AMPK activators suppress breast cancer cell growth by inhibiting DVL3-facilitated Wnt/β-catenin signaling pathway activity.

PubMed

Zou, Yu-Feng; Xie, Chun-Wei; Yang, Shi-Xin; Xiong, Jian-Ping

2017-02-01

Adenosine monophosphate-activated protein kinase (AMPK) is a principal regulator of metabolism and the conservation of energy in cells, and protects them from exposure to various stressors. AMPK activators may exhibit therapeutic potential as suppressors of cell growth; however, the molecular mechanism underlying this phenomenon in various cancer cells remains to be fully elucidated. The present study investigated the effects of AMPK activators on breast cancer cell growth and specified the underlying molecular mechanism. In the present study, the AMPK activator metformin impaired breast cancer cell growth by reducing dishevelled segment polarity protein 3 (DVL3) and β‑catenin levels. Western blotting and immunohistochemistry demonstrated that DVL3 was recurrently upregulated in breast cancer cells that were not treated with metformin, and was significantly associated with enhanced levels of β‑catenin, c‑Myc and cyclin D1. Overexpression of DVL3 resulted in upregulation of β‑catenin and amplification of breast cancer cell growth, which confirmed that Wnt/β‑catenin activation via DVL3 is associated with breast cancer oncogenesis. To elucidate the underlying mechanism of these effects, the present study verified that metformin resulted in a downregulation of DVL3 and β‑catenin in a dose‑dependent manner, and induced phosphorylation of AMPK. Compound C is an AMPK inhibitor, which when administered alongside metformin, significantly abolished the effects of metformin on the reduction of DVL3 and activation of the phosphorylation of AMPK. Notably, the effects of metformin on the mRNA expression levels of DVL3 remain to be fully elucidated; however, a possible interaction with DVL3 at the post‑transcriptional level was observed. It has previously been suggested that the molecular mechanism underlying AMPK activator‑induced suppression of breast cancer cell growth involves an interaction with, and impairment of, DVL3 proteins. The results of the present study are of future clinical importance and advocate the use of metformin as a potential therapeutic agent against breast cancer.

Reducing financial barriers to vaccinating children and adolescents in the USA.

PubMed

Bednarczyk, Robert A; Birkhead, Guthrie S

2011-02-01

To increase awareness of the financial barriers to childhood and adolescent vaccination, recent steps taken to mitigate these barriers, and remaining gaps following passage of Federal healthcare reform legislation. Financial barriers to vaccination remain, even with the safety net of the Vaccines for Children Program. Newly recommended vaccines have substantially increased the cost to fully vaccinate a child up to age 18 years, and the combination of these cost burdens and inadequate reimbursement, in both the private and public sectors, has led some physicians to seriously consider stopping vaccination services. Up to 20% of privately insured children or adolescents have coverage that does not fully cover all costs of immunization, potentially leading to fragmented and inadequate preventive care. Federal healthcare reform legislation, as currently constituted, may not fully address all financing gaps, and the extent to which financial barriers to immunization services remain will need to be evaluated as the legislation is implemented. Recent National Vaccine Advisory Committee recommendations need to be considered to address financial barriers to immunization.

Relationships between media use, body fatness and physical activity in children and youth: a meta-analysis.

PubMed

Marshall, S J; Biddle, S J H; Gorely, T; Cameron, N; Murdey, I

2004-10-01

To review the empirical evidence of associations between television (TV) viewing, video/computer game use and (a) body fatness, and (b) physical activity. Meta-analysis. Published English-language studies were located from computerized literature searches, bibliographies of primary studies and narrative reviews, and manual searches of personal archives. Included studies presented at least one empirical association between TV viewing, video/computer game use and body fatness or physical activity among samples of children and youth aged 3-18 y. The mean sample-weighted corrected effect size (Pearson r). Based on data from 52 independent samples, the mean sample-weighted effect size between TV viewing and body fatness was 0.066 (95% CI=0.056-0.078; total N=44,707). The sample-weighted fully corrected effect size was 0.084. Based on data from six independent samples, the mean sample-weighted effect size between video/computer game use and body fatness was 0.070 (95% CI=-0.048 to 0.188; total N=1,722). The sample-weighted fully corrected effect size was 0.128. Based on data from 39 independent samples, the mean sample-weighted effect size between TV viewing and physical activity was -0.096 (95% CI=-0.080 to -0.112; total N=141,505). The sample-weighted fully corrected effect size was -0.129. Based on data from 10 independent samples, the mean sample-weighted effect size between video/computer game use and physical activity was -0.104 (95% CI=-0.080 to -0.128; total N=119,942). The sample-weighted fully corrected effect size was -0.141. A statistically significant relationship exists between TV viewing and body fatness among children and youth although it is likely to be too small to be of substantial clinical relevance. The relationship between TV viewing and physical activity is small but negative. The strength of these relationships remains virtually unchanged even after correcting for common sources of bias known to impact study outcomes. While the total amount of time per day engaged in sedentary behavior is inevitably prohibitive of physical activity, media-based inactivity may be unfairly implicated in recent epidemiologic trends of overweight and obesity among children and youth. Relationships between sedentary behavior and health are unlikely to be explained using single markers of inactivity, such as TV viewing or video/computer game use.

Unmanned Aerial Systems: Further Actions Needed to Fully Address Air Force and Army Pilot Workforce Challenges

DTIC Science & Technology

2016-03-16

UNMANNED AERIAL SYSTEMS Further Actions Needed to Fully Address Air Force and Army Pilot Workforce Challenges...Armed Services, U.S. Senate March 16, 2016 UNMANNED AERIAL SYSTEMS Further Actions Needed to Fully Address Air Force and Army Pilot Workforce ...High-performing organizations use complete and current data to inform their strategic human capital planning and remain open to reevaluating workforce

"Genetic regulation of Mycobacterium tuberculosis in a lipid-rich environment".

PubMed

Aguilar-Ayala, Diana A; Palomino, Juan Carlos; Vandamme, Peter; Martin, Anandi; Gonzalez-Y-Merchand, Jorge A

2017-11-01

Tuberculosis (TB) remains as one of the leading causes of morbidity and mortality among infectious diseases worldwide. Although lipids (mainly fatty acids and cholesterol) have been reported to play an important role during active and latent infection of M. tuberculosis, there are other molecular aspects of bacterial response to those substrates that are not fully understood, involving gene regulation background. This review highlights recent insights on pathogen gene expression: regulation during its active growth, during survival in presence of lipids and under variable hostile host microenvironments. We also propose several application options of this knowledge that may contribute for improved TB control. Copyright © 2016 Elsevier B.V. All rights reserved.

Bacteriocins active against multi-resistant gram negative bacteria implicated in nosocomial infections.

PubMed

Ghodhbane, Hanen; Elaidi, Sabrine; Sabatier, Jean-Marc; Achour, Sami; Benhmida, Jeannette; Regaya, Imed

2015-01-01

Multiresistant Gram-negative bacteria are the prime mover of nosocomial infections. Some are naturally resistant to antibiotics, their genetic makes them insensitive to certain families of antibiotics and they transmit these resistors to their offspring. Moreover, when bacteria are subjected to antibiotics, they eventually develop resistance against drugs to which they were previously sensitive. In recent years, many bacteriocins active against gram-negative bacteria have been identified proving their efficacy in treating infections. While further investigation remains necessary before the possibilities for bacteriocins in clinical practice can be described more fully, this review provides an overview of bacteriocins acting on the most common infectious gram negative bacteria (Klebsiella, Acinetobacter, Pseudomonas aeruginosa and E. coli).

Strategies for microbial synthesis of high-value phytochemicals

NASA Astrophysics Data System (ADS)

Li, Sijin; Li, Yanran; Smolke, Christina D.

2018-03-01

Phytochemicals are of great pharmaceutical and agricultural importance, but often exhibit low abundance in nature. Recent demonstrations of industrial-scale production of phytochemicals in yeast have shown that microbial production of these high-value chemicals is a promising alternative to sourcing these molecules from native plant hosts. However, a number of challenges remain in the broader application of this approach, including the limited knowledge of plant secondary metabolism and the inefficient reconstitution of plant metabolic pathways in microbial hosts. In this Review, we discuss recent strategies to achieve microbial biosynthesis of complex phytochemicals, including strategies to: (1) reconstruct plant biosynthetic pathways that have not been fully elucidated by mining enzymes from native and non-native hosts or by enzyme engineering; (2) enhance plant enzyme activity, specifically cytochrome P450 activity, by improving efficiency, selectivity, expression or electron transfer; and (3) enhance overall reaction efficiency of multi-enzyme pathways by dynamic control, compartmentalization or optimization with the host's metabolism. We also highlight remaining challenges to — and future opportunities of — this approach.

Effect of Citrus Flavonoids, Naringin and Naringenin, on Metabolic Syndrome and Their Mechanisms of Action12

PubMed Central

Alam, M. Ashraful; Subhan, Nusrat; Rahman, M. Mahbubur; Uddin, Shaikh J.; Reza, Hasan M.; Sarker, Satyajit D.

2014-01-01

Flavonoids are important natural compounds with diverse biologic activities. Citrus flavonoids constitute an important series of flavonoids. Naringin and its aglycone naringenin belong to this series of flavonoids and were found to display strong anti-inflammatory and antioxidant activities. Several lines of investigation suggest that naringin supplementation is beneficial for the treatment of obesity, diabetes, hypertension, and metabolic syndrome. A number of molecular mechanisms underlying its beneficial activities have been elucidated. However, their effect on obesity and metabolic disorder remains to be fully established. Moreover, the therapeutic uses of these flavonoids are significantly limited by the lack of adequate clinical evidence. This review aims to explore the biologic activities of these compounds, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome. PMID:25022990

MICROSCOPIC DETERMINATION OF BONE PHOSPHORUS BY QUANTITATIVE AUTORADIOGRAPHY OF NEUTRON-ACTIVATED SECTIONS

PubMed Central

Vincent, Jacques; Haumont, Stanislas; Roels, Joseph

1965-01-01

Longitudinal sections of human cortical bone were submitted to thermal neutrons. γ-ray spectra were recorded repeatedly during 15 days following irradiation. They showed that Na24 is predominant as early as 3 hours after activation and that all the γ-emitters have decayed on the 15th day. When the γ-rays have disappeared, β-rays are still produced by the sections. It was proved by the absorption curve in aluminium that all these β-rays are issued from the P32 induced in the sections by activation of P31. Therefore autoradiograms registered 15 days after activation reveal the distribution of P32 in the sections. γ-ray spectra and β-ray absorption curves of neutron activated sections of ivory demonstrated a mineral composition similar to that of bone. Autoradiograms of ivory sections activated for various times were used to establish the relation between the optical density of the autoradiograms and the radioactivity in P32. When the bone autoradiograms are compared with the ivory standards of known radioactivity, the optical densities of single osteons (Haversian systems), can be related to their phosphorus contents. Autoradiograms and microradiograms of the same sections were examined side by side. The least calcified osteons, that contain 80 per cent of the calcium of the fully calcified osteons, also contain about 80 per cent of the phosphorus of the fully mineralized osteons. It is concluded that the Ca:P ratio remains constant while mineralization of bone tissue is being completed. PMID:14286295

Planning as an Iterative Process

NASA Technical Reports Server (NTRS)

Smith, David E.

2012-01-01

Activity planning for missions such as the Mars Exploration Rover mission presents many technical challenges, including oversubscription, consideration of time, concurrency, resources, preferences, and uncertainty. These challenges have all been addressed by the research community to varying degrees, but significant technical hurdles still remain. In addition, the integration of these capabilities into a single planning engine remains largely unaddressed. However, I argue that there is a deeper set of issues that needs to be considered namely the integration of planning into an iterative process that begins before the goals, objectives, and preferences are fully defined. This introduces a number of technical challenges for planning, including the ability to more naturally specify and utilize constraints on the planning process, the ability to generate multiple qualitatively different plans, and the ability to provide deep explanation of plans.

Role of adapter function in oncoprotein-mediated activation of NF-kappaB. Human T-cell leukemia virus type I Tax interacts directly with IkappaB kinase gamma.

PubMed

Jin, D Y; Giordano, V; Kibler, K V; Nakano, H; Jeang, K T

1999-06-18

Mechanisms by which the human T-cell leukemia virus type I Tax oncoprotein activates NF-kappaB remain incompletely understood. Although others have described an interaction between Tax and a holo-IkappaB kinase (IKK) complex, the exact details of protein-protein contact are not fully defined. Here we show that Tax binds to neither IKK-alpha nor IKK-beta but instead complexes directly with IKK-gamma, a newly characterized component of the IKK complex. This direct interaction with IKK-gamma correlates with Tax-induced IkappaB-alpha phosphorylation and NF-kappaB activation. Thus, our findings establish IKK-gamma as a key molecule for adapting an oncoprotein-specific signaling to IKK-alpha and IKK-beta.

Prior activity of olfactory receptor neurons is required for proper sensory processing and behavior in Drosophila larvae.

PubMed

Utashiro, Nao; Williams, Claire R; Parrish, Jay Z; Emoto, Kazuo

2018-06-05

Animal responses to their environment rely on activation of sensory neurons by external stimuli. In many sensory systems, however, neurons display basal activity prior to the external stimuli. This prior activity is thought to modulate neural functions, yet its impact on animal behavior remains elusive. Here, we reveal a potential role for prior activity in olfactory receptor neurons (ORNs) in shaping larval olfactory behavior. We show that prior activity in larval ORNs is mediated by the olfactory receptor complex (OR complex). Mutations of Orco, an odorant co-receptor required for OR complex function, cause reduced attractive behavior in response to optogenetic activation of ORNs. Calcium imaging reveals that Orco mutant ORNs fully respond to optogenetic stimulation but exhibit altered temporal patterns of neural responses. These findings together suggest a critical role for prior activity in information processing upon ORN activation in Drosophila larvae, which in turn contributes to olfactory behavior control.

Verification of a Remaining Flying Time Prediction System for Small Electric Aircraft

NASA Technical Reports Server (NTRS)

Hogge, Edward F.; Bole, Brian M.; Vazquez, Sixto L.; Celaya, Jose R.; Strom, Thomas H.; Hill, Boyd L.; Smalling, Kyle M.; Quach, Cuong C.

2015-01-01

This paper addresses the problem of building trust in online predictions of a battery powered aircraft's remaining available flying time. A set of ground tests is described that make use of a small unmanned aerial vehicle to verify the performance of remaining flying time predictions. The algorithm verification procedure described here uses a fully functional vehicle that is restrained to a platform for repeated run-to-functional-failure experiments. The vehicle under test is commanded to follow a predefined propeller RPM profile in order to create battery demand profiles similar to those expected in flight. The fully integrated aircraft is repeatedly operated until the charge stored in powertrain batteries falls below a specified lower-limit. The time at which the lower-limit on battery charge is crossed is then used to measure the accuracy of remaining flying time predictions. Accuracy requirements are considered in this paper for an alarm that warns operators when remaining flying time is estimated to fall below a specified threshold.

Apocrine Secretion in Drosophila Salivary Glands: Subcellular Origin, Dynamics, and Identification of Secretory Proteins

PubMed Central

Farkaš, Robert; Ďatková, Zuzana; Mentelová, Lucia; Löw, Péter; Beňová-Liszeková, Denisa; Beňo, Milan; Sass, Miklós; Řehulka, Pavel; Řehulková, Helena; Raška, Otakar; Kováčik, Lubomír; Šmigová, Jana; Raška, Ivan; Mechler, Bernard M.

2014-01-01

In contrast to the well defined mechanism of merocrine exocytosis, the mechanism of apocrine secretion, which was first described over 180 years ago, remains relatively uncharacterized. We identified apocrine secretory activity in the late prepupal salivary glands of Drosophila melanogaster just prior to the execution of programmed cell death (PCD). The excellent genetic tools available in Drosophila provide an opportunity to dissect for the first time the molecular and mechanistic aspects of this process. A prerequisite for such an analysis is to have pivotal immunohistochemical, ultrastructural, biochemical and proteomic data that fully characterize the process. Here we present data showing that the Drosophila salivary glands release all kinds of cellular proteins by an apocrine mechanism including cytoskeletal, cytosolic, mitochondrial, nuclear and nucleolar components. Surprisingly, the apocrine release of these proteins displays a temporal pattern with the sequential release of some proteins (e.g. transcription factor BR-C, tumor suppressor p127, cytoskeletal β-tubulin, non-muscle myosin) earlier than others (e.g. filamentous actin, nuclear lamin, mitochondrial pyruvate dehydrogenase). Although the apocrine release of proteins takes place just prior to the execution of an apoptotic program, the nuclear DNA is never released. Western blotting indicates that the secreted proteins remain undegraded in the lumen. Following apocrine secretion, the salivary gland cells remain quite vital, as they retain highly active transcriptional and protein synthetic activity. PMID:24732043

The SpaceInn-SISMA Database: Characterization of a Large Sample of Variable and Active Stars by Means of Harps Spectra

NASA Astrophysics Data System (ADS)

Rainer, M.; Poretti, E.; Mistò, A.; Panzera, M. R.; Molinaro, M.; Cepparo, F.; Roth, M.; Michel, E.; Monteiro, M. J. P. F. G.

2016-12-01

We created a large database of physical parameters and variability indicators by fully reducing and analyzing the large number of spectra taken to complement the asteroseismic observations of the COnvection, ROtation and planetary Transits (CoRoT) satellite. 7103 spectra of 261 stars obtained with the ESO echelle spectrograph HARPS have been stored in the VO-compliant database Spectroscopic Indicators in a SeisMic Archive (SISMA), along with the CoRoT photometric data of the 72 CoRoT asteroseismic targets. The remaining stars belong to the same variable classes of the CoRoT targets and were observed to better characterize the properties of such classes. Several useful variability indicators (mean line profiles, indices of differential rotation, activity and emission lines) together with v\\sin I and radial-velocity measurements have been extracted from the spectra. The atmospheric parameters {T}{eff},{log}g, and [Fe/H] have been computed following a homogeneous procedure. As a result, we fully characterize a sample of new and known variable stars by computing several spectroscopic indicators, also providing some cases of simultaneous photometry and spectroscopy.

NREL Explains the Higher Cellulolytic Activity of a Vital Microorganism

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

The discovery of a new mode of action by C. thermocellum to convert biomass to biofuels is significant because the bacterium is already recognized as one of the most effective in the biosphere. Researchers found that, in addition to using common cellulase degradation mechanisms attached to cells, C. thermocellum also uses a new category of cell-free scaffolded enzymes. The new discovery will influence the strategies used to improve the cellulolytic activity of biomass degrading microbes going forward. Better understanding of this bacterium could lead to cheaper production of ethanol and drop-in fuels. Also, this discovery demonstrates that nature's biomass conversionmore » behaviors are not fully understood and remain as opportunities for future microbial/enzyme engineering efforts.« less

Phosphatase activity of the voltage-sensing phosphatase, VSP, shows graded dependence on the extent of activation of the voltage sensor

PubMed Central

Sakata, Souhei; Okamura, Yasushi

2014-01-01

The voltage-sensing phosphatase (VSP) consists of a voltage sensor and a cytoplasmic phosphatase region, and the movement of the voltage sensor is coupled to the phosphatase activity. However, its coupling mechanisms still remain unclear. One possible scenario is that the phosphatase is activated only when the voltage sensor is in a fully activated state. Alternatively, the enzymatic activity of single VSP proteins could be graded in distinct activated states of the voltage sensor, and partial activation of the voltage sensor could lead to partial activation of the phosphatase. To distinguish between these two possibilities, we studied a voltage sensor mutant of zebrafish VSP, where the voltage sensor moves in two steps as evidenced by analyses of charge movements of the voltage sensor and voltage clamp fluorometry. Measurements of the phosphatase activity toward phosphatidylinositol 4,5-bisphosphate revealed that both steps of voltage sensor activation are coupled to the tuning of phosphatase activities, consistent with the idea that the phosphatase activity is graded by the magnitude of the movement of the voltage sensor. PMID:24277865

Phosphatase activity of the voltage-sensing phosphatase, VSP, shows graded dependence on the extent of activation of the voltage sensor.

PubMed

Sakata, Souhei; Okamura, Yasushi

2014-03-01

The voltage-sensing phosphatase (VSP) consists of a voltage sensor and a cytoplasmic phosphatase region, and the movement of the voltage sensor is coupled to the phosphatase activity. However, its coupling mechanisms still remain unclear. One possible scenario is that the phosphatase is activated only when the voltage sensor is in a fully activated state. Alternatively, the enzymatic activity of single VSP proteins could be graded in distinct activated states of the voltage sensor, and partial activation of the voltage sensor could lead to partial activation of the phosphatase. To distinguish between these two possibilities, we studied a voltage sensor mutant of zebrafish VSP, where the voltage sensor moves in two steps as evidenced by analyses of charge movements of the voltage sensor and voltage clamp fluorometry. Measurements of the phosphatase activity toward phosphatidylinositol 4,5-bisphosphate revealed that both steps of voltage sensor activation are coupled to the tuning of phosphatase activities, consistent with the idea that the phosphatase activity is graded by the magnitude of the movement of the voltage sensor.

Scale effect challenges in urban hydrology highlighted with a distributed hydrological model

NASA Astrophysics Data System (ADS)

Ichiba, Abdellah; Gires, Auguste; Tchiguirinskaia, Ioulia; Schertzer, Daniel; Bompard, Philippe; Ten Veldhuis, Marie-Claire

2018-01-01

Hydrological models are extensively used in urban water management, development and evaluation of future scenarios and research activities. There is a growing interest in the development of fully distributed and grid-based models. However, some complex questions related to scale effects are not yet fully understood and still remain open issues in urban hydrology. In this paper we propose a two-step investigation framework to illustrate the extent of scale effects in urban hydrology. First, fractal tools are used to highlight the scale dependence observed within distributed data input into urban hydrological models. Then an intensive multi-scale modelling work is carried out to understand scale effects on hydrological model performance. Investigations are conducted using a fully distributed and physically based model, Multi-Hydro, developed at Ecole des Ponts ParisTech. The model is implemented at 17 spatial resolutions ranging from 100 to 5 m. Results clearly exhibit scale effect challenges in urban hydrology modelling. The applicability of fractal concepts highlights the scale dependence observed within distributed data. Patterns of geophysical data change when the size of the observation pixel changes. The multi-scale modelling investigation confirms scale effects on hydrological model performance. Results are analysed over three ranges of scales identified in the fractal analysis and confirmed through modelling. This work also discusses some remaining issues in urban hydrology modelling related to the availability of high-quality data at high resolutions, and model numerical instabilities as well as the computation time requirements. The main findings of this paper enable a replacement of traditional methods of model calibration by innovative methods of model resolution alteration based on the spatial data variability and scaling of flows in urban hydrology.

12 CFR 966.9 - Joint and several liability.

Code of Federal Regulations, 2010 CFR

2010-01-01

... remain in compliance with the liquidity requirements set forth in section 11(g) of the Act (12 U.S.C... statutory or regulatory liquidity requirements, or will be unable to timely and fully meet all of its... with statutory or regulatory liquidity requirements or to timely and fully meet all of its current...

Dopamine reward prediction error coding.

PubMed

Schultz, Wolfram

2016-03-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.

Dopamine reward prediction error coding

PubMed Central

Schultz, Wolfram

2016-01-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

Two-stage optics - High-acuity performance from low-acuity optical systems

NASA Technical Reports Server (NTRS)

Meinel, Aden B.; Meinel, Marjorie P.

1992-01-01

The concept of two-stage optics, developed under a program to enhance the performance, lower the cost, and increase the reliability of the 20-m Large Deployable Telescope, is examined. The concept permits the large primary mirror to remain as deployed or as space-assembled, with phasing and subsequent control of the system done by a small fully assembled optical active element placed at an exit pupil. The technique is being applied to correction of the fabrication/testing error in the Hubble Space Telescope primary mirror. The advantages offered by this concept for very large space telescopes are discussed.

Goldstone field test activities: Target search

NASA Technical Reports Server (NTRS)

Tarter, J.

1986-01-01

In March of this year prototype SETI equipment was installed at DSS13, the 26 meter research and development antenna at NASA's Goldstone complex of satellite tracking dishes. The SETI equipment will remain at this site at least through the end of the summer so that the hardware and software developed for signal detection and recognition can be fully tested in a dynamic observatory environment. The field tests are expected to help understand which strategies for observing and which signal recognition algorithms perform best in the presence of strong man-made interfering signals (RFI) and natural astronomical sources.

Molecular mechanism of pH-dependent substrate transport by an arginine-agmatine antiporter.

PubMed

Wang, Sheng; Yan, Renhong; Zhang, Xi; Chu, Qi; Shi, Yigong

2014-09-02

Enteropathogenic bacteria, exemplified by Escherichia coli, rely on acid-resistance systems (ARs) to survive the acidic environment of the stomach. AR3 consumes intracellular protons through decarboxylation of arginine (Arg) in the cytoplasm and exchange of the reaction product agmatine (Agm) with extracellular Arg. The latter process is mediated by the Arg:Agm antiporter AdiC, which is activated in response to acidic pH and remains fully active at pH 6.0 and below. Despite our knowledge of structural information, the molecular mechanism by which AdiC senses acidic pH remains completely unknown. Relying on alanine-scanning mutagenesis and an in vitro proteoliposome-based transport assay, we have identified Tyr74 as a critical pH sensor in AdiC. The AdiC variant Y74A exhibited robust transport activity at all pH values examined while maintaining stringent substrate specificity for Arg:Agm. Replacement of Tyr74 by Phe, but not by any other amino acid, led to the maintenance of pH-dependent substrate transport. These observations, in conjunction with structural information, identify a working model for pH-induced activation of AdiC in which a closed conformation is disrupted by cation-π interactions between proton and the aromatic side chain of Tyr74.

Dissolution and characterization of HEV NiMH batteries.

PubMed

Larsson, Kristian; Ekberg, Christian; Ødegaard-Jensen, Arvid

2013-03-01

Metal recovery is an essential part of the recycling of hybrid electric vehicle battery waste and the first step in a hydrometallurgical treatment is dissolution of the solid material. The properties of separated battery electrode materials were investigated. Focus was put on both the solid waste and then the dissolution behaviour. The cathode contains metallic nickel that remains undissolved when utilizing non-oxidizing conditions such as hydrochloric or sulphuric acid in combination with a low oxygen atmosphere. In these conditions the cathode active electrode material is fully dissolved. Not dissolving the nickel metal saves up to 37% of the acid consumption for the cathode electrode material. In the commonly used case of oxidizing conditions the nickel metal dissolves and a cobalt-rich phase remains undissolved from the cathode active material. For the anode material a complete and rapid dissolution can be achieved at mild conditions with hydrochloric, nitric or sulphuric acid. Optimal parameters for all cases of dissolution was pH 1 with a reaction time of approximately ≥ 20,000 s. Copyright © 2012 Elsevier Ltd. All rights reserved.

Telechelic Poly(2-oxazoline)s with a biocidal and a polymerizable terminal as collagenase inhibiting additive for long-term active antimicrobial dental materials

PubMed Central

Fik, Christoph P.; Konieczny, Stefan; Pashley, David H.; Waschinski, Christian J.; Ladisch, Reinhild S.; Salz, Ulrich; Bock, Thorsten; Tiller, Joerg C.

2015-01-01

Although modern dental repair materials show excellent mechanical and adhesion properties, they still face two major problems: First, any microbes that remain alive below the composite fillings actively decompose dentin and thus, subsequently cause secondary caries. Second, even if those microbes are killed, the extracellular proteases such as MMP, remain active and can still degrade collagenousdental tissue. In order to address both problems, a poly(2-methyloxazoline) with a biocidal quaternary ammonium and a polymerizable methacrylate terminal was explored as additive for a commercial dental adhesive. It could be demonstrated that the adhesive rendered the adhesive contact-active antimicrobial against S. mutans at a concentration of only 2.5 wt% and even constant washing with water for 101 days did not diminish this effect. Increasing the amount of the additive to 5 wt% allowed killing S. mutans cells in the tubuli of bovinedentin upon application of the adhesive. Further, the additive fully inhibited bacterial collagenase at a concentration of 0.5 wt% and reduced human recombinant collagenase MMP-9 to 13% of its original activity at that concentration. Human MMPs naturally bound to dentin were inhibited by more than 96% in a medium containing 5 wt% of the additive. Moreover, no adverse effect on the enamel/dentine shear bond strength was detected in combination with a dental composite. PMID:25130877

Structure of a Thermobifida fusca lytic polysaccharide monooxygenase and mutagenesis of key residues

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

Kruer-Zerhusen, Nathan; Alahuhta, Markus; Lunin, Vladimir V.

Auxiliary activity (AA) enzymes are produced by numerous bacterial and fungal species to assist in the degradation of biomass. These enzymes are abundant but have yet to be fully characterized. Here, we report the X-ray structure of Thermobifida fusca AA10A (TfAA10A), investigate mutational characterization of key surface residues near its active site, and explore the importance of the various domains of Thermobifida fusca AA10B (TfAA10B). The structure of TfAA10A is similar to other bacterial LPMOs (lytic polysaccharide monooxygenases), including signs of photo-reduction and a distorted active site, with mixed features showing both type I and II copper coordination. The pointmore » mutation experiments of TfAA10A show that Trp82 and Asn83 are needed for binding, but only Trp82 affects activity. The TfAA10B domain truncation mutants reveal that CBM2 is crucial for the binding of substrate, but that the X1 module does not affect binding or activity. In TfAA10A, Trp82 and Asn83 are needed for binding, but only Trp82 affects activity. The TfAA10B domain truncation mutants reveal that CBM2 is crucial for substrate binding, but that the X1 module does not affect binding or activity. The structure of TfAA10A is similar to other bacterial lytic polysaccharide monooxygenases with mixed features showing both type I and II copper coordination. The role of LPMOs and the variability of abundance in genomes are not fully explored. LPMOs likely perform initial attacks into crystalline cellulose to allow larger processive cellulases to bind and attack, but the precise nature of their synergistic behavior remains to be definitively characterized.« less

Structure of a Thermobifida fusca lytic polysaccharide monooxygenase and mutagenesis of key residues

DOE PAGES

Kruer-Zerhusen, Nathan; Alahuhta, Markus; Lunin, Vladimir V.; ...

2017-11-30

Auxiliary activity (AA) enzymes are produced by numerous bacterial and fungal species to assist in the degradation of biomass. These enzymes are abundant but have yet to be fully characterized. Here, we report the X-ray structure of Thermobifida fusca AA10A (TfAA10A), investigate mutational characterization of key surface residues near its active site, and explore the importance of the various domains of Thermobifida fusca AA10B (TfAA10B). The structure of TfAA10A is similar to other bacterial LPMOs (lytic polysaccharide monooxygenases), including signs of photo-reduction and a distorted active site, with mixed features showing both type I and II copper coordination. The pointmore » mutation experiments of TfAA10A show that Trp82 and Asn83 are needed for binding, but only Trp82 affects activity. The TfAA10B domain truncation mutants reveal that CBM2 is crucial for the binding of substrate, but that the X1 module does not affect binding or activity. In TfAA10A, Trp82 and Asn83 are needed for binding, but only Trp82 affects activity. The TfAA10B domain truncation mutants reveal that CBM2 is crucial for substrate binding, but that the X1 module does not affect binding or activity. The structure of TfAA10A is similar to other bacterial lytic polysaccharide monooxygenases with mixed features showing both type I and II copper coordination. The role of LPMOs and the variability of abundance in genomes are not fully explored. LPMOs likely perform initial attacks into crystalline cellulose to allow larger processive cellulases to bind and attack, but the precise nature of their synergistic behavior remains to be definitively characterized.« less

Conducting a fully mobile and randomised clinical trial for depression: access, engagement and expense.

PubMed

Anguera, Joaquin A; Jordan, Joshua T; Castaneda, Diego; Gazzaley, Adam; Areán, Patricia A

2016-01-01

Advances in mobile technology have resulted in federal and industry-level initiatives to facilitate large-scale clinical research using smart devices. Although the benefits of technology to expand data collection are obvious, assumptions about the reach of mobile research methods ( access ), participant willingness to engage in mobile research protocols ( engagement ), and the cost of this research ( cost ) remain untested. To assess the feasibility of a fully mobile randomised controlled trial using assessments and treatments delivered entirely through mobile devices to depressed individuals. Using a web-based research portal, adult participants with depression who also owned a smart device were screened, consented and randomised to 1 of 3 mental health apps for treatment. Assessments of self-reported mood and cognitive function were conducted at baseline, 4, 8 and 12 weeks. Physical and social activity was monitored daily using passively collected phone use data. All treatment and assessment tools were housed on each participant's smart phone or tablet. A cognitive training application, an application based on problem-solving therapy, and a mobile-sensing application promoting daily activities. Access : We screened 2923 people and enrolled 1098 participants in 5 months. The sample characteristics were comparable to the 2013 US census data. Recruitment via Craigslist.org yielded the largest sample. Engagement : Study engagement was high during the first 2 weeks of treatment, falling to 44% adherence by the 4th week. Cost : The total amount spent on for this project, including staff costs and β testing, was $314 264 over 2 years. These findings suggest that mobile randomised control trials can recruit large numbers of participants in a short period of time and with minimal cost, but study engagement remains challenging. NCT00540865.

The Ω-loop lid domain of phosphoenolpyruvate carboxykinase is essential for catalytic function

PubMed Central

Johnson, Troy A.; Holyoak, Todd

2012-01-01

Phosphoenolpyruvate carboxykinase (PEPCK) is an essential metabolic enzyme operating in the gluconeogenesis and glyceroneogenesis pathways. Recent studies have demonstrated that the enzyme contains a mobile active site lid domain that transitions between an open/disorded conformation to a closed/ordered conformation as the enzyme progresses through the catalytic cycle. The understanding of how this mobile domain functions in catalysis is incomplete. Previous studies show that the closure of the lid domain stabilizes the reaction intermediate and protects the reactive intermediate from spurious protonation and thus contributes to the fidelity of the enzyme. In order to more fully investigate the roles of the lid domain in PEPCK function we created three mutations that replaced the 11-residue lid domain with one, two or three glycine residues. Kinetic analysis of the mutant enzymes demonstrates that none of the enzyme constructs exhibit any measurable kinetic activity resulting in a decrease in the catalytic parameters by at least 106. Structural characterization of the mutants in complexes representing the catalytic cycle suggest that the inactivity is due to a role for the lid domain in the formation of the fully closed state of the enzyme that is required for catalytic function. In the absence of the lid domain, the enzyme is unable to achieve the fully closed state and is rendered inactive despite possessing all of the residues and substrates required for catalytic function. This work demonstrates how enzyme catalytic function can be abolished through the alteration of conformational equilibria despite all elements required for chemical conversion of substrates to products remaining intact. PMID:23127136

Long-term movement patterns of a coral reef predator

NASA Astrophysics Data System (ADS)

Heupel, M. R.; Simpfendorfer, C. A.

2015-06-01

Long-term monitoring is required to fully define periodicity and patterns in animal movement. This is particularly relevant for defining what factors are driving the presence, location, and movements of individuals. The long-term movement and space use patterns of grey reef sharks, Carcharhinus amblyrhynchos, were examined on a whole of reef scale in the southern Great Barrier Reef to define whether movement and activity space varied through time. Twenty-nine C. amblyrhynchos were tracked for over 2 years to define movement patterns. All individuals showed high residency within the study site, but also had high roaming indices. This indicated that individuals remained in the region and used all of the monitored habitat (i.e., the entire reef perimeter). Use of space was consistent through time with high reuse of areas most of the year. Therefore, individuals maintained discrete home ranges, but undertook broader movements around the reef at times. Mature males showed greatest variation in movement with larger activity spaces and movement into new regions during the mating season (August-September). Depth use patterns also differed, suggesting behaviour or resource requirements varied between sexes. Examination of the long-term, reef-scale movements of C. amblyrhynchos has revealed that reproductive activity may play a key role in space use and activity patterns. It was unclear whether mating behaviour or an increased need for food to sustain reproductive activity and development played a greater role in these patterns. Reef shark movement patterns are becoming more clearly defined, but research is still required to fully understand the biological drivers for the observed patterns.

Mapping of oxidative stress response elements of the caveolin-1 promoter.

PubMed

Bartholomew, Janine N; Galbiati, Ferruccio

2010-01-01

According to the "free radical theory" of aging, normal aging occurs as the result of tissue damages inflicted by reactive oxygen species (ROS). ROS are known to induce cellular senescence, and senescent cells are believed to contribute to organismal aging. The molecular mechanisms that mediate the cellular response to oxidants remain to be fully identified. We have shown that oxidative stress induces cellular senescence through activation of the caveolin-1 promoter and upregulation of caveolin-1 protein expression. Here, we describe how reactive oxygen species activate the caveolin-1 promoter and how the signaling may be assayed. These approaches provide insight into the functional role of caveolin-1 and potentially allow the identification of novel ROS-regulated genes that are part of the signaling machinery regulating cellular senescence/aging.

[The maturation steps of human immunodeficiency virus and the role of proteolysis].

PubMed

Bukrinskaia, A G; Grigor'ev, V B; Korablina, E V; Gur'ev, E L; Vorkunova, G K

2010-01-01

HIV-1 virions are as immature noninfectious particles lacking a central core. Shortly after budding, virions temporally mature and acquire cores and infectious activity. The cause of maturation remains poorly studied. We have revealed that the virions produced early after infection following 24-36 hours, never mature and remain noninfectious, and only virions produced 48-72 hours after infection mature. The mature virions contain 3 times more genomic viral RNA than "early" virus. The "early" virions contain the same proteolytically cleaved Gag proteins as mature virions in contrast to the accepted version. The virus protease inhibitor Indinavir sulfate (IS) fully blocks infectivity when added early after infection. The early proteolysis of Gag precursor in the infected cells and inclusion into the virions of cellularly cleaved matrix protein (cMA) are shown in the IS-treated cells. cMA is associated with genomic viral RNA.

[Legal aspects of post-mortem radiology in the Netherlands].

PubMed

Venderink, W; Dute, J C J

2016-01-01

In the Netherlands, the application of post-mortem radiology (virtual autopsy) is on the rise. Contrary to conventional autopsy, with post-mortem radiology the body remains intact. There is uncertainty concerning the legal admissibility of post-mortem radiology, since the Dutch Corpse Disposal Act does not contain any specific regulations for this technique. Autopsy and post-mortem radiology differ significantly from a technical aspect, but these differences do not have far-reaching legal consequences from a legal perspective. Even though the body remains intact during post-mortem radiology, the bodily integrity of a deceased person is breached if it would be applied without previously obtained consent. This permission can only be obtained after the relatives are fully informed about the proposed activity. In this respect, it is not relevant which technique is used, be it post-mortem radiology or autopsy. Therefore, the other legal conditions for post-mortem radiology are essentially identical to those for autopsy.

Physical activity in primary and secondary prevention of cardiovascular disease: Overview updated.

PubMed

Alves, Alberto J; Viana, João L; Cavalcante, Suiane L; Oliveira, Nórton L; Duarte, José A; Mota, Jorge; Oliveira, José; Ribeiro, Fernando

2016-10-26

Although the observed progress in the cardiovascular disease treatment, the incidence of new and recurrent coronary artery disease remains elevated and constitutes the leading cause of death in the developed countries. Three-quarters of deaths due to cardiovascular diseases could be prevented with adequate changes in lifestyle, including increased daily physical activity. New evidence confirms that there is an inverse dose-response relationship between physical activity and cardiovascular disease and mortality risk. However, participation in moderate to vigorous physical activity may not fully attenuate the independent effect of sedentary activities on increased risk for cardiovascular diseases. Physical activity also plays an important role in secondary prevention of cardiovascular diseases by reducing the impact of the disease, slowing its progress and preventing recurrence. Nonetheless, most of eligible cardiovascular patients still do not benefit from secondary prevention/cardiac rehabilitation programs. The present review draws attention to the importance of physical activity in the primary and secondary prevention of cardiovascular diseases. It also addresses the mechanisms by which physical activity and regular exercise can improve cardiovascular health and reduce the burden of the disease.

Metformin Inhibits Advanced Glycation End Products-Induced Inflammatory Response in Murine Macrophages Partly through AMPK Activation and RAGE/NFκB Pathway Suppression

PubMed Central

Zhou, Zhong'e; Tang, Yong; Chen, Chengjun; Lu, Yi; Liu, Liang

2016-01-01

Advanced glycation end products (AGEs) are major inflammatory mediators in diabetes, affecting atherosclerosis progression via macrophages. Metformin slows diabetic atherosclerosis progression through mechanisms that remain to be fully elucidated. The present study of murine bone marrow derived macrophages showed that (1) AGEs enhanced proinflammatory cytokines (interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)) mRNA expression, RAGE expression, and NFκB activation; (2) metformin pretreatment inhibited AGEs effects and AGEs-induced cluster designation 86 (CD86) (M1 marker) expression, while promoting CD206 (M2 marker) surface expression and anti-inflammatory cytokine (IL-10) mRNA expression; and (3) the AMPK inhibitor, Compound C, attenuated metformin effects. In conclusion, metformin inhibits AGEs-induced inflammatory response in murine macrophages partly through AMPK activation and RAGE/NFκB pathway suppression. PMID:27761470

Nucleolus-like bodies of fully-grown mouse oocytes contain key nucleolar proteins but are impoverished for rRNA.

PubMed

Shishova, Kseniya V; Lavrentyeva, Elena A; Dobrucki, Jurek W; Zatsepina, Olga V

2015-01-15

It is well known that fully-grown mammalian oocytes, rather than typical nucleoli, contain prominent but structurally homogenous bodies called "nucleolus-like bodies" (NLBs). NLBs accumulate a vast amount of material, but their biochemical composition and functions remain uncertain. To clarify the composition of the NLB material in mouse GV oocytes, we devised an assay to detect internal oocyte proteins with fluorescein-5-isothiocyanate (FITC) and applied the fluorescent RNA-binding dye acridine orange to examine whether NLBs contain RNA. Our results unequivocally show that, similarly to typical nucleoli, proteins and RNA are major constituents of transcriptionally active (or non-surrounded) NLBs as well as of transcriptionally silent (or surrounded) NLBs. We also show, by exposing fixed oocytes to a mild proteinase K treatment, that the NLB mass in oocytes of both types contains nucleolar proteins that are involved in all major steps of ribosome biogenesis, including rDNA transcription (UBF), early rRNA processing (fibrillarin), and late rRNA processing (NPM1/nucleophosmin/B23, nucleolin/C23), but none of the nuclear proteins tested, including SC35, NOBOX, topoisomerase II beta, HP1α, and H3. The ribosomal RPL26 protein was detected within the NLBs of NSN-type oocytes but is virtually absent from NLBs of SN-type oocytes. Taking into account that the major class of nucleolar RNA is ribosomal RNA (rRNA), we applied fluorescence in situ hybridization with oligonucleotide probes targeting 18S and 28S rRNAs. The results show that, in contrast to active nucleoli, NLBs of fully-grown oocytes are impoverished for the rRNAs, which is consistent with the absence of transcribed ribosomal genes in the NLB mass. Overall, the results of this study suggest that NLBs of fully-grown mammalian oocytes serve for storing major nucleolar proteins but not rRNA. Copyright © 2014 Elsevier Inc. All rights reserved.

Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle

PubMed Central

Mosadeghi, Ruzbeh; Reichermeier, Kurt M; Winkler, Martin; Schreiber, Anne; Reitsma, Justin M; Zhang, Yaru; Stengel, Florian; Cao, Junyue; Kim, Minsoo; Sweredoski, Michael J; Hess, Sonja; Leitner, Alexander; Aebersold, Ruedi; Peter, Matthias; Deshaies, Raymond J; Enchev, Radoslav I

2016-01-01

The COP9-Signalosome (CSN) regulates cullin–RING ubiquitin ligase (CRL) activity and assembly by cleaving Nedd8 from cullins. Free CSN is autoinhibited, and it remains unclear how it becomes activated. We combine structural and kinetic analyses to identify mechanisms that contribute to CSN activation and Nedd8 deconjugation. Both CSN and neddylated substrate undergo large conformational changes upon binding, with important roles played by the N-terminal domains of Csn2 and Csn4 and the RING domain of Rbx1 in enabling formation of a high affinity, fully active complex. The RING domain is crucial for deneddylation, and works in part through conformational changes involving insert-2 of Csn6. Nedd8 deconjugation and re-engagement of the active site zinc by the autoinhibitory Csn5 glutamate-104 diminish affinity for Cul1/Rbx1 by ~100-fold, resulting in its rapid ejection from the active site. Together, these mechanisms enable a dynamic deneddylation-disassembly cycle that promotes rapid remodeling of the cellular CRL network. DOI: http://dx.doi.org/10.7554/eLife.12102.001 PMID:27031283

PHM Enabled Autonomous Propellant Loading Operations

NASA Technical Reports Server (NTRS)

Walker, Mark; Figueroa, Fernando

2017-01-01

The utility of Prognostics and Health Management (PHM) software capability applied to Autonomous Operations (AO) remains an active research area within aerospace applications. The ability to gain insight into which assets and subsystems are functioning properly, along with the derivation of confident predictions concerning future ability, reliability, and availability, are important enablers for making sound mission planning decisions. When coupled with software that fully supports mission planning and execution, an integrated solution can be developed that leverages state assessment and estimation for the purposes of delivering autonomous operations. The authors have been applying this integrated, model-based approach to the autonomous loading of cryogenic spacecraft propellants at Kennedy Space Center.

[Prevention of cardiovascular diseases].

PubMed

Prochaska, J H; Arnold, N; Jünger, C; Münzel, T; Wild, P S

2018-02-01

The incidence of cardiovascular diseases can be reduced by the early detection and targeted treatment of risk factors and subclinical forms of the disease. Primary prevention provides several opportunities for successful interventions. In addition to a drug-based therapy, especially life style-modifying measures, such as physical activity, normalization of body weight, consistent nicotine abstinence and the consideration of psychosocial aspects represent core components of prevention programs. Healthcare data indicate that risk factors still often remain undetected and that the full potential of risk factor management has not yet been fully exploited at a population level. Especially motivation of patients and adherence to therapy represent key elements of successful prevention efforts.

Effect of free ammonia concentration on monochloramine penetration within a nitrifying biofilm and its effect on activity, viability, and recovery.

PubMed

Pressman, Jonathan G; Lee, Woo Hyoung; Bishop, Paul L; Wahman, David G

2012-03-01

Chloramine has replaced free chorine for secondary disinfection at many water utilities because of disinfection by-product (DBP) regulations. Because chloramination provides a source of ammonia, there is a potential for nitrification when using chloramines. Nitrification in drinking water distribution systems is undesirable and may result in degradation of water quality and subsequent non-compliance with existing regulations. Thus, nitrification control is a major issue and likely to become increasingly important as chloramine use increases. In this study, monochloramine penetration and its effect on nitrifying biofilm activity, viability, and recovery was investigated and evaluated using microelectrodes and confocal laser scanning microscopy (CLSM). Monochloramine was applied to nitrifying biofilm for 24 h at two different chlorine to nitrogen (Cl(2):N) mass ratios (4:1 [4.4 mg Cl(2)/L] or 1:1 Cl(2):N [5.3 mg Cl(2)/L]), resulting in either a low (0.23 mg N/L) or high (4.2 mg N/L) free ammonia concentration. Subsequently, these biofilm samples were allowed to recover without monochloramine and receiving 4.2 mg N/L free ammonia. Under both monochloramine application conditions, monochloramine fully penetrated into the nitrifying biofilm within 24 h. Despite this complete monochloramine penetration, complete viability loss did not occur, and both biofilm samples subsequently recovered aerobic activity when fed only free ammonia. When monochloramine was applied with a low free ammonia concentration, dissolved oxygen (DO) fully penetrated, but with a high free ammonia concentration, complete cessation of aerobic activity (i.e., oxygen utilization) did not occur and subsequent analysis indicated that oxygen consumption still remained near the substratum. During the ammonia only recovery phase, different spatial recoveries were seen in each of the samples, based on oxygen utilization. It appears that the presence of higher free ammonia concentration allowed a larger biomass to remain active during monochloramine application, particularly the organisms deeper within the biofilm, leading to faster recovery in oxygen utilization when monochloramine was removed. These results suggest that limiting the free ammonia concentration during monochloramine application will slow the onset of nitrification episodes by maintaining the biofilm biomass at a state of lower activity. Published by Elsevier Ltd.

Safety, pharmacokinetics, and pharmacodynamics of RSLV-132, an RNase-Fc fusion protein in systemic lupus erythematosus: a randomized, double-blind, placebo-controlled study.

PubMed

Burge, D J; Eisenman, J; Byrnes-Blake, K; Smolak, P; Lau, K; Cohen, S B; Kivitz, A J; Levin, R; Martin, R W; Sherrer, Y; Posada, J A

2017-07-01

Blood-borne RNA circulating in association with autoantibodies is a potent stimulator of interferon production and immune system activation. RSLV-132 is a novel fully human biologic Fc fusion protein that is comprised of human RNase fused to the Fc domain of human IgG1. The drug is designed to remain in circulation and digest extracellular RNA with the aim of preventing activation of the immune system via Toll-like receptors and the interferon pathway. The present study describes the first clinical study of nuclease therapy in 32 subjects with systemic lupus erythematosus. The drug was well tolerated with a very favorable safety profile. The approximately 19-day serum half-life potentially supports once monthly dosing. There were no subjects in the study that developed anti-RSLV-132 antibodies. Decreases in B-cell activating factor correlated with decreases in disease activity in a subset of patients.

Does the Sound of a Barking Dog Activate its Corresponding Visual Form? An fMRI Investigation of Modality-Specific Semantic Access

PubMed Central

Reilly, Jamie; Garcia, Amanda; Binney, Richard J.

2016-01-01

Much remains to be learned about the neural architecture underlying word meaning. Fully distributed models of semantic memory predict that the sound of a barking dog will conjointly engage a network of distributed sensorimotor spokes. An alternative framework holds that modality-specific features additionally converge within transmodal hubs. Participants underwent functional MRI while covertly naming familiar objects versus newly learned novel objects from only one of their constituent semantic features (visual form, characteristic sound, or point-light motion representation). Relative to the novel object baseline, familiar concepts elicited greater activation within association regions specific to that presentation modality. Furthermore, visual form elicited activation within high-level auditory association cortex. Conversely, environmental sounds elicited activation in regions proximal to visual association cortex. Both conditions commonly engaged a putative hub region within lateral anterior temporal cortex. These results support hybrid semantic models in which local hubs and distributed spokes are dually engaged in service of semantic memory. PMID:27289210

An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase

NASA Astrophysics Data System (ADS)

Pucheta-Martínez, Encarna; Saladino, Giorgio; Morando, Maria Agnese; Martinez-Torrecuadrada, Jorge; Lelli, Moreno; Sutto, Ludovico; D'Amelio, Nicola; Gervasio, Francesco Luigi

2016-04-01

Phosphorylation of the activation loop is a fundamental step in the activation of most protein kinases. In the case of the Src tyrosine kinase, a prototypical kinase due to its role in cancer and its historic importance, phosphorylation of tyrosine 416 in the activation loop is known to rigidify the structure and contribute to the switch from the inactive to a fully active form. However, whether or not phosphorylation is able per-se to induce a fully active conformation, that efficiently binds ATP and phosphorylates the substrate, is less clear. Here we employ a combination of solution NMR and enhanced-sampling molecular dynamics simulations to fully map the effects of phosphorylation and ATP/ADP cofactor loading on the conformational landscape of Src tyrosine kinase. We find that both phosphorylation and cofactor binding are needed to induce a fully active conformation. What is more, we find a complex interplay between the A-loop and the hinge motion where the phosphorylation of the activation-loop has a significant allosteric effect on the dynamics of the C-lobe.

Early life adversity and/or posttraumatic stress disorder severity are associated with poor diet quality, including consumption of trans fatty acids, and fewer hours of resting or sleeping in a US middle-aged population: A cross-sectional and prospective study

PubMed Central

Gavrieli, Anna; Farr, Olivia M; Davis, Cynthia R; Crowell, Judith A; Mantzoros, Christos S.

2015-01-01

Background Early life adversity (ELA) and post-traumatic stress disorder (PTSD) are associated with poorer psychological and physical health. Potential underlying mechanisms and mediators remain to be elucidated, and the lifestyle habits and characteristics of individuals with ELA and/or PTSD have not been fully explored. We investigated whether the presence of ELA and/or PTSD are associated with nutrition, physical activity, resting and sleeping and smoking. Methods A cross-sectional sample of 151 males and females (age: 45.6±3.5 y, BMI: 30.0±7.1kg/m2) underwent anthropometric measurements, as well as detailed questionnaires for dietary assessment, physical activity, resting and sleeping, smoking habits and psychosocial assessments. A prospective follow-up visit of 49 individuals was performed 2.5 years later and the same outcomes were assessed. ELA and PTSD were evaluated as predictors, in addition to a variable assessing the combined presence/severity of ELA–PTSD. Data were analyzed using analysis of covariance after adjusting for several socioeconomic, psychosocial and anthropometric characteristics. Results Individuals with higher ELA or PTSD severity were found to have a poorer diet quality (DASH score: p=0.006 and p=0.003, respectively; aHEI-2010 score: ELA p=0.009), including further consumption of trans fatty acids (ELA p=0.003); the differences were significantly attenuated null after adjusting mainly for education or income and/or race. Further, individuals with higher ELA severity reported less hours of resting and sleeping (p=0.043) compared to those with zero/lower ELA severity, and the difference remained significant in the fully adjusted model indicating independence from potential confounders. When ELA and PTSD were combined, an additive effect was observed on resting and sleeping (p=0.001); results remained significant in the fully adjusted model. They also consumed more energy from trans fatty acids (p=0.017) tended to smoke more (p=0.008), and have less physical activity (PTSD p=0.024) compared to those with no or lower ELA and PTSD severity. Adjustments for sociodemographic factors and/or BMI rendered results of the above life style parameters non-significant. The analysis of the prospective data showed similar trends to the cross-sectional analysis, further supporting the conclusions, although statistical significance of results was lower due to the lower number of participants. Conclusion Fewer hours of resting and sleeping and poorer diet quality are linked to ELA and/or PTSD, indicating that these pathways might underlie the development of several metabolic abnormalities in individuals with ELA and/or PTSD. Differences in terms of diet quality are significantly attenuated by race and/or education and/or income, whereas differences in other lifestyle habits of individuals with and without ELA and/or PTSD, such as physical activity, are mostly explained by confounding sociodemographic variables and/or body mass index. PMID:26404481

Early life adversity and/or posttraumatic stress disorder severity are associated with poor diet quality, including consumption of trans fatty acids, and fewer hours of resting or sleeping in a US middle-aged population: A cross-sectional and prospective study.

PubMed

Gavrieli, Anna; Farr, Olivia M; Davis, Cynthia R; Crowell, Judith A; Mantzoros, Christos S

2015-11-01

Early life adversity (ELA) and post-traumatic stress disorder (PTSD) are associated with poorer psychological and physical health. Potential underlying mechanisms and mediators remain to be elucidated, and the lifestyle habits and characteristics of individuals with ELA and/or PTSD have not been fully explored. We investigated whether the presence of ELA and/or PTSD are associated with nutrition, physical activity, resting and sleeping and smoking. A cross-sectional sample of 151 males and females (age: 45.6±3.5 years, BMI: 30.0±7.1 kg/m(2)) underwent anthropometric measurements, as well as detailed questionnaires for dietary assessment, physical activity, resting and sleeping, smoking habits and psychosocial assessments. A prospective follow-up visit of 49 individuals was performed 2.5 years later and the same outcomes were assessed. ELA and PTSD were evaluated as predictors, in addition to a variable assessing the combined presence/severity of ELA-PTSD. Data were analyzed using analysis of covariance after adjusting for several socioeconomic, psychosocial and anthropometric characteristics. Individuals with higher ELA or PTSD severity were found to have a poorer diet quality (DASH score: p=0.006 and p=0.003, respectively; aHEI-2010 score: ELA p=0.009), including further consumption of trans fatty acids (ELA p=0.003); the differences were significantly attenuated null after adjusting mainly for education or income and/or race. Further, individuals with higher ELA severity reported less hours of resting and sleeping (p=0.043) compared to those with zero/lower ELA severity, and the difference remained significant in the fully adjusted model indicating independence from potential confounders. When ELA and PTSD were combined, an additive effect was observed on resting and sleeping (p=0.001); results remained significant in the fully adjusted model. They also consumed more energy from trans fatty acids (p=0.017) tended to smoke more (p=0.008), and have less physical activity (PTSD p=0.024) compared to those with no or lower ELA and PTSD severity. Adjustments for sociodemographic factors and/or BMI rendered results of the above lifestyle parameters non-significant. The analysis of the prospective data showed similar trends to the cross-sectional analysis, further supporting the conclusions, although statistical significance of results was lower due to the lower number of participants. Fewer hours of resting and sleeping and poorer diet quality are linked to ELA and/or PTSD, indicating that these pathways might underlie the development of several metabolic abnormalities in individuals with ELA and/or PTSD. Differences in terms of diet quality are significantly attenuated by race and/or education and/or income, whereas differences in other lifestyle habits of individuals with and without ELA and/or PTSD, such as physical activity, are mostly explained by confounding sociodemographic variables and/or body mass index. Copyright © 2015 Elsevier Inc. All rights reserved.

Structural heterogeneity of the μ-opioid receptor’s conformational ensemble in the apo state

NASA Astrophysics Data System (ADS)

Sena, Diniz M.; Cong, Xiaojing; Giorgetti, Alejandro; Kless, Achim; Carloni, Paolo

2017-04-01

G-protein coupled receptors (GPCRs) are the largest and most pharmaceutically relevant family of membrane proteins. Here, fully unbiased, enhanced sampling simulations of a constitutively active mutant (CAM) of a class A GPCR, the μ-opioid receptor (μOR), demonstrates repeated transitions between the inactive (IS) and active-like (AS-L) states. The interconversion features typical activation/inactivation patterns involving established conformational rearrangements of conserved residues. By contrast, wild-type μOR remains in IS during the same course of simulation, consistent with the low basal activity of the protein. The simulations point to an important role of residue W2936.48 at the “toggle switch” in the mutation-induced constitutive activation. Such role has been already observed for other CAMs of class A GPCRs. We also find a significantly populated intermediate state, rather similar to IS. Based on the remarkable accord between simulations and experiments, we suggest here that this state, which has escaped so far experimental characterization, might constitute an early step in the activation process of the apo μOR CAM.

Flexible Ablators

NASA Technical Reports Server (NTRS)

Stackpoole, Margaret M. (Inventor); Ghandehari, Ehson M. (Inventor); Thornton, Jeremy J. (Inventor); Covington, Melmoth Alan (Inventor)

2017-01-01

A low-density article comprising a flexible substrate and a pyrolizable material impregnated therein, methods of preparing, and devices using the article are disclosed. The pyrolizable material pyrolizes above 350 C and does not flow at temperatures below the pyrolysis temperature. The low-density article remains flexible after impregnation and continues to remain flexible when the pyrolizable material is fully pyrolized.

Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network

PubMed Central

Weick, Jason P.; Liu, Yan; Zhang, Su-Chun

2011-01-01

Whether hESC-derived neurons can fully integrate with and functionally regulate an existing neural network remains unknown. Here, we demonstrate that hESC-derived neurons receive unitary postsynaptic currents both in vitro and in vivo and adopt the rhythmic firing behavior of mouse cortical networks via synaptic integration. Optical stimulation of hESC-derived neurons expressing Channelrhodopsin-2 elicited both inhibitory and excitatory postsynaptic currents and triggered network bursting in mouse neurons. Furthermore, light stimulation of hESC-derived neurons transplanted to the hippocampus of adult mice triggered postsynaptic currents in host pyramidal neurons in acute slice preparations. Thus, hESC-derived neurons can participate in and modulate neural network activity through functional synaptic integration, suggesting they are capable of contributing to neural network information processing both in vitro and in vivo. PMID:22106298

Comparison of Transcutaneous Electrical Nerve Stimulation and Cryotherapy for Increasing Quadriceps Activation in Patients With Knee Pathologies.

PubMed

Gabler, Conrad M; Lepley, Adam S; Uhl, Tim L; Mattacola, Carl G

2016-08-01

Proper neuromuscular activation of the quadriceps muscle is essential for maintaining quadriceps (quad) strength and lower-extremity function. Quad activation (QA) failure is a common characteristic observed in patients with knee pathologies, defined as an inability to voluntarily activate the entire alpha-motor-neuron pool innervating the quad. One of the more popular techniques used to assess QA is the superimposed burst (SIB) technique, a force-based technique that uses a supramaximal, percutaneous electrical stimulation to activate all of the motor units in the quad during a maximal, voluntary isometric contraction. Central activation ratio (CAR) is the formula used to calculate QA level (CAR = voluntary force/SIB force) with the SIB technique. People who can voluntarily activate 95% or more (CAR = 0.95-1.0) of their motor units are defined as being fully activated. Therapeutic exercises aimed at improving quad strength in patients with knee pathologies are limited in their effectiveness due to a failure to fully activate the muscle. Within the past decade, several disinhibitory interventions have been introduced to treat QA failure in patients with knee pathologies. Transcutaneous electrical nerve stimulation (TENS) and cryotherapy are sensory-targeted modalities traditionally used to treat pain, but they have been shown to be 2 of the most successful treatments for increasing QA levels in patients with QA failure. Both modalities are hypothesized to positively affect voluntary QA by disinhibiting the motor-neuron pool of the quad. In essence, these modalities provide excitatory afferent stimuli to the spinal cord, which thereby overrides the inhibitory afferent signaling that arises from the involved joint. However, it remains unknown whether 1 is more effective than the other for restoring QA levels in patients with knee pathologies. By knowing the capabilities of each disinhibitory modality, clinicians can tailor treatments based on the rehabilitation goals of their patients. Focused Clinical Question: Is TENS or cryotherapy the more effective disinhibitory modality for treating QA failure (quantified via CAR) in patients with knee pathologies?

Direct behavioral evidence that unique bile acids released by larval sea lamprey (Petromyzon marinus) function as a migratory pheromone

USGS Publications Warehouse

Bjerselius , Rickard; Li, Weiming; Teeter, John H.; Seelye, James G.; Johnson, Peter B.; Maniak, Peter J.; Grant, Gerold C.; Polkinghorne, Christine N.; Sorensen, Peter W.

2000-01-01

Four behavioral experiments conducted in both the laboratory and the field provide evidence that adult sea lamprey (Petromyzon marinus) select spawning rivers based on the odor of larvae that they contain and that bile acids released by the larvae are part of this pheromonal odor. First, when tested in a recirculating maze, migratory adult lamprey spent more time in water scented with larvae. However, when fully mature, adults lost their responsiveness to larvae and preferred instead the odor of mature individuals. Second, when tested in a flowing stream, migratory adults swam upstream more actively when the water was scented with larvae. Third, when migratory adults were tested in a laboratory maze containing still water, they exhibited enhanced swimming activity in the presence of a 0.1 nM concentration of the two unique bile acids released by larvae and detected by adult lamprey. Fourth, when adults were exposed to this bile acid mixture within flowing waters, they actively swam into it. Taken together, these data suggest that adult lamprey use a bile acid based larval pheromone to help them locate spawning rivers and that responsiveness to this cue is influenced by current flow, maturity, and time of day. Although the precise identity and function of the larval pheromone remain to be fully elucidated, we believe that this cue will ultimately prove useful as an attractant in sea lamprey control.

Reduction of protein translation and activation of autophagy protect against PINK1 pathogenesis in Drosophila melanogaster.

PubMed

Liu, Song; Lu, Bingwei

2010-12-09

Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.

Reduction of Protein Translation and Activation of Autophagy Protect against PINK1 Pathogenesis in Drosophila melanogaster

PubMed Central

Liu, Song; Lu, Bingwei

2010-01-01

Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses. PMID:21151574

THERMAL FATIGUE OF INCONEL ALLOY DA718

DTIC Science & Technology

2016-10-27

this material meets the required improvement and offers a low cost alternative to powder metallurgy Rene’95. However, its thermal fatigue resistance ...remains to be fully clarified. Its nominal chemical composition is shown in Table B-1. In the fully heat treated condition, DA718 consists of a γ...chromel-alumel thermocouple , spot-welded to the mid-length of the specimen. The thermal strain, induced by the expansion and contraction of the

20 CFR 404.111 - When we consider a person fully insured based on World War II active military or naval service.

Code of Federal Regulations, 2011 CFR

2011-04-01

... on World War II active military or naval service. 404.111 Section 404.111 Employees' Benefits SOCIAL... Quarters of Coverage Fully Insured Status § 404.111 When we consider a person fully insured based on World... States during World War II; (b) The person died within three years after separation from service and...

Organic micropollutants paracetamol and ibuprofen-toxicity, biodegradation, and genetic background of their utilization by bacteria.

PubMed

Żur, Joanna; Piński, Artur; Marchlewicz, Ariel; Hupert-Kocurek, Katarzyna; Wojcieszyńska, Danuta; Guzik, Urszula

2018-06-19

Currently, analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are classified as one of the most emerging group of xenobiotics and have been detected in various natural matrices. Among them, monocyclic paracetamol and ibuprofen, widely used to treat mild and moderate pain are the most popular. Since long-term adverse effects of these xenobiotics and their biological and pharmacokinetic activity especially at environmentally relevant concentrations are better understood, degradation of such contaminants has become a major concern. Moreover, to date, conventional wastewater treatment plants (WWTPs) are not fully adapted to remove that kind of micropollutants. Bioremediation processes, which utilize bacterial strains with increased degradation abilities, seem to be a promising alternative to the chemical methods used so far. Nevertheless, despite the wide prevalence of paracetamol and ibuprofen in the environment, toxicity and mechanism of their microbial degradation as well as genetic background of these processes remain not fully characterized. In this review, we described the current state of knowledge about toxicity and biodegradation mechanisms of paracetamol and ibuprofen and provided bioinformatics analysis concerning the genetic bases of these xenobiotics decomposition.

Maternal Gdf3 is an obligatory cofactor in Nodal signaling for embryonic axis formation in zebrafish

PubMed Central

Bisgrove, Brent W; Su, Yi-Chu

2017-01-01

Zebrafish Gdf3 (Dvr1) is a member of the TGFβ superfamily of cell signaling ligands that includes Xenopus Vg1 and mammalian Gdf1/3. Surprisingly, engineered homozygous mutants in zebrafish have no apparent phenotype. Elimination of Gdf3 in oocytes of maternal-zygotic mutants results in embryonic lethality that can be fully rescued with gdf3 RNA, demonstrating that Gdf3 is required only early in development, beyond which mutants are viable and fertile. Gdf3 mutants are refractory to Nodal ligands and Nodal repressor Lefty1. Signaling driven by TGFβ ligand Activin and constitutively active receptors Alk4 and Alk2 remain intact in gdf3 mutants, indicating that Gdf3 functions at the same pathway step as Nodal. Targeting gdf3 and ndr2 RNA to specific lineages indicates that exogenous gdf3 is able to fully rescue mutants only when co-expressed with endogenous Nodal. Together, these findings demonstrate that Gdf3 is an essential cofactor of Nodal signaling during establishment of the embryonic axis. PMID:29140249

Subtotal Ablation of Parietal Epithelial Cells Induces Crescent Formation

PubMed Central

Sicking, Eva-Maria; Fuss, Astrid; Uhlig, Sandra; Jirak, Peggy; Dijkman, Henry; Wetzels, Jack; Engel, Daniel R.; Urzynicok, Torsten; Heidenreich, Stefan; Kriz, Wilhelm; Kurts, Christian; Ostendorf, Tammo; Floege, Jürgen; Smeets, Bart

2012-01-01

Parietal epithelial cells (PECs) of the renal glomerulus contribute to the formation of both cellular crescents in rapidly progressive GN and sclerotic lesions in FSGS. Subtotal transgenic ablation of podocytes induces FSGS but the effect of specific ablation of PECs is unknown. Here, we established an inducible transgenic mouse to allow subtotal ablation of PECs. Proteinuria developed during doxycycline-induced cellular ablation but fully reversed 26 days after termination of doxycycline administration. The ablation of PECs was focal, with only 30% of glomeruli exhibiting histologic changes; however, the number of PECs was reduced up to 90% within affected glomeruli. Ultrastructural analysis revealed disruption of PEC plasma membranes with cytoplasm shedding into Bowman’s space. Podocytes showed focal foot process effacement, which was the most likely cause for transient proteinuria. After >9 days of cellular ablation, the remaining PECs formed cellular extensions to cover the denuded Bowman’s capsule and expressed the activation marker CD44 de novo. The induced proliferation of PECs persisted throughout the observation period, resulting in the formation of typical cellular crescents with periglomerular infiltrate, albeit without accompanying proteinuria. In summary, subtotal ablation of PECs leads the remaining PECs to react with cellular activation and proliferation, which ultimately forms cellular crescents. PMID:22282596

Bacteria of the Candidate Phylum TM7 are Prevalent in Acidophilic Nitrifying Sequencing-Batch Reactors

PubMed Central

Hanada, Akiko; Kurogi, Takashi; Giang, Nguyen Minh; Yamada, Takeshi; Kamimoto, Yuki; Kiso, Yoshiaki; Hiraishi, Akira

2014-01-01

Laboratory-scale acidophilic nitrifying sequencing-batch reactors (ANSBRs) were constructed by seeding with sewage-activated sludge and cultivating with ammonium-containing acidic mineral medium (pH 4.0) with or without a trace amount of yeast extract. In every batch cycle, the pH varied between 2.7 and 4.0, and ammonium was completely converted to nitrate. Attempts to detect nitrifying functional genes in the fully acclimated ANSBRs by PCR with previously designed primers mostly gave negative results. 16S rRNA gene-targeted PCR and a subsequent denaturating gradient gel electrophoresis analysis revealed that a marked change occurred in the bacterial community during the overall period of operation, in which members of the candidate phylum TM7 and the class Gammaproteobacteria became predominant at the fully acclimated stage. This result was fully supported by a 16S rRNA gene clone library analysis, as the major phylogenetic groups of clones detected (>5% of the total) were TM7 (33%), Gammaproteobacteria (37%), Actinobacteria (10%), and Alphaproteobacteria (8%). Fluorescence in situ hybridization with specific probes also demonstrated the prevalence of TM7 bacteria and Gammaproteobacteria. These results suggest that previously unknown nitrifying microorganisms may play a major role in ANSBRs; however, the ecophysiological significance of the TM7 bacteria predominating in this process remains unclear. PMID:25241805

Teenage sexual behaviour: attitudes towards and declared sexual activity.

PubMed

Burack, R

1999-01-01

Although the teenage pregnancy rates in the UK are falling in the 16 to 19 year old range, they are still rising in the 13 to 15 year olds. Overall, they remain one of the highest within Western Europe. Teenagers continue to present a challenge to the health services due to the increase in their sexual risk taking behaviour, the earlier age at which they are starting sexual activity and a reluctance to utilise services available to them. In an attempt to develop current services and make them more 'user friendly', a sexual health needs assessment was carried out on teenagers, part of which looked at their attitudes towards risk taking sexual behaviour and their declared sexual behaviour. A quantitative survey, using a questionnaire in schools, was answered by 1500 pupils aged between 13 and 18 years old, and showed that the majority of teenagers had declared some form of sexual contact with a partner with a degree of sexual activity increasing with age. Twenty per cent of 13 year olds reported that they had already had either full or oral sexual intercourse with a partner. Feeling peer pressure, not knowing the facts about sexual risk taking and a declared intent that would increase the likelihood of putting themselves or others at risk sexually were significantly more likely in the younger teenage boys surveyed. This study confirms that there remain many different factors involved in teenagers' decision-making processes, about their developing attitudes towards sex and their resultant behaviour. Despite a lack of maturity, such opinions and attitudes are bringing about definite views and sexual behaviour patterns in teenagers as young as 12 or 13 years old who are becoming fully sexually active. In particular teenage boys are becoming fully sexually active at a younger age than the girls and are taking risks in doing so. They are being influenced by peer pressure, condoning promiscuity and are declaring the intent to practice unsafe sexual intercourse. Their level of maturity would appear to be inadequate for them to comprehend the implications and consequences of their actions. This study has shown a need for developing adequate education and provision of sexual health services for teenagers, particularly for teenage boys, and that this may go some way in helping to address the imbalances found.

Experimental demonstration of a fully inseparable quantum state with nonlocalizable entanglement

PubMed Central

Mičuda, M.; Koutný, D.; Miková, M.; Straka, I.; Ježek, M.; Mišta, L.

2017-01-01

Localizability of entanglement in fully inseparable states is a key ingredient of assisted quantum information protocols as well as measurement-based models of quantum computing. We investigate the existence of fully inseparable states with nonlocalizable entanglement, that is, with entanglement which cannot be localized between any pair of subsystems by any measurement on the remaining part of the system. It is shown, that the nonlocalizable entanglement occurs already in suitable mixtures of a three-qubit GHZ state and white noise. Further, we generalize this set of states to a two-parametric family of fully inseparable three-qubit states with nonlocalizable entanglement. Finally, we demonstrate experimentally the existence of nonlocalizable entanglement by preparing and characterizing one state from the family using correlated single photons and linear optical circuit. PMID:28344336

Experimental demonstration of a fully inseparable quantum state with nonlocalizable entanglement.

PubMed

Mičuda, M; Koutný, D; Miková, M; Straka, I; Ježek, M; Mišta, L

2017-03-27

Localizability of entanglement in fully inseparable states is a key ingredient of assisted quantum information protocols as well as measurement-based models of quantum computing. We investigate the existence of fully inseparable states with nonlocalizable entanglement, that is, with entanglement which cannot be localized between any pair of subsystems by any measurement on the remaining part of the system. It is shown, that the nonlocalizable entanglement occurs already in suitable mixtures of a three-qubit GHZ state and white noise. Further, we generalize this set of states to a two-parametric family of fully inseparable three-qubit states with nonlocalizable entanglement. Finally, we demonstrate experimentally the existence of nonlocalizable entanglement by preparing and characterizing one state from the family using correlated single photons and linear optical circuit.

Fully Screen-Printed, Large-Area, and Flexible Active-Matrix Electrochromic Displays Using Carbon Nanotube Thin-Film Transistors.

PubMed

Cao, Xuan; Lau, Christian; Liu, Yihang; Wu, Fanqi; Gui, Hui; Liu, Qingzhou; Ma, Yuqiang; Wan, Haochuan; Amer, Moh R; Zhou, Chongwu

2016-11-22

Semiconducting single-wall carbon nanotubes are ideal semiconductors for printed electronics due to their advantageous electrical and mechanical properties, intrinsic printability in solution, and desirable stability in air. However, fully printed, large-area, high-performance, and flexible carbon nanotube active-matrix backplanes are still difficult to realize for future displays and sensing applications. Here, we report fully screen-printed active-matrix electrochromic displays employing carbon nanotube thin-film transistors. Our fully printed backplane shows high electrical performance with mobility of 3.92 ± 1.08 cm 2 V -1 s -1 , on-off current ratio I on /I off ∼ 10 4 , and good uniformity. The printed backplane was then monolithically integrated with an array of printed electrochromic pixels, resulting in an entirely screen-printed active-matrix electrochromic display (AMECD) with good switching characteristics, facile manufacturing, and long-term stability. Overall, our fully screen-printed AMECD is promising for the mass production of large-area and low-cost flexible displays for applications such as disposable tags, medical electronics, and smart home appliances.

20 CFR 404.111 - When we consider a person fully insured based on World War II active military or naval service.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false When we consider a person fully insured based on World War II active military or naval service. 404.111 Section 404.111 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY INSURANCE (1950- ) Insured Status and Quarters of Coverage Fully Insured Status §...

Functional impact of the human mobilome.

PubMed

Babatz, Timothy D; Burns, Kathleen H

2013-06-01

The human genome is replete with interspersed repetitive sequences derived from the propagation of mobile DNA elements. Three families of human retrotransposons remain active today: LINE1, Alu, and SVA elements. Since 1988, de novo insertions at previously recognized disease loci have been shown to generate highly penetrant alleles in Mendelian disorders. Only recently has the extent of germline-transmitted retrotransposon insertion polymorphism (RIP) in human populations been fully realized. Also exciting are recent studies of somatic retrotransposition in human tissues and reports of tumor-specific insertions, suggesting roles in tissue heterogeneity and tumorigenesis. Here we discuss mobile elements in human disease with an emphasis on exciting developments from the last several years. Copyright © 2013 Elsevier Ltd. All rights reserved.

View of Mount Hadley as photographed by Apollo 15 during EVA

NASA Image and Video Library

1971-07-31

AS15-87-11849 (31 July-2 Aug. 1971) --- An excellent view of Mount Hadley, fully lighted, showing abundant linear features, as photographed during the Apollo 15 lunar surface extravehicular activity (EVA). This view is looking north from the Apollo Lunar Surface Experiments Package (ALSEP) site. Mount Hadley rises about 4,500 meters (approximately 14,765 feet) above the plain. While astronauts David R. Scott, commander, and James B. Irwin, lunar module pilot, descended in the Apollo 15 Lunar Module (LM) "Falcon" to explore the Hadley-Apennine area of the moon, astronaut Alfred M. Worden, command module pilot, remained with the Command and Service Modules (CSM) in lunar orbit.

[Transdisciplinary Approach for Sarcopenia. Effect of nutritional support for the prevention of sarcopenia].

PubMed

Nishioka, Hiroaki

2014-10-01

Sarcopenia is defined as the age-related loss of muscle mass and function. Sarcopenia is closely related with decreased physical function, fall, bone fracture, osteoporosis, and insulin resistance, which lead to increased morbidity and mortality in elderly people. The pathogenesis of sarcopenia is complex and multifactorial, which remains not to be fully understood. Inappropriate food intake and reduced physical activity are known to increase the risk of developing sarcopenia. Resistance training and nutritional support have been shown to be an effective intervention for prevention of sarcopenia. Protein, especially branched chain amino acid, and vitamin D have been reported to improve sarcopenia. The intervention together with nutrition and exercise are more effective.

Bora and Aurora-A continue to activate Plk1 in mitosis.

PubMed

Bruinsma, Wytse; Macurek, Libor; Freire, Raimundo; Lindqvist, Arne; Medema, René H

2014-02-15

Polo-like kinase-1 (Plk1) is required for proper cell division. Activation of Plk1 requires phosphorylation on a conserved threonine in the T-loop of the kinase domain (T210). Plk1 is first phosphorylated on T210 in G2 phase by the kinase Aurora-A, in concert with its cofactor Bora. However, Bora was shown to be degraded prior to entry into mitosis, and it is currently unclear how Plk1 activity is sustained in mitosis. Here we show that the Bora-Aurora-A complex remains the major activator of Plk1 in mitosis. We show that a small amount of Aurora-A activity is sufficient to phosphorylate and activate Plk1 in mitosis. In addition, a fraction of Bora is retained in mitosis, which is essential for continued Aurora-A-dependent T210 phosphorylation of Plk1. We find that once Plk1 is activated, minimal amounts of the Bora-Aurora-A complex are sufficient to sustain Plk1 activity. Thus, the activation of Plk1 by Aurora-A may function as a bistable switch; highly sensitive to inhibition of Aurora-A in its initial activation, but refractory to fluctuations in Aurora-A activity once Plk1 is fully activated. This provides a cell with robust Plk1 activity once it has committed to mitosis.

Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway

PubMed Central

Haustein, Martin D.; Kracun, Sebastian; Lu, Xiao-Hong; Shih, Tiffany; Jackson-Weaver, Olan; Tong, Xiaoping; Xu, Ji; Yang, X. William; O'Dell, Thomas J.; Marvin, Jonathan S.; Ellisman, Mark H.; Bushong, Eric A.; Looger, Loren L.; Khakh, Baljit S.

2014-01-01

Summary The spatiotemporal activities of astrocyte Ca2+ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca2+ and glutamate indicators as well as pharmacogenetic and electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localised spontaneous Ca2+ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte Ca2+ signaling changed linearly with the number of mossy fiber action potentials. Under these settings astrocyte responses were global, suppressed by neurotransmitter clearance and mediated by glutamate and GABA. Thus, astrocyte engagement in the fully developed mossy fiber pathway was slow and territorial, contrary to that frequently proposed for astrocytes within microcircuits. We show that astrocyte Ca2+ signaling functionally segregates large volumes of neuropil and that these transients are not suited for responding to, or regulating, single synapses in the mossy fiber pathway. PMID:24742463

Stabilizing function for myristoyl group revealed by the crystal structure of a neuronal calcium sensor, guanylate cyclase-activating protein 1.

PubMed

Stephen, Ricardo; Bereta, Grzegorz; Golczak, Marcin; Palczewski, Krzysztof; Sousa, Marcelo Carlos

2007-11-01

Guanylate cyclase-activating proteins (GCAPs) are Ca(2+)-binding proteins myristoylated at the N terminus that regulate guanylate cyclases in photoreceptor cells and belong to the family of neuronal calcium sensors (NCS). Many NCS proteins display a recoverin-like "calcium-myristoyl switch" whereby the myristoyl group, buried inside the protein in the Ca(2+)-free state, becomes fully exposed upon Ca(2+) binding. Here we present a 2.0 A resolution crystal structure of myristoylated GCAP1 with Ca(2+) bound. The acyl group is buried inside Ca(2+)-bound GCAP1. This is in sharp contrast to Ca(2+)-bound recoverin, where the myristoyl group is solvent exposed. Furthermore, we provide direct evidence that the acyl group in GCAP1 remains buried in the Ca(2+)-free state and does not undergo switching. A pronounced kink in the C-terminal helix and the presence of the myristoyl group allow clustering of sequence elements crucial for GCAP1 activity.

Stabilizing Function for Myristoyl Group Revealed by the Crystal Structure of a Neuronal Calcium Sensor, Guanylate Cyclase-Activating Protein 1

PubMed Central

Stephen, Ricardo; Bereta, Grzegorz; Golczak, Marcin; Palczewski, Krzysztof; Sousa, Marcelo Carlos

2008-01-01

SUMMARY Guanylate cyclase-activating proteins (GCAPs) are Ca2+-binding proteins myristoylated at the N terminus that regulate guanylate cyclases in photoreceptor cells and belong to the family of neuronal calcium sensors (NCS). Many NCS proteins display a recoverin-like “calcium-myristoyl switch” whereby the myristoyl group, buried inside the protein in the Ca2+-free state, becomes fully exposed upon Ca2+ binding. Here we present a 2.0 Å resolution crystal structure of myristoylated GCAP1 with Ca2+ bound. The acyl group is buried inside Ca2+-bound GCAP1. This is in sharp contrast to Ca2+-bound recoverin, where the myristoyl group is solvent exposed. Furthermore, we provide direct evidence that the acyl group in GCAP1 remains buried in the Ca2+-free state and does not undergo switching. A pronounced kink in the C-terminal helix and the presence of the myristoyl group allow clustering of sequence elements crucial for GCAP1 activity. PMID:17997965

Duplication of the genome in normal and cancer cell cycles.

PubMed

Bandura, Jennifer L; Calvi, Brian R

2002-01-01

It is critical to discover the mechanisms of normal cell cycle regulation if we are to fully understand what goes awry in cancer cells. The normal eukaryotic cell tightly regulates the activity of origins of DNA replication so that the genome is duplicated exactly once per cell cycle. Over the last ten years much has been learned concerning the cell cycle regulation of origin activity. It is now clear that the proteins and cell cycle mechanisms that control origin activity are largely conserved from yeast to humans. Despite this conservation, the composition of origins of DNA replication in higher eukaryotes remains ill defined. A DNA consensus for predicting origins has yet to emerge, and it is of some debate whether primary DNA sequence determines where replication initiates. In this review we outline what is known about origin structure and the mechanism of once per cell cycle DNA replication with an emphasis on recent advances in mammalian cells. We discuss the possible relevance of these regulatory pathways for cancer biology and therapy.

Habitable Worlds: Delivering on the Promises of Online Education

NASA Astrophysics Data System (ADS)

Horodyskyj, Lev B.; Mead, Chris; Belinson, Zack; Buxner, Sanlyn; Semken, Steven; Anbar, Ariel D.

2018-01-01

Critical thinking and scientific reasoning are central to higher education in the United States, but many courses (in-person and online) teach students information about science much more than they teach the actual process of science and its associated knowledge and skills. In the online arena specifically, the tools available for course construction exacerbate this problem by making it difficult to build the types of active learning activities that research shows to be the most effective. Here, we present a report on Habitable Worlds, offered by Arizona State University for 12 semesters over the past 6 years. This is a unique online course that uses an array of novel technologies to deliver an active, inquiry-driven learning experience. Learning outcomes and quantitative data from more than 3000 students demonstrate the success of our approach but also identify several remaining challenges. The design and development of this course offers valuable lessons for instructional designers and educators who are interested in fully capitalizing on the capabilities of 21st-century technology to achieve educational goals.

Host-Derived Leukotriene B4 Is Critical for Resistance against Invasive Pulmonary Aspergillosis.

PubMed

Caffrey-Carr, Alayna K; Hilmer, Kimberly M; Kowalski, Caitlin H; Shepardson, Kelly M; Temple, Rachel M; Cramer, Robert A; Obar, Joshua J

2017-01-01

Aspergillus fumigatus is a mold that causes severe pulmonary infections. Our knowledge of how immune competent hosts maintain control of fungal infections while constantly being exposed to fungi is rapidly emerging. It is known that timely neutrophil recruitment to and activation in the lungs is critical to the host defense against development of invasive pulmonary aspergillosis, but the inflammatory sequelae necessary remains to be fully defined. Here, we show that 5-Lipoxygenase (5-LO) and Leukotriene B 4 (LTB 4 ) are critical for leukocyte recruitment and resistance to pulmonary A. fumigatus challenge in a fungal-strain-dependent manner. 5-LO activity was needed in radiosensitive cells for an optimal anti-fungal response and in vivo LTB 4 production was at least partially dependent on myeloid-derived hypoxia inducible factor-1α. Overall, this study reveals a role for host-derived leukotriene synthesis in innate immunity to A. fumigatus .

Living bacteria in silica gels

NASA Astrophysics Data System (ADS)

Nassif, Nadine; Bouvet, Odile; Noelle Rager, Marie; Roux, Cécile; Coradin, Thibaud; Livage, Jacques

2002-09-01

The encapsulation of enzymes within silica gels has been extensively studied during the past decade for the design of biosensors and bioreactors. Yeast spores and bacteria have also been recently immobilized within silica gels where they retain their enzymatic activity, but the problem of the long-term viability of whole cells in an inorganic matrix has never been fully addressed. It is a real challenge for the development of sol-gel processes. Generic tests have been performed to check the viability of Escherichia coli bacteria in silica gels. Surprisingly, more bacteria remain culturable in the gel than in an aqueous suspension. The metabolic activity of the bacteria towards glycolysis decreases slowly, but half of the bacteria are still viable after one month. When confined within a mineral environment, bacteria do not form colonies. The exchange of chemical signals between isolated bacteria rather than aggregates can then be studied, a point that could be very important for 'quorum sensing'.

Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

PubMed

Barik, Jacques; Marti, Fabio; Morel, Carole; Fernandez, Sebastian P; Lanteri, Christophe; Godeheu, Gérard; Tassin, Jean-Pol; Mombereau, Cédric; Faure, Philippe; Tronche, François

2013-01-18

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

The role of syncytins in human reproduction and reproductive organ cancers.

PubMed

Soygur, Bikem; Sati, Leyla

2016-11-01

Human life begins with sperm and oocyte fusion. After fertilization, various fusion events occur during human embryogenesis and morphogenesis. For example, the fusion of trophoblastic cells constitutes a key process for normal placental development. Fusion in the placenta is facilitated by syncytin 1 and syncytin 2. These syncytins arose from retroviral sequences that entered the primate genome 25 million and more than 40 million years ago respectively. About 8% of the human genome consists of similar human endogenous retroviral (HERVs) sequences. Many are inactive because of mutations or deletions. However, the role of the few that remain transcriptionally active has not been fully elucidated. Syncytin proteins maintain cell-cell fusogenic activity based on ENV: gene-mediated viral cell entry. In this review, we summarize how syncytins and their receptors are involved in fusion events during human reproduction. The significance of syncytins in tumorigenesis is also discussed. © 2016 Society for Reproduction and Fertility.

Equations of Interdoublet Separation during Flagella Motion Reveal Mechanisms of Wave Propagation and Instability

PubMed Central

Bayly, Philip V.; Wilson, Kate S.

2014-01-01

The motion of flagella and cilia arises from the coordinated activity of dynein motor protein molecules arrayed along microtubule doublets that span the length of axoneme (the flagellar cytoskeleton). Dynein activity causes relative sliding between the doublets, which generates propulsive bending of the flagellum. The mechanism of dynein coordination remains incompletely understood, although it has been the focus of many studies, both theoretical and experimental. In one leading hypothesis, known as the geometric clutch (GC) model, local dynein activity is thought to be controlled by interdoublet separation. The GC model has been implemented as a numerical simulation in which the behavior of a discrete set of rigid links in viscous fluid, driven by active elements, was approximated using a simplified time-marching scheme. A continuum mechanical model and associated partial differential equations of the GC model have remained lacking. Such equations would provide insight into the underlying biophysics, enable mathematical analysis of the behavior, and facilitate rigorous comparison to other models. In this article, the equations of motion for the flagellum and its doublets are derived from mechanical equilibrium principles and simple constitutive models. These equations are analyzed to reveal mechanisms of wave propagation and instability in the GC model. With parameter values in the range expected for Chlamydomonas flagella, solutions to the fully nonlinear equations closely resemble observed waveforms. These results support the ability of the GC hypothesis to explain dynein coordination in flagella and provide a mathematical foundation for comparison to other leading models. PMID:25296329

Biogeochemical processes controlling density stratification in an iron-meromictic lake

NASA Astrophysics Data System (ADS)

Nixdorf, E.; Boehrer, B.

2015-06-01

Biogeochemical processes and mixing regime of a lake can control each other mutually. The prominent case of iron meromixis is investigated in Waldsee near Doebern, a small lake that originated from surface mining of lignite. From a four years data set of monthly measured electrical conductivity profiles, we calculated summed conductivity as a quantitative variable reflecting the amount of electro-active substances in the entire lake. Seasonal variations followed changing chemocline height. Coinciding changes of electrical conductivities in the monimolimnion indicated that a considerable share of substances, precipitated by the advancing oxygenated epilimnion, re-dissolved in the remaining anoxic deep waters and contributed considerably to the density stratification. In addition, we constructed a lab experiment, in which aeration of monimolimnetic waters removed iron compounds and organic material. Precipitates could be identified by visual inspection. Introduced air bubbles ascended through the water column and formed a water mass similar to the mixolimnetic Waldsee water. The remaining less dense water remained floating on the nearly unchanged monimolimnetic water. In conclusion, iron meromixis as seen in Waldsee did not require two different sources of incoming waters, but the inflow of iron rich deep groundwater and the aeration through the lake surface were fully sufficient.

Long-term fuel retention and release in JET ITER-Like Wall at ITER-relevant baking temperatures

NASA Astrophysics Data System (ADS)

Heinola, K.; Likonen, J.; Ahlgren, T.; Brezinsek, S.; De Temmerman, G.; Jepu, I.; Matthews, G. F.; Pitts, R. A.; Widdowson, A.; Contributors, JET

2017-08-01

The fuel outgassing efficiency from plasma-facing components exposed in JET-ILW has been studied at ITER-relevant baking temperatures. Samples retrieved from the W divertor and Be main chamber were annealed at 350 and 240 °C, respectively. Annealing was performed with thermal desoprtion spectrometry (TDS) for 0, 5 and 15 h to study the deuterium removal effectiveness at the nominal baking temperatures. The remained fraction was determined by emptying the samples fully of deuterium by heating W and Be samples up to 1000 and 775 °C,respectively. Results showed the deposits in the divertor having an increasing effect to the remaining retention at temperatures above baking. Highest remaining fractions 54 and 87 % were observed with deposit thicknesses of 10 and 40 μm, respectively. Substantially high fractions were obtained in the main chamber samples from the deposit-free erosion zone of the limiter midplane, in which the dominant fuel retention mechanism is via implantation: 15 h annealing resulted in retained deuterium higher than 90 % . TDS results from the divertor were simulated with TMAP7 calculations. The spectra were modelled with three deuterium activation energies resulting in good agreement with the experiments.

Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca2+ Cycling

PubMed Central

Tocchetti, Carlo G.; Wang, Wang; Froehlich, Jeffrey P.; Huke, Sabine; Aon, Miguel A.; Wilson, Gerald M.; Benedetto, Giulietta Di; O’Rourke, Brian; Gao, Wei Dong; Wink, David A.; Toscano, John P.; Zaccolo, Manuela; Bers, Donald M.; Valdivia, Hector H.; Cheng, Heping; Kass, David A.; Paolocci, Nazareno

2009-01-01

Heart failure remains a leading cause of morbidity and mortality worldwide. Although depressed pump function is common, development of effective therapies to stimulate contraction has proven difficult. This is thought to be attributable to their frequent reliance on cAMP stimulation to increase activator Ca2+. A potential alternative is nitroxyl (HNO), the 1-electron reduction product of nitric oxide (NO) that improves contraction and relaxation in normal and failing hearts in vivo. The mechanism for myocyte effects remains unknown. Here, we show that this activity results from a direct interaction of HNO with the sarcoplasmic reticulum Ca2+ pump and the ryanodine receptor 2, leading to increased Ca2+ uptake and release from the sarcoplasmic reticulum. HNO increases the open probability of isolated ryanodine-sensitive Ca2+-release channels and accelerates Ca2+ reuptake into isolated sarcoplasmic reticulum by stimulating ATP-dependent Ca2+ transport. Contraction improves with no net rise in diastolic calcium. These changes are not induced by NO, are fully reversible by addition of reducing agents (redox sensitive), and independent of both cAMP/protein kinase A and cGMP/protein kinase G signaling. Rather, the data support HNO/thiolate interactions that enhance the activity of intracellular Ca2+ cycling proteins. These findings suggest HNO donors are attractive candidates for the pharmacological treatment of heart failure. PMID:17138943

What kind of noise is brain noise: anomalous scaling behavior of the resting brain activity fluctuations

PubMed Central

Fraiman, Daniel; Chialvo, Dante R.

2012-01-01

The study of spontaneous fluctuations of brain activity, often referred as brain noise, is getting increasing attention in functional magnetic resonance imaging (fMRI) studies. Despite important efforts, much of the statistical properties of such fluctuations remain largely unknown. This work scrutinizes these fluctuations looking at specific statistical properties which are relevant to clarify its dynamical origins. Here, three statistical features which clearly differentiate brain data from naive expectations for random processes are uncovered: First, the variance of the fMRI mean signal as a function of the number of averaged voxels remains constant across a wide range of observed clusters sizes. Second, the anomalous behavior of the variance is originated by bursts of synchronized activity across regions, regardless of their widely different sizes. Finally, the correlation length (i.e., the length at which the correlation strength between two regions vanishes) as well as mutual information diverges with the cluster's size considered, such that arbitrarily large clusters exhibit the same collective dynamics than smaller ones. These three properties are known to be exclusive of complex systems exhibiting critical dynamics, where the spatio-temporal dynamics show these peculiar type of fluctuations. Thus, these findings are fully consistent with previous reports of brain critical dynamics, and are relevant for the interpretation of the role of fluctuations and variability in brain function in health and disease. PMID:22934058

The South Central Superpave Center: Report of Activities

DOT National Transportation Integrated Search

1998-12-01

The planning of the South Central Superpave Center (SCSC) began in mid-1994. The Center hired its first staff in early 1995 and was fully staffed by June 1995, at which point it became fully operational. This report describes SCSC activities that too...

Distinctive Responses of Ribulose-1,5-Bisphosphate Carboxylase and Carbonic Anhydrase in Wheat Leaves to Nitrogen Nutrition and their Possible Relationships to CO2-Transfer Resistance 1

PubMed Central

Makino, Amane; Sakashita, Hiroshi; Hidema, Jun; Mae, Tadahiko; Ojima, Kunihiko; Osmond, Barry

1992-01-01

The amounts of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), total chlorophyll (Chl), and total leaf nitrogen were measured in fully expanded, young leaves of wheat (Triticum aestivum L.), rice (Oryza sativa L.), spinach (Spinacia oleracea L.), bean (Phaseolus vulgaris L.), and pea (Pisum sativum L.). In addition, the activities of whole-chain electron transport and carbonic anhydrase were measured. All plants were grown hydroponically at different nitrogen concentrations. Although a greater than proportional increase in Rubisco content relative to leaf nitrogen content and Chl was found with increasing nitrogen supply for rice, spinach, bean, and pea, the ratio of Rubisco to total leaf nitrogen or Chl in wheat was essentially independent of nitrogen treatment. In addition, the ratio of Rubisco to electron transport activities remained constant only in wheat. Nevertheless, gas-exchange analysis showed that the in vivo balance between the capacities of Rubisco and electron transport in wheat, rice, and spinach remained almost constant, irrespective of nitrogen treatment. The in vitro carbonic anhydrase activity in wheat was very low and strongly responsive to increasing nitrogen content. Such a response was not found for the other C3 plants examined, which had 10- to 30-fold higher carbonic anhydrase activity than wheat at any leaf-nitrogen content. These distinctive responses of carbonic anhydrase activity in wheat were discussed in relation to CO2-transfer resistance and the in vivo balance between the capacities of Rubisco and electron transport. PMID:16653191

Audit of pressure area care and documentation.

PubMed

Cockbill-Black, S; Bond, J; Bersée-Mills, A; Warren, K; Hammerton, S; Found, D; Daley, L

1999-12-01

Intensive care patients are at particular risk of pressure damage. Documentation does not always fully reflect practice. Pressure sore identification remains a subjective issue. Nurses do not always complete patient documentation.

Piezo1 in Smooth Muscle Cells Is Involved in Hypertension-Dependent Arterial Remodeling.

PubMed

Retailleau, Kevin; Duprat, Fabrice; Arhatte, Malika; Ranade, Sanjeev Sumant; Peyronnet, Rémi; Martins, Joana Raquel; Jodar, Martine; Moro, Céline; Offermanns, Stefan; Feng, Yuanyi; Demolombe, Sophie; Patel, Amanda; Honoré, Eric

2015-11-10

The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch-activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Hemodynamic signals in fNIRS.

PubMed

Hoshi, Y

Near-infrared spectroscopy (NIRS) was originally designed for clinical monitoring of tissue oxygenation, and it has also been developed into a useful tool in neuroimaging studies, with the so-called functional NIRS (fNIRS). With NIRS, cerebral activation is detected by measuring the cerebral hemoglobin (Hb), where however, the precise correlation between NIRS signal and neural activity remains to be fully understood. This can in part be attributed to the situation that NIRS signals are inherently subject to contamination by signals arising from extracerebral tissue. In recent years, several approaches have been investigated to distinguish between NIRS signals originating in cerebral tissue and signals originating in extracerebral tissue. Selective measurements of cerebral Hb will enable a further evolution of fNIRS. This chapter is divided into six sections: first a summary of the basic theory of NIRS, NIRS signals arising in the activated areas, correlations between NIRS signals and fMRI signals, correlations between NIRS signals and neural activities, and the influence of a variety of extracerebral tissue on NIRS signals and approaches to this issue are reviewed. Finally, future prospects of fNIRS are described. © 2016 Elsevier B.V. All rights reserved.

Habitable Worlds: Delivering on the Promises of Online Education.

PubMed

Horodyskyj, Lev B; Mead, Chris; Belinson, Zack; Buxner, Sanlyn; Semken, Steven; Anbar, Ariel D

2018-01-01

Critical thinking and scientific reasoning are central to higher education in the United States, but many courses (in-person and online) teach students information about science much more than they teach the actual process of science and its associated knowledge and skills. In the online arena specifically, the tools available for course construction exacerbate this problem by making it difficult to build the types of active learning activities that research shows to be the most effective. Here, we present a report on Habitable Worlds, offered by Arizona State University for 12 semesters over the past 6 years. This is a unique online course that uses an array of novel technologies to deliver an active, inquiry-driven learning experience. Learning outcomes and quantitative data from more than 3000 students demonstrate the success of our approach but also identify several remaining challenges. The design and development of this course offers valuable lessons for instructional designers and educators who are interested in fully capitalizing on the capabilities of 21 st -century technology to achieve educational goals. Key Words: Online education-Active learning-SETI-Astrobiology-Teaching. Astrobiology 17, 86-99.

Bottleneck Effect of N,N-Dimethylformamide in InOF-1: Increasing CO2 Capture in Porous Coordination Polymers.

PubMed

Sánchez-González, Elí; González-Zamora, Eduardo; Martínez-Otero, Diego; Jancik, Vojtech; Ibarra, Ilich A

2017-05-15

The bottleneck effect of confined N,N-dimethylformamide (DMF) molecules was observed in InOF-1 for the first time: CO 2 capture was remarkably enhanced in samples of as-synthesized InOF-1, thermally activated in such a way that a small residual amount of DMF molecules remained confined within the pores (DMF@InOF-1). Dynamic CO 2 adsorption experiments on DMF@InOF-1 exhibited a CO 2 capture of 8.06 wt % [1.5-fold higher than that of a fully activated InOF-1 (5.24%)]. DMF@InOF-1 can reversibly adsorb/desorb 8.09% CO 2 with no loss of CO 2 capacity after 10 cycles, and the desorption is accomplished by only turning the CO 2 flow off. Static CO 2 adsorption experiments (at 196 K) demonstrated a 1.4-fold CO 2 capture increase (from 5.5 mmol·g -1 , fully activated InOF-1, to 7.5 mmol·g -1 , DMF@InOF-1). Therefore, these CO 2 capture properties are the result of the presence of residual-confined DMF molecules within the InOF-1 framework and their interactions via a very strong hydrogen bond with the In 2 (μ-OH) groups, which prevent DMF leaching. The stability of this hydrogen bond is given by a perfect fit of the DMF molecule in the "dent" around the OH group that allows a nearly ideal orientation of the DMF molecule towards the OH group.

Oyster reef restoration in the northern Gulf of Mexico: extent, methods and outcomes

USGS Publications Warehouse

LaPeyre, Megan K.; Furlong, Jessica N.; Brown, Laura A.; Piazza, Bryan P.; Brown, Ken

2014-01-01

Shellfish reef restoration to support ecological services has become more common in recent decades, driven by increasing awareness of the functional decline of shellfish systems. Maximizing restoration benefits and increasing efficiency of shellfish restoration activities would greatly benefit from understanding and measurement of system responses to management activities. This project (1) compiles a database of northern Gulf of Mexico inshore artificial oyster reefs created for restoration purposes, and (2) quantitatively assesses a subset of reefs to determine project outcomes. We documented 259 artificial inshore reefs created for ecological restoration. Information on reef material, reef design and monitoring was located for 94, 43 and 20% of the reefs identified. To quantify restoration success, we used diver surveys to quantitatively sample oyster density and substrate volume of 11 created reefs across the coast (7 with rock; 4 with shell), paired with 7 historic reefs. Reefs were defined as fully successful if there were live oysters, and partially successful if there was hard substrate. Of these created reefs, 73% were fully successful, while 82% were partially successful. These data highlight that critical information related to reef design, cost, and success remain difficult to find and are generally inaccessible or lost, ultimately hindering efforts to maximize restoration success rates. Maintenance of reef creation information data, development of standard reef performance measures, and inclusion of material and reef design testing within reef creation projects would be highly beneficial in implementing adaptive management. Adaptive management protocols seek specifically to maximize short and long-term restoration success, but are critically dependent on tracking and measuring system responses to management activities.

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation.

PubMed

Chaudhary, Vidyanath; Zhang, Shuo; Yuen, Kit-San; Li, Chuan; Lui, Pak-Yin; Fung, Sin-Yee; Wang, Pei-Hui; Chan, Chi-Ping; Li, Dexin; Kok, Kin-Hang; Liang, Mifang; Jin, Dong-Yan

2015-11-01

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen causing significant morbidity and mortality in Asia. NSs protein of SFTSV is known to perturb type I IFN induction and signalling, but the mechanism remains to be fully understood. Here, we showed the suppression of both type I and type III IFN signalling by SFTSV NSs protein is mediated through inhibition of STAT1 phosphorylation and activation. Infection with live SFTSV or expression of NSs potently suppressed IFN-stimulated genes but not NFkB activation. NSs was capable of counteracting the activity of IFN-α1, IFN-β, IFN-λ1 and IFN-λ2. Mechanistically, NSs associated with STAT1 and STAT2, mitigated IFN-β-induced phosphorylation of STAT1 at S727, and reduced the expression and activity of STAT1 protein in IFN-β-treated cells, resulting in the inhibition of STAT1 and STAT2 recruitment to IFNstimulated promoters. Taken together, SFTSV NSs protein is an IFN antagonist that suppresses phosphorylation and activation of STAT1.

CRISPR-on system for the activation of the endogenous human INS gene.

PubMed

Giménez, C A; Ielpi, M; Mutto, A; Grosembacher, L; Argibay, P; Pereyra-Bonnet, F

2016-06-01

Advances in the field of epigenetics have allowed the design of new therapeutic strategies to address complex diseases such as type 1 diabetes (T1D). Clustered regularly interspaced short palindromic repeats (CRISPR)-on is a novel and powerful RNA-guided transcriptional activator system that can turn on specific gene expression; however, it remains unclear whether this system can be widely used or whether its use will be restricted depending on cell types, methylation promoter statuses or the capacity to modulate chromatin state. Our results revealed that the CRISPR-on system fused with transcriptional activators (dCas9-VP160) activated endogenous human INS, which is a silenced gene with a fully methylated promoter. Similarly, we observed a synergistic effect on gene activation when multiple single guide RNAs were used, and the transcriptional activation was maintained until day 21. Regarding the epigenetic profile, the targeted promoter gene did not exhibit alteration in its methylation status but rather exhibited altered levels of H3K9ac following treatment. Importantly, we showed that dCas9-VP160 acts on patients' cells in vitro, particularly the fibroblasts of patients with T1D.

Iodothyronine 5'-deiodinase activity and thyroid hormone content in brown adipose tissue during the breeding cycle of the rat.

PubMed Central

Viñas, O; Giralt, M; Obregón, M J; Iglesias, R; Villarroya, F; Mampel, T

1988-01-01

Brown adipose tissue iodothyronine 5'-deiodinase activity is significantly lower in 17-day pregnant rats compared with virgin controls and remains low during late pregnancy and lactation. It fully recovers with abrupt weaning, but only partially with spontaneous weaning. Even though this profile of changes is remarkably in step with the known pattern of modifications in brown fat thermogenesis during the breeding cycle, the lowered iodothyronine 5'-deiodinase activity appearing between days 15 and 17 of pregnancy occurs earlier than the reduction in brown adipose tissue thermogenesis. Brown fat 3,3',5-tri-iodothyronine content is also reduced in late pregnant, early and mid-lactating rats, most probably as a consequence of the lowered 5'-deiodination of thyroxine in situ. Acute insulin treatment increases brown fat iodothyronine 5'-deiodinase activity in virgin animals as well as in late-pregnant and lactating rats, despite the lowered basal enzyme activity levels in the latter groups. Thus an impaired response to insulin in brown fat does not appear to be a factor leading to the lowered iodothyronine 5'-deiodinase activity during late pregnancy and lactation. PMID:3060112

A Genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) Screen Identifies NEK7 as an Essential Component of NLRP3 Inflammasome Activation.

PubMed

Schmid-Burgk, Jonathan L; Chauhan, Dhruv; Schmidt, Tobias; Ebert, Thomas S; Reinhardt, Julia; Endl, Elmar; Hornung, Veit

2016-01-01

Inflammasomes are high molecular weight protein complexes that assemble in the cytosol upon pathogen encounter. This results in caspase-1-dependent pro-inflammatory cytokine maturation, as well as a special type of cell death, known as pyroptosis. The Nlrp3 inflammasome plays a pivotal role in pathogen defense, but at the same time, its activity has also been implicated in many common sterile inflammatory conditions. To this effect, several studies have identified Nlrp3 inflammasome engagement in a number of common human diseases such as atherosclerosis, type 2 diabetes, Alzheimer disease, or gout. Although it has been shown that known Nlrp3 stimuli converge on potassium ion efflux upstream of Nlrp3 activation, the exact molecular mechanism of Nlrp3 activation remains elusive. Here, we describe a genome-wide CRISPR/Cas9 screen in immortalized mouse macrophages aiming at the unbiased identification of gene products involved in Nlrp3 inflammasome activation. We employed a FACS-based screen for Nlrp3-dependent cell death, using the ionophoric compound nigericin as a potassium efflux-inducing stimulus. Using a genome-wide guide RNA (gRNA) library, we found that targeting Nek7 rescued macrophages from nigericin-induced lethality. Subsequent studies revealed that murine macrophages deficient in Nek7 displayed a largely blunted Nlrp3 inflammasome response, whereas Aim2-mediated inflammasome activation proved to be fully intact. Although the mechanism of Nek7 functioning upstream of Nlrp3 yet remains elusive, these studies provide a first genetic handle of a component that specifically functions upstream of Nlrp3. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeted carbon conservation at national scales with high-resolution monitoring

PubMed Central

Asner, Gregory P.; Knapp, David E.; Martin, Roberta E.; Tupayachi, Raul; Anderson, Christopher B.; Mascaro, Joseph; Sinca, Felipe; Chadwick, K. Dana; Higgins, Mark; Farfan, William; Llactayo, William; Silman, Miles R.

2014-01-01

Terrestrial carbon conservation can provide critical environmental, social, and climate benefits. Yet, the geographically complex mosaic of threats to, and opportunities for, conserving carbon in landscapes remain largely unresolved at national scales. Using a new high-resolution carbon mapping approach applied to Perú, a megadiverse country undergoing rapid land use change, we found that at least 0.8 Pg of aboveground carbon stocks are at imminent risk of emission from land use activities. Map-based information on the natural controls over carbon density, as well as current ecosystem threats and protections, revealed three biogeographically explicit strategies that fully offset forthcoming land-use emissions. High-resolution carbon mapping affords targeted interventions to reduce greenhouse gas emissions in rapidly developing tropical nations. PMID:25385593

The SPIRIT Telescope Initiative: Six Years On (Abstract)

NASA Astrophysics Data System (ADS)

Luckas, P.

2017-12-01

(Abstract only) Now in its sixth year of operation, the SPIRIT initiative remains unique in Australia, as a robust web-enabled robotic telescope initiative funded for education and outreach. With multiple modes of operation catering for a variety of usage scenarios and a fully supported education program, SPIRIT provides free access to contemporary astronomical tools for students and educators in Western Australia and beyond. The technical solution itself provides an excellent model for low cost robotic telescope installations, and the education program has evolved over time to include a broad range of student experiences - from engagement activities to authentic science. This paper details the robotic telescope solution, student interface, and educational philosophy, summarizes achievements and lessons learned, and examines the possibilities for future enhancement including spectroscopy.

Aging accelerates memory extinction and impairs memory restoration in Drosophila.

PubMed

Chen, Nannan; Guo, Aike; Li, Yan

2015-05-15

Age-related memory impairment (AMI) is a phenomenon observed from invertebrates to human. Memory extinction is proposed to be an active inhibitory modification of memory, however, whether extinction is affected in aging animals remains to be elucidated. Employing a modified paradigm for studying memory extinction in fruit flies, we found that only the stable, but not the labile memory component was suppressed by extinction, thus effectively resulting in higher memory loss in aging flies. Strikingly, young flies were able to fully restore the stable memory component 3 h post extinction, while aging flies failed to do so. In conclusion, our findings reveal that both accelerated extinction and impaired restoration contribute to memory impairment in aging animals. Copyright © 2015 Elsevier Inc. All rights reserved.

Targeted carbon conservation at national scales with high-resolution monitoring.

PubMed

Asner, Gregory P; Knapp, David E; Martin, Roberta E; Tupayachi, Raul; Anderson, Christopher B; Mascaro, Joseph; Sinca, Felipe; Chadwick, K Dana; Higgins, Mark; Farfan, William; Llactayo, William; Silman, Miles R

2014-11-25

Terrestrial carbon conservation can provide critical environmental, social, and climate benefits. Yet, the geographically complex mosaic of threats to, and opportunities for, conserving carbon in landscapes remain largely unresolved at national scales. Using a new high-resolution carbon mapping approach applied to Perú, a megadiverse country undergoing rapid land use change, we found that at least 0.8 Pg of aboveground carbon stocks are at imminent risk of emission from land use activities. Map-based information on the natural controls over carbon density, as well as current ecosystem threats and protections, revealed three biogeographically explicit strategies that fully offset forthcoming land-use emissions. High-resolution carbon mapping affords targeted interventions to reduce greenhouse gas emissions in rapidly developing tropical nations.

Neural Network Prediction of Aluminum-Lithium Weld Strengths from Acoustic Emission Amplitude Data

NASA Technical Reports Server (NTRS)

Hill, Eric v. K.; Israel, Peggy L.; Knotts, Gregory L.

1993-01-01

Acoustic Emission (AE) flaw growth activity was monitored in aluminum-lithium weld specimens from the onset tensile loading to failure. Data on actual ultimate strengths together with AE data from the beginning of loading up to 25 percent of the expected ultimate strength were used to train a backpropagation neural network to predict ultimate strengths. Architecturally, the fully interconnected network consisted of an input layer for the AE amplitude data, a hidden layer to accommodate failure mechanism mapping, and an output layer for ultimate strength prediction. The trained network was the applied to the prediction of ultimate strengths in the remaining six specimens. The worst case prediction error was found to be +2.6 percent.

The SPIRIT Telescope Initiative: six years on

NASA Astrophysics Data System (ADS)

Luckas, Paul

2017-06-01

Now in its sixth year of operation, the SPIRIT initiative remains unique in Australia, as a robust web-enabled robotic telescope initiative funded for education and outreach. With multiple modes of operation catering for a variety of usage scenarios and a fully supported education program, SPIRIT provides free access to contemporary astronomical tools for students and educators in Western Australia and beyond. The technical solution itself provides an excellent model for low cost robotic telescope installations, and the education program has evolved over time to include a broad range of student experiences-from engagement activities to authentic science. This paper details the robotic telescope solution, student interface and educational philosophy, summarises achievements and lessons learned and examines the possibilities for future enhancement including spectroscopy.

Dual Role of Water in Heterogeneous Catalytic Hydrolysis of Sarin by Zirconium-Based Metal-Organic Frameworks.

PubMed

Momeni, Mohammad R; Cramer, Christopher J

2018-05-22

Recent experimental studies on Zr IV -based metal-organic frameworks (MOFs) have shown the extraordinary effectiveness of these porous materials for the detoxification of phosphorus-based chemical warfare agents (CWAs). However, pressing challenges remain with respect to characterizing these catalytic processes both at the molecular and crystalline levels. We here use theory to compare the reactivity of different zirconium-based MOFs for the catalytic hydrolysis of the CWA sarin, using both periodic and cluster modeling. We consider both hydrated and dehydrated secondary building units, as well as linker functionalized MOFs, to more fully understand and rationalize available experimental findings as well as to enable concrete predictions for achieving higher activities for the decomposition of CWAs.

Molecular mechanisms of immunosuppression by cyclosporins.

PubMed

Zenke, G; Baumann, G; Wenger, R; Hiestand, P; Quesniaux, V; Andersen, E; Schreier, M H

1993-06-23

Despite the successful clinical application of the immunosuppressive drug cyclosporin A (CsA, Sandimmun), its precise mechanism of action in the process of T cell activation remains elusive. CsA binds to the high-affinity cytosolic receptor cyclophilin whose peptidyl-prolyl cis-trans isomerase activity is inhibited upon binding. The linkage of this effect with the inhibition of the T cell receptor-mediated signal transduction pathway, which leads to a suppression of lymphokine gene transcription, is still unclear. We analyzed the relationship between cyclophilin-binding and immunosuppressive activity (e.g., effect on IL-2 transcription) of cyclosporin derivatives in vitro. The results show that binding to cyclophilin is required, but not sufficient for immunosuppression. Cyclosporin analogues which completely lack immunosuppressive activity but fully retained their cyclophilin-binding capacity antagonize the immunosuppressive activity of CsA. These derivatives inhibit the isomerase activity of cyclophilin, which clearly demonstrates that inhibition of the cyclophilin isomerase activity does not lead to immunosuppression. In analogy to the other immunosuppressants of microbial origin, FK-506 and rapamycin, a specific structure of the "effector" domain of CsA, which is unrelated to the cyclophilin-binding domain, determines the biological activity. In the nucleus, CsA interferes with the DNA-binding of inducible transcription factors to their respective DNA motifs within lymphokine promoters by affecting intracellular translocation of transcription factor subunits.

Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer

PubMed Central

Gai, Wen-Tao; Yu, Da-Peng; Wang, Xin-Sheng; Wang, Pei-Tao

2016-01-01

Ursolic acid is a type of pentacyclic triterpene compound with multiple pharmacological activities including cancer resistance, protection from liver injury, antisepsis, anti-inflammation and antiviral activity. The present study aimed to investigate the anticancer effect of ursolic acid. Ursolic acid activates cell apoptosis and its pro-apoptotic mechanism remains to be fully elucidated. Cell Counting kit-8 assays, flow cytometric analysis and analysis of caspase-3 and caspase-9 activity were used to estimate the anticancer effect of ursolic acid on DU145 prostate cancer cells. The protein expression of cytochrome c, rho-associated protein kinase (ROCK), phosphatase and tensin homolog (PTEN) and cofilin-1 were examined using western blot analysis. In the present study, ursolic acid significantly suppressed cell growth and induced apoptosis, as well as increasing caspase-3 and caspase-9 activities of DU145 cells. Furthermore, cytoplasmic and mitochondrial cytochrome c protein expression was significantly activated and suppressed, respectively, by ursolic acid. Ursolic acid significantly suppressed the ROCK/PTEN signaling pathway and inhibited cofilin-1 protein expression in DU145 cells. The results of the present study indicate that the anticancer effect of ursolic acid activates cell apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer. PMID:27698874

The economics of personalized medicine: commercialization as a driver of return on investment.

PubMed

Keeling, Peter; Roth, Mollie; Zietlow, Tom

2012-09-15

Optimizing commercialization of drugs is the sine qua non of the pharmaceutical industry and intensive work has been done to characterize fully the drivers of drug adoption and understand the resources required to optimize those drivers for full adoption of drugs. Conversely, while the pharmaceutical industry is actively embracing the new personalized medicine (PM) paradigm, much work remains to be done to understand fully what drives adoption of targeted therapies and how to resource those drivers appropriately. While the industry is slowly learning from its early missteps, progress is still inhibited by a lack of understanding of the specific hurdles that individual development teams face in developing and commercializing targeted therapies and the requirement for budgets specifically aimed at driving test adoption. This article considers the benefits of optimizing commercial planning in the PM space and the potential negative impact in potentially failing to optimize that planning. Real world insights are used to illustrate that a far broader commercial lens is required in the PM space and will touch on functional areas not usually included in the context of 'commercial' decisions. Copyright © 2012 Elsevier B.V. All rights reserved.

Helping Children Cope with Medical Tests and Interventions

PubMed Central

Lang, Elvira V.; Viegas, Jacqueline; Bleeker, Chris; Bruhn, Jörgen; Geert-Jan van, Geffen

2016-01-01

Medical procedures and tests become a challenge when anxiety and pain make it difficult for the patient to cooperate or remain still when needed. Fortunately a short intervention with hypnoidal language at the onset of a procedure induces a positive and sustained change in the way pain and anxiety are processed. While anesthesia may appear to be a simple solution to eliminate pain, the adverse effects of pre-anesthesia anxiety on postoperative behavior and recovery are often not fully appreciated. This paper discusses options for self-hypnotic relaxation that are applicable to interactions with children. The high suggestibility of children makes it relatively easy to engage them in make-believe scenarios. Avoidance of negative suggestions is key in avoiding nocebo effects that may be difficult to overcome later. Once a child is immersed in his or her preferred scenario or hobby/activity of choice, environmental and procedural stimuli can be easily integrated in the imagery. Ego-strengthening metaphors that tie in features of strength, confidence, or resilience are particularly empowering. Even when children are fully under general anesthesia they may still have recall of what is said in the room and therefore caution in word choice should be maintained. PMID:28943814

Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

PubMed Central

Ribot, Wilson J.; Panchal, Rekha G.; Brittingham, Katherine C.; Ruthel, Gordon; Kenny, Tara A.; Lane, Douglas; Curry, Bob; Hoover, Timothy A.; Friedlander, Arthur M.; Bavari, Sina

2006-01-01

Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the binary complex virulence factors produced by B. anthracis, on freshly isolated nonhuman primate AM. Exposure of AM to doses of LT that killed susceptible macrophages had no effect on the viability of AM, despite complete MEK1 cleavage. Intoxicated AM remained fully capable of B. anthracis spore phagocytosis. However, pretreatment of AM with LT resulted in a significant decrease in the clearance of both the Sterne strain and the fully virulent Ames strain of B. anthracis, which may have been a result of impaired AM secretion of proinflammatory cytokines. Our data imply that cytolysis does not correlate with MEK1 cleavage, and this is the first report of LT-mediated impairment of nonhuman primate AM bactericidal activity against B. anthracis. PMID:16926394

The complex folding pathways of protein A suggest a multiple-funnelled energy landscape

NASA Astrophysics Data System (ADS)

St-Pierre, Jean-Francois; Mousseau, Normand; Derreumaux, Philippe

2008-01-01

Folding proteins into their native states requires the formation of both secondary and tertiary structures. Many questions remain, however, as to whether these form into a precise order, and various pictures have been proposed that place the emphasis on the first or the second level of structure in describing folding. One of the favorite test models for studying this question is the B domain of protein A, which has been characterized by numerous experiments and simulations. Using the activation-relaxation technique coupled with a generic energy model (optimized potential for efficient peptide structure prediction), we generate more than 50 folding trajectories for this 60-residue protein. While the folding pathways to the native state are fully consistent with the funnel-like description of the free energy landscape, we find a wide range of mechanisms in which secondary and tertiary structures form in various orders. Our nonbiased simulations also reveal the presence of a significant number of non-native β and α conformations both on and off pathway, including the visit, for a non-negligible fraction of trajectories, of fully ordered structures resembling the native state of nonhomologous proteins.

State of the art survey on MRI brain tumor segmentation.

PubMed

Gordillo, Nelly; Montseny, Eduard; Sobrevilla, Pilar

2013-10-01

Brain tumor segmentation consists of separating the different tumor tissues (solid or active tumor, edema, and necrosis) from normal brain tissues: gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). In brain tumor studies, the existence of abnormal tissues may be easily detectable most of the time. However, accurate and reproducible segmentation and characterization of abnormalities are not straightforward. In the past, many researchers in the field of medical imaging and soft computing have made significant survey in the field of brain tumor segmentation. Both semiautomatic and fully automatic methods have been proposed. Clinical acceptance of segmentation techniques has depended on the simplicity of the segmentation, and the degree of user supervision. Interactive or semiautomatic methods are likely to remain dominant in practice for some time, especially in these applications where erroneous interpretations are unacceptable. This article presents an overview of the most relevant brain tumor segmentation methods, conducted after the acquisition of the image. Given the advantages of magnetic resonance imaging over other diagnostic imaging, this survey is focused on MRI brain tumor segmentation. Semiautomatic and fully automatic techniques are emphasized. Copyright © 2013 Elsevier Inc. All rights reserved.

The effect of RAAS blockade on the progression of diabetic nephropathy.

PubMed

Roscioni, Sara S; Heerspink, Hiddo J Lambers; de Zeeuw, Dick

2014-02-01

The renin-angiotensin-aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy.

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

Shoopman, J. D.

This report documents Livermore Computing (LC) activities in support of ASC L2 milestone 5589: Modernization and Expansion of LLNL Archive Disk Cache, due March 31, 2016. The full text of the milestone is included in Attachment 1. The description of the milestone is: Description: Configuration of archival disk cache systems will be modernized to reduce fragmentation, and new, higher capacity disk subsystems will be deployed. This will enhance archival disk cache capability for ASC archive users, enabling files written to the archives to remain resident on disk for many (6–12) months, regardless of file size. The milestone was completed inmore » three phases. On August 26, 2015 subsystems with 6PB of disk cache were deployed for production use in LLNL’s unclassified HPSS environment. Following that, on September 23, 2015 subsystems with 9 PB of disk cache were deployed for production use in LLNL’s classified HPSS environment. On January 31, 2016, the milestone was fully satisfied when the legacy Data Direct Networks (DDN) archive disk cache subsystems were fully retired from production use in both LLNL’s unclassified and classified HPSS environments, and only the newly deployed systems were in use.« less

Effects of the Menopausal Transition on Factors Related to Energy Balance. A MONET group Study

PubMed Central

Karine, Duval; Denis, Prud’homme; Rémi, Rabasa-Lhoret; Irene, Strychar; Martin, Brochu; Jean-Marc, Lavoie; Éric, Doucet

2016-01-01

Objectives Factors that influence weight gain during the menopausal transition are not fully understood. The purpose of this study was to investigate changes in energy expenditure (EE) across the menopausal transition. Methods One hundred and two premenopausal women (age: 49.9 ± 1.9 yrs; BMI: 23.3 ± 2.2 kg/m2) were followed for 5 years. Body composition (DXA), physical activity EE (accelerometer), resting EE and thermic effect of food (indirect calorimetry) were measured annually. Results Total EE decreased significantly over time in postmenopausal women (P < 0.05), which was mostly due to a decrease in physical activity EE (P < 0.05). Although average resting EE remained stable over time in postmenopausal women, a significant increase, over the 5-year period, was noted in women who were in the menopausal transition by year 5 (P < 0.05). Finally, the time spent in moderate physical activity decreased and the time spent in sedentary physical activity increased during the menopausal transition (P < 0.05). Conclusion These results suggest that menopausal transition is accompanied with a decline in EE mainly characterized by a decrease in physical activity EE and a shift to a more sedentary lifestyle. PMID:23422924

Effects of the menopausal transition on energy expenditure: a MONET Group Study.

PubMed

Duval, K; Prud'homme, D; Rabasa-Lhoret, R; Strychar, I; Brochu, M; Lavoie, J-M; Doucet, E

2013-04-01

Factors that influence weight gain during the menopausal transition are not fully understood. The purpose of this study was to investigate changes in energy expenditure (EE) across the menopausal transition. In all, 102 premenopausal women (age: 49.9 ± 1.9 years; body mass index: 23.3 ± 2.2 kg/m(2)) were followed for 5 years. Body composition (dual-energy X-ray absorptiometry), physical activity EE (accelerometer), resting EE and thermic effect of food (indirect calorimetry) were measured annually. Total EE decreased significantly over time in postmenopausal women (P<0.05), which was mostly due to a decrease in physical activity EE (P<0.05). Although average resting EE remained stable over time in postmenopausal women, a significant increase, over the 5-year period, was noted in women who were in the menopausal transition by year 5 (P<0.05). Finally, the time spent in moderate physical activity decreased and the time spent in sedentary physical activity increased during the menopausal transition (P<0.05). These results suggest that menopausal transition is accompanied with a decline in EE mainly characterized by a decrease in physical activity EE and a shift to a more sedentary lifestyle.

Improved toughness of silicon carbide

NASA Technical Reports Server (NTRS)

Palm, J. A.

1976-01-01

Impact energy absorbing layers (EALs) comprised of partially densified silicon carbide were formed in situ on fully sinterable silicon carbide substrates. After final sintering, duplex silicon carbide structures resulted which were comprised of a fully sintered, high density silicon carbide substrate or core, overlayed with an EAL of partially sintered silicon carbide integrally bonded to its core member. Thermal cycling tests proved such structures to be moderately resistant to oxidation and highly resistant to thermal shock stresses. The strength of the developed structures in some cases exceeded but essentially it remained the same as the fully sintered silicon carbide without the EAL. Ballistic impact tests indicated that substantial improvements in the toughness of sintered silicon carbide were achieved by the use of the partially densified silicon carbide EALs.

National physical activity recommendations: systematic overview and analysis of the situation in European countries.

PubMed

Kahlmeier, Sonja; Wijnhoven, Trudy M A; Alpiger, Patrick; Schweizer, Christian; Breda, João; Martin, Brian W

2015-02-12

Developing national physical activity (PA) recommendations is an essential element of an effective national approach to promote PA. Systematic overview and analysis of national PA recommendations across the European Region of the World Health Organization (WHO). The WHO European national information focal points provided information which was complemented through online searches and input from other experts. Information received until summer 2012 from 37 countries was analyzed. Sixteen countries did not have national recommendations while 21 countries did. For 17 countries, the source document was accessible. Seventeen recommendations referred to adults, 14 to young people and 6 to older adults. Most national recommendations for children and young people are quite similar: 12 countries recommend at least 60 minutes of moderate- to vigorous-intensity PA each day, in line with the WHO global recommendation. Three countries recommend longer durations and one a lower one. In some countries, slight variations were found regarding the recommended intensity and minimum bouts. Only one country was fully in line with the WHO recommendations. Two countries have issued separate recommendations for pre-school children. For adults, most countries still follow the 1995 United States recommendations of "at least 30 minutes on 5 days a week". Three countries were fully in line with the WHO recommendations. Four countries give specific recommendations on reducing weight, avoiding weight gain or continuing weight maintenance. The six identified national PA recommendations for older adults are mainly similar to those for adults but underline that particularly for this age group also less activity has important health benefits; four countries also recommend balance training. About half of the countries for which information was available and likely less than 40% of all 53 countries in the WHO European Region have developed national PA recommendations. Further investment is needed to address this important step towards a comprehensive PA promotion approach. Much remains to be done for the 2010 WHO recommendations to be fully reflected in national documents across all parts of the Region and all age groups. In addition, avoiding extended periods of inactivity and overweight are only addressed by a minority of countries yet.

Social media and pharmacovigilance: A review of the opportunities and challenges

PubMed Central

Sloane, Richard; Osanlou, Orod; Lewis, David; Bollegala, Danushka; Maskell, Simon; Pirmohamed, Munir

2015-01-01

Adverse drug reactions come at a considerable cost on society. Social media are a potentially invaluable reservoir of information for pharmacovigilance, yet their true value remains to be fully understood. In order to realize the benefits social media holds, a number of technical, regulatory and ethical challenges remain to be addressed. We outline these key challenges identifying relevant current research and present possible solutions. PMID:26147850

Manipulation of Thermally Activated Delayed Fluorescence of Blue Exciplex Emission: Fully Utilizing Exciton Energy for Highly Efficient Organic Light Emitting Diodes with Low Roll-Off.

PubMed

Wang, Zixing; Wang, Hedan; Zhu, Jun; Wu, Peng; Shen, Bowen; Dou, Dehai; Wei, Bin

2017-06-28

The application of exciplex energy has become a unique way to achieve organic light-emitting diodes (OLEDs) with high efficiencies, low turn-on voltage, and low roll-off. Novel δ-carboline derivatives with high triplet energy (T 1 ≈ 2.92 eV) and high glass transition temperature (T g ≈ 153 °C) were employed to manipulate exciplex emissions in this paper. Deep blue (peak at 436 nm) and pure blue (peak at 468 nm) thermally activated delayed fluorescence (TADF) of exciplex OLEDs were demonstrated by utilizing them as emitters with the maximum current efficiency (CE) of 4.64 cd A -1 , power efficiency (PE) of 2.91 lm W -1 , and external quantum efficiency (EQE) of 2.36%. Highly efficient blue phosphorescent OLEDs doped with FIrpic showed a maximum CE of 55.6 cd A -1 , PE of 52.9 lm W -1 , and EQE of 24.6% respectively with very low turn on voltage at 2.7 V. The devices still remain high CE of 46.5 cd A -1 at 100 cd m -2 , 45.4 cd A -1 at 1000 cd m -2 and 42.3 cd A -1 at 5000 cd m -2 with EQE close to 20% indicating low roll-off. Manipulating blue exciplex emissions by chemical structure gives an ideal strategy to fully utilize all exciton energies for lighting of OLEDs.

Comparison of identical and functional Igh alleles reveals a nonessential role for Eμ in somatic hypermutation and class-switch recombination.

PubMed

Li, Fubin; Yan, Yi; Pieretti, Joyce; Feldman, Danielle A; Eckhardt, Laurel A

2010-11-15

Somatic hypermutation (SHM), coupled with Ag selection, provides a mechanism for generating Abs with high affinity for invading pathogens. Class-switch recombination (CSR) ensures that these Abs attain pathogen-appropriate effector functions. Although the enzyme critical to both processes, activation-induced cytidine deaminase, has been identified, it remains unclear which cis-elements within the Ig loci are responsible for recruiting activation-induced cytidine deaminase and promoting its activity. Studies showed that Ig gene-transcription levels are positively correlated with the frequency of SHM and CSR, making the intronic, transcriptional enhancer Eμ a likely contributor to both processes. Tests of this hypothesis yielded mixed results arising, in part, from the difficulty in studying B cell function in mice devoid of Eμ. In Eμ's absence, V(H) gene assembly is dramatically impaired, arresting B cell development. The current study circumvented this problem by modifying the murine Igh locus through simultaneous insertion of a fully assembled V(H) gene and deletion of Eμ. The behavior of this allele was compared with that of a matched allele carrying the same V(H) gene but with Eμ intact. Although IgH transcription was as great or greater on the Eμ-deficient allele, CSR and SHM were consistently, but modestly, reduced relative to the allele in which Eμ remained intact. We conclude that Eμ contributes to, but is not essential for, these complex processes and that its contribution is not as a transcriptional enhancer but, rather, is at the level of recruitment and/or activation of the SHM/CSR machinery.

Inflammatory Pathways in Parkinson's Disease; A BNE Microarray Study

PubMed Central

Durrenberger, Pascal. F.; Grünblatt, Edna; Fernando, Francesca S.; Monoranu, Camelia Maria; Evans, Jordan; Riederer, Peter; Reynolds, Richard; Dexter, David T.

2012-01-01

The aetiology of Parkinson's disease (PD) is yet to be fully understood but it is becoming more and more evident that neuronal cell death may be multifactorial in essence. The main focus of PD research is to better understand substantia nigra homeostasis disruption, particularly in relation to the wide-spread deposition of the aberrant protein α-synuclein. Microarray technology contributed towards PD research with several studies to date and one gene, ALDH1A1 (Aldehyde dehydrogenase 1 family, member A1), consistently reappeared across studies including the present study, highlighting dopamine (DA) metabolism dysfunction resulting in oxidative stress and most probably leading to neuronal cell death. Neuronal cell death leads to increased inflammation through the activation of astrocytes and microglia. Using our dataset, we aimed to isolate some of these pathways so to offer potential novel neuroprotective therapeutic avenues. To that effect our study has focused on the upregulation of P2X7 (purinergic receptor P2X, ligand-gated ion channel, 7) receptor pathway (microglial activation) and on the NOS3 (nitric oxide synthase 3) pathway (angiogenesis). In summary, although the exact initiator of striatal DA neuronal cell death remains to be determined, based on our analysis, this event does not remain without consequence. Extracellular ATP and reactive astrocytes appear to be responsible for the activation of microglia which in turn release proinflammatory cytokines contributing further to the parkinsonian condition. In addition to tackling oxidative stress pathways we also suggest to reduce microglial and endothelial activation to support neuronal outgrowth. PMID:22548201

RNA polymerase II pausing can be retained or acquired during activation of genes involved in the epithelial to mesenchymal transition

PubMed Central

Samarakkody, Ann; Abbas, Ata; Scheidegger, Adam; Warns, Jessica; Nnoli, Oscar; Jokinen, Bradley; Zarns, Kris; Kubat, Brooke; Dhasarathy, Archana; Nechaev, Sergei

2015-01-01

Promoter-proximal RNA polymerase II (Pol II) pausing is implicated in the regulation of gene transcription. However, the mechanisms of pausing including its dynamics during transcriptional responses remain to be fully understood. We performed global analysis of short capped RNAs and Pol II Chromatin Immunoprecipitation sequencing in MCF-7 breast cancer cells to map Pol II pausing across the genome, and used permanganate footprinting to specifically follow pausing during transcriptional activation of several genes involved in the epithelial to mesenchymal transition (EMT). We find that the gene for EMT master regulator Snail (SNAI1), but not Slug (SNAI2), shows evidence of Pol II pausing before activation. Transcriptional activation of the paused SNAI1 gene is accompanied by a further increase in Pol II pausing signal, whereas activation of non-paused SNAI2 gene results in the acquisition of a typical pausing signature. The increase in pausing signal reflects increased transcription initiation without changes in Pol II pausing. Activation of the heat shock HSP70 gene involves pausing release that speeds up Pol II turnover, but does not change pausing location. We suggest that Pol II pausing is retained during transcriptional activation and can further undergo regulated release in a signal-specific manner. PMID:25820424

THE ENVIRONMENT AND DISTRIBUTION OF EMITTING ELECTRONS AS A FUNCTION OF SOURCE ACTIVITY IN MARKARIAN 421

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

Mankuzhiyil, Nijil; Ansoldi, Stefano; Persic, Massimo

2011-05-20

For the high-frequency-peaked BL Lac object Mrk 421, we study the variation of the spectral energy distribution (SED) as a function of source activity, from quiescent to active. We use a fully automatized {chi}{sup 2}-minimization procedure, instead of the 'eyeball' procedure more commonly used in the literature, to model nine SED data sets with a one-zone synchrotron self-Compton (SSC) model and examine how the model parameters vary with source activity. The latter issue can finally be addressed now, because simultaneous broadband SEDs (spanning from optical to very high energy photon) have finally become available. Our results suggest that in Mrkmore » 421 the magnetic field (B) decreases with source activity, whereas the electron spectrum's break energy ({gamma}{sub br}) and the Doppler factor ({delta}) increase-the other SSC parameters turn out to be uncorrelated with source activity. In the SSC framework, these results are interpreted in a picture where the synchrotron power and peak frequency remain constant with varying source activity, through a combination of decreasing magnetic field and increasing number density of {gamma} {<=} {gamma}{sub br} electrons: since this leads to an increased electron-photon scattering efficiency, the resulting Compton power increases, and so does the total (= synchrotron plus Compton) emission.« less

Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo

PubMed Central

Roux, Clémence; Saviane, Gaëlle; Pini, Jonathan; Belaïd, Nourhène; Dhib, Gihen; Voha, Christine; Ibáñez, Lidia; Boutin, Antoine; Mazure, Nathalie M.; Wakkach, Abdelilah; Blin-Wakkach, Claudine; Rouleau, Matthieu

2018-01-01

Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4+ FoxP3+ regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3+-Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo. They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance. PMID:29422893

Immunosuppressive Mesenchymal Stromal Cells Derived from Human-Induced Pluripotent Stem Cells Induce Human Regulatory T Cells In Vitro and In Vivo.

PubMed

Roux, Clémence; Saviane, Gaëlle; Pini, Jonathan; Belaïd, Nourhène; Dhib, Gihen; Voha, Christine; Ibáñez, Lidia; Boutin, Antoine; Mazure, Nathalie M; Wakkach, Abdelilah; Blin-Wakkach, Claudine; Rouleau, Matthieu

2017-01-01

Despite mesenchymal stromal cells (MSCs) are considered as a promising source of cells to modulate immune functions on cells from innate and adaptive immune systems, their clinical use remains restricted (few number, limited in vitro expansion, absence of a full phenotypic characterization, few insights on their in vivo fate). Standardized MSCs derived in vitro from human-induced pluripotent stem (huIPS) cells, remediating part of these issues, are considered as well as a valuable tool for therapeutic approaches, but their functions remained to be fully characterized. We generated multipotent MSCs derived from huiPS cells (huiPS-MSCs), and focusing on their immunosuppressive activity, we showed that human T-cell activation in coculture with huiPS-MSCs was significantly reduced. We also observed the generation of functional CD4 + FoxP3 + regulatory T (Treg) cells. Further tested in vivo in a model of human T-cell expansion in immune-deficient NSG mice, huiPS-MSCs immunosuppressive activity prevented the circulation and the accumulation of activated human T cells. Intracytoplasmic labeling of cytokines produced by the recovered T cells showed reduced percentages of human-differentiated T cells producing Th1 inflammatory cytokines. By contrast, T cells producing IL-10 and FoxP3 + -Treg cells, absent in non-treated animals, were detected in huiPS-MSCs treated mice. For the first time, these results highlight the immunosuppressive activity of the huiPS-MSCs on human T-cell stimulation with a concomitant generation of human Treg cells in vivo . They may favor the development of new tools and strategies based on the use of huiPS cells and their derivatives for the induction of immune tolerance.

Molecular mechanism of the Syk activation switch.

PubMed

Tsang, Emily; Giannetti, Anthony M; Shaw, David; Dinh, Marie; Tse, Joyce K Y; Gandhi, Shaan; Ho, Hoangdung; Wang, Sandra; Papp, Eva; Bradshaw, J Michael

2008-11-21

Many immune signaling pathways require activation of the Syk tyrosine kinase to link ligation of surface receptors to changes in gene expression. Despite the central role of Syk in these pathways, the Syk activation process remains poorly understood. In this work we quantitatively characterized the molecular mechanism of Syk activation in vitro using a real time fluorescence kinase assay, mutagenesis, and other biochemical techniques. We found that dephosphorylated full-length Syk demonstrates a low initial rate of substrate phosphorylation that increases during the kinase reaction due to autophosphorylation. The initial rate of Syk activity was strongly increased by either pre-autophosphorylation or binding of phosphorylated immune tyrosine activation motif peptides, and each of these factors independently fully activated Syk. Deletion mutagenesis was used to identify regions of Syk important for regulation, and residues 340-356 of the SH2 kinase linker region were identified to be important for suppression of activity before activation. Comparison of the activation processes of Syk and Zap-70 revealed that Syk is more readily activated by autophosphorylation than Zap-70, although both kinases are rapidly activated by Src family kinases. We also studied Syk activity in B cell lysates and found endogenous Syk is also activated by phosphorylation and immune tyrosine activation motif binding. Together these experiments show that Syk functions as an "OR-gate" type of molecular switch. This mechanism of switch-like activation helps explain how Syk is both rapidly activated after receptor binding but also sustains activity over time to facilitate longer term changes in gene expression.

Genetic regulation of cold-induced albinism in the maize inbred line A661

PubMed Central

Rodríguez, Víctor M.; Velasco, Pablo; Garrido, José L.; Revilla, Pedro; Ordás, Amando; Butrón, Ana

2013-01-01

In spite of multiple studies elucidating the regulatory pathways controlling chlorophyll biosynthesis and photosynthetic activity, little is known about the molecular mechanism regulating cold-induced chlorosis in higher plants. Herein the characterization of the maize inbred line A661 which shows a cold-induced albino phenotype is reported. The data show that exposure of seedlings to low temperatures during early leaf biogenesis led to chlorophyll losses in this inbred. A661 shows a high plasticity, recovering resting levels of photosynthesis activity when exposed to optimal temperatures. Biochemical and transcriptome data indicate that at suboptimal temperatures chlorophyll could not be fully accommodated in the photosynthetic antenna in A661, remaining free in the chloroplast. The accumulation of free chlorophyll activates the expression of an early light inducible protein (elip) gene which binds chlorophyll to avoid cross-reactions that could lead to the generation of harmful reactive oxygen species. Higher levels of the elip transcript were observed in plants showing a cold-induced albino phenotype. Forward genetic analysis reveals that a gene located on the short arm of chromosome 2 regulates this protective mechanism. PMID:23881393

Active sites of ligand-protected Au{sub 25} nanoparticle catalysts for CO{sub 2} electroreduction to CO

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

Alfonso, Dominic R., E-mail: alfonso@netl.doe.gov; Kauffman, Douglas; Matranga, Christopher

2016-05-14

Recent experimental studies have reported the electrochemical reduction of carbon dioxide (CO{sub 2}) into CO at atomically precise negatively charged Au{sub 25}{sup −} nanoclusters. The studies showed CO{sub 2} conversion at remarkably low overpotentials, but the exact mechanisms and nature of the active sites remain unclear. We used first-principles density functional theory and continuum solvation models to examine the role of the cluster during electrochemical CO{sub 2} reduction and analyze the free energies of proposed intermediate species. Contrary to previous assumptions, our results show that the fully ligand protected cluster is not an active CO{sub 2} reduction catalyst because formationmore » of the crucial carboxyl intermediate required very high electrochemical potentials. Instead, our calculations suggest that the reduction process likely occurs on a dethiolated gold site, and adsorbed carboxyl intermediate formation was significantly stabilized at dethiolated gold sites. These findings point to the crucial role of exposed metal sites during electrochemical CO{sub 2} reduction at gold nanocluster catalysts.« less

Conditions and constraints for astrocyte calcium signaling in the hippocampal mossy fiber pathway.

PubMed

Haustein, Martin D; Kracun, Sebastian; Lu, Xiao-Hong; Shih, Tiffany; Jackson-Weaver, Olan; Tong, Xiaoping; Xu, Ji; Yang, X William; O'Dell, Thomas J; Marvin, Jonathan S; Ellisman, Mark H; Bushong, Eric A; Looger, Loren L; Khakh, Baljit S

2014-04-16

The spatiotemporal activities of astrocyte Ca²⁺ signaling in mature neuronal circuits remain unclear. We used genetically encoded Ca²⁺ and glutamate indicators as well as pharmacogenetic and electrical control of neurotransmitter release to explore astrocyte activity in the hippocampal mossy fiber pathway. Our data revealed numerous localized, spontaneous Ca²⁺ signals in astrocyte branches and territories, but these were not driven by neuronal activity or glutamate. Moreover, evoked astrocyte Ca²⁺ signaling changed linearly with the number of mossy fiber action potentials. Under these settings, astrocyte responses were global, suppressed by neurotransmitter clearance, and mediated by glutamate and GABA. Thus, astrocyte engagement in the fully developed mossy fiber pathway was slow and territorial, contrary to that frequently proposed for astrocytes within microcircuits. We show that astrocyte Ca²⁺ signaling functionally segregates large volumes of neuropil and that these transients are not suited for responding to, or regulating, single synapses in the mossy fiber pathway. Copyright © 2014 Elsevier Inc. All rights reserved.

Copper activates HIF-1α/GPER/VEGF signalling in cancer cells

PubMed Central

Rigiracciolo, Damiano Cosimo; Scarpelli, Andrea; Lappano, Rosamaria; Pisano, Assunta; Santolla, Maria Francesca; De Marco, Paola; Cirillo, Francesca; Cappello, Anna Rita; Dolce, Vincenza; Belfiore, Antonino; Maggiolini, Marcello; De Francesco, Ernestina Marianna

2015-01-01

Copper promotes tumor angiogenesis, nevertheless the mechanisms involved remain to be fully understood. We have recently demonstrated that the G-protein estrogen receptor (GPER) cooperates with hypoxia inducible factor-1α (HIF-1α) toward the regulation of the pro-angiogenic factor VEGF. Here, we show that copper sulfate (CuSO4) induces the expression of HIF-1α as well as GPER and VEGF in breast and hepatic cancer cells through the activation of the EGFR/ERK/c-fos transduction pathway. Worthy, the copper chelating agent TEPA and the ROS scavenger NAC prevented the aforementioned stimulatory effects. We also ascertained that HIF-1α and GPER are required for the transcriptional activation of VEGF induced by CuSO4. In addition, in human endothelial cells, the conditioned medium from breast cancer cells treated with CuSO4 promoted cell migration and tube formation through HIF-1α and GPER. The present results provide novel insights into the molecular mechanisms involved by copper in triggering angiogenesis and tumor progression. Our data broaden the therapeutic potential of copper chelating agents against tumor angiogenesis and progression. PMID:26415222

Copper activates HIF-1α/GPER/VEGF signalling in cancer cells.

PubMed

Rigiracciolo, Damiano Cosimo; Scarpelli, Andrea; Lappano, Rosamaria; Pisano, Assunta; Santolla, Maria Francesca; De Marco, Paola; Cirillo, Francesca; Cappello, Anna Rita; Dolce, Vincenza; Belfiore, Antonino; Maggiolini, Marcello; De Francesco, Ernestina Marianna

2015-10-27

Copper promotes tumor angiogenesis, nevertheless the mechanisms involved remain to be fully understood. We have recently demonstrated that the G-protein estrogen receptor (GPER) cooperates with hypoxia inducible factor-1α (HIF-1α) toward the regulation of the pro-angiogenic factor VEGF. Here, we show that copper sulfate (CuSO4) induces the expression of HIF-1α as well as GPER and VEGF in breast and hepatic cancer cells through the activation of the EGFR/ERK/c-fos transduction pathway. Worthy, the copper chelating agent TEPA and the ROS scavenger NAC prevented the aforementioned stimulatory effects. We also ascertained that HIF-1α and GPER are required for the transcriptional activation of VEGF induced by CuSO4. In addition, in human endothelial cells, the conditioned medium from breast cancer cells treated with CuSO4 promoted cell migration and tube formation through HIF-1α and GPER. The present results provide novel insights into the molecular mechanisms involved by copper in triggering angiogenesis and tumor progression. Our data broaden the therapeutic potential of copper chelating agents against tumor angiogenesis and progression.

Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

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

Meng, Zhen; Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081; Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn

2015-05-01

Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocationmore » and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.« less

Synthesis, characterization and evaluation of 1,3,5-triazine aminobenzoic acid derivatives for their antimicrobial activity.

PubMed

Al-Zaydi, Khadijah M; Khalil, Hosam H; El-Faham, Ayman; Khattab, Sherine N

2017-05-10

Replacement of chloride ions in cyanuric chloride give several variants of 1,3,5-triazine derivatives which were investigated as biologically active small molecules. These compounds exhibit antimalarial, antimicrobial, anti-cancer and anti-viral activities, among other beneficial properties. On the other hand, treatment of bacterial infections remains a challenging therapeutic problem because of the emerging infectious diseases and the increasing number of multidrug-resistant microbial pathogens. As multidrug-resistant bacterial strains proliferate, the necessity for effective therapy has stimulated research into the design and synthesis of novel antimicrobial molecules. 1,3,5-Triazine 4-aminobenzoic acid derivatives were prepared by conventional method or by using microwave irradiation. Using microwave irradiation gave the desired products in less time, good yield and higher purity. Esterification of the 4-aminobenzoic acid moiety afforded methyl ester analogues. The s-triazine derivatives and their methyl ester analogues were fully characterized by FT-IR, NMR ( 1 H-NMR and 13 C-NMR), mass spectra and elemental analysis. All the synthesized compounds were evaluated for their antimicrobial activity. Some tested compounds showed promising activity against Staphylococcus aureus and Escherichia coli. Three series of mono-, di- and trisubstituted s-triazine derivatives and their methyl ester analogues were synthesized and fully characterized. All the synthesized compounds were evaluated for their antimicrobial activity. Compounds (10), (16), (25) and (30) have antimicrobial activity against S. aureus comparable to that of ampicillin, while the activity of compound (13) is about 50% of that of ampicillin. Compounds (13) and (14) have antimicrobial activity against E. coli comparable to that of ampicillin, while the activity of compounds (9-12) and (15) is about 50% of that of ampicillin. Furthermore, minimum inhibitory concentrations values for clinical isolates of compounds (10), (13), (14), (16), (25) and (30) were measured. Compounds (10) and (13) were more active against MRSA and E. coli than ampicillin. Invitro cytotoxicity results revealed that compounds (10) and (13) were nontoxic up to 250 µg/mL (with SI = 10) and 125 µg/mL (with SI = 5), respectively. Graphical abstract Three series of mono-, di- and trisubstituted s-triazine derivatives and their methyl ester analogues were synthesized and evaluated for their antimicrobial activity. Several compounds have antimicrobial activity against S. aureus and E. coli comparable to that of ampicillin.

Fiberoptic bronchoscopic treatment of blood aspiration and use of sugammadex in a patient with epistaxis: A case report.

PubMed

Ryu, Taeha; Kim, Dong Hyuck; Byun, Sung Hye

2018-04-01

In patients with oropharyngeal and nasopharyngeal bleeding, blood aspiration can make airway management difficult and lead to severe pulmonary complications. A 44-year-old male patient with recurrent epistaxis underwent surgery for hemostasis. The patient aspirated blood through the endotracheal tube when he hiccupped during the surgery. The patient was diagnosed with blood aspiration after intraoperative fiberoptic bronchoscopy revealed a blood clot and viscous mucus in the airways, but no sign of active bleeding. Tracheobronchial suctioning and irrigation with normal saline was performed through the bronchoscope to remove the aspirated blood clot. Prior to emergence from anesthesia, sugammadex was administered to induce complete neuromuscular recovery and enable the patient to cough up any blood remaining in the airways. The patient was successfully extubated and fully recovered with no complications. Blood aspiration due to oropharyngeal or nasopharyngeal bleeding can be diagnosed and treated by tracheobronchial suctioning via fiberoptic bronchoscopy. In addition, sugammadex can enable patients to recover spontaneous breathing, facilitate extubation, and enable patients to cough up any blood remaining in the airways.

Fiberoptic bronchoscopic treatment of blood aspiration and use of sugammadex in a patient with epistaxis

PubMed Central

Ryu, Taeha; Kim, Dong Hyuck; Byun, Sung Hye

2018-01-01

Abstract Rationale: In patients with oropharyngeal and nasopharyngeal bleeding, blood aspiration can make airway management difficult and lead to severe pulmonary complications. Patient concerns: A 44-year-old male patient with recurrent epistaxis underwent surgery for hemostasis. The patient aspirated blood through the endotracheal tube when he hiccupped during the surgery. Diagnosis: The patient was diagnosed with blood aspiration after intraoperative fiberoptic bronchoscopy revealed a blood clot and viscous mucus in the airways, but no sign of active bleeding. Interventions: Tracheobronchial suctioning and irrigation with normal saline was performed through the bronchoscope to remove the aspirated blood clot. Prior to emergence from anesthesia, sugammadex was administered to induce complete neuromuscular recovery and enable the patient to cough up any blood remaining in the airways. Outcomes: The patient was successfully extubated and fully recovered with no complications. Lessons: Blood aspiration due to oropharyngeal or nasopharyngeal bleeding can be diagnosed and treated by tracheobronchial suctioning via fiberoptic bronchoscopy. In addition, sugammadex can enable patients to recover spontaneous breathing, facilitate extubation, and enable patients to cough up any blood remaining in the airways. PMID:29642212

Progress towards biocompatible intracortical microelectrodes for neural interfacing applications

NASA Astrophysics Data System (ADS)

Jorfi, Mehdi; Skousen, John L.; Weder, Christoph; Capadona, Jeffrey R.

2015-02-01

To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing.

Progress Towards Biocompatible Intracortical Microelectrodes for Neural Interfacing Applications

PubMed Central

Jorfi, Mehdi; Skousen, John L.; Weder, Christoph; Capadona, Jeffrey R.

2015-01-01

To ensure long-term consistent neural recordings, next-generation intracortical microelectrodes are being developed with an increased emphasis on reducing the neuro-inflammatory response. The increased emphasis stems from the improved understanding of the multifaceted role that inflammation may play in disrupting both biologic and abiologic components of the overall neural interface circuit. To combat neuro-inflammation and improve recording quality, the field is actively progressing from traditional inorganic materials towards approaches that either minimizes the microelectrode footprint or that incorporate compliant materials, bioactive molecules, conducting polymers or nanomaterials. However, the immune-privileged cortical tissue introduces an added complexity compared to other biomedical applications that remains to be fully understood. This review provides a comprehensive reflection on the current understanding of the key failure modes that may impact intracortical microelectrode performance. In addition, a detailed overview of the current status of various materials-based approaches that have gained interest for neural interfacing applications is presented, and key challenges that remain to be overcome are discussed. Finally, we present our vision on the future directions of materials-based treatments to improve intracortical microelectrodes for neural interfacing. PMID:25460808

The RNA-induced transcriptional silencing complex targets chromatin exclusively via interacting with nascent transcripts.

PubMed

Shimada, Yukiko; Mohn, Fabio; Bühler, Marc

2016-12-01

Small RNAs regulate chromatin modification and transcriptional gene silencing across the eukaryotic kingdom. Although these processes have been well studied, fundamental mechanistic aspects remain obscure. Specifically, it is unclear exactly how small RNA-loaded Argonaute protein complexes target chromatin to mediate silencing. Here, using fission yeast, we demonstrate that transcription of the target locus is essential for RNA-directed formation of heterochromatin. However, high transcriptional activity is inhibitory; thus, a transcriptional window exists that is optimal for silencing. We further found that pre-mRNA splicing is compatible with RNA-directed heterochromatin formation. However, the kinetics of pre-mRNA processing is critical. Introns close to the 5' end of a transcript that are rapidly spliced result in a bistable response whereby the target either remains euchromatic or becomes fully silenced. Together, our results discount siRNA-DNA base pairing in RNA-mediated heterochromatin formation, and the mechanistic insights further reveal guiding paradigms for the design of small RNA-directed chromatin silencing studies in multicellular organisms. © 2016 Shimada et al.; Published by Cold Spring Harbor Laboratory Press.

Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells.

PubMed

Wang, Yue; Xiao, Yongtao; Chen, Kai; Chen, Sheng; Zhang, Min; Wu, Zhixiang; Wu, Yeming

2016-03-01

Hepatoblastoma is the most common type of malignant liver tumor in children. While outcomes have been greatly improved in the past decades, the treatment of advanced hepatoblastoma has remained challenging. Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group regulators of gene activity, is amplified and overexpressed in a variety of cancers. However, the role of EZH2 in hepatoblastoma has remained to be fully elucidated. The purpose of the present study was to investigate the expression patterns of EZH2 in hepatoblastoma cells and to assess the anti‑cancer effects of EZH2 depletion. Western blot analysis revealed that EZH2 expression was significantly higher in hepatoblastoma specimens compared with that in peri‑tumor tissues, while p27 was reduced in hepatoblastoma. Suppression of EHZ2 using lentiviral small hairpin RNA inhibited hepatoblastoma cell proliferation, induced cell cycle arrest in G1 phase and enhanced the expression of G1/S‑phase checkpoint protein p27. These results suggested that EZH2 may represent a potential diagnostic marker and therapeutic target for the treatment of hepatoblastoma.

Social media and pharmacovigilance: A review of the opportunities and challenges.

PubMed

Sloane, Richard; Osanlou, Orod; Lewis, David; Bollegala, Danushka; Maskell, Simon; Pirmohamed, Munir

2015-10-01

Adverse drug reactions come at a considerable cost on society. Social media are a potentially invaluable reservoir of information for pharmacovigilance, yet their true value remains to be fully understood. In order to realize the benefits social media holds, a number of technical, regulatory and ethical challenges remain to be addressed. We outline these key challenges identifying relevant current research and present possible solutions. © 2015 The British Pharmacological Society.

Targeted femtosecond laser driven drug delivery within HIV-1 infected cells: in-vitro studies

NASA Astrophysics Data System (ADS)

Maphanga, Charles; Ombinda-Lemboumba, Saturnin; Manoto, Sello; Maaza, Malik; Mthunzi-Kufa, Patience

2017-02-01

Human immunodeficiency virus (HIV-1) infection still remains one amongst the world's most challenging infections since its discovery. Antiretroviral therapy is the recommended treatment of choice for HIV-1 infection taken by patients orally. The highly active antiretroviral therapy (HAART) prevents the replication of HIV-1 and further destruction of the immune system, therefore enabling the body to fight opportunistic life-threatening infections, cancers, and also arrest HIV infection from advancing to AIDS. The major challenge with HAART is the inability to reach the viral reservoirs where the HIV-1 remains latent and persistent, leading to inability to fully eradicate the virus. This study is aimed at initially designing and assembling a fully functional optical translocation setup to optically deliver antiretroviral drugs into HIV-1 infected cells in a targeted manner using Gaussian beam mode femtosecond laser pulses in-vitro. The main objective of our study is to define the in-vitro drug photo-translocation parameters to allow future design of an efficient drug delivery device with potential in-vivo drug delivery applications. In our experiments, HEK 293T cells were used to produce HIV-1 enveloped pseudovirus (ZM53) to infect TZM-bl cells which were later treated with laser pulses emitted by a titanium sapphire laser (800 nm, 1KHz, 113 fs, 6.5 μW) to create sub-microscopic pores on the cell membrane enabling influx of extracellular media. Following laser treatment, changes in cellular responses were analysed using cell morphology studies, cytotoxicity, and luciferase assay studies. Controls included laser untreated cells incubated with the drug for 72 hours. The data in this study was statistically analysed using the SigmaPlot software version 13.

Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity.

PubMed

Intini, Giuseppe; Nyman, Jeffry S

2015-06-01

Bone fractures remain a serious health burden and prevention and enhanced healing of fractures have been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1(+/-)) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2(c/c);Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1(+/-) mice were crossed with Bmp2(c/c);Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Dkk1 haploinsufficiency requires expression of Bmp2 for bone anabolic activity

PubMed Central

Intini, Giuseppe; Nyman, Jeffry S.

2015-01-01

Bone fractures remain a serious health burden and prevention and enhanced healing of fractures has been obtained by augmenting either BMP or Wnt signaling. However, whether BMP and Wnt signaling are both required or are self-sufficient for anabolic and fracture healing activities has never been fully elucidated. Mice haploinsufficient for Dkk1 (Dkk1+/−) exhibit a high bone mass phenotype due to an up-regulation of canonical Wnt signaling while mice lacking Bmp2 expression in the limbs (Bmp2c/c;Prx1::cre) succumb to spontaneous fracture and are unable to initiate fracture healing; combined, these mice offer an opportunity to examine the requirement for activated BMP signaling on the anabolic and fracture healing activity of Wnts. When Dkk1+/− mice were crossed with Bmp2c/c;Prx1::cre mice, the offspring bearing both genetic alterations were unable to increase bone mass and heal fractures, indicating that increased canonical Wnt signaling is unable to exploit its activity in absence of Bmp2. Thus, our data suggest that BMP signaling is required for Wnt-mediated anabolic activity and that therapies aimed at preventing fractures and fostering fracture repair may need to target both pathways for maximal efficacy. PMID:25603465

Enhancement of high-order harmonic generation by a two-color field: Influence of propagation effects

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

Schiessl, K.; Persson, E.; Burgdoerfer, J.

2006-11-15

Recent calculations of the response of a single atom subjected to a two-color laser pulse with the higher frequency being resonant with an excitation of the target atom revealed a significant enhancement of photoionization as well as high-order harmonic generation [K. Ishikawa, Phy. Rev. Lett. 91, 043002 (2003)]. We investigate the problem in the framework a fully quantum-mechanical pulse propagation algorithm and perform calculations for rare gases in the single-active-electron approximation. The enhancement of harmonic output compared to the corresponding one-color pulse remains intact for short propagation lengths, promising the feasibility of experimental realization. We also study weak second colorsmore » resonant via a two-photon transition where significant enhancements in harmonic yields can be observed as well.« less

Cultural competency training for public health students: integrating self, social, and global awareness into a master of public health curriculum.

PubMed

Cushman, Linda F; Delva, Marlyn; Franks, Cheryl L; Jimenez-Bautista, Ana; Moon-Howard, Joyce; Glover, Jim; Begg, Melissa D

2015-03-01

Cultural competency training in public health, medicine, social work, nursing, dental medicine, and other health professions has been a topic of increasing interest and significance. Despite the now burgeoning literature that describes specific knowledge, attitudes, and skills that promote cultural "competence," fully defining this complex, multidimensional term and implementing activities to enhance it remain a challenge. We describe our experiences in introducing a mandatory, full-day workshop to incoming Master of Public Health students, called "Self, Social, and Global Awareness: Personal Capacity Building for Professional Education and Practice." The purpose of the program is to provide a meaningful, structured environment to explore issues of culture, power, privilege, and social justice, emphasizing the centrality of these issues in effective public health education and practice.

Abnormal mTOR Activation in Autism.

PubMed

Winden, Kellen D; Ebrahimi-Fakhari, Darius; Sahin, Mustafa

2018-01-25

The mechanistic target of rapamycin (mTOR) is an important signaling hub that integrates environmental information regarding energy availability and stimulates anabolic molecular processes and cell growth. Abnormalities in this pathway have been identified in several syndromes in which autism spectrum disorder (ASD) is highly prevalent. Several studies have investigated mTOR signaling in developmental and neuronal processes that, when dysregulated, could contribute to the development of ASD. Although many potential mechanisms still remain to be fully understood, these associations are of great interest because of the clinical availability of mTOR inhibitors. Clinical trials evaluating the efficacy of mTOR Expected final online publication date for the Annual Review of Neuroscience Volume 41 is July 8, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Interface for Light-Driven Electron Transfer by Photosynthetic Complexes Across Block Copolymer Membranes.

PubMed

Kuang, Liangju; Olson, Tien L; Lin, Su; Flores, Marco; Jiang, Yunjiang; Zheng, Wan; Williams, JoAnn C; Allen, James P; Liang, Hongjun

2014-03-06

Incorporation of membrane proteins into nanodevices to mediate recognition and transport in a collective and scalable fashion remains a challenging problem. We demonstrate how nanoscale photovoltaics could be designed using robust synthetic nanomembranes with incorporated photosynthetic reaction centers (RCs). Specifically, RCs from Rhodobacter sphaeroides are reconstituted spontaneously into rationally designed polybutadiene membranes to form hierarchically organized proteopolymer membrane arrays via a charge-interaction-directed reconstitution mechanism. Once incorporated, the RCs are fully active for prolonged periods based upon a variety of spectroscopic measurements, underscoring preservation of their 3D pigment configuration critical for light-driven charge transfer. This result provides a strategy to construct solar conversion devices using structurally versatile proteopolymer membranes with integrated RC functions to harvest broad regions of the solar spectrum.

The origin of the infrared luminosity in Centaurus A

NASA Technical Reports Server (NTRS)

Joy, Marshall; Lester, Daniel F.; Harvey, Paul M.; Ellis, H. Benton

1988-01-01

The origin of the infrared luminosity in Centaurus A is studied using new tracking and data acquisition techniques which yield diffraction-limited profiles at both 50 and 100 microns. Ninety percent of the 100 micron flux is found to originate in a source which extends 5 kpc along the optical dust lane that bisects the galaxy; the remaining 10 percent comes from an unresolved source coincident with the active radio nucleus. The extended 100 micron emission profile is fully consistent with a uniform disk of thermally radiating particles; when combined with results of previous studies at shorter wavelengths, these measurements indicate that nearly all of the infrared luminosity is produced by thermally emitting grains which are heated by massive young stars distributed throughout the optically thick dust lane.

Group B streptococcal infections in the newborn infant and the potential value of maternal vaccination.

PubMed

Berardi, Alberto; Cattelani, Chiara; Creti, Roberta; Berner, Reinhard; Pietrangiolillo, Zaira; Margarit, Immaculada; Maione, Domenico; Ferrari, Fabrizio

2015-01-01

Group B Streptococcus (GBS) is a leading cause of neonatal bacterial infections in developed countries. Early-onset disease (EOD) occurs at day 0-6 and late-onset disease occurs at day 7-89. Currently, the prevention of EOD relies upon intrapartum antibiotic prophylaxis (IAP) given to women who are GBS positive at prenatal screening or women with risk factors for EOD. Although successfully implemented, IAP has not fully eradicated EOD, and incidence rates of late-onset disease remain unchanged. Furthermore, antibiotic resistance may result from widespread antibiotic use. New prophylactic strategies are therefore of critical importance. A vaccine active against GBS, administered during pregnancy and combined with targeted IAP, could overcome these problems and reduce the mortality and morbidity associated with invasive diseases.

Systems approach to walk-off problems for dish-type solar thermal power systems

NASA Technical Reports Server (NTRS)

Jaffe, L. D.; Levin, R. R.; Moynihan, P. I.; Nesmith, B. J.; Owen, W. A.; Roschke, E. J.; Starkey, D. J.; Thostesen, T. O.

1983-01-01

'Walk-off' in a dish-type solar thermal power system is a failure situation in which the concentrator remains fixed while the spot of concentrated sunlight slowly moves across the face of the receiver. The intense local heating may damage the receiver and nearby equipment. Passive protection has advantages in minimizing damage, but in a fully passive design the receiver must be able to withstand full solar input with no forced fluid circulation during the walk-off. An active walk-off emergency subsystem may include an emergency detrack or defocus mechanism or sun-blocking device, emergency power, sensors and logic to detect the emergency and initiate protective action, and cooling or passive protection of emergency and non-emergency components. Each of these elements is discussed and evaluated in the paper.

Biochemistry of Mitochondrial Coenzyme Q Biosynthesis.

PubMed

Stefely, Jonathan A; Pagliarini, David J

2017-10-01

Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid produced across all domains of life that functions in electron transport and oxidative phosphorylation and whose deficiency causes human diseases. Yet, CoQ biosynthesis has not been fully defined in any organism. Several proteins with unclear molecular functions facilitate CoQ biosynthesis through unknown means, and multiple steps in the pathway are catalyzed by currently unidentified enzymes. Here we highlight recent progress toward filling these knowledge gaps through both traditional biochemistry and cutting-edge 'omics' approaches. To help fill the remaining gaps, we present questions framed by the recently discovered CoQ biosynthetic complex and by putative biophysical barriers. Mapping CoQ biosynthesis, metabolism, and transport pathways has great potential to enhance treatment of numerous human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sense and sensitivity in bioprocessing-detecting cellular metabolites with biosensors.

PubMed

Dekker, Linda; Polizzi, Karen M

2017-10-01

Biosensors use biological elements to detect or quantify an analyte of interest. In bioprocessing, biosensors are employed to monitor key metabolites. There are two main types: fully biological systems or biological recognition coupled with physical/chemical detection. New developments in chemical biosensors include multiplexed detection using microfluidics. Synthetic biology can be used to engineer new biological biosensors with improved characteristics. Although there have been few biosensors developed for bioprocessing thus far, emerging trends can be applied in the future. A range of new platform technologies will enable rapid engineering of new biosensors based on transcriptional activation, riboswitches, and Förster Resonance Energy Transfer. However, translation to industry remains a challenge and more research into the robustness biosensors at scale is needed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Telomerase and drug resistance in cancer.

PubMed

Lipinska, Natalia; Romaniuk, Aleksandra; Paszel-Jaworska, Anna; Toton, Ewa; Kopczynski, Przemyslaw; Rubis, Blazej

2017-11-01

It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gene expression. However, association of those mechanisms, i.e., drug resistance and telomerase alterations, is not fully understood yet. We review the current theories on the aspect of the role of telomerase in cancer cells resistance to therapy. We believe that revealing/unravelling this correlation might significantly contribute to an increased efficiency of cancer cells elimination, especially the most difficult ones, i.e., drug resistant.

Modeling and Simulation of Nanoindentation

NASA Astrophysics Data System (ADS)

Huang, Sixie; Zhou, Caizhi

2017-11-01

Nanoindentation is a hardness test method applied to small volumes of material which can provide some unique effects and spark many related research activities. To fully understand the phenomena observed during nanoindentation tests, modeling and simulation methods have been developed to predict the mechanical response of materials during nanoindentation. However, challenges remain with those computational approaches, because of their length scale, predictive capability, and accuracy. This article reviews recent progress and challenges for modeling and simulation of nanoindentation, including an overview of molecular dynamics, the quasicontinuum method, discrete dislocation dynamics, and the crystal plasticity finite element method, and discusses how to integrate multiscale modeling approaches seamlessly with experimental studies to understand the length-scale effects and microstructure evolution during nanoindentation tests, creating a unique opportunity to establish new calibration procedures for the nanoindentation technique.

Relevance of Local Flexibility Near the Active Site for Enzymatic Catalysis: Biochemical Characterization and Engineering of Cellulase Cel5A From Bacillus agaradherans.

PubMed

Saavedra, Juan M; Azócar, Mauricio A; Rodríguez, Vida; Ramírez-Sarmiento, César A; Andrews, Barbara A; Asenjo, Juan A; Parra, Loreto P

2018-03-25

Detailed molecular mechanisms underpinning enzymatic reactions are still a central problem in biochemistry. The need for active site flexibility to sustain catalytic activity constitutes a notion of wide acceptance, although its direct influence remains to be fully understood. With the aim of studying the relationship between structural dynamics and enzyme catalysis, the cellulase Cel5A from Bacillus agaradherans is used as a model for in silico comparative analysis with mesophilic and psychrophilic counterparts. Structural features that determine flexibility are related to kinetic and thermodynamic parameters of catalysis. As a result, three specific positions in the vicinity of the active site of Cel5A are selected for protein engineering via site-directed mutagenesis. Three Cel5A variants are generated, N141L, A137Y and I102A/A137Y, showing a concomitant increase in the catalytic activity at low temperatures and a decrease in activation energy and activation enthalpy, similar to cold-active enzymes. These results are interpreted in structural terms by molecular dynamics simulations, showing that disrupting a hydrogen bond network in the vicinity of the active site increases local flexibility. These results provide a structural framework for explaining the changes in thermodynamic parameters observed between homologous enzymes with varying temperature adaptations. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Handling Real-World Context Awareness, Uncertainty and Vagueness in Real-Time Human Activity Tracking and Recognition with a Fuzzy Ontology-Based Hybrid Method

PubMed Central

Díaz-Rodríguez, Natalia; Cadahía, Olmo León; Cuéllar, Manuel Pegalajar; Lilius, Johan; Calvo-Flores, Miguel Delgado

2014-01-01

Human activity recognition is a key task in ambient intelligence applications to achieve proper ambient assisted living. There has been remarkable progress in this domain, but some challenges still remain to obtain robust methods. Our goal in this work is to provide a system that allows the modeling and recognition of a set of complex activities in real life scenarios involving interaction with the environment. The proposed framework is a hybrid model that comprises two main modules: a low level sub-activity recognizer, based on data-driven methods, and a high-level activity recognizer, implemented with a fuzzy ontology to include the semantic interpretation of actions performed by users. The fuzzy ontology is fed by the sub-activities recognized by the low level data-driven component and provides fuzzy ontological reasoning to recognize both the activities and their influence in the environment with semantics. An additional benefit of the approach is the ability to handle vagueness and uncertainty in the knowledge-based module, which substantially outperforms the treatment of incomplete and/or imprecise data with respect to classic crisp ontologies. We validate these advantages with the public CAD-120 dataset (Cornell Activity Dataset), achieving an accuracy of 90.1% and 91.07% for low-level and high-level activities, respectively. This entails an improvement over fully data-driven or ontology-based approaches. PMID:25268914

MEK-Dependent Negative Feedback Underlies BCR-ABL-Mediated Oncogene Addiction

PubMed Central

Asmussen, Jennifer; Lasater, Elisabeth A.; Tajon, Cheryl; Oses-Prieto, Juan; Jun, Young-wook; Taylor, Barry S.; Burlingame, Alma; Craik, Charles S.; Shah, Neil P.

2014-01-01

The clinical experience with BCR-ABL tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) provides compelling evidence for oncogene addiction. Yet, the molecular basis of oncogene addiction remains elusive. Through unbiased quantitative phosphoproteomic analyses of CML cells transiently exposed to BCR-ABL TKI, we identified persistent downregulation of growth factor receptor (GF-R) signaling pathways. We then established and validated a tissue-relevant isogenic model of BCR-ABL-mediated addiction, and found evidence for myeloid GF-R signaling pathway rewiring that profoundly and persistently dampens physiologic pathway activation. We demonstrate that eventual restoration of ligand-mediated GF-R pathway activation is insufficient to fully rescue cells from a competing apoptotic fate. In contrast to previous work with BRAFV600E in melanoma cells, feedback inhibition following BCR-ABL TKI treatment is markedly prolonged, extending beyond the time required to initiate apoptosis. Mechanistically, BCR-ABL-mediated oncogene addiction is facilitated by persistent high levels of MEK-dependent negative feedback. PMID:24362263

Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

PubMed Central

Brereton, Melissa F.; Iberl, Michaela; Shimomura, Kenju; Zhang, Quan; Adriaenssens, Alice E.; Proks, Peter; Spiliotis, Ioannis I.; Dace, William; Mattis, Katia K.; Ramracheya, Reshma; Gribble, Fiona M.; Reimann, Frank; Clark, Anne; Rorsman, Patrik; Ashcroft, Frances M.

2014-01-01

Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized. PMID:25145789

HIV, human papillomavirus, and cervical neoplasia and cancer in the era of highly active antiretroviral therapy.

PubMed

De Vuyst, Hugo; Lillo, Flavia; Broutet, Nathalie; Smith, Jennifer S

2008-11-01

The objective of this study was to review the literature on the epidemiological association between human papillomavirus (HPV), HIV, and cervical neoplasia, and the impact of highly active antiretroviral therapy (HAART) on this association. MEDLINE was searched using the terms 'human papillomavirus', 'HPV', 'HIV', 'cervix', 'neoplasm', and 'antiretroviral' to identify articles published before December 2006. HIV-infection was strongly associated with a higher prevalence, incidence, and persistence of HPV infection and correlated with prevalence, incidence, persistence, and progression of squamous intraepithelial lesions. The association between HIV and invasive cervical carcinoma has been more difficult to establish, but is now fully recognized. HAART seems to have little, if any, beneficial effect on the natural history of intraepithelial lesions in HIV-positive women. Despite this fact, HAART, does increase the life expectancy of HIV-positive women. Therefore, it remains important to closely monitor HPV-related disease in women with HIV who are receiving HAART, particularly in regions of the world where cervical screening is not available routinely.

Chronic interleukin-1 drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal

PubMed Central

Pietras, Eric M.; Mirantes-Barbeito, Cristina; Fong, Sarah; Loeffler, Dirk; Kovtonyuk, Larisa V.; Zhang, SiYi; Lakshminarasimhan, Ranjani; Chin, Chih Peng; Techner, José-Marc; Will, Britta; Nerlov, Claus; Steidl, Ulrich; Manz, Markus G.; Schroeder, Timm; Passegué, Emmanuelle

2016-01-01

Haematopoietic stem cells (HSC) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs via precocious activation of a PU.1-dependent gene program. While this effect is essential for rapid myeloid recovery following acute injury to the bone marrow (BM), chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges like transplantation. Importantly, these damaging effects are transient and fully reversible upon IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and likely underlies deregulated blood homeostasis in chronic inflammation conditions. PMID:27111842

Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking.

PubMed

Sato, A; Nishida, C; Sato-Kusubata, K; Ishihara, M; Tashiro, Y; Gritli, I; Shimazu, H; Munakata, S; Yagita, H; Okumura, K; Tsuda, Y; Okada, Y; Tojo, A; Nakauchi, H; Takahashi, S; Heissig, B; Hattori, K

2015-01-01

The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.

Mediator MED23 cooperates with RUNX2 to drive osteoblast differentiation and bone development.

PubMed

Liu, Zhen; Yao, Xiao; Yan, Guang; Xu, YiChi; Yan, Jun; Zou, Weiguo; Wang, Gang

2016-04-01

How lineage specifiers are regulated during development is an outstanding question, and the molecular regulation of osteogenic factor RUNX2 remains to be fully understood. Here we report that the Mediator subunit MED23 cooperates with RUNX2 to regulate osteoblast differentiation and bone development. Med23 deletion in mesenchymal stem cells or osteoblast precursors results in multiple bone defects similar to those observed in Runx2(+/-) mice. In vitro, Med23-deficient progenitor cells are refractory to osteoblast differentiation, and Med23 deficiency reduces Runx2-target gene activity without changing Runx2 expression. Mechanistically, MED23 binds to RUNX2 and modulates its transcriptional activity. Moreover, Med23 deficiency in osteoprogenitor cells exacerbates the skeletal abnormalities observed in Runx2(+/-) mice. Collectively, our results establish a genetic and physical interaction between RUNX2 and MED23, suggesting that MED23 constitutes a molecular node in the regulatory network of anabolic bone formation and related diseases.

Robust transmission of rate coding in the inhibitory Purkinje cell to cerebellar nuclei pathway in awake mice

PubMed Central

Abbasi, Samira; Maran, Selva K.; Cao, Ying; Abbasi, Ataollah; Heck, Detlef H.

2017-01-01

Neural coding through inhibitory projection pathways remains poorly understood. We analyze the transmission properties of the Purkinje cell (PC) to cerebellar nucleus (CN) pathway in a modeling study using a data set recorded in awake mice containing respiratory rate modulation. We find that inhibitory transmission from tonically active PCs can transmit a behavioral rate code with high fidelity. We parameterized the required population code in PC activity and determined that 20% of PC inputs to a full compartmental CN neuron model need to be rate-comodulated for transmission of a rate code. Rate covariance in PC inputs also accounts for the high coefficient of variation in CN spike trains, while the balance between excitation and inhibition determines spike rate and local spike train variability. Overall, our modeling study can fully account for observed spike train properties of cerebellar output in awake mice, and strongly supports rate coding in the cerebellum. PMID:28617798

Receptor for Advanced Glycation End Products and Its Involvement in Inflammatory Diseases

PubMed Central

Talib, Herni; Tie, Tung Hing; Nordin, Norshariza

2013-01-01

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF-κB as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions. PMID:24102034

Fiber type-specific afferent nerve activity induced by transient contractions of rat bladder smooth muscle in pathological states

PubMed Central

Kuga, Nahoko; Tanioka, Asao; Hagihara, Koichiro; Kawai, Tomoyuki

2017-01-01

Bladder smooth muscle shows spontaneous phasic contractions, which undergo a variety of abnormal changes depending on pathological conditions. How abnormal contractions affect the activity of bladder afferent nerves remains to be fully tested. In this study, we examined the relationship between transient increases in bladder pressure, representing transient contraction of bladder smooth muscle, and spiking patterns of bladder afferent fibers of the L6 dorsal root, in rat pathological models. All recordings were performed at a bladder pressure of approximately 10 cmH2O by maintaining the degree of bladder filling. In the cyclophosphamide-induced model, both Aδ and C fibers showed increased sensitivity to transient bladder pressure increases. In the prostaglandin E2-induced model, Aδ fibers, but not C fibers, specifically showed overexcitation that was time-locked with transient bladder pressure increases. These fiber type-specific changes in nerve spike patterns may underlie the symptoms of urinary bladder diseases. PMID:29267380

Temperature dependence of tris(2,2'-bipyridine) ruthenium (II) device characteristics

NASA Astrophysics Data System (ADS)

Slinker, Jason D.; Malliaras, George G.; Flores-Torres, Samuel; Abruña, Héctor D.; Chunwachirasiri, Withoon; Winokur, Michael J.

2004-04-01

We have investigated the temperature dependence of the current, radiance, and efficiency from electroluminescent devices based on [Ru(bpy)3]2+(PF6-)2, where bpy is 2,2'-bipyridine. We find that the current increases monotonically with temperature from 200 to 380 K, while the radiance reaches a maximum near room temperature. For temperatures greater than room temperature, an irreversible, current-induced degradation occurs with thermal cycling that diminishes both the radiance and the photoluminescence (PL) quantum yield, but does not affect the current. The temperature dependence of the external quantum efficiency is fully accounted for by the dependence of the PL quantum yield as measured from the emissive area of the device. This implies that the contacts remain ohmic throughout the temperature range investigated. The quenching of the PL with temperature was attributed to thermal activation to a nonradiative d-d transition. The temperature dependence of the current shows a complex behavior in which transport appears to be thermally activated, with distinct low-temperature and high-temperature regimes.

Can deep seated gravitational slope deformations be activated by regional tectonic strain: First insights from displacement measurements in caves from the Eastern Alps

NASA Astrophysics Data System (ADS)

Baroň, Ivo; Plan, Lukas; Grasemann, Bernhard; Mitroviċ, Ivanka; Lenhardt, Wolfgang; Hausmann, Helmut; Stemberk, Josef

2016-04-01

Tectonic elastic strain and ground deformations are documented as the most remarkable environmental phenomena occurring prior to local earthquakes in tectonically active areas. The question arises if such strain would be able to trigger mass movements. We discuss a directly observed fault slip and a subsequent minor activation of a deep-seated gravitational slope deformation prior to the M = 3 Bad Fischau earthquake between end of November and early December 2013 in NE Austria. The data originate from two faults in the Emmerberg and Eisenstein Caves in the transition zone between the Eastern Alps and the Vienna Basin, monitored in the framework of the FWF "Speleotect" project. The fault slips have been observed at the micrometer-level by means of an opto-mechanical 3D crack gauge TM-71. The discussed event started with the fault activation in the Emmerberg Cave on 25 November 2013 recorded by measurements of about 2 μm shortening and 1 μm sinistral parallel slip, which was fully in agreement with the macroscopically documented past fault kinematics. One day later, the mass (micro) movement activated on the opposite side of the mountain ridge in the Eisenstein Cave and it continued on three consecutive days. Further, the fault in the Emmerberg Cave experienced also a subsequent gravitational relaxation on 2/3 December 2013, when the joint opened and the southern block subsided towards the valley, while the original sinistral displacement remained irreversible. The process was followed by the M = 3 earthquake in Bad Fischau on 11 December 2013. Our data suggest that tectonic strain could play a higher role on the activation of slow mass movements in the area than expected. Although we cannot fully exclude the co-activation of the mass movement in the Eisenstein Cave by water saturation, the presented data bring new insight into recent geodynamics of the Eastern Alps and the Vienna Basin. For better interpretations and conclusions however, we need a much longer period of observations.

Correlation of glucosinolate content to myrosinase activity in horseradish (Armoracia rusticana).

PubMed

Li, Xian; Kushad, Mosbah M

2004-11-17

Fully developed horseradish (Armoracia rusticana Gaertn., Mey., & Scherb.) roots from 27 accessions and leaves from a subset of 9 accessions were evaluated for glucosinolates and myrosinase enzyme activity. Eight different glucosinolates were detected (based on HPLC retention times as desulfoglucosinolates) in both root and leaf tissues. The sum of these glucosinolates, referred to as total, ranged from 2 to 296 micromol g(-1) of dry weight (DW) in both tissues. Four glucosinolates (sinigrin, glucobrassicin, neoglucobrassicin, and gluconasturtiin) were detected in major quantities. In fully developed roots, sinigrin concentration represented approximately 83%, gluconasturtiin approximately 11%, and glucobrassicin approximately 1% of the total glucosinolates. Approximately the same proportions of individual glucosinolates appeared in fully developed leaves, except that glucobrassicin was substituted by neoglucobrassicin and gluconasturtiin concentration was significantly lower (<1%). At least four other glucosinolates were detected in very small quantities (<1%) in both roots and leaves. Myrosinase (beta-thioglucoside glucohydrolase, EC 3.2.3.1) is the enzyme responsible for the hydrolysis of the parent glucosinolates into biologically active products. Very little is known about myrosinase activity and the correlation of its activity to total and individual glucosinolates in plant tissues. Significant differences in myrosinase activity were detected between the roots and leaves, ranging from 1.2 to 57.1 units g(-1) of DW. Data showed no correlation between myrosinase activity and total and/or individual glucosinolates in the roots. However, in the leaves, significant correlations were found between myrosinase activity and total glucosinolates (0.78 at P = 0.01) and between myrosinase activity and sinigrin (0.80 at P = 0.01). Glucosinolates content and myrosinase activity were also correlated in young and fully developed roots and leaves and during tissue crushing. Glucobrassicin concentration in the roots and neoglucobrassicin concentration in the leaves were significantly higher in young than in fully developed tissue. Crushing of the tissue resulted in rapid hydrolysis of sinigrin and glucobrassicin, as expected, from the presence of myrosinase. Likewise, myrosinase activity declined rapidly after crushing, perhaps due to inactivation by the reaction products and/or the depletion of its substrates.

How do disabled individuals spend their leisure time?

PubMed

Pagán-Rodríguez, Ricardo

2014-04-01

Despite the important role that leisure time plays in individuals' health, wellness and quality of life, the disability studies addressing leisure remain extremely limited. Examine how people with disabilities allocate their time to leisure activities as compared to their non-disabled counterparts. Using data at an individual level from the Time Use Survey for Spain in 2002-2003 and the social model of disability as a framework, we estimate the determinants of time (minutes per day) spent on three aggregate categories (active, passive and social activities) for non-disabled, non-limited disabled and limited disabled individuals. Individuals who are limited in their daily activities are more likely to allocate their time to passive leisure (e.g., reading, television, video, and radio) and less likely to spend their time in social entertainment (e.g., theater, culture, and social events) as compared to non-disabled individuals. In addition, we find significant differences in minutes per day spent on leisure activities by gender, age, marital status and number of children. Accessible facilities and leisure installations as well as actions aimed at combating barriers and discrimination practices are needed to encourage participation in physical activity and social entertainment of people with disabilities. It is necessary to define, adapt and implement specific leisure activities that allow people with disabilities to fully participate in these activities and increase their levels of social integration and life satisfaction. Copyright © 2014 Elsevier Inc. All rights reserved.

Physical activity: does environment make a difference for tension, stress, emotional outlook, and perceptions of health status?

PubMed

Puett, Robin; Teas, Jane; España-Romero, Vanesa; Artero, Enrique Garcia; Lee, Duck-chul; Baruth, Meghan; Sui, Xuemei; Montresor-López, Jessica; Blair, Steven N

2014-11-01

The importance of physical activity for health is well-established. Questions remain whether outdoor exercise additionally benefits overall mental and physical well-being. Using cross-sectional data from the Aerobics Center Longitudinal Study, we examined relationships of physical activity environment (PAE) with reported tension, stress, emotional outlook, and health. 11,649 participants were included. 18% exercised indoors, 54% outdoors, and 28% in both. Participants who exercised partially or entirely outdoors exercised more. In fully adjusted models, for women combined PAE was protective for worse emotional outlook (OR: 0.72; 95% CI: 0.52-0.98). Combined PAE was also protective for reported poor health (OR for women: 0.63; 95% CI: 0.44-0.91; OR for men: 0.75; 95% CI: 0.61-0.92). Amount of physical activity modified PAE relationships with outcomes. Combined and outdoor PAE were more consistently protective for worse outcomes among high activity participants. Regardless of PAE, better outcomes were observed in active versus inactive participants. The current study suggests addition of outdoor PAE may be linked with better stress management, outlook and health perceptions for more active populations, whereas indoor PAE may be more important for low active populations. Further research should examine the order of causation and whether type of outdoor PAE (eg, urban, natural) is important.

PhcrTx2, a New Crab-Paralyzing Peptide Toxin from the Sea Anemone Phymanthus crucifer

PubMed Central

Garateix, Anoland; Salceda, Emilio; Zaharenko, André Junqueira; Pons, Tirso; Santos, Yúlica; Arreguín, Roberto; Ständker, Ludger; Forssmann, Wolf-Georg; Tytgat, Jan; Vega, Rosario

2018-01-01

Sea anemones produce proteinaceous toxins for predation and defense, including peptide toxins that act on a large variety of ion channels of pharmacological and biomedical interest. Phymanthus crucifer is commonly found in the Caribbean Sea; however, the chemical structure and biological activity of its toxins remain unknown, with the exception of PhcrTx1, an acid-sensing ion channel (ASIC) inhibitor. Therefore, in the present work, we focused on the isolation and characterization of new P. crucifer toxins by chromatographic fractionation, followed by a toxicity screening on crabs, an evaluation of ion channels, and sequence analysis. Five groups of toxic chromatographic fractions were found, and a new paralyzing toxin was purified and named PhcrTx2. The toxin inhibited glutamate-gated currents in snail neurons (maximum inhibition of 35%, IC50 4.7 µM), and displayed little or no influence on voltage-sensitive sodium/potassium channels in snail and rat dorsal root ganglion (DRG) neurons, nor on a variety of cloned voltage-gated ion channels. The toxin sequence was fully elucidated by Edman degradation. PhcrTx2 is a new β-defensin-fold peptide that shares a sequence similarity to type 3 potassium channels toxins. However, its low activity on the evaluated ion channels suggests that its molecular target remains unknown. PhcrTx2 is the first known paralyzing toxin in the family Phymanthidae. PMID:29414882

Impact of Learner's Characteristics and Learning Behaviour on Learning Performance during a Fully Online Course

ERIC Educational Resources Information Center

Nakayama, Minoru; Mutsuura, Kouichi; Yamamoto, Hiroh

2014-01-01

A fully online learning environment requires effective learning management in order to promote pro-active education. Since student's notes are a reflection of the progress of their education, analysis of notes taken can be used to track the learning process of students who participate in fully online courses. This paper presents the causal…

Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation

PubMed Central

Lechtenberg, Bernhard C.; Rajput, Akhil; Sanishvili, Ruslan; Dobaczewska, Małgorzata K.; Ware, Carl F.; Mace, Peter D.; Riedl, Stefan J.

2015-01-01

Ubiquitination is a central process affecting all facets of cellular signaling and function1. A critical step in ubiquitination is the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate or a growing ubiquitin chain, which is mediated by E3 ubiquitin ligases. RING-type E3 ligases typically facilitate the transfer of ubiquitin from the E2 directly to the substrate2,3. The RBR family of RING-type E3 ligases, however, breaks this paradigm by forming a covalent intermediate with ubiquitin similarly to HECT-type E3 ligases4–6. The RBR family includes Parkin4 and HOIP, the central catalytic factor of the linear ubiquitin chain assembly complex (LUBAC)7. While structural insights into the RBR E3 ligases Parkin and HHARI in their overall autoinhibited forms are available8–13, no structures exist of intact fully active RBR E3 ligases or any of their complexes. Thus, the RBR mechanism of action has remained largely enigmatic. Here we present the first structure of the fully active HOIP-RBR in its transfer complex with an E2~ubiquitin conjugate, which elucidates the intricate nature of RBR E3 ligases. The active HOIP-RBR adopts a conformation markedly different from that of autoinhibited RBRs. HOIP-RBR binds the E2~ubiquitin conjugate in an elongated fashion, with the E2 and E3 catalytic centers ideally aligned for ubiquitin transfer, which structurally both requires and enables a HECT-like mechanism. In addition, surprisingly, three distinct helix–IBR-fold motifs inherent to RBRs form ubiquitin-binding regions that engage the activated ubiquitin of the E2~Ub conjugate as well as an additional regulatory ubiquitin molecule. The features uncovered reveal critical states of the HOIP-RBR E3 ligase cycle, and comparison with Parkin and HHARI suggests a general mechanism for RBR E3 ligases. PMID:26789245

Activation of RhoA by Lysophosphatidic Acid and Gα12/13 Subunits in Neuronal Cells: Induction of Neurite Retraction

PubMed Central

Kranenburg, Onno; Poland, Mieke; van Horck, Francis P. G.; Drechsel, David; Hall, Alan; Moolenaar, Wouter H.

1999-01-01

Neuronal cells undergo rapid growth cone collapse, neurite retraction, and cell rounding in response to certain G protein–coupled receptor agonists such as lysophosphatidic acid (LPA). These shape changes are driven by Rho-mediated contraction of the actomyosin-based cytoskeleton. To date, however, detection of Rho activation has been hampered by the lack of a suitable assay. Furthermore, the nature of the G protein(s) mediating LPA-induced neurite retraction remains unknown. We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK). A fusion protein of GST and the Rho-binding domain of ROK pulls down activated but not inactive RhoA from cell lysates. Using GST-ROK, we show that in N1E-115 neuronal cells LPA activates endogenous RhoA within 30 s, concomitant with growth cone collapse. Maximal activation occurs after 3 min when neurite retraction is complete and the actin cytoskeleton is fully contracted. LPA-induced RhoA activation is completely inhibited by tyrosine kinase inhibitors (tyrphostin 47 and genistein). Activated Gα12 and Gα13 subunits mimic LPA both in activating RhoA and in inducing RhoA-mediated cytoskeletal contraction, thereby preventing neurite outgrowth. We conclude that in neuronal cells, LPA activates RhoA to induce growth cone collapse and neurite retraction through a G12/13-initiated pathway that involves protein-tyrosine kinase activity. PMID:10359601

Working paper : national costs of the metropolitan ITS infrastructure : updated with 2005 deployment data

DOT National Transportation Integrated Search

2006-07-01

The purpose of this report, "Working Paper National Costs of the Metropolitan ITS Infrastructure: Updated with 2005 Deployment Data," is to update the estimates of the costs remaining to fully deploy Intelligent Transportation Systems (ITS) infrastru...

9 CFR 381.150 - Requirements for the production of fully cooked poultry products and partially cooked poultry...

Code of Federal Regulations, 2011 CFR

2011-01-01

... standards: (1) Lethality. A 7-log10 reduction of Salmonella or an alternative lethality that achieves an equivalent probability that no viable Salmonella organisms remain in the finished product, as well as the...

Investigation and simulation of lateral buckling in trains

DOT National Transportation Integrated Search

1999-04-13

One of the philosophies of crash energy management for passenger trains is to ensure that the vehicles remain in line during a collision so that the crush zones are fully utilized and impacts with wayside objects is prevented. Our work to develop met...

Living Well with a Serious Illness: Talking with Your Doctor When the Future Is Uncertain

MedlinePlus

... fears? Are you concerned about suffering? Maintaining your dignity? Being a burden to your family? • What is ... help people live their remaining life fully, in dignity, and with little or no pain and other ...

Social-emotional competence and early adolescents' peer acceptance in school: Examining the role of afternoon cortisol.

PubMed

Oberle, Eva

2018-01-01

The present study investigated the role of afternoon cortisol in social-emotional competence and peer acceptance in early adolescence. To date, research on basal cortisol activity and social development in childhood and adolescence has predominately focused on understanding maladjustment and dysfunction in development. The degree to which basal cortisol is also involved in positive adjustment and social functioning remains largely unexplored. A total of 154 early adolescents (46% female; Mean age = 11.26; SD = .65) from diverse ethnic backgrounds provided self-reports of perspective taking, peer reports of acceptance by classmates, peer reports of prosocial behaviors, and saliva samples to assess basal cortisol. As expected and in alignment with previous research, afternoon cortisol, perspective taking, prosocial behaviors, and peer acceptance were all positively correlated. Path analyses followed by bootstrapping analyses revealed that the direct path from higher afternoon cortisol to higher levels of prosocial behavior was fully mediated by perspective taking skills. The direct path from higher afternoon cortisol to peer acceptance was fully mediated by perspective taking skills and prosocial behavior. The findings are discussed within the broader context of previous research on cortisol and social adjustment in childhood and early adolescence. The practical relevance of the findings is considered.

Clavicle fracture associated with atlantoaxial rotatory displacement, type II in an 8-year-old girl: A case report.

PubMed

Karski, Jacek; Matuszewski, Łukasz; Jakubowski, Paweł; Karska, Klaudia; Kandzierski, Grzegorz

2017-11-01

Fracture of the clavicle is a very common injury in children. However, association between clavicle fracture and atlantoaxial rotatory displacement is rarely observed. We present a case of an 8-year-old girl, who suffered a right clavicle fracture as a result of a sledge accident. Six weeks after figure of 8 casting for a right clavicle fracture, an 8-year-old girl was brought to the Pediatric Orthopedic Department due to torticollis. Standard X-ray examination revealed nonunion of the clavicle without any clinical symptoms. Computed tomography (CT) examination was performed and subluxation of cervical vertebrae 1/cervical vertebrae 2 was detected. The use of Glisson's traction followed by a soft cervical collar resulted in the resolution of all the symptoms. Control CT and magnetic resonance imaging confirmed reduction. The patient fully recovered and currently is fully active. The neurological status of the child before and after procedure remained normal. Clavicle fracture rarely may be associated with atlantoaxial rotatory displacement. Therefore, careful examination including rotation of the neck is necessary to confirm that associations. Moreover, three-dimensional CT scan enables proper spine examination and provides correct diagnosis. As shown in available literature and as well in presented case report, none operative treatment is usually effective.

Phacoemulsification and implantation of an accommodating IOL after PRK.

PubMed

Aslanides, loannis M; Plainis, Sotiris; Kumar, Vinod; Ginis, Harilaos

2006-01-01

To present a case of phacoemulsification and implantation of an accommodating intraocular lens (IOL) in a patient with cataract formation after previous refractive surgery. A 50-year-old man, who initially had photorefractive keratectomy to correct moderate myopia, developed a cataract in one eye. He subsequently underwent phacoemulsification and implantation of a 1CU accommodating IOL, as he wished to remain spectacle independent. The patient's distance vision was fully restored. However, accommodative function, which was assessed using subjective and novice objective techniques, was only partially restored. Although the accommodating IOL fully restored the patient's distance vision, accommodative function was only partially restored.

Interactions of the Algicidal Bacterium Kordia algicida with Diatoms: Regulated Protease Excretion for Specific Algal Lysis

PubMed Central

Paul, Carsten; Pohnert, Georg

2011-01-01

Interactions of planktonic bacteria with primary producers such as diatoms have great impact on plankton population dynamics. Several studies described the detrimental effect of certain bacteria on diatoms but the biochemical nature and the regulation mechanism involved in the production of the active compounds remained often elusive. Here, we investigated the interactions of the algicidal bacterium Kordia algicida with the marine diatoms Skeletonema costatum, Thalassiosira weissflogii, Phaeodactylum tricornutum, and Chaetoceros didymus. Algicidal activity was only observed towards the first three of the tested diatom species while C. didymus proved to be not susceptible. The cell free filtrate and the >30 kDa fraction of stationary K. algicida cultures is fully active, suggesting a secreted algicidal principle. The active supernatant from bacterial cultures exhibited high protease activity and inhibition experiments proved that these enzymes are involved in the observed algicidal action of the bacteria. Protease mediated interactions are not controlled by the presence of the alga but dependent on the cell density of the K. algicida culture. We show that protease release is triggered by cell free bacterial filtrates suggesting a quorum sensing dependent excretion mechanism of the algicidal protein. The K. algicida / algae interactions in the plankton are thus host specific and under the control of previously unidentified factors. PMID:21695044

Interactions of the algicidal bacterium Kordia algicida with diatoms: regulated protease excretion for specific algal lysis.

PubMed

Paul, Carsten; Pohnert, Georg

2011-01-01

Interactions of planktonic bacteria with primary producers such as diatoms have great impact on plankton population dynamics. Several studies described the detrimental effect of certain bacteria on diatoms but the biochemical nature and the regulation mechanism involved in the production of the active compounds remained often elusive. Here, we investigated the interactions of the algicidal bacterium Kordia algicida with the marine diatoms Skeletonema costatum, Thalassiosira weissflogii, Phaeodactylum tricornutum, and Chaetoceros didymus. Algicidal activity was only observed towards the first three of the tested diatom species while C. didymus proved to be not susceptible. The cell free filtrate and the >30 kDa fraction of stationary K. algicida cultures is fully active, suggesting a secreted algicidal principle. The active supernatant from bacterial cultures exhibited high protease activity and inhibition experiments proved that these enzymes are involved in the observed algicidal action of the bacteria. Protease mediated interactions are not controlled by the presence of the alga but dependent on the cell density of the K. algicida culture. We show that protease release is triggered by cell free bacterial filtrates suggesting a quorum sensing dependent excretion mechanism of the algicidal protein. The K. algicida / algae interactions in the plankton are thus host specific and under the control of previously unidentified factors.

Bactericidal activity of electrolyzed acid water from solution containing sodium chloride at low concentration, in comparison with that at high concentration.

PubMed

Kiura, Hiromasa; Sano, Kouichi; Morimatsu, Shinichi; Nakano, Takashi; Morita, Chizuko; Yamaguchi, Masaki; Maeda, Toyoyuki; Katsuoka, Yoji

2002-05-01

Electrolyzed strong acid water (ESW) containing free chlorine at various concentrations is becoming to be available in clinical settings as a disinfectant. ESW is prepared by electrolysis of a NaCl solution, and has a corrosive activity against medical instruments. Although lower concentrations of NaCl and free chlorine are desired to eliminate corrosion, the germicidal effect of ESW with low NaCl and free-chlorine concentrations (ESW-L) has not been fully clarified. In this study, we demonstrated that ESW-L possesses bactericidal activity against Mycobacteria and spores of Bacillus subtilis. The effect was slightly weaker than that of ESW containing higher NaCl and free-chlorine concentrations (ESW-H), but acceptable as a disinfectant. To clarify the mechanism of the bactericidal activity, we investigated ESW-L-treated Pseudomonas aeruginosa by transmission electron microscopy, a bacterial enzyme assay and restriction fragment length polymorphism pattern (RFLP) assay. Since the bacterium, whose growth was completely inhibited by ESW-L, revealed the inactivation of cytoplasmic enzyme, blebs and breaks in its outer membrane and remained complete RFLP of DNA, damage of the outer membrane and inactivation of cytoplasmic enzyme are the important determinants of the bactericidal activity.

Routine and active metabolic rates of migrating adult wild sockeye salmon (Oncorhynchus nerka Walbaum) in seawater and freshwater.

PubMed

Wagner, G N; Kuchel, L J; Lotto, A; Patterson, D A; Shrimpton, J M; Hinch, S G; Farrell, A P

2006-01-01

We present the first data on the differences in routine and active metabolic rates for sexually maturing migratory adult sockeye salmon (Oncorhynchus nerka) that were intercepted in the ocean and then held in either seawater or freshwater. Routine and active oxygen uptake rates (MO2) were significantly higher (27%-72%) in seawater than in freshwater at all swimming speeds except those approaching critical swimming speed. During a 45-min recovery period, the declining postexercise oxygen uptake remained 58%-73% higher in seawater than in freshwater. When fish performed a second swim test, active metabolic rates again remained 28%-81% higher for fish in seawater except at the critical swimming speed. Despite their differences in metabolic rates, fish in both seawater and freshwater could repeat the swim test and reach a similar maximum oxygen uptake and critical swimming speed as in the first swim test, even without restoring routine metabolic rate between swim tests. Thus, elevated MO2 related to either being in seawater as opposed to freshwater or not being fully recovered from previous exhaustive exercise did not present itself as a metabolic loading that limited either critical swimming performance or maximum MO2. The basis for the difference in metabolic rates of migratory sockeye salmon held in seawater and freshwater is uncertain, but it could include differences in states of nutrition, reproduction, and restlessness, as well as ionic differences. Regardless, this study elucidates some of the metabolic costs involved during the migration of adult salmon from seawater to freshwater, which may have applications for fisheries conservation and management models of energy use.

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity.

PubMed

Zheng, Zifeng; Yang, Jieyu; Jiang, Xuan; Liu, Yalan; Zhang, Xiaowei; Li, Mei; Zhang, Mudan; Fu, Ming; Hu, Kai; Wang, Hanzhong; Luo, Min-Hua; Gong, Peng; Hu, Qinxue

2018-05-14

Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5-induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention. Copyright © 2018 by The American Association of Immunologists, Inc.

20 CFR 404.111 - When we consider a person fully insured based on World War II active military or naval service.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 2 2014-04-01 2014-04-01 false When we consider a person fully insured based on World War II active military or naval service. 404.111 Section 404.111 Employees' Benefits SOCIAL... States during World War II; (b) The person died within three years after separation from service and...

20 CFR 404.111 - When we consider a person fully insured based on World War II active military or naval service.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 2 2013-04-01 2013-04-01 false When we consider a person fully insured based on World War II active military or naval service. 404.111 Section 404.111 Employees' Benefits SOCIAL... States during World War II; (b) The person died within three years after separation from service and...

20 CFR 404.111 - When we consider a person fully insured based on World War II active military or naval service.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 2 2012-04-01 2012-04-01 false When we consider a person fully insured based on World War II active military or naval service. 404.111 Section 404.111 Employees' Benefits SOCIAL... States during World War II; (b) The person died within three years after separation from service and...

Turbulence Model Behavior in Low Reynolds Number Regions of Aerodynamic Flowfields

NASA Technical Reports Server (NTRS)

Rumsey, Christopher L.; Spalart, Philippe R.

2008-01-01

The behaviors of the widely-used Spalart-Allmaras (SA) and Menter shear-stress transport (SST) turbulence models at low Reynolds numbers and under conditions conducive to relaminarization are documented. The flows used in the investigation include 2-D zero pressure gradient flow over a flat plate from subsonic to hypersonic Mach numbers, 2-D airfoil flow from subsonic to supersonic Mach numbers, 2-D subsonic sink-flow, and 3-D subsonic flow over an infinite swept wing (particularly its leading-edge region). Both models exhibit a range over which they behave transitionally in the sense that the flow is neither laminar nor fully turbulent, but these behaviors are different: the SST model typically has a well-defined transition location, whereas the SA model does not. Both models are predisposed to delayed activation of turbulence with increasing freestream Mach number. Also, both models can be made to achieve earlier activation of turbulence by increasing their freestream levels, but too high a level can disturb the turbulent solution behavior. The technique of maintaining freestream levels of turbulence without decay in the SST model, introduced elsewhere, is shown here to be useful in reducing grid-dependence of the model's transitional behavior. Both models are demonstrated to be incapable of predicting relaminarization; eddy viscosities remain weakly turbulent in accelerating or laterally-strained boundary layers for which experiment and direct simulations indicate turbulence suppression. The main conclusion is that these models are intended for fully turbulent high Reynolds number computations, and using them for transitional (e.g., low Reynolds number) or relaminarizing flows is not appropriate.

Turbulence Model Behavior in Low Reynolds Number Regions of Aerodynamic Flowfields

NASA Technical Reports Server (NTRS)

Rumsey, Christopher L.; Spalart, Philippe R.

2008-01-01

The behaviors of the widely-used Spalart-Allmaras (SA) and Menter shear-stress transport (SST) turbulence models at low Reynolds numbers and under conditions conducive to relaminarization are documented. The flows used in the investigation include 2-D zero pressure gradient flow over a flat plate from subsonic to hypersonic Mach numbers, 2-D airfoil flow from subsonic to supersonic Mach numbers, 2-D subsonic sink-flow, and 3-D subsonic flow over an infinite swept wing (particularly its leading-edge region). Both models exhibit a range over which they behave 'transitionally' in the sense that the flow is neither laminar nor fully turbulent, but these behaviors are different: the SST model typically has a well-defined transition location, whereas the SA model does not. Both models are predisposed to delayed activation of turbulence with increasing freestream Mach number. Also, both models can be made to achieve earlier activation of turbulence by increasing their freestream levels, but too high a level can disturb the turbulent solution behavior. The technique of maintaining freestream levels of turbulence without decay in the SST model, introduced elsewhere, is shown here to be useful in reducing grid-dependence of the model's transitional behavior. Both models are demonstrated to be incapable of predicting relaminarization; eddy viscosities remain weakly turbulent in accelerating or laterally-strained boundary layers for which experiment and direct simulations indicate turbulence suppression. The main conclusion is that these models are intended for fully turbulent high Reynolds number computations, and using them for transitional (e.g., low Reynolds number) or relaminarizing flows is not appropriate.

The role of right and left parietal lobes in the conceptual processing of numbers.

PubMed

Cappelletti, Marinella; Lee, Hwee Ling; Freeman, Elliot D; Price, Cathy J

2010-02-01

Neuropsychological and functional imaging studies have associated the conceptual processing of numbers with bilateral parietal regions (including intraparietal sulcus). However, the processes driving these effects remain unclear because both left and right posterior parietal regions are activated by many other conceptual, perceptual, attention, and response-selection processes. To dissociate parietal activation that is number-selective from parietal activation related to other stimulus or response-selection processes, we used fMRI to compare numbers and object names during exactly the same conceptual and perceptual tasks while factoring out activations correlating with response times. We found that right parietal activation was higher for conceptual decisions on numbers relative to the same tasks on object names, even when response time effects were fully factored out. In contrast, left parietal activation for numbers was equally involved in conceptual processing of object names. We suggest that left parietal activation for numbers reflects a range of processes, including the retrieval of learnt facts that are also involved in conceptual decisions on object names. In contrast, number selectivity in right parietal cortex reflects processes that are more involved in conceptual decisions on numbers than object names. Our results generate a new set of hypotheses that have implications for the design of future behavioral and functional imaging studies of patients with left and right parietal damage.

Psychostimulant addiction treatment

PubMed Central

Phillips, Karran A.; Epstein, David H.; Preston, Kenzie L.

2014-01-01

Treatment of psychostimulant addiction has been a major, and not fully met, challenge. For opioid addiction, there is strong evidence for the effectiveness of several medications. For psychostimulants, there is no corresponding form of agonist maintenance that has met criteria for regulatory approval or generally accepted use. Stimulant-use disorders remain prevalent and can result in both short-term and long-term adverse consequences. The mainstay of treatment remains behavioral interventions. In this paper, we discuss those interventions and some promising candidates in the search for pharmacological interventions. PMID:24727297

The rare-earth metallome of pecan and other Carya

USDA-ARS?s Scientific Manuscript database

The nutritional physiology of pecan [Carya illinoinensis (Wangenh.) K. Koch] and other Carya species remains to be fully understood; thus, presenting a substantial knowledge gap in the horticulture of pecan and similar species. There is an especial lack of knowledge regarding the metabolic, ecophys...

Fathering After Marital Separation

ERIC Educational Resources Information Center

Keshet, Harry Finkelstein; Rosenthal, Kristine M.

1978-01-01

Deals with experiences of a group of separated or divorced fathers who chose to remain fully involved in the upbringing of their children. As they underwent transition from married parenthood to single fatherhood, these men learned that meeting demands of child care contributed to personal stability and growth. (Author)

Prestraining and Its Influence on Subsequent Fatigue Life

NASA Technical Reports Server (NTRS)

Halford, Gary R.; Mcgaw, Michael A.; Kalluri, Sreeramesh

1995-01-01

An experimental program was conducted to study the damaging effects of tensile and compressive prestrains on the fatigue life of nickel-base, Inconel 718 superalloy at room temperature. To establish baseline fatigue behavior, virgin specimens with a solid uniform gage section were fatigued to failure under fully-reversed strain-control. Additional specimens were prestrained to 2 percent, 5 percent, and 10 percent (engineering strains) in the tensile direction and to 2 percent (engineering strain) in the compressive direction under stroke-control, and were subsequently fatigued to failure under fully-reversed strain-control. Experimental results are compared with estimates of remaining fatigue lives (after prestraining) using three life prediction approaches: (1) the Linear Damage Rule; (2) the Linear Strain and Life Fraction Rule; and (3) the nonlinear Damage Curve Approach. The Smith-Watson-Topper parameter was used to estimate fatigue lives in the presence of mean stresses. Among the cumulative damage rules investigated, best remaining fatigue life predictions were obtained with the nonlinear Damage Curve Approach.

Towards black-box calculations of tunneling splittings obtained from vibrational structure methods based on normal coordinates.

PubMed

Neff, Michael; Rauhut, Guntram

2014-02-05

Multidimensional potential energy surfaces obtained from explicitly correlated coupled-cluster calculations and further corrections for high-order correlation contributions, scalar relativistic effects and core-correlation energy contributions were generated in a fully automated fashion for the double-minimum benchmark systems OH3(+) and NH3. The black-box generation of the potentials is based on normal coordinates, which were used in the underlying multimode expansions of the potentials and the μ-tensor within the Watson operator. Normal coordinates are not the optimal choice for describing double-minimum potentials and the question remains if they can be used for accurate calculations at all. However, their unique definition is an appealing feature, which removes remaining errors in truncated potential expansions arising from different choices of curvilinear coordinate systems. Fully automated calculations are presented, which demonstrate, that the proposed scheme allows for the determination of energy levels and tunneling splittings as a routine application. Copyright © 2013 Elsevier B.V. All rights reserved.

A Quasi Experiment to Determine the Effectiveness of a "Partially Flipped" versus "Fully Flipped" Undergraduate Class in Genetics and Evolution

ERIC Educational Resources Information Center

Adams, Alison E. M.; Garcia, Jocelyn; Traustadóttir, Tinna

2016-01-01

Two sections of Genetics and Evolution were taught by one instructor. One group (the fully flipped section) had the entire class period devoted to active learning (with background material that had to be watched before class), and the other group (the partially flipped section) had just a portion of class time spent on active learning (with the…

Pressure overload-dependent membrane type 1-matrix metalloproteinase induction: relationship to LV remodeling and fibrosis.

PubMed

Zile, Michael R; Baicu, Catalin F; Stroud, Robert E; Van Laer, An; Arroyo, Jazmine; Mukherjee, Rupak; Jones, Jeffrey A; Spinale, Francis G

2012-04-01

Increased myocardial extracellular matrix collagen represents an important structural milestone during the development of left ventricular (LV) pressure overload (PO); however, the proteolytic pathways that contribute to this process are not fully understood. This study tested the hypothesis that membrane type 1-matrix metalloproteinase (MT1-MMP) is directly induced at the transcriptional level in vivo during PO and is related to changes in LV collagen content. PO was induced in vivo by transverse aortic constriction in transgenic mice containing the full length human MT1-MMP promoter region ligated to luciferase (MT1-MMP Prom mice). MT1-MMP promoter activation (luciferase expression), expression, and activity; collagen volume fraction (CVF); and left atrial dimension were measured at 1 (n = 8), 2 (n = 12), and 4 (n = 17) wk following PO. Non-PO mice (n = 10) served as controls. Luciferase expression increased by fivefold at 1 wk, fell at 2 wk, and increased again by ninefold at 4 wk of PO (P < 0.05). MT1-MMP expression and activity increased at 1 wk, fell at 2 wk, and increased again at 4 wk after PO. CVF increased at 1 wk, remained unchanged at 2 wk, and increased by threefold at 4 wk of PO (P < 0.05). There was a strong positive correlation between CVF and MT1-MMP activity (r = 0.80, P < 0.05). Left atrial dimension remained unchanged at 1 and 2 wk but increased by 25% at 4 wk of PO. When a mechanical load was applied in vitro to LV papillary muscles isolated from MT1-MMP Prom mice, increased load caused MT1-MMP promoter activation to increase by twofold and MT1-MMP expression to increase by fivefold (P < 0.05). These findings challenge the canonical belief that PO suppresses overall matrix proteolytic activity, but rather supports the concept that certain proteases, such as MT1-MMP, play a pivotal role in PO-induced matrix remodeling and fibrosis.

The MAGIC telescope for gamma-ray astronomy above 30 GeV

NASA Astrophysics Data System (ADS)

Moralejo, A.; Baixeras, C.; Bastieri, D.; Bednarek, W.; Bigongiari, C.; Biland, A.; Blanch, O.; Böck, R.; Bretz, T.; Chilingarian, A.; Coarasa, J. A.; Colombo, E.; Commichau, S.; Contreras, J. L.; Cortina, J.; de Angelis, A.; de los Reyes, R.; de Lotto, B.; Domingo, C.; Domingo, E.; Dorner, D.; Ferenc, D.; Fernández, E.; Flix, J.; Fonseca, V.; Font, L.; Galante, N.; Gaug, M.; Garczarczyk, M.; Gebauer, J.; Giannitrapani, R.; Giller, M.; Goebel, F.; Hengstebeck, T.; Jacon, P.; de Jager, O. C.; Kalekin, O.; Kestel, M.; Kim, K.-S.; Kneiske, T.; Laatiaoui, M.; Laille, A.; Lindfors, E.; Longo, F.; López, M.; López, J.; Lorenz, E.; Lucarelli, F.; Mannheim, K.; Mariotti, M.; Martínez, M.; Mase, K.; Merck, M.; Meucci, M.; Mirzoyan, R.; Mizobuchi, S.; Moralejo, A.; Oña-Wilhelmi, E.; Orduña, R.; Paneque, D.; Paoletti, R.; Pasanen, M.; Pascoli, D.; Pauss, F.; Pavel, N.; Pegna, R.; Peruzzo, L.; Piccioli, A.; Pin, M.; Robert, A.; Saggion, A.; Sánchez, A.; Sartori, P.; Scalzotto, V.; Shinozaki, K.; Sillanpaa, A.; Sobczynska, D.; Stamerra, A.; Stark, L. S.; Stepanian, A.; Stiehler, R.; Takalo, L.; Teshima, M.; Tonello, N.; Torres, A.; Turini, N.; Viertel, G.; Vitale, V.; Volkov, S.; Wagner, R.; Wibig, T.; Wittek, W.

2003-12-01

The MAGIC telescope, presently at its commissioning phase, will become fully operative by the end of 2003. Placed at the Roque de los Muchachos Observatory (ORM) on the island of La Palma, MAGIC is the largest among new generation ground-based gamma ray telescopes, and will reach an energy threshold as low as 30 GeV. The range of the electromagnetic spectrum between 10 and 250 GeV remains to date mostly unexplored. Observations in this energy region are expected to provide key data for the understanding of a wide variety of astrophysical phenomena belonging to the so-called ``non thermal Universe'', like the processes in the nuclei of active galaxies, the radiation mechanisms of pulsars and supernova remnants, and the enigmatic gamma-ray bursts. An overview of the telescope and its physics goals is presented.

Cultural Competency Training for Public Health Students: Integrating Self, Social, and Global Awareness Into a Master of Public Health Curriculum

PubMed Central

Delva, Marlyn; Franks, Cheryl L.; Jimenez-Bautista, Ana; Moon-Howard, Joyce; Glover, Jim; Begg, Melissa D.

2015-01-01

Cultural competency training in public health, medicine, social work, nursing, dental medicine, and other health professions has been a topic of increasing interest and significance. Despite the now burgeoning literature that describes specific knowledge, attitudes, and skills that promote cultural “competence,” fully defining this complex, multidimensional term and implementing activities to enhance it remain a challenge. We describe our experiences in introducing a mandatory, full-day workshop to incoming Master of Public Health students, called “Self, Social, and Global Awareness: Personal Capacity Building for Professional Education and Practice.” The purpose of the program is to provide a meaningful, structured environment to explore issues of culture, power, privilege, and social justice, emphasizing the centrality of these issues in effective public health education and practice. PMID:25706008

The Active Role of the Ocean in the Temporal Evolution of Climate Sensitivity

DOE PAGES

Garuba, Oluwayemi A.; Lu, Jian; Liu, Fukai; ...

2017-11-30

Here, the temporal evolution of the effective climate sensitivity is shown to be influenced by the changing pattern of sea surface temperature (SST) and ocean heat uptake (OHU), which in turn have been attributed to ocean circulation changes. A set of novel experiments are performed to isolate the active role of the ocean by comparing a fully coupled CO 2 quadrupling community Earth System Model (CESM) simulation against a partially coupled one, where the effect of the ocean circulation change and its impact on surface fluxes are disabled. The active OHU is responsible for the reduced effective climate sensitivity andmore » weaker surface warming response in the fully coupled simulation. The passive OHU excites qualitatively similar feedbacks to CO 2 quadrupling in a slab ocean model configuration due to the similar SST spatial pattern response in both experiments. Additionally, the nonunitary forcing efficacy of the active OHU (1.7) explains the very different net feedback parameters in the fully and partially coupled responses.« less

The Active Role of the Ocean in the Temporal Evolution of Climate Sensitivity

NASA Astrophysics Data System (ADS)

Garuba, Oluwayemi A.; Lu, Jian; Liu, Fukai; Singh, Hansi A.

2018-01-01

The temporal evolution of the effective climate sensitivity is shown to be influenced by the changing pattern of sea surface temperature (SST) and ocean heat uptake (OHU), which in turn have been attributed to ocean circulation changes. A set of novel experiments are performed to isolate the active role of the ocean by comparing a fully coupled CO2 quadrupling community Earth System Model (CESM) simulation against a partially coupled one, where the effect of the ocean circulation change and its impact on surface fluxes are disabled. The active OHU is responsible for the reduced effective climate sensitivity and weaker surface warming response in the fully coupled simulation. The passive OHU excites qualitatively similar feedbacks to CO2 quadrupling in a slab ocean model configuration due to the similar SST spatial pattern response in both experiments. Additionally, the nonunitary forcing efficacy of the active OHU (1.7) explains the very different net feedback parameters in the fully and partially coupled responses.

The Active Role of the Ocean in the Temporal Evolution of Climate Sensitivity

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

Garuba, Oluwayemi A.; Lu, Jian; Liu, Fukai

Here, the temporal evolution of the effective climate sensitivity is shown to be influenced by the changing pattern of sea surface temperature (SST) and ocean heat uptake (OHU), which in turn have been attributed to ocean circulation changes. A set of novel experiments are performed to isolate the active role of the ocean by comparing a fully coupled CO 2 quadrupling community Earth System Model (CESM) simulation against a partially coupled one, where the effect of the ocean circulation change and its impact on surface fluxes are disabled. The active OHU is responsible for the reduced effective climate sensitivity andmore » weaker surface warming response in the fully coupled simulation. The passive OHU excites qualitatively similar feedbacks to CO 2 quadrupling in a slab ocean model configuration due to the similar SST spatial pattern response in both experiments. Additionally, the nonunitary forcing efficacy of the active OHU (1.7) explains the very different net feedback parameters in the fully and partially coupled responses.« less

Fully-printed high-performance organic thin-film transistors and circuitry on one-micron-thick polymer films

NASA Astrophysics Data System (ADS)

Fukuda, Kenjiro; Takeda, Yasunori; Yoshimura, Yudai; Shiwaku, Rei; Tran, Lam Truc; Sekine, Tomohito; Mizukami, Makoto; Kumaki, Daisuke; Tokito, Shizuo

2014-06-01

Thin, ultra-flexible devices that can be manufactured in a process that covers a large area will be essential to realizing low-cost, wearable electronic applications including foldable displays and medical sensors. The printing technology will be instrumental in fabricating these novel electronic devices and circuits; however, attaining fully printed devices on ultra-flexible films in large areas has typically been a challenge. Here we report on fully printed organic thin-film transistor devices and circuits fabricated on 1-μm-thick parylene-C films with high field-effect mobility (1.0 cm2 V-1 s-1) and fast operating speeds (about 1 ms) at low operating voltages. The devices were extremely light (2 g m-2) and exhibited excellent mechanical stability. The devices remained operational even under 50% compressive strain without significant changes in their performance. These results represent significant progress in the fabrication of fully printed organic thin-film transistor devices and circuits for use in unobtrusive electronic applications such as wearable sensors.

Breast tumor segmentation in DCE-MRI using fully convolutional networks with an application in radiogenomics

NASA Astrophysics Data System (ADS)

Zhang, Jun; Saha, Ashirbani; Zhu, Zhe; Mazurowski, Maciej A.

2018-02-01

Breast tumor segmentation based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) remains an active as well as a challenging problem. Previous studies often rely on manual annotation for tumor regions, which is not only time-consuming but also error-prone. Recent studies have shown high promise of deep learning-based methods in various segmentation problems. However, these methods are usually faced with the challenge of limited number (e.g., tens or hundreds) of medical images for training, leading to sub-optimal segmentation performance. Also, previous methods cannot efficiently deal with prevalent class-imbalance problems in tumor segmentation, where the number of voxels in tumor regions is much lower than that in the background area. To address these issues, in this study, we propose a mask-guided hierarchical learning (MHL) framework for breast tumor segmentation via fully convolutional networks (FCN). Our strategy is first decomposing the original difficult problem into several sub-problems and then solving these relatively simpler sub-problems in a hierarchical manner. To precisely identify locations of tumors that underwent a biopsy, we further propose an FCN model to detect two landmarks defined on nipples. Finally, based on both segmentation probability maps and our identified landmarks, we proposed to select biopsied tumors from all detected tumors via a tumor selection strategy using the pathology location. We validate our MHL method using data for 272 patients, and achieve a mean Dice similarity coefficient (DSC) of 0.72 in breast tumor segmentation. Finally, in a radiogenomic analysis, we show that a previously developed image features show a comparable performance for identifying luminal A subtype when applied to the automatic segmentation and a semi-manual segmentation demonstrating a high promise for fully automated radiogenomic analysis in breast cancer.

Formation and Reconnection of Three-Dimensional Current Sheets in the Solar Corona

NASA Technical Reports Server (NTRS)

Edmondson, J. K.; Antiochos, S. K.; DeVore, C. R.; Zurbuchen, T. H.

2010-01-01

Current-sheet formation and magnetic reconnection are believed to be the basic physical processes responsible for much of the activity observed in astrophysical plasmas, such as the Sun s corona. We investigate these processes for a magnetic configuration consisting of a uniform background field and an embedded line dipole, a topology that is expected to be ubiquitous in the corona. This magnetic system is driven by a uniform horizontal flow applied at the line-tied photosphere. Although both the initial field and the driver are translationally symmetric, the resulting evolution is calculated using a fully three-dimensional magnetohydrodynamic (3D MHD) simulation with adaptive mesh refinement that resolves the current sheet and reconnection dynamics in detail. The advantage of our approach is that it allows us to apply directly the vast body of knowledge gained from the many studies of 2D reconnection to the fully 3D case. We find that a current sheet forms in close analogy to the classic Syrovatskii 2D mechanism, but the resulting evolution is different than expected. The current sheet is globally stable, showing no evidence for a disruption or a secondary instability even for aspect ratios as high as 80:1. The global evolution generally follows the standard Sweet- Parker 2D reconnection model except for an accelerated reconnection rate at a very thin current sheet, due to the tearing instability and the formation of magnetic islands. An interesting conclusion is that despite the formation of fully 3D structures at small scales, the system remains close to 2D at global scales. We discuss the implications of our results for observations of the solar corona. Subject Headings: Sun: corona Sun: magnetic fields Sun: reconnection

Logics and Models for Concurrency and Type Theory

DTIC Science & Technology

1992-06-16

monoidal) categories, al- though the basic reference still remains the original monograph of Eilenberg and Kelly . Therefore, the paper includes a fully...University of Pisa, Italy " Prof. Pierpaolo Degano, University of Parma, Italy " !,.r. Vladimiro Sassone, Unit Aity of Pisa, Italy " Ms. Maura Cerioli

Metabolic and functional relevance of HDL subspecies

USDA-ARS?s Scientific Manuscript database

Though the association of high-density lipoprotein cholesterol (HDL-C) with cardiovascular disease (CVD) was described as early as 1950, HDL’s role in CVD still remains to be fully elucidated. There are numerous publications showing the inverse relationship between HDL-C and CVD risk; however, in t...

The CXCR4/SDF1 Axis Improves Muscle Regeneration Through MMP-10 Activity

PubMed Central

Bobadilla, Miriam; Sainz, Neira; Abizanda, Gloria; Orbe, Josune; Rodriguez, José Antonio; Páramo, José Antonio; Prósper, Felipe

2014-01-01

The CXCR4/SDF1 axis participates in various cellular processes, including cell migration, which is essential for skeletal muscle repair. Although increasing evidence has confirmed the role of CXCR4/SDF1 in embryonic muscle development, the function of this pathway during adult myogenesis remains to be fully elucidated. In addition, a role for CXCR4 signaling in muscle maintenance and repair has only recently emerged. Here, we have demonstrated that CXCR4 and stromal cell-derived factor-1 (SDF1) are up-regulated in injured muscle, suggesting their involvement in the repair process. In addition, we found that notexin-damaged muscles showed delayed muscle regeneration on treatment with CXCR4 agonist (AMD3100). Accordingly, small-interfering RNA-mediated silencing of SDF1 or CXCR4 in injured muscles impaired muscle regeneration, whereas the addition of SDF1 ligand accelerated repair. Furthermore, we identified that CXCR4/SDF1-regulated muscle repair was dependent on matrix metalloproteinase-10 (MMP-10) activity. Thus, our findings support a model in which MMP-10 activity modulates CXCR4/SDF1 signaling, which is essential for efficient skeletal muscle regeneration. PMID:24548137

Relevance of substrates and products on the desorption of lipases physically adsorbed on hydrophobic supports.

PubMed

Virgen-Ortíz, Jose J; Tacias-Pascacio, Veymar G; Hirata, Daniela B; Torrestiana-Sanchez, Beatriz; Rosales-Quintero, Arnulfo; Fernandez-Lafuente, Roberto

2017-01-01

Lipase B from Candida antarctica (CALB) has been physically immobilized on octyl-agarose via interfacial activation. The incubation of the enzyme in 80% ethanol at pH 5 and 25°C has not significant effect on enzyme activity. Moreover, the hydrolysis of 100mM tributyrin catalyzed by this biocatalyst exhibited a quite linear reaction course. However, a new cycle of tributyrin hydrolysis showed a drastic drop in the activity. SDS-PAGE gels of the supernatant and the biocatalyst showed a significant enzyme desorption after the reaction. Similar results could be appreciated using triacetin or sunflower oil, while using 300mM methyl phenyl acetate, butyl butyrate or ethyl butyrate most enzyme molecules remained immobilized. The results show that the detergent properties of some reaction products increase the enzyme release from the hydrophobic support, and this problem increased if the concentration of the reactants increased. Using 500mM tributyrin, even in fully aqueous medium, some enzyme desorption from the support may be observed. Thus, the results show a limitation of this kind of biocatalysts that should be considered in the selection of an industrial lipase biocatalyst. Copyright © 2016 Elsevier Inc. All rights reserved.

Transequatorial loops interconnecting McMath regions 12472 and 12474

NASA Technical Reports Server (NTRS)

Svestka, Z.; Krieger, A. S.; Chase, R. C.; Howard, R.

1977-01-01

The paper reviews the life history of one transequatorial loop in a system observed in soft X-rays for at least 1.5 days and which interconnected a newly born active region with an old region. The birth of the selected loop is discussed along with properties of the interconnected active regions, sharpening and brightening of the loop, decay of the loop system, and physical relations between the interconnected regions. It is concluded that: (1) the loop was most probably born via reconnection of magnetic-field lines extending from the two active regions toward the equator, which occurred later than 33 hr after the younger region was born; (2) the fully developed interconnection was composed of several loops, all of which appeared to be rooted in a spotless magnetic hill of preceding northern polarity but were spread over two separate spotty regions of southern polarity in the magnetically complex new region; (3) the loop electron temperature increased from 2.1 million to 3.1 million K in one to three hours when the loop system brightened; and (4) the loops became twisted during the brightening, possibly due to their rise in the corona while remaining rooted in moving magnetic features in the younger region.

Glucocorticoid receptor contributes to the altered expression of hepatic cytochrome P450 upon cigarette smoking.

PubMed

Li, Xue; Yan, Zhongfang; Wu, Qi; Sun, Xin; Li, Fan; Zhang, Subei; Li, Kuan; Li, Li; Wu, Junping; Xu, Long; Feng, Jing; Ning, Wen; Liu, Zhixue; Chen, Huaiyong

2016-12-01

Cigarette smoking has been shown to cause pathological alterations in the liver. However, how hepatic metabolism is altered during cigarette smoking‑induced inflammation remains to be fully elucidated. In the present study, a rat model of smoking was established to examine the effects of cigarette smoking on inflammation, autophagy activity, and the expression of nuclear receptor and CYP in the liver. Elevated expression of interleukin 1β and activation of autophagy in the liver were observed upon smoking exposure in rats. Cigarette smoking induced a significant reduction in the mRNA expression levels of cytochromes, including cytochrome P450 (Cyp)1A2, Cyp2D4 and Cyp3A2. Accordingly, a decrease was also observed in glucocorticoid receptor (GR), a regulator of the expression of Cyp. Activation of the GR signal in human hepatic LO2 cells did not affect autophagic genes, however, it led to the upregulation of hCYP1A2, hCYP2C19 and hCYP3A4, and the downregulation of hCYP2C9. The GR antagonist, RU486, eliminated this effect, suggesting the importance of GR in liver metabolism upon cigarette smoking.

YC‑1 reduces inflammatory responses by inhibiting nuclear factor‑κB translocation in mice subjected to transient focal cerebral ischemia.

PubMed

Lee, Wei-Ting; Tai, Shih-Huang; Lin, Yu-Wen; Wu, Tian-Shung; Lee, E-Jian

2018-06-15

3‑(5‑hydroxymethyl‑2‑furyl)‑1‑benzyl‑indazole (YC‑1) is understood to protect against ischemic stroke, but the molecular basis for its neuroprotection remains to be fully characterized. The present study investigated the influence of YC‑1 on inflammatory responses following experimental stroke. Previous studies indicated that nuclear factor (NF)‑κB‑driven signals serve a pivotal role in mediating inflammatory responses following stroke. Ischemic stroke results in activation of NF‑κB to induce gene expression of factors including inducible nitric oxide synthase, interleukin (IL)‑1β, IL‑6 and matrix metalloproteinases (MMPs). The results of the present study demonstrated that YC‑1 effectively reduced brain infarction and brain edema, and improved blood‑brain barrier leakage. Additionally, animals treated with YC‑1 exhibited significant reductions in neutrophil and macrophage infiltration into the ischemic brain. Furthermore, YC‑1 effectively inhibited NF‑κB translocation and binding activity, and the activity and expression of MMP‑9 following ischemic stroke. In conclusion, YC‑1 may effectively attenuate NF‑κB‑induced inflammatory damage following cerebral ischemia‑reperfusion.

A Fully Automated Method to Detect and Segment a Manufactured Object in an Underwater Color Image

NASA Astrophysics Data System (ADS)

Barat, Christian; Phlypo, Ronald

2010-12-01

We propose a fully automated active contours-based method for the detection and the segmentation of a moored manufactured object in an underwater image. Detection of objects in underwater images is difficult due to the variable lighting conditions and shadows on the object. The proposed technique is based on the information contained in the color maps and uses the visual attention method, combined with a statistical approach for the detection and an active contour for the segmentation of the object to overcome the above problems. In the classical active contour method the region descriptor is fixed and the convergence of the method depends on the initialization. With our approach, this dependence is overcome with an initialization using the visual attention results and a criterion to select the best region descriptor. This approach improves the convergence and the processing time while providing the advantages of a fully automated method.

Homeostatic and non-homeostatic appetite control along the spectrum of physical activity levels: An updated perspective.

PubMed

Beaulieu, Kristine; Hopkins, Mark; Blundell, John; Finlayson, Graham

2017-12-28

The current obesogenic environment promotes physical inactivity and food consumption in excess of energy requirements, two important modifiable risk factors influencing energy balance. Habitual physical activity has been shown to impact not only energy expenditure, but also energy intake through mechanisms of appetite control. This review summarizes recent theory and evidence underpinning the role of physical activity in the homeostatic and non-homeostatic mechanisms controlling appetite. Energy intake along the spectrum of physical activity levels (inactive to highly active) appears to be J-shaped, with low levels of physical activity leading to dysregulated appetite and a mismatch between energy intake and expenditure. At higher levels, habitual physical activity influences homeostatic appetite control in a dual-process action by increasing the drive to eat through greater energy expenditure, but also by enhancing post-meal satiety, allowing energy intake to better match energy expenditure in response to hunger and satiety signals. There is clear presumptive evidence that physical activity energy expenditure can act as a drive (determinant) of energy intake. The influence of physical activity level on non-homeostatic appetite control is less clear, but low levels of physical activity may amplify hedonic states and behavioural traits favouring overconsumption indirectly through increased body fat. More evidence is required to understand the interaction between physical activity, appetite control and diet composition on passive overconsumption and energy balance. Furthermore, potential moderators of appetite control along the spectrum of physical activity, such as body composition, sex, and type, intensity and timing of physical activity, remain to be fully understood. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons.

PubMed

Malthankar-Phatak, Gauri H; Patel, Anant B; Xia, Ying; Hong, Soonsun; Chowdhury, Golam M I; Behar, Kevin L; Orina, Isaac A; Lai, James C K

2008-09-10

Mechanisms underlying hypoxia-induced neuronal adaptation have not been fully elucidated. In the present study we investigated glucose metabolism and the activities of glycolytic and TCA cycle enzymes in cerebro-cortical neurons exposed to hypoxia (3 days in 1% of O2) or normoxia (room air). Hypoxia led to increased activities of LDH (194%), PK (90%), and HK (24%) and decreased activities of CS (15%) and GDH (34%). Neurons were incubated with [1-(13)C]glucose for 45 and 120 min under normoxic or hypoxic (120 min only) conditions and 13C enrichment determined in the medium and cell extract using 1H-{13C}-NMR. In hypoxia-treated neurons [3-(13)C]lactate release into the medium was 428% greater than in normoxia-treated controls (45-min normoxic incubation) and total flux through lactate was increased by 425%. In contrast glucose oxidation was reduced significantly in hypoxia-treated neurons, even when expressed relative to total cellular protein, which correlated with the reduced activities of the measured mitochondrial enzymes. The results suggest that surviving neurons adapt to prolonged hypoxia by up-regulation of glycolysis and down-regulation of oxidative energy metabolism, similar to certain other cell types. The factors leading to adaptation and survival for some neurons but not others remain to be determined.

Multiparameter Investigation of a 46,XX/46,XY Tetragametic Chimeric Phenotypical Male Patient with Bilateral Scrotal Ovotestes and Ovulatory Activity.

PubMed

van Bever, Yolande; Wolffenbuttel, Katja P; Brüggenwirth, Hennie T; Blom, Eric; de Klein, Annelies; Eussen, Bert H J; van der Windt, Florijn; Hannema, Sabine E; Dessens, Arianne B; Dorssers, Lambert C J; Biermann, Katharina; Hersmus, Remko; de Rijke, Yolanda B; Looijenga, Leendert H J

2018-01-01

We report on an adult male initially presenting with gynecomastia and a painless scrotal mass without additional genital anomalies. Hyperpigmentation of the skin following the Blaschko's lines was identified. He underwent gonadectomy because of suspected cancer. Histological analyses revealed an ovotestis with ovulatory activity confirmed by immunohistochemistry with multiple markers. Karyotyping of cultured peripheral blood lymphocytes and a buccal smear revealed a 46,XX/46,XY chimeric constitution with different percentages. Multiple molecular analyses as well as blood typing implied a tetragametic origin. After the unilateral gonadectomy, the patient developed recurrent painful cystic swellings of the remaining gonad. Because of the wish to preserve hormonal activity as well as future fertility, the patient underwent surgical resection of a cystic gonadal area. The removed tissue showed ovulation-related features in addition to both testicular and ovarian tissue, diagnosed as an ovotestis. Testosterone therapy was initiated to suppress the persistently elevated gonadotropins and thereby suppress ovarian activity. During treatment, the recurrent pain complaints and cystic swellings ceased, although gonadotropin levels were not fully suppressed. Based on these observations, the importance of a detailed genetic and pathological diagnosis and the clinical dilemmas including the pros and cons of personalized treatment with gonadal preservative surgery are discussed. © 2017 S. Karger AG, Basel.

Dose Dependent Effects of Reactive Oxygen and Nitrogen Species on the Function of Neuronal Nitric Oxide Synthase

PubMed Central

Sun, Jian; Druhan, Lawrence J.; Zweier, Jay L.

2014-01-01

Reactive nitrogen species (RNS) and oxygen species (ROS) have been reported to modulate the function of nitric oxide synthase (NOS); however, the precise dosedependent effects of specific RNS and ROS on NOS function are unknown. Questions remain unanswered regarding whether pathophysiological levels of RNS and ROS alter NOS function, and if this alteration is reversible. We measured the effects of peroxynitrite (ONOO-), superoxide (O2.-), hydroxyl radical (.OH), and H2O2 on nNOS activity. The results showed that NO production was inhibited in a dose-dependent manner by all four oxidants, but only O2.- and ONOO- were inhibitory at pathophysiological concentrations (≤ 50 μM). Subsequent addition of tetrahydrobiopterin (BH4) fully restored activity after O2.- exposure, while BH4 partially rescued the activity decrease induced by the other three oxidants. Furthermore, treatment with either ONOO- or O2.- stimulated nNOS uncoupling with decreased NO and enhanced O2.- generation. Thus, nNOS is reversibly uncoupled by O2.- (≤ 50 μM), but irreversibly uncoupled and inactivated by ONOO-. Additionally, we observed that the mechanism by which oxidative stress alters nNOS activity involves not only BH4 oxidation, but also nNOS monomerization as well as possible degradation of the heme. PMID:18201545

GABAergic ventrolateral pre-optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol

PubMed Central

Yuan, Jie; Luo, Zhuxin; Zhang, Yu; Zhang, Yi; Wang, Yuan; Cao, Song; Fu, Bao; Yang, Hao; Zhang, Lin; Zhou, Wenjing; Yu, Tian

2017-01-01

Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic-induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endogenous sleep-arousal circuits. However, few studies focus on the ventrolateral pre-optic (VLPO) to locus coeruleus (LC) sleep-arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol. The present study additionally investigated if the inhibitory effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target lesion and extracellular single-unit recordings were used to study the role of the VLPO-LC pathway in propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist (gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC noradrenergic neurons. There was no significant difference observed in firing activity between VLPO sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in propofol-induced unconsciousness, however are unlikely to contribute to the inhibitory effect of propofol on LC spontaneous firing activity. PMID:28765955

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

Gilbert, Nathaniel C.; Rui, Zhe; Neau, David B.

The enzyme 5-lipoxygenase (5-LOX) initiates biosynthesis of the proinflammatory leukotriene lipid mediators and, together with 15-LOX, is also required for synthesis of the anti-inflammatory lipoxins. The catalytic activity of 5-LOX is regulated through multiple mechanisms, including Ca{sup 2+}-targeted membrane binding and phosphorylation at specific serine residues. To investigate the consequences of phosphorylation at S663, we mutated the residue to the phosphorylation mimic Asp, providing a homogenous preparation suitable for catalytic and structural studies. The S663D enzyme exhibits robust 15-LOX activity, as determined by spectrophotometric and HPLC analyses, with only traces of 5-LOX activity remaining; synthesis of the anti-inflammatory lipoxin A4more » from arachidonic acid is also detected. The crystal structure of the S663D mutant in the absence and presence of arachidonic acid (in the context of the previously reported Stable-5-LOX) reveals substantial remodeling of helices that define the active site so that the once fully encapsulated catalytic machinery is solvent accessible. Our results suggest that phosphorylation of 5-LOX at S663 could not only down-regulate leukotriene synthesis but also stimulate lipoxin production in inflammatory cells that do not express 15-LOX, thus redirecting lipid mediator biosynthesis to the production of proresolving mediators of inflammation.« less

Multiple Measurements Regarding the Competence of the Andragogical Learner

ERIC Educational Resources Information Center

Boone, Timothy Keith

2013-01-01

Evidence suggests that many adult learners have not developed the competencies needed to fully function effectively in today's society. Questions remain, however, on the levels of influence exerted on self-direction and motivation among this population. The purpose of this correlational study using a multiple measurements assessment approach was…

Recreating Family: Parents Identify Worker-Client Relationships as Paramount in Family Preservation Programs

ERIC Educational Resources Information Center

Gockel, Annemarie; Russell, Mary; Harris, Barbara

2008-01-01

Although existing family preservation program research has focused on identifying the components of effective treatment, we remain far from fully developing empirically supported interventions (Barth, Chamberlain, Reid, Rolls, Hurlburt, Farmer, James, McCabe, & Kohl, 2005; Dufour, Chamberland, & Trocme, 2003). The current longitudinal study…

Recent Developments in HIV/AIDS Prevention for Russian Adolescents

ERIC Educational Resources Information Center

Stothard, Blaine; Romanova, Olga; Ivanova, Larissa

2007-01-01

Rates of sexually transmitted infections and HIV transmission in Russia remain high. Official attitudes do not yet appear to recognise fully their significance. There is increasing knowledge of the population's sexual behaviour and attitudes, including of young people, emerging from local and externally funded programmes. This is leading to…

Practicing Radical Pedagogy: Balancing Ideals with Institutional Constraints.

ERIC Educational Resources Information Center

Sweet, Stephen

1998-01-01

Describes radical pedagogy and observes that an overview of "Teaching Sociology" suggests that few teachers fully practice it. Argues that while professors are free to teach radical theory, radical pedagogy is hindered by institutional constraints. Concludes that radical teachers may benefit from remaining more within the confines imposed by their…

Laplace Boundary-Value Problem in Paraboloidal Coordinates

ERIC Educational Resources Information Center

Duggen, L.; Willatzen, M.; Voon, L. C. Lew Yan

2012-01-01

This paper illustrates both a problem in mathematical physics, whereby the method of separation of variables, while applicable, leads to three ordinary differential equations that remain fully coupled via two separation constants and a five-term recurrence relation for series solutions, and an exactly solvable problem in electrostatics, as a…

Traumatic Optic Neuropathy.

PubMed

Jang, Sun Young

2018-04-01

Traumatic optic neuropathy (TON) refers to optic nerve injury resulting from direct and indirect head and facial trauma. The pathogenesis of indirect TON has not been fully elucidated, and the management of TON remains controversial. In this review article, I review the recent literature regarding TON and discuss how to manage indirect TON.

Re-Conceptualising Graduate Employability: The Importance of Pre-Professional Identity

ERIC Educational Resources Information Center

Jackson, Denise

2016-01-01

Despite efforts to broaden the concept of graduate employability, there remains an overarching focus on developing industry-relevant employability skills. The skills-based approach is, however, too narrow and does not fully capture the complexity of graduate work-readiness. This paper argues for the redefining of graduate employability by…

Creative Writing Strategies of Young Children: Evidence from a Study of Chinese Emergent Writing

ERIC Educational Resources Information Center

Chen, Si; Zhou, Jing

2010-01-01

The ways in which learning graphical representations can encourage the development of creativities in Chinese young children remain to be fully explored. Previous research on children's writing focused on children's symbolization with syllabic languages, providing little information regarding Chinese young children's symbolization and creative…

Inhibiting TLR2 activation attenuates amyloid accumulation and glial activation in a mouse model of Alzheimer's disease.

PubMed

McDonald, Claire L; Hennessy, Edel; Rubio-Araiz, Ana; Keogh, Brian; McCormack, William; McGuirk, Peter; Reilly, Mary; Lynch, Marina A

2016-11-01

The effects of Toll-like receptor (TLR) activation in peripheral cells are well characterized but, although several TLRs are expressed on cells of the brain, the consequences of their activation on neuronal function remain to be fully investigated, particularly in the context of assessing their potential as therapeutic targets in neurodegenerative diseases. Several endogenous TLR ligands have been identified, many of which are soluble factors released from cells exposed to stressors. In addition, amyloid-β (Aβ) the main constituent of the amyloid plaques in Alzheimer's disease (AD), activates TLR2, although it has also been shown to bind to several other receptors. The objective of this study was to determine whether activation of TLR2 played a role in the developing inflammatory changes and Aβ accumulation in a mouse model of AD. Wild type and transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1 mice) were treated with anti-TLR2 antibody for 7months from the age of 7-14months. We demonstrate that microglial and astroglial activation, as assessed by MHCII, CD68 and GFAP immunoreactivity was decreased in anti-TLR2 antibody-treated compared with control (IgG)-treated mice. This was associated with reduced Aβ plaque burden and improved performance in spatial learning. The data suggest that continued TLR2 activation contributes to the developing neuroinflammation and pathology and may be provide a strategy for limiting the progression of AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Navy Collaborative Integrated Information Technology Initiative (NAVCIITI)

DTIC Science & Technology

2004-09-01

We investigated a new type of antenna array consisting of sub- elements that are excited together to form the primary element. All of the sub...elements of the array are excited for the highest operating band. Only the primary elements are excited for the low frequency band. This fractal geometry has...fully active array. The fully active input impedance is the input impedance of an element in an array when all elements are excited . It is a function

Fully inkjet-printed two-dimensional material field-effect heterojunctions for wearable and textile electronics.

PubMed

Carey, Tian; Cacovich, Stefania; Divitini, Giorgio; Ren, Jiesheng; Mansouri, Aida; Kim, Jong M; Wang, Chaoxia; Ducati, Caterina; Sordan, Roman; Torrisi, Felice

2017-10-31

Fully printed wearable electronics based on two-dimensional (2D) material heterojunction structures also known as heterostructures, such as field-effect transistors, require robust and reproducible printed multi-layer stacks consisting of active channel, dielectric and conductive contact layers. Solution processing of graphite and other layered materials provides low-cost inks enabling printed electronic devices, for example by inkjet printing. However, the limited quality of the 2D-material inks, the complexity of the layered arrangement, and the lack of a dielectric 2D-material ink able to operate at room temperature, under strain and after several washing cycles has impeded the fabrication of electronic devices on textile with fully printed 2D heterostructures. Here we demonstrate fully inkjet-printed 2D-material active heterostructures with graphene and hexagonal-boron nitride (h-BN) inks, and use them to fabricate all inkjet-printed flexible and washable field-effect transistors on textile, reaching a field-effect mobility of ~91 cm 2  V -1  s -1 , at low voltage (<5 V). This enables fully inkjet-printed electronic circuits, such as reprogrammable volatile memory cells, complementary inverters and OR logic gates.

Quality improvement of a rice-substituted fried noodle by utilizing the protein-polyphenol interaction between a pea protein isolate and green tea (Camellia sinensis) extract.

PubMed

Song, Youngwoon; Yoo, Sang-Ho

2017-11-15

The quality of rice-substituted fried noodles was improved by applying interaction between pea protein isolate (PPI) and green tea extract (GTE). Radical-scavenging activities of GTE were stably maintained when exposed to acidic pH, UV light, and fluorescent light, but decreased by approximately 65% when exposed to 80°C for 168h. The RVA profiles of noodle dough showed that peak viscosity and breakdown increased significantly but that setback and final viscosity remained unchanged with 20% rice flour replacement. PPI significantly decreased the viscosity parameters of rice-supplemented dough, and the addition of GTE recovered these values significantly. The cooking loss and viscoelasticity (R max ) of cooked rice-supplemented noodles were fully restored by combined treatment of PPI and GTE. GTE decreased the peroxide value of fried noodles by 14% after storage at 63°C for 16days. Therefore, PPI+GTE treatment has great potential for use in fried noodles owing to the reinforced network and antioxidant activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical Defense by Erythrolactones in the Euryhaline Ciliated Protist, Pseudokeronopsis erythrina.

PubMed

Buonanno, Federico; Anesi, Andrea; Giuseppe, Graziano Di; Guella, Graziano; Ortenzi, Claudio

2017-02-01

Pseudokeronopsis erythrina produces three new secondary metabolites, erythrolactones A2, B2 and C2, and their respective sulfate esters (A1, B1, C1), the structures of which have been recently elucidated on the basis of NMR spectroscopic data coupled to high resolution mass measurements (HR-MALDI-TOF). An analysis of the discharge of the protozoan pigment granules revealed that the non-sulfonated erythrolactones are exclusively stored in these cortical organelles, which are commonly used by a number of ciliates as chemical weapons in offense/defense interactions with prey and predators. We evaluated the toxic activity of pigment granule discharge on a panel of free-living ciliates and micro-invertebrates, and the activity of each single purified erythrolactone on three ciliate species. We also observed predator-prey interactions of P. erythrina with unicellular and multicellular predators. Experimental results confirm that only P. erythrina cells with discharged pigment granules were preferentially or exclusively hunted and eaten by at least some of its predators, whereas almost all intact (fully pigmented) cells remained alive. Our results indicate that erythrolactones are very effective as a chemical defense in P. erythrina.

Spatially-resolved mapping of history-dependent coupled electrochemical and electronical behaviors of electroresistive NiO

DOE PAGES

Sugiyama, Issei; Kim, Yunseok; Jesse, Stephen; ...

2014-10-22

Bias-induced oxygen ion dynamics underpins a broad spectrum of electroresistive and memristive phenomena in oxide materials. Although widely studied by device-level and local voltage-current spectroscopies, the relationship between electroresistive phenomena, local electrochemical behaviors, and microstructures remains elusive. Here, the interplay between history-dependent electronic transport and electrochemical phenomena in a NiO single crystalline thin film with a number of well-defined defect types is explored on the nanometer scale using an atomic force microscopy-based technique. A variety of electrochemically-active regions were observed and spatially resolved relationship between the electronic and electrochemical phenomena was revealed. The regions with pronounced electroresistive activity were furthermore » correlated with defects identified by scanning transmission electron microscopy. Using fully coupled mechanical-electrochemical modeling, we illustrate that the spatial distribution of strain plays an important role in electrochemical and electroresistive phenomena. In conclusion, these studies illustrate an approach for simultaneous mapping of the electronic and ionic transport on a single defective structure level such as dislocations or interfaces, and pave the way for creating libraries of defect-specific electrochemical responses.« less

Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats

PubMed Central

Kan, Min Hui; Yang, Ting; Fu, Hui Qun; Fan, Long; Wu, Yan; Terrando, Niccolò; Wang, Tian-Long

2016-01-01

Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-κB (NF-κB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-κB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-α and interleukin-1β (IL-1β) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-κB activity but also affected IL-1β expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure. PMID:27493629

Microbubble-Assisted Ultrasound-Induced Transient Phosphatidylserine Translocation.

PubMed

Escoffre, Jean-Michel; Derieppe, Marc; Lammertink, Bart; Bos, Clemens; Moonen, Chrit

2017-04-01

Microbubble-assisted ultrasound (sonopermeabilization) results in reversible permeabilization of the plasma membrane of cells. This method is increasingly used in vivo because of its potential to deliver therapeutic molecules with limited cell damage. Nevertheless, the effects of sonopermeabilization on the plasma membrane remain not fully understood. We investigated the influence of sonopermeabilization on the transverse mobility of phospholipids, especially on phosphatidylserine (PS) externalization. We performed studies using optical imaging with Annexin V and FM1-43 probes to monitor PS externalization of rat glioma C6 cells. Sonopermeabilization induced transient membrane permeabilization, which is positively correlated with reversible PS externalization. This membrane disorganization was temporary and not associated with loss of cell viability. Sonopermeabilization did not induce PS externalization via activation of the scramblase. We hypothesize that acoustically induced membrane pores may provide a new pathway for PS migration between both membrane leaflets. During the membrane-resealing phase, PS asymmetry may be re-established by amino-phospholipid flippase activity and/or endocytosis, along with exocytosis processes. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel

PubMed Central

Goldschen-Ohm, Marcel P.; Capes, Deborah L.; Oelstrom, Kevin M.; Chanda, Baron

2013-01-01

Voltage-dependent Na+ channels are crucial for electrical signalling in excitable cells. Membrane depolarization initiates asynchronous movements in four non-identical voltage-sensing domains of the Na+ channel. It remains unclear to what extent this structural asymmetry influences pore gating as compared with outwardly rectifying K+ channels, where channel opening results from a final concerted transition of symmetric pore gates. Here we combine single channel recordings, cysteine accessibility and voltage clamp fluorimetry to probe the relationships between voltage sensors and pore conformations in an inactivation deficient Nav1.4 channel. We observe three distinct conductance levels such that DI-III voltage sensor activation is kinetically correlated with formation of a fully open pore, whereas DIV voltage sensor movement underlies formation of a distinct subconducting pore conformation preceding inactivation in wild-type channels. Our experiments reveal that pore gating in sodium channels involves multiple transitions driven by asynchronous movements of voltage sensors. These findings shed new light on the mechanism of coupling between activation and fast inactivation in voltage-gated sodium channels. PMID:23322038

The complete practitioner: still a work in progress.

PubMed

Barnett, Jeffrey E

2009-11-01

When one is reflecting on a career as a practitioner, a number of important influences, themes, and elements that contribute to being a successful practitioner are evident. The achievement of this success is not a solitary activity. Many role models and mentors serve as important influences and guides for developing as a professional over the course of one's career. Ultimately, the goal is to aspire to become a complete practitioner. This includes being a passionate professional, clinically competent, a psychotherapist and clinician, an active consumer of research findings, ethical, a role model, a mentor, psychologically healthy, an advocate, a leader, a volunteer, an educator, a scholar, a colleague, a business person and entrepreneur, and an innovator and visionary; focusing on diversity and multicultural competence; and having a comprehensive vision of health. Because the goal of being a complete practitioner is aspirational, one never fully masters each of these roles and attributes but remains a work in progress. Yet, the process of endeavoring to become a complete practitioner is rewarding, gratifying, and meaningful. It is a journey well worth taking. Copyright 2009 by the American Psychological Association

Biological Mechanisms by Which Antiproliferative Actions of Resveratrol Are Minimized.

PubMed

Ho, Yih; Lin, Yu-Syuan; Liu, Hsuan-Liang; Shih, Ya-Jung; Lin, Shin-Ying; Shih, Ai; Chin, Yu-Tang; Chen, Yi-Ru; Lin, Hung-Yun; Davis, Paul J

2017-09-21

Preclinical and clinical studies have offered evidence for protective effects of various polyphenol-rich foods against cardiovascular diseases, neurodegenerative diseases, and cancers. Resveratrol is among the most widely studied polyphenols. However, the preventive and treatment effectiveness of resveratrol in cancer remain controversial because of certain limitations in existing studies. For example, studies of the activity of resveratrol against cancer cell lines in vitro have often been conducted at concentrations in the low μM to mM range, whereas dietary resveratrol or resveratrol-containing wine rarely achieve nM concentrations in the clinic. While the mechanisms underlying the failure of resveratrol to inhibit cancer growth in the intact organism are not fully understood, the interference by thyroid hormones with the anticancer activity of resveratrol have been well documented in both in vitro and xenograft studies. Thus, endogenous thyroid hormones may explain the failure of anticancer actions of resveratrol in intact animals, or in the clinic. In this review, mechanisms involved in resveratrol-induced antiproliferation and effects of thyroid hormones on these mechanisms are discussed.

Spermidine Suppresses Age-Associated Memory Impairment by Preventing Adverse Increase of Presynaptic Active Zone Size and Release

PubMed Central

Gupta, Varun K.; Pech, Ulrike; Fulterer, Andreas; Ender, Anatoli; Mauermann, Stephan F.; Andlauer, Till F. M.; Beuschel, Christine; Thriene, Kerstin; Quentin, Christine; Schwärzel, Martin; Mielke, Thorsten; Madeo, Frank; Dengjel, Joern; Fiala, André; Sigrist, Stephan J.

2016-01-01

Memories are assumed to be formed by sets of synapses changing their structural or functional performance. The efficacy of forming new memories declines with advancing age, but the synaptic changes underlying age-induced memory impairment remain poorly understood. Recently, we found spermidine feeding to specifically suppress age-dependent impairments in forming olfactory memories, providing a mean to search for synaptic changes involved in age-dependent memory impairment. Here, we show that a specific synaptic compartment, the presynaptic active zone (AZ), increases the size of its ultrastructural elaboration and releases significantly more synaptic vesicles with advancing age. These age-induced AZ changes, however, were fully suppressed by spermidine feeding. A genetically enforced enlargement of AZ scaffolds (four gene-copies of BRP) impaired memory formation in young animals. Thus, in the Drosophila nervous system, aging AZs seem to steer towards the upper limit of their operational range, limiting synaptic plasticity and contributing to impairment of memory formation. Spermidine feeding suppresses age-dependent memory impairment by counteracting these age-dependent changes directly at the synapse. PMID:27684064

Biochemical and biophysical characterization of a plant calmodulin: Role of the N- and C-lobes in calcium binding, conformational change, and target interaction.

PubMed

Astegno, Alessandra; La Verde, Valentina; Marino, Valerio; Dell'Orco, Daniele; Dominici, Paola

2016-03-01

In plants, transient elevation of intracellular Ca(2+) concentration in response to abiotic stress is responsible for glutamate decarboxylase (GAD) activation via association with calmodulin (CaM), an EF-hand protein consisting of two homologous domains (N and C). An unusual 1:2 binding mode of CaM to CaM-binding domains of GAD has long been known, however the contribution of the two CaM domains in target recognition and activation remains to be clarified. Here, we explored the coupling between physicochemical properties of Arabidopsis CaM1 (AtCaM1) and Arabidopsis GAD1 activation, focusing on each AtCaM1 lobe. We found that the four EF-loops of AtCaM1 differently contribute to the ~20 μM apparent affinity for Ca(2+) and the C-lobe shows a ~6-fold higher affinity than N-lobe (Kd(app) 5.6 μM and 32 μM for C- and N-lobes, respectively). AtCaM1 responds structurally to Ca(2+) in a manner similar to vertebrate CaM based on comparison of Ca(2+)-induced changes in hydrophobicity exposure, secondary structure, and hydrodynamic behavior. Molecular dynamics simulations of AtCaM1 apo and Ca(2+)-bound reveal that the latter state is significantly less flexible, although regions of the N-lobe remain quite flexible; this suggests the importance of N-lobe for completing the transition to the extended structure of holoprotein, consistent with data from ANS fluorescence, CD spectroscopy, and SEC analysis. Moreover, enzymatic analysis reveal that mutations in the two lobes affect GAD1 activation in similar ways and only intact AtCaM1 can fully activate GAD1. Taken together, our data provide new insights into the CaM lobes role in interactions between CaM and plant GAD. Copyright © 2015 Elsevier B.V. All rights reserved.

Loss in photosynthesis during senescence is accompanied by an increase in the activity of β-galactosidase in leaves of Arabidopsis thaliana: modulation of the enzyme activity by water stress.

PubMed

Pandey, Jitendra Kumar; Dash, Sidhartha Kumar; Biswal, Basanti

2017-07-01

The precise nature of the developmental modulation of the activity of cell wall hydrolases that breakdown the wall polysaccharides to maintain cellular sugar homeostasis under sugar starvation environment still remains unclear. In this work, the activity of β-galactosidase (EC 3.2.1.23), a cell-wall-bound enzyme known to degrade the wall polysaccharides, has been demonstrated to remarkably enhance during senescence-induced loss in photosynthesis in Arabidopsis thaliana. The enhancement in the enzyme activity reaches a peak at the terminal phase of senescence when the rate of photosynthesis is at its minimum. Although the precise nature of chemistry of the interface between the decline in photosynthesis and enhancement in the activity of the enzyme could not be fully resolved, the enhancement in its activity in dark and its suppression in light or with exogenous sugars may indicate the involvement of loss of photosynthetic production of sugars as a key factor that initiates and stimulates the activity of the enzyme. The hydrolase possibly participates in the catabolic network of cell wall polysaccharides to produce sugars for execution of energy-dependant senescence program in the background of loss of photosynthesis. Drought stress experienced by the senescing leaves accelerates the decline in photosynthesis with further stimulation in the activity of the enzyme. The stress recovery of photosynthesis and suppression of the enzyme activity on withdrawal of stress support the proposition of photosynthetic modulation of the cell-wall-bound enzyme activity.

Methanogenesis limitations in degraded peatlands after their hydrological restoration

NASA Astrophysics Data System (ADS)

Urbanová, Zuzana

2017-04-01

Peatlands are ecosystems that can have a high degree of carbon sequestration due to CO2 fixation and low decomposition rates, but on the other hand, they are a source of CH4. Past drainage or mining can disturb these natural functions with rewetting being the main method used to bring back their original ecosystem properties. Methanogenic community composition and its activity seems to be very sensitive to environmental changes and therefore its limited activity after restoration can reflect the not fully restored functioning of the microbial community and its processes in the rewetted peatlands. To find the cause for this methanogenesis limitation we determined the abundance and composition of the methanogenic community and methane potential production in pristine, long-term drained and rewetted bogs and spruce swamp forests (SSF) in the Šumava Mountains (Czech Republic), using high-throughput barcoded sequencing, qPCR and anaerobic incubation of peat samples in relation to peat biochemical properties. Long-term drainage led to a strongly reduced diversity, abundance and activity of the methanogenic community in both peatland types. In restored sites, methanogenic abundance and community composition reached a pristine like state, however their activity measured as CH4 production remained as low as in drained sites. Substrate limitation was expected; therefore we further added different substrates during anaerobic incubation of the peat samples. In addition to glucose and ethanol, we added natural complex substrates from peatland plants (sedges, Sphagnum) to simulate the effect of the spreading of peatland species and their litter on methanogenic activity. The results unambiguously confirmed the limitation of methanogens by substrate availability due to the previous long-term drainage and strongly decomposed peat. The addition of natural substrates led to an increase in CH4 production, which was close to values in pristine sites. The limited CH4 production reflected a not fully restored vegetation structure with sufficient litter production. Thus, the re-establishment of peatland vegetation structure should lead to regeneration of methanogenic activity and microbial processes in restored peatlands. Moreover, the results showed that there is no risk of increased CH4 emissions in the case of nutrient poor bogs and SSF after re-wetting. For management, the methanogenic community composition, abundance and activity could be used as indicators of restoration success.

The Potential Return on Public Investment in Detecting Adverse Drug Effects.

PubMed

Huybrechts, Krista F; Desai, Rishi J; Park, Moa; Gagne, Joshua J; Najafzadeh, Mehdi; Avorn, Jerry

2017-06-01

Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. We assessed 3 examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the health care system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773-$884 million for rofecoxib, $3-$10 million for cerivastatin, and $38-$63 million for troglitazone in the United States through the prevention of adverse events. By contrast, the yearly public investment in Food and Drug Administration initiated population-based pharmacovigilance activities in the United States is about $42.5 million at present. These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public.

The Potential Return on Public Investment in Detecting Adverse Drug Effects

PubMed Central

Huybrechts, Krista F.; Desai, Rishi J.; Park, Moa; Gagne, Joshua J.; Najafzadeh, Mehdi; Avorn, Jerry

2017-01-01

Background Many countries lack fully functional pharmacovigilance programs, and public budgets allocated to pharmacovigilance in industrialized countries remain low due to resource constraints and competing priorities. Objective Using 3 case examples, we sought to estimate the public health and economic benefits resulting from public investment in active pharmacovigilance programs to detect adverse drug effects. Research Design We assessed three examples in which early signals of safety hazards were not adequately recognized, resulting in continued exposure of a large number of patients to these drugs when safer and effective alternative treatments were available. The drug examples studied were rofecoxib, cerivastatin, and troglitazone. Using an individual patient simulation model and the healthcare system perspective, we estimated the potential costs that could have been averted by early systematic detection of safety hazards through the implementation of active surveillance programs. Results We found that earlier drug withdrawal made possible by active safety surveillance would most likely have resulted in savings in direct medical costs of $773 to $884 million for rofecoxib, $3 to $10 million for cerivastatin, and $38 to $63 million for troglitazone in the US through the prevention of adverse events. By contrast, the yearly public investment in FDA initiated population-based pharmacovigilance activities in the US is about $42.5 million at present. Conclusion These examples illustrate a critical and economically justifiable role for active adverse effect surveillance in protecting the health of the public. PMID:28505041

Mitogen-activated protein kinase Hog1 is activated in response to curcumin exposure in the budding yeast Saccharomyces cerevisiae.

PubMed

Azad, Gajendra Kumar; Singh, Vikash; Thakare, Mayur Jankiram; Baranwal, Shivani; Tomar, Raghuvir Singh

2014-12-19

Curcumin (CUR), an active polyphenol derived from the spice turmeric, has been traditionally used for centuries in ancient Indian medicine to treat a number of diseases. The physiological effects of CUR have been shown to be diverse; however, the target molecules and pathways that CUR affects have yet to be fully described. Here, we demonstrate for the first time that the budding yeast mitogen-activated protein kinase (MAPK) Hog1 is essential for the response to CUR. Moreover, CUR-induced Hog1 phosphorylation was rescued by supplementation of iron to the growth medium. Hog1 was rapidly phosphorylated upon CUR treatment, but unlike the response to hyperosmotic shock (0.8 M NaCl), it remains activated for an extended period of time. A detailed analysis of HOG pathway mutants revealed that Pbs2p, Ptc2p, and Ssk2p are required for optimal CUR-induced Hog1 phosphorylation. We also observed a Hog1 dependent transcriptional response to CUR treatment that involved the up-regulation of glycerol-3-phosphate dehydrogenase 1 (GPD1), a factor that is essential for the hyperosmotic stress response. Our present finding revealed the role of Hog1 MAPK in regulation of CUR-induced transcriptional response. We anticipate that our finding will enhance the understanding on the molecular mode of action of CUR on S. cerevisiae.

Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistance.

PubMed

Leitsch, David; Kolarich, Daniel; Binder, Marina; Stadlmann, Johannes; Altmann, Friedrich; Duchêne, Michael

2009-04-01

Infections with the microaerophilic parasite Trichomonas vaginalis are treated with the 5-nitroimidazole drug metronidazole, which is also in use against Entamoeba histolytica, Giardia intestinalis and microaerophilic/anaerobic bacteria. Here we report that in T. vaginalis the flavin enzyme thioredoxin reductase displays nitroreductase activity with nitroimidazoles, including metronidazole, and with the nitrofuran drug furazolidone. Reactive metabolites of metronidazole and other nitroimidazoles form covalent adducts with several proteins that are known or assumed to be associated with thioredoxin-mediated redox regulation, including thioredoxin reductase itself, ribonucleotide reductase, thioredoxin peroxidase and cytosolic malate dehydrogenase. Disulphide reducing activity of thioredoxin reductase was greatly diminished in extracts of metronidazole-treated cells and intracellular non-protein thiol levels were sharply decreased. We generated a highly metronidazole-resistant cell line that displayed only minimal thioredoxin reductase activity, not due to diminished expression of the enzyme but due to the lack of its FAD cofactor. Reduction of free flavins, readily observed in metronidazole-susceptible cells, was also absent in the resistant cells. On the other hand, iron-depleted T. vaginalis cells, expressing only minimal amounts of PFOR and hydrogenosomal malate dehydrogenase, remained fully susceptible to metronidazole. Thus, taken together, our data suggest a flavin-based mechanism of metronidazole activation and thereby challenge the current model of hydrogenosomal activation of nitroimidazole drugs.

Astaxanthin reduces isoflurane-induced neuroapoptosis via the PI3K/Akt pathway.

PubMed

Wang, Chun-Mei; Cai, Xiao-Lan; Wen, Qing-Ping

2016-05-01

Astaxanthin is an oxygen-containing derivative of carotenoids that effectively suppresses reactive oxygen and has nutritional and medicinal value. The mechanisms underlying the effects of astaxanthin on isoflurane‑induced neuroapoptosis remain to be fully understood. The present study was conducted to evaluate the protective effect of astaxanthin to reduce isoflurane‑induced neuroapoptosis and to investigate the underlying mechanisms. The results demonstrated that isoflurane induced brain damage, increased caspase‑3 activity and suppressed the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (Akt) signaling pathway in an in vivo model. However, treatment with astaxanthin significantly inhibited brain damage, suppressed caspase‑3 activity and upregulated the PI3K/Akt pathway in the isoflurane‑induced rats. Furthermore, isoflurane suppressed cell growth, induced cell apoptosis, enhanced caspase‑3 activity and downregulated the PI3K/Akt pathway in organotypic hippocampal slice culture. Administration of astaxanthin significantly promoted cell growth, reduced cell apoptosis and caspase‑3 activity, and upregulated the PI3K/Akt pathway and isoflurane‑induced neuroapoptosis. The present study demonstrated that downregulation of the PI3K/Akt pathway reduced the effect of astaxanthin to protect against isoflurane‑induced neuroapoptosis in the in vitro model. The results of the current study suggested that the protective effect of astaxanthin reduces the isoflurane-induced neuroapoptosis via activation of the PI3K/Akt signaling pathway.

Quantitative assessment of isolated rapid eye movement (REM) sleep without atonia without clinical REM sleep behavior disorder: clinical and research implications.

PubMed

Sasai-Sakuma, Taeko; Frauscher, Birgit; Mitterling, Thomas; Ehrmann, Laura; Gabelia, David; Brandauer, Elisabeth; Inoue, Yuichi; Poewe, Werner; Högl, Birgit

2014-09-01

Rapid eye movement (REM) sleep without atonia (RWA) is observed in some patients without a clinical history of REM sleep behavior disorder (RBD). It remains unknown whether these patients meet the refined quantitative electromyographic (EMG) criteria supporting a clinical RBD diagnosis. We quantitatively evaluated EMG activity and investigated its overnight distribution in patients with isolated qualitative RWA. Fifty participants with an incidental polysomnographic finding of RWA (isolated qualitative RWA) were included. Tonic, phasic, and 'any' EMG activity during REM sleep on PSG were quantified retrospectively. Referring to the quantitative cut-off values for a polysomnographic diagnosis of RBD, 7/50 (14%) and 6/50 (12%) of the patients showed phasic and 'any' EMG activity in the mentalis muscle above the respective cut-off values. No patient was above the cut-off value for tonic EMG activity or phasic EMG activity in the anterior tibialis muscles. Patients with RWA above the cut-off value showed higher amounts of RWA during later REM sleep periods. This is the first study showing that some subjects with incidental RWA meet the refined quantitative EMG criteria for a diagnosis of RBD. Future longitudinal studies must investigate whether this subgroup with isolated qualitative RWA is at an increased risk of developing fully expressed RBD and/or neurodegenerative disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Biochemical quantitation of the eIF5A hypusination in Arabidopsis thaliana uncovers ABA-dependent regulation

PubMed Central

Belda-Palazón, Borja; Nohales, María A.; Rambla, José L.; Aceña, José L.; Delgado, Oscar; Fustero, Santos; Martínez, M. Carmen; Granell, Antonio; Carbonell, Juan; Ferrando, Alejandro

2014-01-01

The eukaryotic translation elongation factor eIF5A is the only protein known to contain the unusual amino acid hypusine which is essential for its biological activity. This post-translational modification is achieved by the sequential action of the enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The crucial molecular function of eIF5A during translation has been recently elucidated in yeast and it is expected to be fully conserved in every eukaryotic cell, however the functional description of this pathway in plants is still sparse. The genetic approaches with transgenic plants for either eIF5A overexpression or antisense have revealed some activities related to the control of cell death processes but the molecular details remain to be characterized. One important aspect of fully understanding this pathway is the biochemical description of the hypusine modification system. Here we have used recombinant eIF5A proteins either modified by hypusination or non-modified to establish a bi-dimensional electrophoresis (2D-E) profile for the three eIF5A protein isoforms and their hypusinated or unmodified proteoforms present in Arabidopsis thaliana. The combined use of the recombinant 2D-E profile together with 2D-E/western blot analysis from whole plant extracts has provided a quantitative approach to measure the hypusination status of eIF5A. We have used this information to demonstrate that treatment with the hormone abscisic acid produces an alteration of the hypusine modification system in Arabidopsis thaliana. Overall this study presents the first biochemical description of the post-translational modification of eIF5A by hypusination which will be functionally relevant for future studies related to the characterization of this pathway in Arabidopsis thaliana. PMID:24904603

Ten years after the flood: a case of extended geomorphic convalescence in an upland stream

NASA Astrophysics Data System (ADS)

Milan, D. J.; Schwendel, A.; Heritage, G. L.; Entwistle, N. S.; Skinner, C. J.

2017-12-01

Long-term data monitoring the response of fluvial systems to geomorphically effective events is often lacking. In July 2007 a severe event affected the Thinhope Burn, a small (12 km2) tributary to the South Tyne, in Cumbria, UK. The 24-hr rainfall for a 5-km2 radar grid cell located in the headwaters of Thinhope Burn was 236 mm, with maximum hourly rainfall of 30 mm h-1. The event generated peak discharges in the order of 60 m3s-1 and shear stresses of 533 Nm-2, capable of mobilsing metre-size boulders. The Thinhope Burn catchment showed `responsive' behaviour to the event resulting in a substantial net delivery of 3077 m3 of gravel to a 500 m reach, and fully activated the valley floor and slopes, including evidence of peat slides in the headwaters. Since 2007 we have monitored the reach using a combination of dGPS and terrestrial LiDAR data to derive DEMs, and difference these to estimate spatial volumetric patterns of erosion and deposition. Ten years on, there appears to be limited evidence of recovery of the valley floor system, possibly due to the effects of several wet winters (e.g. 2013 and 2015). Sediments remain unconsolidated and free of vegetation, and are easily mobilised during floods. Climate change scenarios for the UK suggest wetter winters, that could prevent recovery of upland rivers where the sediment system has already been fully activated by a large flood, resulting in increased sediment supply to areas downstream and a commensurate increase in flood risk.

Nuts and bolts of running a pulmonary embolism response team: results from an organizational survey of the National PERT™ Consortium members.

PubMed

Barnes, Geoffrey; Giri, Jay; Courtney, D Mark; Naydenov, Soophia; Wood, Todd; Rosovsky, Rachel; Rosenfield, Kenneth; Kabrhel, Christopher

2017-08-01

Pulmonary embolism response teams (PERT) are developing rapidly to operationalize multi-disciplinary care for acute pulmonary embolism patients. Our objective is to describe the core components of PERT necessary for newly developing programs. An online organizational survey of active National PERT™ Consortium members was performed between April and June 2016. Analysis, including descriptive statistics and Kruskal-Wallis tests, was performed on centers self-reporting a fully operational PERT program. The survey response rate was 80%. Of the 31 institutions that responded (71% academic), 19 had fully functioning PERT programs. These programs were run by steering committees (17/19, 89%) more often than individual physicians (2/19, 11%). Most PERT programs involved 3-5 different specialties (14/19, 74%), which did not vary based on hospital size or academic affiliation. Of programs using multidisciplinary discussions, these occurred via phone or conference call (12/18, 67%), with a minority of these utilizing 'virtual meeting' software (2/12, 17%). Guidelines for appropriate activations were provided at 16/19 (84%) hospitals. Most PERT programs offered around-the-clock catheter-based or surgical care (17/19, 89%). Outpatient follow up usually occurred in personal physician clinics (15/19, 79%) or dedicated PERT clinics (9/19, 47%), which were only available at academic institutions. PERT programs can be implemented, with similar structures, at small and large, community and academic medical centers. While all PERT programs incorporate team-based multi-disciplinary care into their core structure, several different models exist with varying personnel and resource utilization. Understanding how different PERT programs impact clinical care remains to be investigated.

Natural killer cells and regulatory T cells in early pregnancy loss

PubMed Central

SHARMA, SURENDRA

2015-01-01

Survival of the allogeneic embryo in the uterus depends on the maintenance of immune tolerance at the maternal-fetal interface. The pregnant uterus is replete with activated maternal immune cells. How this immune tolerance is acquired and maintained has been a topic of intense investigation. The key immune cells that predominantly populate the pregnant uterus are natural killer (NK) cells. In normal pregnancy, these cells are not killers, but rather provide a microenvironment that is pregnancy compatible and supports healthy placentation. In placental mammals, an array of highly orchestrated immune elements to support successful pregnancy outcome has been incorporated. This includes active cooperation between maternal immune cells, particularly NK cells, and trophoblast cells. This intricate process is required for placentation, immune regulation and to remodel the blood supply to the fetus. During the past decade, various types of maternal immune cells have been thought to be involved in cross-talk with trophoblasts and in programming immune tolerance. RegulatoryT cells (Tregs) have attracted a great deal of attention in promoting implantation and immune tolerance beyond implantation. However, what has not been fully addressed is how this immune-trophoblast axis breaks down during adverse pregnancy outcomes, particularly early pregnancy loss, and in response to unscheduled inflammation. Intense research efforts have begun to shed light on the roles of NK cells and Tregs in early pregnancy loss, although much remains to be unraveled in order to fully characterize the mechanisms underlying their detrimental activity. An increased understanding of host-environment interactions that lead to the cytotoxic phenotype of these otherwise pregnancy compatible maternal immune cells is important for prediction, prevention and treatment of pregnancy maladies, particularly recurrent pregnancy loss. In this review, we discuss relevant information from experimental and human models that may explain the pregnancy disrupting roles of these pivotal sentinel cells at the maternal-fetal interface. PMID:25023688

Social networking sites: emerging and essential tools for communication in dermatology.

PubMed

Amir, Mahsa; Sampson, Blake P; Endly, Dawnielle; Tamai, Jennifer M; Henley, Jill; Brewer, Ann Chang; Dunn, Jeffrey H; Dunnick, Cory A; Dellavalle, Robert P

2014-01-01

The use of social media by dermatology journals and professional and patient-centered dermatology organizations remains largely unknown and, to our knowledge, has yet to be fully evaluated. To evaluate and quantify the extent of involvement of dermatology journals, professional dermatology organizations, and dermatology-related patient advocate groups on social networking sites. We obtained an archived list of 102 current dermatology journals from SCImago on the World Wide Web and used the list to investigate Facebook, Twitter, and individual journal websites for the presence of social media accounts. We identified professional and patient-centered dermatology organization activity on social networks through queries of predetermined search terms on Google, Facebook, Twitter, and LinkedIn. The activity of each entity was documented by recording the following metrics of popularity: the numbers of Facebook "likes," Twitter "followers," and LinkedIn "members." The numbers of Facebook likes, Twitter followers, and LinkedIn members corresponding to each dermatology journal and each professional and patient-related dermatology organization. On July 17, 2012, of the 102 dermatology journals ranked by SCImago, 12.7% were present on Facebook and 13.7% on Twitter. We identified popular dermatology journals based on Facebook likes and Twitter followers, led by the Journal of the American Academy of Dermatology and Dermatology Times, respectively. Popular professional dermatology organizations included dermRounds Dermatology Network (11 251 likes on Facebook and 2900 followers on Twitter). The most popular dermatology patient-centered organizations were the Skin Cancer Foundation (20 119 likes on Facebook), DermaTalk (21 542 followers on Twitter), and the National Psoriasis Foundation (200 members on LinkedIn). Patient-centered and professional dermatology organizations use social networking sites; however, academic journals tend to lag behind significantly. Although some journals are active in social media, most have yet to recognize the potential benefits of fully embracing popular social networks.

Reliability of Visual and Somatosensory Feedback in Skilled Movement: The Role of the Cerebellum.

PubMed

Mizelle, J C; Oparah, Alexis; Wheaton, Lewis A

2016-01-01

The integration of vision and somatosensation is required to allow for accurate motor behavior. While both sensory systems contribute to an understanding of the state of the body through continuous updating and estimation, how the brain processes unreliable sensory information remains to be fully understood in the context of complex action. Using functional brain imaging, we sought to understand the role of the cerebellum in weighting visual and somatosensory feedback by selectively reducing the reliability of each sense individually during a tool use task. We broadly hypothesized upregulated activation of the sensorimotor and cerebellar areas during movement with reduced visual reliability, and upregulated activation of occipital brain areas during movement with reduced somatosensory reliability. As specifically compared to reduced somatosensory reliability, we expected greater activations of ipsilateral sensorimotor cerebellum for intact visual and somatosensory reliability. Further, we expected that ipsilateral posterior cognitive cerebellum would be affected with reduced visual reliability. We observed that reduced visual reliability results in a trend towards the relative consolidation of sensorimotor activation and an expansion of cerebellar activation. In contrast, reduced somatosensory reliability was characterized by the absence of cerebellar activations and a trend towards the increase of right frontal, left parietofrontal activation, and temporo-occipital areas. Our findings highlight the role of the cerebellum for specific aspects of skillful motor performance. This has relevance to understanding basic aspects of brain functions underlying sensorimotor integration, and provides a greater understanding of cerebellar function in tool use motor control.

Bacterial Pathogens Induce Abscess Formation by CD4+ T-Cell Activation via the CD28–B7-2 Costimulatory Pathway

PubMed Central

Tzianabos, Arthur O.; Chandraker, Anil; Kalka-Moll, Wiltrud; Stingele, Francesca; Dong, Victor M.; Finberg, Robert W.; Peach, Robert; Sayegh, Mohamed H.

2000-01-01

Abscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naïve rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, including Staphylococcus aureus, Bacteroides fragilis, and a combination of Enterococcus faecium and Bacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28–B7-2 pathway. PMID:11083777

Catalytic and transport cycles of ABC exporters.

PubMed

Al-Shawi, Marwan K

2011-09-07

ABC (ATP-binding cassette) transporters are arguably the most important family of ATP-driven transporters in biology. Despite considerable effort and advances in determining the structures and physiology of these transporters, their fundamental molecular mechanisms remain elusive and highly controversial. How does ATP hydrolysis by ABC transporters drive their transport function? Part of the problem in answering this question appears to be a perceived need to formulate a universal mechanism. Although it has been generally hoped and assumed that the whole superfamily of ABC transporters would exhibit similar conserved mechanisms, this is proving not to be the case. Structural considerations alone suggest that there are three overall types of coupling mechanisms related to ABC exporters, small ABC importers and large ABC importers. Biochemical and biophysical characterization leads us to the conclusion that, even within these three classes, the catalytic and transport mechanisms are not fully conserved, but continue to evolve. ABC transporters also exhibit unusual characteristics not observed in other primary transporters, such as uncoupled basal ATPase activity, that severely complicate mechanistic studies by established methods. In this chapter, I review these issues as related to ABC exporters in particular. A consensus view has emerged that ABC exporters follow alternating-access switch transport mechanisms. However, some biochemical data suggest that alternating catalytic site transport mechanisms are more appropriate for fully symmetrical ABC exporters. Heterodimeric and asymmetrical ABC exporters appear to conform to simple alternating-access-type mechanisms.

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

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. In thismore » paper, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q 6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Finally, given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11.« less

A Wearable Goggle Navigation System for Dual-Mode Optical and Ultrasound Localization of Suspicious Lesions: Validation Studies Using Tissue-Simulating Phantoms and an Ex Vivo Human Breast Tissue Model

PubMed Central

Wang, Dong; Gan, Qi; Ye, Jian; Yue, Jian; Wang, Benzhong; Povoski, Stephen P.; Martin, Edward W.; Hitchcock, Charles L.; Yilmaz, Alper; Tweedle, Michael F.; Shao, Pengfei; Xu, Ronald X.

2016-01-01

Surgical resection remains the primary curative treatment for many early-stage cancers, including breast cancer. The development of intraoperative guidance systems for identifying all sites of disease and improving the likelihood of complete surgical resection is an area of active ongoing research, as this can lead to a decrease in the need of subsequent additional surgical procedures. We develop a wearable goggle navigation system for dual-mode optical and ultrasound imaging of suspicious lesions. The system consists of a light source module, a monochromatic CCD camera, an ultrasound system, a Google Glass, and a host computer. It is tested in tissue-simulating phantoms and an ex vivo human breast tissue model. Our experiments demonstrate that the surgical navigation system provides useful guidance for localization and core needle biopsy of simulated tumor within the tissue-simulating phantom, as well as a core needle biopsy and subsequent excision of Indocyanine Green (ICG)—fluorescing sentinel lymph nodes. Our experiments support the contention that this wearable goggle navigation system can be potentially very useful and fully integrated by the surgeon for optimizing many aspects of oncologic surgery. Further engineering optimization and additional in vivo clinical validation work is necessary before such a surgical navigation system can be fully realized in the everyday clinical setting. PMID:27367051

A Wearable Goggle Navigation System for Dual-Mode Optical and Ultrasound Localization of Suspicious Lesions: Validation Studies Using Tissue-Simulating Phantoms and an Ex Vivo Human Breast Tissue Model.

PubMed

Zhang, Zeshu; Pei, Jing; Wang, Dong; Gan, Qi; Ye, Jian; Yue, Jian; Wang, Benzhong; Povoski, Stephen P; Martin, Edward W; Hitchcock, Charles L; Yilmaz, Alper; Tweedle, Michael F; Shao, Pengfei; Xu, Ronald X

2016-01-01

Surgical resection remains the primary curative treatment for many early-stage cancers, including breast cancer. The development of intraoperative guidance systems for identifying all sites of disease and improving the likelihood of complete surgical resection is an area of active ongoing research, as this can lead to a decrease in the need of subsequent additional surgical procedures. We develop a wearable goggle navigation system for dual-mode optical and ultrasound imaging of suspicious lesions. The system consists of a light source module, a monochromatic CCD camera, an ultrasound system, a Google Glass, and a host computer. It is tested in tissue-simulating phantoms and an ex vivo human breast tissue model. Our experiments demonstrate that the surgical navigation system provides useful guidance for localization and core needle biopsy of simulated tumor within the tissue-simulating phantom, as well as a core needle biopsy and subsequent excision of Indocyanine Green (ICG)-fluorescing sentinel lymph nodes. Our experiments support the contention that this wearable goggle navigation system can be potentially very useful and fully integrated by the surgeon for optimizing many aspects of oncologic surgery. Further engineering optimization and additional in vivo clinical validation work is necessary before such a surgical navigation system can be fully realized in the everyday clinical setting.

Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments

PubMed Central

Kensler, Robert W.; Craig, Roger; Moss, Richard L.

2017-01-01

Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of β1-adrenergic receptors in myocardium. PMID:28167762

Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments.

PubMed

Kensler, Robert W; Craig, Roger; Moss, Richard L

2017-02-21

Cardiac myosin binding protein C (cMyBP-C) has a key regulatory role in cardiac contraction, but the mechanism by which changes in phosphorylation of cMyBP-C accelerate cross-bridge kinetics remains unknown. In this study, we isolated thick filaments from the hearts of mice in which the three serine residues (Ser273, Ser282, and Ser302) that are phosphorylated by protein kinase A in the m-domain of cMyBP-C were replaced by either alanine or aspartic acid, mimicking the fully nonphosphorylated and the fully phosphorylated state of cMyBP-C, respectively. We found that thick filaments from the cMyBP-C phospho-deficient hearts had highly ordered cross-bridge arrays, whereas the filaments from the cMyBP-C phospho-mimetic hearts showed a strong tendency toward disorder. Our results support the hypothesis that dephosphorylation of cMyBP-C promotes or stabilizes the relaxed/superrelaxed quasi-helical ordering of the myosin heads on the filament surface, whereas phosphorylation weakens this stabilization and binding of the heads to the backbone. Such structural changes would modulate the probability of myosin binding to actin and could help explain the acceleration of cross-bridge interactions with actin when cMyBP-C is phosphorylated because of, for example, activation of β 1 -adrenergic receptors in myocardium.

p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis.

PubMed

Napoletano, Francesco; Gibert, Benjamin; Yacobi-Sharon, Keren; Vincent, Stéphane; Favrot, Clémentine; Mehlen, Patrick; Girard, Victor; Teil, Margaux; Chatelain, Gilles; Walter, Ludivine; Arama, Eli; Mollereau, Bertrand

2017-09-01

The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis.

Steady State Thermal Analyses of SCEPTOR X-57 Wingtip Propulsion

NASA Technical Reports Server (NTRS)

Schnulo, Sydney L.; Chin, Jeffrey C.; Smith, Andrew D.; Dubois, Arthur

2017-01-01

Electric aircraft concepts enable advanced propulsion airframe integration approaches that promise increased efficiency as well as reduced emissions and noise. NASA's fully electric Maxwell X-57, developed under the SCEPTOR program, features distributed propulsion across a high aspect ratio wing. There are 14 propulsors in all: 12 high lift motor that are only active during take off and climb, and 2 larger motors positioned on the wingtips that operate over the entire mission. The power electronics involved in the wingtip propulsion are temperature sensitive and therefore require thermal management. This work focuses on the high and low fidelity heat transfer analysis methods performed to ensure that the wingtip motor inverters do not reach their temperature limits. It also explores different geometry configurations involved in the X-57 development and any thermal concerns. All analyses presented are performed at steady state under stressful operating conditions, therefore predicting temperatures which are considered the worst-case scenario to remain conservative.

Convection Enhances Mixing in the Southern Ocean

NASA Astrophysics Data System (ADS)

Sohail, Taimoor; Gayen, Bishakhdatta; Hogg, Andrew McC.

2018-05-01

Mixing efficiency is a measure of the energy lost to mixing compared to that lost to viscous dissipation. In a turbulent stratified fluid the mixing efficiency is often assumed constant at η = 0.2, whereas with convection it takes values closer to 1. The value of mixing efficiency when both stratified shear flow and buoyancy-driven convection are active remains uncertain. We use a series of numerical simulations to determine the mixing efficiency in an idealized Southern Ocean model. The model is energetically closed and fully resolves convection and turbulence such that mixing efficiency can be diagnosed. Mixing efficiency decreases with increasing wind stress but is enhanced by turbulent convection and by large thermal gradients in regions with a strongly stratified thermocline. Using scaling theory and the model results, we predict an overall mixing efficiency for the Southern Ocean that is significantly greater than 0.2 while emphasizing that mixing efficiency is not constant.

Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor.

PubMed

Ryan, J J; McReynolds, L J; Keegan, A; Wang, L H; Garfein, E; Rothman, P; Nelms, K; Paul, W E

1996-02-01

IL-4 causes hematopoietic cells to proliferate and express a series of genes, including CD23. We examined whether IL-4-mediated growth, as measured by 4PS phosphorylation, and gene induction were similarly controlled. Studies of M12.4.1 cells expressing human IL-4R truncation mutants indicated that the region between amino acids 557-657 is necessary for full gene expression, which correlated with Stat6 DNA binding activity. This region was not required for 4PS phosphorylation. Tyrosine-to-phenylalanine mutations in the interval between amino acids 557-657 revealed that as long as one tyrosine remained unmutated, CD23 was fully induced. When all three tyrosines were mutated, the receptor was unable to induce CD23. The results indicate that growth regulation and gene expression are principally controlled by distinct regions of IL-4R.

Comparative diversification dynamics among palaeocontinents during the Ordovician Radiation

NASA Technical Reports Server (NTRS)

Miller, A. I.

1997-01-01

The Ordovician Radiation was among the most extensive intervals of diversification in the history of life. However, a delineation of the proximal cause(s) of the Radiation remains elusive. Any such determination should involve an analysis of geographic overprints on diversification: did the Radiation occur randomly around the world or, alternatively, was it focused in particular geographic or depositional regimes? Here, I present a comparative evaluation of Ordovician diversification among several palaeocontinents to determine whether biotas associated with certain palaeocontinents exhibited different diversification patterns than others; in part, this involves a numerical "correction" to raw diversity trajectories. Clear disparities among palaeocontinents are indicated by the data, which appear to reflect differences in the extent of siliciclastic input partly in association with tectonic activity. Further testing will be required to fully substantiate the implication that siliciclastic influx was a predominant factor in the Ordovician Radiation, affecting a variety of higher taxa among all three Phanerozoic evolutionary faunas.

Greening of the Sahara suppressed ENSO activity during the mid-Holocene

PubMed Central

Pausata, Francesco S. R.; Zhang, Qiong; Muschitiello, Francesco; Lu, Zhengyao; Chafik, Léon; Niedermeyer, Eva M.; Stager, J. Curt; Cobb, Kim M.; Liu, Zhengyu

2017-01-01

The evolution of the El Niño-Southern Oscillation (ENSO) during the Holocene remains uncertain. In particular, a host of new paleoclimate records suggest that ENSO internal variability or other external forcings may have dwarfed the fairly modest ENSO response to precessional insolation changes simulated in climate models. Here, using fully coupled ocean-atmosphere model simulations, we show that accounting for a vegetated and less dusty Sahara during the mid-Holocene relative to preindustrial climate can reduce ENSO variability by 25%, more than twice the decrease obtained using orbital forcing alone. We identify changes in tropical Atlantic mean state and variability caused by the momentous strengthening of the West Africa Monsoon (WAM) as critical factors in amplifying ENSO’s response to insolation forcing through changes in the Walker circulation. Our results thus suggest that potential changes in the WAM due to anthropogenic warming may influence ENSO variability in the future as well. PMID:28685758

Greening of the Sahara suppressed ENSO activity during the mid-Holocene.

PubMed

Pausata, Francesco S R; Zhang, Qiong; Muschitiello, Francesco; Lu, Zhengyao; Chafik, Léon; Niedermeyer, Eva M; Stager, J Curt; Cobb, Kim M; Liu, Zhengyu

2017-07-07

The evolution of the El Niño-Southern Oscillation (ENSO) during the Holocene remains uncertain. In particular, a host of new paleoclimate records suggest that ENSO internal variability or other external forcings may have dwarfed the fairly modest ENSO response to precessional insolation changes simulated in climate models. Here, using fully coupled ocean-atmosphere model simulations, we show that accounting for a vegetated and less dusty Sahara during the mid-Holocene relative to preindustrial climate can reduce ENSO variability by 25%, more than twice the decrease obtained using orbital forcing alone. We identify changes in tropical Atlantic mean state and variability caused by the momentous strengthening of the West Africa Monsoon (WAM) as critical factors in amplifying ENSO's response to insolation forcing through changes in the Walker circulation. Our results thus suggest that potential changes in the WAM due to anthropogenic warming may influence ENSO variability in the future as well.

Is cell aging caused by respiration-dependent injury to the mitochondrial genome

NASA Technical Reports Server (NTRS)

Fleming, J. E.; Yengoyan, L. S.; Miquel, J.; Cottrell, S. F.; Economos, A. C.

1982-01-01

Though intrinsic mitochondrial aging has been considered before as a possible cause of cellular senescence, the mechanisms of such mitochondrial aging have remained obscure. In this article, the hypothesis of free-radical-induced inhibition of mitochondrial replenishment in fixed postmitotic cells is expanded. It is maintained that the respiration-dependent production of superoxide and hydroxyl radicals may not be fully counteracted, leading to a continuous production of lipoperoxides and malonaldehyde in actively respiring mitochondria. These compounds, in turn, can easily react with the mitochondrial DNA which is in close spatial relationship with the inner mitochondrial membrane, producing an injury that the mitochondria may be unable to counteract because of their apparent lack of adequate repair mechanisms. Mitochondrial division may thus be inhibited leading to age-related reduction of mitochondrial numbers, a deficit in energy production with a concomitant decrease in protein synthesis, deterioration of physiological performance, and, therefore, of organismic performance.

The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans

PubMed Central

Chitturi, Jyothsna; Hung, Wesley; Rahman, Anas M. Abdel; Wu, Min; Lim, Maria A.; Calarco, John; Dennis, James W.

2018-01-01

UBR1 is an E3 ubiquitin ligase best known for its ability to target protein degradation by the N-end rule. The physiological functions of UBR family proteins, however, remain not fully understood. We found that the functional loss of C. elegans UBR-1 leads to a specific motor deficit: when adult animals generate reversal movements, A-class motor neurons exhibit synchronized activation, preventing body bending. This motor deficit is rescued by removing GOT-1, a transaminase that converts aspartate to glutamate. Both UBR-1 and GOT-1 are expressed and critically required in premotor interneurons of the reversal motor circuit to regulate the motor pattern. ubr-1 and got-1 mutants exhibit elevated and decreased glutamate level, respectively. These results raise an intriguing possibility that UBR proteins regulate glutamate metabolism, which is critical for neuronal development and signaling. PMID:29649217

Allosteric mechanism of water channel gating by Ca2+–calmodulin

PubMed Central

Reichow, Steve L.; Clemens, Daniel M.; Freites, J. Alfredo; Németh-Cahalan, Karin L.; Heyden, Matthias; Tobias, Douglas J.; Hall, James E.; Gonen, Tamir

2013-01-01

Calmodulin (CaM) is a universal regulatory protein that communicates the presence of calcium to its molecular targets and correspondingly modulates their function. This key signaling protein is important for controlling the activity of hundreds of membrane channels and transporters. However, our understanding of the structural mechanisms driving CaM regulation of full-length membrane proteins has remained elusive. In this study, we determined the pseudo-atomic structure of full-length mammalian aquaporin-0 (AQP0, Bos Taurus) in complex with CaM using electron microscopy to understand how this signaling protein modulates water channel function. Molecular dynamics and functional mutation studies reveal how CaM binding inhibits AQP0 water permeability by allosterically closing the cytoplasmic gate of AQP0. Our mechanistic model provides new insight, only possible in the context of the fully assembled channel, into how CaM regulates multimeric channels by facilitating cooperativity between adjacent subunits. PMID:23893133

Progress Toward Poliomyelitis Eradication--Afghanistan, January 2014‒August 2015.

PubMed

Mbaeyi, Chukwuma; Saatcioglu, Akif; Tangermann, Rudolf H; Hadler, Stephen; Ehrhardt, Derek

2015-10-23

Despite recent progress toward global polio eradication, endemic transmission of wild poliovirus (WPV) continues to be reported in Afghanistan and Pakistan. The Afghanistan program must overcome many challenges to remain on track toward achieving the objectives set in the 2013–2018 strategic plan of the Global Polio Eradication Initiative (GPEI). Cross-border transmission of WPV type 1 (WPV1) continues to occur among children traveling to and from Pakistan. The country's routine immunization system remains weak and unable to reach recommended benchmarks in most regions; hence, the national Polio Eradication Initiative (PEI) relies mainly on providing children aged <5 years with oral poliovirus vaccine (OPV), administered during supplementary immunization activities (SIAs). Because of ongoing conflict and insecurity, some children continue to be missed during SIAs in areas not under government control; however, the majority of missed children live in accessible areas and are often unreached because of a failure to plan, implement, and supervise SIAs efficiently. This report describes polio eradication activities and progress in Afghanistan during January 2014‒August 2015 and updates previous reports. During 2014, a total of 28 WPV1 cases were reported in Afghanistan, compared with 14 cases in 2013; nine cases were reported during January‒August 2015, the same number as during the same period in 2014. To eliminate poliovirus transmission in Afghanistan, emergency operations centers (EOCs) need to be established at the national level and in critical regions without delay to improve overall coordination and oversight of polio eradication activities. The recently revised National Emergency Action Plan for polio eradication needs to be fully implemented, including detailed microplanning and enhanced monitoring and supervision of SIAs, as well as improved cross-border coordination with Pakistan.

FK506-Binding Protein 22 from a Psychrophilic Bacterium, a Cold Shock-Inducible Peptidyl Prolyl Isomerase with the Ability to Assist in Protein Folding

PubMed Central

Budiman, Cahyo; Koga, Yuichi; Takano, Kazufumi; Kanaya, Shigenori

2011-01-01

Adaptation of microorganisms to low temperatures remains to be fully elucidated. It has been previously reported that peptidyl prolyl cis-trans isomerases (PPIases) are involved in cold adaptation of various microorganisms whether they are hyperthermophiles, mesophiles or phsycrophiles. The rate of cis-trans isomerization at low temperatures is much slower than that at higher temperatures and may cause problems in protein folding. However, the mechanisms by which PPIases are involved in cold adaptation remain unclear. Here we used FK506-binding protein 22, a cold shock protein from the psychrophilic bacterium Shewanella sp. SIB1 (SIB1 FKBP22) as a model protein to decipher the involvement of PPIases in cold adaptation. SIB1 FKBP22 is homodimer that assumes a V-shaped structure based on a tertiary model. Each monomer consists of an N-domain responsible for dimerization and a C-catalytic domain. SIB1 FKBP22 is a typical cold-adapted enzyme as indicated by the increase of catalytic efficiency at low temperatures, the downward shift in optimal temperature of activity and the reduction in the conformational stability. SIB1 FKBP22 is considered as foldase and chaperone based on its ability to catalyze refolding of a cis-proline containing protein and bind to a folding intermediate protein, respectively. The foldase and chaperone activites of SIB1 FKBP22 are thought to be important for cold adaptation of Shewanella sp. SIB1. These activities are also employed by other PPIases for being involved in cold adaptation of various microorganisms. Despite other biological roles of PPIases, we proposed that foldase and chaperone activities of PPIases are the main requirement for overcoming the cold-stress problem in microorganisms due to folding of proteins. PMID:21954357

Effect of physical activity level on biomarkers of inflammation and insulin resistance over 5 years in outpatients with coronary heart disease (from the Heart and Soul Study).

PubMed

Jarvie, Jennifer L; Whooley, Mary A; Regan, Mathilda C; Sin, Nancy L; Cohen, Beth E

2014-10-15

Higher levels of physical activity are associated with lower rates of coronary heart disease (CHD). Previous studies have suggested that this is due partly to lower levels of inflammation and insulin resistance. The aim of this study was to determine whether physical activity level was associated with inflammation or insulin resistance during a 5-year period in outpatients with known CHD. A total of 656 participants from the Heart and Soul Study, a prospective cohort study of outpatients with documented CHD, were evaluated. Self-reported physical activity frequency was assessed at baseline and after 5 years of follow-up. Participants were classified as low versus high activity at each visit, yielding 4 physical activity groups: stable low activity, decreasing activity (high at baseline to low at year 5), increasing activity (low at baseline to high at year 5), and stable high activity. Year 5 markers of inflammation (C-reactive protein [CRP], interleukin-6, and fibrinogen) and insulin resistance (insulin, glucose, and glycated hemoglobin) were compared across the 4 activity groups. After 5 years of follow-up, higher activity was associated with lower mean levels of all biomarkers. In the fully adjusted regression models, CRP, interleukin-6, and glucose remained independently associated with physical activity frequency (log CRP, p for trend across activity groups = 0.03; log interleukin-6, p for trend = 0.01; log glucose, p for trend = 0.003). Subjects with stable high activity typically had the lowest levels of biomarkers. In conclusion, in this novel population of outpatients with known CHD followed for 5 years, higher physical activity frequency was independently associated with lower levels of CRP, interleukin-6, and glucose. Copyright © 2014 Elsevier Inc. All rights reserved.

Note: Fully integrated active quenching circuit achieving 100 MHz count rate with custom technology single photon avalanche diodes.

PubMed

Acconcia, G; Labanca, I; Rech, I; Gulinatti, A; Ghioni, M

2017-02-01

The minimization of Single Photon Avalanche Diodes (SPADs) dead time is a key factor to speed up photon counting and timing measurements. We present a fully integrated Active Quenching Circuit (AQC) able to provide a count rate as high as 100 MHz with custom technology SPAD detectors. The AQC can also operate the new red enhanced SPAD and provide the timing information with a timing jitter Full Width at Half Maximum (FWHM) as low as 160 ps.

Math and Science Teachers: Recruiting and Retaining California's Workforce. Policy Brief

ERIC Educational Resources Information Center

EdSource, 2008

2008-01-01

Middle and high school math and science teachers provide the foundation for education in the growing science, technology, engineering, and mathematics fields. They are crucial to California's efforts to remain competitive in a global economy. This policy brief looks at the shortage and challenges involved in recruiting and retaining fully prepared…

Evaluating the Effectiveness of Audio in Hybrid Courses

ERIC Educational Resources Information Center

Ball, Daniel R.; Mosca, Joseph B.; Paul, David P., III

2013-01-01

The prevalence of either completely online or hybrid courses has continued to increase over the past decade, but properly designing the delivery mode of these courses remains a challenge. Whereas fully online institutions of higher education may focus on a purely online delivery format, more traditional colleges and universities have the challenge…

Unifying and Elevating Rehabilitation Counseling through Model-Driven, Diversity-Sensitive Evidence-Based Practice

ERIC Educational Resources Information Center

Chan, Fong; Tarvydas, Vilia; Blalock, Kacie; Strauser, David; Atkins, Bobbie J.

2009-01-01

Rehabilitation counseling must embrace an evidence-based practice paradigm to remain a vital and respected member of the future community of professions in rehabilitation and mental health care and to fully discharge its responsibility to assist consumers in accessing effective rehabilitation interventions and exercising truly informed choice. The…

College Measures Economic Success Metrics Project. Fact Sheet

ERIC Educational Resources Information Center

Institute for Higher Education Policy, 2016

2016-01-01

College Measures was established in 2010 as a partnership between the American Institutes for Research (AIR) and Matrix Knowledge Group (now Optimity Advisors). In 2016, College Measures became fully owned by AIR. It remains focused on using data to drive improvement in higher education outcomes in the United States. Through its Economic Success…

Environmental Forces - Some Esthetic Components.

ERIC Educational Resources Information Center

Severino, D. Alexander

Although our system of mass culture has raised our civilization to an extremely high level of material success and affluence, the fact remains that this system has the inherent flaw of not fully recognizing the esthetic needs of man. To overcome this weakness we need to re-introduce into the system a sizable component of first-hand experience…

A diet containing a nonfat dry milk matrix significantly alters systemic endocannabinoids and oxylipins in diet-induced obese mice

USDA-ARS?s Scientific Manuscript database

BACKGROUND: Diets rich in dairy and/or calcium (Ca) have been associated with reductions in adiposity and inflammation, but the mechanisms underlying this remain to be fully elucidated. Oxylipins and endocannabinoids are bioactive lipids, which influence energy homeostasis, adipose function, insuli...

40 CFR 86.884-7 - Dynamometer operation cycle for smoke emission tests.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 19 2010-07-01 2010-07-01 false Dynamometer operation cycle for smoke... Dynamometer operation cycle for smoke emission tests. (a) The following sequence of operations shall be... the preconditioning prior to the smoke cycle. (ii) With the throttle remaining in the fully open...

Aortic Valve Calcification and Risk of Stroke: The Rotterdam Study.

PubMed

Bos, Daniel; Bozorgpourniazi, Atefeh; Mutlu, Unal; Kavousi, Maryam; Vernooij, Meike W; Moelker, Adriaan; Franco, Oscar H; Koudstaal, Peter J; Ikram, M Arfan; van der Lugt, Aad

2016-11-01

It remains uncertain whether aortic valve calcification (AVC) is a risk factor for stroke. From the population-based Rotterdam Study, 2471 participants (mean age: 69.6 years; 51.8% women) underwent computed tomography to quantify AVC. We assessed prevalent stroke and continuously monitored the remaining participants for the incidence of stroke. Logistic and Cox regression models were used to investigate associations of AVC with prevalent stroke and risk of incident stroke. AVC was present in 33.1% of people. At baseline, 97 participants had ever suffered a stroke. During 18 665 person-years of follow-up (mean: 7.9 years), 135 people experienced a first-ever stroke. The presence of AVC was not associated with prevalent stroke (fully adjusted odds ratio: 0.97 (95% confidence interval, 0.61-1.53]) or with an increased risk of stroke (fully adjusted hazard ratio: 0.99 (95% confidence interval, 0.69-1.44]). Although AVC is a common finding in middle-aged and elderly community-dwelling people, our results suggest that AVC is not associated with an increased risk of stroke. © 2016 American Heart Association, Inc.

Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection

PubMed Central

Hewitson, James P.; Filbey, Kara J.; Esser-von Bieren, Julia; Camberis, Mali; Schwartz, Christian; Murray, Janice; Reynolds, Lisa A.; Blair, Natalie; Robertson, Elaine; Harcus, Yvonne; Boon, Louis; Huang, Stanley Ching-Cheng; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Voehringer, David; Le Gros, Graham; Harris, Nicola; Maizels, Rick M.

2015-01-01

Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations. PMID:25816012

The Contribution of Mosses to the Complex Pattern of Diurnal and Seasonal Metabolism the wet Coastal Tundra Ecosystems Near Barrow Alaska.

NASA Astrophysics Data System (ADS)

Zona, D.; Oechel, W.; Hastings, S.; Oberbauer, S.; Kopetz, I.; Ikawa, H.

2006-12-01

Despite the abundance and importance bryophytes in the Alaskan Arctic tundra there is relatively little information on the role of these plants in determining the CO2 fluxes of Arctic tundra and, in particular, the environmental controls and climate change sensitivities of current and future photosynthesis in Arctic mosses. Studies in the tundra biome during the IBP program implicated high light together with high temperature as causes of decreases in photosynthesis in arctic mosses. Several authors have reported midday depression of moss photosynthesis due to high irradiance, even under optimum temperature and fully hydrated conditions. The focus of this study is to understand the role of Sphagnum ssp. mosses of various species, the dominant moss in the Alaska coastal wet Tundra on the total ecosystem carbon exchange throughout the season and in particular soon after snowmelt when the ecosystem is a carbon source. Our hypothesis is that the ecosystem carbon source activity during this critical period may be a result of sensitivity of mosses to light and photoinhibition in the absence of the protective canopy layer of vascular plants. In this study we measured daily courses of photosynthesis and fluorescence in the moss layer and we compare it to the total ecosystem carbon fluxes determined by the eddy covariance technique. The measurements were conducted in wet coastal tundra from June 2006, right after the snow melt, to August 2006 in the Biological Experimental Observatory (BEO) in Barrow, Alaska. The photosynthesis in the moss layer was found to be strongly inhibited when the radiation exceeded 800 ìmol m-2 s-1. Mosses remained fully hydrated throughout the season, precluding drying as a cause of decreased photosynthesis. Dark-adapted fluorescence measurements (Fv/Fm) showed a relatively low value (0.6) right after the snow melt, and remained fairly stable throughout the season. This low value was previously reported as characteristic of photoinhibited Sphagnum ssp. in the Arctic.

Fully automatic cervical vertebrae segmentation framework for X-ray images.

PubMed

Al Arif, S M Masudur Rahman; Knapp, Karen; Slabaugh, Greg

2018-04-01

The cervical spine is a highly flexible anatomy and therefore vulnerable to injuries. Unfortunately, a large number of injuries in lateral cervical X-ray images remain undiagnosed due to human errors. Computer-aided injury detection has the potential to reduce the risk of misdiagnosis. Towards building an automatic injury detection system, in this paper, we propose a deep learning-based fully automatic framework for segmentation of cervical vertebrae in X-ray images. The framework first localizes the spinal region in the image using a deep fully convolutional neural network. Then vertebra centers are localized using a novel deep probabilistic spatial regression network. Finally, a novel shape-aware deep segmentation network is used to segment the vertebrae in the image. The framework can take an X-ray image and produce a vertebrae segmentation result without any manual intervention. Each block of the fully automatic framework has been trained on a set of 124 X-ray images and tested on another 172 images, all collected from real-life hospital emergency rooms. A Dice similarity coefficient of 0.84 and a shape error of 1.69 mm have been achieved. Copyright © 2018 Elsevier B.V. All rights reserved.

Laboratory Testing Protocols for Heparin-Induced Thrombocytopenia (HIT) Testing.

PubMed

Lau, Kun Kan Edwin; Mohammed, Soma; Pasalic, Leonardo; Favaloro, Emmanuel J

2017-01-01

Heparin-induced thrombocytopenia (HIT) represents a significant high morbidity complication of heparin therapy. The clinicopathological diagnosis of HIT remains challenging for many reasons; thus, laboratory testing represents an important component of an accurate diagnosis. Although there are many assays available to assess HIT, these essentially fall into two categories-(a) immunological assays, and (b) functional assays. The current chapter presents protocols for several HIT assays, being those that are most commonly performed in laboratory practice and have the widest geographic distribution. These comprise a manual lateral flow-based system (STiC), a fully automated latex immunoturbidimetric assay, a fully automated chemiluminescent assay (CLIA), light transmission aggregation (LTA), and whole blood aggregation (Multiplate).

Prospective and Bidirectional Cross-Sectional Associations between Body Mass Index and Physical Activity following Liposuction: A Cohort Study.

PubMed

Valente, Denis Souto; Padoin, Alexandre Vontobel; Carvalho, Lauro Aita; Pereira Filho, Gustavo de Azambuja; Ribeiro, Vinicius Weissheimer; Zanella, Rafaela Koehler

2016-07-01

It has been speculated that the immediate decrease in body fat following liposuction may affect body composition by feedback mechanisms of body fat regain. Physical activity has both short- and long-term impacts on health. Although the lay public often associates higher levels of physical activity with body fat distribution changes, studies on the association between physical activity and body fat distribution present inconsistent results. The aim of this study was to investigate the cross-sectional and prospective associations between physical activity and body mass index following liposuction. This is a prospective, bidirectional, cross-sectional study, including 526 liposuction patients, who were followed up at a mean of 11.7 and 24.3 months after surgery. The sum of skinfolds at 11.7 months was highly correlated with skinfolds at 24.3 months (rho = 0.74, p < 0.001). More than 85 percent of participants remained in the same quintile or changed by not more than one quintile during the 13.6-month period. Tracking of physical activity was considerably lower but still significant; the correlation was 0.24 (p < 0.001), and 61.4 percent of the patients moved one or less quintiles. In fully adjusted models, no significant cross-sectional or longitudinal associations were found between physical activity and body mass index. The authors provide evidence of tracking of physical activity and particularly body mass index following liposuction. The authors' results do not support the hypothesis that physical activity and fatness are strongly related following liposuction.

[Inhibition rate of gamma-aminolevulinic acid dehydratase activity in erythrocytes as a reliable index for individual workers of low lead exposure].

PubMed

Hirano, H; Omichi, M; Ohishi, H; Ishikawa, K; Hirashima, N

1983-09-01

As the delta-aminolevulinic acid dehydratase (ALAD) activity in erythrocytes is decreased by lead exposure, we considered that a net reduction of ALAD activity by lead in blood should be the difference between the activity fully activated with zinc (Zn2+) and dithiothreitol (DTT) and that without activation. The optimal condition of activation of ALAD was found by addition of 0.25 mM of Zn2+ and 10 mM of DTT in the reaction mixture. Judging from our previous results that the amount of inhibition of ALAD activity can be represented as the rate of inhibition and is closely correlated with the dose of lead administered to rabbits, the inhibition rate of ALAD activity and lead content in blood (Pb-B) of lead workers were measured. The scatter diagram obtained from the inhibition rate and lead content in blood has two groups being divided at 50 micrograms/ml of Pb-B. In one group less than 50 micrograms/100 ml of Pb-B, the inhibition rate has been closely related to Pb-B., the regression equation being Y = 1.82 X + 11.7, and the correlation coefficient + 0.926. In another group more than 50 micrograms/100 ml of Pb-B the inhibition rate remained constant at the 90% level. Measurement of the inhibition rate suggests to have practical validity for monitoring lead exposure in workers, and by means of a nomograph lead content in blood can be estimated from the inhibition rate.

Anatomy of the Spinal Meninges.

PubMed

Sakka, Laurent; Gabrillargues, Jean; Coll, Guillaume

2016-06-01

The spinal meninges have received less attention than the cranial meninges in the literature, although several points remain debatable and poorly understood, like their phylogenesis, their development, and their interactions with the spinal cord. Their constancy among the chordates shows their crucial importance in central nervous system homeostasis and suggests a role far beyond mechanical protection of the neuraxis. This work provides an extensive study of the spinal meninges, from an overview of their phylogenesis and embryology to a descriptive and topographic anatomy with clinical implications. It examines their involvement in spinal cord development, functioning, and repair. This work is a review of the literature using PubMed as a search engine on Medline. The stages followed by the meninges along the phylogenesis could not be easily compared with their development in vertebrates for methodological aspects and convergence processes throughout evolution. The distinction between arachnoid and pia mater appeared controversial. Several points of descriptive anatomy remain debatable: the functional organization of the arterial network, and the venous and lymphatic drainages, considered differently by classical anatomic and neuroradiological approaches. Spinal meninges are involved in neurodevelopment and neurorepair producing neural stem cells and morphogens, in cerebrospinal fluid dynamics and neuraxis functioning by the synthesis of active molecules, and the elimination of waste products of central nervous system metabolism. The spinal meninges should be considered as dynamic functional formations evolving over a lifetime, with ultrastructural features and functional interactions with the neuraxis remaining not fully understood.

The content and meaning of administrative work: a qualitative study of nursing practices.

PubMed

Michel, Lucie; Waelli, Mathias; Allen, Davina; Minvielle, Etienne

2017-09-01

To investigate the content and meaning of nurses' administrative work. Nurses often report that administrative work keeps them away from bedside care. The content and meaning of this work remains insufficiently explored. Comparative case studies. The investigation took place in 2014. It was based on 254 hours of observations and 27 interviews with nurses and staff in two contrasting units: intensive care and long-term care. A time and motion study was also performed over a period of 96 hours. Documentation and Organizational Activities is composed of six categories; documenting the patient record, coordination, management of patient flow, transmission of information, reporting quality indicators, ordering supplies- stock management Equal amounts of time were spent on these activities in each case. Nurses did not express complaints about documentation in intensive care, whereas they reported feeling frustrated by it in long-term care. These differences reflected the extent to which these activities could be integrated into nurses' clinical work and this is in turn was related to several factors: staff ratios, informatics, and relevance to nursing work. Documentation and Organizational Activities are a main component of care. The meaning nurses attribute to them is dependent on organizational context. These activities are often perceived as competing with bedside care, but this does not have to be the case. The challenge for managers is to fully integrate them into nursing practice. Results also suggest that nurses' Documentation and Organizational Activities should be incorporated into informatics strategies. © 2017 John Wiley & Sons Ltd.

Complement factor H protects mice from ischemic acute kidney injury but is not critical for controlling complement activation by glomerular IgM.

PubMed

Goetz, Lindsey; Laskowski, Jennifer; Renner, Brandon; Pickering, Matthew C; Kulik, Liudmila; Klawitter, Jelena; Stites, Erik; Christians, Uwe; van der Vlag, Johan; Ravichandran, Kameswaran; Holers, V Michael; Thurman, Joshua M

2018-05-01

Natural IgM binds to glomerular epitopes in several progressive kidney diseases. Previous work has shown that IgM also binds within the glomerulus after ischemia/reperfusion (I/R) but does not fully activate the complement system. Factor H is a circulating complement regulatory protein, and congenital or acquired deficiency of factor H is a strong risk factor for several types of kidney disease. We hypothesized that factor H controls complement activation by IgM in the kidney after I/R, and that heterozygous factor H deficiency would permit IgM-mediated complement activation and injury at this location. We found that mice with targeted heterozygous deletion of the gene for factor H developed more severe kidney injury after I/R than wild-type controls, as expected, but that complement activation within the glomeruli remained well controlled. Furthermore, mice that are unable to generate soluble IgM were not protected from renal I/R, even in the setting of heterozygous factor H deficiency. These results demonstrate that factor H is important for limiting injury in the kidney after I/R, but it is not critical for controlling complement activation by immunoglobulin within the glomerulus in this setting. IgM binds to glomerular epitopes after I/R, but it is not a significant source of injury. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epitaxial Growth of Thin Ferroelectric Polymer Films on Graphene Layer for Fully Transparent and Flexible Nonvolatile Memory.

PubMed

Kim, Kang Lib; Lee, Wonho; Hwang, Sun Kak; Joo, Se Hun; Cho, Suk Man; Song, Giyoung; Cho, Sung Hwan; Jeong, Beomjin; Hwang, Ihn; Ahn, Jong-Hyun; Yu, Young-Jun; Shin, Tae Joo; Kwak, Sang Kyu; Kang, Seok Ju; Park, Cheolmin

2016-01-13

Enhancing the device performance of organic memory devices while providing high optical transparency and mechanical flexibility requires an optimized combination of functional materials and smart device architecture design. However, it remains a great challenge to realize fully functional transparent and mechanically durable nonvolatile memory because of the limitations of conventional rigid, opaque metal electrodes. Here, we demonstrate ferroelectric nonvolatile memory devices that use graphene electrodes as the epitaxial growth substrate for crystalline poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE) polymer. The strong crystallographic interaction between PVDF-TrFE and graphene results in the orientation of the crystals with distinct symmetry, which is favorable for polarization switching upon the electric field. The epitaxial growth of PVDF-TrFE on a graphene layer thus provides excellent ferroelectric performance with high remnant polarization in metal/ferroelectric polymer/metal devices. Furthermore, a fully transparent and flexible array of ferroelectric field effect transistors was successfully realized by adopting transparent poly[bis(4-phenyl)(2,4,6-trimethylphenyl)amine] semiconducting polymer.

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

A fully-active fine-grained detector with three readout views

NASA Astrophysics Data System (ADS)

Blondel, A.; Cadoux, F.; Fedotov, S.; Khabibullin, M.; Khotjantsev, A.; Korzenev, A.; Kostin, A.; Kudenko, Y.; Longhin, A.; Mefodiev, A.; Mermod, P.; Mineev, O.; Noah, E.; Sgalaberna, D.; Smirnov, A.; Yershov, N.

2018-02-01

This paper describes a novel idea of a fine-grained fully-active plastic scintillator detector made of many optically independent 1×1×1 cm3 cubes with readout on three orthogonal projections by wavelength shifting fibers. The original purpose of this detector is to serve as an active neutrino target for the detection, measurement and identification of the final state particles down to a few tenths MeV kinetic energies. The three readout views as well as the fine granularity ensure powerful localization and measurement of the deposited energy combined with good timing properties and isotropic acceptance. The possible application as a new active target for the T2K near detector, initial simulation studies and R&D test results are reported.

7 CFR 3560.352 - Agency monitoring scope, purpose, and borrower responsibilities.

Code of Federal Regulations, 2010 CFR

2010-01-01

... monitoring activities. The Agency will review reports, records, and other materials related to the housing...) Purpose of Agency monitoring activities. Agency monitoring activities are designed to assess borrower and... responsible for cooperating fully and promptly with Agency monitoring activities. Agency monitoring activities...

7 CFR 3560.352 - Agency monitoring scope, purpose, and borrower responsibilities.

Code of Federal Regulations, 2011 CFR

2011-01-01

... monitoring activities. The Agency will review reports, records, and other materials related to the housing...) Purpose of Agency monitoring activities. Agency monitoring activities are designed to assess borrower and... responsible for cooperating fully and promptly with Agency monitoring activities. Agency monitoring activities...

7 CFR 3560.352 - Agency monitoring scope, purpose, and borrower responsibilities.

Code of Federal Regulations, 2013 CFR

2013-01-01

... monitoring activities. The Agency will review reports, records, and other materials related to the housing...) Purpose of Agency monitoring activities. Agency monitoring activities are designed to assess borrower and... responsible for cooperating fully and promptly with Agency monitoring activities. Agency monitoring activities...

7 CFR 3560.352 - Agency monitoring scope, purpose, and borrower responsibilities.

Code of Federal Regulations, 2014 CFR

2014-01-01

... monitoring activities. The Agency will review reports, records, and other materials related to the housing...) Purpose of Agency monitoring activities. Agency monitoring activities are designed to assess borrower and... responsible for cooperating fully and promptly with Agency monitoring activities. Agency monitoring activities...

7 CFR 3560.352 - Agency monitoring scope, purpose, and borrower responsibilities.

Code of Federal Regulations, 2012 CFR

2012-01-01

... monitoring activities. The Agency will review reports, records, and other materials related to the housing...) Purpose of Agency monitoring activities. Agency monitoring activities are designed to assess borrower and... responsible for cooperating fully and promptly with Agency monitoring activities. Agency monitoring activities...

Premature aging/senescence in cancer cells facing therapy: good or bad?

PubMed

Gonzalez, Llilians Calvo; Ghadaouia, Sabrina; Martinez, Aurélie; Rodier, Francis

2016-02-01

Normal and cancer cells facing their demise following exposure to radio-chemotherapy can actively participate in choosing their subsequent fate. These programmed cell fate decisions include true cell death (apoptosis-necroptosis) and therapy-induced cellular senescence (TIS), a permanent "proliferative arrest" commonly portrayed as premature cellular aging. Despite a permanent loss of proliferative potential, senescent cells remain viable and are highly bioactive at the microenvironment level, resulting in a prolonged impact on tissue architecture and functions. Cellular senescence is primarily documented as a tumor suppression mechanism that prevents cellular transformation. In the context of normal tissues, cellular senescence also plays important roles in tissue repair, but contributes to age-associated tissue dysfunction when senescent cells accumulate. Theoretically, in multi-step cancer progression models, cancer cells have already bypassed cellular senescence during their immortalization step (see hallmarks of cancer). It is then perhaps surprising to find that cancer cells often retain the ability to undergo TIS, or premature aging. This occurs because cellular senescence results from multiple signalling pathways, some retained in cancer cells, aiming to prevent cell cycle progression in damaged cells. Since senescent cancer cells persist after therapy and secrete an array of cytokines and growth factors that can modulate the tumor microenvironment, these cells may have beneficial and detrimental effects regarding immune modulation and survival of remaining proliferation-competent cancer cells. Similarly, while normal cells undergoing senescence are believed to remain indefinitely growth arrested, whether this is true for senescent cancer cells remains unclear, raising the possibility that these cells may represent a reservoir for cancer recurrence after treatment. This review discusses our current knowledge on cancer cell senescence and highlight questions that must be addressed to fully understand the beneficial and detrimental impacts of cellular senescence during cancer therapy.

Totally endoscopic implant to effect a gastric bypass: 12-month safety and efficacy outcomes.

PubMed

Sandler, Bryan J; Biertho, Laurent; Anvari, Mehran; Rumbaut, Roberto; Morales-Garza, Luis Alonso; Torres-Barrera, Gustavo; Marceau, Simon; Hong, Dennis; Smith, C Daniel; Horgan, Santiago

2018-04-20

Only a small percentage of candidates for bariatric surgery ever undergo a procedure for weight loss. Devices duplicating key effects of bariatric surgeries with removable, fully trans-oral implants could extend their benefits to patients unwilling to undergo anatomy-altering abdominal surgeries. Thirty-two obese subjects (mean BMI: 42.3) were enrolled in a prospective, multicenter, single-arm, feasibility trial of the first fully trans-oral endoscopic gastrointestinal bypass device. The device is a cuff attached to the distal esophagus by transmural anchors and connected to a 120-cm sleeve diverting undigested nutrients to the jejunum. Bodyweight, vital signs, adverse events, medications, HbA1c, fasting glucose, and lipids were collected at baseline and follow-up visits. Device status was endoscopically assessed every 6 months. The fully trans-oral procedure was successful in all subjects without intraoperative adverse events or postoperative infections. Twenty-eight of 32 subjects (88%) remained implanted with continuing follow-up beyond their 12-month visit. At 12 months, the 32 subjects had lost an average of 44.8% of excess body weight, 17.6% of total body weight, 20.8 kg, and 7.5 BMI points. Weight loss depended on capture of ingesta by the esophageal cuff, with 18 of 32 subjects without visible gaps around their cuffs at the 6 month endoscopy having significantly greater EWL (53.6 vs. 33.4% in the remaining subjects, p < 0.002). Mean HbA1c and fasting glucose declined by 1.1% points and 29 mg/dL in type 2 diabetic subjects, 80% of whom had remission of their diabetes at 12 months. This study demonstrates the feasibility, safety, and efficacy of a fully trans-oral gastrointestinal bypass implant. This purely endoscopic device may provide a valuable addition to the armamentarium of treatment available for the management of morbid obesity.

Leanness and heightened nonresting energy expenditure: role of skeletal muscle activity thermogenesis

PubMed Central

Mukherjee, Sromona; Shukla, Charu; Britton, Steven L.; Koch, Lauren G.; Shi, Haifei; Novak, Colleen M.

2014-01-01

A high-calorie diet accompanied by low levels of physical activity (PA) accounts for the widespread prevalence of obesity today, and yet some people remain lean even in this obesogenic environment. Here, we investigate the cause for this exception. A key trait that predicts high PA in both humans and laboratory rodents is intrinsic aerobic capacity. Rats artificially selected as high-capacity runners (HCR) are lean and consistently more physically active than their low-capacity runner (LCR) counterparts; this applies to both males and females. Here, we demonstrate that HCR show heightened total energy expenditure (TEE) and hypothesize that this is due to higher nonresting energy expenditure (NREE; includes activity EE). After matching for body weight and lean mass, female HCR consistently had heightened nonresting EE, but not resting EE, compared with female LCR. Because of the dominant role of skeletal muscle in nonresting EE, we examined muscle energy use. We found that lean female HCR had higher muscle heat dissipation during activity, explaining their low economy of activity and high activity EE. This may be due to the amplified skeletal muscle expression levels of proteins involved in EE and reduced expression levels of proteins involved in energy conservation in HCR relative to LCR. This is also associated with an increased sympathetic drive to skeletal muscle in HCR compared with LCR. We find little support for the hypothesis that resting metabolic rate is correlated with maximal aerobic capacity if body size and composition are fully considered; rather, the critical factor appears to be activity thermogenesis. PMID:24398400

Inflammasome genetics contributes to the development and control of active pulmonary tuberculosis.

PubMed

Souza de Lima, D; Ogusku, M M; Sadahiro, A; Pontillo, A

2016-07-01

Tuberculosis (TB) continues to be a major public health problem. An estimated one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb) but remains asymptomatic (latent TB) and only 5% to 10% of these latent individuals will develop active pulmonary TB. Factors affecting the balance between latent and active TB are mostly unknown, even if host genome has been shown to contribute to the outcome of Mtb response. Acute inflammation and Th1 response are important in the early clearance of the bacteria as it was emphasized by the association between immune genes (i.e.: HLA, IFNG, TNF, NRPAM1, IL10) variants and the development of active pulmonary TB. Recently, the role of the inflammasome in experimental TB has been demonstrated, however, to our knowledge, no data still exist about the contribution of inflammasome genetics to Mtb susceptibility and/or to the development of active TB. For this reason, selected polymorphisms in inflammasome genes were analysed in a case/control cohort of individuals with active pulmonary TB from an endemic area of Brazil Amazon. Our data evidence the novel association between polymorphisms in NLRP3-inflammasome encoding genes and active pulmonary TB, and replicated the association between P2X7 and TB observed in other populations. These results emphasize the role of NLRP3-inflammasome also in human TB, and contribute to our knowledge about pathways involved in the development of active TB, even if deeper investigation are needed to fully elucidate the role of the complex in Mtb infection. Copyright © 2016 Elsevier B.V. All rights reserved.

Can we be (and stay) friends? Remaining friends after dissolution of a romantic relationship.

PubMed

Bullock, Melinda; Hackathorn, Jana; Clark, Eddie M; Mattingly, Brent A

2011-01-01

Although many individuals report being friends with their ex-romantic partners (Wilmot, Carbaugh, & Baxter, 1985), the literature regarding post-romantic friendships is very limited. We investigated whether satisfaction in the dissolved romantic relationship could predict post-romantic friendships and friendship maintenance. We found that the more satisfied individuals were during the dissolved romance, the more likely they were to remain friends and the more likely they were to engage in friendship maintenance behaviors. We also found that friendship maintenance fully mediated the association between past romantic satisfaction and current friendship satisfaction.

75 FR 8763 - Self-Regulatory Organizations; NASDAQ OMX BX, Inc.; Notice of Filing and Immediate Effectiveness...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-25

... at http://www.sec.gov and also on the Exchange's Internet Web site at http://nasdaqomxbx... Options Order Protection and Locked/Crossed Market Plan (``Decentralized Plan'').\\6\\ \\5\\ See Securities... mechanisms to remain fully compliant with the Decentralized Plan and BOX Rules and to no longer rely upon a...

Melorheostosis: a rare entity: a case report.

PubMed

Kherfani, Abdelhakim; Mahjoub, Hachem

2014-01-01

Melorheostosis is a rare entity belonging to the group of sclerotic bone dysplasias. Described for the first time in 1922 by Leri, it remains imperfectly known as clinical presentations are highly variable, and the etiological diagnosis is not fully elucidated. We report a case of polyostoticmelorheostosis for which radiological investigations were complete, in order to study this disease.

Melorheostosis: a rare entity: a case report

PubMed Central

Kherfani, Abdelhakim; Mahjoub, Hachem

2014-01-01

Melorheostosis is a rare entity belonging to the group of sclerotic bone dysplasias. Described for the first time in 1922 by Leri, it remains imperfectly known as clinical presentations are highly variable, and the etiological diagnosis is not fully elucidated. We report a case of polyostoticmelorheostosis for which radiological investigations were complete, in order to study this disease. PMID:25489356

"Mass Effect 2": A Case Study in the Design of Game Narrative

ERIC Educational Resources Information Center

Bizzocchi, Jim; Tanenbaum, Joshua

2012-01-01

Digital games have matured substantially as a narrative medium in the last decade. However, there is still much work to be done to more fully understand the poetics of story-based-games. Game narrative remains an important issue with significant cultural, economic and scholarly implications. In this article, we undertake a critical analysis of the…

The Scaffolding of Emergent Literacy Skills in the Home Environment: A Case Study

ERIC Educational Resources Information Center

Neumann, Michelle M.; Hood, Michelle; Neumann, David L.

2009-01-01

The ways in which parent-child interactions can encourage the development of emergent literacy skills in young children remains to be fully explored. The present report describes how one parent scaffolded her young child's emergent writing and letter knowledge in the home. Environmental print provided many rich and meaningful examples for the…

What Does "Inclusion" Mean for Pupils on the Autistic Spectrum in Mainstream Secondary Schools?

ERIC Educational Resources Information Center

Humphrey, Neil; Lewis, Sarah

2008-01-01

The last decade has seen a groundswell of developments in educational policy in the UK relating to inclusive education for students with special educational needs (SEN). However, whether government policy has been fully implemented in schools remains a concern. The experience of students with autistic spectrum disorders (ASDs) provides an…

The Role of Motor Processes in Three-Dimensional Mental Rotation: Shaping Cognitive Processing via Sensorimotor Experience

ERIC Educational Resources Information Center

Moreau, David

2012-01-01

An extensive body of literature has explored the involvement of motor processes in mental rotation, yet underlying individual differences are less documented and remain to be fully understood. We propose that sensorimotor experience shapes spatial abilities such as assessed in mental rotation tasks. Elite wrestlers' and non-athletes' mental…

Comments on "How Child Protective Services Investigators Decide to Substantiate Mothers for Failure-to-Protect in Sexual Abuse Cases"

ERIC Educational Resources Information Center

Shadoin, Amy L.; Carnes, Connie N.

2006-01-01

This commentary discusses the decisions of child protective service (CPS) investigators to substantiate mothers for failure-to-protect (FTP) in child sexual abuse cases. Four areas are identified in which the scientific literature remains inadequate to fully inform child maltreatment researchers, CPS practitioners and child welfare policymakers on…

Labor Market Effects of Pensions and Implications for Teachers

ERIC Educational Resources Information Center

Friedberg, Leora; Turner, Sarah

2010-01-01

While the retirement security landscape has changed drastically for most workers over the last twenty years, traditional defined benefit (DB) pension plans remain the overwhelming norm for K-12 teachers. Because DB plans pay off fully with a fixed income after retirement only if a teacher stays in the profession for decades and yield little or…

78 FR 59090 - Nissan North America, Incorporated, Grant of Petition for Decision of Inconsequential Noncompliance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-25

... alert a driver exiting the vehicle if the key remained in the starting system. Furthermore, if the..., buses or multipurpose passenger vehicles (MPVs) manufactured from December 20, 2010 to July 17, 2012, do not fully comply with paragraph S3.1.4.1 of Federal Motor Vehicle Safety Standard (FMVSS) No. 102...

A Complexity Perspective on Leadership and Change in the Post-Merger Integration Process

ERIC Educational Resources Information Center

Lauser, Barbel; Peters, Mike

2008-01-01

After 30 years of research in mergers and acquisitions and advances in the research of post-merger integration (PMI) processes, the outcome of a merger remains hardly predicable. Traditional leadership and change theories have not succeeded in fully explaining PMI processes and therefore new theories are needed. This article offers new insights…

Buber from the Cartesian Perspective? A Critical Review of Reading Buber's Pedagogy

ERIC Educational Resources Information Center

Woo, Jeong-Gil

2012-01-01

The positive reception of Buber's philosophy does not fully match Buber's intention in terms of overcoming the problem of the subject-object binary. In other words, a number of authors have remained within the traditional way of thinking by merely replacing the subject and object with Buber's I and You, establishing a more dogmatic normative…

Speaking the Language of Today's Digital Natives

ERIC Educational Resources Information Center

Neibling, John

2010-01-01

While most college presidents have mastered many basic tools of the digital environment, such as e-mail, Internet browsing, text messaging, most of them have yet to figure out social media--a glaring omission that remains one of the clearest dividing lines between generations young and old. Though most of them have yet to fully embrace social…

College Measures 2-Year and 4-Year Data Tools. Fact Sheet

ERIC Educational Resources Information Center

Institute for Higher Education Policy, 2016

2016-01-01

College Measures was established in 2010 as a partnership between the American Institutes for Research (AIR) and Matrix Knowledge Group (now Optimity Advisors). In 2016, College Measures became fully owned by AIR. It remains focused on using data to drive improvement in higher education outcomes in the United States. This fact sheet presents a…

Confirmation of Neozygites floridana azygospore formation in two-spotted spider mite (Tetranychus urticae) in strains from tropical and temperature regions

USDA-ARS?s Scientific Manuscript database

Neozygites floridana is an obligate fungal pathogen of mites in the family Tetranychidae and is an important natural enemy of the two-spotted spider mite (Tetranychus urticae). Until now, information about the formation of azygospores remained to be fully confirmed. In this study, we document the fo...

Cognitive-behavioral therapy induces sensorimotor and specific electrocortical changes in chronic tic and Tourette's disorder.

PubMed

Morand-Beaulieu, Simon; O'Connor, Kieron P; Sauvé, Geneviève; Blanchet, Pierre J; Lavoie, Marc E

2015-12-01

Tic disorders, such as the Gilles de la Tourette syndrome and persistent tic disorder, are neurodevelopmental movement disorders involving impaired motor control. Hence, patients show repetitive unwanted muscular contractions in one or more parts of the body. A cognitive-behavioral therapy, with a particular emphasis on the psychophysiology of tic expression and sensorimotor activation, can reduce the frequency and intensity of tics. However, its impact on motor activation and inhibition is not fully understood. To study the effects of a cognitive-behavioral therapy on electrocortical activation, we recorded the event-related potentials (ERP) and lateralized readiness potentials (LRP), before and after treatment, of 20 patients with tic disorders and 20 healthy control participants (matched on age, sex and intelligence), during a stimulus-response compatibility inhibition task. The cognitive-behavioral therapy included informational, awareness training, relaxation, muscle discrimination, cognitive restructuration and relapse prevention strategies. Our results revealed that prior to treatment; tic patients had delayed stimulus-locked LRP onset latency, larger response-locked LRP peak amplitude, and a frontal overactivation during stimulus inhibition processing. Both stimulus-locked LRP onset latency and response-locked LRP peak amplitude normalized after the cognitive behavioral therapy completion. However, the frontal overactivation related to inhibition remained unchanged following therapy. Our results showed that P300 and reaction times are sensitive to stimulus-response compatibility, but are not related to tic symptoms. Secondly, overactivity of the frontal LPC and impulsivity in TD patients were not affected by treatment. Finally, CBT had normalizing effects on the activation of the pre-motor and motor cortex in TD patients. These results imply specific modifications of motor processes following therapy, while inhibition processes remained unchanged. Given that LRPs are partially generated within the sensorimotor and supplementary motor area, the reported reduction in tic frequency and improvements of LRPs components suggest that CBT induced a physiological change in patients' motor area. Copyright © 2015 Elsevier Ltd. All rights reserved.

Continuous activation of Nrf2 and its target antioxidant enzymes leads to arsenite-induced malignant transformation of human bronchial epithelial cells

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

Yang, Xu; Wang, Dapeng; Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, Guizhou

Long-term exposure to arsenite leads to human lung cancer, but the underlying mechanisms of carcinogenesis remain obscure. The transcription factor of nuclear factor-erythroid-2 p45-related factor (Nrf2)-mediated antioxidant response represents a critical cellular defense mechanism and protection against various diseases. Paradoxically, emerging data suggest that the constitutive activation of Nrf2 is associated with cancer development, progression and chemotherapy resistance. However, the role of Nrf2 in the occurrence of cancer induced by long-term arsenite exposure remains to be fully understood. By establishing transformed human bronchial epithelial (HBE) cells via chronic low-dose arsenite treatment, we showed that, in acquiring this malignant phenotype, continuousmore » low level of ROS and sustained enhancement of Nrf2 and its target antioxidant enzyme levels were observed in the later-stage of arsenite-induced cell transformation. The downregulation of Keap1 level may be responsible for the over-activation of Nrf2 and its target enzymes. To validate these observations, Nrf2 was knocked down in arsenite-transformed HBE cells by SiRNA transfection, and the levels of Nrf2 and its target antioxidant enzymes, ROS, cell proliferation, migration, and colony formation were determined following these treatments. Results showed that blocked Nrf2 expression significantly reduced Nrf2 and its target antioxidant enzyme levels, restored ROS levels, and eventually suppressed cell proliferation, migration, and colony formation of the transformed cells. In summary, the results of the study strongly suggested that the continuous activation of Nrf2 and its target antioxidant enzymes led to the over-depletion of intracellular ROS levels, which contributed to arsenite-induced HBE cell transformation. - Highlights: • Low level, long term arsenite exposure induces malignant transformation in vitro. • Long term arsenite exposure reduces ROS and MDA levels. • Long term arsenite exposure enhances Nrf2-mediated antioxidant levels. • Knockdown of Nrf2 reduces malignant degree of arsenite-transformed cells.« less

Soluble microbial products (SMPs) release in activated sludge systems: a review

PubMed Central

2012-01-01

This review discusses the characterization, production and implications of soluble microbial products (SMPs) in biological wastewater treatment. The precise definition of SMPs is open to talk about, but is currently regarded as “the pool of organic compounds that are released into solution from substrate metabolism and biomass decay”'. Some of the SMPs have been identified as humic acids, polysaccharides, proteins, amino acids, antibiotics, extracellular enzymes and structural components of cells and products of energy metabolism. They adversely affect the kinetic activity, flocculating and settling properties of sludge. This review outlines some important findings with regard to biodegradability and treatability of SMPs and also the effect of process parameters on their production. As SMPs are produced during biological treatment process, their trace amounts normally remain in the effluent that defines the highest COD removal efficiency. Their presence in effluent represents a high potential risk of toxic by-product formation during chlorine disinfection. Studies have indicated that among all wastewater post-treatment processes, the adsorption by granular activated carbon combined with biologically induced degradation is the most effective method for removal of SMPs. However, it may be concludes that the knowledge regarding SMPs is still under progress and more work is required to fully understand their contribution to the treatment process. PMID:23369231

Prothrombin fragments in cardiovascular disease.

PubMed

Páramo, J A

2010-01-01

Prothrombin fragment 1+2 (F1+2), which comes from in vivo cleavage of prothrombin by factor Xa, is considered to be useful for diagnosis of thrombosis. Recognition of the central role of thrombosis in the pathogenesis ofcardiovascular disease has prompted growing interest in the association o F1+2 with cardiovascular clinical syndromes. Increased F1+2 levels have reported in venous thromboembolism, inflammation, cancer, sepsis, acute coronary syndromes, stroke, peripheral arterial disease, atrial fibrillation and during the postoperative period. However, a clear relationship with the appearance of thrombosis has not always been consistently demonstrated. Besides its potential prognostic and diagnostic value, it could also be usefu in assessing the impact of various therapies. However, it should be kept in mind that measurement of hemostasis activation markers has several important biological and methodological disadvantages. Activation markers reflect the presence of thrombosis in any vascular bed, so they are not specific. Furthermore, elevations occur not only in the presence of overt thrombosis but also during the hypercoagulable state. The cutoff level to be used for the definition of elevations is still largely unknown due to the use of different analytical methods, none of which have been standardized until know. Finally, the prognostic value of F1+2 and other markers of coagulation activation remains to be fully defined in future studies.

A Common Core for Active Conceptual Modeling for Learning from Surprises

NASA Astrophysics Data System (ADS)

Liddle, Stephen W.; Embley, David W.

The new field of active conceptual modeling for learning from surprises (ACM-L) may be helpful in preserving life, protecting property, and improving quality of life. The conceptual modeling community has developed sound theory and practices for conceptual modeling that, if properly applied, could help analysts model and predict more accurately. In particular, we need to associate more semantics with links, and we need fully reified high-level objects and relationships that have a clear, formal underlying semantics that follows a natural, ontological approach. We also need to capture more dynamic aspects in our conceptual models to more accurately model complex, dynamic systems. These concepts already exist, and the theory is well developed; what remains is to link them with the ideas needed to predict system evolution, thus enabling risk assessment and response planning. No single researcher or research group will be able to achieve this ambitious vision alone. As a starting point, we recommend that the nascent ACM-L community agree on a common core model that supports all aspects—static and dynamic—needed for active conceptual modeling in support of learning from surprises. A common core will more likely gain the traction needed to sustain the extended ACM-L research effort that will yield the advertised benefits of learning from surprises.

Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses.

PubMed

Liu, Yanhui; Padmanabhan, Jagannath; Cheung, Bettina; Liu, Jingbei; Chen, Zheng; Scanley, B Ellen; Wesolowski, Donna; Pressley, Mariyah; Broadbridge, Christine C; Altman, Sidney; Schwarz, Udo D; Kyriakides, Themis R; Schroers, Jan

2016-05-27

Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design.

Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses

NASA Astrophysics Data System (ADS)

Liu, Yanhui; Padmanabhan, Jagannath; Cheung, Bettina; Liu, Jingbei; Chen, Zheng; Scanley, B. Ellen; Wesolowski, Donna; Pressley, Mariyah; Broadbridge, Christine C.; Altman, Sidney; Schwarz, Udo D.; Kyriakides, Themis R.; Schroers, Jan

2016-05-01

Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design.

Penetration-enhancement underlies synergy of plant essential oil terpenoids as insecticides in the cabbage looper, Trichoplusia ni

PubMed Central

Tak, Jun-Hyung; Isman, Murray B.

2017-01-01

Many plant essential oils and their terpenoid constituents possess bioactivities including insecticidal activity, and they sometimes act synergistically when mixed. Although several hypotheses for this have been proposed, the underlying mechanism has not been fully elucidated thus far. In the present study, we report that in larvae of the cabbage looper, Trichoplusia ni, most synergistic or antagonistic insecticidal activities among mixtures of plant essential oil constituents are pharmacokinetic effects, owing to changes in solubility as well as spreadability on a wax layer. Among the major constituents of rosemary (Rosmarinus officinalis) oil, in vitro analysis revealed up to a 19-fold increase in penetration of camphor in a binary mixture with 1,8-cineole through the larval integument, suggesting increased penetration as the major mechanism for synergy. A total of 138 synergistic or antagonistic interactions among 39 compounds were identified in binary mixtures via topical application, and these were highly correlated to changes in surface tension as measured by contact angle of the mixtures on a beeswax layer. Among compounds tested, trans-anethole alone showed evidence of internal synergy, whereas most of remaining synergistic or antagonistic combinations among the three most active compounds were identified as penetration-related interactions, confirmed via a divided-application bioassay. PMID:28181580

LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

PubMed Central

Xiang, Shaoxun; Gu, Hao; Thorne, Rick F.; Zhang, Xu Dong; Wu, Mian

2018-01-01

The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity. This resulted in increased α-KG and decreased ROS production and subsequent HIF1α down-regulation, leading to attenuation of glycolysis. Hence, c-Myc repression of IDH1-AS1 promotes activation of the Warburg effect by HIF1α. As such, IDH1-AS1 overexpression inhibited cell proliferation, whereas silencing of IDH1-AS1 promoted cell proliferation and cancer xenograft growth. Restoring IDH1-AS1 expression may therefore represent a potential metabolic approach for cancer treatment. PMID:29378948

Wide-scale quantitative phosphoproteomic analysis reveals that cold treatment of T cells closely mimics soluble antibody stimulation

PubMed Central

Ji, Qinqin; Salomon, Arthur R.

2015-01-01

The activation of T-lymphocytes through antigen-mediated T-cell receptor (TCR) clustering is vital in regulating the adaptive-immune response. Although T cell receptor signaling has been extensively studied, the fundamental mechanisms for signal initiation are not fully understood. Reduced temperature initiated some of the hallmarks of TCR signaling such as increased phosphorylation and activation on ERK and calcium release from the endoplasmic reticulum as well as coalesce T-cell membrane microdomains. The precise mechanism of TCR signaling initiation due to temperature change remains obscure. One critical question is whether signaling initiated by cold treatment of T cells differs from signaling initiated by crosslinking of the T cell receptor. To address this uncertainty, a wide-scale, quantitative mass spectrometry-based phosphoproteomic analysis was performed on T cells stimulated either by temperature shift or through crosslinking of the TCR. Careful statistical comparison between the two stimulations revealed a striking level of identity between the subset of 339 sites that changed significantly with both stimulations. This study demonstrates for the first time, at unprecedented detail, that T cell cold treatment was sufficient to initiate signaling patterns nearly identical to soluble antibody stimulation, shedding new light on the mechanism of activation of these critically important immune cells. PMID:25839225

Combinatorial development of antibacterial Zr-Cu-Al-Ag thin film metallic glasses

PubMed Central

Liu, Yanhui; Padmanabhan, Jagannath; Cheung, Bettina; Liu, Jingbei; Chen, Zheng; Scanley, B. Ellen; Wesolowski, Donna; Pressley, Mariyah; Broadbridge, Christine C.; Altman, Sidney; Schwarz, Udo D.; Kyriakides, Themis R.; Schroers, Jan

2016-01-01

Metallic alloys are normally composed of multiple constituent elements in order to achieve integration of a plurality of properties required in technological applications. However, conventional alloy development paradigm, by sequential trial-and-error approach, requires completely unrelated strategies to optimize compositions out of a vast phase space, making alloy development time consuming and labor intensive. Here, we challenge the conventional paradigm by proposing a combinatorial strategy that enables parallel screening of a multitude of alloys. Utilizing a typical metallic glass forming alloy system Zr-Cu-Al-Ag as an example, we demonstrate how glass formation and antibacterial activity, two unrelated properties, can be simultaneously characterized and the optimal composition can be efficiently identified. We found that in the Zr-Cu-Al-Ag alloy system fully glassy phase can be obtained in a wide compositional range by co-sputtering, and antibacterial activity is strongly dependent on alloy compositions. Our results indicate that antibacterial activity is sensitive to Cu and Ag while essentially remains unchanged within a wide range of Zr and Al. The proposed strategy not only facilitates development of high-performing alloys, but also provides a tool to unveil the composition dependence of properties in a highly parallel fashion, which helps the development of new materials by design. PMID:27230692

PI(4,5)P2-binding effector proteins for vesicle exocytosis

PubMed Central

Martin, Thomas F. J.

2014-01-01

PI(4,5)P2 participates directly in priming and possibly fusion steps of Ca2+-triggered vesicle exocytosis. High concentration nanodomains of PI(4,5)P2 reside on the plasma membrane of neuroendocrine cells. A subset of vesicles that co-localize with PI(4,5)P2 domains appear to undergo preferential exocytosis in stimulated cells. PI(4,5)P2 directly regulates vesicle exocytosis by recruiting and activating PI(4,5)P2-binding proteins that regulate SNARE protein function including CAPS, Munc13-1/2, synaptotagmin-1, and other C2 domain-containing proteins. These PI(4,5)P2 effector proteins are coincidence detectors that engage in multiple interactions at vesicle exocytic sites. The SNARE protein syntaxin-1 also binds to PI(4,5)P2, which promotes clustering, but an activating role for PI(4,5)P2 in syntaxin-1 function remains to be fully characterized. Similar principles underlie polarized constitutive vesicle fusion mediated in part by the PI(4,5)P2-binding subunits of the exocyst complex (Sec3, Exo70). Overall, focal vesicle exocytosis occurs at sites landmarked by PI(4,5)P2, which serves to recruit and/or activate multifunctional PI(4,5)P2-binding proteins. PMID:25280637

IVIg Promote Cross-Tolerance against Inflammatory Stimuli In Vitro and In Vivo.

PubMed

Domínguez-Soto, Ángeles; Simón-Fuentes, Miriam; de Las Casas-Engel, Mateo; Cuevas, Víctor D; López-Bravo, María; Domínguez-Andrés, Jorge; Saz-Leal, Paula; Sancho, David; Ardavín, Carlos; Ochoa-Grullón, Juliana; Sánchez-Ramón, Silvia; Vega, Miguel A; Corbí, Angel L

2018-05-09

IVIg is an approved therapy for immunodeficiency and for several autoimmune and inflammatory diseases. However, the molecular basis for the IVIg anti-inflammatory activity remains to be fully explained and cannot be extrapolated from studies on animal models of disease. We now report that IVIg impairs the generation of human monocyte-derived anti-inflammatory macrophages by inducing JNK activation and activin A production and limits proinflammatory macrophage differentiation by inhibiting GM-CSF-driven STAT5 activation. In vivo, IVIg provokes a rapid increase in peripheral blood activin A, CCL2, and IL-6 levels, an effect that can be recapitulated in vitro on human monocytes. On differentiating monocytes, IVIg promotes the acquisition of altered transcriptional and cytokine profiles, reduces TLR expression and signaling, and upregulates negative regulators of TLR-initiated intracellular signaling. In line with these effects, in vivo IVIg infusion induces a state tolerant toward subsequent stimuli that results in reduced inflammatory cytokine production after LPS challenge in human peripheral blood and significant protection from LPS-induced death in mice. Therefore, IVIg conditions human macrophages toward the acquisition of a state of cross-tolerance against inflammatory stimuli, an effect that correlates with the net anti-inflammatory action of IVIg in vivo. Copyright © 2018 by The American Association of Immunologists, Inc.

Ascorbic acid metabolism during bilberry (Vaccinium myrtillus L.) fruit development.

PubMed

Cocetta, Giacomo; Karppinen, Katja; Suokas, Marko; Hohtola, Anja; Häggman, Hely; Spinardi, Anna; Mignani, Ilaria; Jaakola, Laura

2012-07-15

Bilberry (Vaccinium myrtillus L.) possesses a high antioxidant capacity in berries due to the presence of anthocyanins and ascorbic acid (AsA). Accumulation of AsA and the expression of the genes encoding the enzymes of the main AsA biosynthetic route and of the ascorbate-glutathione cycle, as well as the activities of the enzymes involved in AsA oxidation and recycling were investigated for the first time during the development and ripening of bilberry fruit. The results showed that the AsA level remained relatively stable during fruit maturation. The expression of the genes encoding the key enzymes in the AsA main biosynthetic route showed consistent trends with each other as well as with AsA levels, especially during the first stages of fruit ripening. The expression of genes and activities of the enzyme involved in the AsA oxidation and recycling route showed more prominent developmental stage-dependent changes during the ripening process. Different patterns of activity were found among the studied enzymes and the results were, for some enzymes, in accordance with AsA levels. In fully ripe berries, both AsA content and gene expression were significantly higher in skin than in pulp. Copyright © 2012 Elsevier GmbH. All rights reserved.

Penetration-enhancement underlies synergy of plant essential oil terpenoids as insecticides in the cabbage looper, Trichoplusia ni

NASA Astrophysics Data System (ADS)

Tak, Jun-Hyung; Isman, Murray B.

2017-02-01

Many plant essential oils and their terpenoid constituents possess bioactivities including insecticidal activity, and they sometimes act synergistically when mixed. Although several hypotheses for this have been proposed, the underlying mechanism has not been fully elucidated thus far. In the present study, we report that in larvae of the cabbage looper, Trichoplusia ni, most synergistic or antagonistic insecticidal activities among mixtures of plant essential oil constituents are pharmacokinetic effects, owing to changes in solubility as well as spreadability on a wax layer. Among the major constituents of rosemary (Rosmarinus officinalis) oil, in vitro analysis revealed up to a 19-fold increase in penetration of camphor in a binary mixture with 1,8-cineole through the larval integument, suggesting increased penetration as the major mechanism for synergy. A total of 138 synergistic or antagonistic interactions among 39 compounds were identified in binary mixtures via topical application, and these were highly correlated to changes in surface tension as measured by contact angle of the mixtures on a beeswax layer. Among compounds tested, trans-anethole alone showed evidence of internal synergy, whereas most of remaining synergistic or antagonistic combinations among the three most active compounds were identified as penetration-related interactions, confirmed via a divided-application bioassay.

Soluble microbial products (SMPs) release in activated sludge systems: a review.

PubMed

Azami, Hamed; Sarrafzadeh, Mohammad Hossein; Mehrnia, Mohammad Reza

2012-12-18

This review discusses the characterization, production and implications of soluble microbial products (SMPs) in biological wastewater treatment. The precise definition of SMPs is open to talk about, but is currently regarded as "the pool of organic compounds that are released into solution from substrate metabolism and biomass decay"'. Some of the SMPs have been identified as humic acids, polysaccharides, proteins, amino acids, antibiotics, extracellular enzymes and structural components of cells and products of energy metabolism. They adversely affect the kinetic activity, flocculating and settling properties of sludge. This review outlines some important findings with regard to biodegradability and treatability of SMPs and also the effect of process parameters on their production. As SMPs are produced during biological treatment process, their trace amounts normally remain in the effluent that defines the highest COD removal efficiency. Their presence in effluent represents a high potential risk of toxic by-product formation during chlorine disinfection. Studies have indicated that among all wastewater post-treatment processes, the adsorption by granular activated carbon combined with biologically induced degradation is the most effective method for removal of SMPs. However, it may be concludes that the knowledge regarding SMPs is still under progress and more work is required to fully understand their contribution to the treatment process.

A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells

PubMed Central

Huang, Peixin; Riordan, Sean M.; Heruth, Daniel P.; Grigoryev, Dmitry N.; Zhang, Li Qin; Ye, Shui Qing

2015-01-01

Aging is the predominant risk factor for cardiovascular diseases and contributes to a considerably more severe outcome in patients with acute myocardial infarction. Resveratrol, a polyphenol found in red wine, is a caloric restriction mimetic with potential anti-aging properties which has emerged as a beneficial nutraceutical for patients with cardiovascular disease. Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully. Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells. Similar observations were obtained in resveratrol treated C57BL/6J mouse heart and liver tissues. Resverotrol can also augment telomerase activity in both human pulmonary microvascular endothelial cells and A549 cells. Blocking NAMPT and SIRT4 expression prevents induction of hTERT in human aortic smooth muscle cells while overexpression of NAMPT elevates the telomerase activity induced by resveratrol in A549 cells. Together, these results identify a NAMPT-SIRT4-hTERT axis as a novel mechanism by which resveratrol may affect the anti-aging process in human aortic smooth muscle cells, mouse hearts and other cells. These findings enrich our understanding of the positive effects of resveratrol in human cardiovascular diseases. PMID:25926556

Alternative splicing at exon 2 results in the loss of the catalytic activity of mouse DNA polymerase iota in vitro.

PubMed

Kazachenko, Konstantin Y; Miropolskaya, Nataliya A; Gening, Leonid V; Tarantul, Vyacheslav Z; Makarova, Alena V

2017-02-01

Y-family DNA polymerase iota (Pol ι) possesses both DNA polymerase and dRP lyase activities and was suggested to be involved in DNA translesion synthesis and base excision repair in mammals. The 129 strain of mice and its derivatives have a natural nonsense codon mutation in the second exon of the Pol ι gene resulting in truncation of the Pol ι protein. These mice were widely used as a Pol ι-null model for in vivo studies of the Pol ι function. However whether 129-derived strains of mice are fully deficient in the Pol ι functions was a subject of discussion since Pol ι mRNA undergoes alternative splicing at exon 2. Here we report purification of mouse Pol ι lacking the region encoded by exon 2, which includes several conserved residues involved in catalysis. We show that the deletion abrogates both the DNA polymerase and dRP lyase activities of Pol ι in the presence of either Mg 2+ or Mn 2+ ions. Thus, 129-derived strains of mice express catalytically inactive alternatively spliced Pol ι variant, whose cellular functions, if any exist, remain to be established. Copyright © 2017 Elsevier B.V. All rights reserved.

The TAT-RasGAP317-326 anti-cancer peptide can kill in a caspase-, apoptosis-, and necroptosis-independent manner

PubMed Central

Puyal, Julien; Margue, Christiane; Michel, Sébastien; Kreis, Stephanie; Kulms, Dagmar; Barras, David; Nahimana, Aimable; Widmann, Christian

2016-01-01

Tumor cell resistance to apoptosis, which is triggered by many anti-tumor therapies, remains a major clinical problem. Therefore, development of more efficient therapies is a priority to improve cancer prognosis. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP317-326, bears anti-malignant activities in vitro and in vivo, such as inhibition of metastatic progression and tumor cell sensitization to cell death induced by various anti-cancer treatments. Recently, we discovered that this RasGAP-derived peptide possesses the ability to directly kill some cancer cells. TAT-RasGAP317-326 can cause cell death in a manner that can be either partially caspase-dependent or fully caspase-independent. Indeed, TAT-RasGAP317-326-induced toxicity was not or only partially prevented when apoptosis was inhibited. Moreover, blocking other forms of cell death, such as necroptosis, parthanatos, pyroptosis and autophagy did not hamper the killing activity of the peptide. The death induced by TAT-RasGAP317-326 can therefore proceed independently from these modes of death. Our finding has potentially interesting clinical relevance because activation of a death pathway that is distinct from apoptosis and necroptosis in tumor cells could lead to the generation of anti-cancer drugs that target pathways not yet considered for cancer treatment. PMID:27602963

The interaction between abiotic photodegradation and microbial decomposition under ultraviolet radiation.

PubMed

Wang, Jing; Liu, Lingli; Wang, Xin; Chen, Yiwei

2015-05-01

Elevated ultraviolet (UV) radiation has been demonstrated to stimulate litter decomposition. Despite years of research, it is still not fully understood whether the acceleration in litter degradation is primarily attributed to abiotic photodegradation or the combined effects of abiotic photodegradation and microbial decomposition. In this study, we used meta-analysis to synthesize photodegradation studies and compared the effects of UV radiation on litter decomposition between abiotic and biotic conditions. We also conducted a microcosm experiment to assess the effects of UV radiation on litter biodegradability and microbial activity. Overall, our meta-analysis found that under abiotic photodegradation, UV radiation reduced the remaining litter mass by 1.44% (95% CI: 0.85% to 2.08%), did not affect the remaining lignin and increased the dissolved organic carbon (DOC) concentration by 14.01% (1.49-23.67%). Under combined abiotic photodegradation and microbial decomposition, UV radiation reduced the remaining litter mass and lignin by 1.60% (0.04-3.58%) and 16.07% (9.27-24.23%), respectively, but did not alter DOC concentration. UV radiation had no significant impact on soil microbial biomass carbon (MBC), but it reduced microbial respiration by 44.91% (2.26-78.62%) and altered the composition of the microbial community. In addition, UV radiation reduced nitrogen (N) immobilization by 19.44% (4.77-37.92%). Our microcosm experiment further indicated that DOC concentration and the amount of respired C in UV-treated litter increased with UV exposure time, suggesting that longer UV exposure resulted in greater biodegradability. Overall, our study suggested that UV exposure could increase litter biodegradability by increasing the microbial accessibility of lignin, as well as the labile carbon supply to microbes. However, the remaining litter mass was not different between the abiotic and biotic conditions, most likely because the positive effect of UV radiation on litter biodegradability was offset by its negative effect on microbial activity. Our results also suggested that UV radiation could alter the N cycle during decomposition, primarily by inhibiting N immobilization. © 2014 John Wiley & Sons Ltd.

Role of fetal DNA in preeclampsia (review).

PubMed

Konečná, Barbora; Vlková, Barbora; Celec, Peter

2015-02-01

Preeclampsia is an autoimmune disorder characterized by hypertension. It begins with abnormal cytotrophoblast apoptosis, which leads to inflammation and an increase in the levels of anti-angiogenic factors followed by the disruption of the angiogenic status. Increased levels of fetal DNA and RNA coming from the placenta, one of the most commonly affected organs in pregnancies complicated by preeclampsia, have been found in pregnant women with the condition. However, it remains unknown as to whether this is a cause or a consequence of preeclampsia. Few studies have been carried out on preeclampsia in which an animal model of preeclampsia was induced by an injection of different types of DNA that are mimic fetal DNA and provoke inflammation through Toll-like receptor 9 (TLR9) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The specific mechanisms involved in the development of preeclampsia are not yet fully understood. It is hypothesized that the presence of different fragments of fetal DNA in maternal plasma may cause for the development of preeclampsia. The function of DNase during preeclampsia also remains unresolved. Studies have suggested that its activity is decreased or the DNA is protected against its effects. Further research is required to uncover the pathogenesis of preeclampsia and focus more on the condition of patients with the condition.

An extraovarian aspartic protease accumulated in tick oocytes with vitellin-degradation activity.

PubMed

Pohl, Paula C; Sorgine, Marcos Henrique F; Leal, Alexandre T; Logullo, Carlos; Oliveira, Pedro L; Vaz, Itabajara da Silva; Masuda, Aoi

2008-12-01

An aspartic endopeptidase named THAP, from the eggs of the tick Riphicephalus (Boophilus) microplus, has been suggested to be involved in vitellin-degradation. Here we characterized this enzyme further, showing that THAP mRNA is present in the fat body, midgut and ovary of ticks, in two developmental stages (partially and fully engorged females). However, higher transcription levels were found in fully engorged vitellogenic females. The THAP protein was detected in the haemolymph, midgut and fat body and, in higher quantity, in the ovary of fully engorged females, and it was present throughout embryo development. The protein is synthesized as a higher molecular mass form and after the onset of embryogenesis THAP is converted into an active form by autocatalysis. We also produced a recombinant protein (rTHAP) in E. coli that was active in the fluorogenic peptide substrate and able to hydrolyze vitellin from 7-day-old eggs in a reaction that is heme-sensitive and inhibited by pepstatin A. However, rTHAP does not hydrolyze vitellin from 1 and 12-day-old eggs. As a result, we suggest a model for THAP synthesis, transport, storage and activation and for the role it plays in embryonic development by participating in vitellin processing.

A reduced energy supply strategy in active vibration control

NASA Astrophysics Data System (ADS)

Ichchou, M. N.; Loukil, T.; Bareille, O.; Chamberland, G.; Qiu, J.

2011-12-01

In this paper, a control strategy is presented and numerically tested. This strategy aims to achieve the potential performance of fully active systems with a reduced energy supply. These energy needs are expected to be comparable to the power demands of semi-active systems, while system performance is intended to be comparable to that of a fully active configuration. The underlying strategy is called 'global semi-active control'. This control approach results from an energy investigation based on management of the optimal control process. Energy management encompasses storage and convenient restitution. The proposed strategy monitors a given active law without any external energy supply by considering purely dissipative and energy-demanding phases. Such a control law is offered here along with an analysis of its properties. A suboptimal form, well adapted for practical implementation steps, is also given. Moreover, a number of numerical experiments are proposed in order to validate test findings.

Application of the Institution of Exclusive Rights in the Field of Science

NASA Astrophysics Data System (ADS)

Yakovlev, D.; Yushkov, E.; Zanardo, A.; Bogatyreova, M.

2017-01-01

The problem of legal protection of scientific research results is of growing interest nowadays. However, none of the three hitherto existing rights (the right for trade secrets, patent and copyright) is able to fully take into account the characteristics of scientific activities. In Russia, the problem of legal protection of scientific research results has been developed actively since the 50-ies of the last century, in connection with the introduction of the system of state registration of scientific discoveries. A further concept allowed for not only the registration of discoveries, but also the entire array of scientific results. However, theoretical applicability of exclusive rights institutions in the sphere of science remained unstudied. The article describes a new system, which is not fixed in legislation and remains unnoticed by the vast majority of researchers. That is the institution of scientific and positional rights, focused on the recognition procedure of authorship, priority, and other characteristics of intellectual scientific results value. In case of complex intellectual results, comprising scientific results, the recognition of result-oriented exclusive rights proves to be unsustainable. This circumstance urges us to foreground the institution of scientific and positional exclusive rights. Its scope is budget science where non-fee published scientific results are generated. Any exclusive right to use open scientific results is out of the question. The sphere of open (budget) science is dominated by scientific and positional exclusive rights, sanctioned both by the state (S-sanctioned), the bodies of the scientific community (BSC-sanctioned) and scientific community (SC-sanctioned) rights.

Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

PubMed Central

2015-01-01

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

MDMA (3,4-Methylenedioxymethamphetamine) Analogues as Tools to Characterize MDMA-Like Effects: An Approach to Understand Entactogen Pharmacology

PubMed Central

Sáez-Briones, P.; Hernández, A.

2013-01-01

Besides stimulants and hallucinogens, whose psychotropic effects are shared by many structurally related molecules exhibiting different efficacies and potencies in humans, the phenylisopropylamine MDMA (3,4-methylenedioxymethamphetamine, XTC, “Ecstasy”) is the prototypical representative of a separate class of psychotropic substance, able to elicit the so-called entactogenic syndrome in healthy humans. This reversible altered state of consciousness, usually described as an “open mind state”, may have relevant therapeutic applications, both in psychotherapy and as a pharmacological support in many neuropsychiatric disorders with a high rate of treatment failure. Nevertheless, a comprehensive and systematic exploration of the structure-activity relationships associated with entactogenic activity has remained incomplete and controversial, highlighting the possibility that MDMA might represent a pharmacological rarity in the field of psychotropics. As the latter is still an open question, the pharmacological characterization of MDMA analogues remains the logical strategy to attempt the elucidation of the structural requirements needed to elicit typical MDMA-like effects. Intriguingly, almost no experimental evidence supports the existence of actual MDMA analogues that truly resemble the whole pharmacological profile of MDMA, probably due to its complex (and partially not fully understood) mechanism of action that includes a disruption of monoaminergic neurotransmission. The present review presents a brief summary of the pharmacology of MDMA, followed by the evidence accumulated over the years regarding the characterization of classical structurally related MDMA analogues in different models and how this state of the art highlights the need to develop new and better MDMA analogues. PMID:24403876

Entamoeba histolytica: a snapshot of current research and methods for genetic analysis

PubMed Central

Morf, Laura; Singh, Upinder

2012-01-01

Entamoeba histolytica represents one of the leading causes of parasitic death worldwide. Although identified as the causative agent of amebiasis since 1875, the molecular mechanisms by which the parasite causes disease are still not fully understood. Studying Entamoeba reveals insights into a eukaryotic cell that differs in many ways from better-studied model organisms. Thus, much can be learned from this protozoan parasite on evolution, cell biology and RNA biology. In this review we discuss selected research highlights in Entamoeba research and focus on the development of molecular biological techniques to study this pathogen. We end by highlighting some of the many questions that remain to be answered in order to fully understand this important human pathogen. PMID:22664276

How I Learned to Stop Worrying and Love 3D Printing

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

Pete, Cassandra; Morrell, Sean; Maloney, Jillian

The nuclear nonproliferation regime has many robust measures in place to prevent the acquisition of a nuclear weapon, a key pillar of which is denying or preventing the transfer of technology to specific actors. Additive manufacturing (AM) is a rapidly advancing, not fully understood technology that could dramatically alter the landscape of the safeguarded fuel cycle. However, many of the benefits of AM could also be used to circumvent or defeat current safeguard practices and controls. Because the AM capability is not fully understood, research and integration is necessary early in the technology development stages in order for nonproliferation tomore » remain on the leading edge of discovery and not the tail end of technology deployment.« less

Bathymetric controls on Pliocene North Atlantic and Arctic sea surface temperature and deepwater production

USGS Publications Warehouse

Robinson, M.M.; Valdes, P.J.; Haywood, A.M.; Dowsett, H.J.; Hill, D.J.; Jones, S.M.

2011-01-01

The mid-Pliocene warm period (MPWP; ~. 3.3 to 3.0. Ma) is the most recent interval in Earth's history in which global temperatures reached and remained at levels similar to those projected for the near future. The distribution of global warmth, however, was different than today in that the high latitudes warmed more than the tropics. Multiple temperature proxies indicate significant sea surface warming in the North Atlantic and Arctic Oceans during the MPWP, but predictions from a fully coupled ocean-atmosphere model (HadCM3) have so far been unable to fully predict the large scale of sea surface warming in the high latitudes. If climate proxies accurately represent Pliocene conditions, and if no weakness exists in the physics of the model, then model boundary conditions may be in error. Here we alter a single boundary condition (bathymetry) to examine if Pliocene high latitude warming was aided by an increase in poleward heat transport due to changes in the subsidence of North Atlantic Ocean ridges. We find an increase in both Arctic sea surface temperature and deepwater production in model experiments that incorporate a deepened Greenland-Scotland Ridge. These results offer both a mechanism for the warming in the North Atlantic and Arctic Oceans indicated by numerous proxies and an explanation for the apparent disparity between proxy data and model simulations of Pliocene northern North Atlantic and Arctic Ocean conditions. Determining the causes of Pliocene warmth remains critical to fully understanding comparisons of the Pliocene warm period to possible future climate change scenarios. ?? 2011.

Serine Proteolytic Pathway Activation Reveals an Expanded Ensemble of Wound Response Genes in Drosophila

PubMed Central

Patterson, Rachel A.; Juarez, Michelle T.; Hermann, Anita; Sasik, Roman; Hardiman, Gary; McGinnis, William

2013-01-01

After injury to the animal epidermis, a variety of genes are transcriptionally activated in nearby cells to regenerate the missing cells and facilitate barrier repair. The range and types of diffusible wound signals that are produced by damaged epidermis and function to activate repair genes during epidermal regeneration remains a subject of very active study in many animals. In Drosophila embryos, we have discovered that serine protease function is locally activated around wound sites, and is also required for localized activation of epidermal repair genes. The serine protease trypsin is sufficient to induce a striking global epidermal wound response without inflicting cell death or compromising the integrity of the epithelial barrier. We developed a trypsin wounding treatment as an amplification tool to more fully understand the changes in the Drosophila transcriptome that occur after epidermal injury. By comparing our array results with similar results on mammalian skin wounding we can see which evolutionarily conserved pathways are activated after epidermal wounding in very diverse animals. Our innovative serine protease-mediated wounding protocol allowed us to identify 8 additional genes that are activated in epidermal cells in the immediate vicinity of puncture wounds, and the functions of many of these genes suggest novel genetic pathways that may control epidermal wound repair. Additionally, our data augments the evidence that clean puncture wounding can mount a powerful innate immune transcriptional response, with different innate immune genes being activated in an interesting variety of ways. These include puncture-induced activation only in epidermal cells in the immediate vicinity of wounds, or in all epidermal cells, or specifically in the fat body, or in multiple tissues. PMID:23637905

Trainability of Muscular Activity Level during Maximal Voluntary Co-Contraction: Comparison between Bodybuilders and Nonathletes

PubMed Central

Maeo, Sumiaki; Takahashi, Takumi; Takai, Yohei; Kanehisa, Hiroaki

2013-01-01

Antagonistic muscle pairs cannot be fully activated simultaneously, even with maximal effort, under conditions of voluntary co-contraction, and their muscular activity levels are always below those during agonist contraction with maximal voluntary effort (MVE). Whether the muscular activity level during the task has trainability remains unclear. The present study examined this issue by comparing the muscular activity level during maximal voluntary co-contraction for highly experienced bodybuilders, who frequently perform voluntary co-contraction in their training programs, with that for untrained individuals (nonathletes). The electromyograms (EMGs) of biceps brachii and triceps brachii muscles during maximal voluntary co-contraction of elbow flexors and extensors were recorded in 11 male bodybuilders and 10 nonathletes, and normalized to the values obtained during the MVE of agonist contraction for each of the corresponding muscles (% EMGMVE). The involuntary coactivation level in antagonist muscle during the MVE of agonist contraction was also calculated. In both muscles, % EMGMVE values during the co-contraction task for bodybuilders were significantly higher (P<0.01) than those for nonathletes (biceps brachii: 66±14% in bodybuilders vs. 46±13% in nonathletes, triceps brachii: 74±16% vs. 57±9%). There was a significant positive correlation between a length of bodybuilding experience and muscular activity level during the co-contraction task (r = 0.653, P = 0.03). Involuntary antagonist coactivation level during MVE of agonist contraction was not different between the two groups. The current result indicates that long-term participation in voluntary co-contraction training progressively enhances muscular activity during maximal voluntary co-contraction. PMID:24260233

PINK1-Mediated Phosphorylation of Parkin Boosts Parkin Activity in Drosophila

PubMed Central

Shiba-Fukushima, Kahori; Inoshita, Tsuyoshi; Hattori, Nobutaka; Imai, Yuzuru

2014-01-01

Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. We have reported that Parkin is phosphorylated at Ser65 within the ubiquitin-like domain by PINK1 in mammalian cultured cells. However, it remains unclear whether Parkin phosphorylation is involved in mitochondrial maintenance and activity of dopaminergic neurons in vivo. Here, we examined the effects of Parkin phosphorylation in Drosophila, in which the phosphorylation residue is conserved at Ser94. Morphological changes of mitochondria caused by the ectopic expression of wild-type Parkin in muscle tissue and brain dopaminergic neurons disappeared in the absence of PINK1. In contrast, phosphomimetic Parkin accelerated mitochondrial fragmentation or aggregation and the degradation of mitochondrial proteins regardless of PINK1 activity, suggesting that the phosphorylation of Parkin boosts its ubiquitin-ligase activity. A non-phosphorylated form of Parkin fully rescued the muscular mitochondrial degeneration due to the loss of PINK1 activity, whereas the introduction of the non-phosphorylated Parkin mutant in Parkin-null flies led to the emergence of abnormally fused mitochondria in the muscle tissue. Manipulating the Parkin phosphorylation status affected spontaneous dopamine release in the nerve terminals of dopaminergic neurons, the survivability of dopaminergic neurons and flight activity. Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions. PMID:24901221

75 FR 27782 - Federal Acquisition Regulation; Submission for OMB Review; Rights in Data and Copyrights

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-18

... experimental, developmental, research, or demonstration work (other than basic or applied research to be... fully evaluate the research in order to ascertain future activities and to insure that the research was completed and fully reported, as well as to give the public an opportunity to assess the research results...

Effect of a ban on extracurricular sports activities by secondary school teachers on physical activity levels of adolescents: a multilevel analysis.

PubMed

Pabayo, Roman; O'Loughlin, Jennifer; Gauvin, Lise; Paradis, Gilles; Gray-Donald, Katherine

2006-10-01

To study the effect of a teachers' ban on supervising sports-related extracurricular physical activities (ECAs), levels of physical activity among 979 grade 7 students (mean age=12.7 [0.5] years at baseline) were compared during and after the ban in seven schools that fully implemented the ban, and three schools that did not implement the ban fully. On average, schools offered 18.0 (SD=5.1) ECAs during a no-ban school year. Students attending full implementation schools were significantly more likely than students in nonimplementation schools to be active after the ban ended (odds ratio for being active=1.89 [95% confidence interval: 1.39, 2.58]). They also increased the number of physical activities in which they participated (coefficient=4.04; SE=1.01). Ending a teachers' ban on sports-related ECAs was associated with increased involvement in physical activity among secondary school students.

Regulation of hepatic 7 alpha-hydroxylase expression by dietary psyllium in the hamster.

PubMed Central

Horton, J D; Cuthbert, J A; Spady, D K

1994-01-01

Soluble fiber consistently lowers plasma total and low density lipoprotein (LDL)-cholesterol concentrations in humans and various animal models including the hamster; however, the mechanism of this effect remains incompletely defined. We performed studies to determine the activity of dietary psyllium on hepatic 7 alpha-hydroxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and LDL receptor expression in the hamster. In animals fed a cholesterol-free semisynthetic diet containing 7.5% cellulose (avicel) as a fiber source, substitution of psyllium for avicel increased hepatic 7 alpha-hydroxylase activity and mRNA levels by 3-4-fold. Comparable effects on 7 alpha-hydroxylase expression were observed with 1% cholestyramine. Psyllium also increased hepatic 7 alpha-hydroxylase activity and mRNA in animals fed a diet enriched with cholesterol and triglyceride. Activation of 7 alpha-hydroxylase was associated with an increase in hepatic cholesterol synthesis that was apparently not fully compensatory since the cholesterol content of the liver declined. Although dietary psyllium did not increase hepatic LDL receptor expression in animals fed the cholesterol-free, very-low-fat diet, it did increase (or at least restore) receptor expression that had been downregulated by dietary cholesterol and triglyceride. Thus, 7.5% dietary psyllium produced effects on hepatic 7 alpha-hydroxylase and LDL metabolism that were similar to those of 1% cholestyramine. Induction of hepatic 7 alpha-hydroxylase activity by dietary psyllium may account, in large part, for the hypocholesterolemic effect of this soluble fiber. Images PMID:8182140

2015 Site Environmental Report Fernald Preserve

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

Hertel, Bill; Hooten, Gwen

The Fernald Preserve 2015 Site Environmental Report provides stakeholders with the results from the Fernald, Ohio, Site’s environmental monitoring programs for 2015; a summary of the U.S. Department of Energy’s (DOE’s) activities conducted onsite; and a summary of the Fernald Preserve’s compliance with the various environmental regulations, compliance agreements, and DOE policies that govern site activities. This report has been prepared in accordance with the “Integrated Environmental Monitoring Plan,” which is Attachment D of the Comprehensive Legacy Management and Institutional Controls Plan (LMICP) (DOE 2016). Remediation of the Fernald Preserve has been successfully completed with the exception of the groundwater.more » During 2015, activities at the Fernald Preserve included: environmental monitoring activities related to direct radiation, groundwater, and surface water; ecological restoration monitoring and maintenance as well as inspections, care, and monitoring of the site and the OSDF to ensure that provisions of the LMICP are fully implemented; OSDF leak detection monitoring and collection, monitoring, and treatment of leachate from the OSDF; extraction, monitoring, and treatment of contaminated groundwater from the Great Miami Aquifer (Operable Unit 5); ongoing operation of the Fernald Preserve Visitors Center, associated outreach, and educational activities; and monitoring as specified in the site’s National Pollutant Discharge Elimination System (NPDES) permit. Environmental monitoring programs were developed to ensure that the remedy remains protective of the environment. The requirements of these programs are described in detail in the LMICP and reported in this Site Environmental Report.« less

The beneficial effects of treadmill step training on activity-dependent synaptic and cellular plasticity markers after complete spinal cord injury.

PubMed

Ilha, Jocemar; Centenaro, Lígia A; Broetto Cunha, Núbia; de Souza, Daniela F; Jaeger, Mariane; do Nascimento, Patrícia S; Kolling, Janaína; Ben, Juliana; Marcuzzo, Simone; Wyse, Angela T S; Gottfried, Carmem; Achaval, Matilde

2011-06-01

Several studies have shown that treadmill training improves neurological outcomes and promotes plasticity in lumbar spinal cord of spinal animals. The morphological and biochemical mechanisms underlying these phenomena remain unclear. The purpose of this study was to provide evidence of activity-dependent plasticity in spinal cord segment (L5) below a complete spinal cord transection (SCT) at T8-9 in rats in which the lower spinal cord segments have been fully separated from supraspinal control and that subsequently underwent treadmill step training. Five days after SCT, spinal animals started a step-training program on a treadmill with partial body weight support and manual step help. Hindlimb movements were evaluated over time and scored on the basis of the open-field BBB scale and were significantly improved at post-injury weeks 8 and 10 in trained spinal animals. Treadmill training also showed normalization of withdrawal reflex in trained spinal animals, which was significantly different from the untrained animals at post-injury weeks 8 and 10. Additionally, compared to controls, spinal rats had alpha motoneuronal soma size atrophy and reduced synaptophysin protein expression and Na(+), K(+)-ATPase activity in lumbar spinal cord. Step-trained rats had motoneuronal soma size, synaptophysin expression and Na(+), K(+)-ATPase activity similar to control animals. These findings suggest that treadmill step training can promote activity-dependent neural plasticity in lumbar spinal cord, which may lead to neurological improvements without supraspinal descending control after complete spinal cord injury.

Cardiac imaging: working towards fully-automated machine analysis & interpretation.

PubMed

Slomka, Piotr J; Dey, Damini; Sitek, Arkadiusz; Motwani, Manish; Berman, Daniel S; Germano, Guido

2017-03-01

Non-invasive imaging plays a critical role in managing patients with cardiovascular disease. Although subjective visual interpretation remains the clinical mainstay, quantitative analysis facilitates objective, evidence-based management, and advances in clinical research. This has driven developments in computing and software tools aimed at achieving fully automated image processing and quantitative analysis. In parallel, machine learning techniques have been used to rapidly integrate large amounts of clinical and quantitative imaging data to provide highly personalized individual patient-based conclusions. Areas covered: This review summarizes recent advances in automated quantitative imaging in cardiology and describes the latest techniques which incorporate machine learning principles. The review focuses on the cardiac imaging techniques which are in wide clinical use. It also discusses key issues and obstacles for these tools to become utilized in mainstream clinical practice. Expert commentary: Fully-automated processing and high-level computer interpretation of cardiac imaging are becoming a reality. Application of machine learning to the vast amounts of quantitative data generated per scan and integration with clinical data also facilitates a move to more patient-specific interpretation. These developments are unlikely to replace interpreting physicians but will provide them with highly accurate tools to detect disease, risk-stratify, and optimize patient-specific treatment. However, with each technological advance, we move further from human dependence and closer to fully-automated machine interpretation.

Beneficial and limiting factors for return to work following anterior cruciate ligament reconstruction: a retrospective cohort study.

PubMed

Groot, Judith A M; Jonkers, Freerk J; Kievit, Arthur J; Kuijer, P Paul F M; Hoozemans, Marco J M

2017-02-01

Evidence-based advice for return to work (RTW) after anterior cruciate ligament (ACL) reconstruction is not available. Therefore, the objectives of this study were to determine when patients achieve full RTW, and to explore the beneficial and limiting factors for fully RTW after ACL reconstruction. A retrospective cohort study was performed after ACL reconstruction among 185 patients in one hospital. Data from patient files and a questionnaire were used to explore whether patient-, injury-, surgery-, sports-, work- and rehabilitation-related factors are beneficial or limiting for fully RTW after ACL reconstruction, using a backward stepwise logistic regression analysis. Of the 125 (68%) patients that returned the questionnaire, 36 were not part of the working population. Of the remaining 89 patients, 82 patients (92%) had returned fully to work at follow-up. The median time to fully RTW was 78 days. In the final regression model, which explained 29% of the variance, a significant OR of 5.4 (90% CI 2.2-13.1) for RTW > 78 days was observed for patients performing heavy knee-demanding work compared to patients performing light knee-demanding work. In addition, a significant and positive OR (1.6, 90% CI 1.2-1.9) for the number of weeks walking with the aid of crutches for RTW > 78 days was observed in the final model. After ACL reconstruction, 92% of the patients fully return to work at a median time of 78 days. The significant predictors for fully RTW > 78 days are performing heavy knee-demanding work and a longer period of walking aided with crutches after ACL reconstruction.

Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration.

PubMed

Farkas, Johanna E; Freitas, Polina D; Bryant, Donald M; Whited, Jessica L; Monaghan, James R

2016-08-01

The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration. © 2016. Published by The Company of Biologists Ltd.

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae*

PubMed Central

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.; Shirasaki, Dyna I.; Wang, Charles; Blaby-Haas, Crysten E.; Merchant, Sabeeha S.; Loo, Joseph A.; Clarke, Catherine F.

2015-01-01

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. Here, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11. PMID:25631044

Who is that masked educator? Deconstructing the teaching and learning processes of an innovative humanistic simulation technique.

PubMed

McAllister, Margaret; Searl, Kerry Reid; Davis, Susan

2013-12-01

Simulation learning in nursing has long made use of mannequins, standardized actors and role play to allow students opportunity to practice technical body-care skills and interventions. Even though numerous strategies have been developed to mimic or amplify clinical situations, a common problem that is difficult to overcome in even the most well-executed simulation experiences, is that students may realize the setting is artificial and fail to fully engage, remember or apply the learning. Another problem is that students may learn technical competence but remain uncertain about communicating with the person. Since communication capabilities are imperative in human service work, simulation learning that only achieves technical competence in students is not fully effective for the needs of nursing education. Furthermore, while simulation learning is a burgeoning space for innovative practices, it has been criticized for the absence of a basis in theory. It is within this context that an innovative simulation learning experience named "Mask-Ed (KRS simulation)", has been deconstructed and the active learning components examined. Establishing a theoretical basis for creative teaching and learning practices provides an understanding of how, why and when simulation learning has been effective and it may help to distinguish aspects of the experience that could be improved. Three conceptual theoretical fields help explain the power of this simulation technique: Vygotskian sociocultural learning theory, applied theatre and embodiment. Copyright © 2013 Elsevier Ltd. All rights reserved.

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

DOE PAGES

Allan, Christopher M.; Awad, Agape M.; Johnson, Jarrett S.; ...

2015-01-28

Coenzyme Q (Q or ubiquinone) is a redox active lipid composed of a fully substituted benzoquinone ring and a polyisoprenoid tail and is required for mitochondrial electron transport. In the yeast Saccharomyces cerevisiae, Q is synthesized by the products of 11 known genes, COQ1–COQ9, YAH1, and ARH1. The function of some of the Coq proteins remains unknown, and several steps in the Q biosynthetic pathway are not fully characterized. Several of the Coq proteins are associated in a macromolecular complex on the matrix face of the inner mitochondrial membrane, and this complex is required for efficient Q synthesis. In thismore » paper, we further characterize this complex via immunoblotting and proteomic analysis of tandem affinity-purified tagged Coq proteins. We show that Coq8, a putative kinase required for the stability of the Q biosynthetic complex, is associated with a Coq6-containing complex. Additionally Q 6 and late stage Q biosynthetic intermediates were also found to co-purify with the complex. A mitochondrial protein of unknown function, encoded by the YLR290C open reading frame, is also identified as a constituent of the complex and is shown to be required for efficient de novo Q biosynthesis. Finally, given its effect on Q synthesis and its association with the biosynthetic complex, we propose that the open reading frame YLR290C be designated COQ11.« less

Autism and Folate Deficiency

DTIC Science & Technology

2010-05-01

social interaction that remains to be characterized more fully. Conclusion Ablation of genes in the folate pathway may result in abnormal adult...W81XWH-09-1-0246 TITLE: Autism and Folate Deficiency PRINCIPAL INVESTIGATOR: Richard H. Finnell, Ph.D...5a. CONTRACT NUMBER W81XWH-09-1-0246 Autism and Folate Deficiency 5b. GRANT NUMBER AR080064-Concept Award 5c. PROGRAM ELEMENT NUMBER

A comparison of techniques for generating forest ownership spatial products

Treesearch

Brett J. Butler; Jaketon H. Hewes; Greg C. Liknes; Mark D. Nelson; Stephanie A. Snyder

2014-01-01

To fully understand forest resources, it is imperative to understand the social context in which the forests exist. A pivotal part of that context is the forest ownership. It is the owners, operating within biophysical and social constraints, who ultimately decide if the land will remain forested, how the resources will be used, and by whom. Forest ownership patterns...

46 CFR 171.080 - Damage stability standards for vessels with Type I or Type II subdivision.

Code of Federal Regulations, 2011 CFR

2011-10-01

... to which the vessel heels after sustained damage, are swung out if necessary, fully loaded and ready...; and (C) Survival craft on the side of the vessel opposite that to which the vessel heels remain stowed... damage occurs. (3) The estimated maximum angle of heel before equalization must be approved by the...

African American Males in Foster Care and the Risk of Delinquency: The Value of Social Bonds and Permanence

ERIC Educational Resources Information Center

Ryan, Joseph P.; Testa, Mark F.; Zhai, Fuhua

2008-01-01

Juvenile delinquency remains a significant problem for child welfare systems throughout the United States. Victims of child abuse and neglect are more likely relative to children in the general population to engage in delinquency (Ryan & Testa, 2005; Widom, 1989). Although the magnitude of this relationship is not fully understood (Zingraff,…

Unlocking the Secrets of High-Performing Charters: Tight Management and "No Excuses"

ERIC Educational Resources Information Center

Peyser, James A.

2011-01-01

Charter schools are approaching the ripe old age of 20. Although more work remains if one is to fully understand this complex education reform "movement," a growing body of data and research is being compiled about its strengths, weaknesses, and impact. An important subset of the charter school sector is just now receiving a similar level of…

WMC Database Evaluation. Case Study Report

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

Palounek, Andrea P. T

The WMC Database is ultimately envisioned to hold a collection of experimental data, design information, and information from computational models. This project was a first attempt at using the Database to access experimental data and extract information from it. This evaluation shows that the Database concept is sound and robust, and that the Database, once fully populated, should remain eminently usable for future researchers.

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

Derrida, B.; Nadal, J.P.

It is possible to construct diluted asymmetric models of neural networks for which the dynamics can be calculated exactly. The authors test several learning schemes, in particular, models for which the values of the synapses remain bounded and depend on the history. Our analytical results on the relative efficiencies of the various learning schemes are qualitatively similar to the corresponding ones obtained numerically on fully connected symmetric networks.

Twitter for Teaching: Can Social Media Be Used to Enhance the Process of Learning?

ERIC Educational Resources Information Center

Evans, Chris

2014-01-01

Can social media be used to enhance the process of learning by students in higher education? Social media have become widely adopted by students in their personal lives. However, the application of social media to teaching and learning remains to be fully explored. In this study, the use of the social media tool Twitter for teaching was…

An Energy- and Charge-conserving, Implicit, Electrostatic Particle-in-Cell Algorithm in curvilinear geometry

NASA Astrophysics Data System (ADS)

Chen, G.; Chacón, L.; Barnes, D. C.

2012-03-01

A recent proof-of-principle study proposes an energy- and charge-conserving, fully implicit particle-in-cell algorithm in one dimension [1], which is able to use timesteps comparable to the dynamical timescale of interest. Here, we generalize the method to employ non-uniform meshes via a curvilinear map. The key enabling technology is a hybrid particle pusher [2], with particle positions updated in logical space and particle velocities updated in physical space. The self-adaptive, charge-conserving particle mover of Ref. [1] is extended to the non-uniform mesh case. The fully implicit implementation, using a Jacobian-free Newton-Krylov iterative solver, remains exactly charge- and energy-conserving. The extension of the formulation to multiple dimensions will be discussed. We present numerical experiments of 1D electrostatic, long-timescale ion-acoustic wave and ion-acoustic shock wave simulations, demonstrating that charge and energy are conserved to round-off for arbitrary mesh non-uniformity, and that the total momentum remains well conserved.[4pt] [1] Chen, Chac'on, Barnes, J. Comput. Phys. 230 (2011). [0pt] [2] Camporeale and Delzanno, Bull. Am. Phys. Soc. 56(6) (2011); Wang, et al., J. Plasma Physics, 61 (1999).

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes.

PubMed

Taruno, Akiyuki; Vingtdeux, Valérie; Ohmoto, Makoto; Ma, Zhongming; Dvoryanchikov, Gennady; Li, Ang; Adrien, Leslie; Zhao, Haitian; Leung, Sze; Abernethy, Maria; Koppel, Jeremy; Davies, Peter; Civan, Mortimer M; Chaudhari, Nirupa; Matsumoto, Ichiro; Hellekant, Göran; Tordoff, Michael G; Marambaud, Philippe; Foskett, J Kevin

2013-03-14

Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel, is indispensable for taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas their recognition of sour and salty tastes remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells by taste stimuli. Thus, CALHM1 is a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception.

Integrity of the Pericentriolar Material Is Essential for Maintaining Centriole Association during M Phase

PubMed Central

Rhee, Kunsoo

2015-01-01

A procentriole is assembled next to the mother centriole during S phase and remains associated until M phase. After functioning as a spindle pole during mitosis, the mother centriole and procentriole are separated at the end of mitosis. A close association of the centriole pair is regarded as an intrinsic block to the centriole reduplication. Therefore, deregulation of this process may cause a problem in the centriole number control, resulting in increased genomic instability. Despite its importance for faithful centriole duplication, the mechanism of centriole separation is not fully understood yet. Here, we report that centriole pairs are prematurely separated in cells whose cell cycle is arrested at M phase by STLC. Dispersal of the pericentriolar material (PCM) was accompanied. This phenomenon was independent of the separase activity but needed the PLK1 activity. Nocodazole effectively inhibited centriole scattering in STLC-treated cells, possibly by reducing the microtubule pulling force around centrosomes. Inhibition of PLK1 also reduced the premature separation of centrioles and the PCM dispersal as well. These results revealed the importance of PCM integrity in centriole association. Therefore, we propose that PCM disassembly is one of the driving forces for centriole separation during mitotic exit. PMID:26407333

Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

PubMed

Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

2012-08-01

Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Carbon elimination from silicon kerf: Thermogravimetric analysis and mechanistic considerations

NASA Astrophysics Data System (ADS)

Vazquez-Pufleau, Miguel; Chadha, Tandeep S.; Yablonsky, Gregory; Biswas, Pratim

2017-01-01

40% of ultrapure silicon is lost as kerf during slicing to produce wafers. Kerf is currently not being recycled due to engineering challenges and costs associated with removing its abundant impurities. Carbon left behind from the lubricant remains as one of the most difficult contaminants to remove in kerf without significant silicon oxidation. The present work enables to better understand the mechanism of carbon elimination in kerf which can aid the design of better processes for kef recycling and low cost photovoltaics. In this paper, we studied the kinetics of carbon elimination from silicon kerf in two atmospheres: air and N2, under a regime of no-diffusion-limitation. We report the apparent activation energy in both atmospheres using three methods: Kissinger, and two isoconversional approaches. In both atmospheres, a bimodal apparent activation energy is observed, suggesting a two stage process. A reaction mechanism is proposed in which (a) C-C and C-O bond cleavage reactions occur in parallel with polymer formation; (b) at higher temperatures, this polymer fully degrades in air but leaves a tarry residue in N2 that accounts for about 12% of the initial total carbon.

Brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning.

PubMed

Maier, Jonathan G; Piosczyk, Hannah; Holz, Johannes; Landmann, Nina; Deschler, Christoph; Frase, Lukas; Kuhn, Marion; Klöppel, Stefan; Spiegelhalder, Kai; Sterr, Annette; Riemann, Dieter; Feige, Bernd; Voderholzer, Ulrich; Nissen, Christoph

2017-11-01

Sleep modulates motor learning, but its detailed impact on performance curves remains to be fully characterized. This study aimed to further determine the impact of brief daytime periods of NREM sleep on 'offline' (task discontinuation after initial training) and 'on-task' (performance within the test session) changes in motor skill performance (finger tapping task). In a mixed design (combined parallel group and repeated measures) sleep laboratory study (n=17 'active' wake vs. sleep, n=19 'passive' wake vs. sleep), performance curves were assessed prior to and after a 90min period containing either sleep, active or passive wakefulness. We observed a highly significant, but state- (that is, sleep/wake)-independent early offline gain and improved on-task performance after sleep in comparison to wakefulness. Exploratory curve fitting suggested that the observed sleep effect most likely emerged from an interaction of training-induced improvement and detrimental 'time-on-task' processes, such as fatigue. Our results indicate that brief periods of NREM sleep do not promote early offline gains but subsequent on-task performance in motor skill learning. Copyright © 2017 Elsevier Inc. All rights reserved.

Two-photon induced collagen cross-linking in bioartificial cardiac tissue

NASA Astrophysics Data System (ADS)

Kuetemeyer, Kai; Kensah, George; Heidrich, Marko; Meyer, Heiko; Martin, Ulrich; Gruh, Ina; Heisterkamp, Alexander

2011-08-01

Cardiac tissue engineering is a promising strategy for regenerative therapies to overcome the shortage of donor organs for transplantation. Besides contractile function, the stiffness of tissue engineered constructs is crucial to generate transplantable tissue surrogates with sufficient mechanical stability to withstand the high pressure present in the heart. Although several collagen cross-linking techniques have proven to be efficient in stabilizing biomaterials, they cannot be applied to cardiac tissue engineering, as cell death occurs in the treated area. Here, we present a novel method using femtosecond (fs) laser pulses to increase the stiffness of collagen-based tissue constructs without impairing cell viability. Raster scanning of the fs laser beam over riboflavin-treated tissue induced collagen cross-linking by two-photon photosensitized singlet oxygen production. One day post-irradiation, stress-strain measurements revealed increased tissue stiffness by around 40% being dependent on the fibroblast content in the tissue. At the same time, cells remained viable and fully functional as demonstrated by fluorescence imaging of cardiomyocyte mitochondrial activity and preservation of active contraction force. Our results indicate that two-photon induced collagen cross-linking has great potential for studying and improving artificially engineered tissue for regenerative therapies.

Different activation of ACTH and corticosterone release in response to various stressors in rats.

PubMed

Djordjević, J; Cvijić, G; Davidović, V

2003-01-01

The aim of this study was to investigate the reaction of the hypothalamo-pituitary-adrenocortical (HPA) system to various stressors (fasting, crowding, cold and heat) by measuring blood ACTH and corticosterone (CORT) concentration as well as the cholesterol (CHOL) content in the adrenals. To examine the effects of stress termination, the rats were returned and kept under control conditions for the same period as that of stress duration (supposed recovery period). According to our results HPA system was activated by all the stressors applied. Heat seems to be the strongest stressor since the exposure of animals to a high ambient temperature resulted in the greatest rise of plasma ACTH concentration as well as CORT synthesis and secretion. These values remained elevated after the stress termination i.e. after the rats had been returned to room temperature. Fasting seems to be the weakest stressor given because it causes the smallest increase in blood ACTH and CORT concentrations. Moreover, in refed rats the HPA function was fully recovered. In conclusion, the various stressors applied seem to induce a different response of the HPA system as judged by quantitative changes in ACTH and CORT release.

Alterations of 86Rb+ fluxes in poliovirus-infected HeLa cells and their dependence on virus replication

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

Schaefer, A.; Geck, P.; Zibirre, R.

1984-07-30

Components of the 86Rb+ influx were investigated subsequent to poliovirus infection in the presence and absence of guanidine-HCl, both under normal steady-state conditions and after Na+ preloading of the cells. Measurements of the ouabain-sensitive 86Rb+ uptake indicated a biphasic change in the activity of the Na+, K+ pump in the course of virus infection: a transient increase in the second hour postinfection, that was detectable only after Na+ preloading and inhibition after 3 hr. The enhanced activity of the Na+, K+ pump was not affected, while the decrease later was fully prevented by the antiviral agent guanidine-HCl. The piretanide-sensitive 86Rb+more » uptake due to the Na+, K+, 2 Cl- cotransport system also became strongly inhibited beginning in the second hour postinfection. The inhibition of this transport system was partially antagonized by guanidine-HCl. The remaining 86Rb+ influx in the presence of ouabain and piretanide increased in the third hour postinfection. The latter change in 86Rb+ influx, indicating an increased permeability to monovalent cations was completely abolished by guanidine-HCl.« less

Carbon elimination from silicon kerf: Thermogravimetric analysis and mechanistic considerations

PubMed Central

Vazquez-Pufleau, Miguel; Chadha, Tandeep S.; Yablonsky, Gregory; Biswas, Pratim

2017-01-01

40% of ultrapure silicon is lost as kerf during slicing to produce wafers. Kerf is currently not being recycled due to engineering challenges and costs associated with removing its abundant impurities. Carbon left behind from the lubricant remains as one of the most difficult contaminants to remove in kerf without significant silicon oxidation. The present work enables to better understand the mechanism of carbon elimination in kerf which can aid the design of better processes for kef recycling and low cost photovoltaics. In this paper, we studied the kinetics of carbon elimination from silicon kerf in two atmospheres: air and N2, under a regime of no-diffusion-limitation. We report the apparent activation energy in both atmospheres using three methods: Kissinger, and two isoconversional approaches. In both atmospheres, a bimodal apparent activation energy is observed, suggesting a two stage process. A reaction mechanism is proposed in which (a) C-C and C-O bond cleavage reactions occur in parallel with polymer formation; (b) at higher temperatures, this polymer fully degrades in air but leaves a tarry residue in N2 that accounts for about 12% of the initial total carbon. PMID:28098187

Dramatic pressure-sensitive ion conduction in conical nanopores.

PubMed

Jubin, Laetitia; Poggioli, Anthony; Siria, Alessandro; Bocquet, Lydéric

2018-04-17

Ion transporters in Nature exhibit a wealth of complex transport properties such as voltage gating, activation, and mechanosensitive behavior. When combined, such processes result in advanced ionic machines achieving active ion transport, high selectivity, or signal processing. On the artificial side, there has been much recent progress in the design and study of transport in ionic channels, but mimicking the advanced functionalities of ion transporters remains as yet out of reach. A prerequisite is the development of ionic responses sensitive to external stimuli. In the present work, we report a counterintuitive and highly nonlinear coupling between electric and pressure-driven transport in a conical nanopore, manifesting as a strong pressure dependence of the ionic conductance. This result is at odds with standard linear response theory and is akin to a mechanical transistor functionality. We fully rationalize this behavior on the basis of the coupled electrohydrodynamics in the conical pore by extending the Poisson-Nernst-Planck-Stokes framework. The model is shown to capture the subtle mechanical balance occurring within an extended spatially charged zone in the nanopore. The pronounced sensitivity to mechanical forcing offers leads in tuning ion transport by mechanical stimuli. The results presented here provide a promising avenue for the design of tailored membrane functionalities.

Identifying obstacles to return to duty in severely injured combat-related servicemembers with amputation.

PubMed

Hurley, Richard K; Rivera, Jessica C; Wenke, Joseph C; Krueger, Chad A

2015-01-01

The capacity of servicemembers with amputation to return to duty after combat-related amputation and the associated disabilities remains largely unknown. The purpose of this study was to examine the disabling conditions and return to duty rates of servicemembers with amputation across all service branches following major limb amputations from September 2001 through July 2011. Pertinent medical information, military occupation status, return to duty designation, disabling conditions, and disability ratings for each servicemember were obtained from the Physical Evaluation Board Liaison Office (PEBLO). Across all service branches, 16 (2%) servicemembers were found fit for duty (Fit) and allowed to continue with their preinjury occupation. Another 103 (11%) were allowed to continue on Active Duty (COAD) in a less physically demanding role. More than half (554, 56%) were determined fully disabled (PEBLO rating > 75); the average disability rating was 73. COAD and Fit Army servicemembers had lower Injury Severity Scores than other servicemembers (17.4, p = 0.009 and 11.2, p < 0.001, respectively). Despite improvements in their care and rehabilitation, only 13% of all servicemembers with amputation are able to return to Active Duty and many have multiple disabling conditions that contribute to a very high level of disability.

Naviculocuneiform Coalition: Case Reports of Two Sibling Soccer Players.

PubMed

Saxena, Amol; Fournier, Magali

2016-01-01

Tarsal coalitions are an abnormal union between 2 tarsal bones. They occur most commonly between the calcaneus and talus or the calcaneus and navicular but can also arise from other joints in the foot. Isolated cases of coalitions between the medial cuneiform and navicular are extremely rare, and only a few cases have been reported. Treatment recommendations are, therefore, sparse, and no long-term follow-up data have been reported. We present the case of 2 sisters, each diagnosed with a symptomatic naviculocuneiform coalition. To our knowledge, this is the first reported case in 2 first-degree relatives. Both sisters were involved in sports and presented with pain during physical activities. After conservative treatment had failed, they were both treated successfully with surgical excision of the coalition and arthrodiastasis, followed by a progressive return to activities. At the last follow-up examination at 5 and 3 years postoperatively, they remained pain free and fully involved in college soccer, making excision of a naviculocuneiform coalition with arthrodiastasis a valid treatment in the young athletic population. Copyright © 2015 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Carbon elimination from silicon kerf: Thermogravimetric analysis and mechanistic considerations

DOE PAGES

Vazquez-Pufleau, Miguel; Chadha, Tandeep S.; Yablonsky, Gregory; ...

2017-01-18

40% of ultrapure silicon is lost as kerf during slicing to produce wafers. Currently, kerf is not recycled due to engineering challenges and costs associated with removing its abundant impurities. Carbon left behind from the lubricant remains as one of the most difficult contaminants to remove in kerf without significant silicon oxidation. The present work enables to better understand the mechanism of carbon elimination in kerf which can aid the design of better processes for kef recycling and low cost photovoltaics. In this paper, we studied the kinetics of carbon elimination from silicon kerf in two atmospheres: air and Nmore » 2, under a regime of no-diffusion-limitation. Here, we report the apparent activation energy in both atmospheres using three methods: Kissinger, and two isoconversional approaches. In both atmospheres, a bimodal apparent activation energy is observed, suggesting a two stage process. Furthermore, a reaction mechanism is proposed in which (a) C-C and C-O bond cleavage reactions occur in parallel with polymer formation; (b) at higher temperatures, this polymer fully degrades in air but leaves a tarry residue in N 2 that accounts for about 12% of the initial total carbon.« less

Physical exercise induces structural alterations in the hippocampal astrocytes: exploring the role of BDNF-TrkB signaling.

PubMed

Fahimi, Atoossa; Baktir, Mehmet Akif; Moghadam, Sarah; Mojabi, Fatemeh S; Sumanth, Krithika; McNerney, M Windy; Ponnusamy, Ravikumar; Salehi, Ahmad

2017-05-01

While it has been known that physical activity can improve cognitive function and protect against neurodegeneration, the underlying mechanisms for these protective effects are yet to be fully elucidated. There is a large body of evidence indicating that physical exercise improves neurogenesis and maintenance of neurons. Yet, its possible effects on glial cells remain poorly understood. Here, we tested whether physical exercise in mice alters the expression of trophic factor-related genes and the status of astrocytes in the dentate gyrus of the hippocampus. In addition to a significant increase in Bdnf mRNA and protein levels, we found that 4 weeks of treadmill and running wheel exercise in mice, led to (1) a significant increase in synaptic load in the dentate gyrus, (2) alterations in astrocytic morphology, and (3) orientation of astrocytic projections towards dentate granule cells. Importantly, these changes were possibly linked to increased TrkB receptor levels in astrocytes. Our study suggests that astrocytes actively respond and could indeed mediate the positive effects of physical exercise on the central nervous system and potentially counter degenerative processes during aging and neurodegenerative disorders.

On the Role of Interchange Reconnection in the Generation of the Slow Solar Wind

NASA Astrophysics Data System (ADS)

Edmondson, J. K.

2012-11-01

The heating of the solar corona and therefore the generation of the solar wind, remain an active area of solar and heliophysics research. Several decades of in situ solar wind plasma observations have revealed a rich bimodal solar wind structure, well correlated with coronal magnetic field activity. Therefore, the reconnection processes associated with the large-scale dynamics of the corona likely play a major role in the generation of the slow solar wind flow regime. In order to elucidate the relationship between reconnection-driven coronal magnetic field structure and dynamics and the generation of the slow solar wind, this paper reviews the observations and phenomenology of the solar wind and coronal magnetic field structure. The geometry and topology of nested flux systems, and the (interchange) reconnection process, in the context of coronal physics is then explained. Once these foundations are laid out, the paper summarizes several fully dynamic, 3D MHD calculations of the global coronal system. Finally, the results of these calculations justify a number of important implications and conclusions on the role of reconnection in the structural dynamics of the coronal magnetic field and the generation of the solar wind.

RETINOIC ACID SYNTHESIS AND DEGRADATION

PubMed Central

Kedishvili, Natalia Y.

2017-01-01

Retinoic acid was identified as the biologically active form of vitamin A almost 70 years ago, but the exact enzymes and control mechanisms that regulate its biosynthesis and degradation are yet to be fully defined. The currently accepted model postulates that RA is produced in two sequential oxidative steps: first, retinol is oxidized reversibly to retinaldehyde, and then retinaldehyde is oxidized irreversibly to RA, which is inactivated by conversion to hydroxylated derivatives. This chapter describes the history, development and recent advances in our understanding of the enzymatic pathways and mechanisms that control the rate of RA production and degradation. Gene knockout studies provided strong evidence that the members of the short chain dehydrogenase reductase superfamily of proteins play indispensable roles in retinoic acid biosynthesis during development. Furthermore, recent finding that two of these proteins regulate the rate of retinoic acid biosynthesis by mutually activating each other provided a novel insight into the mechanism of this regulation. Despite significant progress made since the middle of the 20th century many unanswered questions still remain, and there is much to be learned, especially about trafficking of the hydrophobic retinoid substrates between membrane bound and cytosolic enzymes and the roles of the retinoid binding proteins. PMID:27830503

Total daily activity measured with actigraphy and motor function in community-dwelling older persons with and without dementia.

PubMed

James, Bryan D; Boyle, Patricia A; Bennett, David A; Buchman, Aron S

2012-01-01

Actigraphic measures of physical activity do not rely on participants' self-report and may be of particular importance for examining the health benefits of physical activity across the full spectrum of older individuals, especially those with dementia, a group in which loss of motor function is particularly salient. We tested whether actigraphy could be used to examine the relationship between total daily physical activity and motor function in community-dwelling older persons both with (n = 70) and without (n = 624) clinical dementia. Total daily activity was measured using actigraphy for a median of 9 (range: 2-16) days. All participants also underwent a structured examination, including 9 muscle strength and 9 motor performance measures summarized as a composite measure. In linear regression models controlling for age, sex, and education, total daily activity was associated with global motor scores (β = 0.13, SD = 0.01, P < 0.001). This association remained significant after adjusting for body composition, cognition, depressive symptoms, disability, vascular risk factors, and diseases (β = 0.07, SD = 0.01, P < 0.001). The association did not vary by dementia status (interaction P = 0.53). In persons without dementia, the association was independent of self-reported physical activity. Total daily activity was associated with both muscle strength (β = 0.10, SD = 0.02, P < 0.001) and motor performance (β = 0.16, SD = 0.02, P < 0.001). Actigraphy can be used in the community setting to provide objective measures of total daily activity that are associated with a broad range of motor performances. These associations did not vary by dementia status. Actigraphy may provide a means to more fully explicate the nature and course of motor impairment in old age.

Total Daily Activity Measured With Actigraphy and Motor Function in Community-Dwelling Older Persons With and Without Dementia

PubMed Central

James, Bryan D.; Boyle, Patricia A.; Bennett, David A.; Buchman, Aron S.

2011-01-01

Actigraphic measures of physical activity do not rely on participant self-report and may be of particular importance for efforts to examine the health benefits of physical activity across the full spectrum of older individuals especially those with dementia, a group in which loss of motor function is particularly salient. We tested whether actigraphy could be employed to examine the relationship between total daily physical activity and motor function in community-dwelling older persons both with (n=70) and without clinical dementia (n=624). Total daily activity was measured with actigraphy for a median of 9 (range 2–16) days. All participants also underwent a structured examination including 9 muscle strength and 9 motor performance measures summarized as a composite measure. In linear regression models controlling for age, sex, and education, total daily activity was associated with global motor scores (β=0.13, SD=0.01, p<0.001). This association remained significant after adjusting for body composition, cognition, depressive symptoms, disability, vascular risk factors and diseases (β=0.07, SD=0.01, p < 0.001). The association did not vary by dementia status (interaction p=0.53). In persons without dementia, the association was independent of self-reported physical activity. Total daily activity was associated with both muscle strength (β=0.10, SD=0.02, p<0.001) and motor performance (β=0.16, SD=0.02, p<0.001). Actigraphy can be employed in the community-setting to provide objective measures of total daily activity that are associated with a broad range of motor performances and these associations did not vary by dementia status. Actigraphy may provide a means to more fully explicate the nature and course of motor impairment in old age. PMID:21946015

Understanding Which Residues of the Active Site and Loop Structure of a Tyrosine Aminomutase Define Its Mutase and Lyase Activities.

PubMed

Attanayake, Gayanthi; Walter, Tyler; Walker, Kevin D

2018-05-30

Site-directed mutations and substrate analogues were used to gain insights into the branch-point reaction of the 3,5-dihydro-5-methylidene-4 H-imidazol-4-one (MIO)-tyrosine aminomutase from Oryza sativa ( OsTAM). Exchanging the active residues of OsTAM (Y125C/N446K) for those in a phenylalanine aminomutase TcPAM altered its substrate specificity from tyrosine to phenylalanine. The aminomutase mechanism of OsTAM surprisingly changed almost exclusively to that of an ammonia lyase making cinnamic acid (>95%) over β-phenylalanine [Walter, T., et al. (2016) Biochemistry 55, 3497-3503]. We hypothesized that the missing electronics or sterics on the aryl ring of the phenylalanine substrate, compared with the sizable electron-donating hydroxyl of the natural tyrosine substrate, influenced the unexpected lyase reactivity of the OsTAM mutant. The double mutant was incubated with 16 α-phenylalanine substituent analogues of varying electronic strengths and sterics. The mutant converted each analogue principally to its acrylate with ∼50% conversion of the p-Br substrate, making only a small amount of the β-amino acid. The inner loop structure over the entrance to the active site was also mutated to assess how the lyase and mutase activities are affected. An OsTAM loop mutant, matching the loop residues of TcPAM, still chiefly made >95% of the acrylate from each substrate. A combined active site:loop mutant was most reactive but remained a lyase, making 10-fold more acrylates than other mutants did. While mutations within the active site changed the substrate specificity of OsTAM, continued exploration is needed to fully understand the interplay among the inner loop, the substrate, and the active site in defining the mutase and lyase activities.

Antioxidative activity of organic versus conventional milk

USDA-ARS?s Scientific Manuscript database

Some dairy proteins exhibit antioxidative activity, a property used for marketing foods as beneficial to American consumers. However, factors in milk production and processing that influence this activity are not fully understood. In this study, commercially available homogenized and pasteurized mi...

A density functional theory study on the active center of Fe-only hydrogenase: characterization and electronic structure of the redox states.

PubMed

Liu, Zhi-Pan; Hu, P

2002-05-08

We have carried out extensive density functional theory (DFT) calculations for possible redox states of the active center in Fe-only hydrogenases. The active center is modeled by [(H(CH(3))S)(CO)(CN(-))Fe(p)(mu-DTN)(mu-CO)Fe(d)(CO)(CN(-))(L)](z)() (z is the net charge in the complex; Fe(p)= the proximal Fe, Fe(d) = the distal Fe, DTN = (-SCH(2)NHCH(2)S-), L is the ligand that bonds with the Fe(d) at the trans position to the bridging CO). Structures of possible redox states are optimized, and CO stretching frequencies are calculated. By a detailed comparison of all the calculated structures and the vibrational frequencies with the available experimental data, we find that (i) the fully oxidized, inactive state is an Fe(II)-Fe(II) state with a hydroxyl (OH(-)) group bonded at the Fe(d), (ii) the oxidized, active state is an Fe(II)-Fe(I) complex which is consistent with the assignment of Cao and Hall (J. Am. Chem. Soc. 2001, 123, 3734), and (iii) the fully reduced state is a mixture with the major component being a protonated Fe(I)-Fe(I) complex and the other component being its self-arranged form, Fe(II)-Fe(II) hydride. Our calculations also show that the exogenous CO can strongly bond with the Fe(II)-Fe(I) species, but cannot bond with the Fe(I)-Fe(I) complex. This result is consistent with experiments that CO tends to inhibit the oxidized, active state, but not the fully reduced state. The electronic structures of all the redox states have been analyzed. It is found that a frontier orbital which is a mixing state between the e(g) of Fe and the 2 pi of the bridging CO plays a key role concerning the reactivity of Fe-only hydrogenases: (i) it is unoccupied in the fully oxidized, inactive state, half-occupied in the oxidized, active state, and fully occupied in the fully reduced state; (ii) the e(g)-2 pi orbital is a bonding state, and this is the key reason for stability of the low oxidation states, such as Fe(I)-Fe(I) complexes; and (iii) in the e(g)-2 pi orbital more charge accumulates between the bridging CO and the Fe(d) than between the bridging CO and the Fe(p), and the occupation increase in this orbital will enhance the bonding between the bridging CO and the Fe(d), leading to the bridging-CO shift toward the Fe(d).

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

PubMed

Gatch, Michael B; Dolan, Sean B; Forster, Michael J

2017-08-01

There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

Intricate but tight coupling of spiracular activity and abdominal ventilation during locust discontinuous gas exchange cycles.

PubMed

Talal, Stav; Gefen, Eran; Ayali, Amir

2018-03-15

Discontinuous gas exchange (DGE) is the best studied among insect gas exchange patterns. DGE cycles comprise three phases, which are defined by their spiracular state: closed, flutter and open. However, spiracle status has rarely been monitored directly; rather, it is often assumed based on CO 2 emission traces. In this study, we directly recorded electromyogram (EMG) signals from the closer muscle of the second thoracic spiracle and from abdominal ventilation muscles in a fully intact locust during DGE. Muscular activity was monitored simultaneously with CO 2 emission, under normoxia and under various experimental oxic conditions. Our findings indicate that locust DGE does not correspond well with the commonly described three-phase cycle. We describe unique DGE-related ventilation motor patterns, coupled to spiracular activity. During the open phase, when CO 2 emission rate is highest, the thoracic spiracles do not remain open; rather, they open and close rapidly. This fast spiracle activity coincides with in-phase abdominal ventilation, while alternating with the abdominal spiracle and thus facilitating a unidirectional air flow along the main trachea. A change in the frequency of rhythmic ventilation during the open phase suggests modulation by intra-tracheal CO 2 levels. A second, slow ventilatory movement pattern probably serves to facilitate gas diffusion during spiracle closure. Two flutter-like patterns are described in association with the different types of ventilatory activity. We offer a modified mechanistic model for DGE in actively ventilating insects, incorporating ventilatory behavior and changes in spiracle state. © 2018. Published by The Company of Biologists Ltd.

Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity.

PubMed

Jeong, Hyeon-Ju; Lee, Hye-Jin; Vuong, Tuan Anh; Choi, Kyu-Sil; Choi, Dahee; Koo, Sung-Hoi; Cho, Sung Chun; Cho, Hana; Kang, Jong-Sun

2016-07-01

Maintenance of skeletal muscle function is critical for metabolic health and the disruption of which exacerbates many chronic diseases such as obesity and diabetes. Skeletal muscle responds to exercise or metabolic demands by a fiber-type switch regulated by signaling-transcription networks that remains to be fully defined. Here, we report that protein arginine methyltransferase 7 (Prmt7) is a key regulator for skeletal muscle oxidative metabolism. Prmt7 is expressed at the highest levels in skeletal muscle and decreased in skeletal muscles with age or obesity. Prmt7(-/-) muscles exhibit decreased oxidative metabolism with decreased expression of genes involved in muscle oxidative metabolism, including PGC-1α. Consistently, Prmt7(-/-) mice exhibited significantly reduced endurance exercise capacities. Furthermore, Prmt7(-/-) mice exhibit decreased energy expenditure, which might contribute to the exacerbated age-related obesity of Prmt7(-/-) mice. Similarly to Prmt7(-/-) muscles, Prmt7 depletion in myoblasts also reduces PGC-1α expression and PGC-1α-promoter driven reporter activities. Prmt7 regulates PGC-1α expression through interaction with and activation of p38 mitogen-activated protein kinase (p38MAPK), which in turn activates ATF2, an upstream transcriptional activator for PGC-1α. Taken together, Prmt7 is a novel regulator for muscle oxidative metabolism via activation of p38MAPK/ATF2/PGC-1α. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Modelling the dynamo in fully convective M-stars

NASA Astrophysics Data System (ADS)

Yadav, Rakesh Kumar; Christensen, Ulrich; Morin, Julien; Wolk, Scott; Poppenhaeger, Katja; Reiners, Ansgar; gastine, Thomas

2017-05-01

M-stars are among the most active and numerous stars in our galaxy. Their activity plays a fundamentally important role in shaping the exoplanetary biosphere since the habitable zones are very close to these stars. Therefore, modeling M-star activity has become a focal point in habitability studies. The fully convective members of the M-star population demand more immediate attention due to the discovery of Earth-like exoplanets around our stellar neighbors Proxima Centauri and TRAPPIST-1 which are both fully convective. The activity of these stars is driven by their convective dynamo, which may be fundamentally different from the solar dynamo due the absence of radiative cores. We model this dynamo mechanism using high-resolution 3D anelastic MHD simulations. To understand the evolution of the dynamo mechanism we simulate two cases, one with a fast enough rotation period to model a star in the `saturated' regime of the rotation-activity realtionship and the other with a slower period to represent cases in the `unsaturated' regime. We find the rotation period fundamentally controls the behavior of the dynamo solution: faster rotation promotes strong magnetic fields (of order kG) on both small and large length scales and the dipolar component of the magnetic field is dominant and stable, however, slower rotation leads to weaker magnetic fields which exhibit cyclic behavior. In this talk, I will present the simulation results and discuss how we can use them to interpret several observed features of the M-star activity.

Inactive Gingipains from P. gingivalis Selectively Skews T Cells toward a Th17 Phenotype in an IL-6 Dependent Manner.

PubMed

Glowczyk, Izabela; Wong, Alicia; Potempa, Barbara; Babyak, Olena; Lech, Maciej; Lamont, Richard J; Potempa, Jan; Koziel, Joanna

2017-01-01

Gingipain cysteine proteases are considered key virulence factors of Porphyromonas gingivalis . They significantly influence antibacterial and homeostatic functions of macrophages, neutrophils, the complement system, and cytokine networks. Recent data indicate the role of P. gingivalis in T cell differentiation; however, the involvement of gingipains in this process remains elusive. Therefore, the aim of this study was to investigate the contribution of danger signals triggered by the gingipains on the generation of Th17 cells, which play a key role in protection against bacterial diseases but may cause chronic inflammation and bone resorption. To this end we compared the effects of the wild-type strain of P. gingivalis (W83) with its isogenic mutant devoid of gingipain activity (ΔKΔRAB), and bacterial cells pretreated with a highly-specific inhibitor of gingipains activity (KYTs). Antigen presenting cells (APCs), both professional (dendritic cells), and non-professional (gingival keratinocytes), exposed to viable bacteria expressed high amounts of cytokines (IL-6, IL-21, IL-23). These cytokines are reported to either stimulate or balance the Th17-dependent immune response. Surprisingly, cells infected with P. gingivalis devoid of gingipain activity showed increased levels of all tested cytokines compared to bacteria with fully active enzymes. The effect was dependent on both the reduction of cytokine proteolysis and the lack of cross-talk with other bacterial virulence factors, including LPS and fimbriae that induce de novo synthesis of cytokines. The profile of lymphocyte T differentiation from naive T cells showed enhanced generation of Th17 in response to bacteria with inactive gingipains. Moreover, we found that gingipain-dependent induction of Th17 cells was highly specific, since other T cell-subsets remained unchanged. Finally, inhibition of IL-6 signaling in dendritic cells led to a significant depletion of the Th17 population. Cumulatively, this study revealed a previously undisclosed role of gingipain activity in the process of Th17 differentiation reliant on blocking signaling through IL-6. Since inactivation of gingipains accelerates the skewing of T cells toward Th17 cells, which are detrimental in periodontitis, IL-6 signaling may serve as an attractive target for treatment of the disease.

Equipment for fully homologous bulb turbine model testing in Laval University

NASA Astrophysics Data System (ADS)

R, Fraser; D, Vallée; Y, Jean; C, Deschênes

2014-03-01

Within the context of liberalisation of the energy market, hydroelectricity remains a first class source of clean and renewable energy. Combining the growing demand of energy, its increasing value and the appreciation associated to the sustainable development, low head sites formerly considered as non-profitable are now exploitable. Bulb turbines likely to equip such sites are traditionally developed on model using right angle transmission leading to piers enlargement for power take off shaft passage, thus restricting possibilities to have fully homologous hydraulic passages. Aiming to sustain good quality development on fully homologous scale model of bulb turbines, the Hydraulic Machines Laboratory (LAMH) of Laval University has developed a brake with an enhanced power to weight ratio. This powerful brake is small enough to be located in the bulb shell while dissipating power without mandatory test head reduction. This paper first presents the basic technology of this brake and its application. Then both its main performance capabilities and dimensional characteristics will be detailed. The instrumentation used to perform accurate measurements will be finally presented.

On Flexible Tubes Conveying Fluid: Geometric Nonlinear Theory, Stability and Dynamics

NASA Astrophysics Data System (ADS)

Gay-Balmaz, François; Putkaradze, Vakhtang

2015-08-01

We derive a fully three-dimensional, geometrically exact theory for flexible tubes conveying fluid. The theory also incorporates the change of the cross section available to the fluid motion during the dynamics. Our approach is based on the symmetry-reduced, exact geometric description for elastic rods, coupled with the fluid transport and subject to the volume conservation constraint for the fluid. We first derive the equations of motion directly, by using an Euler-Poincaré variational principle. We then justify this derivation with a more general theory elucidating the interesting mathematical concepts appearing in this problem, such as partial left (elastic) and right (fluid) invariance of the system, with the added holonomic constraint (volume). We analyze the fully nonlinear behavior of the model when the axis of the tube remains straight. We then proceed to the linear stability analysis and show that our theory introduces important corrections to previously derived results, both in the consistency at all wavelength and in the effects arising from the dynamical change of the cross section. Finally, we derive and analyze several analytical, fully nonlinear solutions of traveling wave type in two dimensions.

Spatial distribution and expression of intracellular and extracellular acid phosphatases of cluster roots at different developmental stages in white lupin.

PubMed

Tang, Hongliang; Li, Xiaoqing; Zu, Chao; Zhang, Fusuo; Shen, Jianbo

2013-09-15

Acid phosphatases (APases) play a key role in phosphorus (P) acquisition and recycling in plants. White lupin (Lupinus albus L.) forms cluster roots (CRs) and produces large amounts of APases under P deficiency. However, the relationships between the activity of intracellular and extracellular APases (EC 3.1.3.2) and CR development are not fully understood. Here, comparative studies were conducted to examine the spatial variation pattern of APase activity during CR development using the enzyme-labelled fluorescence-97 (ELF-97) and the p-nitrophenyl phosphate methods. The activity of intracellular and extracellular APases was significantly enhanced under P deficiency in the non-CRs and CRs at different developmental stages. These two APases exhibited different spatial distribution patterns during CR development, and these distribution patterns were highly modified by P deficiency. The activity of extracellular APase increased steadily with CR development from meristematic, juvenile, mature to senescent stages under P deficiency. In comparison, P deficiency-induced increase in the activity of intracellular APase remained relatively constant during CR development. Increased activity of intracellular and extracellular APases was associated with enhanced expression of LaSAP1 encoding intracellular APase and LaSAP2 encoding extracellular APase. The expression levels of these two genes were significantly higher at transcriptional level in both mature and senescent CRs. Taken together, these findings demonstrate that both activity and gene expression of intracellular or extracellular APases exhibit a differential response pattern during CR development, depending on root types, CR developmental stages and P supply. Simultaneous in situ determination of intracellular and extracellular APase activity has proved to be an effective approach for studying spatial variation of APases during CR development. Copyright © 2013 Elsevier GmbH. All rights reserved.

Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells.

PubMed

Wang, Rui; Kozhaya, Lina; Mercer, Frances; Khaitan, Alka; Fujii, Hodaka; Unutmaz, Derya

2009-08-11

The molecules that define human regulatory T cells (Tregs) phenotypically and functionally remain to be fully characterized. We recently showed that activated human Tregs express mRNA for a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32). Here, using a GARP-specific mAb, we demonstrate that expression of GARP on activated Tregs correlates with their suppressive capacity. However, GARP was not induced on T cells activated in the presence of TGFbeta, which expressed high levels of FOXP3 and lacked suppressive function. Ectopic expression of FOXP3 in conventional T cells was also insufficient for induction of GARP expression in most donors. Functionally, silencing GARP in Tregs only moderately attenuated their suppressive activity. CD25+ T cells sorted for high GARP expression displayed more potent suppressive activity compared with CD25+GARP- cells. Remarkably, CD25+GARP- T cells expanded in culture contained 3-5 fold higher IL-17-secreting cells compared with either CD25+GARP+ or CD25-GARP- cells, suggesting that high GARP expression can potentially discriminate Tregs from those that have switched to Th17 lineage. We also determined whether GARP expression correlates with FOXP3-expressing T cells in human immunodeficiency virus (HIV) -infected subjects. A subset of HIV+ individuals with high percentages of FOXP3+ T cells did not show proportionate increase in GARP+ T cells. This finding suggests that higher FOXP3 levels observed in these HIV+ individuals is possibly due to immune activation rather than to an increase in Tregs. Our findings highlight the significance of GARP both in dissecting duality of Treg/Th17 cell differentiation and as a marker to identify bona fide Tregs during diseases with chronic immune activation.

Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells

PubMed Central

Wang, Rui; Kozhaya, Lina; Mercer, Frances; Khaitan, Alka; Fujii, Hodaka; Unutmaz, Derya

2009-01-01

The molecules that define human regulatory T cells (Tregs) phenotypically and functionally remain to be fully characterized. We recently showed that activated human Tregs express mRNA for a transmembrane protein called glycoprotein A repetitions predominant (GARP, or LRRC32). Here, using a GARP-specific mAb, we demonstrate that expression of GARP on activated Tregs correlates with their suppressive capacity. However, GARP was not induced on T cells activated in the presence of TGFβ, which expressed high levels of FOXP3 and lacked suppressive function. Ectopic expression of FOXP3 in conventional T cells was also insufficient for induction of GARP expression in most donors. Functionally, silencing GARP in Tregs only moderately attenuated their suppressive activity. CD25+ T cells sorted for high GARP expression displayed more potent suppressive activity compared with CD25+GARP− cells. Remarkably, CD25+GARP− T cells expanded in culture contained 3–5 fold higher IL-17-secreting cells compared with either CD25+GARP+ or CD25−GARP− cells, suggesting that high GARP expression can potentially discriminate Tregs from those that have switched to Th17 lineage. We also determined whether GARP expression correlates with FOXP3-expressing T cells in human immunodeficiency virus (HIV) −infected subjects. A subset of HIV+ individuals with high percentages of FOXP3+ T cells did not show proportionate increase in GARP+ T cells. This finding suggests that higher FOXP3 levels observed in these HIV+ individuals is possibly due to immune activation rather than to an increase in Tregs. Our findings highlight the significance of GARP both in dissecting duality of Treg/Th17 cell differentiation and as a marker to identify bona fide Tregs during diseases with chronic immune activation. PMID:19666573

Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation.

PubMed

Tanaka, Tomohiro; Zhou, Yue; Ozawa, Tatsuhiko; Okizono, Ryuya; Banba, Ayako; Yamamura, Tomohiro; Oga, Eiji; Muraguchi, Atsushi; Sakurai, Hiroaki

2018-02-16

The canonical description of transmembrane receptor function is initial binding of ligand, followed by initiation of intracellular signaling and then internalization en route to degradation or recycling to the cell surface. It is known that low concentrations of extracellular ligand lead to a higher proportion of receptor that is recycled and that non-canonical mechanisms of receptor activation, including phosphorylation by the kinase p38, can induce internalization and recycling. However, no connections have been made between these pathways; i.e. it has yet to be established what happens to unbound receptors following stimulation with ligand. Here we demonstrate that a minimal level of activation of epidermal growth factor receptor (EGFR) tyrosine kinase by low levels of ligand is sufficient to fully activate downstream mitogen-activated protein kinase (MAPK) pathways, with most of the remaining unbound EGFR molecules being efficiently phosphorylated at intracellular serine/threonine residues by activated mitogen-activated protein kinase. This non-canonical, p38-mediated phosphorylation of the C-tail of EGFR, near Ser-1015, induces the clathrin-mediated endocytosis of the unliganded EGFR monomers, which occurs slightly later than the canonical endocytosis of ligand-bound EGFR dimers via tyrosine autophosphorylation. EGFR endocytosed via the non-canonical pathway is largely recycled back to the plasma membrane as functional receptors, whereas p38-independent populations are mainly sorted for lysosomal degradation. Moreover, ligand concentrations balance these endocytic trafficking pathways. These results demonstrate that ligand-activated EGFR signaling controls unliganded receptors through feedback phosphorylation, identifying a dual-mode regulation of the endocytic trafficking dynamics of EGFR. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC.

PubMed

Alvarado, Diego; Ligon, Gwenda F; Lillquist, Jay S; Seibel, Scott B; Wallweber, Gerald; Neumeister, Veronique M; Rimm, David L; McMahon, Gerald; LaVallee, Theresa M

2017-01-01

Head and neck squamous cell carcinoma (HNSCC) accounts for 3-5% of all tumor types and remains an unmet medical need with only two targeted therapies approved to date. ErbB3 (HER3), the kinase-impaired member of the EGFR/ErbB family, has been implicated as a disease driver in a number of solid tumors, including a subset of HNSCC. Here we show that the molecular components required for ErbB3 activation, including its ligand neuregulin-1 (NRG1), are highly prevalent in HNSCC and that HER2, but not EGFR, is the major activating ErbB3 kinase partner. We demonstrate that cetuximab treatment primarily inhibits the ERK signaling pathway and KTN3379, an anti-ErbB3 monoclonal antibody, inhibits the AKT signaling pathway, and that dual ErbB receptor inhibition results in enhanced anti-tumor activity in HNSCC models. Surprisingly, we found that while NRG1 is required for ErbB3 activation, it was not sufficient to fully predict for KTN3379 activity. An evaluation of HNSCC patient samples demonstrated that NRG1 expression was significantly associated with expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα). Furthermore, NRG1-positive HNSCC cell lines that secreted high levels of AREG and TGFα or contained high levels of EGFR homodimers (H11D) demonstrated a better response to KTN3379. Although ErbB3 and EGFR activation are uncoupled at the receptor level, their respective signaling pathways are linked through co-expression of their respective ligands. We propose that NRG1 expression and EGFR activation signatures may enrich for improved efficacy of anti-ErbB3 therapeutic mAb approaches when combined with EGFR-targeting therapies in HNSCC.

Earth-moon system: Dynamics and parameter estimation

NASA Technical Reports Server (NTRS)

Breedlove, W. J., Jr.

1975-01-01

A theoretical development of the equations of motion governing the earth-moon system is presented. The earth and moon were treated as finite rigid bodies and a mutual potential was utilized. The sun and remaining planets were treated as particles. Relativistic, non-rigid, and dissipative effects were not included. The translational and rotational motion of the earth and moon were derived in a fully coupled set of equations. Euler parameters were used to model the rotational motions. The mathematical model is intended for use with data analysis software to estimate physical parameters of the earth-moon system using primarily LURE type data. Two program listings are included. Program ANEAMO computes the translational/rotational motion of the earth and moon from analytical solutions. Program RIGEM numerically integrates the fully coupled motions as described above.

Widespread mechanosensing controls the structure behind the architecture in plants.

PubMed

Hamant, Olivier

2013-10-01

Mechanical forces play an instructing role for many aspects of animal cell biology, such as division, polarity and fate. Although the associated mechanoperception pathways still remain largely elusive in plants, physical cues have long been thought to guide development in parallel to biochemical factors. With the development of new imaging techniques, micromechanics tools and modeling approaches, the role of mechanical signals in plant development is now re-examined and fully integrated with modern cell biology. Using recent examples from the literature, I propose to use a multiscale perspective, from the whole plant down to the cell wall, to fully appreciate the diversity of developmental processes that depend on mechanical signals. Incidentally, this also illustrates how conceptually rich this field is. Copyright © 2013 Elsevier Ltd. All rights reserved.

Using partial site aggregation to reduce bias in random utility travel cost models

NASA Astrophysics Data System (ADS)

Lupi, Frank; Feather, Peter M.

1998-12-01

We propose a "partial aggregation" strategy for defining the recreation sites that enter choice sets in random utility models. Under the proposal, the most popular sites and sites that will be the subject of policy analysis enter choice sets as individual sites while remaining sites are aggregated into groups of similar sites. The scheme balances the desire to include all potential substitute sites in the choice sets with practical data and modeling constraints. Unlike fully aggregate models, our analysis and empirical applications suggest that the partial aggregation approach reasonably approximates the results of a disaggregate model. The partial aggregation approach offers all of the data and computational advantages of models with aggregate sites but does not suffer from the same degree of bias as fully aggregate models.

A transition from using multi-step procedures to a fully integrated system for performing extracorporeal photopheresis: A comparison of costs and efficiencies.

PubMed

Azar, Nabih; Leblond, Veronique; Ouzegdouh, Maya; Button, Paul

2017-12-01

The Pitié Salpêtrière Hospital Hemobiotherapy Department, Paris, France, has been providing extracorporeal photopheresis (ECP) since November 2011, and started using the Therakos ® CELLEX ® fully integrated system in 2012. This report summarizes our single-center experience of transitioning from the use of multi-step ECP procedures to the fully integrated ECP system, considering the capacity and cost implications. The total number of ECP procedures performed 2011-2015 was derived from department records. The time taken to complete a single ECP treatment using a multi-step technique and the fully integrated system at our department was assessed. Resource costs (2014€) were obtained for materials and calculated for personnel time required. Time-driven activity-based costing methods were applied to provide a cost comparison. The number of ECP treatments per year increased from 225 (2012) to 727 (2015). The single multi-step procedure took 270 min compared to 120 min for the fully integrated system. The total calculated per-session cost of performing ECP using the multi-step procedure was greater than with the CELLEX ® system (€1,429.37 and €1,264.70 per treatment, respectively). For hospitals considering a transition from multi-step procedures to fully integrated methods for ECP where cost may be a barrier, time-driven activity-based costing should be utilized to gain a more comprehensive understanding the full benefit that such a transition offers. The example from our department confirmed that there were not just cost and time savings, but that the time efficiencies gained with CELLEX ® allow for more patient treatments per year. © 2017 The Authors Journal of Clinical Apheresis Published by Wiley Periodicals, Inc.

Motivating patients to exercise: translating high blood pressure into equivalent risk of inactivity.

PubMed

Li, Chu-Shiu; Liu, Chwen-Chi; Tsai, Min-Kuang; Tai, Ya-Ping; Wai, Jackson Pui Man; Tsao, Chwen-Keng; Wen, Chi-Pang

2015-02-01

Even with the 2008 physical activity guidelines for Americans and the strong epidemiological evidence, physicians are not routinely emphasizing the importance of exercise. We try to explore an innovative way to communicate the benefits of physical activity in a term familiar to patients. A cohort of 470, 163 adults from a medical screening program in Taiwan were recruited between 1994 and 2008. Their vital status was followed up by matching with the National Death File. Individuals were classified as 'inactive', 'low active', or 'fully active', with 'fully active' meeting the current exercise recommendation of 150  min per week or more. Cox proportional model was used to calculate the hazard ratio. More than one-half of the cohort was inactive (54%), with one-quarter fully active (24%). One in seven was hypertensive (14%), defined as SBP at least 140  mmHg. Among the hypertensive individuals, mortality risks were increased by 37% for the inactive. Inactive individuals had higher all-cause mortality than active ones across all blood pressure (BP) levels. At 110-119  mmHg, the inactive had a risk as high as the risk at 155  mmHg, an increased mortality risk equivalent to a risk of BP increase of 41.2 mmHg. The mortality risk of being inactive was equivalent to an increase of around 40  mmHg in SBP or 20  mmHg in DBP, a number relevant to hypertensive patients. Appreciating this relationship may convince the inactive to start exercising, a behavior as important as controlling BP.

p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis

PubMed Central

Napoletano, Francesco; Vincent, Stéphane; Favrot, Clémentine; Mehlen, Patrick; Girard, Victor; Chatelain, Gilles; Walter, Ludivine; Arama, Eli

2017-01-01

The importance of regulated necrosis in pathologies such as cerebral stroke and myocardial infarction is now fully recognized. However, the physiological relevance of regulated necrosis remains unclear. Here, we report a conserved role for p53 in regulating necrosis in Drosophila and mammalian spermatogenesis. We found that Drosophila p53 is required for the programmed necrosis that occurs spontaneously in mitotic germ cells during spermatogenesis. This form of necrosis involved an atypical function of the initiator caspase Dronc/Caspase 9, independent of its catalytic activity. Prevention of p53-dependent necrosis resulted in testicular hyperplasia, which was reversed by restoring necrosis in spermatogonia. In mouse testes, p53 was required for heat-induced germ cell necrosis, indicating that regulation of necrosis is a primordial function of p53 conserved from invertebrates to vertebrates. Drosophila and mouse spermatogenesis will thus be useful models to identify inducers of necrosis to treat cancers that are refractory to apoptosis. PMID:28945745

Calibration of low-cost gas sensors for an urban air quality monitoring network

NASA Astrophysics Data System (ADS)

Scott, A.; Kelley, C.; He, C.; Ghugare, P.; Lehman, A.; Benish, S.; Stratton, P.; Dickerson, R. R.; Zuidema, C.; Azdoud, Y.; Ren, X.

2017-12-01

In a warming world, environmental pollution may be exacerbated by anthropogenic activities, such as climate change and the urban heat island effect, as well as natural phenomena such as heat waves. However, monitoring air pollution at federal reference standards (approximately 1 part per billion or ppb for ambient ozone) is cost-prohibitive in heterogeneous urban areas as many expensive devices are required to fully capture a region's geo-spatial variability. Innovation in low-cost sensors provide a potential solution, yet technical challenges remain to overcome possible imprecision in the data. We present the calibrations of ozone and nitrous dioxide from a low-cost air quality monitoring device designed for the Baltimore Open Air Project. The sensors used in this study are commercially available thin film electrochemical sensors from SPEC Sensor, which are amperometric, meaning they generate current proportional to volumetric fraction of gas. The results of sensor calibrations in the laboratory and field are presented.

Nitrous oxide emissions from wastewater treatment processes

PubMed Central

Law, Yingyu; Ye, Liu; Pan, Yuting; Yuan, Zhiguo

2012-01-01

Nitrous oxide (N2O) emissions from wastewater treatment plants vary substantially between plants, ranging from negligible to substantial (a few per cent of the total nitrogen load), probably because of different designs and operational conditions. In general, plants that achieve high levels of nitrogen removal emit less N2O, indicating that no compromise is required between high water quality and lower N2O emissions. N2O emissions primarily occur in aerated zones/compartments/periods owing to active stripping, and ammonia-oxidizing bacteria, rather than heterotrophic denitrifiers, are the main contributors. However, the detailed mechanisms remain to be fully elucidated, despite strong evidence suggesting that both nitrifier denitrification and the chemical breakdown of intermediates of hydroxylamine oxidation are probably involved. With increased understanding of the fundamental reactions responsible for N2O production in wastewater treatment systems and the conditions that stimulate their occurrence, reduction of N2O emissions from wastewater treatment systems through improved plant design and operation will be achieved in the near future. PMID:22451112

Emergent dynamics of spatio-temporal chaos in a heterogeneous excitable medium.

PubMed

Bittihn, Philip; Berg, Sebastian; Parlitz, Ulrich; Luther, Stefan

2017-09-01

Self-organized activation patterns in excitable media such as spiral waves and spatio-temporal chaos underlie dangerous cardiac arrhythmias. While the interaction of single spiral waves with different types of heterogeneity has been studied extensively, the effect of heterogeneity on fully developed spatio-temporal chaos remains poorly understood. We investigate how the complexity and stability properties of spatio-temporal chaos in the Bär-Eiswirth model of excitable media depend on the heterogeneity of the underlying medium. We employ different measures characterizing the chaoticity of the system and find that the spatial arrangement of multiple discrete lower excitability regions has a strong impact on the complexity of the dynamics. Varying the number, shape, and spatial arrangement of the heterogeneities, we observe strong emergent effects ranging from increases in chaoticity to the complete cessation of chaos, contrasting the expectation from the homogeneous behavior. The implications of our findings for the development and treatment of arrhythmias in the heterogeneous cardiac muscle are discussed.

Reducing Obesity Among People With Disabilities

PubMed Central

Fox, Michael H.; Witten, Mary Helen; Lullo, Carolyn

2015-01-01

Achieving healthy weight for people with disabilities in the United States is a challenge. Obesity rates for adults and children with disabilities are significantly higher than for those without disabilities, with differences remaining even when controlling for other factors. Reasons for this disparity include lack of healthy food options for many people with disabilities living in restrictive environments, difficulty with chewing or swallowing food, medication use contributing to changes in appetite, physical limitations that can reduce a person’s ability to exercise, constant pain, energy imbalance, lack of accessible environments in which to exercise or fully participate in other activities, and resource scarcity among many segments of the disability population. In order for there to be a coordinated national effort to address this issue, a framework needs to be developed from which research, policy, and practice can emerge. This paper reviews existing literature and presents a conceptual model that can be used to inform such a framework, provides examples of promising practices, and discusses challenges and opportunities moving forward. PMID:26113785

Emergent dynamics of spatio-temporal chaos in a heterogeneous excitable medium

NASA Astrophysics Data System (ADS)

Bittihn, Philip; Berg, Sebastian; Parlitz, Ulrich; Luther, Stefan

2017-09-01

Self-organized activation patterns in excitable media such as spiral waves and spatio-temporal chaos underlie dangerous cardiac arrhythmias. While the interaction of single spiral waves with different types of heterogeneity has been studied extensively, the effect of heterogeneity on fully developed spatio-temporal chaos remains poorly understood. We investigate how the complexity and stability properties of spatio-temporal chaos in the Bär-Eiswirth model of excitable media depend on the heterogeneity of the underlying medium. We employ different measures characterizing the chaoticity of the system and find that the spatial arrangement of multiple discrete lower excitability regions has a strong impact on the complexity of the dynamics. Varying the number, shape, and spatial arrangement of the heterogeneities, we observe strong emergent effects ranging from increases in chaoticity to the complete cessation of chaos, contrasting the expectation from the homogeneous behavior. The implications of our findings for the development and treatment of arrhythmias in the heterogeneous cardiac muscle are discussed.

Domain architecture and oligomerization properties of the paramyxovirus PIV 5 hemagglutinin-neuraminidase (HN) protein

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

Yuan Ping; Leser, George P.; Demeler, Borries

2008-09-01

The mechanism by which the paramyxovirus hemagglutinin-neuraminidase (HN) protein couples receptor binding to activation of virus entry remains to be fully understood, but the HN stalk is thought to play an important role in the process. We have characterized ectodomain constructs of the parainfluenza virus 5 HN to understand better the underlying architecture and oligomerization properties that may influence HN functions. The PIV 5 neuraminidase (NA) domain is monomeric whereas the ectodomain forms a well-defined tetramer. The HN stalk also forms tetramers and higher order oligomers with high {alpha}-helical content. Together, the data indicate that the globular NA domains formmore » weak intersubunit interactions at the end of the HN stalk tetramer, while stabilizing the stalk and overall oligomeric state of the ectodomain. Electron microscopy of the HN ectodomain reveals flexible arrangements of the NA and stalk domains, which may be important for understanding how these two HN domains impact virus entry.« less

Putting a finishing touch on GECIs.

PubMed

Rose, Tobias; Goltstein, Pieter M; Portugues, Ruben; Griesbeck, Oliver

2014-01-01

More than a decade ago genetically encoded calcium indicators (GECIs) entered the stage as new promising tools to image calcium dynamics and neuronal activity in living tissues and designated cell types in vivo. From a variety of initial designs two have emerged as promising prototypes for further optimization: FRET (Förster Resonance Energy Transfer)-based sensors and single fluorophore sensors of the GCaMP family. Recent efforts in structural analysis, engineering and screening have broken important performance thresholds in the latest generation for both classes. While these improvements have made GECIs a powerful means to perform physiology in living animals, a number of other aspects of sensor function deserve attention. These aspects include indicator linearity, toxicity and slow response kinetics. Furthermore creating high performance sensors with optically more favorable emission in red or infrared wavelengths as well as new stably or conditionally GECI-expressing animal lines are on the wish list. When the remaining issues are solved, imaging of GECIs will finally have crossed the last milestone, evolving from an initial promise into a fully matured technology.

Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions.

PubMed

Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L; Chen, Siyu S; Ng, Amy; Xu, Yong; Morozov, Alexei; Fukuda, Makoto

2016-09-13

The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Variation in Extrafloral Nectary Productivity Influences the Ant Foraging

PubMed Central

2017-01-01

Extrafloral nectar is the main food source offered by plants to predatory ants in most land environments. Although many studies have demonstrated the importance of extrafloral nectaries (EFNs) to plant defense against herbivores, the influence of EFNs secretory activity pattern on predatory ants remains yet not fully understood. Here, we verified the relation between the extrafloral nectar production of a plant community in Cerrado in different times of the day, and its attractiveness to ants. The extrafloral nectaries (EFNs) of seven plant species showed higher productivity overnight. Ant abundance was higher in times of large extrafloral nectar production, however, there was no positive relation between ant richness on plants and EFNs productivity. There was temporal resource partitioning among ant species, and it indicates strong resource competition. The nectar productivity varied among plant species and time of the day, and it influenced the visitation patterns of ants. Therefore, EFNs are a key ant-plant interaction driver in the studied system. PMID:28046069

Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta.

PubMed Central

Bossaller, C; Habib, G B; Yamamoto, H; Williams, C; Wells, S; Henry, P D

1987-01-01

The dependence of vascular relaxation on an intact endothelium and the relationship between relaxation and cyclic GMP accumulation were determined in coronary arteries isolated from cardiac transplantation patients with or without coronary atherosclerosis. In nonatherosclerotic arteries, the endothelium-dependent agent acetylcholine produced concentration-related relaxations. In atherosclerotic arteries, endothelium-dependent relaxations were abolished with acetylcholine, partly suppressed with substance P and histamine, and completely preserved with the ionophore A23187. In these arteries, the endothelium-independent agent nitroglycerin remained fully active. Accumulation of cyclic GMP in atherosclerotic strips was suppressed with acetylcholine but unattenuated with A23187 and nitroglycerin. In aortas from rabbits with diet-induced atherosclerosis, there was likewise an impaired cholinergic relaxation and cyclic GMP accumulation in the presence of preserved responses to A23187 and nitroglycerin. The results demonstrate that impaired cholinergic responses in atherosclerotic arteries reflect a muscarinic defect and not an inability of endothelium to release endothelial factor or smooth muscle to respond to it. PMID:2432088

Fully Synthetic Granulocyte Colony-Stimulating Factor Enabled by Isonitrile-Mediated Coupling of Large, Side-Chain-Unprotected Peptides

PubMed Central

Roberts, Andrew G.; Johnston, Eric V.; Shieh, Jae-Hung; Sondey, Joseph P.; Hendrickson, Ronald C.; Moore, Malcolm A. S.; Danishefsky, Samuel J.

2015-01-01

Human granulocyte colony-stimulating factor (G-CSF) is an endogenous glycoprotein involved in hematopoiesis. Natively glycosylated and nonglycosylated recombinant forms, lenograstim and filgrastim, respectively, are used clinically to manage neutropenia in patients undergoing chemotherapeutic treatment. Despite their comparable therapeutic potential, the purpose of O-linked glycosylation at Thr133 remains a subject of controversy. In light of this, we have developed a synthetic platform to prepare G-CSF aglycone with the goal of enabling access to native and designed glycoforms with site-selectivity and glycan homogeneity. To address the synthesis of a relatively large, aggregation-prone sequence, we advanced an isonitrile-mediated ligation method. The chemoselective activation and coupling of C-terminal peptidyl Gly thioacids with the N-terminus of an unprotected peptide provide ligated peptides directly in a manner complementary to that with conventional native chemical ligation–desulfurization strategies. Herein, we describe the details and application of this method as it enabled the convergent total synthesis of G-CSF aglycone. PMID:26401918

Review on fate and mechanism of removal of pharmaceutical pollutants from wastewater using biological approach.

PubMed

Tiwari, Bhagyashree; Sellamuthu, Balasubramanian; Ouarda, Yassine; Drogui, Patrick; Tyagi, Rajeshwar D; Buelna, Gerardo

2017-01-01

Due to research advancement and discoveries in the field of medical science, maintains and provides better human health and safer life, which lead to high demand for production of pharmaceutical compounds with a concomitant increase in population. These pharmaceutical (biologically active) compounds were not fully metabolized by the body and excreted out in wastewater. This micro-pollutant remains unchanged during wastewater treatment plant operation and enters into the receiving environment via the discharge of treated water. Persistence of pharmaceutical compounds in both surface and ground waters becomes a major concern due to their potential eco-toxicity. Pharmaceuticals (emerging micro-pollutants) deteriorate the water quality and impart a toxic effect on living organisms. Therefore, from last two decades, plenty of studies were conducted on the occurrence, impact, and removal of pharmaceutical residues from the environment. This review provides an overview on the fate and removal of pharmaceutical compounds via biological treatment process. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structural Studies of the Parainfluenza Virus 5 Hemagglutinin-Neuraminidase Tetramer in Complex with Its Receptor, Sialyllactose

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

Yuan, Ping; Thompson, Thomas B.; Wurzburg, Beth A.

2010-03-08

The paramyxovirus hemagglutinin-neuraminidase (HN) functions in virus attachment to cells, cleavage of sialic acid from oligosaccharides, and stimulating membrane fusion during virus entry into cells. The structural basis for these diverse functions remains to be fully understood. We report the crystal structures of the parainfluenza virus 5 (SV5) HN and its complexes with sialic acid, the inhibitor DANA, and the receptor sialyllactose. SV5 HN shares common structural features with HN of Newcastle disease virus (NDV) and human parainfluenza 3 (HPIV3), but unlike the previously determined HN structures, the SV5 HN forms a tetramer in solution, which is thought to bemore » the physiological oligomer. The sialyllactose complex reveals intact receptor within the active site, but no major conformational changes in the protein. The SV5 HN structures do not support previously proposed models for HN action in membrane fusion and suggest alternative mechanisms by which HN may promote virus entry into cells.« less

Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

NASA Astrophysics Data System (ADS)

Kugel, Susann; Baunach, Martin; Baer, Philipp; Ishida-Ito, Mie; Sundaram, Srividhya; Xu, Zhongli; Groll, Michael; Hertweck, Christian

2017-06-01

Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.

Mediator-regulated transcription through the +1 nucleosome.

PubMed

Nock, Adam; Ascano, Janice M; Barrero, Maria J; Malik, Sohail

2012-12-28

Many genes are regulated at the level of a Pol II that is recruited to a nucleosome-free region upstream of the +1 nucleosome. How the Mediator coactivator complex, which functions at multiple steps, affects transcription through the promoter proximal region, including this nucleosome, remains largely unaddressed. We have established a fully defined in vitro assay system to delineate mechanisms for Pol II transit across the +1 nucleosome. Our results reveal cooperative functions of multiple cofactors, particularly of Mediator and elongation factor SII, in transcribing into this nucleosome. This is achieved, in part, through an unusual activity of SII that alters the intrinsic catalytic properties of promoter-proximal Pol II and, in concert with the Mediator, leads to enhancement in transcription of nucleosomal DNA. Our data provide additional mechanistic bases for Mediator function after recruitment of Pol II and, potentially, for regulation of genes controlled via nucleosome-mediated promoter-proximal pausing. Copyright © 2012 Elsevier Inc. All rights reserved.

Biocatalytic Synthesis of the Rare Sugar Kojibiose: Process Scale-Up and Application Testing.

PubMed

Beerens, Koen; De Winter, Karel; Van de Walle, Davy; Grootaert, Charlotte; Kamiloglu, Senem; Miclotte, Lisa; Van de Wiele, Tom; Van Camp, John; Dewettinck, Koen; Desmet, Tom

2017-07-26

Cost-efficient (bio)chemical production processes are essential to evaluate the commercial and industrial applications of promising carbohydrates and also are essential to ensure economically viable production processes. Here, the synthesis of the naturally occurring disaccharide kojibiose (2-O-α-d-glucopyranosyl-d-glucopyranoside) was evaluated using different Bifidobacterium adolescentis sucrose phosphorylase variants. Variant L341I_Q345S was found to efficiently synthesize kojibiose while remaining fully active after 1 week of incubation at 55 °C. Process optimization allowed kojibiose production at the kilogram scale, and simple but efficient downstream processing, using a yeast treatment and crystallization, resulted in more than 3 kg of highly pure crystalline kojibiose (99.8%). These amounts allowed a deeper characterization of its potential in food applications. It was found to have possible beneficial health effects, including delayed glucose release and potential to trigger SCFA production. Finally, we compared the bulk functionality of highly pure kojibiose to that of sucrose, hereby mapping its potential as a new sweetener in confectionery products.

Thermally stable, highly efficient, ultraflexible organic photovoltaics

PubMed Central

Xu, Xiaomin; Fukuda, Kenjiro; Karki, Akchheta; Park, Sungjun; Kimura, Hiroki; Jinno, Hiroaki; Watanabe, Nobuhiro; Yamamoto, Shuhei; Shimomura, Satoru; Kitazawa, Daisuke; Yokota, Tomoyuki; Umezu, Shinjiro; Nguyen, Thuc-Quyen; Someya, Takao

2018-01-01

Flexible photovoltaics with extreme mechanical compliance present appealing possibilities to power Internet of Things (IoT) sensors and wearable electronic devices. Although improvement in thermal stability is essential, simultaneous achievement of high power conversion efficiency (PCE) and thermal stability in flexible organic photovoltaics (OPVs) remains challenging due to the difficulties in maintaining an optimal microstructure of the active layer under thermal stress. The insufficient thermal capability of a plastic substrate and the environmental influences cannot be fully expelled by ultrathin barrier coatings. Here, we have successfully fabricated ultraflexible OPVs with initial efficiencies of up to 10% that can endure temperatures of over 100 °C, maintaining 80% of the initial efficiency under accelerated testing conditions for over 500 hours in air. Particularly, we introduce a low-bandgap poly(benzodithiophene-cothieno[3,4-b]thiophene) (PBDTTT) donor polymer that forms a sturdy microstructure when blended with a fullerene acceptor. We demonstrate a feasible way to adhere ultraflexible OPVs onto textiles through a hot-melt process without causing severe performance degradation. PMID:29666257

Development of whole sporozoite malaria vaccines.

PubMed

Hollingdale, Michael R; Sedegah, Martha

2017-01-01

Despite recent advances, malaria remains a major health threat both to populations in endemic areas as well travelers, including military personnel, to these areas. Subunit vaccines have not yet achieved sufficient efficacy needed for use in any of these at risk populations. Areas covered: This review discusses the current status of various whole sporozoite vaccine approaches and is mainly focused on current clinical trials. Expert commentary: Nearly 100% efficacy was achieved by administering multiple bites of radiation-attenuated sporozoite (RAS) Plasmodium falciparum-infected mosquitoes; this is impractical for widespread use. Now, this high level efficacy has been reproduced using purified, metabolically active RAS (PfSPZ Sanaria® Vaccine), which is undergoing extensive clinical testing. Alternative whole sporozoite vaccines include immunization with fully infectious sporozoites under chloroquine prophylaxis (CPS) or as genetically-attenuated parasites (GAP). By also manufacturing purified infectious sporozoites, it is now possible to combine these with CPS and GAP, as well as perform challenge studies using controlled doses of sporozoites.

Interaction of a Model Peptide with a Water--Bilayer System

NASA Technical Reports Server (NTRS)

Pohorille, A.; Wilson, M. A.

1994-01-01

We discuss a molecular dynamics study of the alanine dipeptide at the interface between water and a glycerol-1-monooleate (GMO) bilayer. The dipeptide is interfacially active and incorporates into the bilayer without disrupting its structure. The interfacial region that is readily penetrated by the dipeptide spans the entire head group portion of the bilayer. The polar groups of the alanine dipeptide mostly remain well solvated by water and the oxygen atoms of GMO, and conformations of the dipeptide are characterized by (phi, psi) angles typical of alpha-helix and beta-sheet structures. When the molecule is deeper in the bilayer, the C(sub 7eq) state also becomes stable. The barrier to the isomerization reaction at the interface is lower than in bulk phases. After 7 ns of trajectories, the system is not fully equilibrated, due to slow collective motions involving GMO head groups. These result in decreased mobility and lower rates of isomerization of the dipeptide at the interface.

Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps

PubMed Central

Zegkos, Thomas; Kitas, George; Dimitroulas, Theodoros

2016-01-01

Rheumatoid arthritis (RA) is associated with increased cardiovascular (CV) morbidity and mortality which cannot be fully explained by traditional CV risk factors; cumulative inflammatory burden and antirheumatic medication-related cardiotoxicity seem to be important contributors. Despite the acknowledgment and appreciation of CV disease burden in RA, optimal management of individuals with RA represents a challenging task which remains suboptimal. To address this need, the European League Against Rheumatism (EULAR) published recommendations suggesting the adaptation of traditional risk scores by using a multiplication factor of 1.5 if two of three specific criteria are fulfilled. Such guidance requires proper coordination of several medical specialties, including general practitioners, rheumatologists, cardiologists, exercise physiologists and psychologists to achieve a desirable result. Tight control of disease activity, management of traditional risk factors and lifestyle modification represent, amongst others, the most important steps in improving CV disease outcomes in RA patients. Rather than enumerating studies and guidelines, this review attempts to critically appraise current literature, highlighting future perspectives of CV risk management in RA. PMID:27247635

Mental Spatial Transformations in 14-and 16-Month-Old Infants: Effects of Action and Observational Experience

ERIC Educational Resources Information Center

Frick, Andrea; Wang, Su-hua

2014-01-01

Infants' ability to mentally track the orientation of an object during a hidden rotation was investigated (N = 28 in each experiment). A toy on a turntable was fully covered and then rotated 90°. When revealed, the toy had turned with the turntable (probable event), remained at its starting orientation (improbable event in Experiment 1), or…

Toward an Integrated Theory of Relational Youth Violence: Bridging a Gap among the Theory, Research, and Practice of Bullying Prevention

ERIC Educational Resources Information Center

Brion-Meisels, Gretchen; Garnett, Bernice Raveche

2016-01-01

Despite an increased interest in bullying prevention programming over the last 10 years, significant gaps remain among theory, research, and practice in this critical area of school psychology. This article argues that the current Centers for Disease Control and Prevention (CDC) definition of bullying does not fully capture the experiences of many…

Analysis of Cell Biomechanics Response to Gravity:A Fluids for Biology Study Utilizing NASA Glenns Zero Gravity Research Facility

NASA Technical Reports Server (NTRS)

Bomani, Bilal M. M.; Kassemi, Mohammad; Neumann, Eric S.

2016-01-01

It remains unclear how biological cells sense and respond to gravitational forces. Leading scientists state that a large gap exists in the understanding of physiological and molecular adaptation that occurs as biology enters the spaceflight realm. We are seeking a method to fully understand how cells sense microgravity/gravity and what triggers their response.

Family Reintegration Following Guard Deployment

DTIC Science & Technology

2010-09-20

P15 before they reach a crisis, or divorce is imminent. Many participants in this study were not fully aware of the resources that the Family...accommodations made by the wives during separation. Wartime Separation and Marital Adversity Historical records indicate an increase in divorce ...before separation remains unclear, with several researchers finding the men with less satisfying marriages were the ones more likely to divorce (Pavalko

Project WET Curriculum and Activity Guide 2.0

ERIC Educational Resources Information Center

Project WET Foundation, 2011

2011-01-01

The "Project WET Curriculum and Activity Guide 2.0" continues Project WET's dedication to 21st-century, cutting-edge water education. Now in full color, Guide 2.0 offers new activities on topics such as National Parks and storm water, fully revised and updated activities from the original Guide and the very best activities gathered from all of…

Fully automated MR liver volumetry using watershed segmentation coupled with active contouring.

PubMed

Huynh, Hieu Trung; Le-Trong, Ngoc; Bao, Pham The; Oto, Aytek; Suzuki, Kenji

2017-02-01

Our purpose is to develop a fully automated scheme for liver volume measurement in abdominal MR images, without requiring any user input or interaction. The proposed scheme is fully automatic for liver volumetry from 3D abdominal MR images, and it consists of three main stages: preprocessing, rough liver shape generation, and liver extraction. The preprocessing stage reduced noise and enhanced the liver boundaries in 3D abdominal MR images. The rough liver shape was revealed fully automatically by using the watershed segmentation, thresholding transform, morphological operations, and statistical properties of the liver. An active contour model was applied to refine the rough liver shape to precisely obtain the liver boundaries. The liver volumes calculated by the proposed scheme were compared to the "gold standard" references which were estimated by an expert abdominal radiologist. The liver volumes computed by using our developed scheme excellently agreed (Intra-class correlation coefficient was 0.94) with the "gold standard" manual volumes by the radiologist in the evaluation with 27 cases from multiple medical centers. The running time was 8.4 min per case on average. We developed a fully automated liver volumetry scheme in MR, which does not require any interaction by users. It was evaluated with cases from multiple medical centers. The liver volumetry performance of our developed system was comparable to that of the gold standard manual volumetry, and it saved radiologists' time for manual liver volumetry of 24.7 min per case.

Mechanosensory organ regeneration in zebrafish depends on a population of multipotent progenitor cells kept latent by Schwann cells.

PubMed

Sánchez, Mario; Ceci, Maria Laura; Gutiérrez, Daniela; Anguita-Salinas, Consuelo; Allende, Miguel L

2016-04-07

Regenerating damaged tissue is a complex process, requiring progenitor cells that must be stimulated to undergo proliferation, differentiation and, often, migratory behaviors and morphological changes. Multiple cell types, both resident within the damaged tissue and recruited to the lesion site, have been shown to participate. However, the cellular and molecular mechanisms involved in the activation of progenitor cell proliferation and differentiation after injury, and their regulation by different cells types, are not fully understood. The zebrafish lateral line is a suitable system to study regeneration because most of its components are fully restored after damage. The posterior lateral line (PLL) is a mechanosensory system that develops embryonically and is initially composed of seven to eight neuromasts distributed along the trunk and tail, connected by a continuous stripe of interneuromastic cells (INCs). The INCs remain in a quiescent state owing to the presence of underlying Schwann cells. They become activated during development to form intercalary neuromasts. However, no studies have described if INCs can participate in a regenerative event, for example, after the total loss of a neuromast. We used electroablation in transgenic larvae expressing fluorescent proteins in PLL components to completely ablate single neuromasts in larvae and adult fish. This injury results in discontinuity of the INCs, Schwann cells, and the PLL nerve. In vivo imaging showed that the INCs fill the gap left after the injury and can regenerate a new neuromast in the injury zone. Further, a single INC is able to divide and form all cell types in a regenerated neuromast and, during this process, it transiently expresses the sox2 gene, a neural progenitor cell marker. We demonstrate a critical role for Schwann cells as negative regulators of INC proliferation and neuromast regeneration, and that this inhibitory property is completely dependent on active ErbB signaling. The potential to regenerate a neuromast after damage requires that progenitor cells (INCs) be temporarily released from an inhibitory signal produced by nearby Schwann cells. This simple yet highly effective two-component niche offers the animal robust mechanisms for organ growth and regeneration, which can be sustained throughout life.

Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types.

PubMed Central

Satoh, T; Fantl, W J; Escobedo, J A; Williams, L T; Kaziro, Y

1993-01-01

A series of pieces of evidence have shown that Ras protein acts as a transducer of the platelet-derived growth factor (PDGF) receptor-mediated signaling pathway: (i) formation of Ras.GTP is detected immediately on PDGF stimulation, and (ii) a dominant inhibitory mutant Ras, as well as a neutralizing anti-Ras antibody, can interfere with PDGF-induced responses. On the other hand, several signal transducing molecules including phosphatidylinositol 3-kinase (PI3-K), GTPase-activating protein (GAP), and phospholipase C gamma (PLC gamma) bind directly to the PDGF receptor and become tyrosine phosphorylated. Recently, it was shown that specific phosphorylated tyrosines of the PDGF receptor are responsible for interaction between the receptor and each signaling molecule. However, the roles of these signaling molecules have not been elucidated, and it remains unclear which molecules are implicated in the Ras pathway. In this study, we measured Ras activation in cell lines expressing mutant PDGF receptors that are deficient in coupling with specific molecules. In fibroblast CHO cells, a mutant receptor (Y708F/Y719F [PI3-K-binding sites]) was unable to stimulate Ras, whereas another mutant (Y739F [the GAP-binding site]) could do so, suggesting an indispensable role of PI3-K or a protein that binds to the same sites as PI3-K for PDGF-stimulated Ras activation. By contrast, both of the above mutants were capable of stimulating Ras protein in a pro-B-cell line, BaF3. Furthermore, a mutant receptor (Y977F/Y989F [PLC gamma-binding sites]) could fully activate Ras, and the direct activation of protein kinase C and calcium mobilization had almost no effect on the GDP/GTP state of Ras in this cell line. These results suggest that, in the pro-B-cell transfectants, each of the above pathways (PI3-K, GAP, and PLC gamma) can be eliminated without a loss of Ras activation. It remains unclear whether another unknown essential pathway which regulates Ras protein exists within BaF3 cells. Therefore, it is likely that several different PDGF receptor-mediated signaling pathways function upstream of Ras, and the extent of the contribution of each pathway for the regulation of Ras may differ among different cell types. Images PMID:8388543

Prescribed computer games in addition to occlusion versus standard occlusion treatment for childhood amblyopia: a pilot randomised controlled trial.

PubMed

Tailor, Vijay K; Glaze, Selina; Khandelwal, Payal; Davis, Alison; Adams, Gillian G W; Xing, Wen; Bunce, Catey; Dahlmann-Noor, Annegret

2015-01-01

Amblyopia ("lazy eye") is the commonest vision deficit in children. If not fully corrected by glasses, amblyopia is treated by patching or blurring the better-seeing eye. Compliance with patching is often poor. Computer-based activities are increasingly topical, both as an adjunct to standard treatment and as a platform for novel treatments. Acceptability by families has not been explored, and feasibility of a randomised controlled trial (RCT) using computer games in terms of recruitment and treatment acceptability is uncertain. We carried out a pilot RCT to test whether computer-based activities are acceptable and accessible to families and to test trial methods such as recruitment and retention rates, randomisation, trial-specific data collection tools and analysis. The trial had three arms: standard near activity advice, Eye Five, a package developed for children with amblyopia, and an off-the-shelf handheld games console with pre-installed games. We enrolled 60 children age 3-8 years with moderate or severe amblyopia after completion of optical treatment. This trial was registered as UKCRN-ID 11074. Pre-screening of 3600 medical notes identified 189 potentially eligible children, of whom 60 remained eligible after optical treatment, and were enrolled between April 2012 and March 2013. One participant was randomised twice and withdrawn from the study. Of the 58 remaining, 37 were boys. The mean (SD) age was 4.6 (1.7) years. Thirty-seven had moderate and 21 severe amblyopia. Three participants were withdrawn at week 6, and in total, four were lost to follow-up at week 12. Most children and parents/carers found the study procedures, i.e. occlusion treatment, usage of the allocated near activity and completion of a study diary, easy. The prescribed cumulative dose of near activity was 84 h at 12 weeks. Reported near activity usage numbers were close to prescribed numbers in moderate amblyopes (94 % of prescribed) but markedly less in severe amblyopes (64 %). Reported occlusion usage at 12 weeks was 90 % of prescribed dose for moderate and 33 % for severe amblyopes. Computer-based games and activities appear acceptable to families as part of their child's amblyopia treatment. Trial methods were appropriate and accepted by families.

Aviator's Heart: A Case of Athlete's Heart in an Active Duty Male Naval Aviator.

PubMed

Ryaboy, Ilya V; Watts, James A; Barnwell, Megan L

2018-05-31

Athlete's heart is the condition of cardiac remodeling as a result of physiologic stress induced by regular strenuous physical activity by professional or elite amateur individuals. The literature describes several characteristics of the athletic heart, including left ventricular hypertrophy, increased left ventricular mass, right ventricular dilatation, atrial enlargement, electrocardiographic changes, and abnormalities on cardiac magnetic resonance imaging. We present a case of athletic heart in an exceptionally physically fit active duty naval aviator who experienced syncope and underwent extensive cardiac testing. He was found to have borderline hypertrophic changes as well as delayed gadolinium enhancement initially concerning for myocarditis. Cardiopulmonary exercise testing revealed an exercise capacity of 120% above the maximum measurable value for his age and gender. He was then diagnosed with athlete's heart and released to active duty with no limitations to his flight status. A challenge is posed to the practicing clinician in differentiating the athletic heart from the heart of an athlete suffering from underlying pathophysiology. Athlete's heart is an elusive diagnosis and may be associated with findings concerning for more insidious pathology, including hypertrophic cardiomyopathy and dilated cardiomyopathy. Additionally, patients with athlete's heart have been noted to have delayed gadolinium enhancement similar to that seen in patients with a history of myocarditis; the clinical significance of this finding is yet to be fully elucidated. In a military setting, distinguishing the heart of the healthy and athletic service member from the unfortunate one who has cardiomyopathy remains an important clinical distinction warranting further study.

Glucose oxidase stabilization against thermal inactivation using high hydrostatic pressure and hydrophobic modification.

PubMed

Halalipour, Ali; Duff, Michael R; Howell, Elizabeth E; Reyes-De-Corcuera, José I

2017-03-01

High hydrostatic pressure (HHP) stabilized glucose oxidase (GOx) against thermal inactivation. The apparent first-order kinetics of inactivation of GOx were investigated at 0.1-300 MPa and 58.8-80.0°C. At 240 MPa and 74.5°C, GOx inactivated at a rate 50 times slower than at atmospheric pressure at the same temperature. The apparent activation energy of inactivation at 300 MPa was 281.0 ± 17.4 kJ mol -1 or 1.3-fold smaller than for the inactivation at atmospheric pressure (378.1 ± 25.6 kJ mol -1 ). The stabilizing effect of HHP was greatest at 74.5°C, where the activation volume of 57.0 ± 12.0 cm 3  mol -1 was highest compared to all other studied temperatures. Positive apparent activation volumes for all the treatment temperatures confirmed that HHP favors GOx stabilization. A second approach to increase GOx stability involved crosslinking with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and either aniline or benzoate. The modified enzyme remained fully active with only slight increases in K M (1.3-1.9-fold increases for aniline and benzoate modification, respectively). The thermal stability of GOx increased by 8°C with aniline modification, while it decreased by 0.9°C upon modification with benzoate. Biotechnol. Bioeng. 2017;114: 516-525. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Arf6 guanine-nucleotide exchange factor, cytohesin-2, interacts with actinin-1 to regulate neurite extension.

PubMed

Torii, Tomohiro; Miyamoto, Yuki; Nakamura, Kazuaki; Maeda, Masahiro; Yamauchi, Junji; Tanoue, Akito

2012-09-01

Proper regulation of morphological changes in neuronal cells is essential for their differentiation. Complex signaling mechanisms mediate a variety of morphological changes such as formation of neurites. It is well established that a number of small GTPases control neurite behavior before the connection with the target tissue. However, their regulatory mechanisms remain to be fully understood. Here, we show that the Arf6 guanine-nucleotide exchange factor (GEF), cytohesin-2 (CYTH2), interacts with the cytoskeletal protein actinin-1 (ACTN1) and regulates neurite extension in N1E-115 cells used as the model. Knockdown of ACTN1, as well as that of CYTH2, in cells inhibits cellular Arf6 activity and neurite extension. The C-terminal polybasic region of CYTH2 participates in interacting directly with the EFh2 domain of ACTN1. Expression of CYTH2 mutant deficient of the EFh2 domain in cells also inhibits Arf6 activation and neurite extension. Furthermore, FRET analysis detects that the respective interactive region peptides, tagged with cell-permeable short peptides, greatly decrease Arf6 activation at growth cones in a time-dependent manner. Collectively, the signaling through CYTH2 and ACTN1 properly regulates neurite extension in N1E-115 cells, demonstrating the unexpected interaction of CYTH2 and ACTN1 in the regulation of cellular Arf6 activity involved in neurite extension. Copyright © 2012 Elsevier Inc. All rights reserved.

DNA-repair scaffolds dampen checkpoint signalling by counteracting the adaptor Rad9.

PubMed

Ohouo, Patrice Y; Bastos de Oliveira, Francisco M; Liu, Yi; Ma, Chu Jian; Smolka, Marcus B

2013-01-03

In response to genotoxic stress, a transient arrest in cell-cycle progression enforced by the DNA-damage checkpoint (DDC) signalling pathway positively contributes to genome maintenance. Because hyperactivated DDC signalling can lead to a persistent and detrimental cell-cycle arrest, cells must tightly regulate the activity of the kinases involved in this pathway. Despite their importance, the mechanisms for monitoring and modulating DDC signalling are not fully understood. Here we show that the DNA-repair scaffolding proteins Slx4 and Rtt107 prevent the aberrant hyperactivation of DDC signalling by lesions that are generated during DNA replication in Saccharomyces cerevisiae. On replication stress, cells lacking Slx4 or Rtt107 show hyperactivation of the downstream DDC kinase Rad53, whereas activation of the upstream DDC kinase Mec1 remains normal. An Slx4-Rtt107 complex counteracts the checkpoint adaptor Rad9 by physically interacting with Dpb11 and phosphorylated histone H2A, two positive regulators of Rad9-dependent Rad53 activation. A decrease in DDC signalling results from hypomorphic mutations in RAD53 and H2A and rescues the hypersensitivity to replication stress of cells lacking Slx4 or Rtt107. We propose that the Slx4-Rtt107 complex modulates Rad53 activation by a competition-based mechanism that balances the engagement of Rad9 at replication-induced lesions. Our findings show that DDC signalling is monitored and modulated through the direct action of DNA-repair factors.

Microoxic Niches within the Thylakoid Stroma of Air-Grown Chlamydomonas reinhardtii Protect [FeFe]-Hydrogenase and Support Hydrogen Production under Fully Aerobic Environment1[OPEN

PubMed Central

Liran, Oded; Milrad, Yuval; Eilenberg, Haviva; Weiner, Iddo

2016-01-01

Photosynthetic hydrogen production in the microalga Chlamydomonas reinhardtii is catalyzed by two [FeFe]-hydrogenase isoforms, HydA1 and HydA2, both irreversibly inactivated upon a few seconds exposure to atmospheric oxygen. Until recently, it was thought that hydrogenase is not active in air-grown microalgal cells. In contrast, we show that the entire pool of cellular [FeFe]-hydrogenase remains active in air-grown cells due to efficient scavenging of oxygen. Using membrane inlet mass spectrometry, 18O2 isotope, and various inhibitors, we were able to dissect the various oxygen uptake mechanisms. We found that both chlororespiration, catalyzed by plastid terminal oxidase, and Mehler reactions, catalyzed by photosystem I and Flavodiiron proteins, significantly contribute to oxygen uptake rate. This rate is considerably enhanced with increasing light, thus forming local anaerobic niches at the proximity of the stromal face of the thylakoid membrane. Furthermore, we found that in transition to high light, the hydrogen production rate is significantly enhanced for a short duration (100 s), thus indicating that [FeFe]-hydrogenase functions as an immediate sink for surplus electrons in aerobic as well as in anaerobic environments. In summary, we show that an anaerobic locality in the chloroplast preserves [FeFe]-hydrogenase activity and supports continuous hydrogen production in air-grown microalgal cells. PMID:27443604

LINE dancing in the human genome: transposable elements and disease.

PubMed

Belancio, Victoria P; Deininger, Prescott L; Roy-Engel, Astrid M

2009-10-27

Transposable elements (TEs) have been consistently underestimated in their contribution to genetic instability and human disease. TEs can cause human disease by creating insertional mutations in genes, and also contributing to genetic instability through non-allelic homologous recombination and introduction of sequences that evolve into various cis-acting signals that alter gene expression. Other outcomes of TE activity, such as their potential to cause DNA double-strand breaks or to modulate the epigenetic state of chromosomes, are less fully characterized. The currently active human transposable elements are members of the non-LTR retroelement families, LINE-1, Alu (SINE), and SVA. The impact of germline insertional mutagenesis by TEs is well established, whereas the rate of post-insertional TE-mediated germline mutations and all forms of somatic mutations remain less well quantified. The number of human diseases discovered to be associated with non-allelic homologous recombination between TEs, and particularly between Alu elements, is growing at an unprecedented rate. Improvement in the technology for detection of such events, as well as the mounting interest in the research and medical communities in resolving the underlying causes of the human diseases with unknown etiology, explain this increase. Here, we focus on the most recent advances in understanding of the impact of the active human TEs on the stability of the human genome and its relevance to human disease.

Redox-Regulated Pathway of Tyrosine Phosphorylation Underlies NF-κB Induction by an Atypical Pathway Independent of the 26S Proteasome

PubMed Central

Cullen, Sarah; Ponnappan, Subramaniam; Ponnappan, Usha

2015-01-01

Alternative redox stimuli such as pervanadate or hypoxia/reoxygenation, induce transcription factor NF-κB by phospho-tyrosine-dependent and proteasome-independent mechanisms. While considerable attention has been paid to the absence of proteasomal regulation of tyrosine phosphorylated IκBα, there is a paucity of information regarding proteasomal regulation of signaling events distinct from tyrosine phosphorylation of IκBα. To delineate roles for the ubiquitin-proteasome pathway in the phospho-tyrosine dependent mechanism of NF-κB induction, we employed the proteasome inhibitor, Aclacinomycin, and the phosphotyrosine phosphatase inhibitor, pervanadate (PV). Results from these studies demonstrate that phospho-IκBα (Tyr-42) is not subject to proteasomal degradation in a murine stromal epithelial cell line, confirming results previously reported. Correspondingly, proteasome inhibition had no discernable effect on the key signaling intermediaries, Src and ERK1/2, involved in the phospho-tyrosine mechanisms regulating PV-mediated activation of NF-κB. Consistent with previous reports, a significant redox imbalance leading to the activation of tyrosine kinases, as occurs with pervanadate, is required for the induction of NF-κB. Strikingly, our studies demonstrate that proteasome inhibition can potentiate oxidative stress associated with PV-stimulation without impacting kinase activation, however, other cellular implications for this increase in intracellular oxidation remain to be fully delineated. PMID:25671697

Cannabinoids and the kidney: effects in health and disease.

PubMed

Park, Frank; Potukuchi, Praveen K; Moradi, Hamid; Kovesdy, Csaba P

2017-11-01

Consumption of cannabis and various related products (cannabinoids) for both medicinal and recreational use is gaining popularity. Furthermore, regulatory changes are fostering a cultural shift toward increasing liberalization of cannabis use, thereby increasing the likelihood of even larger numbers of individuals being exposed in the future. The two different types of receptors (CB 1 and CB 2 ) that are activated by the pharmacologically active ingredients of cannabis are found in numerous tissues, including the kidneys. Experimental studies suggest that stimulation of these receptors using pharmacologic agents or their naturally occurring ligands could have both deleterious and beneficial effects on the kidneys, depending on receptor distribution, type of renal insult, or the timing of the activation during acute or chronic states of kidney injury. To date, the mechanisms by which the CB 1 or CB 2 receptors are involved in the pathology of these renal conditions remain to be fully described. Furthermore, a better understanding of the impact of exocannabinoids and endocannabinoids on the renal system may lead to the development of new drugs to treat kidney disease and its complications. Given the increasing public health relevance of cannabis exposure, it is clear that more research is necessary to clarify the various physiological and pathophysiological effects of cannabis and related analogs on the kidney. This will help limit the deleterious effects of these substances while promoting their potential beneficial impact on renal function in various types of kidney diseases.

HIV and Hepatitis B Virus Coinfection: Approach to Management

PubMed Central

Chasan, Rachel; Reese, Lindsey; Fishbein, Dawn

2010-01-01

Objective To review diagnosis and treatment in patients with HIV and hepatitis B virus (HBV) coinfection. Methods Review of the literature in the context of a clinical case. Results All patients with HIV should be screened for the presence of coinfection with HBV. Following diagnosis with HBV infection, the level of HBV activity should be assessed with testing for HBeAg, HBV DNA, and potentially a biopsy for staging the degree of fibrosis present. Based on the results of this workup, a decision regarding the role of anti-hepatitis treatment should be made. According to the latest chronic hepatitis B and HIV treatment guidelines, coinfected patients who require treatment for chronic hepatitis B should be started on a regimen that is fully active against both HIV and HBV. A first-line regimen for coinfected patients is generally composed of tenofovir and emtricitabine, plus one other agent active against HIV. In coinfected patients, durable responses are rare, and therefore patients are usually required to remain on therapy indefinitely. Conclusion Intensification of surveillance techniques and education programs should be developed to help prevent transmission of infection and integrate coinfected patients into the health care system. Once engaged in care, coinfected patients should receive treatment for both HIV and chronic hepatitis B with the goal of a decrease in liver failure, cirrhosis, hepatocellular carcinoma, and chronic hepatitis B–related mortality. PMID:23761953

Intravenous immunoglobulins – understanding properties and mechanisms

PubMed Central

Durandy, A; Kaveri, S V; Kuijpers, T W; Basta, M; Miescher, S; Ravetch, J V; Rieben, R

2009-01-01

High-dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro- and anti-inflammatory activities, depending on its concentration. The proinflammatory activity of low-dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG-specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not yet been elucidated fully, and several mutually non-exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg-mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti-inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy. PMID:19883419

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.

PubMed

Zhang, Shanshan; Wang, Jingxiao; Wang, Haichuan; Fan, Lingling; Fan, Biao; Zeng, Billy; Tao, Junyan; Li, Xiaolei; Che, Li; Cigliano, Antonio; Ribback, Silvia; Dombrowski, Frank; Chen, Bin; Cong, Wenming; Wei, Lixin; Calvisi, Diego F; Chen, Xin

2018-04-01

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Dissection of combinatorial control by the Met4 transcriptional complex.

PubMed

Lee, Traci A; Jorgensen, Paul; Bognar, Andrew L; Peyraud, Caroline; Thomas, Dominique; Tyers, Mike

2010-02-01

Met4 is the transcriptional activator of the sulfur metabolic network in Saccharomyces cerevisiae. Lacking DNA-binding ability, Met4 must interact with proteins called Met4 cofactors to target promoters for transcription. Two types of DNA-binding cofactors (Cbf1 and Met31/Met32) recruit Met4 to promoters and one cofactor (Met28) stabilizes the DNA-bound Met4 complexes. To dissect this combinatorial system, we systematically deleted each category of cofactor(s) and analyzed Met4-activated transcription on a genome-wide scale. We defined a core regulon for Met4, consisting of 45 target genes. Deletion of both Met31 and Met32 eliminated activation of the core regulon, whereas loss of Met28 or Cbf1 interfered with only a subset of targets that map to distinct sectors of the sulfur metabolic network. These transcriptional dependencies roughly correlated with the presence of Cbf1 promoter motifs. Quantitative analysis of in vivo promoter binding properties indicated varying levels of cooperativity and interdependency exists between members of this combinatorial system. Cbf1 was the only cofactor to remain fully bound to target promoters under all conditions, whereas other factors exhibited different degrees of regulated binding in a promoter-specific fashion. Taken together, Met4 cofactors use a variety of mechanisms to allow differential transcription of target genes in response to various cues.

Pacific Ciguatoxin Induces Excitotoxicity and Neurodegeneration in the Motor Cortex Via Caspase 3 Activation: Implication for Irreversible Motor Deficit.

PubMed

Asthana, Pallavi; Zhang, Ni; Kumar, Gajendra; Chine, Virendra Bhagawan; Singh, Kunal Kumar; Mak, Yim Ling; Chan, Leo Lai; Lam, Paul Kwan Sing; Ma, Chi Him Eddie

2018-01-18

Consumption of fish containing ciguatera toxins or ciguatoxins (CTXs) causes ciguatera fish poisoning (CFP). In some patients, CFP recurrence occurs even years after exposure related to CTXs accumulation. Pacific CTX-1 (P-CTX-1) is one of the most potent natural substances known that causes predominantly neurological symptoms in patients; however, the underlying pathogenies of CFP remain unknown. Using clinically relevant neurobehavioral tests and electromyography (EMG) to assess effects of P-CTX-1 during the 4 months after exposure, recurrent motor strength deficit occurred in mice exposed to P-CTX-1. We detected irreversible motor strength deficits accompanied by reduced EMG activity, demyelination, and slowing of motor nerve conduction, whereas control unexposed mice fully recovered in 1 month after peripheral nerve injury. Finally, to uncover the mechanism underlying CFP, we detected reduction of spontaneous firing rate of motor cortical neurons even 6 months after exposure and increased number of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Increased numbers of motor cortical neuron apoptosis were detected by dUTP-digoxigenin nick end labeling assay along with activation of caspase 3. Taken together, our study demonstrates that persistence of P-CTX-1 in the nervous system induces irreversible motor deficit that correlates well with excitotoxicity and neurodegeneration detected in the motor cortical neurons.

Robust Long-Range Coordination of Spontaneous Neural Activity in Waking, Sleep and Anesthesia.

PubMed

Liu, Xiao; Yanagawa, Toru; Leopold, David A; Fujii, Naotaka; Duyn, Jeff H

2015-09-01

Although the emerging field of functional connectomics relies increasingly on the analysis of spontaneous fMRI signal covariation to infer the spatial fingerprint of the brain's large-scale functional networks, the nature of the underlying neuro-electrical activity remains incompletely understood. In part, this lack in understanding owes to the invasiveness of electrophysiological acquisition, the difficulty in their simultaneous recording over large cortical areas, and the absence of fully established methods for unbiased extraction of network information from these data. Here, we demonstrate a novel, data-driven approach to analyze spontaneous signal variations in electrocorticographic (ECoG) recordings from nearly entire hemispheres of macaque monkeys. Based on both broadband analysis and analysis of specific frequency bands, the ECoG signals were found to co-vary in patterns that resembled the fMRI networks reported in previous studies. The extracted patterns were robust against changes in consciousness associated with sleep and anesthesia, despite profound changes in intrinsic characteristics of the raw signals, including their spectral signatures. These results suggest that the spatial organization of large-scale brain networks results from neural activity with a broadband spectral feature and is a core aspect of the brain's physiology that does not depend on the state of consciousness. Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

The Effect of Two Amino acid Residue Substitutions via RNA Editing on Dark-operative Protochlorophyllide Oxidoreductase in the Black Pine Chloroplasts.

PubMed

Yamamoto, Haruki; Kusumi, Junko; Yamakawa, Hisanori; Fujita, Yuichi

2017-05-24

Dark-operative protochlorophyllide oxidoreductase (DPOR) is a key enzyme to produce chlorophyll in the dark. Among photosynthetic eukaryotes, all three subunits chlL, chlN, and chlB are encoded by plastid genomes. In some gymnosperms, two codons of chlB mRNA are changed by RNA editing to codons encoding evolutionarily conserved amino acid residues. However, the effect of these substitutions on DPOR activity remains unknown. We first prepared cyanobacterial ChlB variants with amino acid substitution(s) to mimic ChlB translated from pre-edited mRNA. Their activities were evaluated by measuring chlorophyll content of dark-grown transformants of a chlB-lacking mutant of the cyanobacterium Leptolyngbya boryana that was complemented with pre-edited mimic chlB variants. The chlorophyll content of the transformant cells expressing the ChlB variant from the fully pre-edited mRNA was only one-fourth of the control cells. Co-purification experiments of ChlB with Strep-ChlN suggested that a stable complex with ChlN is greatly impaired in the substituted ChlB variant. We then confirmed that RNA editing efficiency was markedly greater in the dark than in the light in cotyledons of the black pine Pinus thunbergii. These results indicate that RNA editing on chlB mRNA is important to maintain appropriate DPOR activity in black pine chloroplasts.

Demand Creation for Polio Vaccine in Persistently Poor-Performing Communities of Northern Nigeria: 2013-2014.

PubMed

Warigon, Charity; Mkanda, Pascal; Muhammed, Ado; Etsano, Andrew; Korir, Charles; Bawa, Samuel; Gali, Emmanuel; Nsubuga, Peter; Erbeto, Tesfaya B; Gerlong, George; Banda, Richard; Yehualashet, Yared G; Vaz, Rui G

2016-05-01

Poliomyelitis remains a global threat despite availability of oral polio vaccine (OPV), proven to reduce the burden of the paralyzing disease. In Nigeria, children continue to miss the opportunity to be fully vaccinated, owing to factors such as unmet health needs and low uptake in security-compromised and underserved communities. We describe the implementation and evaluation of several activities to create demand for polio vaccination in persistently poor-performing local government areas (LGAs). We assessed the impact of various polio-related interventions, to measure the contribution of demand creation activities in 77 LGAs at very high risk for polio, located across 10 states in northern Nigeria. Interventions included provision of commodities along with the polio vaccine. There was an increasing trend in the number of children reached by different demand creation interventions. A total of 4 819 847 children were vaccinated at health camps alone. There was a reduction in the number of wards in which >10% of children were missed by supplementary immunization activities due to noncompliance with vaccination recommendations, a rise in the proportion of children who received ≥4 OPV doses, and a decrease in the proportion of children who were underimmunized or unimmunized. Demand creation interventions increased the uptake of polio vaccines in persistently poor-performing high-risk communities in northern Nigeria during September 2013-November 2014. © 2016 World Health Organization; licensee Oxford Journals.

Adult brains don't fully overcome biases that lead to incorrect performance during cognitive development: an fMRI study in young adults completing a Piaget-like task.

PubMed

Leroux, Gaëlle; Spiess, Jeanne; Zago, Laure; Rossi, Sandrine; Lubin, Amélie; Turbelin, Marie-Renée; Mazoyer, Bernard; Tzourio-Mazoyer, Nathalie; Houdé, Olivier; Joliot, Marc

2009-03-01

A current issue in developmental science is that greater continuity in cognition between children and adults may exist than is usually appreciated in Piaget-like (stages or 'staircase') models. This phenomenon has been demonstrated at the behavioural level, but never at the brain level. Here we show with functional magnetic resonance imaging (fMRI), for the first time, that adult brains do not fully overcome the biases of childhood. More specifically, the aim of this fMRI study was to evaluate whether the perceptual bias that leads to incorrect performance during cognitive development in a Piaget-like task is still a bias in the adult brain and hence requires an executive network to overcome it. Here, we compared two numerical-judgment tasks, one being a Piaget-like task with number-length interference (called 'INT') and the other being a control task with number-length covariation ('COV'). We also used a colour-detection task to control for stimuli numerosity, spatial distribution, and frequency. Our behavioural results confirmed that INT remains a difficult task for young adults. Indeed, response times were significantly higher in INT than in COV. Moreover, we observed that only in INT did response times increase linearly as a function of the number of items. The fMRI results indicate that the brain network common to INT and COV shows a large rightward functional asymmetry, emphasizing the visuospatial nature of these two tasks. When INT was compared with COV, activations were found within a right frontal network, including the pre-supplementary motor area, the anterior cingulate cortex, and the middle frontal gyrus, which probably reflect detection of the number/length conflict and inhibition of the 'length-equals-number' response strategy. Finally, activations related to visuospatial and quantitative processing, enhanced or specifically recruited in the Piaget-like task, were found in bilateral posterior areas.

Profiling lethal factor interacting proteins from human stomach using T7 phage display screening.

PubMed

Cardona-Correa, Albin; Rios-Velazquez, Carlos

2016-05-01

The anthrax lethal factor (LF) is a zinc dependent metalloproteinase that cleaves the majority of mitogen-activated protein kinase kinases and a member of NOD-like receptor proteins, inducing cell apoptosis. Despite efforts to fully understand the Bacillus anthracis toxin components, the gastrointestinal (GI) anthrax mechanisms have not been fully elucidated. Previous studies demonstrated gastric ulceration, and a substantial bacterial growth rate in Peyer's patches. However, the complete molecular pathways of the disease that results in tissue damage by LF proteolytic activity remains unclear. In the present study, to identify the profile of the proteins potentially involved in GI anthrax, protein‑protein interactions were investigated using human stomach T7 phage display (T7PD) cDNA libraries. T7PD is a high throughput technique that allows the expression of cloned DNA sequences as peptides on the phage surface, enabling the selection and identification of protein ligands. A wild type and mutant LF (E687A) were used to differentiate interaction sites. A total of 124 clones were identified from 194 interacting‑phages, at both the DNA and protein level, by in silico analysis. Databases revealed that the selected candidates were proteins from different families including lipase, peptidase‑A1 and cation transport families, among others. Furthermore, individual T7PD candidates were tested against LF in order to detect their specificity to the target molecule, resulting in 10 LF‑interacting peptides. With a minimum concentration of LF for interaction at 1 µg/ml, the T7PD isolated pepsin A3 pre‑protein (PAP) demonstrated affinity to both types of LF. In addition, PAP was isolated in various lengths for the same protein, exhibiting common regions following PRALINE alignment. These findings will help elucidate and improve the understanding of the molecular pathogenesis of GI anthrax, and aid in the development of potential therapeutic agents.

The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

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

Cheng, Yahui; Tian, Yuanyao; Xia, Jialu

Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantlymore » decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.« less

Building Extraction from Remote Sensing Data Using Fully Convolutional Networks

NASA Astrophysics Data System (ADS)

Bittner, K.; Cui, S.; Reinartz, P.

2017-05-01

Building detection and footprint extraction are highly demanded for many remote sensing applications. Though most previous works have shown promising results, the automatic extraction of building footprints still remains a nontrivial topic, especially in complex urban areas. Recently developed extensions of the CNN framework made it possible to perform dense pixel-wise classification of input images. Based on these abilities we propose a methodology, which automatically generates a full resolution binary building mask out of a Digital Surface Model (DSM) using a Fully Convolution Network (FCN) architecture. The advantage of using the depth information is that it provides geometrical silhouettes and allows a better separation of buildings from background as well as through its invariance to illumination and color variations. The proposed framework has mainly two steps. Firstly, the FCN is trained on a large set of patches consisting of normalized DSM (nDSM) as inputs and available ground truth building mask as target outputs. Secondly, the generated predictions from FCN are viewed as unary terms for a Fully connected Conditional Random Fields (FCRF), which enables us to create a final binary building mask. A series of experiments demonstrate that our methodology is able to extract accurate building footprints which are close to the buildings original shapes to a high degree. The quantitative and qualitative analysis show the significant improvements of the results in contrast to the multy-layer fully connected network from our previous work.

Cardiac imaging: working towards fully-automated machine analysis & interpretation

PubMed Central

Slomka, Piotr J; Dey, Damini; Sitek, Arkadiusz; Motwani, Manish; Berman, Daniel S; Germano, Guido

2017-01-01

Introduction Non-invasive imaging plays a critical role in managing patients with cardiovascular disease. Although subjective visual interpretation remains the clinical mainstay, quantitative analysis facilitates objective, evidence-based management, and advances in clinical research. This has driven developments in computing and software tools aimed at achieving fully automated image processing and quantitative analysis. In parallel, machine learning techniques have been used to rapidly integrate large amounts of clinical and quantitative imaging data to provide highly personalized individual patient-based conclusions. Areas covered This review summarizes recent advances in automated quantitative imaging in cardiology and describes the latest techniques which incorporate machine learning principles. The review focuses on the cardiac imaging techniques which are in wide clinical use. It also discusses key issues and obstacles for these tools to become utilized in mainstream clinical practice. Expert commentary Fully-automated processing and high-level computer interpretation of cardiac imaging are becoming a reality. Application of machine learning to the vast amounts of quantitative data generated per scan and integration with clinical data also facilitates a move to more patient-specific interpretation. These developments are unlikely to replace interpreting physicians but will provide them with highly accurate tools to detect disease, risk-stratify, and optimize patient-specific treatment. However, with each technological advance, we move further from human dependence and closer to fully-automated machine interpretation. PMID:28277804

Anelastic Models of Fully-Convective Stars: Differential Rotation, Meridional Circulation and Residual Entropy

NASA Astrophysics Data System (ADS)

Sainsbury-Martinez, Felix; Browning, Matthew; Miesch, Mark; Featherstone, Nicholas A.

2018-01-01

Low-Mass stars are typically fully convective, and as such their dynamics may differ significantly from sun-like stars. Here we present a series of 3D anelastic HD and MHD simulations of fully convective stars, designed to investigate how the meridional circulation, the differential rotation, and residual entropy are affected by both varying stellar parameters, such as the luminosity or the rotation rate, and by the presence of a magnetic field. We also investigate, more specifically, a theoretical model in which isorotation contours and residual entropy (σ‧ = σ ‑ σ(r)) are intrinsically linked via the thermal wind equation (as proposed in the Solar context by Balbus in 2009). We have selected our simulation parameters in such as way as to span the transition between Solar-like differential rotation (fast equator + slow poles) and ‘anti-Solar’ differential rotation (slow equator + fast poles), as characterised by the convective Rossby number and △Ω. We illustrate the transition from single-celled to multi-celled MC profiles, and from positive to negative latitudinal entropy gradients. We show that an extrapolation involving both TWB and the σ‧/Ω link provides a reasonable estimate for the interior profile of our fully convective stars. Finally, we also present a selection of MHD simulations which exhibit an almost unsuppressed differential rotation profile, with energy balances remaining dominated by kinetic components.

Strategies for halting the rise of multidrug resistant TB epidemics: assessing the effect of early case detection and isolation.

PubMed

Espindola, Aquino L; Varughese, Marie; Laskowski, Marek; Shoukat, Affan; Heffernan, Jane M; Moghadas, Seyed M

2017-03-01

The increasing rates of multidrug resistant TB (MDR-TB) have posed the question of whether control programs under enhanced directly observed treatment, short-course (DOTS-Plus) are sufficient or implemented optimally. Despite enhanced efforts on early case detection and improved treatment regimens, direct transmission of MDR-TB remains a major hurdle for global TB control. We developed an agent-based simulation model of TB dynamics to evaluate the effect of transmission reduction measures on the incidence of MDR-TB. We implemented a 15-day isolation period following the start of treatment in active TB cases. The model was parameterized with the latest estimates derived from the published literature. We found that if high rates (over 90%) of TB case identification are achieved within 4 weeks of developing active TB, then a 15-day patient isolation strategy with 50% effectiveness in interrupting disease transmission leads to 10% reduction in the incidence of MDR-TB over 10 years. If transmission is fully prevented, the rise of MDR-TB can be halted within 10 years, but the temporal reduction of MDR-TB incidence remains below 20% in this period. The impact of transmission reduction measures on the TB incidence depends critically on the rates and timelines of case identification. The high costs and adverse effects associated with MDR-TB treatment warrant increased efforts and investments on measures that can interrupt direct transmission through early case detection. © The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PKCα promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma

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

Wang, Jiajun; Shao, Miaomiao; Liu, Min

2015-08-07

Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCα), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCα is commonly observed in human HCC and associated with its poor prognosis. However, how PKCα is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCα,more » but not PKCβI or βII, promoted ROS production in HCC cells. PKCα stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCα-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCα was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCα plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCα/DUOX2 as a potential adjuvant therapy for HCC treatment. - Highlights: • PKCα promotes the generation of ROS in hepatocellular carcinoma. • PKCα induces ROS production by up-regulating DUOX2 at post-transcriptional level. • DUOX2 is required for PKCα-induced AKT/MAPK activation and tumor progression in HCC. • The expression of PKCα is positively correlated with DUOX2 in HCC.« less

Widening of xylem conduits in a conifer tree depends on the longer time of cell expansion downwards along the stem

PubMed Central

Anfodillo, Tommaso; Deslauriers, Annie; Menardi, Roberto; Tedoldi, Laura; Petit, Giai; Rossi, Sergio

2012-01-01

The diameter of vascular conduits increases towards the stem base. It has been suggested that this profile is an efficient anatomical feature for reducing the hydraulic resistance when trees grow taller. However, the mechanism that controls the cell diameter along the plant is not fully understood. The timing of cell differentiation along the stem was investigated. Cambial activity and cell differentiation were investigated in a Picea abies tree (11.5 m in height) collecting microsamples at nine different heights (from 1 to 9 m) along the stem with a 4 d time interval. Wood sections (8–12 μm thick) were stained and observed under a light microscope with polarized light to differentiate the developing xylem cells. Cell wall lignification was detected using cresyl violet acetate. The first enlarging cells appeared almost simultaneously along the tree axis indicating that cambium activation is not height-dependent. A significant increase in the duration of the cell expansion phase was observed towards the tree base: at 9 m from the ground, xylem cells expanded for 7 d, at 6 m for 14 d, and at 3 m for 19 d. The duration of the expansion phase is positively correlated with the lumen area of the tracheids (r2=0.68, P < 0.01) at the same height. By contrast, thickness of the cell wall of the earlywood did not show any trend with height. The lumen area of the conduits down the stem appeared linearly dependent on time during which differentiating cells remained in the expansion phase. However, the inductive signal of such long-distance patterned differentiation remains to be identified. PMID:22016427

Widening of xylem conduits in a conifer tree depends on the longer time of cell expansion downwards along the stem.

PubMed

Anfodillo, Tommaso; Deslauriers, Annie; Menardi, Roberto; Tedoldi, Laura; Petit, Giai; Rossi, Sergio

2012-01-01

The diameter of vascular conduits increases towards the stem base. It has been suggested that this profile is an efficient anatomical feature for reducing the hydraulic resistance when trees grow taller. However, the mechanism that controls the cell diameter along the plant is not fully understood. The timing of cell differentiation along the stem was investigated. Cambial activity and cell differentiation were investigated in a Picea abies tree (11.5 m in height) collecting microsamples at nine different heights (from 1 to 9 m) along the stem with a 4 d time interval. Wood sections (8-12 μm thick) were stained and observed under a light microscope with polarized light to differentiate the developing xylem cells. Cell wall lignification was detected using cresyl violet acetate. The first enlarging cells appeared almost simultaneously along the tree axis indicating that cambium activation is not height-dependent. A significant increase in the duration of the cell expansion phase was observed towards the tree base: at 9 m from the ground, xylem cells expanded for 7 d, at 6 m for 14 d, and at 3 m for 19 d. The duration of the expansion phase is positively correlated with the lumen area of the tracheids (r(2)=0.68, P < 0.01) at the same height. By contrast, thickness of the cell wall of the earlywood did not show any trend with height. The lumen area of the conduits down the stem appeared linearly dependent on time during which differentiating cells remained in the expansion phase. However, the inductive signal of such long-distance patterned differentiation remains to be identified.

Computational Reconstruction of NFκB Pathway Interaction Mechanisms during Prostate Cancer

PubMed Central

Börnigen, Daniela; Tyekucheva, Svitlana; Wang, Xiaodong; Rider, Jennifer R.; Lee, Gwo-Shu; Mucci, Lorelei A.; Sweeney, Christopher; Huttenhower, Curtis

2016-01-01

Molecular research in cancer is one of the largest areas of bioinformatic investigation, but it remains a challenge to understand biomolecular mechanisms in cancer-related pathways from high-throughput genomic data. This includes the Nuclear-factor-kappa-B (NFκB) pathway, which is central to the inflammatory response and cell proliferation in prostate cancer development and progression. Despite close scrutiny and a deep understanding of many of its members’ biomolecular activities, the current list of pathway members and a systems-level understanding of their interactions remains incomplete. Here, we provide the first steps toward computational reconstruction of interaction mechanisms of the NFκB pathway in prostate cancer. We identified novel roles for ATF3, CXCL2, DUSP5, JUNB, NEDD9, SELE, TRIB1, and ZFP36 in this pathway, in addition to new mechanistic interactions between these genes and 10 known NFκB pathway members. A newly predicted interaction between NEDD9 and ZFP36 in particular was validated by co-immunoprecipitation, as was NEDD9's potential biological role in prostate cancer cell growth regulation. We combined 651 gene expression datasets with 1.4M gene product interactions to predict the inclusion of 40 additional genes in the pathway. Molecular mechanisms of interaction among pathway members were inferred using recent advances in Bayesian data integration to simultaneously provide information specific to biological contexts and individual biomolecular activities, resulting in a total of 112 interactions in the fully reconstructed NFκB pathway: 13 (11%) previously known, 29 (26%) supported by existing literature, and 70 (63%) novel. This method is generalizable to other tissue types, cancers, and organisms, and this new information about the NFκB pathway will allow us to further understand prostate cancer and to develop more effective prevention and treatment strategies. PMID:27078000

Remarkable NO oxidation on single supported platinum atoms

DOE PAGES

Narula, Chaitanya K.; Allard, Lawrence F.; Stocks, G. M.; ...

2014-11-28

Our first-principles density functional theoretical modeling suggests that NO oxidation is feasible on fully oxidized single θ-alumina-supported platinum atoms via a modified Langmuir-Hinshelwood pathway. This is in contrast to the known decrease in NO oxidation activity of supported platinum with decreasing Pt particle size believed to be due to increased platinum oxidation. In order to validate our theoretical study, we evaluated single θ-Al 2O 3-supported platinum atoms and found them to exhibit remarkable NO oxidation activity. A comparison of turnover frequencies (TOF) of single supported Pt atoms with those of platinum particles for NO oxidation shows that single supported Ptmore » atoms are as active as fully formed platinum particles. The overall picture of NO oxidation on supported Pt is that NO oxidation activity decreases with decreasing Pt particle size but accelerates when Pt is present only as single atoms.« less

Electronic collection of solved physics problems to encourage students’ active approach (not only to self study)

NASA Astrophysics Data System (ADS)

Koupilová, Zdeňka; Mandíková, Dana; Snětinová, Marie

2017-09-01

Ten years ago we started to develop a Collection of Fully Solved Problems aimed at introductory undergraduate and high school level students. The collection is specially designed to encourage students in an active approach to problem solving, e.g. to solve at least some parts of a problem on their own. Nowadays the Collection contains about 800 fully solved problems in physics in Czech and nearly 180 problems in English. It has several hundreds of unique visitors per school day. Based on user feedback, the collection is used by students mainly for their home study and by teachers as a supplementary material. The creation of the structured solution of the physics problems has proved to be a beneficial activity for prospective physics teachers (students of our department).

Covalent chromatography. Preparation of fully active papain from dried papaya latex

PubMed Central

Brocklehurst, Keith; Carlsson, Jan; Kierstan, Marek P. J.; Crook, Eric M.

1973-01-01

1. A Sepharose–(glutathione–2-pyridyl disulphide) conjugate has been prepared. 2. Its use in a new type of chromatography, covalent chromatography by thiol–disulphide interchange, is described. 3. With this technique, papain containing 1 intact catalytic site [thiol with high reactivity towards 2,2′-dipyridyl disulphide (2-Py-S-S-2-Py) at pH4] per mol of protein is readily prepared both from dried papaya latex and from commercial 2×crystallized partially active papain. 4. The catalysis of the hydrolysis of α-N-benzoyl-l-arginine ethyl ester at pH6.0, 25.0°C, I=0.3 by fully active papain thus prepared is characterized by Km=18.2±<0.1mm and kcat.=16.4±0.5s−1. PMID:4733241

Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats.

PubMed

Walsh, Kathryn R; Kuwabara, Jill T; Shim, Joon W; Wainford, Richard D

2016-01-15

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (μeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension. Copyright © 2016 the American Physiological Society.

How Secure Is Your Radiology Department? Mapping Digital Radiology Adoption and Security Worldwide.

PubMed

Stites, Mark; Pianykh, Oleg S

2016-04-01

Despite the long history of digital radiology, one of its most critical aspects--information security--still remains extremely underdeveloped and poorly standardized. To study the current state of radiology security, we explored the worldwide security of medical image archives. Using the DICOM data-transmitting standard, we implemented a highly parallel application to scan the entire World Wide Web of networked computers and devices, locating open and unprotected radiology servers. We used only legal and radiology-compliant tools. Our security-probing application initiated a standard DICOM handshake to remote computer or device addresses, and then assessed their security posture on the basis of handshake replies. The scan discovered a total of 2774 unprotected radiology or DICOM servers worldwide. Of those, 719 were fully open to patient data communications. Geolocation was used to analyze and rank our findings according to country utilization. As a result, we built maps and world ranking of clinical security, suggesting that even the most radiology-advanced countries have hospitals with serious security gaps. Despite more than two decades of active development and implementation, our radiology data still remains insecure. The results provided should be applied to raise awareness and begin an earnest dialogue toward elimination of the problem. The application we designed and the novel scanning approach we developed can be used to identify security breaches and to eliminate them before they are compromised.

A Global Perspective of Atmospheric CO2 Concentrations

NASA Technical Reports Server (NTRS)

Putman, William M.; Ott, Lesley; Darmenov, Anton; daSilva, Arlindo

2016-01-01

Carbon dioxide (CO2) is the most important greenhouse gas affected by human activity. About half of the CO2 emitted from fossil fuel combustion remains in the atmosphere, contributing to rising temperatures, while the other half is absorbed by natural land and ocean carbon reservoirs. Despite the importance of CO2, many questions remain regarding the processes that control these fluxes and how they may change in response to a changing climate. The Orbiting Carbon Observatory-2 (OCO-2), launched on July 2, 2014, is NASA's first satellite mission designed to provide the global view of atmospheric CO2 needed to better understand both human emissions and natural fluxes. This visualization shows how column CO2 mixing ratio, the quantity observed by OCO-2, varies throughout the year. By observing spatial and temporal gradients in CO2 like those shown, OCO-2 data will improve our understanding of carbon flux estimates. But, CO2 observations can't do that alone. This visualization also shows that column CO2 mixing ratios are strongly affected by large-scale weather systems. In order to fully understand carbon flux processes, OCO-2 observations and atmospheric models will work closely together to determine when and where observed CO2 came from. Together, the combination of high-resolution data and models will guide climate models towards more reliable predictions of future conditions.

Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target.

PubMed

Gilbert, Hamish T J; Hodson, Nathan; Baird, Pauline; Richardson, Stephen M; Hoyland, Judith A

2016-11-17

The aetiology of intervertebral disc (IVD) degeneration remains poorly understood. Painful IVD degeneration is associated with an acidic intradiscal pH but the response of NP cells to this aberrant microenvironmental factor remains to be fully characterised. The aim here was to address the hypothesis that acidic pH, similar to that found in degenerate IVDs, leads to the altered cell/functional phenotype observed during IVD degeneration, and to investigate the involvement of acid-sensing ion channel (ASIC) -3 in the response. Human NP cells were treated with a range of pH, from that of a non-degenerate (pH 7.4 and 7.1) through to mildly degenerate (pH 6.8) and severely degenerate IVD (pH 6.5 and 6.2). Increasing acidity of pH caused a decrease in cell proliferation and viability, a shift towards matrix catabolism and increased expression of proinflammatory cytokines and pain-related factors. Acidic pH resulted in an increase in ASIC-3 expression. Importantly, inhibition of ASIC-3 prevented the acidic pH induced proinflammatory and pain-related phenotype in NP cells. Acidic pH causes a catabolic and degenerate phenotype in NP cells which is inhibited by blocking ASIC-3 activity, suggesting that this may be a useful therapeutic target for treatment of IVD degeneration.

A simple new filter for nonlinear high-dimensional data assimilation

NASA Astrophysics Data System (ADS)

Tödter, Julian; Kirchgessner, Paul; Ahrens, Bodo

2015-04-01

The ensemble Kalman filter (EnKF) and its deterministic variants, mostly square root filters such as the ensemble transform Kalman filter (ETKF), represent a popular alternative to variational data assimilation schemes and are applied in a wide range of operational and research activities. Their forecast step employs an ensemble integration that fully respects the nonlinear nature of the analyzed system. In the analysis step, they implicitly assume the prior state and observation errors to be Gaussian. Consequently, in nonlinear systems, the analysis mean and covariance are biased, and these filters remain suboptimal. In contrast, the fully nonlinear, non-Gaussian particle filter (PF) only relies on Bayes' theorem, which guarantees an exact asymptotic behavior, but because of the so-called curse of dimensionality it is exposed to weight collapse. This work shows how to obtain a new analysis ensemble whose mean and covariance exactly match the Bayesian estimates. This is achieved by a deterministic matrix square root transformation of the forecast ensemble, and subsequently a suitable random rotation that significantly contributes to filter stability while preserving the required second-order statistics. The forecast step remains as in the ETKF. The proposed algorithm, which is fairly easy to implement and computationally efficient, is referred to as the nonlinear ensemble transform filter (NETF). The properties and performance of the proposed algorithm are investigated via a set of Lorenz experiments. They indicate that such a filter formulation can increase the analysis quality, even for relatively small ensemble sizes, compared to other ensemble filters in nonlinear, non-Gaussian scenarios. Furthermore, localization enhances the potential applicability of this PF-inspired scheme in larger-dimensional systems. Finally, the novel algorithm is coupled to a large-scale ocean general circulation model. The NETF is stable, behaves reasonably and shows a good performance with a realistic ensemble size. The results confirm that, in principle, it can be applied successfully and as simple as the ETKF in high-dimensional problems without further modifications of the algorithm, even though it is only based on the particle weights. This proves that the suggested method constitutes a useful filter for nonlinear, high-dimensional data assimilation, and is able to overcome the curse of dimensionality even in deterministic systems.

Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine.

PubMed

Zhang, Wei; Modén, Olof; Mannervik, Bengt

2010-07-30

Azathioprine has been clinically used for decades in connection with organ transplantation, autoimmune disease, and treatment of cancer. Toxic side-reactions are common and have been linked to the liberation of excessively high concentrations of 6-mercaptopurine and corresponding toxic metabolites. An allelic variant of thiopurine methyltransferase with low activity is associated with elevated concentrations of 6-mercaptopurine. However, other genetic markers remain to be identified in order to fully account for adverse reactions and efficacy failure. In the present study, we studied the five known allelic variants of human glutathione transferase A2-2 (GST A2-2) (EC 2.5.1.18), abundantly expressed in liver and efficiently catalyzing the bioactivation of azathioprine to release 6-mercaptopurine. All five variants exhibited high activity with azathioprine, but allelic variant E of GST A2-2 displayed a 3-4-fold elevated catalytic efficiency compared to the other variants. High GST activity can lead to overproduction of 6-mercaptopurine, and the nature of the multiple forms of GSTs in a patient will obviously affect the metabolism of azathioprine. In addition to GST A2-2, the polymorphic GST M1-1 is also highly active with azathioprine. Considering our findings, it appears that the genotypic and phenotypic variations in the GST complement may influence the presentation of adverse reactions in patients treated with azathioprine. Clinical trials will be required to clarify the impact of the GST expression in comparison with the established biomarker thiopurine methyltransferase as predictors of adverse reactions. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone

PubMed Central

Hutchinson, Mark R.; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

2008-01-01

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain. PMID:18662331

Initiation of ART during Early Acute HIV Infection Preserves Mucosal Th17 Function and Reverses HIV-Related Immune Activation

PubMed Central

Schuetz, Alexandra; Deleage, Claire; Sereti, Irini; Rerknimitr, Rungsun; Phanuphak, Nittaya; Phuang-Ngern, Yuwadee; Estes, Jacob D.; Sandler, Netanya G.; Sukhumvittaya, Suchada; Marovich, Mary; Jongrakthaitae, Surat; Akapirat, Siriwat; Fletscher, James L. K.; Kroon, Eugene; Dewar, Robin; Trichavaroj, Rapee; Chomchey, Nitiya; Douek, Daniel C.; O′Connell, Robert J.; Ngauy, Viseth; Robb, Merlin L.; Phanuphak, Praphan; Michael, Nelson L.; Excler, Jean-Louis; Kim, Jerome H.; de Souza, Mark S.; Ananworanich, Jintanat

2014-01-01

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNγ. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation. PMID:25503054

The role of telomeres and telomerase complex in haematological neoplasia: the length of telomeres as a marker of carcinogenesis and prognosis of disease.

PubMed

Gancarcíková, M; Zemanová, Z; Brezinová, J; Berková, A; Vcelíková, S; Smigová, J; Michalová, K

2010-01-01

Human telomeres (discovery of telomere structure and function has been recently awarded The Nobel Prize) consist of approximately 5-12 kb of tandem repeated sequences (TTAGGG)n and associated proteins capping chromosome ends which prevent degradation, loss of genetic information, end-to-end fusion, senescence and apoptosis. Due to the end-replication problem, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence when telomeres become critically short. Stabilization of the telomeric DNA through telomerase activation, unique reverse transcriptase, or activation of the alternative mechanism of telomere maintenance is essential if the cells are to survive and proliferate indefinitely. Telomerase is expressed during early development and remains fully active in specific germline cells, but is undetectable in most normal somatic cells. High level of telomerase activity is detected in almost 90% of human tumours and immortalized cell lines. The hematopoietic compartment may develop genetic instability as a consequence of telomere erosion, resulting in aplastic anaemia (AA) and increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Genetic instability associated with telomere dysfunction (i.e. short telomeres) is an early event in carcinogenesis. The molecular cytogenetic method telomere/centromere fluorescence in situ hybridization (T/C-FISH) can be used to characterize the telomere length of hematopoietic cells. This review describes recent advances in the molecular characterization of telomere system, the regulation of telomerase activity in cancer pathogenesis and shows that the telomeric length could be a potential clinical marker of hematologic neoplasia and prognosis of disease.

ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis

PubMed Central

Lagares, David; Ghassemi-Kakroodi, Parisa; Tremblay, Caroline; Santos, Alba; Probst, Clemens K.; Franklin, Alicia; Santos, Daniela M.; Grasberger, Paula; Ahluwalia, Neil; Montesi, Sydney B.; Shea, Barry S.; Black, Katharine E.; Knipe, Rachel; Blati, Meryem; Baron, Murray; Wu, Brian; Fahmi, Hassan; Gandhi, Rajiv; Pardo, Annie; Selman, Moisés; Wu, Jiangping; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne; Tager, Andrew M.; Kapoor, Mohit

2017-01-01

Maladaptive wound healing responses to chronic tissue injury result in organ fibrosis. Fibrosis, which entails excessive extracellular matrix (ECM) deposition and tissue remodelling by activated myofibroblasts, leads to loss of proper tissue architecture and organ function; however the molecular mediators of myofibroblast activation remain to be fully identified. Here we identify soluble ephrin-B2 as a novel pro-fibrotic mediator in lung and skin fibrosis. We provide molecular, functional and translational evidence that the ectodomain of membrane-bound ephrin-B2 is shed from fibroblasts into the alveolar airspace after lung injury. Shedding of soluble ephrin-B2 (sEphrin-B2) promotes fibroblast chemotaxis and activation via EphB3/EphB4 receptor signaling. We found that mice lacking ephrin-B2 in fibroblasts are protected from skin and lung fibrosis and that a distintegrin and metalloproteinase 10 (ADAM10) is the major ephrin-B2 sheddase in fibroblasts. ADAM10 is induced by transforming growth factor-β1 (TGF-β1), and ADAM10-mediated sEphrin-B2 generation is required for TGF-β1–induced myofibroblast activation. Pharmacological inhibition of ADAM10 reduces sEphrin-B2 levels in bronchoalveolar lavage and prevents lung fibrosis in mice. Consistent with the mouse data, ADAM10/sEphrin-B2 signaling is upregulated in fibroblasts from human subjects with idiopathic pulmonary fibrosis. These results uncover a new molecular mechanism of tissue fibrogenesis and identify sEphrin-B2, its receptors Eph3/Eph4, and ADAM10 as potential therapeutic targets in the treatment of fibrotic diseases. PMID:29058717