian

2015-01-01

Long-term potentiation (LTP) of synaptic strength between hippocampal neurons is associated with learning and memory, and LTP dysfunction is thought to underlie memory loss. LTP can be temporally and mechanistically classified into decaying (early-phase) LTP and nondecaying (late-phase) LTP. While the nondecaying nature of LTP is thought to depend on protein synthesis and contribute to memory maintenance, little is known about the mechanisms and roles of decaying LTP. Here, we demonstrated that inhibiting endocytosis of postsynaptic α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid receptors (AMPARs) prevents LTP decay, thereby converting it into nondecaying LTP. Conversely, restoration of AMPAR endocytosis by inhibiting protein kinase Mζ (PKMζ) converted nondecaying LTP into decaying LTP. Similarly, inhibition of AMPAR endocytosis prolonged memory retention in normal animals and reduced memory loss in a murine model of Alzheimer's disease. These results strongly suggest that an active process that involves AMPAR endocytosis mediates the decay of LTP and that inhibition of this process can prolong the longevity of LTP as well as memory under both physiological and pathological conditions.

Recombinant luteinizing hormone priming in early follicular phase for women undergoing in vitro fertilization: systematic review and meta-analysis.

PubMed

Hu, Linli; Bu, Zhiqin; Wang, Keyan; Sun, Yingpu

2014-04-01

To investigate the effect of recombinant human luteinizing hormone supplementation (rLH priming) during the early follicular phase on in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) outcomes. In order to evaluate available evidence regarding the efficacy of rLH priming in IVF/ICSI procedures, a systematic review and meta-analysis was preformed. Searches were conducted on MEDLINE®, EMBASE and the Cochrane Database of Clinical Trials without language limitation, but were restricted to randomized controlled trials (RCTs). Three RCTs including 346 patients were included in this meta-analysis, which demonstrated that rLH priming did not increase ongoing pregnancy rate. Although less recombinant follicle-stimulating hormone (rFSH) was required and the oestradiol level was higher on the day of human chorionic gonadotropin administration in the rLH priming group, the numbers of oocytes retrieved and embryos produced were comparable between patients treated with rLH priming and those treated with rFSH alone. This systematic review and meta-analysis has demonstrated that at present there is insufficient evidence that patients undergoing IVF/ICSI may benefit from rLH priming during the early follicular phase.

Childhood family disruption and adult height: is there a mediating role of puberty?

PubMed

Sheppard, Paula; Garcia, Justin R; Sear, Rebecca

2015-11-24

Childhood family background is known to be associated with child growth and development, including the onset of puberty, but less is known about the influence of childhood family disruption on outcomes in later life. Given the associations between early family disruption and childhood development, we predicted that there may be long-term health-relevant consequences of childhood disruption. Using data from a large US interview sample (n = 16 207), we test if death or divorce of parents, at different childhood periods, was associated with adult stature, and whether age at puberty mediated this relationship, for men and women. RESULTS MEN: : parental death and divorce during early childhood was associated with shorter adult height, and later puberty. Later puberty was associated with shorter adult height. Path analyses demonstrated that the relationship between parental divorce and height was completely mediated by age at puberty; although parental death was only partially mediated by age at puberty. WOMEN: the father's death during early childhood was associated with earlier puberty, which was in turn associated with shorter adult stature. The relationship between paternal death and height is entirely mediated by age at puberty; no evidence of a direct relationship between childhood family disruption and adult height. Early childhood familial disruption is associated with shorter height for men, and is partially mediated by later puberty. For women, the relationship between father's death, and height was completely mediated by earlier puberty. These findings indicate that disruption during childhood can have long-reaching health repercussions, particularly for boys. © The Author(s) 2015. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.

Early intervention for psychosis

PubMed Central

Marshall, Max; Rathbone, John

2014-01-01

Background Proponents of early intervention have argued that outcomes might be improved if more therapeutic efforts were focused on the early stages of schizophrenia or on people with prodromal symptoms. Early intervention in schizophrenia has two elements that are distinct from standard care: early detection, and phase-specific treatment (phase-specific treatment is a psychological, social or physical treatment developed, or modified, specifically for use with people at an early stage of the illness). Early detection and phase-specific treatment may both be offered as supplements to standard care, or may be provided through a specialised early intervention team. Early intervention is now well established as a therapeutic approach in America, Europe and Australasia. Objectives To evaluate the effects of: (a) early detection; (b) phase-specific treatments; and (c) specialised early intervention teams in the treatment of people with prodromal symptoms or first-episode psychosis. Search methods We searched the Cochrane Schizophrenia Group Trials Register (March 2009), inspected reference lists of all identified trials and reviews and contacted experts in the field. Selection criteria We included all randomised controlled trials (RCTs) designed to prevent progression to psychosis in people showing prodromal symptoms, or to improve outcome for people with first-episode psychosis. Eligible interventions, alone and in combination, included: early detection, phase-specific treatments, and care from specialised early intervention teams. We accepted cluster-randomised trials but excluded non-randomised trials. Data collection and analysis We reliably selected studies, quality rated them and extracted data. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis (ITT). Main results Studies were diverse, mostly small

RNA transcription modulates phase transition-driven nuclear body assembly

PubMed Central

Berry, Joel; Weber, Stephanie C.; Vaidya, Nilesh; Haataja, Mikko; Brangwynne, Clifford P.

2015-01-01

Nuclear bodies are RNA and protein-rich, membraneless organelles that play important roles in gene regulation. The largest and most well-known nuclear body is the nucleolus, an organelle whose primary function in ribosome biogenesis makes it key for cell growth and size homeostasis. The nucleolus and other nuclear bodies behave like liquid-phase droplets and appear to condense from the nucleoplasm by concentration-dependent phase separation. However, nucleoli actively consume chemical energy, and it is unclear how such nonequilibrium activity might impact classical liquid–liquid phase separation. Here, we combine in vivo and in vitro experiments with theory and simulation to characterize the assembly and disassembly dynamics of nucleoli in early Caenorhabditis elegans embryos. In addition to classical nucleoli that assemble at the transcriptionally active nucleolar organizing regions, we observe dozens of “extranucleolar droplets” (ENDs) that condense in the nucleoplasm in a transcription-independent manner. We show that growth of nucleoli and ENDs is consistent with a first-order phase transition in which late-stage coarsening dynamics are mediated by Brownian coalescence and, to a lesser degree, Ostwald ripening. By manipulating C. elegans cell size, we change nucleolar component concentration and confirm several key model predictions. Our results show that rRNA transcription and other nonequilibrium biological activity can modulate the effective thermodynamic parameters governing nucleolar and END assembly, but do not appear to fundamentally alter the passive phase separation mechanism. PMID:26351690

Early-life adversity-induced long-term epigenetic programming associated with early onset of chronic physical aggression: Studies in humans and animals.

PubMed

Chistiakov, Dimitry A; Chekhonin, Vladimir P

2017-06-05

To examine whether chronic physical aggression (CPA) in adulthood can be epigenetically programmed early in life due to exposure to early-life adversity. Literature search of public databases such as PubMed/MEDLINE and Scopus. Children/adolescents susceptible for CPA and exposed to early-life abuse fail to efficiently cope with stress that in turn results in the development of CPA later in life. This phenomenon was observed in humans and animal models of aggression. The susceptibility to aggression is a complex trait that is regulated by the interaction between environmental and genetic factors. Epigenetic mechanisms mediate this interaction. Subjects exposed to stress early in life exhibited long-term epigenetic programming that can influence their behaviour in adulthood. This programming affects expression of many genes not only in the brain but also in other systems such as neuroendocrine and immune. The propensity to adult CPA behaviour in subjects experienced to early-life adversity is mediated by epigenetic programming that involves long-term systemic epigenetic alterations in a whole genome.

TRAVELLERS: a school-based early intervention programme helping young people manage and process change, loss and transition. Pilot phase findings.

PubMed

Dickinson, Pauline; Coggan, Carolyn; Bennett, Sara

2003-06-01

This paper outlines the conceptual background and findings from the pilot phase of TRAVELLERS--an early intervention programme designed to enhance protective factors for young people experiencing change, loss and transition events and early signs of emotional distress. The pilot study aimed to determine whether TRAVELLERS was a feasible, acceptable and promising intervention for young people within secondary schools in Aotearoa/New Zealand. The conceptual origins of the TRAVELLERS programme are described in terms of: adolescent mental health concerns; emerging mental health promotion theory and practice; and prevention and early intervention models. The key elements of the TRAVELLERS programme are described. The programme was piloted in two secondary schools, one rural and one urban with 34 participants (females n = 24, males n = 10). Evaluation methods included: review of programme materials; identification of potential selection tools appropriate to Year 9 students; analysis of selection questionnaire; and conduct of feedback from participants, facilitators and parents/caregivers. The TRAVELLERS programme provides a means of identifying and selecting young people who may benefit from participating in an early intervention programme. The programme has achieved a statistically significant reduction in participants' distress (p < 0.01). Young people were overwhelmingly enthusiastic about most aspects of TRAVELLERS. School personnel reported that TRAVELLERS was an appropriate and acceptable programme to the school. Targeted interventions provided within a supportive school environment can contribute to enhancing protective factors such as personal and interpersonal coping strategies, increased help-seeking behaviour, and young people feeling more positive about themselves and their lives. The pilot programme has been amended and prepared for a two year trial phase in 10 secondary schools during 2002-2003.

Early-Time Solution of the Horizontal Unconfined Aquifer in the Buildup Phase

NASA Astrophysics Data System (ADS)

Gravanis, Elias; Akylas, Evangelos

2017-10-01

We derive the early-time solution of the Boussinesq equation for the horizontal unconfined aquifer in the buildup phase under constant recharge and zero inflow. The solution is expressed as a power series of a suitable similarity variable, which is constructed so that to satisfy the boundary conditions at both ends of the aquifer, that is, it is a polynomial approximation of the exact solution. The series turns out to be asymptotic and it is regularized by resummation techniques that are used to define divergent series. The outflow rate in this regime is linear in time, and the (dimensionless) coefficient is calculated to eight significant figures. The local error of the series is quantified by its deviation from satisfying the self-similar Boussinesq equation at every point. The local error turns out to be everywhere positive, hence, so is the integrated error, which in turn quantifies the degree of convergence of the series to the exact solution.

Role of phase instabilities in the early response of bulk fused silica during laser-induced breakdown

NASA Astrophysics Data System (ADS)

Demange, P.; Negres, R. A.; Raman, R. N.; Colvin, J. D.; Demos, S. G.

2011-08-01

We report on the experimental and hydrocode modeling investigation of the early material response to localized energy deposition via nanosecond laser pulses in bulk fused silica. A time-resolved microscope system was used to acquire transient images with adequate spatial and temporal resolution to resolve the material behavior from the onset of the process. These images revealed a high-pressure shock front propagating at twice the speed of sound at ambient conditions and bounding a region of modified material at delays up to one nanosecond. Hydrocode simulations matching the experimental conditions were also performed and indicated initial pressures of ˜40 GPa and temperatures of ˜1 eV at the absorption region. Both the simulations and the image data show a clear boundary between distinct material phases, a hot plasma and solid silica, with a suggestion that growth of perturbations at the Rayleigh-Taylor unstable interface between the two phases is the seed mechanism for the growth of cracks into the stressed solid.

Modulated phase matching and high-order harmonic enhancement mediated by the carrier-envelope phase

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

Faccio, Daniele; CNISM and Department of Physics and Mathematics, Universita dell'Insubria, Via Valleggio 11, I-22100 Como; Serrat, Carles

2010-01-15

The process of high-order harmonic generation in gases is numerically investigated in the presence of a few-cycle pulsed-Bessel-beam pump, featuring a periodic modulation in the peak intensity due to large carrier-envelope-phase mismatch. A two-decade enhancement in the conversion efficiency is observed and interpreted as the consequence of a mechanism known as a nonlinearly induced modulation in the phase mismatch.

Revealing Early Steps of α2β1 Integrin-mediated Adhesion to Collagen Type I by Using Single-Cell Force Spectroscopy

PubMed Central

Taubenberger, Anna; Cisneros, David A.; Friedrichs, Jens; Puech, Pierre-Henri; Muller, Daniel J.

2007-01-01

We have characterized early steps of α2β1 integrin-mediated cell adhesion to a collagen type I matrix by using single-cell force spectroscopy. In agreement with the role of α2β1 as a collagen type I receptor, α2β1-expressing Chinese hamster ovary (CHO)-A2 cells spread rapidly on the matrix, whereas α2β1-negative CHO wild-type cells adhered poorly. Probing CHO-A2 cell detachment forces over a contact time range of 600 s revealed a nonlinear adhesion response. During the first 60 s, cell adhesion increased slowly, and forces associated with the smallest rupture events were consistent with the breakage of individual integrin–collagen bonds. Above 60 s, a fraction of cells rapidly switched into an activated adhesion state marked by up to 10-fold increased detachment forces. Elevated overall cell adhesion coincided with a rise of the smallest rupture forces above the value required to break a single-integrin–collagen bond, suggesting a change from single to cooperative receptor binding. Transition into the activated adhesion mode and the increase of the smallest rupture forces were both blocked by inhibitors of actomyosin contractility. We therefore propose a two-step mechanism for the establishment of α2β1-mediated adhesion as weak initial, single-integrin–mediated binding events are superseded by strong adhesive interactions involving receptor cooperativity and actomyosin contractility. PMID:17314408

ASSOCIATION BETWEEN VISUAL FUNCTION AND SUBRETINAL DRUSENOID DEPOSITS IN NORMAL AND EARLY AGE-RELATED MACULAR DEGENERATION EYES.

PubMed

Neely, David; Zarubina, Anna V; Clark, Mark E; Huisingh, Carrie E; Jackson, Gregory R; Zhang, Yuhua; McGwin, Gerald; Curcio, Christine A; Owsley, Cynthia

2017-07-01

To examine the association between subretinal drusenoid deposits (SDDs) identified by multimodal retinal imaging and visual function in older eyes with normal macular health or in the earliest phases of age-related macular degeneration (AMD). Age-related macular degeneration status for each eye was defined according to the Age-Related Eye Disease Study (AREDS) 9-step classification system (normal = Step 1, early AMD = Steps 2-4) based on color fundus photographs. Visual functions measured were best-corrected photopic visual acuity, contrast and light sensitivity, mesopic visual acuity, low-luminance deficit, and rod-mediated dark adaptation. Subretinal drusenoid deposits were identified through multimodal imaging (color fundus photographs, infrared reflectance and fundus autofluorescence images, and spectral domain optical coherence tomography). The sample included 1,202 eyes (958 eyes with normal health and 244 eyes with early AMD). In normal eyes, SDDs were not associated with any visual function evaluated. In eyes with early AMD, dark adaptation was markedly delayed in eyes with SDDs versus no SDD (a 4-minute delay on average), P = 0.0213. However, this association diminished after age adjustment, P = 0.2645. Other visual functions in early AMD eyes were not associated with SDDs. In a study specifically focused on eyes in normal macular health and in the earliest phases of AMD, early AMD eyes with SDDs have slower dark adaptation, largely attributable to the older ages of eyes with SDD; they did not exhibit deficits in other visual functions. Subretinal drusenoid deposits in older eyes in normal macular health are not associated with any visual functions evaluated.

A novel fully-humanised 3D skin equivalent to model early melanoma invasion

PubMed Central

Hill, David S; Robinson, Neil D P; Caley, Matthew P; Chen, Mei; O’Toole, Edel A; Armstrong, Jane L; Przyborski, Stefan; Lovat, Penny E

2015-01-01

Metastatic melanoma remains incurable, emphasising the acute need for improved research models to investigate the underlying biological mechanisms mediating tumour invasion and metastasis, and to develop more effective targeted therapies to improve clinical outcome. Available animal models of melanoma do not accurately reflect human disease and current in vitro human skin equivalent models incorporating melanoma cells are not fully representative of the human skin microenvironment. We have developed a robust and reproducible, fully-humanised 3D skin equivalent comprising a stratified, terminally differentiated epidermis and a dermal compartment consisting of fibroblast-generated extracellular matrix. Melanoma cells incorporated into the epidermis were able to invade through the basement membrane and into the dermis, mirroring early tumour invasion in vivo. Comparison of our novel 3D melanoma skin equivalent with melanoma in situ and metastatic melanoma indicates this model accurately recreates features of disease pathology, making it a physiologically representative model of early radial and vertical growth phase melanoma invasion. PMID:26330548

[Semiquantitative measurement of progesterone receptors in luteal-phase-defect endometrial cells during secretory phase].

PubMed

Ma, Q; Han, Z; Huang, W

1998-03-01

To investigate the changes of endometrial progesterone receptor (PR) of luteal-phase-defect (LPD) patients during the secretory phase, thirteen patients with complaints of infertility or habitual abortion were studied. During the early-mid secretory phase, endometrial tissue was obtained by dilatation and curettage (D & C) for histological and receptor study: meanwhile serum E2, P, FSH, LH and PRL were measured. Based on histologic diagnosis, the patients were divided into two groups: the LPD group (n = 7) and the normal control group(n = 6). PR content was determined by immunohisto-chemical (IHC) assay. The results showed that during the early-mid luteal phase a significantly low PR content on endometrial glandular nucleus was observed in LPD group, compared with normal control(6.75 +/- 2.57 vs 9.50 +/- 1.64 P < 0.05), but no difference in serum progesterone was noted between the two groups. These findings suggest that during early-mid secretory phase, PR content on endometrial glandular nucleus decreases in LPD cases, which results in deficient response of endometrium to proper stimulus of progesterone. This change may cause endometrial secretory deficiency and blockade of embreyo implantation. That is why infertility or habitual abortion happened.

Cross-border marriage and disparities in early childhood development in a population-based birth cohort study: the mediation of the home environment.

PubMed

Wu, J C-L; Bradley, R H; Chiang, T-L

2012-07-01

Taiwan has experienced a large influx of cross-border marriage migrants in recent years. The majority have been women in their childbearing ages and have come from countries with lower average standards of living than Taiwan. This trend has changed the ethnic composition of children who live in Taiwan, and it has generated considerable social concern over the future health status of Taiwan's citizens. This study aimed to examine: (1) whether there are disparities in development between children reared in families characterized by cross-border marriages and children reared in families with two Taiwanese-born parents; and (2) whether the quality of home environment explains the group differences in early childhood development. Data came from the Taiwan Birth Cohort Study. A total of 19,499 participants who completed 6-month, 18-month and 3-year surveys were included for analysis. Cross-border marriage status was defined by mother's original nationality and categorized into three broad groups: Taiwanese-born, Chinese cross-border and South-East Asian (SEA) cross-border. Early childhood development was measured at age 3 years, and covered the domains of gross motor, fine motor, language and socio-emotional competence. Hierarchical linear regressions were used to examine the mediation effects of the home environment. Children of Chinese and SEA cross-border groups scored lower in fine motor, language and socio-emotional competence than those of their Taiwanese-born counterpart at age 3 years. Chinese-Taiwanese group differences in all three developmental domains became insignificant after the addition of home environment, while SEA-Taiwanese group differences in fine motor and language development remained, yet were noticeably reduced. The mediation of home environment was further confirmed using the Sobel test. Home environment plays a central role in reducing the disparities in developmental outcomes among children of different marriage groups. Interventions should be

Feeding Behavior Modulates Biofilm-Mediated Transmission of Yersinia pestis by the Cat Flea, Ctenocephalides felis

PubMed Central

Bland, David M.; Hinnebusch, B. Joseph

2016-01-01

Background The cat flea, Ctenocephalides felis, is prevalent worldwide, will parasitize animal reservoirs of plague, and is associated with human habitations in known plague foci. Despite its pervasiveness, limited information is available about the cat flea’s competence as a vector for Yersinia pestis. It is generally considered to be a poor vector, based on studies examining early-phase transmission during the first week after infection, but transmission potential by the biofilm-dependent proventricular-blocking mechanism has never been systematically evaluated. In this study, we assessed the vector competence of cat fleas by both mechanisms. Because the feeding behavior of cat fleas differs markedly from important rat flea vectors, we also examined the influence of feeding behavior on transmission dynamics. Methodology/Principal Findings Groups of cat fleas were infected with Y. pestis and subsequently provided access to sterile blood meals twice-weekly, 5 times per week, or daily for 4 weeks and monitored for infection, the development of proventricular biofilm and blockage, mortality, and the ability to transmit. In cat fleas allowed prolonged, daily access to blood meals, mimicking their natural feeding behavior, Y. pestis did not efficiently colonize the digestive tract and could only be transmitted during the first week after infection. In contrast, cat fleas that were fed intermittently, mimicking the feeding behavior of the efficient vector Xenopsylla cheopis, could become blocked and regularly transmitted Y. pestis for 3–4 weeks by the biofilm-mediated mechanism, but early-phase transmission was not detected. Conclusions The normal feeding behavior of C. felis, more than an intrinsic resistance to infection or blockage by Y. pestis, limits its vector competence. Rapid turnover of midgut contents results in bacterial clearance and disruption of biofilm accumulation in the proventriculus. Anatomical features of the cat flea foregut may also restrict

Feeding Behavior Modulates Biofilm-Mediated Transmission of Yersinia pestis by the Cat Flea, Ctenocephalides felis.

PubMed

Bland, David M; Hinnebusch, B Joseph

2016-02-01

The cat flea, Ctenocephalides felis, is prevalent worldwide, will parasitize animal reservoirs of plague, and is associated with human habitations in known plague foci. Despite its pervasiveness, limited information is available about the cat flea's competence as a vector for Yersinia pestis. It is generally considered to be a poor vector, based on studies examining early-phase transmission during the first week after infection, but transmission potential by the biofilm-dependent proventricular-blocking mechanism has never been systematically evaluated. In this study, we assessed the vector competence of cat fleas by both mechanisms. Because the feeding behavior of cat fleas differs markedly from important rat flea vectors, we also examined the influence of feeding behavior on transmission dynamics. Groups of cat fleas were infected with Y. pestis and subsequently provided access to sterile blood meals twice-weekly, 5 times per week, or daily for 4 weeks and monitored for infection, the development of proventricular biofilm and blockage, mortality, and the ability to transmit. In cat fleas allowed prolonged, daily access to blood meals, mimicking their natural feeding behavior, Y. pestis did not efficiently colonize the digestive tract and could only be transmitted during the first week after infection. In contrast, cat fleas that were fed intermittently, mimicking the feeding behavior of the efficient vector Xenopsylla cheopis, could become blocked and regularly transmitted Y. pestis for 3-4 weeks by the biofilm-mediated mechanism, but early-phase transmission was not detected. The normal feeding behavior of C. felis, more than an intrinsic resistance to infection or blockage by Y. pestis, limits its vector competence. Rapid turnover of midgut contents results in bacterial clearance and disruption of biofilm accumulation in the proventriculus. Anatomical features of the cat flea foregut may also restrict transmission by both early-phase and proventricular biofilm

Expectations of Benefit in Early-Phase Clinical Trials: Implications for Assessing the Adequacy of Informed Consent

PubMed Central

Weinfurt, Kevin P.; Seils, Damon M.; Tzeng, Janice P.; Compton, Kate L.; Sulmasy, Daniel P.; Astrow, Alan B.; Solarino, Nicholas A.; Schulman, Kevin A.; Meropol, Neal J.

2009-01-01

Background Participants in early-phase clinical trials have reported high expectations of benefit from their participation. There is concern that participants misunderstand the trials to which they have consented. Such concern is based on assumptions about what patients mean when they respond to questions about likelihood of benefit. Methods Participants were 27 women and 18 men in early-phase oncology trials at 2 academic medical centers in the United States. To determine whether expectations of benefit differ depending on how patients are queried, we randomly assigned participants to 1 of 3 interviews corresponding to 3 questions about likelihood of benefit: frequency-type, belief-type, and vague. In semistructured interviews, we queried participants about how they understood and answered the question. Participants then answered and discussed one of the other questions. Results Expectations of benefit in response to the belief-type question were significantly greater than expectations in response to the frequency-type and vague questions (P = .02). The most common justifications involved positive attitude (n = 27 [60%]) and references to physical health (n = 23 [51%]). References to positive attitude were most common among participants with higher (> 70%) expectations (n = 11 [85%]) and least common among those with lower (< 50%) expectations (n = 3 [27%]). Conclusions The wording of questions about likelihood of benefit shapes the expectations that patients express. Also, patients who express high expectations may not do so to communicate understanding, but rather to register optimism. Ongoing research will clarify the meaning of high expectations and examine methods for assessing understanding in this context. PMID:18378940

A qualitative study evaluating causality attribution for serious adverse events during early phase oncology clinical trials.

PubMed

Mukherjee, Som D; Coombes, Megan E; Levine, Mitch; Cosby, Jarold; Kowaleski, Brenda; Arnold, Andrew

2011-10-01

In early phase oncology trials, novel targeted therapies are increasingly being tested in combination with traditional agents creating greater potential for enhanced and new toxicities. When a patient experiences a serious adverse event (SAE), investigators must determine whether the event is attributable to the investigational drug or not. This study seeks to understand the clinical reasoning, tools used and challenges faced by the researchers who assign causality to SAE's. Thirty-two semi-structured interviews were conducted with medical oncologists and trial coordinators at six Canadian academic cancer centres. Interviews were recorded and transcribed verbatim. Individual interview content analysis was followed by thematic analysis across the interview set. Our study found that causality assessment tends to be a rather complex process, often without complete clinical and investigational data at hand. Researchers described using a common processing strategy whereby they gather pertinent information, eliminate alternative explanations, and consider whether or not the study drug resulted in the SAE. Many of the interviewed participants voiced concern that causality assessments are often conducted quickly and tend to be highly subjective. Many participants were unable to identify any useful tools to help in assigning causality and welcomed more objectivity in the overall process. Attributing causality to SAE's is a complex process. Clinical trial researchers apply a logical system of reasoning, but feel that the current method of assigning causality could be improved. Based on these findings, future research involving the development of a new causality assessment tool specifically for use in early phase oncology clinical trials may be useful.

Concanavalin A-mediated polyclonal helper assay of normal thymocytes and its use for the analysis of ontogeny.

PubMed

Kina, T; Nishikawa, S; Amagai, T; Katsura, Y

1987-01-01

A concanavalin A (Con A)-mediated polyclonal helper assay system was established by using the thymus cells or splenic T cells as a source of helper T cells. When splenic B cells were cocultured with thymus cells or splenic Lyt-2- T cells in the presence of an optimal dose of Con A, B Cells were polyclonally activated and differentiated into immunoglobulin-secreting cells. This Con A-mediated helper activity was completely inhibited by the addition of alpha-methyl-D-mannoside and could not be substituted by culture supernatant of Con A-stimulated thymocytes or splenic T cells. Almost all the activity of the thymus cells was carried by peanut agglutinin low binding population. Genetic restriction between T and B cells was not observed in this helper function. In ontogeny, Con A-mediated helper activity in the thymus was first detected at a few days after birth and reached the adult level at about 1 week of age. The polyclonal helper assay system developed in the present study provides a sensitive system to analyse the helper function of thymus cells and also to delineate the early phase of the differentiation of helper T cell population.

Endogenous anti-inflammatory neuropeptides and pro-resolving lipid mediators: a new therapeutic approach for immune disorders

PubMed Central

Anderson, Per; Delgado, Mario

2008-01-01

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of inflammatory and autoimmune diseases. Although much is known about the molecular basis of initiating signals and pro-inflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation. Some neuropeptides and lipid mediators that are produced during the ongoing inflammatory response have emerged as endogenous anti-inflammatory agents that participate in the regulation of the processes that ensure self-tolerance and/or inflammation resolution. Here we examine the latest research findings, which indicate that neuropeptides participate in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T-cell effectors. On the other hand, we also focus on lipid mediators biosynthesized from ω-3 and ω-6 polyunsaturated fatty-acids in inflammatory exudates that promote the resolution phase of acute inflammation by regulating leucocyte influx to and efflux from local inflamed sites. Both anti-inflammatory neuropeptides and pro-resolving lipid mediators have shown therapeutic potential for a variety of inflammatory and autoimmune disorders and could be used as biotemplates for the development of novel pharmacologic agents. PMID:18554314

Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding1234

PubMed Central

Ziemke, Florencia; Magkos, Faidon; Barrios, Fernando A; Brinkoetter, Mary; Boyd, Ingrid; Rifkin-Graboi, Anne; Yannakoulia, Mary; Rojas, Rafael; Pascual-Leone, Alvaro; Mantzoros, Christos S

2011-01-01

Background: Food intake fluctuates throughout the menstrual cycle; it is greater during the early follicular and luteal phases than in the late follicular (periovulatory) phase. Ovarian steroids can influence brain areas that process food-related information, but the specific contribution of individual hormones and the importance of the prandial state remain unknown. Objective: The objective was to examine whether brain activation during food visualization is affected by changes in estradiol concentration in the fasted and fed conditions. Design: Nine eumenorrheic, lean young women [mean (±SD) age: 26.2 ± 3.2 y; body mass index (in kg/m2): 22.4 ± 1.2] completed 2 visits, one in the early (low estradiol) and one in the late (high estradiol) follicular phase of their menstrual cycle. At each visit, subjects underwent functional magnetic resonance imaging while they viewed food and nonfood images, before and after a standardized meal. Region-of-interest analysis was used to examine the effect of follicular phase and prandial state on brain activation (food > nonfood contrast) and its association with estradiol concentration. Results: Differences were identified in the inferior frontal and fusiform gyri. In these areas, visualization of food elicited greater activation in the fed state than during fasting but only in the late follicular phase, when estradiol concentration was high. The change in estradiol concentration across the follicular phase (late minus early) was inversely correlated with the change in fusiform gyrus activation in the fasted state but not in the fed state. Conclusion: Our findings suggest that estradiol may reduce food intake by decreasing sensitivity to food cues in the ventral visual pathway under conditions of energy deprivation. This trial was registered at clinicaltrials.gov as NCT00130117. PMID:21593494

Inflammatory Mediator Profiles Differ in Sepsis Patients With and Without Bacteremia.

PubMed

Mosevoll, Knut Anders; Skrede, Steinar; Markussen, Dagfinn Lunde; Fanebust, Hans Rune; Flaatten, Hans Kristian; Aßmus, Jörg; Reikvam, Håkon; Bruserud, Øystein

2018-01-01

Systemic levels of cytokines are altered during infection and sepsis. This prospective observational study aimed to investigate whether plasma levels of multiple inflammatory mediators differed between sepsis patients with and those without bacteremia during the initial phase of hospitalization. A total of 80 sepsis patients with proven bacterial infection and no immunosuppression were included in the study. Plasma samples were collected within 24 h of hospitalization, and Luminex ® analysis was performed on 35 mediators: 16 cytokines, six growth factors, four adhesion molecules, and nine matrix metalloproteases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs). Forty-two patients (52.5%) and 38 (47.5%) patients showed positive and negative blood cultures, respectively. There were significant differences in plasma levels of six soluble mediators between the two "bacteremia" and "non-bacteremia" groups, using Mann-Whitney U test ( p  < 0.0014): tumor necrosis factor alpha (TNFα), CCL4, E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and TIMP-1. Ten soluble mediators also significantly differed in plasma levels between the two groups, with p -values ranging between 0.05 and 0.0014: interleukin (IL)-1ra, IL-10, CCL2, CCL5, CXCL8, CXCL11, hepatocyte growth factor, MMP-8, TIMP-2, and TIMP-4. VCAM-1 showed the most robust results using univariate and multivariate logistic regression. Using unsupervised hierarchical clustering, we found that TNFα, CCL4, E-selectin, VCAM-1, ICAM-1, and TIMP-1 could be used to discriminate between patients with and those without bacteremia. Patients with bacteremia were mainly clustered in two separate groups (two upper clusters, 41/42, 98%), with higher levels of the mediators. One (2%) patient with bacteremia was clustered in the lower cluster, which compromised most of the patients without bacteremia (23/38, 61%) (χ 2 test, p  < 0.0001). Our study showed that analysis

Linking Family Economic Hardship to Early Childhood Health: An Investigation of Mediating Pathways.

PubMed

Hsu, Hui-Chin; Wickrama, Kandauda A S

2015-12-01

The underlying mechanisms through which family economic adversity influences child health are less understood. Taking a process-oriented approach, this study examined maternal mental health and investment in children, child health insurance, and child healthcare as mediators linking family economic hardship (FEH) to child health. A structural equation modeling was applied to test the hypothesized mediating model. After adjustment for sociodemographic risk factors, results revealed: (1) a significant direct path linking FEH to poor child health (effect size = .372), and (2) six significant mediating pathways (total effect size = .089). In two mediating pathways, exposures to FEH undermined mothers' mental health: in the first pathway poor maternal mental health led to decreased parental investment, which, in turn, contributed to poor child health, whereas in the second pathway the adverse effect of poor maternal mental health was cascaded through child unmet healthcare need, which resulted in poor child health. One pathway involved child insurance status, where the effect of FEH increased the likelihood to be uninsured, which led to unmet healthcare need, and, in turn, to poor health. Three pathways involved preventive care: in one pathway FEH contributed to poor preventive care, which led to unmet healthcare need and then to poor health; in the other two pathways where poor preventive care respectively gave rise to decreased investment in children or poor maternal mental health, which further contributed to poor child health. Results suggest that the association between FEH and children's health is mediated by multiple pathways.

Rapamycin ameliorates inflammation and fibrosis in the early phase of cirrhotic portal hypertension in rats through inhibition of mTORC1 but not mTORC2.

PubMed

Wang, Weijie; Yan, Jiqi; Wang, Huakai; Shi, Minmin; Zhang, Mingjun; Yang, Weiping; Peng, Chenghong; Li, Hongwei

2014-01-01

Hepatic stellate cells (HSCs) transdifferentiation and subsequent inflammation are important pathological processes involved in the formation of cirrhotic portal hypertension. This study characterizes the pathogenetic mechanisms leading to cholestatic liver fibrosis and portal hypertension, and focuses on mammalian target of rapamycin (mTOR) pathway as a potential modulator in the early phase of cirrhotic portal hypertension. Early cirrhotic portal hypertension was induced by bile duct ligation (BDL) for three weeks. One week after operation, sham-operated (SHAM) and BDL rats received rapamycin (2 mg/kg/day) by intraperitoneal injection for fourteen days. Vehicle-treated SHAM and BDL rats served as controls. Fibrosis, inflammation, and portal pressure were evaluated by histology, morphometry, and hemodynamics. Expressions of pro-fibrogenic and pro-inflammatory genes in liver were measured by RT-PCR; alpha smooth muscle actin (α-SMA) and antigen Ki67 were detected by immunohistochemistry; expressions of AKT/mTOR signaling molecules, extracellular-signal-regulated kinase 1/2 (ERK1/2), p-ERK1/2, and interleukin-1 beta (IL-1β) were assessed by western blot. The AKT/mTOR signaling pathway was markedly activated in the early phase of cirrhotic portal hypertension induced by BDL in rats. mTOR blockade by rapamycin profoundly improved liver function by limiting inflammation, fibrosis and portal pressure. Rapamycin significantly inhibited the expressions of phosphorylated 70KD ribosomal protein S6 kinase (p-P70S6K) and phosphorylated ribosomal protein S6 (p-S6) but not p-AKT Ser473 relative to their total proteins in BDL-Ra rats. Those results suggested that mTOR Complex 1 (mTORC1) rather than mTORC2 was inhibited by rapamycin. Interestingly, we also found that the level of p-ERK1/2 to ERK1/2 was significantly increased in BDL rats, which was little affected by rapamycin. The AKT/mTOR signaling pathway played an important role in the early phase of cirrhotic portal

Child abuse, early maladaptive schemas, and risky sexual behavior in college women.

PubMed

Roemmele, Melissa; Messman-Moore, Terri L

2011-05-01

Previous research suggests that individuals abused as children are more likely to engage in risky sexual behavior during adulthood. The present study examined early maladaptive schemas as mediators of the child abuse-risky sexual behavior relationship among 653 college women. Self-report surveys assessed three forms of child abuse: Sexual, physical, and emotional, and assessed early maladaptive schemas within two domains: Disconnection/rejection and Other-Directedness. Disconnection/rejection schemas fully mediated the relation between child emotional abuse and number of sexual partners and partially mediated the relationship for sexual and physical abuse. However, when frequency of specific risky sexual acts (e.g., sex without contraception) was examined in the previous six months, only abandonment was a partial mediator. Implications for intervention and future research are discussed.

Full trans-activation mediated by the immediate-early protein of equine herpesvirus 1 requires a consensus TATA box, but not its cognate binding sequence.

PubMed

Kim, Seong K; Shakya, Akhalesh K; O'Callaghan, Dennis J

2016-01-04

The immediate-early protein (IEP) of equine herpesvirus 1 (EHV-1) has extensive homology to the IEP of alphaherpesviruses and possesses domains essential for trans-activation, including an acidic trans-activation domain (TAD) and binding domains for DNA, TFIIB, and TBP. Our data showed that the IEP directly interacted with transcription factor TFIIA, which is known to stabilize the binding of TBP and TFIID to the TATA box of core promoters. When the TATA box of the EICP0 promoter was mutated to a nonfunctional TATA box, IEP-mediated trans-activation was reduced from 22-fold to 7-fold. The IEP trans-activated the viral promoters in a TATA motif-dependent manner. Our previous data showed that the IEP is able to repress its own promoter when the IEP-binding sequence (IEBS) is located within 26-bp from the TATA box. When the IEBS was located at 100 bp upstream of the TATA box, IEP-mediated trans-activation was very similar to that of the minimal IE(nt -89 to +73) promoter lacking the IEBS. As the distance from the IEBS to the TATA box decreased, IEP-mediated trans-activation progressively decreased, indicating that the IEBS located within 100 bp from the TATA box sequence functions as a distance-dependent repressive element. These results indicated that IEP-mediated full trans-activation requires a consensus TATA box of core promoters, but not its binding to the cognate sequence (IEBS). Copyright © 2015 Elsevier B.V. All rights reserved.

Full trans–activation mediated by the immediate–early protein of equine herpesvirus 1 requires a consensus TATA box, but not its cognate binding sequence

PubMed Central

Kim, Seong K.; Shakya, Akhalesh K.; O'Callaghan, Dennis J.

2015-01-01

The immediate-early protein (IEP) of equine herpesvirus 1 (EHV-1) has extensive homology to the IEP of alphaherpesviruses and possesses domains essential for trans-activation, including an acidic trans-activation domain (TAD) and binding domains for DNA, TFIIB, and TBP. Our data showed that the IEP directly interacted with transcription factor TFIIA, which is known to stabilize the binding of TBP and TFIID to the TATA box of core promoters. When the TATA box of the EICP0 promoter was mutated to a nonfunctional TATA box, IEP-mediated trans-activation was reduced from 22-fold to 7-fold. The IEP trans-activated the viral promoters in a TATA motif-dependent manner. Our previous data showed that the IEP is able to repress its own promoter when the IEP-binding sequence (IEBS) is located within 26-bp from the TATA box. When the IEBS was located at 100 bp upstream of the TATA box, IEP-mediated trans-activation was very similar to that of the minimal IE(nt −89 to +73) promoter lacking the IEBS. As the distance from the IEBS to the TATA box decreased, IEP-mediated trans-activation progressively decreased, indicating that the IEBS located within 100 bp from the TATA box sequence functions as a distance-dependent repressive element. These results indicated that IEP-mediated full trans-activation requires a consensus TATA box of core promoters, but not its binding to the cognate sequence (IEBS). PMID:26541315

Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

PubMed

Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

2017-01-01

Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison

Neural dynamics in motor preparation: From phase-mediated global computation to amplitude-mediated local computation.

PubMed

Kajihara, Takafumi; Anwar, Muhammad Nabeel; Kawasaki, Masahiro; Mizuno, Yuji; Nakazawa, Kimitaka; Kitajo, Keiichi

2015-09-01

Oscillatory activity plays a critical role in the brain. Here, we illustrate the dynamics of neural oscillations in the motor system of the brain. We used a non-directional cue to instruct participants to prepare a motor response with either the left or the right hand and recorded electroencephalography during the preparation of the response. Consistent with previous findings, the amplitude of alpha-band (8-14Hz) oscillations significantly decreased over the motor region contralateral to the hand prepared for the response. Prior to this decrease, there were a number of inter-regional phase synchronies at lower frequencies (2-4Hz; delta band). Cross-frequency coupling was quantified to further explore the direct link between alpha amplitudes and delta synchrony. The cross-frequency coupling of showed response-specific modulation, whereby the motor region contralateral to the preparation hand exhibited an increase in coupling relative to the baseline. The amplitude of alpha oscillations had an unpreferred and a preferred delta phase, in which the amplitude was modulated negatively and positively, respectively. Given the amplitude of alpha-band oscillations decreased over the analyzed period, the alpha amplitude might be down-regulated by the phase-amplitude coupling, although we do not have direct evidence for that. Taken together, these results show global-to-local computation in the motor system, which started from inter-regional delta phase synchrony and ended at an effector-specific decrease in the amplitude of alpha-band oscillations, with phase-amplitude coupling connecting both computations. Copyright © 2015. Published by Elsevier Inc.

Early-phase transmission of Yersinia pestis by unblocked fleas as a mechanism explaining rapidly spreading plague epizootics.

PubMed

Eisen, Rebecca J; Bearden, Scott W; Wilder, Aryn P; Montenieri, John A; Antolin, Michael F; Gage, Kenneth L

2006-10-17

Plague is a highly virulent disease believed to have killed millions during three historic human pandemics. Worldwide, it remains a threat to humans and is a potential agent of bioterrorism. Dissemination of Yersinia pestis, the etiological agent of plague, by blocked fleas has been the accepted paradigm for flea-borne transmission. However, this mechanism, which requires a lengthy extrinsic incubation period before a short infectious window often followed by death of the flea, cannot sufficiently explain the rapid rate of spread that typifies plague epidemics and epizootics. Inconsistencies between the expected rate of spread by blocked rat fleas and that observed during the Black Death has even caused speculation that plague was not the cause of this medieval pandemic. We used the primary vector to humans in North America, Oropsylla montana, which rarely becomes blocked, as a model for studying alternative flea-borne transmission mechanisms. Our data revealed that, in contrast to the classical blocked flea model, O. montana is immediately infectious, transmits efficiently for at least 4 d postinfection (early phase) and may remain infectious for a long time because the fleas do not suffer block-induced mortality. These factors match the criteria required to drive plague epizootics as defined by recently published mathematical models. The scenario of efficient early-phase transmission by unblocked fleas described in our study calls for a paradigm shift in concepts of how Y. pestis is transmitted during rapidly spreading epizootics and epidemics, including, perhaps, the Black Death.

Skin manifestations in sulfur mustard exposed victims with ophthalmologic complications: Association between early and late phase.

PubMed

Hejazi, Somayeh; Soroush, Mohammadreza; Moradi, Ahmad; Khalilazar, Sara; Mousavi, Batool; Firooz, Alireza; Younespour, Shima

2016-01-01

Sulfur mustard (SM) was used during the Iraq-Iran war (1980-1988). Exposed veterans continue to suffer from its ocular, skin, and respiratory complications. We aimed to evaluate associations between early (at the time of acute exposure) and decades later skin manifestations in individuals with severe ophthalmologic complications secondary to sulfur mustard exposure. One hundred forty-nine veterans with severe ocular injuries were evaluated for acute and chronic skin complications. Logistic regression models were used to examine the associations between early and late skin manifestations. Late skin complaints were observed in nearly all survivors who had early skin lesions (131 out of 137; 95.62%). Seven out of 12 patients (58.33%) who did not have early skin lesions ultimately developed late skin complications. There was a significant relationship between the presence of lesions at the time of exposure and developing late skin complaints (two-sided Fisher's exact test, OR = 15.59, p < 0.001). There was an association between having at least one early skin lesion and occurrence of late skin complications. Survivors with blisters at the time of chemical exposure were more likely to complain of itching (95% CI: 3.63-25.97, p < 0.001), burning (OR = 11.16; 95% CI: 2.97-41.89, p < 0.001), pigmentation changes (OR = 10.17; 95% CI: 2.54-40.75, p = 0.001), dryness (OR = 6.71, 95% CI: 1.22-37.01, p = 0.03) or cherry angioma (OR = 2.59; 95% CI:1.21-5.55, p = 0.01) during the late phase. Using multivariate logistic models, early blisters remained significantly associated with latent skin complaints. Of note, the genitalia and great flexure areas were the most involved anatomical sites for both early and late skin lesions in SM exposed survivors. According to this study, the presence of blisters at the time of exposure to SM is the most important predictor of developing dermatologic complications decades later in patients with severe ophthalmologic

Carrier mediated hollow fiber liquid phase microextraction combined with HPLC-UV for preconcentration and determination of some tetracycline antibiotics.

PubMed

Shariati, Shahab; Yamini, Yadollah; Esrafili, Ali

2009-02-01

In the present study, a simple and efficient preconcentration method was developed using carrier mediated three phase liquid phase microextraction prior to HPLC-UV for simultaneous extraction and determination of trace amounts of highly hydrophilic tetracycline antibiotics including tetracycline (TCN), oxytetracycline (OTCN) and doxycycline (DCN) in bovine milk, human plasma and water samples. For extraction, 11.0 mL of the aqueous sample containing TCNs and 0.05 M Na(2)HPO(4) (9.1phase (RP, 24 microL of 0.1M H(3)PO(4) and 1.0M NaCl with pH=1.6) was located inside the lumen of hollow fiber and the fiber was transferred into the aqueous sample. After the extraction period, the receiving phase was directly injected into HPLC. In order to obtain high extraction efficiency, the parameters affecting the liquid phase microextraction were evaluated and optimized. Under the optimized conditions, the calibration curves were linear in the range of 0.5-1,000 microgL(-1) for TCN and OTCN, and in the range of 5-1,000 microgL(-1) for DCN with good linearity (r(2)>0.995). Finally, applicability of the proposed method was successfully confirmed by extraction and determination of the drugs in water and plasma samples as well as in bovine milk samples with low and high fat contents. Comparing to the traditional methods, the proposed method exhibits high sensitivity and high preconcentration factors as well as good precision. The extraction setup is simple and due to active transport of analytes, high cleanup effect and good selectivity are obtained in extraction process.

Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION)

PubMed Central

Jabbour, Elias; Saglio, Giuseppe; Steegmann, Juan Luis; Shah, Neil P.; Boqué, Concepción; Chuah, Charles; Pavlovsky, Carolina; Mayer, Jiří; Cortes, Jorge; Baccarani, Michele; Kim, Dong-Wook; Bradley-Garelik, M. Brigid; Mohamed, Hesham; Wildgust, Mark; Hochhaus, Andreas

2014-01-01

This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 DASatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247. PMID:24311723

Human cytomegalovirus and Herpes Simplex type I virus can engage RNA polymerase I for transcription of immediate early genes

PubMed Central

Kostopoulou, Ourania N.; Wilhelmi, Vanessa; Raiss, Sina; Ananthaseshan, Sharan; Lindström, Mikael S.; Bartek, Jiri; Söderberg-Naucler, Cecilia

2017-01-01

Human cytomegalovirus (HCMV) utilizes RNA polymerase II to transcribe viral genes and produce viral mRNAs. It can specifically target the nucleolus to facilitate viral transcription and translation. As RNA polymerase I (Pol I)-mediated transcription is active in the nucleolus, we investigated the role of Pol I, along with relative contributions of the human Pol II and Pol III, to early phases of viral transcription in HCMV infected cells, compared with Herpes Simplex Virus-1 (HSV-1) and Murine cytomegalovirus (MCMV). Inhibition of Pol I with siRNA or the Pol I inhibitors CX-5461 or Actinomycin D (5nM) resulted in significantly decreased IE and pp65 mRNA and protein levels in human fibroblasts at early times post infection. This initially delayed replication was compensated for later during the replication process, at which stage it didn’t significantly affect virus production. Pol I inhibition also reduced HSV-1 ICP0 and gB transcripts, suggesting that some herpesviruses engage Pol I for their early transcription. In contrast, inhibition of Pol I failed to affect MCMV transcription. Collectively, our results contribute to better understanding of the functional interplay between RNA Pol I-mediated nucleolar events and the Herpes viruses, particularly HCMV whose pathogenic impact ranges from congenital malformations and potentially deadly infections among immunosuppressed patients, up to HCMV’s emerging oncomodulatory role in human tumors. PMID:29228551

Prognostic Performance Evaluation of the International Society on Thrombosis and Hemostasis and the Korean Society on Thrombosis and Hemostasis Scores in the Early Phase of Trauma.

PubMed

Kim, Hong Sug; Lee, Dong Hun; Lee, Byung Kook; Cho, Yong Soo

2018-01-15

Disseminated intravascular coagulation (DIC) contributes to poor outcome in the early phase of trauma. We aimed to analyze and compare the prognostic performances of the International Society on Thrombosis and Hemostasis (ISTH) and the Korean Society on Thrombosis and Hemostasis (KSTH) scores in the early phase of trauma. Receiver operating characteristics analysis was used to examine the prognostic performance of both scores, and multivariate analysis was used to estimate the prognostic impact of the ISTH and KSTH scores in the early phase of trauma. The primary outcome was 24-hour mortality and the secondary outcome was massive transfusion. Of 1,229 patients included in the study, the 24-hour mortality rate was 7.6% (n = 93), and 8.1% (n = 99) of patients who received massive transfusions. The area under the curves (AUCs) of the KSTH and ISTH scores for 24-hour mortality were 0.784 (95% confidence interval [CI], 0.760-0.807) and 0.744 (95% CI, 0.718-0.768), respectively. The AUC of KSTH and ISTH scores for massive transfusion were 0.758 (95% CI, 0.734-0.782) and 0.646 (95% CI, 0.619-0.673), respectively. The AUCs of the KSTH score was significantly different from those of the ISTH score. Overt DIC according to KSTH criteria only, was independently associated with 24-hour mortality (odds ratio [OR], 2.630; 95% CI, 1.456-4.752). Only the KSTH score was independently associated with massive transfusion (OR, 1.563; 95% CI, 1.182-2.068). The KSTH score demonstrates a better prognostic performance for outcomes than the ISTH score in the early phase of trauma. © 2018 The Korean Academy of Medical Sciences.

Temperament in early childhood and peer interactions in third grade: the role of teacher-child relationships in early elementary grades.

PubMed

Rudasill, Kathleen Moritz; Niehaus, Kate; Buhs, Eric; White, Jamie M

2013-12-01

Children's interactions with peers in early childhood have been consistently linked to their academic and social outcomes. Although both child and classroom characteristics have been implicated as contributors to children's success, there has been scant research linking child temperament, teacher-child relationship quality, and peer interactions in the same study. The purpose of this study is to examine children's early temperament, rated at preschool age, as a predictor of interactions with peers (i.e., aggression, relational aggression, victimization, and prosociality) in third grade while considering teacher-child relationship quality in kindergarten through second grades as a moderator and mediator of this association. The sample (N=1364) was drawn from the NICHD Study of Early Child Care and Youth Development. Results from structural equation models indicated that teacher-child conflict in early elementary grades mediated links between children's temperament and later peer interactions. Findings underscore the importance of considering children's temperament traits and teacher-child relationship quality when examining the mechanisms of the development of peer interactions. © 2013.

Relationships between Childhood Traumatic Experiences, Early Maladaptive Schemas and Interpersonal Styles

PubMed Central

KAYA TEZEL, Fulya; TUTAREL KIŞLAK, Şennur; BOYSAN, Murat

2015-01-01

Introduction Cognitive theories of psychopathology have generally proposed that early experiences of childhood abuse and neglect may result in the development of early maladaptive self-schemas. Maladaptive core schemas are central in the development and maintenance of psychological symptoms in a schema-focused approach. Psychosocial dysfunction in individuals with psychological problems has been consistently found to be associated with symptom severity. However, till date, linkages between psychosocial functioning, early traumatic experiences and core schemas have received little attention. The aim of the present study was to explore the relations among maladaptive interpersonal styles, negative experiences in childhood and core self-schemas in non-clinical adults. Methods A total of 300 adults (58% women) participated in the study. The participants completed a socio-demographic questionnaire, Young Schema Questionnaire, Childhood Trauma Questionnaire and Interpersonal Style Scale. Results Hierarchical regression analyses revealed that the Disconnection and Rejection and Impaired Limits schema domains were significant antecedents of maladaptive interpersonal styles after controlling for demographic characteristics and childhood abuse and neglect. Associations of child sexual abuse with Emotionally Avoidant, Manipulative and Abusive interpersonal styles were mediated by early maladaptive schemas. Early maladaptive schemas mediated the relations of emotional abuse with Emotionally Avoidant and Avoidant interpersonal styles as well as the relations of physical abuse with Avoidant and Abusive interpersonal styles. Conclusion Interpersonal styles in adulthood are significantly associated with childhood traumatic experiences. Significant relations between early traumatic experiences and maladaptive interpersonal styles are mediated by early maladaptive schemas. PMID:28360715

Relationships between Childhood Traumatic Experiences, Early Maladaptive Schemas and Interpersonal Styles.

PubMed

Kaya Tezel, Fulya; Tutarel Kişlak, Şennur; Boysan, Murat

2015-09-01

Cognitive theories of psychopathology have generally proposed that early experiences of childhood abuse and neglect may result in the development of early maladaptive self-schemas. Maladaptive core schemas are central in the development and maintenance of psychological symptoms in a schema-focused approach. Psychosocial dysfunction in individuals with psychological problems has been consistently found to be associated with symptom severity. However, till date, linkages between psychosocial functioning, early traumatic experiences and core schemas have received little attention. The aim of the present study was to explore the relations among maladaptive interpersonal styles, negative experiences in childhood and core self-schemas in non-clinical adults. A total of 300 adults (58% women) participated in the study. The participants completed a socio-demographic questionnaire, Young Schema Questionnaire, Childhood Trauma Questionnaire and Interpersonal Style Scale. Hierarchical regression analyses revealed that the Disconnection and Rejection and Impaired Limits schema domains were significant antecedents of maladaptive interpersonal styles after controlling for demographic characteristics and childhood abuse and neglect. Associations of child sexual abuse with Emotionally Avoidant, Manipulative and Abusive interpersonal styles were mediated by early maladaptive schemas. Early maladaptive schemas mediated the relations of emotional abuse with Emotionally Avoidant and Avoidant interpersonal styles as well as the relations of physical abuse with Avoidant and Abusive interpersonal styles. Interpersonal styles in adulthood are significantly associated with childhood traumatic experiences. Significant relations between early traumatic experiences and maladaptive interpersonal styles are mediated by early maladaptive schemas.

Social anxiety symptoms and suicidal ideation in a clinical sample of early adolescents: examining loneliness and social support as longitudinal mediators.

PubMed

Gallagher, Michelle; Prinstein, Mitchell J; Simon, Valerie; Spirito, Anthony

2014-08-01

Recent research has shown that social anxiety may be related to increased risk for suicidal ideation in teens, although this research largely has been cross-sectional and has not examined potential mediators of this relationship. A clinical sample of 144 early adolescents (72 % female; 12-15 years old) was assessed during psychiatric inpatient hospitalization and followed up at 9 and 18 months post-baseline. Symptoms of social anxiety, depression, suicidal ideation, loneliness, and perceived social support were assessed via structured interviews and self-report instruments. Structural equation modeling revealed a significant direct relationship between social anxiety symptoms at baseline and suicidal ideation at 18 months post-baseline, even after controlling for baseline depressive symptoms and ideation. A second multiple mediation model revealed that baseline social anxiety had a significant indirect effect on suicidal ideation at 18 months post-baseline through loneliness at 9 months post-baseline. Social anxiety did not have a significant indirect effect on suicidal ideation through perceived social support from either parents or close friends. Findings suggest that loneliness may be particularly implicated in the relationship between social anxiety and suicidality in teens. Clinicians should assess and address feelings of loneliness when treating socially anxious adolescents.

2015 Guidance on cancer immunotherapy development in early-phase clinical studies.