MD Simulations of tRNA and Aminoacyl-tRNA Synthetases: Dynamics, Folding, Binding, and Allostery

PubMed Central

Li, Rongzhong; Macnamara, Lindsay M.; Leuchter, Jessica D.; Alexander, Rebecca W.; Cho, Samuel S.

2015-01-01

While tRNA and aminoacyl-tRNA synthetases are classes of biomolecules that have been extensively studied for decades, the finer details of how they carry out their fundamental biological functions in protein synthesis remain a challenge. Recent molecular dynamics (MD) simulations are verifying experimental observations and providing new insight that cannot be addressed from experiments alone. Throughout the review, we briefly discuss important historical events to provide a context for how far the field has progressed over the past few decades. We then review the background of tRNA molecules, aminoacyl-tRNA synthetases, and current state of the art MD simulation techniques for those who may be unfamiliar with any of those fields. Recent MD simulations of tRNA dynamics and folding and of aminoacyl-tRNA synthetase dynamics and mechanistic characterizations are discussed. We highlight the recent successes and discuss how important questions can be addressed using current MD simulations techniques. We also outline several natural next steps for computational studies of AARS:tRNA complexes. PMID:26184179

Database security and encryption technology research and application

NASA Astrophysics Data System (ADS)

Zhu, Li-juan

2013-03-01

The main purpose of this paper is to discuss the current database information leakage problem, and discuss the important role played by the message encryption techniques in database security, As well as MD5 encryption technology principle and the use in the field of website or application. This article is divided into introduction, the overview of the MD5 encryption technology, the use of MD5 encryption technology and the final summary. In the field of requirements and application, this paper makes readers more detailed and clearly understood the principle, the importance in database security, and the use of MD5 encryption technology.

Empathic and Self-Regulatory Processes Governing Doping Behavior

PubMed Central

Boardley, Ian D.; Smith, Alan L.; Mills, John P.; Grix, Jonathan; Wynne, Ceri

2017-01-01

Evidence associating doping behavior with moral disengagement (MD) has accumulated over recent years. However, to date, research examining links between MD and doping has not considered key theoretically grounded influences and outcomes of MD. As such, there is a need for quantitative research in relevant populations that purposefully examines the explanatory pathways through which MD is thought to operate. Toward this end, the current study examined a conceptually grounded model of doping behavior that incorporated empathy, doping self-regulatory efficacy (SRE), doping MD, anticipated guilt and self-reported doping/doping susceptibility. Participants were specifically recruited to represent four key physical-activity contexts and consisted of team- (n = 195) and individual- (n = 169) sport athletes and hardcore- (n = 125) and corporate- (n = 121) gym exercisers representing both genders (nmale = 371; nfemale = 239); self-reported lifetime prevalence of doping across the sample was 13.6%. Each participant completed questionnaires assessing the aforementioned variables. Structural equation modeling indicated strong support for all study hypotheses. Specifically, we established: (a) empathy and doping SRE negatively predicted reported doping; (b) the predictive effects of empathy and doping SRE on reported doping were mediated by doping MD and anticipated guilt; (c) doping MD positively predicted reported doping; (d) the predictive effects of doping MD on reported doping were partially mediated by anticipated guilt. Substituting self-reported doping for doping susceptibility, multisample analyses then demonstrated these predictive effects were largely invariant between males and females and across the four physical-activity contexts represented. These findings extend current knowledge on a number of levels, and in doing so aid our understanding of key psychosocial processes that may govern doping behavior across key physical-activity contexts. PMID:29018370

Empathic and Self-Regulatory Processes Governing Doping Behavior.

PubMed

Boardley, Ian D; Smith, Alan L; Mills, John P; Grix, Jonathan; Wynne, Ceri

2017-01-01

Evidence associating doping behavior with moral disengagement (MD) has accumulated over recent years. However, to date, research examining links between MD and doping has not considered key theoretically grounded influences and outcomes of MD. As such, there is a need for quantitative research in relevant populations that purposefully examines the explanatory pathways through which MD is thought to operate. Toward this end, the current study examined a conceptually grounded model of doping behavior that incorporated empathy, doping self-regulatory efficacy (SRE), doping MD, anticipated guilt and self-reported doping/doping susceptibility. Participants were specifically recruited to represent four key physical-activity contexts and consisted of team- ( n = 195) and individual- ( n = 169) sport athletes and hardcore- ( n = 125) and corporate- ( n = 121) gym exercisers representing both genders ( n male = 371; n female = 239); self-reported lifetime prevalence of doping across the sample was 13.6%. Each participant completed questionnaires assessing the aforementioned variables. Structural equation modeling indicated strong support for all study hypotheses. Specifically, we established: (a) empathy and doping SRE negatively predicted reported doping; (b) the predictive effects of empathy and doping SRE on reported doping were mediated by doping MD and anticipated guilt; (c) doping MD positively predicted reported doping; (d) the predictive effects of doping MD on reported doping were partially mediated by anticipated guilt. Substituting self-reported doping for doping susceptibility, multisample analyses then demonstrated these predictive effects were largely invariant between males and females and across the four physical-activity contexts represented. These findings extend current knowledge on a number of levels, and in doing so aid our understanding of key psychosocial processes that may govern doping behavior across key physical-activity contexts.

Influence of the electron cyclotron resonance plasma confinement on reducing the bremsstrahlung production of an electron cyclotron resonance ion source with metal-dielectric structures.

PubMed

Schachter, L; Stiebing, K E; Dobrescu, S

2009-01-01

The influence of metal-dielectric (MD) layers (MD structures) inserted into the plasma chamber of an electron cyclotron resonance ion source (ECRIS) onto the production of electron bremsstrahlung radiation has been studied in a series of dedicated experiments at the 14 GHz ECRIS of the Institut für Kernphysik der Universität Frankfurt. The IKF-ECRIS was equipped with a MD liner, covering the inner walls of the plasma chamber, and a MD electrode, covering the plasma-facing side of the extraction electrode. On the basis of similar extracted currents of highly charged ions, significantly reduced yields of bremsstrahlung radiation for the "MD source" as compared to the standard (stainless steel) source have been measured and can be explained by the significantly better plasma confinement in a MD source as compared to an "all stainless steel" ECRIS.

Volumetrics relate to the development of depression after traumatic brain injury.

PubMed

Maller, Jerome J; Thomson, Richard H S; Pannek, Kerstin; Bailey, Neil; Lewis, Philip M; Fitzgerald, Paul B

2014-09-01

Previous research suggests that many people who sustain a traumatic brain injury (TBI), even of the mild form, will develop major depression (MD). We previously reported white matter integrity differences between those who did and did not develop MD after mild TBI. In this current paper, we aimed to investigate whether there were also volumetric differences between these groups, as suggested by previous volumetric studies in mild TBI populations. A sample of TBI-with-MD subjects (N=14), TBI-without-MD subjects (N=12), MD-without-TBI (N=26) and control subjects (no TBI or MD, N=23), received structural MRI brain scans. T1-weighted data were analysed using the Freesurfer software package which produces automated volumetric results. The findings of this study indicate that (1) TBI patients who develop MD have reduced volume in temporal, parietal and lingual regions compared to TBI patients who do not develop MD, and (2) MD patients with a history of TBI have decreased volume in the temporal region compared to those who had MD but without a history of TBI. We also found that more severe MD in those with TBI-with-MD significantly correlated with reduced volume in anterior cingulate, temporal lobe and insula. These findings suggest that volumetric reduction to specific regions, including parietal, temporal and occipital lobes, after a mild TBI may underlie the susceptibility of these patients developing major depression, in addition to altered white matter integrity. Copyright © 2014 Elsevier B.V. All rights reserved.

Using molecular simulation to explore the nanoscale dynamics of the plant kinome.

PubMed

Moffett, Alexander S; Shukla, Diwakar

2018-03-09

Eukaryotic protein kinases (PKs) are a large family of proteins critical for cellular response to external signals, acting as molecular switches. PKs propagate biochemical signals by catalyzing phosphorylation of other proteins, including other PKs, which can undergo conformational changes upon phosphorylation and catalyze further phosphorylations. Although PKs have been studied thoroughly across the domains of life, the structures of these proteins are sparsely understood in numerous groups of organisms, including plants. In addition to efforts towards determining crystal structures of PKs, research on human PKs has incorporated molecular dynamics (MD) simulations to study the conformational dynamics underlying the switching of PK function. This approach of experimental structural biology coupled with computational biophysics has led to improved understanding of how PKs become catalytically active and why mutations cause pathological PK behavior, at spatial and temporal resolutions inaccessible to current experimental methods alone. In this review, we argue for the value of applying MD simulation to plant PKs. We review the basics of MD simulation methodology, the successes achieved through MD simulation in animal PKs, and current work on plant PKs using MD simulation. We conclude with a discussion of the future of MD simulations and plant PKs, arguing for the importance of molecular simulation in the future of plant PK research. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Swiss national MD-PhD-program: an outcome analysis.

PubMed

Kuehnle, Katrin; Winkler, David T; Meier-Abt, Peter J

2009-09-19

This study aims at a first evaluation of the outcome of the Swiss national MD-PhD program during the last 16 years. One hundred and twenty six former and current students in the Swiss national MD-PhD program were surveyed via a Web-based questionnaire in September 2007. Twenty-four questions assessed information regarding participant demographics, information on the PhD thesis and publication activity, current positions and research activity, as well as participant's opinions, attitudes and career goals. Eighty questionnaires were received from 126 MD-PhD students and graduates (63.5% response rate). The responders consisted of present students (36%), former graduates (56%), and dropouts (8%). The percentage of women in the program was 23%, and the average duration of the program was 4.2 +/- 1.4 years. Research interests were predominantly in the fields of neuroscience, immunology, molecular biology and cancer research. A considerable portion of the MD-PhD graduates had an excellent publication record stemming from their PhD research work, and 89% were planning to continue a research-orientated career. Over 50% of those MD-PhD graduates completing their thesis before 2002 had already reached an assistant or full professor position at the time of the survey. Nearly all participants considered the MD-PhD training helpful to their career and high quality standards were assigned to the acquired practical and intellectual skills. However, criticism was expressed concerning the general mentoring and the career related mentoring. Moreover, general mentoring and career related mentoring were significantly less well perceived in research groups employing more than seven PhD students at the same time. The MD-PhD students and graduates surveyed were satisfied with their education and most of them continued a research-orientated career. Regarding the overall positive evaluation, this study supports the view that MD-PhD graduates are well qualified for a successful career in academic medicine.

Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies.

PubMed

Omotuyi, Olaposi; Matsunaga, Hayato; Ueda, Hiroshi

2015-01-01

During preconditioning, lipopolysaccharide (LPS) selectively activates TLR4/MD-2/Toll/IL-1 receptor-domain-containing adaptor inducing IFN-β (TRIF) pathway instead of pro-inflammatory myeloid differentiation protein-88 (MyD88)/MyD88-adaptor-like protein (MAL) pathway. Extracellular prothymosin alpha (ProTα) is also known to selectively activate the TLR4/MD2/TRIF-IRF3 pathway in certain diseased conditions. In the current study, biophysical evidence for ProTα/TLR4/MD-2 complex formation and its interaction dynamics have been studied. Gravimetric assay was used to investigate ProTα/TLR4/MD-2 complex formation while molecular dynamics (MD) simulation was used to study its interaction dynamics. Through electrostatic interaction, full-length ProTα (F-ProTα) C-terminal peptide (aa 91 - 111) superficially interacts with similar TLR4/MD-2 (KD = 273.36 nm vs 16.07 μg/ml [LPS]) conformation with LPS at an overlapping three-dimensional space while F-ProTα is hinged to the TLR4 scaffold by one-amino acid shift-Mosoian domain (aa-51 - 90). Comparatively, F-ProTα better stabilizes MD-2 metastable states transition and mediates higher TLR4/MD-2 interaction than LPS. ProTα via its C-terminal peptide (aa 91 - 111) exhibits in vitro biophysical contact with TLR4/MD-2 complex conformation recognized by LPS at overlapping LPS-binding positions.

Enhanced conformational sampling of nucleic acids by a new Hamiltonian replica exchange molecular dynamics approach.

PubMed

Curuksu, Jeremy; Zacharias, Martin

2009-03-14

Although molecular dynamics (MD) simulations have been applied frequently to study flexible molecules, the sampling of conformational states separated by barriers is limited due to currently possible simulation time scales. Replica-exchange (Rex)MD simulations that allow for exchanges between simulations performed at different temperatures (T-RexMD) can achieve improved conformational sampling. However, in the case of T-RexMD the computational demand grows rapidly with system size. A Hamiltonian RexMD method that specifically enhances coupled dihedral angle transitions has been developed. The method employs added biasing potentials as replica parameters that destabilize available dihedral substates and was applied to study coupled dihedral transitions in nucleic acid molecules. The biasing potentials can be either fixed at the beginning of the simulation or optimized during an equilibration phase. The method was extensively tested and compared to conventional MD simulations and T-RexMD simulations on an adenine dinucleotide system and on a DNA abasic site. The biasing potential RexMD method showed improved sampling of conformational substates compared to conventional MD simulations similar to T-RexMD simulations but at a fraction of the computational demand. It is well suited to study systematically the fine structure and dynamics of large nucleic acids under realistic conditions including explicit solvent and ions and can be easily extended to other types of molecules.

Neurology Falls. Patient Falls Risk Assessment, Neurology Clinic, Johns Hopkins Hospital, Baltimore, MD

DTIC Science & Technology

2009-07-06

currently valid ()MB control number. PLEASE DO NOT RETURN YOf IR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE (DD-MM-YYYY) 21 JUL 2008 2. REPORT TYPE Final...Hospital, Baltimore, MD 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) LT John M Gardner, MSC, USN 5d. PROJECT...NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) Johns Hopkins Hospital, Baltimore, MD Residency Site

A Survey of Invasive Catheter Practices in US Burn Centers

DTIC Science & Technology

2012-12-01

exist. The purpose of this study was to define the breadth of current practices and identify areas of practice variation that may be targets for...Centers Robert L . Sheridan, MD,*|| Alice N. Neely, PhD,† Mayra A. Castillo, RN, BS,‡ Heather A. Shankowsky, RN,§ Shawn P. Fagan, MD,*|| Kevin K. Chung, MD...Practices in US Burn Centers 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sheridan R. L ., Neely A. N., Castillo M. A

Symptoms of muscle dysmorphia, body dysmorphic disorder, and eating disorders in a nonclinical population of adult male weightlifters in Australia.

PubMed

Nieuwoudt, Johanna E; Zhou, Shi; Coutts, Rosanne A; Booker, Ray

2015-05-01

The current study aimed to (a) determine the rates of symptoms of muscle dysmorphia (MD), body dysmorphic disorder (BDD), and eating disorder; (b) determine the relationships among symptoms of MD, BDD, and eating disorders; and (c) provide a comprehensive comparison of symptoms of MD, BDD, and eating disorders in a nonclinical population of adult male weightlifters in Australia. The participants (N = 648, mean age = 29.5 years, SD = 10.1) participated in an online survey, consisting of Muscle Appearance Satisfaction Scale, the Body Dysmorphic Disorder Questionnaire, and the Eating Attitude Test-26. Results indicated that 110 participants (17%) were at risk of having MD, 69 participants (10.6%) were at risk of having BDD, and 219 participants (33.8%) were at risk of having an eating disorder. Furthermore, 36 participants (5.6%) were found at risk of having both MD and BDD, and 60 participants (9.3%) were at risk of having both MD and an eating disorder. Significant correlations and associations were found between symptoms of MD and BDD, and symptoms of MD and eating disorders. Support was provided for the comorbidity of, and symptomatic similarities between, symptoms of MD and BDD, and symptoms of MD and eating disorders. This may reflect a shared pathogenesis between symptoms of MD, BDD, and eating disorders. Strength and conditioning professionals, exercise scientists, athletic trainers, and personal trainers should be aware that adult males who are working out with weights (i.e., free weights or machines) may be at increased risk of having MD, BDD, and eating disorders.

The Multidimensional Curriculum Model (MdCM)

ERIC Educational Resources Information Center

Vidergor, Hava E.

2010-01-01

The multidimensional Curriculum Model (MdCM) helps teachers to better prepare gifted and able students for our changing world, acquiring much needed skills. It is influenced by general learning theory of constructivism, notions of preparing students for 21st century, Teaching the Future Model, and current comprehensive curriculum models for…

Plasma effects on the passive external thermal control coating of Space Station Freedom

NASA Technical Reports Server (NTRS)

Carruth, Ralph, Jr.; Vaughn, Jason A.; Holt, James M.; Werp, Richard; Sudduth, Richard D.

1992-01-01

The current baseline chromic acid anodized thermal control coating on 6061-T6 aluminum meteoroid debris (M/D) shields for SSF has been evaluated. The degradation of the solar absorptance, alpha, and the thermal emittance, epsilon, of chromic acid anodized aluminum due to dielectric breakdown in plasma was measured to predict the on-orbit lifetime of the SSF M/D shields. The lifetime of the thermal control coating was based on the surface temperatures achieved with degradation of the thermal control properties, alpha and epsilon. The temperatures of each M/D shield from first element launch (FEL) through FEL+15 years were analyzed. It is shown that the baseline thermal control coating cannot withstand the -140 V potential between the conductive structure of the SSF and the current plasma environment.

Rates of glaucomatous visual field change in a large clinical population.

PubMed

Chauhan, Balwantray C; Malik, Rizwan; Shuba, Lesya M; Rafuse, Paul E; Nicolela, Marcelo T; Artes, Paul H

2014-06-10

To determine the rate of glaucomatous visual field change in routine clinical care. Mean deviation (MD) rate was computed in one randomly selected eye of all glaucoma patients and suspects with ≥5 examinations in a tertiary eye-care center. Proportions of "fast" (MD rate, <-1 to -2 dB/y) and "catastrophic" (<-2 dB/y) progressors were determined. The MD rates were computed in tertile groups by the number of examinations, baseline age, and MD. The MD rates were compared to the Canadian Glaucoma Study (CGS), a prospective study with IOP interventions mandated by visual field progression, by pairwise matching of patients by baseline MD. There were 2324 patients with median (interquartile range) baseline age and MD of 65 (56, 74) years and -2.44 (-5.44, -0.86) dB, and follow-up of 7.1 (4.8, 10.2) years with 8 (6, 11) examinations. The median MD rate was -0.05 (0.13, -0.30) dB/y, while the mean follow-up IOP was 17.1 (15.0, 19.7) mm Hg. The MD rate was progressively worse, with a doubling of fast and catastrophic progressors, with each tertile of increasing age. Worse MD rate was associated with lower follow-up IOP. Neither MD rate nor the number of fast and catastrophic progressors was significantly different in clinical care patients matched to CGS patients. Most patients under routine glaucoma care demonstrate slow rates of visual field progression. The MD rate in the current study was similar to an interventional prospective study, but considerably less negative compared to published studies with similar design. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

How are Canadian universities training and supporting undergraduate medical, physiotherapy and occupational therapy students for global health experiences in international low-resource settings?

PubMed

Bessette, Jennifer; Camden, Chantal

2016-12-27

Canadian medical (MD), physiotherapy (PT) and occupational therapy (OT) students increasingly show an interest in global health experiences (GHEs). As certain moral hazards can occur as a result of student GHEs, a growing consensus exists that universities must have an established selection process, in-depth pre-departure training (PDT), adequate onsite supervision and formal debriefing for their students. This study aimed to identify current practices in Canadian MD, PT and OT programs and discuss areas for improvement by comparing them with recommendations found in the literature. Canadian MD, PT and OT programs (n = 45) were invited to answer an online survey about their current practices for GHE support and training. The survey included 24 close-ended questions and 18 open-ended questions. Descriptive statistics and a thematic analysis were performed on the data and results were discussed in comparison with recommendations found in the literature. Twenty-three programs responded to the survey. Student selection processes varied across universities; examples included using academic performance, interviews and motivation letters. All but one MD program had mandatory PDT; content and teaching formats varied, as did training duration (2-38 hours). All but one MD program had onsite supervision; local clinicians were frequently involved. Debriefing, although not systematic, covered similar content; debriefing was variable in duration (1-8 hours). Many current practices are encouraging, but areas for improvement exist. Integrating global health content into the regular curriculum, with advanced study options for students participating in GHEs, could help universities standardize support and training.

Neurobiological Underpinnings of Math and Reading Learning Disabilities

ERIC Educational Resources Information Center

Ashkenazi, Sarit; Black, Jessica M.; Abrams, Daniel A.; Hoeft, Fumiko; Menon, Vinod

2013-01-01

The primary goal of this review is to highlight current research and theories describing the neurobiological basis of math (MD), reading (RD), and comorbid math and reading disability (MD+RD). We first describe the unique brain and cognitive processes involved in acquisition of math and reading skills, emphasizing similarities and differences in…

The relationship between anabolic androgenic steroids and muscle dysmorphia: a review.

PubMed

Rohman, Lebur

2009-01-01

This review explores the condition of muscle dysmorphia (MD) and its relationship with anabolic androgenic steroids (AAS). Particular emphasis is placed upon whether anabolic steroids are a predisposing, precipitating or perpetuating factor of MD. Furthermore, psychiatric complications of AAS abuse are examined. The current evidence from the literature suggests that AAS (ab)use is possibly a perpetuating factor in the evolution of MD. Psychiatric complications of AAS include mood and behavior changes, perceptual abnormalities, and withdrawal symptoms. In addition, there appears to be a credible dependence theory to AAS in fruition.

Advanced, Energy-Efficient Hybrid Membrane System for Industrial Water Reuse

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

Toy, Lora; Choi, Young Chul; Hendren, Zachary

In the U.S. manufacturing sector, current industrial water use practices are energy-intensive and utilize and discharge high volumes of waters, rendering them not sustainable especially in light of the growing scarcity of suitable water supplies. To help address this problem, the goal of this project was to develop an advanced, cost-effective, hybrid membrane-based water treatment system that can improve the energy efficiency of industrial wastewater treatment while allowing at least 50% water reuse efficiency. This hybrid process would combine emerging Forward Osmosis (FO) and Membrane Distillation (MD) technology components into an integrated FO-MD system that can beneficially utilize low-grade wastemore » heat (i.e., T < 450 °F) in industrial facilities to produce distilled-quality product water for reuse. In this project, laboratory-, bench-, and pilot-scale experiments on the hybrid FO-MD system were conducted for industrial wastewater treatment. It was demonstrated at laboratory, bench, and pilot scales that FO-MD membrane technology can concentrate brine to very high total dissolved solids (TDS) levels (>200,000 ppm) that are at least 2.5 times higher than the TDS level to which RO can achieve. In laboratory testing, currently available FO and MD membranes were tested to select for high-performing membranes with high salt rejection and high water flux. Multiple FO membrane/draw-salt solution combinations that gave high water flux with higher than 98% salt rejection were also identified. Reverse draw-salt fluxes were observed to be much lower for divalent salts than for monovalent salts. MD membranes were identified that had 99.9+% salt rejection and water flux as high as 50-90 L/(m 2·h) for flat-sheet membranes and >20 L/(m 2·h) for hollow fibers. In bench-scale testing, a single unit of commercially available FO and MD membrane modules were evaluated for continuous, integrated operation. Using the laboratory- and bench-scale test data, numerical modeling was performed on the FO and MD processes to estimate engineering parameters for a larger-scale pilot unit. Based on the experimental studies and modeling results, a pilot-scale, integrated FO-MD prototype unit was designed and built for trailer-mounted operation. This prototype system was fed real industrial wastewater, which could not be further treated by conventional technologies, from an oil production facility and was successfully operated for over 15 weeks without major stoppage. About 90% water recovery was possible, while concentrating the TDS from 12,000 ppm up to 190,500 ppm. The FO-MD prototype rejected most wastewater contaminants while producing water with <300 ppm TDS, even when the feed TDS was higher than 150,000 ppm. No chemical cleaning was necessary during the pilot testing period. Flushing the system with dechlorinated tap water was sufficient to reset the membranes for the next set of test conditions. Pilot performance and membrane autopsy showed that, even though the feed was concentrated more than 10 times, membrane fouling was unnoticeable and no defects were detected on the FO and MD membrane surfaces. This project demonstrated the technical feasibility of the hybrid FO-MD process by taking water already treated to the limit with the highest level of current technologies and further concentrating it 10-fold by using mostly low-cost materials. Because no membranes suitable for full-scale plant applications are available at present, economical feasibility of the hybrid technology is still uncertain, but it is expected that broader industry participation can further reduce FO-MD process costs.« less

Molecular dynamics simulations of metallic friction and of its dependence on electric currents - development and first results

NASA Astrophysics Data System (ADS)

Meintanis, Evangelos Anastasios

We have extended the HOLA molecular dynamics (MD) code to run slider-on-block friction experiments for Al and Cu. Both objects are allowed to evolve freely and show marked deformation despite the hardness difference. We recover realistic coefficients of friction and verify the importance of cold-welding and plastic deformations in dry sliding friction. Our first data also show a mechanism for decoupling between load and friction at high velocities. Such a mechanism can explain an increase in the coefficient of friction of metals with velocity. The study of the effects of currents on our system required the development of a suitable electrodynamic (ED) solver, as the disparity of MD and ED time scales threatened the efficiency of our code. Our first simulations combining ED and MD are presented.

Isolation and purification of Gallid herpesvirus 2 strains currently distributed in Japan.

PubMed

Machida, Yuka; Murata, Shiro; Matsuyama-Kato, Ayumi; Isezaki, Masayoshi; Taneno, Akira; Sakai, Eishi; Konnai, Satoru; Ohashi, Kazuhiko

2017-01-20

Gallid herpesvirus 2 (GaHV-2) causes malignant lymphomas in chickens (Marek's disease, MD). Although MD is controlled through vaccination efforts, field isolates of GaHV-2 have increased in virulence worldwide and even cause MD in vaccinated chickens. GaHV-2 strains are classified into four categories (mild, virulent, very virulent and very virulent +) based on the virulence exhibited in experimental infection in unvaccinated or MD-vaccinated susceptible chickens. Although MD cases are sporadically reported in Japan, the recent field strains of GaHV-2 in Japan have not been characterized. During isolation of recent field strains by using primary chicken kidney cell cultures, a method classically used for GaHV-2 isolation, vaccine strains were simultaneously isolated. Therefore, it is necessary to separate vaccine strains to characterize the virulence and pathogenicity of the GaHV-2 strains currently distributed in Japan. In this study, we prepared cell suspensions from the spleens of MD-symptomatic chickens, inoculated day-old-chicks and isolated GaHV-2 strains by primary chicken kidney cell cultures at 2-3 weeks post inoculation. The isolated strains were passaged several times on chicken embryo fibroblast cells, and PCR analysis revealed that the isolated strains were not contaminated with vaccine strains. Moreover, the contaminant vaccine strains were completely removed by the purification of plaques observed in chicken kidney cells. These procedures are necessary to isolate GaHV-2 field strains from vaccine strains in order to carry out future studies to characterize these strains and glean insights into GaHV-2 virulence and pathogenicity.

No Girls Allowed: Women in Male-Dominated Majors Experience Increased Gender Harassment and Bias.

PubMed

Dresden, Brooke E; Dresden, Alexander Y; Ridge, Robert D; Yamawaki, Niwako

2018-06-01

The prevalence of gender harassment in male-dominated workforces has been well established, but little is known regarding the experiences of women in male-dominated majors within academia. The current study examines the experiences and gender-related biases of 146 male and female students in male-dominated (MD) and gender-equivalent (GE) majors. This study hypothesizes that men from MD majors, as opposed to GE majors, will exhibit more explicit and implicit bias regarding women in positions of power and authority, resulting in a higher prevalence of gender harassment towards women in MD majors. Results showed that there was no significant difference in self-reported explicit bias against women in positions of power and authority between men from MD and GE majors, but there was significantly more implicit bias among men from MD majors as opposed to GE majors. Additionally, women from MD majors experienced significantly more gender harassment than women from GE majors. Implications of these findings and suggestions to assist those working in education to combat these biases and instances of harassment are discussed.

[MD PhD programs: Providing basic science education for ophthalmologists].

PubMed

Spaniol, K; Geerling, G

2015-06-01

Enrollment in MD PhD programs offers the opportunity of a basic science education for medical students and doctors. These programs originated in the USA where structured programs have been offered for many years, but now German universities also run MD PhD programs. The MD PhD programs provided by German universities were investigated regarding entrance requirements, structure and financing modalities. An internet and telephone-based search was carried out. Out of 34 German universities 22 offered MD PhD programs. At 15 of the 22 universities a successfully completed course of studies in medicine was required for enrollment, 7 programs admitted medical students in training and 7 programs required a medical doctoral thesis, which had to be completed with at least a grade of magna cum laude in 3 cases. Financing required scholarships in many cases. Several German universities currently offer MD PhD programs; however, these differ considerably regarding entrance requirements, structure and financing. A detailed analysis investigating the success rates of these programs (e.g. successful completion and career paths of graduates) would be of benefit.

Molecular dynamics-driven drug discovery: leaping forward with confidence.

PubMed

Ganesan, Aravindhan; Coote, Michelle L; Barakat, Khaled

2017-02-01

Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery. From classical MD methods to more sophisticated hybrid classical/quantum mechanical (QM) approaches, MD simulations are now able to offer extraordinary insights into ligand-receptor interactions. In this review, we discuss how the applications of MD approaches are significantly transforming current drug discovery and development efforts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Microsatellite markers associated with resistance to Marek's disease in commercial layer chickens.

PubMed

McElroy, J P; Dekkers, J C M; Fulton, J E; O'Sullivan, N P; Soller, M; Lipkin, E; Zhang, W; Koehler, K J; Lamont, S J; Cheng, H H

2005-11-01

The objective of the current study was to identify QTL conferring resistance to Marek's disease (MD) in commercial layer chickens. To generate the resource population, 2 partially inbred lines that differed in MD-caused mortality were intermated to produce 5 backcross families. Vaccinated chicks were challenged with very virulent plus (vv+) MD virus strain 648A at 6 d and monitored for MD symptoms. A recent field isolate of the MD virus was used because the lines were resistant to commonly used older laboratory strains. Selective genotyping was employed using 81 microsatellites selected based on prior results with selective DNA pooling. Linear regression and Cox proportional hazard models were used to detect associations between marker genotypes and survival. Significance thresholds were validated by simulation. Seven and 6 markers were significant based on proportion of false positive and false discovery rate thresholds less than 0.2, respectively. Seventeen markers were associated with MD survival considering a comparison-wise error rate of 0.10, which is about twice the number expected by chance, indicating that at least some of the associations represent true effects. Thus, the present study shows that loci affecting MD resistance can be mapped in commercial layer lines. More comprehensive studies are under way to confirm and extend these results.

The Future of Prostate Cancer Research and Treatment

Cancer.gov

On January 12, 2017 prostate cancer experts William Dahut, M.D. of the National Cancer Institute and Dr. Heather Cheng, M.D. of the University of Washington had a vibrant discussion about current and future research areas and treatment options for prostate cancer. The panel was moderated by Ana Fadich, MPH, CHES Vice President at Men’s Health of the Men's Health Network.

PuReMD-GPU: A reactive molecular dynamics simulation package for GPUs

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

Kylasa, S.B., E-mail: skylasa@purdue.edu; Aktulga, H.M., E-mail: hmaktulga@lbl.gov; Grama, A.Y., E-mail: ayg@cs.purdue.edu

2014-09-01

We present an efficient and highly accurate GP-GPU implementation of our community code, PuReMD, for reactive molecular dynamics simulations using the ReaxFF force field. PuReMD and its incorporation into LAMMPS (Reax/C) is used by a large number of research groups worldwide for simulating diverse systems ranging from biomembranes to explosives (RDX) at atomistic level of detail. The sub-femtosecond time-steps associated with ReaxFF strongly motivate significant improvements to per-timestep simulation time through effective use of GPUs. This paper presents, in detail, the design and implementation of PuReMD-GPU, which enables ReaxFF simulations on GPUs, as well as various performance optimization techniques wemore » developed to obtain high performance on state-of-the-art hardware. Comprehensive experiments on model systems (bulk water and amorphous silica) are presented to quantify the performance improvements achieved by PuReMD-GPU and to verify its accuracy. In particular, our experiments show up to 16× improvement in runtime compared to our highly optimized CPU-only single-core ReaxFF implementation. PuReMD-GPU is a unique production code, and is currently available on request from the authors.« less

Presence of muscle dysmorphia symptomology among male weightlifters.

PubMed

Hildebrandt, Tom; Schlundt, David; Langenbucher, James; Chung, Tammy

2006-01-01

Limited research exists on muscle dysmorphia (MD) in men and in nonclinical populations. The current study evaluated types of body image disturbance among 237 male weightlifters. Latent class analysis of 8 measures of body image disturbance revealed 5 independent types of respondents: Dysmorphic, Muscle Concerned, Fat Concerned, Normal Behavioral, and Normal. One-way analysis of variance of independent measures of body image disturbance and associated psychopathology confirmed significant differences between groups. The Dysmorphic group reported a pattern of body image disturbance consistent with MD by displaying a high overall level of body image disturbance, symptoms of associated psychopathology, steroid use, and appearance-controlling behavior. Findings generally supported classifying MD as a subtype of body dysmorphic disorder and an obsessive-compulsive spectrum disorder. Implications for studying body image disturbance in male weightlifters, and further evaluation of the MD diagnostic criteria are discussed.

Development of thalamocortical connections between the mediodorsal thalamus and the prefrontal cortex and its implication in cognition

PubMed Central

Ferguson, Brielle R.; Gao, Wen-Jun

2015-01-01

The mediodorsal thalamus (MD) represents a fundamental subcortical relay to the prefrontal cortex (PFC), and is thought to be highly implicated in modulation of cognitive performance. Additionally, it undergoes highly conserved developmental stages, which, when dysregulated, can have detrimental consequences. Embryonically, the MD experiences a tremendous surge in neurogenesis and differentiation, and disruption of this process may underlie the pathology in certain neurodevelopmental disorders. However, during the postnatal period, a vast amount of cell loss in the MD occurs. These together may represent an extended critical period for postnatal development, in which disturbances in the normal growth or reduction of the MD afferents to the PFC, can result in PFC-dependent cognitive, affective, or psychotic abnormalities. In this review, we explore the current knowledge supporting this hypothesis of a protracted critical period, and propose how developmental changes in the MD contribute to successful prefrontal cortical development and function. Specifically, we elaborate on the unique properties of MD-PFC connections compared with other thalamocortical afferents in sensory cortices, examine how MD-PFC innervation modulates synaptic transmission in the local prefrontal circuitry, and speculate on what occurs during postnatal development, particularly within the early neonatal stage, as well as juvenile and adolescent periods. Finally, we discuss the questions that remain and propose future experiments in order to provide perspective and novel insights into the cause of neuropsychiatric disorders associated with MD-PFC development. PMID:25620923

Online distribution channel increases article usage on Mendeley: a randomized controlled trial.

PubMed

Kudlow, Paul; Cockerill, Matthew; Toccalino, Danielle; Dziadyk, Devin Bissky; Rutledge, Alan; Shachak, Aviv; McIntyre, Roger S; Ravindran, Arun; Eysenbach, Gunther

2017-01-01

Prior research shows that article reader counts (i.e. saves) on the online reference manager, Mendeley, correlate to future citations. There are currently no evidenced-based distribution strategies that have been shown to increase article saves on Mendeley. We conducted a 4-week randomized controlled trial to examine how promotion of article links in a novel online cross-publisher distribution channel (TrendMD) affect article saves on Mendeley. Four hundred articles published in the Journal of Medical Internet Research were randomized to either the TrendMD arm ( n  = 200) or the control arm ( n  = 200) of the study. Our primary outcome compares the 4-week mean Mendeley saves of articles randomized to TrendMD versus control. Articles randomized to TrendMD showed a 77% increase in article saves on Mendeley relative to control. The difference in mean Mendeley saves for TrendMD articles versus control was 2.7, 95% CI (2.63, 2.77), and statistically significant ( p  < 0.01). There was a positive correlation between pageviews driven by TrendMD and article saves on Mendeley (Spearman's rho r  = 0.60). This is the first randomized controlled trial to show how an online cross-publisher distribution channel (TrendMD) enhances article saves on Mendeley. While replication and further study are needed, these data suggest that cross-publisher article recommendations via TrendMD may enhance citations of scholarly articles.

Brain Microstructure and Impulsivity Differ between Current and Past Methamphetamine Users.

PubMed

Andres, Tamara; Ernst, Thomas; Oishi, Kenichi; Greenstein, David; Nakama, Helenna; Chang, Linda

2016-09-01

Methamphetamine (Meth) use disorder continues to be highly prevalent worldwide. Meth users have higher impulsivity and brain abnormalities that may be different between current and past Meth users. The current study assessed impulsivity and depressive symptoms in 94 participants (27 current Meth users, 32 past Meth users and 35 non-drug user controls). Additionally, brain microstructure was assessed using diffusion tensor imaging (DTI); fractional anisotropy (FA) and mean diffusivity (MD) were assessed in the striatum, and FA, MD, radial and axial diffusivity were quantified in five white matter structures using DtiStudio.Across the three subject groups, current users had the highest self-reported impulsivity scores, while both Meth user groups had larger striatal structures than the controls. Past Meth users had the highest FA and lowest MD in the striatum, which is likely due to greater magnetic susceptibility from higher iron content and greater dendritic spine density. In white matter tracts, current Meth users had higher AD than past users, indicating greater water diffusion along the axons, and suggesting inflammation with axonal swelling. In contrast, past users had the lowest AD, indicating more restricted diffusion, which might have resulted from reactive gliosis. Although current Meth users had greater impulsivity than past users, the brain microstructural abnormalities showed differences that may reflect different stages of neuroinflammation or iron-induced neurodegeneration. Combining current and past Meth users may lead to greater variability in studies of Meth users. Longitudinal studies are needed to further evaluate the relationship between recency of Meth use and brain microstructure.

The relationship of deiodinase 1 genotype and thyroid function to lifetime history of major depression in three independent populations.

PubMed

Philibert, Robert A; Beach, Steven R H; Gunter, Tracy D; Todorov, Alexandre A; Brody, Gene H; Vijayendran, Meeshanthini; Elliott, Lilly; Hollenbeck, Nancy; Russell, Daniel; Cutrona, Carolyn

2011-07-01

Major depression (MD) is often associated with disturbances of the hypothalamic/pituitary/thyroid (HPT) axis. Unfortunately, whether this association is secondary to common underlying genetic variation or whether the MD-associated disturbances in HPT function are chronic or state-dependent is unknown. To examine these questions, we genotyped 12 single nucleotide polymorphisms identified in previous genome wide association analyses of thyroid function in DNA contributed by 1,555 subjects from three longitudinal ethnically diverse studies that are well-characterized for lifetime MD and thyroid function. We then examined associations between genetic variants and key outcomes of thyroid stimulating hormone, free thyroxine (FT4) and depression. We confirmed prior findings that two variants in deiodinase 1 (DIO1), including a variant in the 3'UTR of DIO1 (rs11206244), were associated with altered FT4 levels in both White and African American subjects. We also found that rs11206244 genotype was associated with lifetime MD in White female subjects, in particular those from high-risk cohorts. However, we found no association of current FT4 levels with lifetime MD in either ethnic group. We conclude that genetic variation influencing thyroid function is a risk factor for MD. Given the evidence from prior studies, further investigations of role of HPT variation in etiology and treatment of MD are indicated. Copyright © 2011 Wiley-Liss, Inc.

The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

PubMed

Ozoe, Yoshihisa; Asahi, Miho; Ozoe, Fumiyo; Nakahira, Kunimitsu; Mita, Takeshi

2010-01-01

A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels. Copyright 2009 Elsevier Inc. All rights reserved.

Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS-induced acute lung injury

PubMed Central

Zhang, Yali; Wu, Jianzhang; Ying, Shilong; Chen, Gaozhi; Wu, Beibei; Xu, Tingting; Liu, Zhiguo; Liu, Xing; Huang, Lehao; Shan, Xiaoou; Dai, Yuanrong; Liang, Guang

2016-01-01

Acute lung injury (ALI) is a life-threatening acute inflammatory disease with limited options available for therapy. Myeloid differentiation protein 2, a co-receptor of TLR4, is absolutely required for TLR4 sense LPS, and represents an attractive target for treating severe inflammatory diseases. In this study, we designed and synthesized 31 chalcone derivatives that contain the moiety of (E)-4-phenylbut-3-en-2-one, which we consider the core structure of current MD2 inhibitors. We first evaluated the anti-inflammatory activities of these compounds in MPMs. For the most active compound 20, we confirmed that it is a specific MD2 inhibitor through a series of biochemical experiments and elucidated that it binds to the hydrophobic pocket of MD2 via hydrogen bonds with Arg90 and Tyr102 residues. Compound 20 also blocked the LPS-induced activation of TLR4/MD2 -downstream pro-inflammatory MAPKs/NF-κB signaling pathways. In a rat model with ALI induced by intracheal LPS instillation, administration with compound 20 exhibited significant protective effect against ALI, accompanied by the inhibition of TLR4/MD2 complex formation in lung tissues. Taken together, the results of this study suggest the specific MD2 inhibitor from chalcone derivatives we identified is a potential candidate for treating acute inflammatory diseases. PMID:27118147

A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer

PubMed Central

Cheeseman, S L; Joel, S P; Chester, J D; Wilson, G; Dent, J T; Richards, F J; Seymour, M T

2002-01-01

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified ‘Modified de Gramont’ (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m−2), then ambulatory 46-h fluorouracil infusion (2000–3600 mg m−2, cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m−2. Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m−2 bolus + 2800 mg m−2 46-h infusion. A lower dose of 400 mg m−2 bolus + 2400 mg m−2 infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC0–48 h) at this lower dose is equivalent to dG. With OxMdG, grade 3–4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial. British Journal of Cancer (2002) 87, 393–399. doi:10.1038/sj.bjc.6600467 www.bjcancer.com © 2002 Cancer Research UK PMID:12177775

ELF: An Extended-Lagrangian Free Energy Calculation Module for Multiple Molecular Dynamics Engines.

PubMed

Chen, Haochuan; Fu, Haohao; Shao, Xueguang; Chipot, Christophe; Cai, Wensheng

2018-06-18

Extended adaptive biasing force (eABF), a collective variable (CV)-based importance-sampling algorithm, has proven to be very robust and efficient compared with the original ABF algorithm. Its implementation in Colvars, a software addition to molecular dynamics (MD) engines, is, however, currently limited to NAMD and LAMMPS. To broaden the scope of eABF and its variants, like its generalized form (egABF), and make them available to other MD engines, e.g., GROMACS, AMBER, CP2K, and openMM, we present a PLUMED-based implementation, called extended-Lagrangian free energy calculation (ELF). This implementation can be used as a stand-alone gradient estimator for other CV-based sampling algorithms, such as temperature-accelerated MD (TAMD) and extended-Lagrangian metadynamics (MtD). ELF provides the end user with a convenient framework to help select the best-suited importance-sampling algorithm for a given application without any commitment to a particular MD engine.

Application of the multi-disciplinary thematic seminar method in two homecare cases - a comparative study.

PubMed

Scandurra, Isabella; Hägglund, Maria; Koch, Sabine

2008-01-01

A significant problem with current health information technologies is that they poorly support collaborative work of healthcare professionals, sometimes leading to a fragmentation of workflow and disruption of healthcare processes. This paper presents two homecare cases, both applying multi-disciplinary thematic seminars (MdTS) as a collaborative method for user needs elicitation and requirements specification. This study describes the MdTS application to elicit user needs from different perspectives to coincide with collaborative professions' work practices in two cases. Despite different objectives, the two cases validated that MdTS emphasized the "points of intersection" in cooperative work. Different user groups with similar, yet distinct needs reached a common understanding of the entire work process, agreed upon requirements and participated in the design of prototypes supporting cooperative work. MdTS was applicable in both exploratory and normative studies aiming to elicit the specific requirements in a cooperative environment.

Ligand Binding Pathways and Conformational Transitions of the HIV Protease.

PubMed

Miao, Yinglong; Huang, Yu-Ming M; Walker, Ross C; McCammon, J Andrew; Chang, Chia-En A

2018-03-06

It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein-drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500-2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ∼5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug-receptor interactions for the HIV protease and by extension many other target proteins.

Cognitive control dysfunction in emotion dysregulation and psychopathology of major depression (MD): Evidence from transcranial brain stimulation of the dorsolateral prefrontal cortex (DLPFC).

PubMed

Salehinejad, Mohammad Ali; Ghanavai, Elham; Rostami, Reza; Nejati, Vahid

2017-03-01

Previous studies showed that MD is associated with a variety of cognitive deficits and executive dysfunctions which can persist even in remitted states. However, the role of cognitive impairments in MD psychopathology and treatment is not fully understood. This article aims to discuss how executive functions central components (e.g., Working memory and attention) mediate MD psychopathology considering the role of dorsolateral prefrontal cortex (dLPFC) and present findings of a brain stimulation experiment to support this notion. The effect of transcranial direct current stimulation (tDCS) of the dLPFC on enhancing cognitive control functions was investigated. Twenty-four patients with MD (Experimental group=12, Control group=12) received 10 sessions of tDCS (2mA for 30min) over 10 consecutive days. The experimental group received active stimulation and the control group received sham stimulation. Participant's performance on cognitive functions (PAL, SRM, RVP and CRT from CANTAB) and their depression scores were assessed before and after tDCS. Results showed that brain stimulation of the dLPFC improved executive dysfunction in patients and a significant improvement on depression scores was also observed suggesting that cognitive control dysfunction may be a mediator in emotional dysregulation and psychopathology of MD. No follow-up investigation was done in this study which does not allow to infer long-term effect of tDCS. Low-focality of tDCS might have stimulated adjacent areas too. Cognitive components, namely cognitive control dysfunction, play role in MD psychopathology as they are involved in emotion dysregulation in MD. The amount of contribution of cognitive components in MD psychopathology is however, an open question. tDCS can be used as an intervention to improve cognitive dysfunction in MD. Copyright © 2017 Elsevier B.V. All rights reserved.

A novel matrix dispersion based on phospholipid complex for improving oral bioavailability of baicalein: preparation, in vitro and in vivo evaluations.

PubMed

Zhou, Yang; Dong, Wujun; Ye, Jun; Hao, Huazhen; Zhou, Junzhuo; Wang, Renyun; Liu, Yuling

2017-11-01

Phospholipid complex is one of the most successful approaches for enhancing oral bioavailability of poorly absorbed plant constituents. But the sticky property of phospholipids results in an unsatisfactory dissolution of drugs. In this study, a matrix dispersion of baicalein based on phospholipid complex (BaPC-MD) was first prepared by a discontinuous solvent evaporation method, in which polyvinylpyrrolidone-K30 (PVP-K30) was employed for improving the dispersibility of baicalein phospholipid complex (BaPC) and increasing dissolution of baicalein. The combination ratio of baicalein and phospholipids in BaPC-MD was 99.39% and baicalein was still in a complete complex state with phospholipid in BaPC-MD. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier Transform Infrared (FTIR) analyzes demonstrated that baicalein was fully transformed to an amorphous state in BaPC-MD and phospholipid complex formed. The water-solubility and n-octanol solubility of baicalein in BaPC-MD significantly increased compared with those of pure baicalein. Compared with baicalein and BaPC, the cumulative dissolution of BaPC-MD at 120 min increased 2.77- and 1.23-fold, respectively. In vitro permeability study in Caco-2 cells indicated that the permeability of BaPC-MD was remarkably higher than those of baicalein and BaPC. Pharmacokinetic study showed that the average C max of BaPC-MD was significantly increased compared to baicalein and BaPC. AUC 0-14 h of BaPC-MD was 5.01- and 1.91-fold of baicalein and BaPC, respectively. The novel BaPC-MD significantly enhanced the oral bioavailability of baicalein by improving the dissolution and permeability of baicalein without destroying the complexation state of baicalein and phospholipids. The current drug delivery system provided an optimal strategy to significantly enhance oral bioavailability for poorly water-soluble drugs.

Should MD-PhD programs encourage graduate training in disciplines beyond conventional biomedical or clinical sciences?

PubMed

O'Mara, Ryan J; Hsu, Stephen I; Wilson, Daniel R

2015-02-01

The goal of MD-PhD training programs is to produce physician-scientists with unique capacities to lead the future biomedical research workforce. The current dearth of physician-scientists with expertise outside conventional biomedical or clinical sciences raises the question of whether MD-PhD training programs should allow or even encourage scholars to pursue doctoral studies in disciplines that are deemed nontraditional, yet are intrinsically germane to major influences on health. This question is especially relevant because the central value and ultimate goal of the academic medicine community is to help attain the highest level of health and health equity for all people. Advances in medical science and practice, along with improvements in health care access and delivery, are steps toward health equity, but alone they will not come close to eliminating health inequalities. Addressing the complex health issues in our communities and society as a whole requires a biomedical research workforce with knowledge, practice, and research skills well beyond conventional biomedical or clinical sciences. To make real progress in advancing health equity, educational pathways must prepare physician-scientists to treat both micro and macro determinants of health. The authors argue that MD-PhD programs should allow and encourage their scholars to cross boundaries into less traditional disciplines such as epidemiology, statistics, anthropology, sociology, ethics, public policy, management, economics, education, social work, informatics, communications, and marketing. To fulfill current and coming health care needs, nontraditional MD-PhD students should be welcomed and supported as valuable members of our biomedical research workforce.

Construction, MD simulation, and hydrodynamic validation of an all-atom model of a monoclonal IgG antibody.

PubMed

Brandt, J Paul; Patapoff, Thomas W; Aragon, Sergio R

2010-08-04

At 150 kDa, antibodies of the IgG class are too large for their structure to be determined with current NMR methodologies. Because of hinge-region flexibility, it is difficult to obtain atomic-level structural information from the crystal, and questions regarding antibody structure and dynamics in solution remain unaddressed. Here we describe the construction of a model of a human IgG1 monoclonal antibody (trastuzumab) from the crystal structures of fragments. We use a combination of molecular-dynamics (MD) simulation, continuum hydrodynamics modeling, and experimental diffusion measurements to explore antibody behavior in aqueous solution. Hydrodynamic modeling provides a link between the atomic-level details of MD simulation and the size- and shape-dependent data provided by hydrodynamic measurements. Eight independent 40 ns MD trajectories were obtained with the AMBER program suite. The ensemble average of the computed transport properties over all of the MD trajectories agrees remarkably well with the value of the translational diffusion coefficient obtained with dynamic light scattering at 20 degrees C and 27 degrees C, and the intrinsic viscosity measured at 20 degrees C. Therefore, our MD results likely represent a realistic sampling of the conformational space that an antibody explores in aqueous solution. 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Combining Rosetta with molecular dynamics (MD): A benchmark of the MD-based ensemble protein design.

PubMed

Ludwiczak, Jan; Jarmula, Adam; Dunin-Horkawicz, Stanislaw

2018-07-01

Computational protein design is a set of procedures for computing amino acid sequences that will fold into a specified structure. Rosetta Design, a commonly used software for protein design, allows for the effective identification of sequences compatible with a given backbone structure, while molecular dynamics (MD) simulations can thoroughly sample near-native conformations. We benchmarked a procedure in which Rosetta design is started on MD-derived structural ensembles and showed that such a combined approach generates 20-30% more diverse sequences than currently available methods with only a slight increase in computation time. Importantly, the increase in diversity is achieved without a loss in the quality of the designed sequences assessed by their resemblance to natural sequences. We demonstrate that the MD-based procedure is also applicable to de novo design tasks started from backbone structures without any sequence information. In addition, we implemented a protocol that can be used to assess the stability of designed models and to select the best candidates for experimental validation. In sum our results demonstrate that the MD ensemble-based flexible backbone design can be a viable method for protein design, especially for tasks that require a large pool of diverse sequences. Copyright © 2018 Elsevier Inc. All rights reserved.

Genome-wide single-nucleotide polymorphism arrays demonstrate high fidelity of multiple displacement-based whole-genome amplification.

PubMed

Tzvetkov, Mladen V; Becker, Christian; Kulle, Bettina; Nürnberg, Peter; Brockmöller, Jürgen; Wojnowski, Leszek

2005-02-01

Whole-genome DNA amplification by multiple displacement (MD-WGA) is a promising tool to obtain sufficient DNA amounts from samples of limited quantity. Using Affymetrix' GeneChip Human Mapping 10K Arrays, we investigated the accuracy and allele amplification bias in DNA samples subjected to MD-WGA. We observed an excellent concordance (99.95%) between single-nucleotide polymorphisms (SNPs) called both in the nonamplified and the corresponding amplified DNA. This concordance was only 0.01% lower than the intra-assay reproducibility of the genotyping technique used. However, MD-WGA failed to amplify an estimated 7% of polymorphic loci. Due to the algorithm used to call genotypes, this was detected only for heterozygous loci. We achieved a 4.3-fold reduction of noncalled SNPs by combining the results from two independent MD-WGA reactions. This indicated that inter-reaction variations rather than specific chromosomal loci reduced the efficiency of MD-WGA. Consistently, we detected no regions of reduced amplification, with the exception of several SNPs located near chromosomal ends. Altogether, despite a substantial loss of polymorphic sites, MD-WGA appears to be the current method of choice to amplify genomic DNA for array-based SNP analyses. The number of nonamplified loci can be substantially reduced by amplifying each DNA sample in duplicate.

Effective Use of Females to Support Nation Building Operations in Afghanistan

DTIC Science & Technology

2009-04-01

Building. Santa Monica, CA: RAND Corporation, 2008. Donini , Antonio, et al,eds. Nation-Building Unraveled? Aid, Peace and Justice in Afghanistan...Conflict, and Peacekeeping, ed. Mazurana et al. Lanham, MD: Rowman and Littlefield Publishers, 2005. Frels, M . “Women Warriors: Oxymoron or Reality...MD: Rowman and Littlefield Publishers, 2005. McSally, M . “Women in Combat: Is the Current Policy Obsolete?” Master’s Thesis, Maxwell AFB, AL: Air

Dynamics of electrical double layer formation in room-temperature ionic liquids under constant-current charging conditions

NASA Astrophysics Data System (ADS)

Jiang, Xikai; Huang, Jingsong; Zhao, Hui; Sumpter, Bobby G.; Qiao, Rui

2014-07-01

We report detailed simulation results on the formation dynamics of an electrical double layer (EDL) inside an electrochemical cell featuring room-temperature ionic liquids (RTILs) enclosed between two planar electrodes. Under relatively small charging currents, the evolution of cell potential from molecular dynamics (MD) simulations during charging can be suitably predicted by the Landau-Ginzburg-type continuum model proposed recently (Bazant et al 2011 Phys. Rev. Lett. 106 046102). Under very large charging currents, the cell potential from MD simulations shows pronounced oscillation during the initial stage of charging, a feature not captured by the continuum model. Such oscillation originates from the sequential growth of the ionic space charge layers near the electrode surface. This allows the evolution of EDLs in RTILs with time, an atomistic process difficult to visualize experimentally, to be studied by analyzing the cell potential under constant-current charging conditions. While the continuum model cannot predict the potential oscillation under such far-from-equilibrium charging conditions, it can nevertheless qualitatively capture the growth of cell potential during the later stage of charging. Improving the continuum model by introducing frequency-dependent dielectric constant and density-dependent ion diffusion coefficients may help to further extend the applicability of the model. The evolution of ion density profiles is also compared between the MD and the continuum model, showing good agreement.

Dynamics of electrical double layer formation in room-temperature ionic liquids under constant-current charging conditions.

PubMed

Jiang, Xikai; Huang, Jingsong; Zhao, Hui; Sumpter, Bobby G; Qiao, Rui

2014-07-16

We report detailed simulation results on the formation dynamics of an electrical double layer (EDL) inside an electrochemical cell featuring room-temperature ionic liquids (RTILs) enclosed between two planar electrodes. Under relatively small charging currents, the evolution of cell potential from molecular dynamics (MD) simulations during charging can be suitably predicted by the Landau-Ginzburg-type continuum model proposed recently (Bazant et al 2011 Phys. Rev. Lett. 106 046102). Under very large charging currents, the cell potential from MD simulations shows pronounced oscillation during the initial stage of charging, a feature not captured by the continuum model. Such oscillation originates from the sequential growth of the ionic space charge layers near the electrode surface. This allows the evolution of EDLs in RTILs with time, an atomistic process difficult to visualize experimentally, to be studied by analyzing the cell potential under constant-current charging conditions. While the continuum model cannot predict the potential oscillation under such far-from-equilibrium charging conditions, it can nevertheless qualitatively capture the growth of cell potential during the later stage of charging. Improving the continuum model by introducing frequency-dependent dielectric constant and density-dependent ion diffusion coefficients may help to further extend the applicability of the model. The evolution of ion density profiles is also compared between the MD and the continuum model, showing good agreement.

MD-miniRNA could be a more accurate biomarker for prostate cancer screening compared with serum prostate-specific antigen level.

PubMed

Xue, Dong; Zhou, Cui-Xing; Shi, Yun-Bo; Lu, Hao; He, Xiao-Zhou

2015-05-01

Prostate cancer and prostatic hyperplasia detection remains a great challenge, lacking of effective non-invasive and specific diagnostic biomarkers. In the current study, we aimed to identify the relative expression of plasma MD-miniRNA and its diagnostic performance in differentiating prostate cancer and prostatic hyperplasia patients from healthy controls, compared with serum prostate-specific antigen (PSA) level. All of the clinical participants (63 prostate cancer patients, 32 prostatic hyperplasia patients, and 50 healthy controls) were obtained from the Third Affiliated Hospital of Suzhou University in China between January 2013 and April 2014. Clinical characteristics were well matched. Plasma samples were extracted to test the relative expression of MD-miniRNA using the method of qRT-PCR. SPSS 22.0 statistical software package was used to analyze the data and GraphPad Prism 6.0 was used to generate the graphs. Relativity expression of plasma MD-miniRNA was significantly upregulated in prostate cancer, compared with prostatic hyperplasia patients and healthy controls. Serum PSA level revealed similar differences among these groups. MD-miniRNA presented a relatively high diagnostic accuracy with AUC of 0.86 (95 % CI 0.80-0.93) in differentiating prostate cancer patients from healthy controls. Simultaneously, MD-miniRNA was able to discriminate prostate cancer patients from prostatic hyperplasia controls with AUC of 0.79 (95 % CI 0.70-0.88). In addition, MD-miniRNA displayed a better diagnostic performance than PSA level. However, the panel of these two biomarkers revealed the best diagnostic performance, compared with either single biomarker. Results of this study showed that plasma MD-miniRNA could serve as a promising and noninvasive biomarker for diagnosing prostate cancer. Further large-scale studies are needed to confirm its clinical diagnosis accuracy.

CallFUSE Version 3: A Data Reduction Pipeline for the Far Ultraviolet Spectroscopic Explorer

DTIC Science & Technology

2007-05-01

Earth orbit with an inclination of 25 to the equator and an approximately 100 minute orbital period. Data obtained with the instrument are reduced...throughout the mis- sion reveal that the gratings’ orbital motion depends on three parameters: beta angle (the angle between the target and the anti- Sun ...University, Bal- timore, MD; wvd@pha.jhu.edu. 3 Space Telescope Science Institute, ESS/SSG, Baltimore, MD. 4 Current address: Earth Orientation Department

A Fast Response Capability within NOAA/NOS/CO-OPS

DTIC Science & Technology

2007-01-01

A Fast Response Capability within NOAA/NOS/CO-OPS P. B. Burke NOAA/National Ocean Service/CO-OPS 1305 East-West Hwy. Silver Spring, MD 20910...USA pat.burke@noaa.gov T. Graff NOAA/National Ocean Service/CO-OPS 1305 East-West Hwy. Silver Spring, MD 20910 USA tammy.graff@noaa.gov... flotation hull, an instrumentation tower mounted atop the hull and a current meter mount with a mooring attachment. The triangular tower housed two

Hybrid MD-Nernst Planck Model of Alpha-hemolysin Conductance Properties

NASA Technical Reports Server (NTRS)

Cozmuta, Ioana; O'Keefer, James T.; Bose, Deepak; Stolc, Viktor

2006-01-01

Motivated by experiments in which an applied electric field translocates polynucleotides through an alpha-hemolysin protein channel causing ionic current transient blockade, a hybrid simulation model is proposed to predict the conductance properties of the open channel. Time scales corresponding to ion permeation processes are reached using the Poisson-Nemst-Planck (PNP) electro-diffusion model in which both solvent and local ion concentrations are represented as a continuum. The diffusion coefficients of the ions (K(+) and Cl(-)) input in the PNP model are, however, calculated from all-atom molecular dynamics (MD). In the MD simulations, a reduced representation of the channel is used. The channel is solvated in a 1 M KCI solution, and an external electric field is applied. The pore specific diffusion coefficients for both ionic species are reduced 5-7 times in comparison to bulk values. Significant statistical variations (17-45%) of the pore-ions diffusivities are observed. Within the statistics, the ionic diffusivities remain invariable for a range of external applied voltages between 30 and 240mV. In the 2D-PNP calculations, the pore stem is approximated by a smooth cylinder of radius approx. 9A with two constriction blocks where the radius is reduced to approx. 6A. The electrostatic potential includes the contribution from the atomistic charges. The MD-PNP model shows that the atomic charges are responsible for the rectifying behaviour and for the slight anion selectivity of the a-hemolysin pore. Independent of the hierarchy between the anion and cation diffusivities, the anionic contribution to the total ionic current will dominate. The predictions of the MD-PNP model are in good agreement with experimental data and give confidence in the present approach of bridging time scales by combining a microscopic and macroscopic model.

Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study.

PubMed

Buckland, G; Ros, M M; Roswall, N; Bueno-de-Mesquita, H B; Travier, N; Tjonneland, A; Kiemeney, L A; Sacerdote, C; Tumino, R; Ljungberg, B; Gram, I T; Weiderpass, E; Skeie, G; Malm, J; Ehrnström, R; Chang-Claude, J; Mattiello, A; Agnoli, C; Peeters, P H; Boutron-Ruault, M C; Fagherazzi, G; Clavel-Chapelon, F; Nilsson, L M; Amiano, P; Trichopoulou, A; Oikonomou, E; Tsiotas, K; Sánchez, M J; Overvad, K; Quirós, J R; Chirlaque, M D; Barricarte, A; Key, T J; Allen, N E; Khaw, K T; Wareham, N; Riboli, E; Kaaks, R; Boeing, H; Palli, D; Romieu, I; Romaguera, D; Gonzalez, C A

2014-05-15

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers. © 2013 UICC.

The Relationship of Deiodinase 1 Genotype and Thyroid Function to Lifetime History of Major Depression in Three Independent Populations

PubMed Central

Philibert, Robert A.; Beach, Steven R. H.; Gunter, Tracy D.; Todorov, Alexandre A.; Brody, Gene H.; Vijayendran, Meeshanthini; Elliott, Lilly; Hollenbeck, Nancy; Russell, Daniel; Cutrona, Carolyn

2011-01-01

Major depression (MD) is often associated with disturbances of the hypothalamic/pituitary/thyroid (HPT) axis. Unfortunately, whether this association is secondary to common underlying genetic variation or whether the MD-associated disturbances in HPT function are chronic or state-dependent is unknown. To examine these questions, we genotyped 12 single nucleotide polymorphisms identified in previous genome wide association analyses of thyroid function in DNA contributed by 1555 subjects from three longitudinal ethnically diverse studies that are well-characterized for lifetime major depression and thyroid function. We then examined associations between genetic variants and key outcomes of thyroid stimulating hormone (TSH), free thyroxine (FT4) and depression. We confirmed prior findings that two variants in deiodinase 1 (DIO1), including a variant in the 3’ UTR of DIO1 (rs11206244), were associated with altered free thyroxine (FT4) levels in both White and African American subjects. We also found that rs11206244 genotype was associated with lifetime MD in White female subjects, in particular those from high-risk cohorts. However, we found no association of current FT4 levels with lifetime MD in either ethnic group. We conclude that genetic variation influencing thyroid function is a risk factor for MD. Given the evidence from prior studies, further investigations of role of HPT variation in etiology and treatment of MD are indicated. PMID:21563302

Surgical physician assistants help solve contemporary problems.

PubMed

Blumm, Robert M; Condit, Doug

2003-06-01

Recent surveys performed by the AAPA estimate that in 2002 approximately 183 million visits were made to PAs and 223 million medications were prescribed or recommended by PAs. The AAPA estimates that just more than 46,000 PAs currently are in clinical practice, with New York and California having the largest numbers of practicing PAs. Helen Keller said, "The most pathetic person in the world is the person who has sight but no vision." Most individuals accept life and its shortcomings, but visionaries are different. They see not only that which is evident, but also that which exists in imagination. Visionary physicians and surgeons who aided in the creation of the physician assistant and use of PAs in surgery include: Eugene Stead, MD; John Kirklin, MD, FACS; E. Harvey Estes, Jr., MD; Richard Smith, MD, FACS; and Marvin Giledman, MD. They believed that well-educated nonphysicians could work alongside physicians as a team and, thus, expand the delivery of health care in America. PAs have crossed into the new millennium with new challenges. Together, as a team with supervising surgeons, PAs can meet the challenges and establish new alliances that will alleviate today's constraints. As Rear Adm. Kenneth P. Moritsugu, MD, MPH, Deputy Surgeon General, said, "Physician assistants are ideal partners and professionals in the nation's health system. They are colleagues with physicians to assure improved access to quality health care in a cost-effective manner.

Anesthetic Management of a Child With Unspecified Mitochondrial Disease in an Outpatient Dental Setting.

PubMed

Gordon, Taylor R; Montandon, Richard J

2017-01-01

Mitochondrial disease (MD) represents a category of metabolic disorders with a wide range of symptoms across a variety of organ systems. It occurs with an incidence of greater than 1:5000 and can be difficult to specifically diagnose because of the variety of clinical presentations and multiple genomic origins. Although phenotypically variable, MD symptoms often include hypotonia, cardiac defects, dysautonomia, and metabolic dysfunction. Mitochondrial disease presents a unique challenge in terms of anesthetic management, as many anesthetic drugs suppress mitochondrial function. Additional considerations may need to be made in order to evaluate the patient's metabolic compensation prior to surgery. This article presents an in-depth discussion of a case involving a nearly 10-year-old boy with a history of an unspecified form of MD, who presented for endodontic treatment of tooth No. 30 under deep sedation. The article also provides a thorough review of the current literature surrounding the anesthetic management of patients with MD.

Rational design of novel TLR4 ligands by in silico screening and their functional and structural characterization in vitro.

PubMed

Honegr, Jan; Malinak, David; Dolezal, Rafael; Soukup, Ondrej; Benkova, Marketa; Hroch, Lukas; Benek, Ondrej; Janockova, Jana; Kuca, Kamil; Prymula, Roman

2018-02-25

The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Microsecond Simulations of DNA and Ion Transport in Nanopores with Novel Ion-Ion and Ion-Nucleotides Effective Potentials

PubMed Central

De Biase, Pablo M.; Markosyan, Suren; Noskov, Sergei

2014-01-01

We developed a novel scheme based on the Grand-Canonical Monte-Carlo/Brownian Dynamics (GCMC/BD) simulations and have extended it to studies of ion currents across three nanopores with the potential for ssDNA sequencing: solid-state nanopore Si3N4, α-hemolysin, and E111N/M113Y/K147N mutant. To describe nucleotide-specific ion dynamics compatible with ssDNA coarse-grained model, we used the Inverse Monte-Carlo protocol, which maps the relevant ion-nucleotide distribution functions from an all-atom MD simulations. Combined with the previously developed simulation platform for Brownian Dynamic (BD) simulations of ion transport, it allows for microsecond- and millisecond-long simulations of ssDNA dynamics in nanopore with a conductance computation accuracy that equals or exceeds that of all-atom MD simulations. In spite of the simplifications, the protocol produces results that agree with the results of previous studies on ion conductance across open channels and provide direct correlations with experimentally measured blockade currents and ion conductances that have been estimated from all-atom MD simulations. PMID:24738152

Evolution of the Antidepressant Prescribing in Alzheimer's Disease and Related Disorders Between 2010 and 2014: Results from the French National Database on Alzheimer's Disease (BNA).

PubMed

David, Renaud; Manera, Valeria; Fabre, Roxane; Pradier, Christian; Robert, Philippe; Tifratene, Karim

2016-07-02

Safety warnings from health authorities are currently intended to limit the use of psychotropic agents in dementia-related conditions. Evidence concerning the use of antidepressants in dementia is, however, scarce and contradictory. To evaluate antidepressant use among individuals with Alzheimer's disease (AD) and related disorders in the French population between 2010 and 2014. Antidepressant prescriptions in individuals with AD, mixed dementia (MD), and vascular dementia (VaD) in the French National Alzheimer Database between 2010 and 2014 were analyzed (N = 199,544). Multivariate analysis showed an annual significant increase (p < 0.001) in the prescription rate of antidepressants from 26% (2010) to 31% (2014), and identified female gender, younger age, higher education, living in long-term facilities, more severe cognitive decline, and presence of vascular signs (VaD and MD) as associated factors for antidepressant prescribing. The annual increase of antidepressant prescribing among individuals with AD, MD, and VaD in French specialized settings may be partially related to the lack of current valuable medications for dementia-related behavioral symptoms.

Feature-selective Attention in Frontoparietal Cortex: Multivoxel Codes Adjust to Prioritize Task-relevant Information.

PubMed

Jackson, Jade; Rich, Anina N; Williams, Mark A; Woolgar, Alexandra

2017-02-01

Human cognition is characterized by astounding flexibility, enabling us to select appropriate information according to the objectives of our current task. A circuit of frontal and parietal brain regions, often referred to as the frontoparietal attention network or multiple-demand (MD) regions, are believed to play a fundamental role in this flexibility. There is evidence that these regions dynamically adjust their responses to selectively process information that is currently relevant for behavior, as proposed by the "adaptive coding hypothesis" [Duncan, J. An adaptive coding model of neural function in prefrontal cortex. Nature Reviews Neuroscience, 2, 820-829, 2001]. Could this provide a neural mechanism for feature-selective attention, the process by which we preferentially process one feature of a stimulus over another? We used multivariate pattern analysis of fMRI data during a perceptually challenging categorization task to investigate whether the representation of visual object features in the MD regions flexibly adjusts according to task relevance. Participants were trained to categorize visually similar novel objects along two orthogonal stimulus dimensions (length/orientation) and performed short alternating blocks in which only one of these dimensions was relevant. We found that multivoxel patterns of activation in the MD regions encoded the task-relevant distinctions more strongly than the task-irrelevant distinctions: The MD regions discriminated between stimuli of different lengths when length was relevant and between the same objects according to orientation when orientation was relevant. The data suggest a flexible neural system that adjusts its representation of visual objects to preferentially encode stimulus features that are currently relevant for behavior, providing a neural mechanism for feature-selective attention.

Comorbidity and Suicidality in Patients Diagnosed with Panic Disorder/Agoraphobia and Major Depression.

PubMed

Batinic, Borjanka; Opacic, Goran; Ignjatov, Tijana; Baldwin, David S

2017-06-01

Comorbidity of anxiety and depression (both current and lifetime) is associated with greater chronicity and an increased risk of suicidality. We wished to ascertain which symptom clusters had the strongest association with suicidality. Our aims were (1) to examine the presence of current comorbidity and suicidality in patients diagnosed with panic disorder/agoraphobia (PD/A) and major depression (MD), and their relationship with duration of psychiatric treatment and frequency of hospital admission; and (2) to examine which coexisting symptoms were most strongly predictive of suicidality in sub-groups and the overall group. The study sample comprised 100 patients with PD/A and MD. The following assessment instruments were applied: the Panic and Agoraphobia Scale, the Beck Anxiety Inventory, the Beck Depression Inventory-II, the Beck Scale for Suicide Ideation, the Obsessive-Compulsive Inventory-Revised, the Liebowitz Social Anxiety Scale and the Whiteley Index of Hypochondriasis. High rates of current comorbidity were seen in both groups. Patients with MD had significantly higher suicidality scores, but were also older, with a longer duration of psychiatric treatment and more frequent hospitalizations. In the overall group, psychiatric comorbidity was correlated with duration of psychiatric treatment and frequency of hospitalizations (with the exception of hypochondriasis which was not correlated with frequency of hospitalization). In both sub-groups and the overall group, suicidality was correlated with scores for all examined comorbidity (with the exception of hypochondriasis in the PD/A group): however, after multiple regression only obsessive-compulsive symptomatology predicted suicidality in all sub-groups and the overall group, as well as depression in the overall group. Depression supposed as dependent variable and obsessive-compulsive symptomatology as a mediator explained around 37% of the variance in suicidal ideation. Patients with PD/A or MD show high rates of current comorbidity. The effect of depression on suicidality was significant, but a non-trivial impact was also mediated by obsessive-compulsive symptomatology.

DEFINING THE RELEVANT OUTCOME MEASURES IN MEDICAL DEVICE ASSESSMENTS: AN ANALYSIS OF THE DEFINITION PROCESS IN HEALTH TECHNOLOGY ASSESSMENT.

PubMed

Jacobs, Esther; Antoine, Sunya-Lee; Prediger, Barbara; Neugebauer, Edmund; Eikermann, Michaela

2017-01-01

Defining relevant outcome measures for clinical trials on medical devices (MD) is complex, as there is a large variety of potentially relevant outcomes. The chosen outcomes vary widely across clinical trials making the assessment in evidence syntheses very challenging. The objective is to provide an overview on the current common procedures of health technology assessment (HTA) institutions in defining outcome measures in MD trials. In 2012-14, the Web pages of 126 institutions involved in HTA were searched for methodological manuals written in English or German that describe methods for the predefinition process of outcome measures. Additionally, the institutions were contacted by email. Relevant information was extracted. All process steps were performed independently by two reviewers. Twenty-four manuals and ten responses from the email request were included in the analysis. Overall, 88.5 percent of the institutions describe the type of outcomes that should be considered in detail and 84.6 percent agree that the main focus should be on patient relevant outcomes. Specifically related to MD, information could be obtained in 26 percent of the included manuals and email responses. Eleven percent of the institutions report a particular consideration of MD related outcomes. This detailed analysis on common procedures of HTA institutions in the context of defining relevant outcome measures for the assessment of MD shows that standardized procedures for MD from the perspective of HTA institutions are not widespread. This leads to the question if a homogenous approach should be implemented in the field of HTA on MD.

[Autism, genetics and synaptic function alterations].

PubMed

Perche, O; Laumonnier, F; Baala, L; Ardourel, M-Y; Menuet, A; Robin, V; Mortaud, S; Montécot-Dubourg, C; Richard, O; Pichon, J; Briault, S

2010-10-01

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

77 FR 64709 - Airworthiness Directives; MD Helicopters, Inc.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-23

... visual inspection, and if necessary, an eddy current inspection of the main rotor lower hub assembly... specifies an initial 100-hour and recurring 300-hour visual and eddy current inspections of the lower hub... a total cost per helicopter of $85 and a total cost of $1,020 for the fleet. Eddy current inspecting...

Power Projection: The Current and Future Relevance of the M1A1Tank to Marine Corps Capabilities

DTIC Science & Technology

2002-01-01

Kenneth W. Estes, Marines under Armor : The Marine Corps and the Armored Fighting Vehicle, 1916-2000 (Annapolis, MD: Naval institute Press, 2000), 183...is the M2 heavy barrel machine gun that has been in the U.S. inventory for decades. It can be fired from under armor and has a range of 1800 meters...Accessed 9 January 2002. Estes, Kenneth W. Marines under Armor : The Marine Corps and the Armored Fighting Vehicle, 1916-2000. Annapolis, MD

Cardiac involvement in female Duchenne and Becker muscular dystrophy carriers in comparison to their first-degree male relatives: a comparative cardiovascular magnetic resonance study.

PubMed

Florian, Anca; Rösch, Sabine; Bietenbeck, Michael; Engelen, Markus; Stypmann, Jörg; Waltenberger, Johannes; Sechtem, Udo; Yilmaz, Ali

2016-03-01

Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked recessive disorders associated with both skeletal myopathy and progressive cardiomyopathy in males. Female DMD/BMD carriers (DMDc/BMDc) are mostly free of skeletal muscle symptoms, but they are also prone to cardiomyopathy. The aim of the current study was to characterize the frequency, pattern, and extent of cardiomyopathy in female DMD/BMD carriers (DMDc/BMDc) in comparison to their first-degree male MD relatives. Thirty-six (age 44 ± 14 years) female MD carriers (20 DMDc and 16 BMDc) constituted the 'MD carrier group' and were prospectively enrolled. All MD carriers underwent a complete CMR study comprising cine- and late gadolinium enhancement (LGE) imaging. In 22 of these women ('female MD carrier comparison group', 7 DMD and 15 BMD), at least one first-degree male relative with a previously established diagnosis of MD underwent the same CMR protocol and was assigned to the 'male MD comparison group' (n = 24, 6 DMD and 18 BMD). In the total MD carrier group, 17 (47%) MD carriers had at least one pathological CMR finding [5 (14%) with a reduced left ventricular ejection fraction (LV-EF) and 16 (44%) with the presence of LGE]. All LGE-positive patients (n = 16) showed non-ischaemic LGE with subepicardial involvement of the LV lateral free wall being the most frequent pattern (13/16, 81%). Compared with BMDc, DMDc demonstrated more frequently a pathological CMR result (65 vs. 19%; P = 0.008)--in spite of being significantly younger (40 ± 11 vs. 50 ± 16 years, P = 0.038). In the male MD comparison group, the same LGE pattern as in female carriers was seen, but with a significantly higher prevalence of cardiac abnormalities compared with their female carrier relatives constituting the female MD comparison group (75 vs. 27%; P = 0.003). Cardiac involvement is a frequent finding in female carriers of DMD, but less frequently observed in carriers of BMD. Those DMDc and BMDc with cardiac involvement demonstrate the same myocardial fibrosis pattern as their male counterparts with overt disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Multiscale Modeling of Damage Processes in fcc Aluminum: From Atoms to Grains

NASA Technical Reports Server (NTRS)

Glaessgen, E. H.; Saether, E.; Yamakov, V.

2008-01-01

Molecular dynamics (MD) methods are opening new opportunities for simulating the fundamental processes of material behavior at the atomistic level. However, current analysis is limited to small domains and increasing the size of the MD domain quickly presents intractable computational demands. A preferred approach to surmount this computational limitation has been to combine continuum mechanics-based modeling procedures, such as the finite element method (FEM), with MD analyses thereby reducing the region of atomic scale refinement. Such multiscale modeling strategies can be divided into two broad classifications: concurrent multiscale methods that directly incorporate an atomistic domain within a continuum domain and sequential multiscale methods that extract an averaged response from the atomistic simulation for later use as a constitutive model in a continuum analysis.

European National Society Cardiovascular Journals

PubMed Central

Alfonso, F.; Ambrosio, G.; Pinto, F.J.; van der Wall, E.E.

2008-01-01

Anesti Kondili MD, Djamaleddine Nibouche MD, Karlen Adamyan MD, Kurt Huber MD, Hugo Ector MD, Izet Masic MD, Rumiana Tarnovska MD, Mario Ivanusa MD, Vladimír Stane˘k MD, Jørgen Videbæk MD, Mohamed Hamed MD, Alexandras Laucevicius MD, Pirjo Mustonen MD, Jean-Yves Artigou MD, Ariel Cohen MD, Mamanti Rogava MD, Michael Böhm MD, Eckart Fleck MD, Gerd Heusch MD, Rainer Klawki MD, Panos Vardas MD, Christodoulos Stefanadis MD, József Tenczer MD, Massimo Chiariello MD, Aleksandras Laucevicius MD, Joseph Elias MD, Halima Benjelloun MD, Olaf Rødevand MD, Piotr Kul/akowski MD, Edvard Apetrei MD, Victor A. Lusov MD, Rafael G. Oganov MD, Velibor Obradovic MD, Gabriel Kamensky MD, Miran F. Kenda MD, Christer Höglund MD, Thomas F. Lüscher MD, René Lerch MD, Moufid Jokhadar MD, Habib Haouala MD, Vedat Sansoy MD, Valentin Shumakov MD, Adam Timmis MD. (European National Society Cardiovascular Journals Editors, see Appendix for complete affiliations) PMID:18665206

Free-Energy Calculations. A Mathematical Perspective

NASA Technical Reports Server (NTRS)

Pohorille, Andrzej

2015-01-01

Ion channels are pore-forming assemblies of transmembrane proteins that mediate and regulate ion transport through cell walls. They are ubiquitous to all life forms. In humans and other higher organisms they play the central role in conducting nerve impulses. They are also essential to cardiac processes, muscle contraction and epithelial transport. Ion channels from lower organisms can act as toxins or antimicrobial agents, and in a number of cases are involved in infectious diseases. Because of their important and diverse biological functions they are frequent targets of drug action. Also, simple natural or synthetic channels find numerous applications in biotechnology. For these reasons, studies of ion channels are at the forefront of biophysics, structural biology and cellular biology. In the last decade, the increased availability of X-ray structures has greatly advanced our understanding of ion channels. However, their mechanism of action remains elusive. This is because, in order to assist controlled ion transport, ion channels are dynamic by nature, but X-ray crystallography captures the channel in a single, sometimes non-native state. To explain how ion channels work, X-ray structures have to be supplemented with dynamic information. In principle, molecular dynamics (MD) simulations can aid in providing this information, as this is precisely what MD has been designed to do. However, MD simulations suffer from their own problems, such as inability to access sufficiently long time scales or limited accuracy of force fields. To assess the reliability of MD simulations it is only natural to turn to the main function of channels - conducting ions - and compare calculated ionic conductance with electrophysiological data, mainly single channel recordings, obtained under similar conditions. If this comparison is satisfactory it would greatly increase our confidence that both the structures and our computational methodologies are sufficiently accurate. Channel conductance, defined as the ratio of ionic current through the channel to applied voltage, can be calculated in MD simulations by way of applying an external electric field to the system and counting the number of ions that traverse the channel per unit time. If the current is small, a voltage significantly higher than the experimental one needs to be applied to collect sufficient statistics of ion crossing events. Then, the calculated conductance has to be extrapolated to the experimental voltage using procedures of unknown accuracy. Instead, we propose an alternative approach that applies if ion transport through channels can be described with sufficient accuracy by the one-dimensional diffusion equation in the potential given by the free energy profile and applied voltage. Then, it is possible to test the assumptions of the equation, recover the full voltage/current dependence, determine the reliability of the calculated conductance and reconstruct the underlying (equilibrium) free energy profile, all from MD simulations at a single voltage. We will present the underlying theory, model calculations that test this theory and simulations on ion conductance through a channel that has been extensively studied experimentally. To our knowledge this is the first case in which the complete, experimentally measured dependence of the current on applied voltage has been reconstructed from MD simulations.

Practical landmarks for visual field disability in glaucoma.

PubMed

Saunders, Luke J; Russell, Richard A; Crabb, David P

2012-09-01

To assess whether mean deviation (MD) from automated perimetry is related to the visual field (VF) component for legal fitness to drive (LFTD) in glaucoma patients. Monocular 24-2 VFs of 2604 patients with bilateral VF damage were retrospectively investigated. Integrated visual fields were calculated and used as a surrogate to assess LFTD according to current UK driving licence criteria. The better eye MD (BEMD), worse eye MD (WEMD) and a measure utilising MD of both eyes were compared, to assess respective diagnostic capabilities to predict LFTD (using the integrated visual field surrogate test as the gold standard) and a 'Probability of Failure' (PoF) for various defect levels was calculated. BEMD appears to be a good predictor of the VF component for a patient's LFTD (receiver operating characteristic area under the curve: 96.2%); MDs from both eyes offered no significant extra diagnostic power (area under the curve: 96.4%). PoF for BEMD thresholds of ≤-10 dB and ≤-14 dB were 70 (95% CI 66% to 74%) and 92% (87% to 95%), respectively. There is a strong relationship between BEMD and a patient's LFTD. PoF values for LFTD associated with readily available MD values provide practical landmarks for VF disability in glaucoma.

Single-session tDCS-supported retraining does not improve fine motor control in musician's dystonia.

PubMed

Buttkus, Franziska; Baur, Volker; Jabusch, Hans-Christian; de la Cruz Gomez-Pellin, Maria; Paulus, Walter; Nitsche, Michael A; Altenmüller, Eckart

2011-01-01

Focal dystonia in musicians (MD) is a task-specific movement disorder with a loss of voluntary motor control during instrumental playing. Defective inhibition on different levels of the central nervous system is involved in the pathophysiology. Sensorimotor retraining is a therapeutic approach to MD and aims to establish non-dystonic movements. Transcranial direct current stimulation (tDCS) modulates cortical excitability and alters motor performance. In this study, tDCS of the motor cortex was expected to assist retraining at the instrument. Nine professional pianists suffering from MD were included in a placebo-controlled double-blinded study. Retraining consisted of slow, voluntarily controlled movements on the piano and was combined with tDCS. Patients were treated with three stimulation protocols: anodal tDCS, cathodal tDCS and placebo stimulation. No beneficial effects of single-session tDCS-supported sensorimotor retraining on fine motor control in pianists with MD were found in all three conditions. The main cause of the negative result of this study may be the short intervention time. One retraining session with a duration of 20 min seems not sufficient to improve symptoms of MD. Additionally, a single tDCS session might not be sufficient to modify sensorimotor learning of a highly skilled task in musicians with dystonia.

Cherry-picking functionally relevant substates from long md trajectories using a stratified sampling approach.

PubMed

Chandramouli, Balasubramanian; Mancini, Giordano

2016-01-01

Classical Molecular Dynamics (MD) simulations can provide insights at the nanoscopic scale into protein dynamics. Currently, simulations of large proteins and complexes can be routinely carried out in the ns-μs time regime. Clustering of MD trajectories is often performed to identify selective conformations and to compare simulation and experimental data coming from different sources on closely related systems. However, clustering techniques are usually applied without a careful validation of results and benchmark studies involving the application of different algorithms to MD data often deal with relatively small peptides instead of average or large proteins; finally clustering is often applied as a means to analyze refined data and also as a way to simplify further analysis of trajectories. Herein, we propose a strategy to classify MD data while carefully benchmarking the performance of clustering algorithms and internal validation criteria for such methods. We demonstrate the method on two showcase systems with different features, and compare the classification of trajectories in real and PCA space. We posit that the prototype procedure adopted here could be highly fruitful in clustering large trajectories of multiple systems or that resulting especially from enhanced sampling techniques like replica exchange simulations. Copyright: © 2016 by Fabrizio Serra editore, Pisa · Roma.

Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension.

PubMed

Elgebaly, Ahmed; Abdelazeim, Bassant; Mattar, Omar; Gadelkarim, Mohamed; Salah, Rehab; Negida, Ahmed

2016-06-01

Droxidopa has been approved for the treatment of neurogenic orthostatic hypotension (NOH) under the US Food and Drug Administration accelerated approval program, which warrants confirmatory evidence on long-term efficacy of droxidopa. Hereby, we synthesize evidence from published randomized controlled trials (RCTs) about the safety and efficacy of droxidopa for patients with neurogenic orthostatic hypotension. A computer literature search of PubMed, Scopus, Web of Science, and Cochrane Central was conducted using relevant keywords. Records were screened for eligible studies and data were extracted and synthesized using Review Manager version 5.3 for Windows. Subgroup analysis and sensitivity analysis were conducted to investigate long-term durability of droxidopa against placebo. Four RCTs with a total of 485 patients (droxidopa, n = 246; placebo, n = 239) were eligible for the final analysis. The mean difference (MD) of change in the main outcomes from baseline to endpoint favored droxidopa than placebo [Orthostatic Hypotension Questionnaire (OHQ) MD -0.61, P = 0.004; dizziness/lightheadedness score MD -0.83, P = 0.008; and standing systolic blood pressure (SBP) MD 4.09, P = 0.03]. The efficacy of droxidopa decreased gradually after 2 weeks, and its statistical significance was lost after 8 weeks (OHQ score MD -0.18, P = 0.61; dizziness/lightheadedness score MD -0.71, P = 0.11; and standing SBP MD 2.96, P = 0.29). None of the adverse events were significantly higher in the case of droxidopa compared to placebo. Droxidopa is a safe and effective drug for the short-term management of NOH symptoms. However, current evidence is insufficient to confirm the efficacy of droxidopa for long-term use. Therefore, further studies with increased sample size are needed.

All-atom molecular dynamics simulations of spin labelled double and single-strand DNA for EPR studies.

PubMed

Prior, C; Danilāne, L; Oganesyan, V S

2018-05-16

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of electron paramagnetic resonance (EPR) spectra of spin labelled DNA. Models for two structurally different DNA spin probes with either the rigid or flexible position of the nitroxide group in the base pair, employed in experimental studies previously, have been developed. By the application of the combined MD-EPR simulation methodology we aimed at the following. Firstly, to provide a test bed against a sensitive spectroscopic technique for the recently developed improved version of the parmbsc1 force field for MD modelling of DNA. The predicted EPR spectra show good agreement with the experimental ones available from the literature, thus confirming the accuracy of the currently employed DNA force fields. Secondly, to provide a quantitative interpretation of the motional contributions into the dynamics of spin probes in both duplex and single-strand DNA fragments and to analyse their perturbing effects on the local DNA structure. Finally, a combination of MD and EPR allowed us to test the validity of the application of the Model-Free (M-F) approach coupled with the partial averaging of magnetic tensors to the simulation of EPR spectra of DNA systems by comparing the resultant EPR spectra with those simulated directly from MD trajectories. The advantage of the M-F based EPR simulation approach over the direct propagation techniques is that it requires motional and order parameters that can be calculated from shorter MD trajectories. The reported MD-EPR methodology is transferable to the prediction and interpretation of EPR spectra of higher order DNA structures with novel types of spin labels.

Ensemble MD simulations restrained via crystallographic data: Accurate structure leads to accurate dynamics

PubMed Central

Xue, Yi; Skrynnikov, Nikolai R

2014-01-01

Currently, the best existing molecular dynamics (MD) force fields cannot accurately reproduce the global free-energy minimum which realizes the experimental protein structure. As a result, long MD trajectories tend to drift away from the starting coordinates (e.g., crystallographic structures). To address this problem, we have devised a new simulation strategy aimed at protein crystals. An MD simulation of protein crystal is essentially an ensemble simulation involving multiple protein molecules in a crystal unit cell (or a block of unit cells). To ensure that average protein coordinates remain correct during the simulation, we introduced crystallography-based restraints into the MD protocol. Because these restraints are aimed at the ensemble-average structure, they have only minimal impact on conformational dynamics of the individual protein molecules. So long as the average structure remains reasonable, the proteins move in a native-like fashion as dictated by the original force field. To validate this approach, we have used the data from solid-state NMR spectroscopy, which is the orthogonal experimental technique uniquely sensitive to protein local dynamics. The new method has been tested on the well-established model protein, ubiquitin. The ensemble-restrained MD simulations produced lower crystallographic R factors than conventional simulations; they also led to more accurate predictions for crystallographic temperature factors, solid-state chemical shifts, and backbone order parameters. The predictions for 15N R1 relaxation rates are at least as accurate as those obtained from conventional simulations. Taken together, these results suggest that the presented trajectories may be among the most realistic protein MD simulations ever reported. In this context, the ensemble restraints based on high-resolution crystallographic data can be viewed as protein-specific empirical corrections to the standard force fields. PMID:24452989

Impact of Ménière's Disease on Significant Others' Health and Lives.

PubMed

Manchaiah, Vinaya; Pyykkő, Ilmari; Levo, Hilla; Kentala, Erna

2018-01-01

Ménière's disease (MD) is a chronic and, in part, intermittent illness that poses multiple challenges for both the physical and psychological well-being of patients, as well as on those around them. The patients face psychosocial consequences, which include disruptions to life goals, employment, income, relationships, leisure activities, and daily living activities that also influence their family members and friends. However, there is a limited understanding of the impact of MD on significant others (SOs). The current study was aimed at identifying how the SOs of patients with MD respond to different aspects of the impact of the disorder on health and life (i.e., psychological aspects, activities, participation, and positive aspects). The study employed a cross-sectional survey design. The study sample was 186 SOs of patients with MD who were recruited through Finnish Ménière's Federation. Participants completed a 25-item structured questionnaire focusing on different aspects of the impact of the disorder on health and life, and also provided some demographic information. Data were analyzed using Kruskal-Wallis test, Pearson's correlation, and K-means cluster analysis techniques. Examination of response patterns suggests that the disorder had, on average, a marginal effect on SOs' psychological aspects, activities, and participation as the SOs generally focused on complaints. Interestingly, SOs reported some positive consequences as a result of their partners' condition. The results show a limited association between SOs' demographic variables and response patterns. The Pearson's correlation suggested a strong association between the subscales psychological aspects, activity limitations, and participation restrictions. Also, a weak negative correlation was observed among positive aspects and participation restrictions. The cluster analysis resulted in three clusters, namely, (1) "nonengaged," (2) "supportive," and (3) "concerned." The current study results identify that the SOs' reaction to patients' condition varies and this may be from coping with victimization. Although the impact of MD on SOs is limited, some of the SOs may have more severe consequences and may require rehabilitation. The information gathered about SOs' coping and adjustment in this study can also help while developing management and/or rehabilitation plan for people with MD. American Academy of Audiology

75 FR 59605 - National Veterinary Accreditation Program; Currently Accredited Veterinarians Performing...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

.... APHIS-2006-0093] RIN 0579-AC04 National Veterinary Accreditation Program; Currently Accredited... Veterinary Accreditation Program (NVAP) may continue to perform accredited duties and to elect to continue to..., National Veterinary Accreditation Program, VS, APHIS, 4700 River Road Unit 200, Riverdale, MD 20737; (301...

Characteristics and outcomes of Canadian MD/PhD program graduates: a cross-sectional survey

PubMed Central

Skinnider, Michael A.; Squair, Jordan W.; Twa, David D.W.; Ji, Jennifer X.; Kuzyk, Alexandra; Wang, Xin; Steadman, Patrick E.; Zaslavsky, Kirill; Dey, Ayan K.; Eisenberg, Mark J.; Gagné, Ève-Reine; HayGlass, Kent T.; Lewis, James F.; Margetts, Peter J.; Underhill, D. Alan; Rosenblum, Norman D.; Raymond, Lynn A.

2017-01-01

Background: Combined MD/PhD programs provide a structured path for physician-scientist training, but assessment of their success within Canada is limited by a lack of quantitative data. We collected outcomes data for graduates of Canadian MD/PhD programs. Methods: We developed and implemented a Web-based survey consisting of 41 questions designed to collect outcomes data for Canadian MD/PhD program alumni from 8 Canadian universities who had graduated before September 2015. Respondents were categorized into 2 groups according to whether they had or had not completed all training. Results: Of the 186 eligible alumni of MD/PhD programs, 139 (74.7%) completed the survey. A total of 136/138 respondents (98.6%) had completed or were currently completing residency training, and 66/80 (82%) had completed at least 1 postgraduate fellowship. Most (58 [83%]) of the 70 respondents who had completed all training were appointed as faculty at academic institutions, and 37 (53%) had been principal investigators on at least 1 recent funded project. Among the 58 respondents appointed at academic institutions, 44/57 (77%) dedicated at least 20% of their time to research, and 25/57 (44%) dedicated at least 50% to research. During their combined degree, 102/136 respondents (75.0%) published 3 or more first-author papers, and 133/136 (97.8%) matched with their first choice of specialty. The median length of physician-scientist training was 13.5 years. Most respondents graduated with debt despite having been supported by Canadian Institutes of Health Research MD/PhD studentships. Interpretation: Most Canadian MD/PhD program alumni pursued careers consistent with their physician-scientist training, which indicates that these programs are meeting their primary objective. Nevertheless, our findings highlight that a minority of these positions are research intensive; this finding warrants further study. Our data provide a baseline for future monitoring of the output of Canadian MD/PhD programs. PMID:28442493

Towards validated chemistry at extreme conditions: reactive MD simulations of shocked Polyvinyl Nitrate and Nitromethane

NASA Astrophysics Data System (ADS)

Islam, Md Mahbubul; Strachan, Alejandro

A detailed atomistic-level understanding of the ultrafast chemistry of detonation processes of high energy materials is crucial to understand their performance and safety. Recent advances in laser shocks and ultra-fast spectroscopy is yielding the first direct experimental evidence of chemistry at extreme conditions. At the same time, reactive molecular dynamics (MD) in current high-performance computing platforms enable an atomic description of shock-induced chemistry with length and timescales approaching those of experiments. We use MD simulations with the reactive force field ReaxFF to investigate the shock-induced chemical decomposition mechanisms of polyvinyl nitrate (PVN) and nitromethane (NM). The effect of shock pressure on chemical reaction mechanisms and kinetics of both the materials are investigated. For direct comparison of our simulation results with experimentally derived IR absorption data, we performed spectral analysis using atomistic velocity at various shock conditions. The combination of reactive MD simulations and ultrafast spectroscopy enables both the validation of ReaxFF at extreme conditions and contributes to the interpretation of the experimental data relating changes in spectral features to atomic processes. Office of Naval Research MURI program.

Constructing high-accuracy intermolecular potential energy surface with multi-dimension Morse/Long-Range model

NASA Astrophysics Data System (ADS)

Zhai, Yu; Li, Hui; Le Roy, Robert J.

2018-04-01

Spectroscopically accurate Potential Energy Surfaces (PESs) are fundamental for explaining and making predictions of the infrared and microwave spectra of van der Waals (vdW) complexes, and the model used for the potential energy function is critically important for providing accurate, robust and portable analytical PESs. The Morse/Long-Range (MLR) model has proved to be one of the most general, flexible and accurate one-dimensional (1D) model potentials, as it has physically meaningful parameters, is flexible, smooth and differentiable everywhere, to all orders and extrapolates sensibly at both long and short ranges. The Multi-Dimensional Morse/Long-Range (mdMLR) potential energy model described herein is based on that 1D MLR model, and has proved to be effective and accurate in the potentiology of various types of vdW complexes. In this paper, we review the current status of development of the mdMLR model and its application to vdW complexes. The future of the mdMLR model is also discussed. This review can serve as a tutorial for the construction of an mdMLR PES.

Dual diagnosis in Depression: treatment recommendations.

PubMed

Tirado Muñoz, Judit; Farré, Adriana; Mestre-Pintó, Joan; Szerman, Nestor; Torrens, Marta

2018-01-01

Comorbidity between substance use disorders (SUD) and major depression (MD) is the most common dual pathology in the field of addiction to substances and has prevalence rates ranging between 12% and 80%, which complicates the response to treatment and worsens the prognosis of patients. Differentiating between diagnoses of induced depressive episodes and primary depressive episodes concurrent to substance use is especially relevant for therapeutic management. This article presents the state of the art of the currently available pharmacologic treatments of comorbid depression in patients with SUD, taking into account the safety and risk of abuse of antidepressant drugs. Due to the fact that comorbidity of MD and SUD is frequent and presents greater psychopathological and medical severity, as well as worse social functioning, it is crucial to treat MD and SUD simultaneously using the integrated treatment model and not to treat both conditions separately.

Optimization of the molecular dynamics method for simulations of DNA and ion transport through biological nanopores.

PubMed

Wells, David B; Bhattacharya, Swati; Carr, Rogan; Maffeo, Christopher; Ho, Anthony; Comer, Jeffrey; Aksimentiev, Aleksei

2012-01-01

Molecular dynamics (MD) simulations have become a standard method for the rational design and interpretation of experimental studies of DNA translocation through nanopores. The MD method, however, offers a multitude of algorithms, parameters, and other protocol choices that can affect the accuracy of the resulting data as well as computational efficiency. In this chapter, we examine the most popular choices offered by the MD method, seeking an optimal set of parameters that enable the most computationally efficient and accurate simulations of DNA and ion transport through biological nanopores. In particular, we examine the influence of short-range cutoff, integration timestep and force field parameters on the temperature and concentration dependence of bulk ion conductivity, ion pairing, ion solvation energy, DNA structure, DNA-ion interactions, and the ionic current through a nanopore.

Enabling grand-canonical Monte Carlo: extending the flexibility of GROMACS through the GromPy python interface module.

PubMed

Pool, René; Heringa, Jaap; Hoefling, Martin; Schulz, Roland; Smith, Jeremy C; Feenstra, K Anton

2012-05-05

We report on a python interface to the GROMACS molecular simulation package, GromPy (available at https://github.com/GromPy). This application programming interface (API) uses the ctypes python module that allows function calls to shared libraries, for example, written in C. To the best of our knowledge, this is the first reported interface to the GROMACS library that uses direct library calls. GromPy can be used for extending the current GROMACS simulation and analysis modes. In this work, we demonstrate that the interface enables hybrid Monte-Carlo/molecular dynamics (MD) simulations in the grand-canonical ensemble, a simulation mode that is currently not implemented in GROMACS. For this application, the interplay between GromPy and GROMACS requires only minor modifications of the GROMACS source code, not affecting the operation, efficiency, and performance of the GROMACS applications. We validate the grand-canonical application against MD in the canonical ensemble by comparison of equations of state. The results of the grand-canonical simulations are in complete agreement with MD in the canonical ensemble. The python overhead of the grand-canonical scheme is only minimal. Copyright © 2012 Wiley Periodicals, Inc.

Wheeled mobility device transportation safety in fixed route and demand-responsive public transit vehicles within the United States.

PubMed

Frost, Karen L; van Roosmalen, Linda; Bertocci, Gina; Cross, Douglas J

2012-01-01

An overview of the current status of wheelchair transportation safety in fixed route and demand-responsive, non-rail, public transportation vehicles within the US is presented. A description of each mode of transportation is provided, followed by a discussion of the primary issues affecting safety, accessibility, and usability. Technologies such as lifts, ramps, securement systems, and occupant restraint systems, along with regulations and voluntary industry standards have been implemented with the intent of improving safety and accessibility for individuals who travel while seated in their wheeled mobility device (e.g., wheelchair or scooter). However, across both fixed route and demand-responsive transit systems a myriad of factors such as nonuse and misuse of safety systems, oversized wheeled mobility devices, vehicle space constraints, and inadequate vehicle operator training may place wheeled mobility device (WhMD) users at risk of injury even under non-impact driving conditions. Since WhMD-related incidents also often occur during the boarding and alighting process, the frequency of these events, along with factors associated with these events are described for each transit mode. Recommendations for improving WhMD transportation are discussed given the current state of

Theoretical analysis of oscillatory terms in lattice heat-current time correlation functions and their contributions to thermal conductivity

NASA Astrophysics Data System (ADS)

Pereverzev, Andrey; Sewell, Tommy

2018-03-01

Lattice heat-current time correlation functions for insulators and semiconductors obtained using molecular dynamics (MD) simulations exhibit features of both pure exponential decay and oscillatory-exponential decay. For some materials the oscillatory terms contribute significantly to the lattice heat conductivity calculated from the correlation functions. However, the origin of the oscillatory terms is not well understood, and their contribution to the heat conductivity is accounted for by fitting them to empirical functions. Here, a translationally invariant expression for the heat current in terms of creation and annihilation operators is derived. By using this full phonon-picture definition of the heat current and applying the relaxation-time approximation we explain, at least in part, the origin of the oscillatory terms in the lattice heat-current correlation function. We discuss the relationship between the crystal Hamiltonian and the magnitude of the oscillatory terms. A solvable one-dimensional model is used to illustrate the potential importance of terms that are omitted in the commonly used phonon-picture expression for the heat current. While the derivations are fully quantum mechanical, classical-limit expressions are provided that enable direct contact with classical quantities obtainable from MD.

Prediction of EPR Spectra of Lyotropic Liquid Crystals using a Combination of Molecular Dynamics Simulations and the Model-Free Approach.

PubMed

Prior, Christopher; Oganesyan, Vasily S

2017-09-21

We report the first application of fully atomistic molecular dynamics (MD) simulations to the prediction of the motional electron paramagnetic resonance (EPR) spectra of lyotropic liquid crystals in different aggregation states doped with a paramagnetic spin probe. The purpose of this study is twofold. First, given that EPR spectra are highly sensitive to the motions and order of the spin probes doped within lyotropic aggregates, simulation of EPR line shapes from the results of MD modelling provides an ultimate test bed for the force fields currently employed to model such systems. Second, the EPR line shapes are simulated using the motional parameters extracted from MD trajectories using the Model-Free (MF) approach. Thus a combined MD-EPR methodology allowed us to test directly the validity of the application of the MF approach to systems with multi-component molecular motions. All-atom MD simulations using the General AMBER Force Field (GAFF) have been performed on sodium dodecyl sulfate (SDS) and dodecyltrimethylammonium chloride (DTAC) liquid crystals. The resulting MD trajectories were used to predict and interpret the EPR spectra of pre-micellar, micellar, rod and lamellar aggregates. The predicted EPR spectra demonstrate good agreement with most of experimental line shapes thus confirming the validity of both the force fields employed and the MF approach for the studied systems. At the same time simulation results confirm that GAFF tends to overestimate the packing and the order of the carbonyl chains of the surfactant molecules. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Recovery from the anatomical effects of long-term monocular deprivation in cat lateral geniculate nucleus.

PubMed

Duffy, Kevin R; Fong, Ming-Fai; Mitchell, Donald E; Bear, Mark F

2018-02-01

Monocular deprivation (MD) imposed early in postnatal life elicits profound structural and functional abnormalities throughout the primary visual pathway. The ability of MD to modify neurons within the visual system is restricted to a so-called critical period that, for cats, peaks at about one postnatal month and declines thereafter so that by about 3 months of age MD has little effect. Recovery from the consequences of MD likewise adheres to a critical period that ends by about 3 months of age, after which the effects of deprivation are thought to be permanent and without capacity for reversal. The attenuation of plasticity beyond early development is a formidable obstacle for conventional therapies to stimulate recovery from protracted visual deprivation. In the current study we examined the efficacy of dark exposure and retinal inactivation with tetrodotoxin to promote anatomical recovery in the dorsal lateral geniculate nuclues (dLGN) from long-term MD started at the peak of the critical period. Whereas 10 days of dark exposure or binocular retinal inactivation were not better at promoting recovery than conventional treatment with reverse occlusion, inactivation of only the non-deprived (fellow) eye for 10 days produced a complete restoration of neuron soma size, and also reversed the significant loss of neurofilament protein within originally deprived dLGN layers. These results reveal a capacity for neural plasticity and recovery that is larger than anything previously observed following protracted MD in cat, and they highlight a possibility for alternative therapies applied at ages thought to be recalcitrant to recovery. © 2017 Wiley Periodicals, Inc.

Rhodotorula taiwanensis MD1149 produces hypoacetylated PEFA compounds with increased surface activity compared to Rhodotorula babjevae MD1169.

PubMed

Lyman, Mathew; Rubinfeld, Bonnee; Leif, Roald; Mulcahy, Heather; Dugan, Lawrence; Souza, Brian

2018-01-01

Biosurfactants have several desirable characteristics in the industrial sector: detergency, antimicrobial effects, skin hydration, and emulsibility. Several yeast glycolipids are currently being utilized in these capacities: sophorolipids, ustilagic acid, and mannosylerythritol lipids (MELs). An emerging class of glycolipids, termed polyol esters of fatty acids (PEFA), have recently been reported for Rhodotorula babjevae, a basidiomycetous yeast species that secretes hyperacetylated congeners of PEFA (typically with 3-6 acetylation modifications). While screening Rhodotorula species for surfactant production, we identified a new environmental isolate identified as Rhodotorula taiwanensis MD1149 that dropped the surface tension of the liquid medium, indicating that it produced a potent biosurfactant. Acid depolymerization of the purified biosurfactants, followed by gas chromatography-mass spectrometry (GC-MS) analysis revealed that the biosurfactants were composed of PEFA compounds composed mainly of mannitol and arabitol esters of 3-hydroxy fatty acid, 3-methoxy fatty acid, and fatty acids with a single double bond; chain lengths were mainly C16 and C18. Liquid chromatography-mass spectrometry (LC-MS) confirmed the predicted accurate mass of these compounds. Interestingly, PEFA compounds produced by Rhodotorula taiwanensis MD1149 were more surface active due to their hypoacetylation profile (0-4 acetylation modifications) compared to Rhodotorula babjevae MD1169. These disparate surface active properties, based on acetylation, change the hydrophilic-lipophilic balance (HLB) of these compounds, and their potential utility within industrial applications.

Current status of Marek’s disease in the United States & worldwide based on a questionnaire survey

USDA-ARS?s Scientific Manuscript database

A questionnaire was widely distributed in 2011 to estimate the global prevalence of Marek’s disease (MD) and gain a better understanding of current control strategies and future concerns. A total of 112 questionnaires were returned representing 116 countries from sources including national branch s...

Aqua: Current Status and Future

NASA Technical Reports Server (NTRS)

Oreopoulos, Lazaros; Parkinson, Claire L.

2014-01-01

This document was presented at the NASA Sounder Science Team Meeting held in Greenbelt, MD, September 30-October 2, 2014. The organizers of the meeting plan to post the presentations to a public website.

75 FR 52461 - Drawbridge Operation Regulation; Pocomoke River, Snow Hill, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-26

... this single leaf bascule drawbridge, has requested a temporary deviation from the current operating schedule to facilitate cleaning and painting the structure. Under the regular operating schedule, the...

75 FR 35611 - Airworthiness Directives; McDonnell Douglas Corporation Model DC-10-10, DC-10-10F, and MD-10-10F...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-23

... one-time high frequency eddy current inspection of fastener holes for cracks at the left and right... frequency eddy current inspection of fastener holes for cracks at the left and right side wing rear spar... frequency eddy current inspection for cracking of fastener holes at the left and right side wing rear spar...

75 FR 2831 - Airworthiness Directives; McDonnell Douglas Corporation Model DC-10-10, DC-10-10F, and MD-10-10F...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-19

... proposed AD would require a one-time high frequency eddy current inspection of fastener holes for cracks at... high frequency eddy current inspection of fastener holes for cracking at the left and right side wing... of this AD, do a one-time high frequency eddy current inspection for cracking of fastener holes at...

Omega-3 fatty acids supplementation for autism spectrum disorders (ASD).

PubMed

James, Stephen; Montgomery, Paul; Williams, Katrina

2011-11-09

It has been suggested that impairments associated with autism spectrum disorders (ASD) may be partially explained by deficits of omega-3 fatty acids, and that supplementation of these essential fatty acids may lead to improvement of symptoms. To review the efficacy of omega-3 fatty acids for improving core features of ASD (for example, social interaction, communication, and stereotypies) and associated symptoms. We searched the following databases on 2 June 2010: CENTRAL (2010, Issue 2), MEDLINE (1950 to May Week 3 2010), EMBASE (1980 to 2010 Week 21), PsycINFO (1806 to current), BIOSIS (1985 to current), CINAHL (1982 to current), Science Citation Index (1970 to current), Social Science Citation Index (1970 to current), metaRegister of Controlled Trials (20 November 2008) and ClinicalTrials.gov (10 December 2010). Dissertation Abstracts International was searched on 10 December 2008, but was no longer available to the authors or editorial base in 2010. All randomised controlled trials of omega-3 fatty acids supplementation compared to placebo in individuals with ASD. Three authors independently selected studies, assessed them for risk of bias and extracted relevant data. We conducted meta-analysis of the included studies for three primary outcomes (social interaction, communication, and stereotypy) and one secondary outcome (hyperactivity). We included two trials with a total of 37 children diagnosed with ASD who were randomised into groups that received either omega-3 fatty acids supplementation or a placebo. We excluded six trials because they were either non-randomised controlled trials, did not contain a control group, or the control group did not receive a placebo. Overall, there was no evidence that omega-3 supplements had an effect on social interaction (mean difference (MD) 0.82, 95% confidence interval (CI) -2.84 to 4.48, I(2) = 0%), communication (MD 0.62, 95% CI -0.89 to 2.14, I(2) = 0%), stereotypy (MD 0.77, 95% CI -0.69 to 2.22, I(2) = 8%), or hyperactivity (MD 3.46, 95% CI -0.79 to 7.70, I(2) = 0%). To date there is no high quality evidence that omega-3 fatty acids supplementation is effective for improving core and associated symptoms of ASD. Given the paucity of rigorous studies in this area, there is a need for large well-conducted randomised controlled trials that examine both high and low functioning individuals with ASD, and that have longer follow-up periods.

Thalamocortical and corticothalamic pathways differentially contribute to goal-directed behaviors in the rat

PubMed Central

Alcaraz, Fabien; Fresno, Virginie; Marchand, Alain R; Kremer, Eric J; Coutureau, Etienne

2018-01-01

Highly distributed neural circuits are thought to support adaptive decision-making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat. Using a chemogenetic approach to inhibit projection-defined dmPFC and MD neurons during an instrumental learning task, we show that thalamocortical and corticothalamic pathways differentially support goal attributes. Both pathways participate in adaptation to the current goal value, but only thalamocortical neurons are required to integrate current causal relationships. These data indicate that antiparallel flow of information within thalamocortical circuits may convey qualitatively distinct aspects of adaptive decision-making and highlight the importance of the direction of information flow within neural circuits. PMID:29405119

Current status and future challenges in T-cell receptor/peptide/MHC molecular dynamics simulations.

PubMed

Knapp, Bernhard; Demharter, Samuel; Esmaielbeiki, Reyhaneh; Deane, Charlotte M

2015-11-01

The interaction between T-cell receptors (TCRs) and major histocompatibility complex (MHC)-bound epitopes is one of the most important processes in the adaptive human immune response. Several hypotheses on TCR triggering have been proposed. Many of them involve structural and dynamical adjustments in the TCR/peptide/MHC interface. Molecular Dynamics (MD) simulations are a computational technique that is used to investigate structural dynamics at atomic resolution. Such simulations are used to improve understanding of signalling on a structural level. Here we review how MD simulations of the TCR/peptide/MHC complex have given insight into immune system reactions not achievable with current experimental methods. Firstly, we summarize methods of TCR/peptide/MHC complex modelling and TCR/peptide/MHC MD trajectory analysis methods. Then we classify recently published simulations into categories and give an overview of approaches and results. We show that current studies do not come to the same conclusions about TCR/peptide/MHC interactions. This discrepancy might be caused by too small sample sizes or intrinsic differences between each interaction process. As computational power increases future studies will be able to and should have larger sample sizes, longer runtimes and additional parts of the immunological synapse included. © The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Mathematical difficulties as decoupling of expectation and developmental trajectories

PubMed Central

McLean, Janet F.; Rusconi, Elena

2014-01-01

Recent years have seen an increase in research articles and reviews exploring mathematical difficulties (MD). Many of these articles have set out to explain the etiology of the problems, the possibility of different subtypes, and potential brain regions that underlie many of the observable behaviors. These articles are very valuable in a research field, which many have noted, falls behind that of reading and language disabilities. Here will provide a perspective on the current understanding of MD from a different angle, by outlining the school curriculum of England and the US and connecting these to the skills needed at different stages of mathematical understanding. We will extend this to explore the cognitive skills which most likely underpin these different stages and whose impairment may thus lead to mathematics difficulties at all stages of mathematics development. To conclude we will briefly explore interventions that are currently available, indicating whether these can be used to aid the different children at different stages of their mathematical development and what their current limitations may be. The principal aim of this review is to establish an explicit connection between the academic discourse, with its research base and concepts, and the developmental trajectory of abstract mathematical skills that is expected (and somewhat dictated) in formal education. This will possibly help to highlight and make sense of the gap between the complexity of the MD range in real life and the state of its academic science. PMID:24567712

Fibronectin-based scaffold domain proteins that bind myostatin: a patent evaluation of WO2014043344.

PubMed

Walker, Ryan G; Thompson, Thomas B

2015-05-01

Muscular dystrophies (MD) are commonly characterized by progressive loss of muscle mass and function. It is hypothesized that therapeutic blockade of the TGF-β ligand myostatin, a negative regulator of muscle mass, will stimulate muscle growth and restore muscle function. Although many anti-myostatin targets are currently being pursued in the clinical setting, the efficacies of the tested molecules have shown mixed results. The patent WO2014043344 describes a novel approach for myostatin inhibition using a modified fibronectin type III domain that could potentially be used to treat MD and other muscle-related pathologies.

Atomistic modeling of shock-induced void collapse in copper

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

Davila, L P; Erhart, P; Bringa, E M

2005-03-09

Nonequilibrium molecular dynamics (MD) simulations show that shock-induced void collapse in copper occurs by emission of shear loops. These loops carry away the vacancies which comprise the void. The growth of the loops continues even after they collide and form sessile junctions, creating a hardened region around the collapsing void. The scenario seen in our simulations differs from current models that assume that prismatic loop emission is responsible for void collapse. We propose a new dislocation-based model that gives excellent agreement with the stress threshold found in the MD simulations for void collapse as a function of void radius.

Potential of membrane distillation for production of high quality fruit juice concentrate.

PubMed

Onsekizoglu Bagci, Pelin

2015-01-01

Fruit juices are generally concentrated in order to improve the stability during storage and to reduce handling, packaging, and transportation costs. Thermal evaporation is the most widely used technique in industrial fruit juice concentrate production. In addition to high energy consumption, a large part of the characteristics determining the quality of the fresh juice including aroma, color, vitamins, and antioxidants undergoes remarkable alterations through the use of high operation temperatures. Increasing consumer demand for minimally or naturally processed stable products able to retain as much possible the uniqueness of the fresh fruit has engendered a growing interest for development of nonthermal approaches for fruit juice concentration. Among them, membrane distillation (MD) and its variants have attracted much attention for allowing very high concentrations to be reached under atmospheric pressure and temperatures near ambient temperature. This review will provide an overview of the current status and recent developments in the use of MD for concentration of fruit juices. In addition to the most basic concepts of MD variants, crucial suggestions for membrane selection and operating parameters will be presented. Challenges and future trends for industrial adaptation taking into account the possibility of integrating MD with other existing processes will be discussed.

Current activities and results of the Long Duration Exposure Facility Meteoroid and Debris Special Investigation Group

NASA Astrophysics Data System (ADS)

See, Thomas H.; Leago, Kimberly S.; Warren, Jack L.; Bernhard, Ronald P.; Zolensky, Michael E.

1994-03-01

Fiscal Year 1994 will bring to a close the initial investigative activities associated with the Long Duration Exposure Facility (LDEF). LDEF was a 14-faced spacecraft (i.e., 12-sided cylinder and two ends) which housed 54 different experimental packages in low-Earth orbit (LEO) from Apr. 1984 to Jan. 1990 (i.e., for approx. 5.75 years). Since LDEF's return, the Meteoroid & Debris Special Investigation Group (M&D SIG) has been examining various LDEF components in order to better understand and define the LEO particulate environment. Members of the M&D SIG at JSC in Houston, TX have been contributing to these studies by carefully examining and documenting all impact events found on LDEF's 6061-T6 aluminum Intercostals (i.e., one of the spacecraft's structural frame components). Unlike all other hardware on LDEF, the frame exposed significantly large surface areas of a single homogeneous material in all (i.e., 26) possible LDEF pointing directions. To date, 28 of the 68 Intercostals in the possession of the M&D SIG have been documented. This data, as well as similar information from various LDEF investigators, can be accessed through the M&D SIG Database which is maintained at JSC.

Current activities and results of the Long Duration Exposure Facility Meteoroid and Debris Special Investigation Group

NASA Technical Reports Server (NTRS)

See, Thomas H.; Leago, Kimberly S.; Warren, Jack L.; Bernhard, Ronald P.; Zolensky, Michael E.

1994-01-01

Fiscal Year 1994 will bring to a close the initial investigative activities associated with the Long Duration Exposure Facility (LDEF). LDEF was a 14-faced spacecraft (i.e., 12-sided cylinder and two ends) which housed 54 different experimental packages in low-Earth orbit (LEO) from Apr. 1984 to Jan. 1990 (i.e., for approx. 5.75 years). Since LDEF's return, the Meteoroid & Debris Special Investigation Group (M&D SIG) has been examining various LDEF components in order to better understand and define the LEO particulate environment. Members of the M&D SIG at JSC in Houston, TX have been contributing to these studies by carefully examining and documenting all impact events found on LDEF's 6061-T6 aluminum Intercostals (i.e., one of the spacecraft's structural frame components). Unlike all other hardware on LDEF, the frame exposed significantly large surface areas of a single homogeneous material in all (i.e., 26) possible LDEF pointing directions. To date, 28 of the 68 Intercostals in the possession of the M&D SIG have been documented. This data, as well as similar information from various LDEF investigators, can be accessed through the M&D SIG Database which is maintained at JSC.

The first nationwide survey of MD-PhDs in the social sciences and humanities: training patterns and career choices.

PubMed

Holmes, Seth M; Karlin, Jennifer; Stonington, Scott D; Gottheil, Diane L

2017-03-21

While several articles on MD-PhD trainees in the basic sciences have been published in the past several years, very little research exists on physician-investigators in the social sciences and humanities. However, the numbers of MD-PhDs training in these fields and the number of programs offering training in these fields are increasing, particularly within the US. In addition, accountability for the public funding for MD-PhD programs requires knowledge about this growing population of trainees and their career trajectories. The aim of this paper is to describe the first cohorts of MD-PhDs in the social sciences and humanities, to characterize their training and career paths, and to better understand their experiences of training and subsequent research and practice. This paper utilizes a multi-pronged recruitment method and novel survey instrument to examine an understudied population of MD-PhD trainees in the social sciences and humanities, many of whom completed both degrees without formal programmatic support. The survey instrument was designed to collect demographic, training and career trajectory data, as well as experiences of and perspectives on training and career. It describes their routes to professional development, characterizes obstacles to and predictors of success, and explores career trends. The average length of time to complete both degrees was 9 years. The vast majority (90%) completed a clinical residency, almost all (98%) were engaged in research, the vast majority (88%) were employed in academic institutions, and several others (9%) held leadership positions in national and international health organizations. Very few (4%) went into private practice. The survey responses supply recommendations for supporting current trainees as well as areas for future research. In general, MD-PhDs in the social sciences and humanities have careers that fit the goals of agencies providing public funding for training physician-investigators: they are involved in mutually-informative medical research, clinical practice, and teaching - working to improve our responses to the social, cultural, and political determinants of health and health care. These findings provide strong evidence for continued and improved funding and programmatic support for MD-PhD trainees in the social sciences and humanities.

Resting Energy Expenditure in Adults with Becker’s Muscular Dystrophy

PubMed Central

Jacques, Matthew F.; Orme, Paul; Smith, Jonathon; Morse, Christopher I.

2017-01-01

Purpose The purpose of this study was: 1) To compare Resting energy expenditure (REE) in adult males with Becker’s Muscular Dystrophy (BeMD, n = 21, 39 ±12 years) and healthy controls (CTRL, n = 12, 37 ±12 years) 2) Determine whether other physiological parameters correlate with REE in BeMD, and 3) Compare current prediction methods of REE with measured REE. Methods REE was calculated via indirect calorimetry using continuous, expired gas analysis following an overnight fast. Fat free mass (FFM) and fat mass were measured by bioelectrical impedance. B-mode ultrasound measured Tibialis Anterior (TA) and Gastrocnemius Medialis (GM) anatomical cross sectional area (ACSA). The Bone Specific Physical Activity Questionnaire measured physical activity. Results No difference in REE was found between CTRL and BeMD groups (1913 ±203 & 1786 ±324 Kcal respectively). Other physiological comparisons showed increased fat mass (+54%), decreased TA ACSA (-42%), increased GM ACSA (+25%) as well as reduced respiratory function (FVC -28%; FEV1−27%) in BeMD adults compared to controls. REE estimated from prediction equations (Schofield’s) in Muscular Dystrophy were different from measured REE (P<0.05, bias = -728kcal), while the Mifflin equation was no different from measured REE (r2 = 0.58, Bias = -8kcal). Within the present BeMD, REE predicted from FFM (REE = FFM x 34.57–270; r2 = 0.85) and body mass (REE = BM x 15.65 + 421.5; r2 = 0.66), were not different from measured REE (bias equals 0 and 0.2kcals, respectively) Conclusions Despite no differences in REE between CTRL and BeMD adults, increased fat masses highlights the requirement for explicit nutritional guidelines, as well as maintenance of physical activity levels, where possible. Prediction equations are frequently used in clinical settings, however these have been shown to be less accurate in BeMD; therefore, the equations proposed here should be used where possible. PMID:28060911

Spinal Cord Stimulation for Refractory Angina Pectoris

PubMed Central

Bao, Hongguang; Si, Yanna; Xu, Chenjie; Chen, Hao; Gao, Xianzhong; Xie, Xinyi; Xu, Yajie; Sun, Fan; Zeng, Lingqing

2017-01-01

Objectives: Paresthesia-free stimulation such as high frequency and burst have been demonstrated as effective therapies for neuropathic pain. The aim of this meta-analysis was to evaluate the efficacy and safety of conventional spinal cord stimulation (SCS) in the treatment of refractory angina pectoris (RAP). Materials and Methods: Relevant randomized controlled trials that investigated SCS for patients with RAP were comprehensively searched in Medline, Pubmed, Embase, and Cochrane Library. Five meta-analyses were performed examining the changes in Canadian Cardiovascular Society classes, exercise time, Visual Analog Scale (VAS) scores of pain, Seattle Angina Questionnaire, and nitroglycerin use in RAP patients after SCS therapy. We analyzed standardized mean differences (MD) and 95% confidence intervals (CIs) for each outcome by Review Manager 5.0 and STATA 12.0. Results: A total of 12 randomized controlled trials involving 476 RAP patients were identified. A trend of reduction in the angina frequency (MD=−9.03, 95% CI, −15.70 to −2.36) and nitroglycerin consumption (MD=−0.64, 95% CI, −0.84 to −0.45) could be observed in the SCS group. Compared with the control group, SCS showed benefit on increasing exercise time (MD=0.49, 95% CI, 0.13-0.85) and treatment satisfaction (MD=6.87, 95% CI, 2.07-11.66) with decreased VAS scores of pain (MD=−0.50, 95% CI, −0.81 to −0.20) and disease perception (MD=−8.34, 95% CI, −14.45 to −2.23). However, the result did not reach the significance level in terms of physical limitation (95% CI, −8.75 to 3.38; P=0.39) or angina stability (95% CI, −7.55 to 3.67; P=0.50). Discussion: The current meta-analysis suggested that SCS was a potential alternative in the treatment of PAP patients. Further investigation for finding the appropriate intensity of stimulation is required before this treatment should be widely recommended and applied. PMID:27875377

Spinal Cord Stimulation for Refractory Angina Pectoris: A Systematic Review and Meta-analysis.

PubMed

Pan, Xiaoxiao; Bao, Hongguang; Si, Yanna; Xu, Chenjie; Chen, Hao; Gao, Xianzhong; Xie, Xinyi; Xu, Yajie; Sun, Fan; Zeng, Lingqing

2017-06-01

Paresthesia-free stimulation such as high frequency and burst have been demonstrated as effective therapies for neuropathic pain. The aim of this meta-analysis was to evaluate the efficacy and safety of conventional spinal cord stimulation (SCS) in the treatment of refractory angina pectoris (RAP). Relevant randomized controlled trials that investigated SCS for patients with RAP were comprehensively searched in Medline, Pubmed, Embase, and Cochrane Library. Five meta-analyses were performed examining the changes in Canadian Cardiovascular Society classes, exercise time, Visual Analog Scale (VAS) scores of pain, Seattle Angina Questionnaire, and nitroglycerin use in RAP patients after SCS therapy. We analyzed standardized mean differences (MD) and 95% confidence intervals (CIs) for each outcome by Review Manager 5.0 and STATA 12.0. A total of 12 randomized controlled trials involving 476 RAP patients were identified. A trend of reduction in the angina frequency (MD=-9.03, 95% CI, -15.70 to -2.36) and nitroglycerin consumption (MD=-0.64, 95% CI, -0.84 to -0.45) could be observed in the SCS group. Compared with the control group, SCS showed benefit on increasing exercise time (MD=0.49, 95% CI, 0.13-0.85) and treatment satisfaction (MD=6.87, 95% CI, 2.07-11.66) with decreased VAS scores of pain (MD=-0.50, 95% CI, -0.81 to -0.20) and disease perception (MD=-8.34, 95% CI, -14.45 to -2.23). However, the result did not reach the significance level in terms of physical limitation (95% CI, -8.75 to 3.38; P=0.39) or angina stability (95% CI, -7.55 to 3.67; P=0.50). The current meta-analysis suggested that SCS was a potential alternative in the treatment of PAP patients. Further investigation for finding the appropriate intensity of stimulation is required before this treatment should be widely recommended and applied.

The integration of the risk management process with the lifecycle of medical device software.

PubMed

Pecoraro, F; Luzi, D

2014-01-01

The application of software in the Medical Device (MD) domain has become central to the improvement of diagnoses and treatments. The new European regulations that specifically address software as an important component of MD, require complex procedures to make software compliant with safety requirements, introducing thereby new challenges in the qualification and classification of MD software as well as in the performance of risk management activities. Under this perspective, the aim of this paper is to propose an integrated framework that combines the activities to be carried out by the manufacturer to develop safe software within the development lifecycle based on the regulatory requirements reported in US and European regulations as well as in the relevant standards and guidelines. A comparative analysis was carried out to identify the main issues related to the application of the current new regulations. In addition, standards and guidelines recently released to harmonise procedures for the validation of MD software have been used to define the risk management activities to be carried out by the manufacturer during the software development process. This paper highlights the main issues related to the qualification and classification of MD software, providing an analysis of the different regulations applied in Europe and the US. A model that integrates the risk management process within the software development lifecycle has been proposed too. It is based on regulatory requirements and considers software risk analysis as a central input to be managed by the manufacturer already at the initial stages of the software design, in order to prevent MD failures. Relevant changes in the process of MD development have been introduced with the recognition of software being an important component of MDs as stated in regulations and standards. This implies the performance of highly iterative processes that have to integrate the risk management in the framework of software development. It also makes it necessary to involve both medical and software engineering competences to safeguard patient and user safety.

Features of mood associated with high body weight in females with fibromyalgia.

PubMed

Alciati, Alessandra; Atzeni, Fabiola; Grassi, Massimiliano; Caldirola, Daniela; Sarzi-Puttini, Piercarlo; Angst, Jules; Perna, Giampaolo

2018-01-01

Fibromyalgia (FM) is a common syndrome whose main characteristic is chronic widespread musculoskeletal pain, the severity of which is frequently worsened by concomitant obesity. Major depression (MD), particularly as part of a bipolar spectrum disorder (BSD), is associated with both obesity and FM. To evaluate the relationship between lifetime MD, hypomanic symptoms and the body mass index (BMI) in patients with FM. Of the 115 patients originally screened, 87 women with FM finally entered the study. Forty-nine patients (57%) had a lifetime diagnosis of MD, assessed by a structured clinical interview based on DSM-IV criteria, and four of them (4.6%) had a current MD episode. Lifetime hypomanic symptoms were measured by means of the self-rated Hypomania Checklist. According to the international criteria for BMI, FM patients were classified as under/normal-weight (61%), overweight (30%) and obese (9%). 62 patients (71.2%) with FM had a bipolar spectrum disorder (BSD). Thirty (48.3%) of them met criteria for bipolar II disorder, 32 (51,6%) for bipolar disorder NOS (18 FM patients with MD associated to sub-syndromal hypomanic syndrome and 14 with hypomanic syndrome without MD). No patient had a bipolar I disorder. Only one patient met the criteria for a major depressive disorder (MDD). There was no significant difference in mean BMI between the patients with and without a lifetime diagnosis of MD, but there was a positive association between the level of hypomanic symptoms and BMI values (p<0.009). When hypomania was considered categorically as hypomanic syndrome there was no significant effect on BMI. Our finding adds to previous evidence indicating that hypomanic symptoms are a central feature of FM. In the case of the early identification of high-level hypomanic symptoms, body weight should be closely monitored in order to prevent obesity and its detrimental impact on females with FM. Copyright © 2017 Elsevier Inc. All rights reserved.

The Maastricht-Duke bridge: An era of mentoring in clinical research - A model for mentoring in clinical research - A tribute to Dr. Galen Wagner.

PubMed

Meijs, Loek; Zusterzeel, Robbert; Wellens, Hein Jj; Gorgels, Anton Pm

With the passing of Dr. Galen Wagner, an exceptional collaboration between Maastricht University Medical Center, The Netherlands, and Duke Clinical Research Institute, USA, has come to an end. This article focuses on the background of what Galen coined the Maastricht-Duke bridge (MD-bridge), its merits, limitations and development throughout the years, and his special role. Between 2004 and 2015, 23 Maastricht University medical students and post-graduate students were enrolled in the 4-month research elective, mentored by Galen and the Maastricht co-mentor. They were asked to complete a survey about their MD-bridge experience. Sixteen out of the 23 students responded. None but 1 participant had prior research experience. Following their MD bridge-program most participants published 1 or more manuscripts and/or presented their research in an international setting. They felt they had full responsibility as a leader of their project with all participants developing meaningful skills useful in their current job. Fourteen out of 16 would recommend the MD-bridge experience to others. Participants considered the program of great value for their personal growth and independence, giving a feeling of achievement. In addition, for some participants it led to careers in foreign countries including medical practice and research, or obtaining PhDs. With Galen's impressive career of mentoring students, including the 23 MD-bridge participants, he has left behind an amazing concept of self-development in research and personal life. The successes of the MD-bridge prove that it is possible for students to be young investigators during or just after medical school with the potential to contribute to developing meaningful skills and noteworthy careers. Collaborations between international universities, such as the MD-bridge, are feasible and should be embraced by other institutions. Published by Elsevier Inc.

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features

PubMed Central

Ruiz, Duncan D. A.; Norberto de Souza, Osmar

2015-01-01

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward’s, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes. PMID:26218832

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features.

PubMed

De Paris, Renata; Quevedo, Christian V; Ruiz, Duncan D A; Norberto de Souza, Osmar

2015-01-01

Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (k-means and k-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward's, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes.

What will it take? Pathways, time and funding: Australian medical students' perspective on clinician-scientist training.

PubMed

Eley, Diann S; Jensen, Charmaine; Thomas, Ranjeny; Benham, Helen

2017-12-08

Clinician-scientists are in decline worldwide. They represent a unique niche in medicine by bridging the gap between scientific discovery and patient care. A national, integrated approach to training clinician-scientists, typically programs that comprise a comprehensive MD-PhD pathway, are customary. Such a pathway is lacking in Australia. The objective was to gather perceptions from Australian medical students on factors they perceive would influence their decision to pursue clinician-scientist training. A cross-sectional mixed methods design used quantitative and qualitative questions in an online self-report survey with medical students from a four-year MD program. Quantitative measures comprised scaled response questions regarding prior experience and current involvement in research, and short- and long-term opinions about factors that influence their decisions to undertake a research higher degree (RHD) during medical school. Qualitative questions gathered broader perceptions of what a career pathway as a clinician-scientist would include and what factors are most conducive to a medical student's commitment to MD-PhD training. Respondents (N = 418; 51% female) indicated Time, Funding and Pathway as the major themes arising from the qualitative data, highlighting negative perceptions rather than possible benefits to RHD training. The lack of an evident Pathway was inter-related to Time and Funding. Themes were supported by the quantitative data. Sixty percent of students have previous research experience of varying forms, and 90% report a current interest, mainly to improve their career prospects. The data emphasise the need for an MD-PhD pathway in Australia. A model that provides an early, integrated, and exclusive approach to research training pathways across all stages of medical education is suggested as the best way to rejuvenate the clinician-scientist. A national pathway that addresses factors influencing career decision making throughout the medical education continuum should include an appropriate funding structure, and provide early and continuing advice and mentoring. It should be flexible, gender equitable, and include post-graduate training. The implications of implementing MD-PhD programs represent a substantial investment. However this should not be a deterrent to Australia's commitment to an MD-PhD pathway, but rather a challenge to help ensure our future healthcare is guided by highly trained and competent clinician-scientists.

General practitioners' management of mental disorders: a rewarding practice with considerable obstacles.

PubMed

Fleury, Marie-Josée; Imboua, Armelle; Aubé, Denise; Farand, Lambert; Lambert, Yves

2012-03-16

Primary care improvement is the cornerstone of current reforms. Mental disorders (MDs) are a leading cause of morbidity worldwide and widespread in industrialised countries. MDs are treated mainly in primary care by general practitioners (GPs), even though the latter ability to detect, diagnose, and treat patients with MDs is often considered unsatisfactory. This article examines GPs' management of MDs in an effort to acquire more information regarding means by which GPs deal with MD cases, impact of such cases on their practices, factors that enable or hinder MD management, and patient-management strategies. This study employs a mixed-method approach with emphasis on qualitative investigation. Based on a previous survey of 398 GPs in Quebec, Canada, 60 GPs representing a variety of practice settings were selected for further study. A 10-minute-long questionnaire comprising 27 items was administered, and 70-minute-long interviews were conducted. Quantitative (SPSS) and qualitative (NVivo) analyses were performed. At least 20% of GP visits were MD-related. GPs were comfortable managing common MDs, but not serious MDs. GPs' based their treatment of MDs on pharmacotherapy, support therapy, and psycho-education. They used clinical intuition with few clinical tools, and closely followed their patients with MDs. Practice features (salary or hourly fees payment; psycho-social teams on-site; strong informal networks), and GPs' individual characteristics (continuing medical education; exposure and interest in MDs; traits like empathy) favoured MD management. Collaboration with psychologists and psychiatrists was considered key to good MD management. Limited access to specialists, system fragmentation, and underdeveloped group practice and shared-care models were impediments. MD management was seen as burdensome because it required more time, flexibility, and emotional investment. Strategies exist to reduce the burden (one-problem-per-visit rule; longer time slots). GPs found MD practice rewarding as patients were seen as grateful and more complying with medical recommendations compared to other patients, generally leading to positive outcomes. To improve MD management, this study highlights the importance of extending multidisciplinary GP practice settings with salary or hourly fee payment; access to psychotherapeutic and psychiatric expertise; and case-discussion training involving local networks of GPs and MD specialists that encourage both knowledge transfer and shared care.

General practitioners' management of mental disorders: A rewarding practice with considerable obstacles

PubMed Central

2012-01-01

Background Primary care improvement is the cornerstone of current reforms. Mental disorders (MDs) are a leading cause of morbidity worldwide and widespread in industrialised countries. MDs are treated mainly in primary care by general practitioners (GPs), even though the latter ability to detect, diagnose, and treat patients with MDs is often considered unsatisfactory. This article examines GPs' management of MDs in an effort to acquire more information regarding means by which GPs deal with MD cases, impact of such cases on their practices, factors that enable or hinder MD management, and patient-management strategies. Methods This study employs a mixed-method approach with emphasis on qualitative investigation. Based on a previous survey of 398 GPs in Quebec, Canada, 60 GPs representing a variety of practice settings were selected for further study. A 10-minute-long questionnaire comprising 27 items was administered, and 70-minute-long interviews were conducted. Quantitative (SPSS) and qualitative (NVivo) analyses were performed. Results At least 20% of GP visits were MD-related. GPs were comfortable managing common MDs, but not serious MDs. GPs' based their treatment of MDs on pharmacotherapy, support therapy, and psycho-education. They used clinical intuition with few clinical tools, and closely followed their patients with MDs. Practice features (salary or hourly fees payment; psycho-social teams on-site; strong informal networks), and GPs' individual characteristics (continuing medical education; exposure and interest in MDs; traits like empathy) favoured MD management. Collaboration with psychologists and psychiatrists was considered key to good MD management. Limited access to specialists, system fragmentation, and underdeveloped group practice and shared-care models were impediments. MD management was seen as burdensome because it required more time, flexibility, and emotional investment. Strategies exist to reduce the burden (one-problem-per-visit rule; longer time slots). GPs found MD practice rewarding as patients were seen as grateful and more complying with medical recommendations compared to other patients, generally leading to positive outcomes. Conclusions To improve MD management, this study highlights the importance of extending multidisciplinary GP practice settings with salary or hourly fee payment; access to psychotherapeutic and psychiatric expertise; and case-discussion training involving local networks of GPs and MD specialists that encourage both knowledge transfer and shared care. PMID:22423592

Comparison of the 2008-2011 and 1993-1995 Surges of Bering Glacier, Alaska

NASA Astrophysics Data System (ADS)

Molnia, B. F.; Angeli, K.

2011-12-01

The 1993-1995 surge of Bering Glacier, Earth's largest surging temperate glacier, was intensively studied. A new surge, which began prior to March 9, 2009, was still active in early August 2011. As was the 1993-1995 surge, the current surge is being studied using multiple remote sensing and ground-based methodologies. The wealth of observations available of both surges permit comparisons to be drawn about similarities and differences regarding processes, timing, intensities, and related topics. For more than a year prior to each surge, the intensity of calving and the rate of terminus retreat in Tashalich Arm increased dramatically, approaching 4 m/d in late 2010. This was abruptly followed by a significant terminus advance. In the current surge, maximum advance rates exceeded 19 m/d between March 18 and May 10, 2011. Through July 20, maximum terminus advance approached 3.2 km with velocities above 8 m/d. Similar rates applied in the earlier surge. Each surge has resulted in a rapid and significant advance of the central Bering Lobe's terminus into Vitus Lake. The terminus advance results from the transfer of a substantial volume of ice from the Bagley Ice Valley into the expanding piedmont lobe. In both surges, conspicuous evidence of tens of meters of glacier surface lowering is visible on the south wall of Juniper Island. In the 1993-1995 surge, terminus advance between October 17, 1993 and May 16, 1994 was nearly 7.8 km, an average advance rate of more than 36 m/d. With the current surge, between January 8 and 14, 2011, the terminus advanced a maximum of 125 m, averaging nearly 21 m/d. By July 11, 2011, maximum velocities still approached 15 m per day, with maximum ice displacements of nearly 2 km and a maximum terminus advance of 1.7 km. In the 1993-1995 surge, the first evidence of surge activity was observed in April 1993, the development of a fractured ice bulge on the northwest side of the Grindle Hills. The surge front reached Bering's terminus at the end of August 1993 and left it heavily fractured. With the current surge, until July 2009, surface displacements were restricted to the area from west of, to northeast of the Grindle Hills. By November 18, 2010, the surge front reached Bering's terminus and left it more heavily fractured than in 1993. The current surge shows the same style and types of surface disruptions and deformations at the same locations as did the earlier surge. For example, in both surges, sinusoidal crevasses were first noted north of the Grindle Hills, while rifts were noted in the upper central piedmont lobe. The current surge has produced much more fracturing of the Medial Moraine Band than did the 1993-95 surge. Similarly, the extent of surface fracturing up-glacier from the piedmont lobe is significantly greater in the current surge. During the 1993-95 surge, surface expression of the surge extended about 45 km east of the western end of Juniper Island. In late July 2011, surge-related surface fractures extended nearly 90 km to the east. The Steller lobe of the Bering Glacier System has not been involved in either surge. Continued observations of the current surge, in the context of the 1993-95 surge, are providing significant insights into repeatable patterns of surging glacier behavior. Bering Glacier is an amazing natural laboratory at which to conduct these observations.

Service provider perceptions of telerehabilitation as an additional service delivery option within an Australian neurosurgical and orthopaedic physiotherapy screening clinic: A qualitative study.

PubMed

Cottrell, Michelle A; Hill, Anne J; O'Leary, Shaun P; Raymer, Maree E; Russell, Trevor G

2017-12-01

The Neurosurgical & Orthopaedic Physiotherapy Screening Clinic and Multidisciplinary Service (N/OPSC&MDS) originated as a complementary, non-surgical pathway for patients referred to public neurosurgical and orthopaedic specialist services. Patient access to the N/OPSC&MDS could potentially be improved with the implementation of telerehabilitation as an additional method of service delivery. To evaluate service provider's views on (1) current barriers to patients' accessing N/OPSC & MD services, and (2) the implementation of telerehabilitation within the N/OPSC&MDS. Qualitative descriptive study design. Healthcare providers (n = 26) were recruited from six N/OPSC&MD services located throughout Queensland, Australia. Semi-structured interviews were conducted to explore service providers' views with respect to existing barriers to patients accessing the N/OPSC&MDS, and if telerehabilitation could be feasibly adopted to address current barriers. Template analysis resulted in six themes: (1) barriers to some patients' accessing current N/OPSC&MD services are complex & multifaceted; (2) telerehabilitation could improve patient access to appropriate management for their musculoskeletal condition; (3) telerehabilitation may have limitations when compared to face-to-face healthcare; (4) the delivery of telerehabilitation needs to be flexible; (5) perceived barriers, and (6) facilitators to the successful implementation of telerehabilitation within the N/OPSC&MDS. This study represents a critical step in determining the readiness of service providers for the implementation of telerehabilitation within the N/OPSC&MDS. Although cautious, service providers are overall accepting of the implementation of telerehabilitation, acknowledging that it could eliminate several current barriers, subsequently achieving more equitable access to the service. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Combination of treatment with death receptor 5-specific antibody with therapeutic HPV DNA vaccination generates enhanced therapeutic antitumor effects

PubMed Central

Tseng, Chih-Wen; Trimble, Cornelia; Monie, Archana; Alvarez, Ronald D.; Huh, Warner K.; Buchsbaum, Donald J.; Straughn, J. Michael; Wang, Mei-Cheng; Yagita, Hideo; Hung, Chien-Fu; Wu, T.-C.

2008-01-01

There is currently a vital need for the development of novel therapeutic strategies for the control of advanced stage cancers. Antigen-specific immunotherapy and the employment of antibodies against the death receptor 5 (DR5) have emerged as two potentially promising strategies for cancer treatment. In the current study, we hypothesize that the combination of treatment with the anti-DR5 monoclonal antibody, MD5-1 with a DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7(detox)) administered via gene gun would lead to further enhancement of E7-specific immune responses as well as antitumor effects. Our results indicated that mice bearing the E7-expressing tumor, TC-1 treated with MD5-1 monoclonal antibody followed by CRT/E7(detox) DNA vaccination generated the most potent therapeutic anti-tumor effects as well as highest levels of E7-specific CD8+ T cells among all the groups tested. In addition, treatment with MD5-1 monoclonal antibody was capable of rendering the TC-1 tumor cells more susceptible to lysis by E7-specific cytotoxic T lymphocytes. Our findings serve as an important foundation for future clinical translation. PMID:18598733

Meningococcal disease in the Middle East and Africa: Findings and updates from the Global Meningococcal Initiative.

PubMed

Borrow, Ray; Caugant, Dominique A; Ceyhan, Mehmet; Christensen, Hannah; Dinleyici, Ener Cagri; Findlow, Jamie; Glennie, Linda; Von Gottberg, Anne; Kechrid, Amel; Vázquez Moreno, Julio; Razki, Aziza; Smith, Vincent; Taha, Muhamed-Kheir; Tali-Maamar, Hassiba; Zerouali, Khalid

2017-07-01

The Global Meningococcal Initiative (GMI) has recently considered current issues in Middle Eastern and African countries, and produced two recommendations: (i) that vaccination of attendees should be considered for some types of mass-gathering events, as some countries mandate for the Hajj, and (ii) vaccination of people with human immunodeficiency virus should be used routinely, because of increased meningococcal disease (MD) risk. Differences exist between Middle Eastern and African countries regarding case and syndrome definitions, surveillance, and epidemiologic data gaps. Sentinel surveillance provides an overview of trends and prevalence of different capsular groups supporting vaccine selection and planning, whereas cost-effectiveness decisions require comprehensive disease burden data, ideally counting every case. Surveillance data showed importance of serogroup B MD in North Africa and serogroup W expansion in Turkey and South Africa. Success of MenAfriVac ® in the African "meningitis belt" was reviewed; the GMI believes similar benefits may follow development of a low-cost meningococcal pentavalent vaccine, currently in phase 1 clinical trial, by 2022. The importance of carriage and herd protection for controlling invasive MD and the importance of advocacy and awareness campaigns were also highlighted. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Towards an explanation of orbits in the extreme trans-Neptunian region: The effect of Milgromian dynamics

NASA Astrophysics Data System (ADS)

Paučo, R.

2017-06-01

Context. Milgromian dynamics (MD or MOND) uniquely predicts motion in a galaxy from the distribution of its stars and gas in a remarkable agreement with observations so far. In the solar system, MD predicts the existence of some possibly non-negligible dynamical effects, which can be used to constrain the freedom in MD theories. Known extreme trans-Neptunian objects (ETNOs) have their argument of perihelion, longitude of ascending node, and inclination distributed in highly non-uniform fashion; ETNOs are bodies with perihelion distances greater than the orbit of Neptune and with semimajor axes greater than 150 au and less than 1500 au. It is as if these bodies have been systematically perturbed by some external force. Aims: We investigated a hypothesis that the puzzling orbital characteristics of ETNOs are a consequence of MD. Methods: We set up a dynamical model of the solar system incorporating the external field effect (EFE), which is anticipated to be the dominant effect of MD in the ETNOs region. We used constraints available on the strength of EFE coming from radio tracking of the Cassini spacecraft. We performed several numerical experiments, concentrating on the long-term orbital evolution of primordial (randomised) ETNOs in MD. Results: The EFE could produce distinct non-uniform distributions of the orbital elements of ETNOs that are related to the orientation of an orbit in space. If we demand that EFE is solely responsible for the detachment of Sedna and 2012 VP113, then these distributions are at odds with the currently observed statistics on ETNOs unless the EFE quadrupole strength parameter Q2 has values that are unlikely (with probability <1%) in light of the Cassini data.

Scrutinizing Molecular Mechanics Force Fields on the Submicrosecond Timescale with NMR Data

PubMed Central

Lange, Oliver F.; van der Spoel, David; de Groot, Bert L.

2010-01-01

Abstract Protein dynamics on the atomic level and on the microsecond timescale has recently become accessible from both computation and experiment. To validate molecular dynamics (MD) at the submicrosecond timescale against experiment we present microsecond MD simulations in 10 different force-field configurations for two globular proteins, ubiquitin and the gb3 domain of protein G, for which extensive NMR data is available. We find that the reproduction of the measured NMR data strongly depends on the chosen force field and electrostatics treatment. Generally, particle-mesh Ewald outperforms cut-off and reaction-field approaches. A comparison to measured J-couplings across hydrogen bonds suggests that there is room for improvement in the force-field description of hydrogen bonds in most modern force fields. Our results show that with current force fields, simulations beyond hundreds of nanoseconds run an increased risk of undergoing transitions to nonnative conformational states or will persist within states of high free energy for too long, thus skewing the obtained population frequencies. Only for the AMBER99sb force field have such transitions not been observed. Thus, our results have significance for the interpretation of data obtained with long MD simulations, for the selection of force fields for MD studies and for force-field development. We hope that this comprehensive benchmark based on NMR data applied to many popular MD force fields will serve as a useful resource to the MD community. Finally, we find that for gb3, the force-field AMBER99sb reaches comparable accuracy in back-calculated residual dipolar couplings and J-couplings across hydrogen bonds to ensembles obtained by refinement against NMR data. PMID:20643085

Ventral pallidal projections to mediodorsal thalamus and ventral tegmental area play distinct roles in outcome-specific Pavlovian-instrumental transfer.

PubMed

Leung, Beatrice K; Balleine, Bernard W

2015-03-25

Outcome-specific Pavlovian-instrumental transfer (PIT) demonstrates the way that reward-related cues influence choice between instrumental actions. The nucleus accumbens shell (NAc-S) contributes critically to this effect, particularly through its output to the rostral medial ventral pallidum (VP-m). Using rats, we investigated in two experiments the role in the PIT effect of the two major outputs of this VP-m region innervated by the NAc-S, the mediodorsal thalamus (MD) and the ventral tegmental area (VTA). First, two retrograde tracers were injected into the MD and VTA to compare the neuronal activity of the two populations of projection neurons in the VP-m during PIT relative to controls. Second, the functional role of the connection between the VP-m and the MD or VTA was assessed using asymmetrical pharmacological manipulations before a PIT test. It was found that, whereas neurons in the VP-m projecting to the MD showed significantly more neuronal activation during PIT than those projecting to the VTA, neuronal activation of these latter neurons correlated with the size of the PIT effect. Disconnection of the two pathways during PIT also revealed different deficits in performance: disrupting the VP-m to MD pathway removed the response biasing effects of reward-related cues, whereas disrupting the VP-m to VTA pathway preserved the response bias but altered the overall rate of responding. The current results therefore suggest that the VP-m exerts distinct effects on the VTA and MD and that these latter structures mediate the motivational and cognitive components of specific PIT, respectively. Copyright © 2015 the authors 0270-6474/15/354953-12$15.00/0.

Storm Prediction Center Forecast Products

Science.gov Websites

thunderstorm and tornado watches which are in effect over the contiguous United States. Please read about the Discussions This is the current graphic showing any mesoscale discussions (MD's) which are in effect over the

77 FR 49024 - Sai Wentum, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-15

... in lieu of a hearing and issue this Decision and Final Order based on relevant evidence contained in..., the Show Cause Order alleged that Registrant is currently unlicensed to practice medicine and without...

75 FR 21005 - National Advisory Council on the National Health Service Corps; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-22

... (BCRS), discuss recruitment and marketing strategies for the NHSC, and address current workforce issues.... Place: Bethesda North Marriott Hotel & Conference Center, 5701 Marinelli Road, Bethesda, MD 20852, Phone...

76 FR 52353 - Assumption Buster Workshop: “Current Implementations of Cloud Computing Indicate a New Approach...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-22

... explored in this series is cloud computing. The workshop on this topic will be held in Gaithersburg, MD on October 21, 2011. Assertion: ``Current implementations of cloud computing indicate a new approach to security'' Implementations of cloud computing have provided new ways of thinking about how to secure data...

75 FR 6162 - Airworthiness Directives; McDonnell Douglas Corporation Model DC-9-81 (MD-81), DC-9-82 (MD-82...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-08

... Corporation Model DC- 9-81 (MD-81), DC-9-82 (MD-82), DC-9-83 (MD-83), DC-9-87 (MD-87), and MD-88 Airplanes... Model DC-9-81 (MD-81), DC-9-82 (MD-82), DC-9-83 (MD-83), DC-9-87 (MD-87), and MD-88 airplanes. This...., Washington, DC 20590, between 9 a.m. and 5 p.m., Monday through Friday, except Federal holidays. For service...

Impact of Tumarkin attacks on complaints and work ability in Ménière's disease.

PubMed

Pyykkö, Ilmari; Manchaiah, Vinaya; Zou, Jing; Levo, Hilla; Kentala, Erna

2018-05-22

The purpose of the present study was to characterize the occurrence of Tumarkin attacks in patients with Ménière'sdisease (MD), and to study its association with reported complaints, severity of consequences, and also self-reported work ability. The study used a cross-sectional design. Data obtained from the Finnish Ménière Federation using an electronic survey was analyzed. 602 people with MD responded to the survey (62% response rate) with a mean age of 56.7 years and a mean duration of the disease 12.4 years. 49% of the respondents experienced Tumarkin attacks, which lasted for a few seconds to a few minutes. There were significant differences in complaints reported by MD patients with and without Tumarkin attacks. Respondents with Tumarkin attacks experienced various consequences, including tripping, falls, fear, anxiety, problems in dyadic life, and even transient loss of consciousness. Respondents with Tumarkin attacks had more frequently applied for pension than those not having Tumarkin attacks. On an average, respondents with Tumarkin attacks had less self-reported working ability when compared to those without Tumarkin attacks. The current study results suggest various differences in terms of complaints reported, severity of consequences, and the self-reported working ability in MD patients with and without Tumarkin attacks. Hearing healthcare professionals must examine Tumarkin attacks and their consequences in patients with MD during clinical examinations. In addition, the therapy should focus on alleviating the consequences and improving work ability.

Rhodotorula taiwanensis MD1149 produces hypoacetylated PEFA compounds with increased surface activity compared to Rhodotorula babjevae MD1169

PubMed Central

Rubinfeld, Bonnee; Leif, Roald; Mulcahy, Heather; Dugan, Lawrence; Souza, Brian

2018-01-01

Biosurfactants have several desirable characteristics in the industrial sector: detergency, antimicrobial effects, skin hydration, and emulsibility. Several yeast glycolipids are currently being utilized in these capacities: sophorolipids, ustilagic acid, and mannosylerythritol lipids (MELs). An emerging class of glycolipids, termed polyol esters of fatty acids (PEFA), have recently been reported for Rhodotorula babjevae, a basidiomycetous yeast species that secretes hyperacetylated congeners of PEFA (typically with 3–6 acetylation modifications). While screening Rhodotorula species for surfactant production, we identified a new environmental isolate identified as Rhodotorula taiwanensis MD1149 that dropped the surface tension of the liquid medium, indicating that it produced a potent biosurfactant. Acid depolymerization of the purified biosurfactants, followed by gas chromatography-mass spectrometry (GC-MS) analysis revealed that the biosurfactants were composed of PEFA compounds composed mainly of mannitol and arabitol esters of 3-hydroxy fatty acid, 3-methoxy fatty acid, and fatty acids with a single double bond; chain lengths were mainly C16 and C18. Liquid chromatography-mass spectrometry (LC-MS) confirmed the predicted accurate mass of these compounds. Interestingly, PEFA compounds produced by Rhodotorula taiwanensis MD1149 were more surface active due to their hypoacetylation profile (0–4 acetylation modifications) compared to Rhodotorula babjevae MD1169. These disparate surface active properties, based on acetylation, change the hydrophilic-lipophilic balance (HLB) of these compounds, and their potential utility within industrial applications. PMID:29293588

Validation of the ERS standard citric acid cough challenge in healthy adult volunteers

PubMed Central

2010-01-01

Protocols measuring cough sensitivity can vary in terms of nebuliser, tussive agent, single and dose response. A definitive method for measuring cough sensitivity needs to be established. The ERS guidelines recommend the KoKo DigiDoser (KD) delivery system. Study aim, was to compare the reproducibility of this citric acid (CA) cough challenge and previously established Mefar dosimeter (MD) protocol. 39 (female 26) volunteers mean age (40.4 yrs) were randomised to either KD or MD. Intra-day and inter-day reproducibility was compared. We calculated the concentration of citric acid evoking 2 coughs (C2). The geometric mean C2 (95%CI) was similar for both KD and MD, of 263 (200,339) mM and 209 (151,288) mM respectively. The mean KD C2 was not significantly different. (F = 0.807, p = 0.93) from baseline over 1, 2, and 4 hrs however, the MD demonstrated significant variability (F = 7.85, P < 0.001) Measuring mean log C2 at baseline and at 2 weeks, the KD demonstrated a stronger intraclass correlation of log C2 at baseline with 2 week log C2, ICC = 0.70 than was shown with the Mefar, ICC = 0.41 Administering CA from KD offers a reproducible cough challenge in healthy volunteers. The results correlate well with the MD challenge but offer greater intra-day and inter-day reproducibility. Trial Registration Current controlled trials ISRCTN98385033 PMID:20698995

Pathways to Firesetting for Mentally Disordered Offenders: A Preliminary Examination.

PubMed

Tyler, Nichola; Gannon, Theresa A

2017-06-01

The current study aimed to investigate the specific pathways in the offence process for mentally disordered firesetters. In a previous study, an offence chain model was constructed (i.e., the Firesetting Offence Chain for Mentally Disordered Offenders, FOC-MD) using offence descriptions obtained from 23 mentally disordered firesetters, detailing the sequence of contextual, behavioural, affective, and cognitive factors that precipitate an incidence of firesetting for this population. The current study examines the prevalence of the specific pathways to firesetting for the original 23 mentally disordered firesetters and a further sample of 13 mentally disordered firesetters. Three distinct pathways to firesetting are identified within the FOC-MD: fire interest-childhood mental health, no fire interest-adult mental health, fire interest-adult mental health. In this article, we describe these three pathways in detail using illustrative case studies. The practice implications of these identified pathways are also discussed.

Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy.

PubMed

Hull, Stephen; Kelley, Seán; Clarke, Janice L

2017-09-01

Sexually Transmitted Infections: Compelling Case for an Improved Screening Strategy Stephen Hull, MHS, Seán Kelley, MD, MSc, and Janice L. Clarke, RN, BBA Editorial: Sexually Transmitted Infections-A Fixable Problem: David B. Nash, MD, MBA   S-3 Introduction   S-3 Rising Prevalence of Sexually Transmitted Diseases (STIs)   S-4 Current Screening Rates for Chlamydia and Gonorrhea   S-4 The Human Toll and Economic Burden of STI-Related Illness   S-5 Current Screening Guidelines for Chlamydia and Gonorrhea   S-5 Factors Contributing to Inadequate Screening, Diagnosis, and Treatment for STIs   S-6 Methods Used to Improve Screening Rates   S-7 Benefits of Opt-Out Screening Strategies for STIs   S-8 Cost-Effectiveness of Screening for STIs   S-8 Discussion   S-9 Conclusion   S-10.

Mode-dependent templates and scan order for H.264/AVC-based intra lossless coding.

PubMed

Gu, Zhouye; Lin, Weisi; Lee, Bu-Sung; Lau, Chiew Tong; Sun, Ming-Ting

2012-09-01

In H.264/advanced video coding (AVC), lossless coding and lossy coding share the same entropy coding module. However, the entropy coders in the H.264/AVC standard were original designed for lossy video coding and do not yield adequate performance for lossless video coding. In this paper, we analyze the problem with the current lossless coding scheme and propose a mode-dependent template (MD-template) based method for intra lossless coding. By exploring the statistical redundancy of the prediction residual in the H.264/AVC intra prediction modes, more zero coefficients are generated. By designing a new scan order for each MD-template, the scanned coefficients sequence fits the H.264/AVC entropy coders better. A fast implementation algorithm is also designed. With little computation increase, experimental results confirm that the proposed fast algorithm achieves about 7.2% bit saving compared with the current H.264/AVC fidelity range extensions high profile.

Roster of NSAP (Navy Science Assistance Program) Field Team Members, Fiscal Years 1971-1986

DTIC Science & Technology

1985-08-05

CAPTOR Evaluation Program, NSWC. Current Job/Position: Operational Requirements Analyst for a new generation of mines. Current Address: Officer in...to NSAP Field Assignment: General Engineer; combat systems engineering on new ship design concepts, NSWC. Current Job/Position: Electronic Engineer...ADDRESS 12. REPORT DATE Naval Surface Weapons Center (Code D23) 5 August 1985 10901 New Hampshire Avenue 13. NUMBER OF PAGES Silver Spring, MD 20910

Md-miR156ab and Md-miR395 Target WRKY Transcription Factors to Influence Apple Resistance to Leaf Spot Disease.

PubMed

Zhang, Qiulei; Li, Yang; Zhang, Yi; Wu, Chuanbao; Wang, Shengnan; Hao, Li; Wang, Shengyuan; Li, Tianzhong

2017-01-01

MicroRNAs (miRNAs) are key regulators of gene expression that post-transcriptionally regulate transcription factors involved in plant physiological activities. Little is known about the effects of miRNAs in disease resistance in apple ( Malus × domestica ). We globally profiled miRNAs in the apple cultivar Golden Delicious (GD) infected or not with the apple leaf spot fungus Alternaria alternaria f. sp. mali (ALT1), and identified 58 miRNAs that exhibited more than a 2-fold upregulation upon ALT1 infection. We identified a pair of miRNAs that target protein-coding genes involved in the defense response against fungal pathogens; Md-miR156ab targets a novel WRKY transcription factor, MdWRKYN1, which harbors a TIR and a WRKY domain. Md-miR395 targets another transcription factor, MdWRKY26, which contains two WRKY domains. Real-time PCR analysis showed that Md-miR156ab and Md-miR395 levels increased, while MdWRKYN1 and MdWRKY26 expression decreased in ALT1-inoculated GD leaves; furthermore, the overexpression of Md-miR156ab and Md-miR395 resulted in a significant reduction in MdWRKYN1 and MdWRKY26 expression. To investigate whether these miRNAs and their targets play a crucial role in plant defense, we overexpressed MdWRKYN1 or knocked down Md-miR156ab activity, which in both cases enhanced the disease resistance of the plants by upregulating the expression of the WRKY-regulated pathogenesis-related (PR) protein-encoding genes MdPR3-1, MdPR3-2, MdPR4, MdPR5, MdPR10-1 , and MdPR10-2 . In a similar analysis, we overexpressed MdWRKY26 or suppressed Md-miR395 activity, and found that many PR protein-encoding genes were also regulated by MdWRKY26 . In GD, ALT-induced Md-miR156ab and Md-miR395 suppress MdWRKYN1 and MdWRKY26 expression, thereby decreasing the expression of some PR genes, and resulting in susceptibility to ALT1.

Apple MdACS6 Regulates Ethylene Biosynthesis During Fruit Development Involving Ethylene-Responsive Factor.

PubMed

Li, Tong; Tan, Dongmei; Liu, Zhi; Jiang, Zhongyu; Wei, Yun; Zhang, Lichao; Li, Xinyue; Yuan, Hui; Wang, Aide

2015-10-01

Ethylene biosynthesis in plants involves different 1-aminocyclopropane-1-carboxylic acid synthase (ACS) genes. The regulation of each ACS gene during fruit development is unclear. Here, we characterized another apple (Malus×domestica) ACS gene, MdACS6. The transcript of MdACS6 was observed not only in fruits but also in other tissues. During fruit development, MdACS6 was initiated at a much earlier stage, whereas MdACS3a and MdACS1 began to be expressed at 35 d before harvest and immediateley after harvest, respectively. Moreover, the enzyme activity of MdACS6 was significantly lower than that of MdACS3a and MdACS1, accounting for the low ethylene biosynthesis in young fruits. Overexpression of MdACS6 (MdACS6-OE) by transient assay in apple showed enhanced ethylene production, and MdACS3a was induced in MdACS6-OE fruits but not in control fruits. In MdACS6 apple fruits silenced by the virus-induced gene silencing (VIGS) system (MdACS6-AN), neither ethylene production nor MdACS3a transcript was detectable. In order to explore the mechanism through which MdACS3a was induced in MdACS6-OE fruits, we investigated the expression of apple ethylene-responsive factor (ERF) genes. The results showed that the expression of MdERF2 was induced in MdACS6-OE fruits and inhibited in MdACS6-AN fruits. Yeast one-hybrid assay showed that MdERF2 protein could bind to the promoter of MdACS3a. Moreover, down-regulation of MdERF2 in apple flesh callus led to a decrease of MdACS3a expression, demonstrating the regulation of MdERF2 on MdACS3a. The mechanism through which MdACS6 regulates the action of MdACS3a was discussed. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Multiscale Modeling of Novel Carbon Nanotube/Copper-Composite Material Used in Microelectronics

NASA Astrophysics Data System (ADS)

Awad, Ibrahim; Ladani, Leila

2016-06-01

Current carrying capacity is one of the elements that hinders further miniaturization of Copper (Cu) interconnects. Therefore, there is a need to propose new materials with higher ampacity (current carrying capacity) that have the potential to replace Cu. Experimental observations have shown that Carbon Nanotube (CNT)/Cu-composite material has a hundredfold ampacity of Cu, which makes it a good candidate to replace Cu. However, sufficient information about the mechanical behavior of the novel CNT/Cu-composite is not available. In the current paper, the CNT/Cu-composite is utilized to construct Through Silicon Via (TSV). The mechanical behavior, specifically the fatigue life, of the CNT/Cu-TSV is evaluated by applying a multiscale modeling approach. Molecular Dynamics (MD) simulations are conducted to evaluate the tensile strength and the coefficient of thermal expansion of CNTs. MD simulation is also used to determine the interface behavior between CNTs and Cu. MD simulation results are integrated into Finite Element analysis at the micro-level to estimate the fatigue life of the CNT/Cu-TSV. A comparison is made with base material; Cu. CNTs addition has redistributed the plastic deformation in Cu to occur at two different locations (Si/Cu interface and Cu/CNT interface) instead of only one location (Si/Cu interface) in the case of Cu-only-TSV. Thus, the maximum equivalent plastic strain has been alleviated in the CNT/Cu-TSV. Accordingly, CNT/Cu-TSV has shown a threefold increase in the fatigue life. This is a solid indication of the improvement in the fatigue life that is attributed to the addition of CNTs.

Annual Financial Report: Fiscal Year Ended June 30, 2008. Creating a University System for the 21st Century

ERIC Educational Resources Information Center

North Dakota University System, 2008

2008-01-01

The North Dakota University System's (the "System") discussion and analysis (MD&A) provides an overview of the System's financial activities and issues for the year ended June 30, 2008. It is designed to focus on the current year's activities, resulting changes and currently known facts to assist readers in understanding the…

Beyond Standard Molecular Dynamics: Investigating the Molecular Mechanisms of G Protein-Coupled Receptors with Enhanced Molecular Dynamics Methods

PubMed Central

Johnston, Jennifer M.

2014-01-01

The majority of biological processes mediated by G Protein-Coupled Receptors (GPCRs) take place on timescales that are not conveniently accessible to standard molecular dynamics (MD) approaches, notwithstanding the current availability of specialized parallel computer architectures, and efficient simulation algorithms. Enhanced MD-based methods have started to assume an important role in the study of the rugged energy landscape of GPCRs by providing mechanistic details of complex receptor processes such as ligand recognition, activation, and oligomerization. We provide here an overview of these methods in their most recent application to the field. PMID:24158803

pyPcazip: A PCA-based toolkit for compression and analysis of molecular simulation data

NASA Astrophysics Data System (ADS)

Shkurti, Ardita; Goni, Ramon; Andrio, Pau; Breitmoser, Elena; Bethune, Iain; Orozco, Modesto; Laughton, Charles A.

The biomolecular simulation community is currently in need of novel and optimised software tools that can analyse and process, in reasonable timescales, the large generated amounts of molecular simulation data. In light of this, we have developed and present here pyPcazip: a suite of software tools for compression and analysis of molecular dynamics (MD) simulation data. The software is compatible with trajectory file formats generated by most contemporary MD engines such as AMBER, CHARMM, GROMACS and NAMD, and is MPI parallelised to permit the efficient processing of very large datasets. pyPcazip is a Unix based open-source software (BSD licenced) written in Python.

National Information Utility Seeks to Serve Schools Nationwide.

ERIC Educational Resources Information Center

Platzer, Nancy

1985-01-01

Outlines the pros and cons of the National Information Utility Program, which is designed to provide current updatable courseware to schools nationwide. The information is broadcast over FM radio and television signals to facilities subscribing to the utility. (MD)

77 FR 58854 - Office of the Director, National Institutes of Health; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-24

... current understanding of the basic biology of the genital tract for HIV prevention. An update will be... Level, Suite T-500, Rockville, MD 20852. Contact Person: Robert Eisinger, Ph.D., Executive Secretary...

A Massive Galaxy Cluster At z=1.45 From The XMM Cluster Survey: Discovery, Confirmation And Implications For The L-T Relation And Cosmology

NASA Astrophysics Data System (ADS)

Sabirli, Kivanc; Romer, A. K.; Davidson, M.; Stanford, S. A.; Viana, P. T.; Hilton, M.; Collins, C. A.; Kay, S. T.; Liddle, A. R.; Mann, R. G.; Miller, C. J.; Nichol, R. C.; West, M. J.; Conselice, C. J.; Spinrad, H.; Stern, D.; XCS Collaboration

2006-06-01

We report the discovery of the hottest cluster known at z > 1. It was identified as an extended X-ray source in the XMM Cluster Survey (XCS, Romer et al., 2001) and optical spectroscopy shows that 6 galaxies within a 60 arcsec diameter region lie at z = 1.45 ± 0.01. Hence its redshift is the highest currently known for a spectroscopically-confirmed cluster. Analysis of the X-ray spectra yields kT = 7.9+2.8-1.8 keV (90% confidence) and suggests that it is relatively massive for such a high redshift cluster.We acknowledge financial support from NASA grant NAG-11634 (AKR, RCN, KS, MD, PTPV), The Royal Astronomical Society's Hosie Request (MD, KS), PPARC (ARL, STK, RGM), the NASA XMM program (KS), the Institute of Astronomy at the University of Edinburgh (MD), Liverpool John Moores University (MH), Carnegie Mellon University (KS, AKR), and NSF grant AST-0205960 (MJW).

Methane emissions from Alaska Arctic tundra - An assessment of local spatial variability

NASA Technical Reports Server (NTRS)

Morrissey, L. A.; Livingston, G. P.

1992-01-01

The findings of an extensive midsummer survey of CH4 emissions measurements representing the Alaska Arctic tundra are presented. Variability in rates of emissions was similar in magnitude on local and regional scales, ranging from 0 to 286.5 mg/sq m/d overall and often varying across two orders of magnitude within 0.5 m distances. Primary control on rates of emission was determined by the substrate and position of the water table relative to the surface. Emission rates in the Arctic Foothills ranged from 0.2 mg/sq m/d for tussock tundra to 55.53 mg/sq m/d over wet meadows. Plant-mediated release of CH4 to the atmosphere was directly proportional to green leaf area and represented 92-98 percent of the total emission rates over vegetated sites. The results suggest the current published emission rates may have overestimated the contribution of boreal ecosystems to the global CH4 budget by several fold.

Molecular dynamics calculation of rotational diffusion coefficient of a carbon nanotube in fluid.

PubMed

Cao, Bing-Yang; Dong, Ruo-Yu

2014-01-21

Rotational diffusion processes are correlated with nanoparticle visualization and manipulation techniques, widely used in nanocomposites, nanofluids, bioscience, and so on. However, a systematical methodology of deriving this diffusivity is still lacking. In the current work, three molecular dynamics (MD) schemes, including equilibrium (Green-Kubo formula and Einstein relation) and nonequilibrium (Einstein-Smoluchowski relation) methods, are developed to calculate the rotational diffusion coefficient, taking a single rigid carbon nanotube in fluid argon as a case. We can conclude that the three methods produce same results on the basis of plenty of data with variation of the calculation parameters (tube length, diameter, fluid temperature, density, and viscosity), indicative of the validity and accuracy of the MD simulations. However, these results have a non-negligible deviation from the theoretical predictions of Tirado et al. [J. Chem. Phys. 81, 2047 (1984)], which may come from several unrevealed factors of the theory. The three MD methods proposed in this paper can also be applied to other situations of calculating rotational diffusion coefficient.

Left-Hemispheric Microstructural Abnormalities in Children With High Functioning Autism Spectrum Disorder

PubMed Central

Peterson, Daniel; Mahajan, Rajneesh; Crocetti, Deana; Mejia, Amanda; Mostofsky, Stewart

2014-01-01

Current theories of the neurobiological basis of Autism Spectrum Disorder (ASD) posit an altered pattern of connectivity in large-scale brain networks. Here we used Diffusion Tensor Imaging to investigate the microstructural properties of the white matter that mediates inter-regional connectivity in 36 high-functioning children with ASD (HF-ASD), as compared to 37 controls. By employing an atlas-based analysis using LDDMM registration, a widespread, but left-lateralized pattern of abnormalities was revealed. The Mean Diffusivity (MD) of water in the white matter of HF-ASD children was significantly elevated throughout the left hemisphere, particularly in the outer-zone cortical white matter. Across diagnostic groups there was a significant effect of age on left hemisphere MD, with a similar reduction in MD during childhood in both TD and HF-ASD children. The increased MD in children with HF-ASD suggests hypomyelination, and may reflect increased short-range cortico-cortical connections subsequent to early white matter overgrowth. These findings also highlight left hemispheric connectivity as relevant to the pathophysiology of ASD, and indicate that the spatial distribution of microstructural abnormalities in HF-ASD is widespread, and left-lateralized. This altered left-hemispheric connectivity may contribute to deficits in communication and praxis observed in ASD. PMID:25256103

Effect of a metal-dielectric structure introduced in the plasma chamber of the Frankfurt 14 GHz electron cyclotron resonance ion source

NASA Astrophysics Data System (ADS)

Schächter, L.; Stiebing, K. E.; Dobrescu, S.; Badescu-Singureanu, Al. I.; Schmidt, L.; Hohn, O.; Runkel, S.

1999-02-01

A new approach of the possibility to significantly increase the high charge state ion beams delivered by electron cyclotron resonance (ECR) ion sources by using metal-dielectric (MD) structures characterized by high secondary electron emission properties is presented. The intensities of argon ion beams extracted from the 14 GHz electron cyclotron resonance ion source of the Institut für Kernphysik (IKF) der Johann Wolfgang Goethe-Universität in Frankfurt/Main were measured when a 26 mm diam disk of a specially treated MD structure (Al-Al2O3) was introduced axially close to the ECR plasma. The Ar beam intensities and charge-state distributions obtained with this disk are compared to measurements with disks of iron and pure aluminum at the same position relative to the plasma. All measurements were performed with the disk at the plasma chamber potential. The results with the MD structure show a net shift of the beam intensity towards higher charge states as compared with the other disk materials. Enhancement factors of the beam current of up to 10 (for Ar12+) when using a MD disk compared to the output when using an aluminum disk and up to 40 (for Ar11+) when using an iron disk were measured.

Morphostructural MRI abnormalities related to neuropsychiatric disorders associated to multiple sclerosis.

PubMed

Bonavita, Simona; Tedeschi, Gioacchino; Gallo, Antonio

2013-01-01

Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD), obsessive-compulsive disorder (OCD), bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI) studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS), euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role) or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions), which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS.

Morphostructural MRI Abnormalities Related to Neuropsychiatric Disorders Associated to Multiple Sclerosis

PubMed Central

Bonavita, Simona; Tedeschi, Gioacchino; Gallo, Antonio

2013-01-01

Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD), obsessive-compulsive disorder (OCD), bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI) studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS), euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role) or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions), which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS. PMID:23691320

A Comparison of HAART Outcomes between the US Military HIV Natural History Study (NHS) and HIV Atlanta Veterans Affairs Cohort Study (HAVACS)

DTIC Science & Technology

2013-05-01

Acknowledgments The IDCRP HIV Working Group includes: Susan Banks, RN, CAPT Mary Bavaro, MD, Ionut Bebu, PhD, Helen Chun, MD, Nancy Crum- Cianflone, MD, MPH...Cathy Decker, MD, Conner Eggleston, LTC Tomas Ferguson, MD, COL Susan Fraser, MD, MAJ Joshua Hartzell, MD, MAJ Joshua Hawley, MD, LTC Gunther Hsue, MD

The Jasmonate-Activated Transcription Factor MdMYC2 Regulates ETHYLENE RESPONSE FACTOR and Ethylene Biosynthetic Genes to Promote Ethylene Biosynthesis during Apple Fruit Ripening[OPEN

PubMed Central

Xu, Yaxiu; Zhang, Lichao; Ji, Yinglin; Tan, Dongmei; Yuan, Hui

2017-01-01

The plant hormone ethylene is critical for ripening in climacteric fruits, including apple (Malus domestica). Jasmonate (JA) promotes ethylene biosynthesis in apple fruit, but the underlying molecular mechanism is unclear. Here, we found that JA-induced ethylene production in apple fruit is dependent on the expression of MdACS1, an ACC synthase gene involved in ethylene biosynthesis. The expression of MdMYC2, encoding a transcription factor involved in the JA signaling pathway, was enhanced by MeJA treatment in apple fruits, and MdMYC2 directly bound to the promoters of both MdACS1 and the ACC oxidase gene MdACO1 and enhanced their transcription. Furthermore, MdMYC2 bound to the promoter of MdERF3, encoding a transcription factor involved in the ethylene-signaling pathway, thereby activating MdACS1 transcription. We also found that MdMYC2 interacted with MdERF2, a suppressor of MdERF3 and MdACS1. This protein interaction prevented MdERF2 from interacting with MdERF3 and from binding to the MdACS1 promoter, leading to increased transcription of MdACS1. Collectively, these results indicate that JA promotes ethylene biosynthesis through the regulation of MdERFs and ethylene biosynthetic genes by MdMYC2. PMID:28550149

The Jasmonate-Activated Transcription Factor MdMYC2 Regulates ETHYLENE RESPONSE FACTOR and Ethylene Biosynthetic Genes to Promote Ethylene Biosynthesis during Apple Fruit Ripening.

PubMed

Li, Tong; Xu, Yaxiu; Zhang, Lichao; Ji, Yinglin; Tan, Dongmei; Yuan, Hui; Wang, Aide

2017-06-01

The plant hormone ethylene is critical for ripening in climacteric fruits, including apple ( Malus domestica ). Jasmonate (JA) promotes ethylene biosynthesis in apple fruit, but the underlying molecular mechanism is unclear. Here, we found that JA-induced ethylene production in apple fruit is dependent on the expression of MdACS1 , an ACC synthase gene involved in ethylene biosynthesis. The expression of MdMYC2 , encoding a transcription factor involved in the JA signaling pathway, was enhanced by MeJA treatment in apple fruits, and MdMYC2 directly bound to the promoters of both MdACS1 and the ACC oxidase gene MdACO1 and enhanced their transcription. Furthermore, MdMYC2 bound to the promoter of MdERF3 , encoding a transcription factor involved in the ethylene-signaling pathway, thereby activating MdACS1 transcription. We also found that MdMYC2 interacted with MdERF2, a suppressor of MdERF3 and MdACS1 This protein interaction prevented MdERF2 from interacting with MdERF3 and from binding to the MdACS1 promoter, leading to increased transcription of MdACS1 Collectively, these results indicate that JA promotes ethylene biosynthesis through the regulation of MdERFs and ethylene biosynthetic genes by MdMYC2. © 2017 American Society of Plant Biologists. All rights reserved.

Apple FLOWERING LOCUS T proteins interact with transcription factors implicated in cell growth and organ development.

PubMed

Mimida, Naozumi; Kidou, Shin-Ichiro; Iwanami, Hiroshi; Moriya, Shigeki; Abe, Kazuyuki; Voogd, Charlotte; Varkonyi-Gasic, Erika; Kotoda, Nobuhiro

2011-05-01

Understanding the flowering process in apple (Malus × domestica Borkh.) is essential for developing methods to shorten the breeding period and regulate fruit yield. It is known that FLOWERING LOCUS T (FT) acts as a transmissible floral inducer in the Arabidopsis flowering network system. To clarify the molecular network of two apple FT orthologues, MdFT1 and MdFT2, we performed a yeast two-hybrid screen to identify proteins that interact with MdFT1. We identified several transcription factors, including two members of the TCP (TEOSINTE BRANCHED1, CYCLOIDEA and PROLIFERATING CELL FACTORs) family, designated MdTCP2 and MdTCP4, and an Arabidopsis thaliana VOZ1 (Vascular plant One Zinc finger protein1)-like protein, designated MdVOZ1. MdTCP2 and MdVOZ1 also interacted with MdFT2 in yeast. The expression domain of MdTCP2 and MdVOZ1 partially overlapped with that of MdFT1 and MdFT2, most strikingly in apple fruit tissue, further suggesting a potential interaction in vivo. Constitutive expression of MdTCP2, MdTCP4 and MdVOZ1 in Arabidopsis affected plant size, leaf morphology and the formation of leaf primordia on the adaxial side of cotyledons. On the other hand, chimeric MdTCP2, MdTCP4 and MdVOZ1 repressors that included the ethylene-responsive transcription factors (ERF)-associated amphiphilic repression (EAR) domain motif influenced reproduction and inflorescence architecture in transgenic Arabidopsis. These results suggest that MdFT1 and/or MdFT2 might be involved in the regulation of cellular proliferation and the formation of new tissues and that they might affect leaf and fruit development by interacting with TCP- and VOZ-family proteins. DDBJ accession nos. AB531019 (MdTCP2a mRNA), AB531020 (MdTCP2b mRNA), AB531021 (MdTCP4a mRNA), AB531022 (MdTCP4b mRNA) and AB531023 (MdVOZ1a mRNA). © The Author 2011. Published by Oxford University Press. All rights reserved.

Safety and efficacy of rasagiline in addition to levodopa for the treatment of idiopathic Parkinson's disease: a meta-analysis of randomised controlled trials.

PubMed

Cai, Jiang-Ping; Chen, Wan-Jin; Lin, Yu; Cai, Bin; Wang, Ning

2015-01-01

To assess the safety and efficacy of rasagiline for the treatment of Parkinson's disease (PD) among individuals currently receiving levodopa. A systematic literature search was conducted to identify randomised controlled trials (RCT) comparing rasagiline with placebo/no treatment in individuals with PD currently receiving levodopa. Outcome measures included improvement in motor functions; symptomatic improvement; improvement in quality of life; adverse effects. Random-effect meta-analytical techniques were conducted for the outcome measure and subgroup analyses. Three RCTs were included (n = 1002). The results showed significantly greater improvements in daily 'on' time without dyskinesia in levodopa-treated participants with idiopathic PD receiving 1 mg/day rasagiline compared to placebo (n = 712, 2 RCTs, MD 0.80, CI 0.45 to 1.15; p < 0.00001), and significantly greater improvements in Unified Parkinson's Disease Rating Scale motor performance scores during 'on' time in participants receiving 0.5-1 mg/day rasagiline (0.5 mg/day: n = 282, MD -2.91, CI -4.59 to -1.23; p = 0.0007; 1 mg/day: n = 712, 2 RCTs, MD -2.91, CI -4.02 to -1.80; p < 0.00001). There were no significant differences in adverse effects. 0.5 to 1 mg/day rasagiline in addition to levodopa is a safe and well-tolerated combination therapy for individuals with Parkinson's disease.

Application of imaging techniques to evaluate polishing characteristics of aggregates : final report.

DOT National Transportation Integrated Search

2016-12-01

Previous research conducted at the University of Florida (UF) to investigate the use of the Aggregate Image Measurement System (AIMS) and Micro-Deval (MD) to evaluate frictional performance of aggregates concluded that the current AIMS system cannot ...

ST-analyzer: a web-based user interface for simulation trajectory analysis.

PubMed

Jeong, Jong Cheol; Jo, Sunhwan; Wu, Emilia L; Qi, Yifei; Monje-Galvan, Viviana; Yeom, Min Sun; Gorenstein, Lev; Chen, Feng; Klauda, Jeffery B; Im, Wonpil

2014-05-05

Molecular dynamics (MD) simulation has become one of the key tools to obtain deeper insights into biological systems using various levels of descriptions such as all-atom, united-atom, and coarse-grained models. Recent advances in computing resources and MD programs have significantly accelerated the simulation time and thus increased the amount of trajectory data. Although many laboratories routinely perform MD simulations, analyzing MD trajectories is still time consuming and often a difficult task. ST-analyzer, http://im.bioinformatics.ku.edu/st-analyzer, is a standalone graphical user interface (GUI) toolset to perform various trajectory analyses. ST-analyzer has several outstanding features compared to other existing analysis tools: (i) handling various formats of trajectory files from MD programs, such as CHARMM, NAMD, GROMACS, and Amber, (ii) intuitive web-based GUI environment--minimizing administrative load and reducing burdens on the user from adapting new software environments, (iii) platform independent design--working with any existing operating system, (iv) easy integration into job queuing systems--providing options of batch processing either on the cluster or in an interactive mode, and (v) providing independence between foreground GUI and background modules--making it easier to add personal modules or to recycle/integrate pre-existing scripts utilizing other analysis tools. The current ST-analyzer contains nine main analysis modules that together contain 18 options, including density profile, lipid deuterium order parameters, surface area per lipid, and membrane hydrophobic thickness. This article introduces ST-analyzer with its design, implementation, and features, and also illustrates practical analysis of lipid bilayer simulations. Copyright © 2014 Wiley Periodicals, Inc.

Development of evaluation technique of GMAW welding quality based on statistical analysis

NASA Astrophysics Data System (ADS)

Feng, Shengqiang; Terasaki, Hidenri; Komizo, Yuichi; Hu, Shengsun; Chen, Donggao; Ma, Zhihua

2014-11-01

Nondestructive techniques for appraising gas metal arc welding(GMAW) faults plays a very important role in on-line quality controllability and prediction of the GMAW process. On-line welding quality controllability and prediction have several disadvantages such as high cost, low efficiency, complication and greatly being affected by the environment. An enhanced, efficient evaluation technique for evaluating welding faults based on Mahalanobis distance(MD) and normal distribution is presented. In addition, a new piece of equipment, designated the weld quality tester(WQT), is developed based on the proposed evaluation technique. MD is superior to other multidimensional distances such as Euclidean distance because the covariance matrix used for calculating MD takes into account correlations in the data and scaling. The values of MD obtained from welding current and arc voltage are assumed to follow a normal distribution. The normal distribution has two parameters: the mean µ and standard deviation σ of the data. In the proposed evaluation technique used by the WQT, values of MD located in the range from zero to µ+3 σ are regarded as "good". Two experiments which involve changing the flow of shielding gas and smearing paint on the surface of the substrate are conducted in order to verify the sensitivity of the proposed evaluation technique and the feasibility of using WQT. The experimental results demonstrate the usefulness of the WQT for evaluating welding quality. The proposed technique can be applied to implement the on-line welding quality controllability and prediction, which is of great importance to design some novel equipment for weld quality detection.

Peer and cyber aggression in secondary school students: the role of moral disengagement, hostile attribution bias, and outcome expectancies.

PubMed

Pornari, Chrisa D; Wood, Jane

2010-01-01

This study investigated the relationship between cognitive mechanisms, applied by people to rationalize and justify harmful acts, and engagement in traditional peer and cyber aggression among school children. We examined the contribution of moral disengagement (MD), hostile attribution bias, and outcome expectancies, and we further explored the individual contribution of each MD mechanism. Our aim was to identify shared and unique cognitive factors of the two forms of aggression. Three hundred and thirty-nine secondary school children completed self-report measures that assessed MD, hostile attribution bias, outcome expectancies, and their roles and involvement in traditional and cyber aggression. We found that the MD total score positively related to both forms of peer-directed aggression. Furthermore, traditional peer aggression positively related to children's moral justification, euphemistic language, displacement of responsibility and outcome expectancies, and negatively associated with hostile attribution bias. Moral justification also related positively to cyber aggression. Cyber aggression and cyber victimization were associated with high levels of traditional peer aggression and victimization, respectively. The results suggest that MD is a common feature of both traditional and cyber peer aggression, but it seems that traditional forms of aggression demand a higher level of rationalization or justification. Moreover, the data suggest that the expectation of positive outcomes from harmful behavior facilitates engagement in traditional peer aggression. The differential contribution of specific cognitive mechanisms indicates the need for future research to elaborate on the current findings, in order to advance theory and inform existing and future school interventions tackling aggression and bullying. (c) 2009 Wiley-Liss, Inc.

Outcomes of laparoscopic resection of Meckel's diverticulum are equivalent to open laparotomy.

PubMed

Ezekian, Brian; Leraas, Harold J; Englum, Brian R; Gilmore, Brian F; Reed, Christopher; Fitzgerald, Tamara N; Rice, Henry E; Tracy, Elisabeth T

2018-03-15

Meckel's diverticulum (MD) is a common congenital anomaly caused by failure of involution of the omphalomesenteric duct. Enthusiasm for minimally invasive surgery (MIS) in children has burgeoned as technologies have advanced, but the outcomes of laparoscopic resection in comparison to open laparotomy for MD remain poorly defined. We queried a large national database to compare current practice patterns and clinical outcomes between surgical approaches for MD in the pediatric population. The National Surgical Quality Improvement Program-Pediatric (NSQIP-Ped) database was queried for patients undergoing surgical intervention for MD (2011-2014). Patients were stratified by surgical approach. Baseline characteristics, intraoperative variables, and perioperative complications were compared by univariate analysis using Pearson's χ 2 test for categorical variables and Kruskall-Wallis test for continuous variables. Primary outcomes of interest were length of stay (LOS), rate of readmission, and 30-day mortality. Secondary outcomes included operative time, anesthesia time, postoperative complications, and rates of reoperation. A total of 148 cases of MD were identified, of which 73 (49.3%) were initially managed with a laparoscopic approach and 75 (50.7%) were managed with an open approach. We found a high rate of conversion from laparoscopy to an open approach (20/73 or 27.4%). The median age of the laparoscopic group was higher than the open group (8.3 vs. 2.5years, p<0.001). Operative and anesthesia time, LOS, 30-day mortality, post-operative complications, and rates of reoperation and readmission were similar between groups (all p>0.05). Nearly half of all resections for MD in children are now approached laparoscopically. This approach has equivalent outcomes to traditional open laparotomy. More widespread use of a hybrid approach with laparoscopy and exteriorization of the small bowel through an extended port site may facilitate avoiding open laparotomy. Routine conversion to open for palpation of the MD or segmental small bowel resection should be avoided in the absence of compelling intra-operative findings or operative complications. Level III (retrospective comparative study). Copyright © 2018 Elsevier Inc. All rights reserved.

Relationship between visual field progression and baseline refraction in primary open-angle glaucoma.

PubMed

Naito, Tomoko; Yoshikawa, Keiji; Mizoue, Shiro; Nanno, Mami; Kimura, Tairo; Suzumura, Hirotaka; Umeda, Yuzo; Shiraga, Fumio

2016-01-01

To analyze the relationship between visual field (VF) progression and baseline refraction in Japanese patients with primary open-angle glaucoma (POAG) including normal-tension glaucoma. In this retrospective study, the subjects were patients with POAG who had undergone VF tests at least ten times with a Humphrey Field Analyzer (Swedish interactive thresholding algorithm standard, Central 30-2 program). VF progression was defined as a significantly negative value of mean deviation (MD) slope at the final VF test. Multivariate logistic regression models were applied to detect an association between MD slope deterioration and baseline refraction. A total of 156 eyes of 156 patients were included in this analysis. Significant deterioration of MD slope was observed in 70 eyes of 70 patients (44.9%), whereas no significant deterioration was evident in 86 eyes of 86 patients (55.1%). The eyes with VF progression had significantly higher baseline refraction compared to those without apparent VF progression (-1.9±3.8 diopter [D] vs -3.5±3.4 D, P=0.0048) (mean ± standard deviation). When subject eyes were classified into four groups by the level of baseline refraction applying spherical equivalent (SE): no myopia (SE > -1D), mild myopia (-1D ≥ SE > -3D), moderate myopia (-3D ≥ SE > -6D), and severe myopia (-6D ≥ SE), the Cochran-Armitage trend analysis showed a decreasing trend in the proportion of MD slope deterioration with increasing severity of myopia (P=0.0002). The multivariate analysis revealed that baseline refraction (P=0.0108, odds ratio [OR]: 1.13, 95% confidence interval [CI]: 1.03-1.25) and intraocular pressure reduction rate (P=0.0150, OR: 0.97, 95% CI: 0.94-0.99) had a significant association with MD slope deterioration. In the current analysis of Japanese patients with POAG, baseline refraction was a factor significantly associated with MD slope deterioration as well as intraocular pressure reduction rate. When baseline refraction was classified into four groups, MD slope in myopia groups was less deteriorated as compared to those in the emmetropic/hyperopic group.

Genome-wide identification of allele-specific expression (ASE) in response to Marek's disease virus infection using next generation sequencing.

PubMed

Maceachern, Sean; Muir, William M; Crosby, Seth; Cheng, Hans H

2011-06-03

Marek's disease (MD), a T cell lymphoma induced by the highly oncogenic α-herpesvirus Marek's disease virus (MDV), is the main chronic infectious disease concern threatening the poultry industry. Enhancing genetic resistance to MD in commercial poultry is an attractive method to augment MD vaccines, which is currently the control method of choice. In order to optimally implement this control strategy through marker-assisted selection (MAS) and to gain biological information, it is necessary to identify specific genes that influence MD incidence. A genome-wide screen for allele-specific expression (ASE) in response to MDV infection was conducted. The highly inbred ADOL chicken lines 6 (MD resistant) and 7 (MD susceptible) were inter-mated in reciprocal crosses and half of the progeny challenged with MDV. Splenic RNA pools at a single time after infection for each treatment group point were generated, sequenced using a next generation sequencer, then analyzed for allele-specific expression (ASE). To validate and extend the results, Illumina GoldenGate assays for selected cSNPs were developed and used on all RNA samples from all 6 time points following MDV challenge. RNA sequencing resulted in 11-13+ million mappable reads per treatment group, 1.7+ Gb total sequence, and 22,655 high-confidence cSNPs. Analysis of these cSNPs revealed that 5360 cSNPs in 3773 genes exhibited statistically significant allelic imbalance. Of the 1536 GoldenGate assays, 1465 were successfully scored with all but 19 exhibiting evidence for allelic imbalance. ASE is an efficient method to identify potentially all or most of the genes influencing this complex trait. The identified cSNPs can be further evaluated in resource populations to determine their allelic direction and size of effect on genetic resistance to MD as well as being directly implemented in genomic selection programs. The described method, although demonstrated in inbred chicken lines, is applicable to all traits in any diploid species, and should prove to be a simple method to identify the majority of genes controlling any complex trait.

Exploring intentions of physician-scientist trainees: factors influencing MD and MD/PhD interest in research careers.

PubMed

Kwan, Jennifer M; Daye, Dania; Schmidt, Mary Lou; Conlon, Claudia Morrissey; Kim, Hajwa; Gaonkar, Bilwaj; Payne, Aimee S; Riddle, Megan; Madera, Sharline; Adami, Alexander J; Winter, Kate Quinn

2017-07-11

Prior studies have described the career paths of physician-scientist candidates after graduation, but the factors that influence career choices at the candidate stage remain unclear. Additionally, previous work has focused on MD/PhDs, despite many physician-scientists being MDs. This study sought to identify career sector intentions, important factors in career selection, and experienced and predicted obstacles to career success that influence the career choices of MD candidates, MD candidates with research-intense career intentions (MD-RI), and MD/PhD candidates. A 70-question survey was administered to students at 5 academic medical centers with Medical Scientist Training Programs (MSTPs) and Clinical and Translational Science Awards (CTSA) from the NIH. Data were analyzed using bivariate or multivariate analyses. More MD/PhD and MD-RI candidates anticipated or had experienced obstacles related to balancing academic and family responsibilities and to balancing clinical, research, and education responsibilities, whereas more MD candidates indicated experienced and predicted obstacles related to loan repayment. MD/PhD candidates expressed higher interest in basic and translational research compared to MD-RI candidates, who indicated more interest in clinical research. Overall, MD-RI candidates displayed a profile distinct from both MD/PhD and MD candidates. MD/PhD and MD-RI candidates experience obstacles that influence their intentions to pursue academic medical careers from the earliest training stage, obstacles which differ from those of their MD peers. The differences between the aspirations of and challenges facing MD, MD-RI and MD/PhD candidates present opportunities for training programs to target curricula and support services to ensure the career development of successful physician-scientists.

JPRS Report, Science & Technology. Europe: Economic Competitiveness

DTIC Science & Technology

1991-08-09

cost . Under the current funding scheme, support is only available through a system of reimbursable interest-free loans. With the currently proposed... system , basic indus- trial research will henceforth be financed by subsidies (of up to 50 percent of gross costs ). Small- and medium- sized...extremely cost -effective installations. • To market the MD110 as a foundation for office automation facilities. • To target very large system

Growth Failure in Children with Kidney Disease

MedlinePlus

... Ira Davis, M.D.; Ann Guillott, M.D.; Steve Alexander, M.D.; Deborah Kees-Folts, M.D.; Alicia Neu, M.D.; Steve Wassner, M.D.; John Brandt, M.D.; and ... Coordinating Committees Strategic Plans & Reports Research Areas FAQs Jobs at NIDDK Visit Us Contact Us News News ...

Planned Change in Education: Current Trends of Inquiry.

ERIC Educational Resources Information Center

Van Meter, Eddy J.; Scollay, Susan J.

1985-01-01

Four trends within planned change literature are identified: the increased use of the concept of limited rationality; a better understanding of the implementation process; more exploration of issues dealing with evaluation; and the development of new models for understanding planned change. (MD)

An eHealth program versus a standard care supervised health program and associated health outcomes in individuals with mobility disability: study protocol for a randomized controlled trial.

PubMed

Berglind, Daniel; Nyberg, Gisela; Willmer, Mikaela; Persson, Margareta; Wells, Michael; Forsell, Yvonne

2018-04-27

Young adults with mobility disability (MD) are less likely to engage in regular physical activity (PA) compared with their able-bodied peers and inactive adults with a MD are more likely to report one or more chronic diseases compared to those who are physically active. Despite the vast amount of research published in the field of PA interventions over the past decades, little attention has been focused on interventions aiming to increase PA among individuals with MD. Thus, we propose to compare the effects of an eHealth program compared to a usual care supervised health program on levels of PA and other health behaviors. The current intervention will use a randomized controlled trial (RCT) design with two treatment groups (an eHealth program and a usual care supervised health program) in young adults with newly acquired MD. In total, 110 young adults (aged 18-40 years) with a MD, acquired within the past 3 years, will be recruited to participate in a 12-week intervention. The primary study outcome is accelerometer-measured time spent in moderate to vigorous PA. Secondary outcomes includes health-related quality of life, depression, stress, fitness, body composition, diet, musculoskeletal pain, motivation to exercise and work ability. There is a lack of RCTs investigating effective ways to increase levels of PA in young adults with MD. Increased levels of PA among this physically inactive population have the potential to substantially improve health-related outcomes, possibly more so than in the general population. The trial will put strong emphasis on optimizing exercise adherence and investigating feasibility in the two treatment programs. The Ethical Review Board (EPN) at Karolinska Institutet has approved the study (2017/1206-31/1). International Standard Randomised Controlled Trial Number (ISRCTN), reference number ISRCTN22387524 . Prospectively registered February 4, 2018.

Analysis of the acceleration profile according to initial speed and positional role in elite professional male soccer players.

PubMed

de Hoyo, Moisés; Sañudo, Borja; Suárez-Arrones, Luis; Carrasco, Luis; Joel, Tom; Domínguez-Cobo, Sergio; Núñez, Francisco J

2017-12-01

The aim of the current study was to analyse the acceleration profile in elite professional soccer players according to their initial speed but also considering players' position. Players' accelerations profiles were analysed using a relative acceleration profile according to the initial speed (S1, from 0 to 7 km/h; S2, from 7.1 to 14.3 km/h; and S3, ≥14.4 km/h) and the maximum acceleration. Within-group analyses showed that Center Backs (CB) performed more high intensity accelerations (likely) when they started in S1 than S2 (ES: 0.50). Strikers (S) and Wide Midfielders (W-MD) achieved more accelerations (likely to almost certain) starting in S3 than S1 (ES: 0.80 and 0.59, respectively) and S2 (ES: 0.67 and 1.09, respectively). Full Backs (FB) completed more accelerations (almost certain) starting in S1 and S3 than S2 (ES: 1.39 and 1.36, respectively). Finally, Midfielders (MD) executed a greater number of high intensity accelerations (likely to almost certain) when they started in S1 than S2 (ES: 0.83) and S3 (ES: 0.66), and in S3 than S2 (ES: 4.72). Between-group analyses showed that S, W-MD, and FB performed a greater total number of high intensity accelerations (very likely to almost certain) than CB (ES: 1.94, 1.57, and 1.51, respectively) and MD (ES: 1.23, 0.92; and 0.81, respectively). Furthermore, MD performed substantially greater total number of high intensity accelerations (likely) than CB (ES: 0.56). Results suggest that CB achieved more high-intensity accelerations starting in low and moderate speed, S and W-MD in high speed, and FB combined low and high speed.

Apple (Malus domestica) MdERF2 negatively affects ethylene biosynthesis during fruit ripening by suppressing MdACS1 transcription.

PubMed

Li, Tong; Jiang, Zhongyu; Zhang, Lichao; Tan, Dongmei; Wei, Yun; Yuan, Hui; Li, Tianlai; Wang, Aide

2016-12-01

Ripening in climacteric fruit requires the gaseous phytohormone ethylene. Although ethylene signaling has been well studied, knowledge of the transcriptional regulation of ethylene biosynthesis is still limited. Here we show that an apple (Malus domestica) ethylene response factor, MdERF2, negatively affects ethylene biosynthesis and fruit ripening by suppressing the transcription of MdACS1, a gene that is critical for biosynthesis of ripening-related ethylene. Expression of MdERF2 was suppressed by ethylene during ripening of apple fruit, and we observed that MdERF2 bound to the promoter of MdACS1 and directly suppressed its transcription. Moreover, MdERF2 suppressed the activity of the promoter of MdERF3, a transcription factor that we found to bind to the MdACS1 promoter, thereby increasing MdACS1 transcription. We determined that the MdERF2 and MdERF3 proteins directly interact, and this interaction suppresses the binding of MdERF3 to the MdACS1 promoter. Moreover, apple fruit with transiently downregulated MdERF2 expression showed higher ethylene production and faster ripening. Our results indicate that MdERF2 negatively affects ethylene biosynthesis and fruit ripening in apple by suppressing the transcription of MdACS1 via multiple mechanisms, thereby acting as an antagonist of positive ripening regulators. Our findings offer a deep understanding of the transcriptional regulation of ethylene biosynthesis during climacteric fruit ripening. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Apple RING E3 ligase MdMIEL1 inhibits anthocyanin accumulation by ubiquitinating and degrading MdMYB1 protein.

PubMed

An, Jian-Ping; Liu, Xin; Li, Hao-Hao; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2017-11-01

MdMYB1 is an important regulator for anthocyanin accumulation in apple (Malus × domestica). Here, an apple RING E3 ligase, MdMIEL1, was screened out as a partner of MdMYB1 with a yeast two-hybrid approach. Pull-down, bimolecular fluorescence complementation and coimmunoprecipitation assays further verified the interaction between MdMIEL1 and MdMYB1 proteins. Subsequently, in vitro and in vivo experiments indicated that MdMIEL1 functioned as a ubiquitin E3 ligase to ubiquitinate MdMYB1 protein, followed by degradation through a 26S proteasome pathway. Furthermore, transgenic studies in apple calli and Arabidopsis demonstrated that MdMIEL1 negatively regulated anthocyanin accumulation by modulating the degradation of MdMYB1 protein. Taken together, our findings provide a new insight into the molecular mechanism by which MdMIEL1 negatively regulates anthocyanin biosynthesis by ubiquitinating and degrading MdMYB1 protein. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

The Clinical Utility of Vestibular-Evoked Myogenic Potentials in the Diagnosis of Ménière’s Disease

PubMed Central

Maheu, Maxime; Alvarado-Umanzor, Jenny Marylin; Delcenserie, Audrey; Champoux, François

2017-01-01

Ménière’s disease (MD) is a condition that has been proposed over 150 years ago, which involves audiological and vestibular manifestations, such as aural fullness, tinnitus, vertigo, and fluctuating hearing thresholds. Over the past few years, many researchers have assessed different techniques to help diagnose this pathology. Vestibular-evoked myogenic potential (VEMP) is an electrophysiological method assessing the saccule (cVEMP) and the utricule (oVEMP). Its clinical utility in the diagnosis of multiple pathologies, such as superior canal dehiscence, has made this tool a common method used in otologic clinics. The main objective of the present review is to determine the current state of knowledge of the VEMP in the identification of MD, such as the type of stimuli, the frequency tuning, and the interaural asymmetry ratio of the cVEMP and the oVEMP. Results show that the type of stimulation, the frequency sensitivity shift and the interaural asymmetry ratio (IAR) could be useful tool to diagnose and describe the evolution of MD. It is, however, important to emphasize that further studies are needed to confirm the utility of VEMP in the identification of MD in its early stage, using either bone-conduction vibration or air-conduction stimulation, which is of clinical importance when it comes to early intervention. PMID:28861037

Extremity War Injuries X: Return to Health and Function.

PubMed

Davila, Col Jeffrey N; Swiontkowski, Marc F; Andersen, Col Ret Romney C

2016-09-01

The symposium Extremity War Injuries X: Return to Health and Function, presented by the American Academy of Orthopaedic Surgeons, the Orthopaedic Trauma Association, the Society of Military Orthopaedic Surgeons, and the Orthopaedic Research Society, was held in Washington, DC, on January 27 and 28, 2015. Course chairs Marc F. Swiontkowski, MD, and COL Jeffrey N. Davila, MD, presided over 2 days of general session lectures focusing on war/trauma-related musculoskeletal injuries resulting in service member disability, followed by small group discussions, with a goal of identifying knowledge gaps in the treatment of these injuries. Recognized civilian and military clinicians and researchers summarized the current state of knowledge in their topic areas and led these discussion groups with meeting participants. Musculoskeletal conditions discussed included posttraumatic osteoarthritis of the knee, foot, and ankle and their relationship to chronic ligament injuries; back disability; peripheral nerve injury; hand transplantation updates; the role of biologics; and prosthetic acceptance and function. A scientific program highlighting research presented by 12 investigators was led by COL (Ret) Romney C. Andersen, MD. Keynote speaker LT GEN Douglas J. Robb, MD, discussed the future of military research funding and the anticipated consolidation of medical care among the three military branches. Additional presentations referencing the impact of military medical care and the government's continued commitment to funding medical research occurred throughout the symposium and were given by five congressional representatives.

Challenges to the Mediterranean diet at a time of economic crisis.

PubMed

Bonaccio, M; Bes-Rastrollo, M; de Gaetano, G; Iacoviello, L

2016-12-01

The traditional Mediterranean diet (MD) is reportedly associated with lower risk of major chronic diseases and long considered to contribute to the reduced rates of cardiovascular and cerebrovascular events and to the highest life expectancy in adults who lived near the Mediterranean Sea. But despite its widely documented health benefits, adherence to this dietary pattern has been rapidly declining over the last decades due to a clear socioeconomic influence. The present review provides an overview of the evidence on the current major determinants of adherence to the Mediterranean diet, with a particular emphasis on Mediterranean Countries at a time of economic crisis; second it explores emerging socioeconomic inequalities in other domains of healthy dietary behaviours such as dietary variety, access to organic foods and food purchasing behaviour. According to ecological evidence, the Mediterranean Countries that used to have the highest adherence to the Mediterranean pattern in the Sixties, more recently experienced the greatest decrease, while Countries in Northern Europe and some other Countries around the world are currently embracing a Mediterranean-like dietary pattern. A potential cause of this downward trend could be the increasing prices of some food items of the Mediterranean diet pyramid. Recent evidence has shown a possible involvement of the economic crisis, material resources becoming strong determinants of the adherence to the MD just after the recession started in 2007-2008. Beyond intake, the MD also encourages increasing dietary diversity, while international dietary recommendations suggest replacing regular foods with healthier ones. Socioeconomic factors appear to be major determinants of the adherence to MD and disparities also hold for other indices of diet quality closely related to this dietary pattern. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Physical properties of two core samples from Well 34-9RD2 at the Coso geothermal field, California

USGS Publications Warehouse

Morrow, C.A.; Lockner, D.A.

2006-01-01

The Coso geothermal field, located along the Eastern California Shear Zone, is composed of fractured granitic rocks above a shallow heat source. Temperatures exceed 640 ?F (~338 ?C) at a depth of less than 10000 feet (3 km). Permeability varies throughout the geothermal field due to the competing processes of alteration and mineral precipitation, acting to reduce the interconnectivity of faults and fractures, and the generation of new fractures through faulting and brecciation. Currently, several hot regions display very low permeability, not conducive to the efficient extraction of heat. Because high rates of seismicity in the field indicate that the area is highly stressed, enhanced permeability can be stimulated by increasing the fluid pressure at depth to induce faulting along the existing network of fractures. Such an Enhanced Geothermal System (EGS), planned for well 46A-19RD, would greatly facilitate the extraction of geothermal fluids from depth by increasing the extent and depth of the fracture network. In order to prepare for and interpret data from such a stimulation experiment, the physical properties and failure behavior of the target rocks must be fully understood. Various diorites and granodiorites are the predominant rock types in the target area of the well, which will be pressurized from 10000 feet measured depth (MD) (3048m MD) to the bottom of the well at 13,000 feet MD (3962 m MD). Because there are no core rocks currently available from well 46A-19RD, we report here on the results of compressive strength, frictional sliding behavior, and elastic measurements of a granodiorite and diorite from another well, 34-9RD2, at the Coso site. Rocks cored from well 34-9RD2 are the deepest samples to date available for testing, and are representative of rocks from the field in general.

Meta-Analysis of Creatine for Neuroprotection Against Parkinson's Disease.

PubMed

Attia; Ahmed, Hussien; Gadelkarim, Mohamed; Morsi, Mahmoud; Awad, Kamal; Elnenny, Mohamed; Ghanem, Esraa; El-Jaafary, Shaimaa; Negida, Ahmed

2017-01-01

Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Detection of IFN-γ+IL-17+ cells in salivary glands of patients with Sjögren's syndrome and Mikulicz's disease: Potential role of Th17•Th1 in the pathogenesis of autoimmune diseases.

PubMed

Nanke, Yuki; Kobashigawa, Tsuyoshi; Yago, Toru; Kawamoto, Manabu; Yamanaka, Hisashi; Kotake, Shigeru

2016-01-01

  Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.

Health technology assessment of medical devices: a survey of non-European union agencies.

PubMed

Ciani, Oriana; Wilcher, Britni; Blankart, Carl Rudolf; Hatz, Maximilian; Rupel, Valentina Prevolnik; Erker, Renata Slabe; Varabyova, Yauheniya; Taylor, Rod S

2015-01-01

The aim of this study was to review and compare current health technology assessment (HTA) activities for medical devices across non-European Union HTA agencies. HTA activities for medical devices were evaluated from three perspectives: organizational structure, processes, and methods. Agencies were primarily selected upon membership of existing HTA networks. The data collection was performed in two stages: stage 1-agency Web-site assessment using a standardized questionnaire, followed by review and validation of the collected data by a representative of the agency; and stage 2-semi-structured telephone interviews with key informants of a sub-sample of agencies. In total, thirty-six HTA agencies across twenty non-EU countries assessing medical devices were included. Twenty-seven of thirty-six (75 percent) agencies were judged at stage 1 to have adopted HTA-specific approaches for medical devices (MD-specific agencies) that were largely organizational or procedural. There appeared to be few differences in the organization, process and methods between MD-specific and non-MD-specific agencies. Although the majority (69 percent) of both categories of agency had specific methods guidance or policy for evidence submission, only one MD-specific agency had developed methodological guidelines specific to medical devices. In stage 2, many MD-specific agencies cited insufficient resources (budget, skilled employees), lack of coordination (between regulator and reimbursement bodies), and the inability to generalize findings from evidence synthesis to be key challenges in the HTA of medical devices. The lack of evidence for differentiation in scientific methods for HTA of devices raises the question of whether HTA needs to develop new methods for medical devices but rather adapt existing methodological approaches. In contrast, organizational and/or procedural adaptation of existing HTA agency frameworks to accommodate medical devices appear relatively commonplace.

Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series

PubMed Central

Lenartz, Doris; Kuhn, Jens; Sturm, Volker

2016-01-01

Background The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. Methods In this retrospective trial, four patients (three female, one male) aged 31–48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. Results Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed “partial response” on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. Conclusion MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. PMID:27504631

Sensitivity of simulated snow cloud properties to mass-diameter parameterizations.

NASA Astrophysics Data System (ADS)

Duffy, G.; Nesbitt, S. W.; McFarquhar, G. M.

2015-12-01

Mass to diameter (m-D) relationships are used in model parameterization schemes to represent ice cloud microphysics and in retrievals of bulk cloud properties from remote sensing instruments. One of the most common relationships, used in the current Global Precipitation Measurement retrieval algorithm for example, assigns the density of snow as a constant tenth of the density of ice (0.1g/m^3). This assumption stands in contrast to the results of derived m-D relationships of snow particles, which imply decreasing particle densities at larger sizes and result in particle masses orders of magnitude below the constant density relationship. In this study, forward simulations of bulk cloud properties (e.g., total water content, radar reflectivity and precipitation rate) derived from measured size distributions using several historical m-D relationships are presented. This expands upon previous studies that mainly focused on smaller ice particles because of the examination of precipitation-sized particles here. In situ and remote sensing data from the GPM Cold season Experiment (GCPEx) and Canadian CloudSAT/Calypso Validation Program (C3VP), both synoptic snowstorm field experiments in southern Ontario, Canada, are used to evaluate the forward simulations against total water content measured by the Nevzorov and Cloud Spectrometer and Impactor (CSI) probe, radar reflectivity measured by a C band ground based radar and a nadir pointing Ku/Ka dual frequency airborne radar, and precipitation rate measured by a 2D video disdrometer. There are differences between the bulk cloud properties derived using varying m-D relations, with constant density assumptions producing results differing substantially from the bulk measured quantities. The variability in bulk cloud properties derived using different m-D relations is compared against the natural variability in those parameters seen in the GCPEx and C3VP field experiments.

The R2R3-MYB transcription factor MdMYB73 is involved in malate accumulation and vacuolar acidification in apple.

PubMed

Hu, Da-Gang; Li, Yuan-Yuan; Zhang, Quan-Yan; Li, Ming; Sun, Cui-Hui; Yu, Jian-Qiang; Hao, Yu-Jin

2017-08-01

Malate, the predominant organic acid in many fruits, is a crucial component of the organoleptic quality of fruit, including taste and flavor. The genetic and environmental mechanisms affecting malate metabolism in fruit cells have been studied extensively. However, the transcriptional regulation of malate-metabolizing enzymes and vacuolar transporters remains poorly understood. Our previous studies demonstrated that MdMYB1 modulates anthocyanin accumulation and vacuolar acidification by directly activating vacuolar transporters, including MdVHA-B1, MdVHA-E, MdVHP1 and MdtDT. Interestingly, we isolated and identified a MYB transcription factor, MdMYB73, a distant relative of MdMYB1 in this study. It was subsequently found that MdMYB73 protein bound directly to the promoters of MdALMT9 (aluminum-activated malate transporter 9), MdVHA-A (vacuolar ATPase subunit A) and MdVHP1 (vacuolar pyrophosphatase 1), transcriptionally activating their expression and thereby enhancing their activities. Analyses of transgenic apple calli demonstrated that MdMYB73 influenced malate accumulation and vacuolar pH. Furthermore, MdCIbHLH1 interacted with MdMYB73 and enhanced its activity upon downstream target genes. These findings help to elucidate how MdMYB73 directly modulates the vacuolar transport system to affect malate accumulation and vacuolar pH in apple. © 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.

Using Local States To Drive the Sampling of Global Conformations in Proteins

PubMed Central

2016-01-01

Conformational changes associated with protein function often occur beyond the time scale currently accessible to unbiased molecular dynamics (MD) simulations, so that different approaches have been developed to accelerate their sampling. Here we investigate how the knowledge of backbone conformations preferentially adopted by protein fragments, as contained in precalculated libraries known as structural alphabets (SA), can be used to explore the landscape of protein conformations in MD simulations. We find that (a) enhancing the sampling of native local states in both metadynamics and steered MD simulations allows the recovery of global folded states in small proteins; (b) folded states can still be recovered when the amount of information on the native local states is reduced by using a low-resolution version of the SA, where states are clustered into macrostates; and (c) sequences of SA states derived from collections of structural motifs can be used to sample alternative conformations of preselected protein regions. The present findings have potential impact on several applications, ranging from protein model refinement to protein folding and design. PMID:26808351

Massively parallel first-principles simulation of electron dynamics in materials

DOE PAGES

Draeger, Erik W.; Andrade, Xavier; Gunnels, John A.; ...

2017-08-01

Here we present a highly scalable, parallel implementation of first-principles electron dynamics coupled with molecular dynamics (MD). By using optimized kernels, network topology aware communication, and by fully distributing all terms in the time-dependent Kohn–Sham equation, we demonstrate unprecedented time to solution for disordered aluminum systems of 2000 atoms (22,000 electrons) and 5400 atoms (59,400 electrons), with wall clock time as low as 7.5 s per MD time step. Despite a significant amount of non-local communication required in every iteration, we achieved excellent strong scaling and sustained performance on the Sequoia Blue Gene/Q supercomputer at LLNL. We obtained up tomore » 59% of the theoretical sustained peak performance on 16,384 nodes and performance of 8.75 Petaflop/s (43% of theoretical peak) on the full 98,304 node machine (1,572,864 cores). Lastly, scalable explicit electron dynamics allows for the study of phenomena beyond the reach of standard first-principles MD, in particular, materials subject to strong or rapid perturbations, such as pulsed electromagnetic radiation, particle irradiation, or strong electric currents.« less

Generation of Well-Relaxed All-Atom Models of Large Molecular Weight Polymer Melts: A Hybrid Particle-Continuum Approach Based on Particle-Field Molecular Dynamics Simulations.

PubMed

De Nicola, Antonio; Kawakatsu, Toshihiro; Milano, Giuseppe

2014-12-09

A procedure based on Molecular Dynamics (MD) simulations employing soft potentials derived from self-consistent field (SCF) theory (named MD-SCF) able to generate well-relaxed all-atom structures of polymer melts is proposed. All-atom structures having structural correlations indistinguishable from ones obtained by long MD relaxations have been obtained for poly(methyl methacrylate) (PMMA) and poly(ethylene oxide) (PEO) melts. The proposed procedure leads to computational costs mainly related on system size rather than to the chain length. Several advantages of the proposed procedure over current coarse-graining/reverse mapping strategies are apparent. No parametrization is needed to generate relaxed structures of different polymers at different scales or resolutions. There is no need for special algorithms or back-mapping schemes to change the resolution of the models. This characteristic makes the procedure general and its extension to other polymer architectures straightforward. A similar procedure can be easily extended to the generation of all-atom structures of block copolymer melts and polymer nanocomposites.

Massively parallel first-principles simulation of electron dynamics in materials

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

Draeger, Erik W.; Andrade, Xavier; Gunnels, John A.

Here we present a highly scalable, parallel implementation of first-principles electron dynamics coupled with molecular dynamics (MD). By using optimized kernels, network topology aware communication, and by fully distributing all terms in the time-dependent Kohn–Sham equation, we demonstrate unprecedented time to solution for disordered aluminum systems of 2000 atoms (22,000 electrons) and 5400 atoms (59,400 electrons), with wall clock time as low as 7.5 s per MD time step. Despite a significant amount of non-local communication required in every iteration, we achieved excellent strong scaling and sustained performance on the Sequoia Blue Gene/Q supercomputer at LLNL. We obtained up tomore » 59% of the theoretical sustained peak performance on 16,384 nodes and performance of 8.75 Petaflop/s (43% of theoretical peak) on the full 98,304 node machine (1,572,864 cores). Lastly, scalable explicit electron dynamics allows for the study of phenomena beyond the reach of standard first-principles MD, in particular, materials subject to strong or rapid perturbations, such as pulsed electromagnetic radiation, particle irradiation, or strong electric currents.« less

Using Local States To Drive the Sampling of Global Conformations in Proteins.

PubMed

Pandini, Alessandro; Fornili, Arianna

2016-03-08

Conformational changes associated with protein function often occur beyond the time scale currently accessible to unbiased molecular dynamics (MD) simulations, so that different approaches have been developed to accelerate their sampling. Here we investigate how the knowledge of backbone conformations preferentially adopted by protein fragments, as contained in precalculated libraries known as structural alphabets (SA), can be used to explore the landscape of protein conformations in MD simulations. We find that (a) enhancing the sampling of native local states in both metadynamics and steered MD simulations allows the recovery of global folded states in small proteins; (b) folded states can still be recovered when the amount of information on the native local states is reduced by using a low-resolution version of the SA, where states are clustered into macrostates; and (c) sequences of SA states derived from collections of structural motifs can be used to sample alternative conformations of preselected protein regions. The present findings have potential impact on several applications, ranging from protein model refinement to protein folding and design.

Prevalence of DSM-IV major depression among U.S. military personnel: meta-analysis and simulation.

PubMed

Gadermann, Anne M; Engel, Charles C; Naifeh, James A; Nock, Matthew K; Petukhova, Maria; Santiago, Patcho N; Wu, Benjamin; Zaslavsky, Alan M; Kessler, Ronald C

2012-08-01

A meta-analysis of 25 epidemiological studies estimated the prevalence of recent Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) major depression (MD) among U.S. military personnel. Best estimates of recent prevalence (standard error) were 12.0% (1.2) among currently deployed, 13.1% (1.8) among previously deployed, and 5.7% (1.2) among never deployed. Consistent correlates of prevalence were being female, enlisted, young (ages 17-25), unmarried, and having less than a college education. Simulation of data from a national general population survey was used to estimate expected lifetime prevalence of MD among respondents with the sociodemographic profile and none of the enlistment exclusions of Army personnel. In this Simulated sample, 16.2% (3.1) of respondents had lifetime MD and 69.7% (8.5) of first onsets occurred before expected age of enlistment. Numerous methodological problems limit the results of the meta-analysis and simulation. The article closes with a discussion of recommendations for correcting these problems in future surveillance and operational stress studies.

MdSOS2L1 phosphorylates MdVHA-B1 to modulate malate accumulation in response to salinity in apple.

PubMed

Hu, Da-Gang; Sun, Cui-Hui; Sun, Mei-Hong; Hao, Yu-Jin

2016-03-01

Salt-induced phosphorylation of MdVHA-B1 protein was mediated by MdSOS2L1 protein kinase, and thereby increasing malate content in apple. Salinity is an important environmental factor that influences malate accumulation in apple. However, the molecular mechanism by which salinity regulates this process is poorly understood. In this work, we found that MdSOS2L1, a novel AtSOS2-LIKE protein kinase, interacts with V-ATPase subunit MdVHA-B1. Furthermore, MdSOS2L1 directly phosphorylates MdVHA-B1 at Ser(396) site to modulate malate accumulation in response to salt stress. Meanwhile, a series of transgenic analyses in apple calli showed that the MdSOS2L1-MdVHAB1 pathway was involved in the regulation of malate accumulation. Finally, a viral vector-based transformation approach demonstrated that the MdSOS2L1-MdVHAB1 pathway also modulated malate accumulation in apple fruits with or without salt stress. Collectively, our findings provide a new insight into the mechanism by which MdSOS2L1 phosphorylates MdVHA-B1 to modulate malate accumulation in response to salinity in apple.

Vision for Control: Optimality and Usability

DTIC Science & Technology

2003-01-15

units etc. The laboratory currently houses 12 full-time members: 2 postdocs (D. Cremers , A. Duci), one M.D. pursuing his Ph.D. (G. Scarlatis), 8 Ph.D...having performed research under my direction, both students have demonstrated leadership abilities by supervising younger students, such as summer interns

New trial engineers immune cells to treat solid tumors | Center for Cancer Research

Cancer.gov

No existing systemic treatments can currently eradicate the great majority of metastatic solid cancers. To meet that need, Steve Rosenberg, M.D., Ph.D., is testing a new immunotherapy that targets each tumor’s unique genetic mutations in a clinical trial.

Identification of SFBB-containing canonical and noncanonical SCF complexes in pollen of apple (Malus × domestica).

PubMed

Minamikawa, Mai F; Koyano, Ruriko; Kikuchi, Shinji; Koba, Takato; Sassa, Hidenori

2014-01-01

Gametophytic self-incompatibility (GSI) of Rosaceae, Solanaceae and Plantaginaceae is controlled by a single polymorphic S locus. The S locus contains at least two genes, S-RNase and F-box protein encoding gene SLF/SFB/SFBB that control pistil and pollen specificity, respectively. Generally, the F-box protein forms an E3 ligase complex, SCF complex with Skp1, Cullin1 (CUL1) and Rbx1, however, in Petunia inflata, SBP1 (S-RNase binding protein1) was reported to play the role of Skp1 and Rbx1, and form an SCFSLF-like complex for ubiquitination of non-self S-RNases. On the other hand, in Petunia hybrida and Petunia inflata of Solanaceae, Prunus avium and Pyrus bretschneideri of Rosaceae, SSK1 (SLF-interacting Skp1-like protein1) is considered to form the SCFSLF/SFB complex. Here, we isolated pollen-expressed apple homologs of SSK1 and CUL1, and named MdSSK1, MdCUL1A and MdCUL1B. MdSSK1 was preferentially expressed in pollen, but weakly in other organs analyzed, while, MdCUL1A and MdCUL1B were almost equally expressed in all the organs analyzed. MdSSK1 transcript abundance was significantly (>100 times) higher than that of MdSBP1. In vitro binding assays showed that MdSSK1 and MdSBP1 interacted with MdSFBB1-S9 and MdCUL1, and MdSFBB1-S9 interacted more strongly with MdSSK1 than with MdSBP1. The results suggest that both MdSSK1-containing SCFSFBB1 and MdSBP1-containing SCFSFBB1-like complexes function in pollen of apple, and the former plays a major role.

Back Schools for chronic non-specific low back pain.

PubMed

Parreira, Patrícia; Heymans, Martijn W; van Tulder, Maurits W; Esmail, Rosmin; Koes, Bart W; Poquet, Nolwenn; Lin, Chung-Wei Christine; Maher, Christopher G

2017-08-03

Many people with low back pain (LBP) become frequent users of healthcare services in their attempt to find treatments that minimise the severity of their symptoms. Back School consists of a therapeutic programme given to groups of people that includes both education and exercise. However, the content of Back School has changed over time and appears to vary widely today. This review is an update of a Cochrane review of randomised controlled trials (RCTs) evaluating the effectiveness of Back School. We split the Cochrane review into two reviews, one focusing on acute and subacute LBP, and one on chronic LBP. The objective of this systematic review was to determine the effect of Back School on pain and disability for adults with chronic non-specific LBP; we included adverse events as a secondary outcome. In trials that solely recruited workers, we also examined the effect on work status. We searched for trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, two other databases and two trials registers to 15 November 2016. We also searched the reference lists of eligible papers and consulted experts in the field of LBP management to identify any potentially relevant studies we may have missed. We placed no limitations on language or date of publication. We included only RCTs and quasi-RCTs evaluating pain, disability, and/or work status as outcomes. The primary outcomes for this update were pain and disability, and the secondary outcomes were work status and adverse events. Two review authors independently performed the 'Risk of bias' assessment of the included studies using the 'Risk of bias' assessment tool recommended by The Cochrane Collaboration. We summarised the results for the short-, intermediate-, and long-term follow-ups. We evaluated the overall quality of evidence using the GRADE approach. For the outcome pain, at short-term follow-up, we found very low-quality evidence that Back School is more effective than no treatment (mean difference (MD) -6.10, 95% confidence interval (CI) -10.18 to -2.01). However, we found very low-quality evidence that there is no significant difference between Back School and no treatment at intermediate-term (MD -4.34, 95% CI -14.37 to 5.68) or long-term follow-up (MD -12.16, 95% CI -29.14 to 4.83). There was very low-quality evidence that Back School reduces pain at short-term follow-up compared to medical care (MD -10.16, 95% CI -19.11 to -1.22). Very low-quality evidence showed there to be no significant difference between Back School and medical care at intermediate-term (MD -9.65, 95% CI -22.46 to 3.15) or long-term follow-up (MD -5.71, 95% CI -20.27 to 8.84). We found very low-quality evidence that Back School is no more effective than passive physiotherapy at short-term (MD 1.96, 95% CI -9.51 to 13.43), intermediate-term (MD -16.89, 95% CI -66.56 to 32.79), or long-term follow-up (MD -12.86, 95% CI -61.22 to 35.50). There was very low-quality evidence that Back School is no better than exercise at short- term follow-up (MD -2.06, 95% CI -14.58 to 10.45). There was low-quality evidence that Back School is no better than exercise at intermediate-term (MD -4.46, 95% CI -19.44 to 10.52) and long-term follow-up (MD 4.58, 95% CI -0.20 to 9.36).For the outcome disability, we found very low-quality evidence that Back School is no more effective than no treatment at intermediate-term (MD -5.92, 95% CI -12.08 to 0.23) and long-term follow-up (MD -7.36, 95% CI -22.05 to 7.34); medical care at short-term (MD -1.19, 95% CI -7.02 to 4.64) and long-term follow-up (MD -0.40, 95% CI -7.33 to 6.53); passive physiotherapy at short-term (MD 2.57, 95% CI -15.88 to 21.01) and intermediate-term follow-up (MD 6.88, 95% CI -4.86 to 18.63); and exercise at short-term (MD -1.65, 95% CI -8.66 to 5.37), intermediate-term (MD 1.57, 95% CI -3.86 to 7.00), and long-term follow-up (MD 4.54, 95% CI -4.44 to 13.52). We found very low-quality evidence of a small difference between Back School and no treatment at short-term follow-up (MD -3.38, 95% CI -6.70 to -0.05) and medical care at intermediate-term follow-up (MD -6.34, 95% CI -10.89 to -1.79). Still, at long-term follow-up there was very low-quality evidence that passive physiotherapy is better than Back School (MD 9.60, 95% CI 3.65 to 15.54).Few studies measured adverse effects. The results were reported as means without standard deviations or group size was not reported. Due to this lack of information, we were unable to statistically pool the adverse events data. Work status was not reported. Due to the low- to very low-quality of the evidence for all treatment comparisons, outcomes, and follow-up periods investigated, it is uncertain if Back School is effective for chronic low back pain. Although the quality of the evidence was mostly very low, the results showed no difference or a trivial effect in favour of Back School. There are myriad potential variants on the Back School approach regarding the employment of different exercises and educational methods. While current evidence does not warrant their use, future variants on Back School may have different effects and will need to be studied in future RCTs and reviews.

Long Range Transport of War-Related Burn Casualties

DTIC Science & Technology

2008-02-01

Long Range Transport of War-Related Burn Casualties Evan M. Renz, MD, FACS, Leopoldo C . Cancio, MD, FACS, David J. Barillo, MD, FACS, Christopher E...White, MD, FACS, Michael C . Albrecht, MD, Charles K. Thompson, PA- C , Jody L. Ennis, RN, BSN, Sandra M. Wanek, MD, James A. King, MD, FACEP, Kevin K...sched- Submitted for publication October 29, 2007. Accepted for publication October 30, 2007. Copyright © 2008 by Lippincott Williams & Wilkins From the

Scheduling of eccentric lower limb injury prevention exercises during the soccer micro-cycle: Which day of the week?

PubMed

Lovell, R; Whalan, M; Marshall, P W M; Sampson, J A; Siegler, J C; Buchheit, M

2018-05-24

Scheduling eccentric-based injury prevention programs (IPP) during the common 6-day micro-cycle in soccer is challenged by recovery and tapering phases. This study profiled muscle damage, neuromuscular performance, and perceptual responses to a lower limb eccentric-based IPP administered 1 (MD+1) vs 3 days (MD+3) postmatch. A total of 18 semi-professional players were monitored daily during 3 in-season 6-day micro-cycles, including weekly competitive fixtures. Capillary creatine kinase concentration (CK), posterior lower limb isometric peak force (PF), counter-movement jump (CMJ) performance, and muscle soreness were assessed 24 hours prior to match-day (baseline), and every 24 hours up to 120 hours postmatch. The IPP consisted of lunges, single stiff leg dead-lifts, single leg-squats, and Nordic hamstring exercises. Performing the IPP on MD+1 attenuated the decline in CK normally observed following match play (CON: 142%; MD+3: 166%; small differences). When IPP was delivered on MD+3, CK was higher vs CON and MD+1 trials on both MD+4 (MD+3: 260%; CON: 146%; MD+1: 151%; moderate differences) and MD+5 (MD+3: 209%; CON: 125%; MD+1: 127%; small differences). Soreness ratings were not exacerbated when the IPP was delivered on MD+1, but when prescribed on MD+3, hamstring soreness ratings remained higher on MD+4 and MD+5 (small differences). No between-trial differences were observed for PF and CMJ. Administering the IPP in the middle of the micro-cycle (MD+3) increased measures of muscle damage and soreness, which remained elevated on the day prior to the next match (MD+5). Accordingly, IPP should be scheduled early in the micro-cycle, to avoid compromising preparation for the following match. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Colloquia | Cancer Prevention Fellowship Program

Cancer.gov

The Cancer Prevention and Control Colloquia Series features current research findings from guest researchers from a variety of research disciplines. Topics cover current challenges and methods used by investigators to address gaps, advance the field of cancer prevention and control, and promote the application of successful strategies. When Usually twice a month on Tuesday from 11:00 am - noon between September and June. Where NCI's Shady Grove Campus, 9609 Medical Center Drive, Rockville, MD (conference room locations vary).

Variation of the North Equatorial Current, Mindanao Current, and Kuroshio Current in a high-resolution data assimilation during 2008-2012

NASA Astrophysics Data System (ADS)

Zhai, Fangguo; Wang, Qingye; Wang, Fujun; Hu, Dunxin

2014-11-01

Outputs from a high-resolution data assimilation system, the global Hybrid Coordinate Ocean Model and Navy Coupled Ocean Data Assimilation (HYCOM+NCODA) 1/12° analysis, were analyzed for the period September 2008 to February 2012. The objectives were to evaluate the performance of the system in simulating ocean circulation in the tropical northwestern Pacific and to examine the seasonal to interannual variations of the western boundary currents. The HYCOM assimilation compares well with altimetry observations and mooring current measurements. The mean structures and standard deviations of velocities of the North Equatorial Current (NEC), Mindanao Current (MC) and Kuroshio Current (KC) also compare well with previous observations. Seasonal to interannual variations of the NEC transport volume are closely correlated with the MC transport volume, instead of that of the KC. The NEC and MC transport volumes mainly show well-defined annual cycles, with their maxima in spring and minima in fall, and are closely related to the circulation changes in the Mindanao Dome (MD) region. In seasons of transport maxima, the MD region experiences negative SSH anomalies and a cyclonic gyre anomaly, and in seasons of transport minima the situation is reversed. The sea surface NEC bifurcation latitude (NBL) in the HYCOM assimilation also agrees well with altimetry observations. In 2009, the NBL shows an annual cycle similar to previous studies, reaching its southernmost position in summer and its northernmost position in winter. In 2010 and 2011, the NBL variations are dominantly influenced by La Niña events. The dynamics responsible for the seasonal to interannual variations of the NEC-MC-KC current system are also discussed.

Microdialysis Monitoring of CSF Parameters in Severe Traumatic Brain Injury Patients: A Novel Approach

PubMed Central

Thelin, Eric P.; Nelson, David W.; Ghatan, Per Hamid; Bellander, Bo-Michael

2014-01-01

Background: Neuro-intensive care following traumatic brain injury (TBI) is focused on preventing secondary insults that may lead to irreversible brain damage. Microdialysis (MD) is used to detect deranged cerebral metabolism. The clinical usefulness of the MD is dependent on the regional localization of the MD catheter. The aim of this study was to analyze a new method of continuous cerebrospinal fluid (CSF) monitoring using the MD technique. The method was validated using conventional laboratory analysis of CSF samples. MD-CSF and regional MD-Brain samples were correlated to patient outcome. Materials and Methods: A total of 14 patients suffering from severe TBI were analyzed. They were monitored using (1) a MD catheter (CMA64-iView, n = 7448 MD samples) located in a CSF-pump connected to the ventricular drain and (2) an intraparenchymal MD catheter (CMA70, n = 8358 MD samples). CSF-lactate and CSF-glucose levels were monitored and were compared to MD-CSF samples. MD-CSF and MD-Brain parameters were correlated to favorable (Glasgow Outcome Score extended, GOSe 6–8) and unfavorable (GOSe 1–5) outcome. Results: Levels of glucose and lactate acquired with the CSF-MD technique could be correlated to conventional levels. The median MD recovery using the CMA64 catheter in CSF was 0.98 and 0.97 for glucose and lactate, respectively. Median MD-CSF (CMA 64) lactate (p = 0.0057) and pyruvate (p = 0.0011) levels were significantly lower in the favorable outcome group compared to the unfavorable group. No significant difference in outcome was found using the lactate:pyruvate ratio (LPR), or any of the regional MD-Brain monitoring in our analyzed cohort. Conclusion: This new technique of global MD-CSF monitoring correlates with conventional CSF levels of glucose and lactate, and the MD recovery is higher than previously described. Increase in lactate and pyruvate, without any effect on the LPR, correlates to unfavorable outcome, perhaps related to the presence of erythrocytes in the CSF. PMID:25228896

A dual positional specific lipoxygenase functions in the generation of flavor compounds during climacteric ripening of apple

PubMed Central

Schiller, Doreen; Contreras, Carolina; Vogt, Jörg; Dunemann, Frank; Defilippi, Bruno G; Beaudry, Randolph; Schwab, Wilfried

2015-01-01

Lipoxygenase (LOX) is an important contributor to the formation of aroma-active C6 aldehydes in apple (Malus × domestica) fruit upon tissue disruption but little is known about its role in autonomously produced aroma volatiles from intact tissue. We explored the expression of 22 putative LOX genes in apple throughout ripening, but only six LOXs were expressed in a ripening-dependent manner. Recombinant LOX1:Md:1a, LOX1:Md:1c, LOX2:Md:2a and LOX2:Md:2b proteins showed 13/9-LOX, 9-LOX, 13/9-LOX and 13-LOX activity with linoleic acid, respectively. While products of LOX1:Md:1c and LOX2:Md:2b were S-configured, LOX1:Md:1a and LOX2:Md:2a formed 13(R)-hydroperoxides as major products. Site-directed mutagenesis of Gly567 to an alanine converted the dual positional specific LOX1:Md:1a to an enzyme with a high specificity for 9(S)-hydroperoxide formation. The high expression level of the corresponding MdLOX1a gene in stored apple fruit, the genetic association with a quantitative trait locus for fruit ester and the remarkable agreement in regio- and stereoselectivity of the LOX1:Md:1a reaction with the overall LOX activity found in mature apple fruits, suggest a major physiological function of LOX1:Md:1a during climacteric ripening of apples. While LOX1:Md:1c, LOX2:Md:2a and LOX2:Md:2b may contribute to aldehyde production in immature fruit upon cell disruption our results furnish additional evidence that LOX1:Md:1a probably regulates the availability of precursors for ester production in intact fruit tissue. PMID:26504564

75 FR 49979 - Tony T. Bui, M.D.; Revocation of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-16

... physical medicine and rehabilitation who currently practices geriatric medicine in Dallas, Texas. Tr. 261... 104-05. At R.G.'s first visit, he completed a questionnaire and Respondent performed a physical exam... ``did have low testosterone.'' Id. at 106. Respondent reviewed the physical exam findings and various...

Early Schooling and the Nation's Future.

ERIC Educational Resources Information Center

Boyer, Ernest L.

1987-01-01

Currently 40 percent of those classified as poor are children. The social implications for the educational reform movement require that educators develop programs to confront poverty, health, and family problems. Within the next two decades the majority of students will be ethnically and linguistically diverse, poorer, and more handicapped. (MD)

Trends in Medical Education in the South: Enrollments and Financing.

ERIC Educational Resources Information Center

Hebbeler, Evangeline L.

Enrollment and financial trends in Southern medical schools are examined and comparisons are made to national trends. Statistical tables and supporting text cover trends and current status of undergraduate (preparation for the M.D. degree) and graduate (training of resident physicians) medical education enrollment, graduation, and financing.…

76 FR 78695 - Barry M. Schultz, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-19

... Government argues that summary disposition is appropriate where the Respondent lacks state authority to... currently lacks state authority to handle controlled substances. [Govt. at 1-2]. The Government attached to...]. Specifically, the Respondent avers that that order is invalid because of its lack of particularized allegations...

77 FR 73967 - Drawbridge Operation Regulation; Bear Creek, Dundalk, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-12

... owner displayed on the Wise Avenue Bridge signage that stated a 48-hour advance notice was required to open the draw bridge. This signage portrayed improper operational information since the current operation regulation had not changed. The Coast Guard determined the signage that stated a 48-hour advance...

MdCOP1 Ubiquitin E3 Ligases Interact with MdMYB1 to Regulate Light-Induced Anthocyanin Biosynthesis and Red Fruit Coloration in Apple1[W][OA

PubMed Central

Li, Yuan-Yuan; Mao, Ke; Zhao, Cheng; Zhao, Xian-Yan; Zhang, Hua-Lei; Shu, Huai-Rui; Hao, Yu-Jin

2012-01-01

MdMYB1 is a crucial regulator of light-induced anthocyanin biosynthesis and fruit coloration in apple (Malus domestica). In this study, it was found that MdMYB1 protein accumulated in the light but degraded via a ubiquitin-dependent pathway in the dark. Subsequently, the MdCOP1-1 and MdCOP1-2 genes were isolated from apple fruit peel and were functionally characterized in the Arabidopsis (Arabidopsis thaliana) cop1-4 mutant. Yeast (Saccharomyces cerevisiae) two-hybrid, bimolecular fluorescence complementation, and coimmunoprecipitation assays showed that MdMYB1 interacts with the MdCOP1 proteins. Furthermore, in vitro and in vivo experiments indicated that MdCOP1s are necessary for the ubiquitination and degradation of MdMYB1 protein in the dark and are therefore involved in the light-controlled stability of the MdMYB1 protein. Finally, a viral vector-based transformation approach demonstrated that MdCOP1s negatively regulate the peel coloration of apple fruits by modulating the degradation of the MdMYB1 protein. Our findings provide new insight into the mechanism by which light controls anthocyanin accumulation and red fruit coloration in apple and even other plant species. PMID:22855936

Cognitive arithmetic and problem solving: a comparison of children with specific and general mathematics difficulties.

PubMed

Jordan, N C; Montani, T O

1997-01-01

This study examined problem-solving and number-fact skills in two subgroups of third-grade children with mathematics difficulties (MD): MD-specific (n = 12) and MD-general (n = 12). The MD-specific group had difficulties in mathematics but not in reading, and the MD-general group had difficulties in reading as well as in mathematics. A comparison group of nonimpaired children (n = 24) also was included. The findings showed that on both story and number-fact problems, the MD-specific group performed worse than the nonimpaired group in timed conditions but not in untimed conditions. The MD-general group, on the other hand, performed worse than the nonimpaired group, regardless of whether tasks were timed or not. An analysis of children's strategies in untimed conditions showed that both the MD-specific and the MD-general groups relied more on backup strategies than the nonimpaired group. However, children in the MD-specific group executed backup strategies more skillfully than children in the MD-general group, allowing them to achieve parity with children in the nonimpaired group when tasks were not timed. The findings suggest that children with specific MD have circumscribed deficits associated with fact retrieval, whereas children with general MD have more basic delays associated with problem conceptualization and execution of calculation procedures.

Development of a Free-Electron Laser Center and Research in Medicine, Biology and Materials Science,

DTIC Science & Technology

1992-05-14

Elastin Production in Tissue Culture", Debra A.Gonzalez MD, David L. Zealear, PhD., J.M. Davidson, PhD., Robert H. Ossoff, MD, DMD , August 1990...Otolaryngoloty-Head and Neck Surgery. K. "CO2 Laser Micromanipulator Parallax Error Resolved, Jay Werkhaven,MD, Jerri Tribble, and Robert H. Ossoff, MD, DMD ...of the Upper Aerodigestive Tract, Robert H. Ossoff, MD, DMD , Al Aly, MD, Nick Houchin, AAS, and Debra Gonzalez, MD, Vanderbilt University, Nashville

Medical Department, United States Army. Surgery in World War 2. Neurosurgery. Volume 2

DTIC Science & Technology

1959-01-01

that there was no obstruction distal to the opening. They might close spontaneously in either area. If the fistula was small and spontaneous closure did...States Army Editor in Chief Colonel JOHN BOYD COATES, Jr ., MC Editors for Neurosurgery R. GLEN SPURLING, M.D. BARNES WOODHALL, M.D. Associate Editor...M.D. M. ELAOT RANDOLPH, M.D. STERLING BUNNELL, M.D. (dec.) ISIDOR S. RAVDIN, M.D. NORTON CANFIELD, M.D. ALFRED R. SHANDS, Jr ., M.D. B. NOLAND CARTER

Prematch salivary secretory immunoglobulin a in soccer players from the 2014 World Cup qualifying campaign.

PubMed

Morgans, Ryland; Owen, Adam; Doran, Dominic; Drust, Barry; Morton, James P

2015-04-01

To monitor resting salivary secretory immunoglobulin A (SIgA) levels in international soccer players during the short-term training period that precedes international match play. In a repeated-measure design, saliva samples were obtained from 13 outfield soccer players who participated in the training camps preceding 7 games (5 home and 2 away) of the 2014 FIFA World Cup qualifying campaign. Samples were obtained daily for 4 d preceding each game (and analyzed for SIgA using the IPRO oral-fluid-collection system) at match day minus 1 (MD-1), minus 2 (MD-2), minus 3 (MD-3), and minus 4 (MD-4). SIgA displayed a progressive decline (P = .01) during the 4-d training period (MD-4, 365 ± 127 μg/mL; MD-3, 348 ± 154 μg/mL; MD-2, 290 ± 138 μg/mL; MD-1, 256 ± 90 μg/mL) such that MD-1 values were significantly lower (P = .01) than both MD-4 and MD-3. The 95% confidence intervals for the differences between MD-1 and MD-4 were -191 to -26 and between MD-1 and MD-3 were -155 to -28. Data demonstrate that a short-term soccer-training camp in preparation for international competition induces detectable perturbations to mucosal immunity. Future studies should monitor SIgA (as a practical and noninvasive measure of immunity) alongside internal and external measures of training load in an attempt to strategically individualize training and nutritional strategies that may support optimal preparation for high-level competition.

Improved Statistical Sampling and Accuracy with Accelerated Molecular Dynamics on Rotatable Torsions.

PubMed

Doshi, Urmi; Hamelberg, Donald

2012-11-13

In enhanced sampling techniques, the precision of the reweighted ensemble properties is often decreased due to large variation in statistical weights and reduction in the effective sampling size. To abate this reweighting problem, here, we propose a general accelerated molecular dynamics (aMD) approach in which only the rotatable dihedrals are subjected to aMD (RaMD), unlike the typical implementation wherein all dihedrals are boosted (all-aMD). Nonrotatable and improper dihedrals are marginally important to conformational changes or the different rotameric states. Not accelerating them avoids the sharp increases in the potential energies due to small deviations from their minimum energy conformations and leads to improvement in the precision of RaMD. We present benchmark studies on two model dipeptides, Ace-Ala-Nme and Ace-Trp-Nme, simulated with normal MD, all-aMD, and RaMD. We carry out a systematic comparison between the performances of both forms of aMD using a theory that allows quantitative estimation of the effective number of sampled points and the associated uncertainty. Our results indicate that, for the same level of acceleration and simulation length, as used in all-aMD, RaMD results in significantly less loss in the effective sample size and, hence, increased accuracy in the sampling of φ-ψ space. RaMD yields an accuracy comparable to that of all-aMD, from simulation lengths 5 to 1000 times shorter, depending on the peptide and the acceleration level. Such improvement in speed and accuracy over all-aMD is highly remarkable, suggesting RaMD as a promising method for sampling larger biomolecules.

Apple fruit acidity is genetically diversified by natural variations in three hierarchical epistatic genes MdSAUR37, MdPP2CH and MdALMTII.

PubMed

Jia, Dongjie; Shen, Fei; Wang, Yi; Wu, Ting; Xu, Xuefeng; Zhang, Xinzhong; Han, Zhenhai

2018-05-11

Many efforts have been made to map quantitative trait loci (QTLs) to facilitate practical marker-assisted selection (MAS) in plants. In the present study, we identified four genome-wide major QTLs responsible for apple fruit acidity by MapQTL and BSA-seq analyses using two independent pedigree-based populations. Candidate genes were screened in major QTL regions, and three functional gene markers, including a non-synonymous A/G single nucleotide polymorphism (SNP) in the coding region of MdPP2CH, a 36-bp insertion in the promoter of MdSAUR37, and a previously reported SNP in MdALMTII, were validated to influence the malate content of apple fruits. In addition, MdPP2CH inactivated three vacuolar H + -ATPases (MdVHA-A3, MdVHA-B2 and MdVHA-D2) and one aluminium-activated malate transporter (MdALMTII) via dephosphorylation and negatively influenced fruit malate accumulation. The dephosphotase activity of MdPP2CH was suppressed by MdSAUR37, which implied a higher hierarchy of genetic interaction. Therefore, the MdSAUR37/MdPP2CH/MdALMTII chain cascaded hierarchical epistatic genetic effects to precisely determine apple fruit malate content. An A/G SNP (-1010) on MdMYB44 promoter region from a major QTL (qtl08.1) was closely associated with fruit malate content. The predicted phenotype values (PPVs) were estimated using the tentative genotype values of the gene markers, and the PPVs were significantly correlated with the observed phenotype values. Our findings provide an insight into plant genome-based selection in apples and will aid in conducting research to understand the physiological fundamentals of quantitative genetics. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

An Apple Protein Kinase MdSnRK1.1 Interacts with MdCAIP1 to Regulate ABA Sensitivity.

PubMed

Liu, Xiao-Juan; Liu, Xin; An, Xiu-Hong; Han, Peng-Liang; You, Chun-Xiang; Hao, Yu-Jin

2017-10-01

ABA is a crucial phytohormone for development and stress responses in plants. Snf1-related protein kinase 1.1 (SnRK1.1) is involved in the ABA response. However, the molecular mechanism underlying the SnRK1.1 response to ABA is largely unknown. Here, it was found that overexpression of the apple MdSnRK1.1 gene enhanced ABA sensitivity in both transgenic apple calli and Arabidopsis seedlings. Subsequently, a yeast two-hybrid screen demonstrated that MdCAIP1 (C2-domain ABA Insensitive Protein1) interacted with MdSnRK1.1. Their interaction was further confirmed by pull-down and co-immunoprecipitation assays. Expression of the MdCAIP1 gene was positively induced by ABA. Its overexpression enhanced ABA sensitivity in transgenic apple calli. Furthermore, it was found that MdSnRK1.1 phosphorylated the MdCAIP1 protein in vivo and promoted its degradation in vitro and in vivo. As a result, MdSnRK1.1 inhibited MdCAIP1-mediated ABA sensitivity, and MdCAIP1 partially reduced MdSnRK1.1-mediated ABA sensitivity. Our findings indicate that MdSnRK1.1 plays an important role in the ABA response, partially by controlling the stability of the MdCAIP1 protein. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Relaxation techniques for pain management in labour.

PubMed

Smith, Caroline A; Levett, Kate M; Collins, Carmel T; Crowther, Caroline A

2011-12-07

Many women would like to avoid pharmacological or invasive methods of pain management in labour and this may contribute towards the popularity of complementary methods of pain management. This review examined currently available evidence supporting the use of relaxation therapies for pain management in labour. To examine the effects of relaxation methods for pain management in labour on maternal and perinatal morbidity. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2010), The Cochrane Complementary Medicine Field's Trials Register (November 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 4), MEDLINE (1966 to 30 November 2010), CINAHL (1980 to 30 November 2010), the Australian and New Zealand Clinical Trial Registry (30 November 2010), Chinese Clinical Trial Register (30 November 2010), Current Controlled Trials (30 November 2010), ClinicalTrials.gov, (30 November 2010) ISRCTN Register (30 November 2010), National Centre for Complementary and Alternative Medicine (NCCAM) (30 November 2010) and the WHO International Clinical Trials Registry Platform (30 November 2010). Randomised controlled trials comparing relaxation methods with standard care, no treatment, other non-pharmacological forms of pain management in labour or placebo. Three review authors independently assessed trials for inclusion and extracted data. Data were checked for accuracy. Two review authors independently assessed trial quality. We attempted to contact study authors for additional information. We included 11 studies (1374 women) in the review. Relaxation was associated with a reduction in pain intensity during the latent phase (mean difference (MD) -1.25, 95% confidence interval (CI) -1.97 to -0.53, one trial, 40 women) and active phase of labour (MD -2.48, 95% CI -3.13 to 0.83, two trials, 74 women). There was evidence of improved outcomes from relaxation instruction with increased satisfaction with pain relief (risk ratio (RR) 8.00, 95% CI 1.10 to 58.19, one trial, 40 women) and lower assisted vaginal delivery (RR 0.07, 95% CI 0.01 to 0.50, two trials, 86 women). Yoga was associated with reduced pain (mean difference (MD) -6.12, 95% CI -11.77 to -0.47), one trial, 66 women), increased satisfaction with pain relief (MD 7.88, 95% CI 1.51 to 14.25, one trial, 66 women), satisfaction with the childbirth experience (MD) 6.34, 95% CI 0.26 to 12.42, one trial, 66 women), and reduced length of labour when compared to usual care (MD -139.91, 95% CI -252.50 to -27.32, one trial, 66 women) and when compared with supine position (MD -191.34, 95% CI -243.72 to -138.96, one trial, 83 women). Trials evaluating music and audio analgesia found no difference between groups in the primary outcomes pain intensity, satisfaction with pain relief, and caesarean delivery. The risk of bias was unclear for the majority of trials. Relaxation and yoga may have a role with reducing pain, increasing satisfaction with pain relief and reducing the rate of assisted vaginal delivery. There was insufficient evidence for the role of music and audio-analgesia. However, there is a need for further research.

Registration of cotton germplasm USDA MD 16-1 and USDA MD 16-2 with enhanced lint yield and fiber quality.

USDA-ARS?s Scientific Manuscript database

Upland cotton germplasm USDA MD 16-1 (Reg. No. __ and PI ___ ), and USDA MD 16-2 (Reg. No. ___ and PI___) (Gossypium hirsutum L.), have enhanced yield and good fiber quality. These germplasm lines were developed by the USDA-ARS, Stoneville, MS and released in 2017. Two crosses, MD 25-51 X MD 10-9-1 ...

78 FR 14547 - Praxedes E. Alverez Santiago, M.D., Daniel Perez Brisebois, M.D., Jorge Grillasca Palou, M.D...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-06

...., Angel B. Rivera Santos, M.D., Cosme D. Santos Torres, M.D., and Juan L. Vilaro Chardon, M.D.; Analysis... attached Analysis to Aid Public Comment describes both the allegations in the draft complaint and the terms... record for a period of thirty (30) days. The following Analysis to Aid Public Comment describes the terms...

mdFoam+: Advanced molecular dynamics in OpenFOAM

NASA Astrophysics Data System (ADS)

Longshaw, S. M.; Borg, M. K.; Ramisetti, S. B.; Zhang, J.; Lockerby, D. A.; Emerson, D. R.; Reese, J. M.

2018-03-01

This paper introduces mdFoam+, which is an MPI parallelised molecular dynamics (MD) solver implemented entirely within the OpenFOAM software framework. It is open-source and released under the same GNU General Public License (GPL) as OpenFOAM. The source code is released as a publicly open software repository that includes detailed documentation and tutorial cases. Since mdFoam+ is designed entirely within the OpenFOAM C++ object-oriented framework, it inherits a number of key features. The code is designed for extensibility and flexibility, so it is aimed first and foremost as an MD research tool, in which new models and test cases can be developed and tested rapidly. Implementing mdFoam+ in OpenFOAM also enables easier development of hybrid methods that couple MD with continuum-based solvers. Setting up MD cases follows the standard OpenFOAM format, as mdFoam+ also relies upon the OpenFOAM dictionary-based directory structure. This ensures that useful pre- and post-processing capabilities provided by OpenFOAM remain available even though the fully Lagrangian nature of an MD simulation is not typical of most OpenFOAM applications. Results show that mdFoam+ compares well to another well-known MD code (e.g. LAMMPS) in terms of benchmark problems, although it also has additional functionality that does not exist in other open-source MD codes.

Optimal feeding frequency of captive head-started green turtles (Chelonia mydas).

PubMed

Kanghae, H; Thongprajukaew, K; Yeetam, P; Jarit-Ngam, T; Hwan-Air, W; Rueangjeen, S; Kittiwattanawong, K

2017-08-01

Optimal feeding frequency was investigated to improve head-started propagation programme of juvenile green turtles (Chelonia mydas). The 15-day-old turtles (25-26 g body weight) were fed for ad libitum intake at one (1MD), two (2MD), three (3MD) or four (4MD) meals daily over a 3-month trial. Responses in growth, feed utilization, faecal characteristics, haematological parameters and carapace elemental composition were used to compare treatment effects. At the end of the feeding trial, no treatment had induced mortality. Growth performance in terms of weight gain and specific growth rate was similar in turtles fed 2MD, 3MD or 4MD (p > 0.05), but 1MD differed from these (p < 0.05), and feeding at excess frequency (3MD and 4MD) increased the within-group size variation. Turtles fed 2MD had significantly lower feed intake than in 3MD and 4MD groups, but the feed conversion ratios were similar. Faecal digestive enzyme analysis indicated higher catabolism of lipid and protein in the deprivation group (1MD), when compared with turtles fed at least twice daily. The feeding frequency did not affect the specific activities of carbohydrate-digesting enzymes. The results on enzymes activities were corroborated by the transition enthalpy characteristics of faeces, indicating nutrients remaining after digestion. The 2MD treatment also improved the haematological characteristics and the carapace quality, relative to low or excess feeding. Overall, the findings indicate that feeding juvenile green turtles twice a day is the preferred option in their head-started propagation. This promotes growth, reduces feed consumption, and improves health and carapace quality. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

An apple B-box protein, MdCOL11, is involved in UV-B- and temperature-induced anthocyanin biosynthesis.

PubMed

Bai, Songling; Saito, Takanori; Honda, Chikako; Hatsuyama, Yoshimichi; Ito, Akiko; Moriguchi, Takaya

2014-11-01

Our studies showed that an apple B-box protein, MdCOL11, the homolog of AtBBX22, is involved in UV-B- and temperature-induced anthocyanin biosynthesis in apple peel. Anthocyanin is responsible for the red pigmentation in apple peel and a R2R3 MYB gene, MdMYBA/1/10, a homolog of MdMYBA, controls its accumulation. Arabidopsis PAP1 is under the control of a series of upstream factors involved in light signal transduction and photomorphogenesis, such as ELONGATED HYPOCOTYL 5 (HY5) and B-box family (BBX) proteins. In this study, we identified and characterized the homolog of Arabidopsis BBX22 in apple, designated as MdCOL11. Overexpression of MdCOL11 in Arabidopsis enhanced the accumulation of anthocyanin. In apples, MdCOL11 was differentially expressed in all tissues, with the highest expression in petals and the lowest expression in the xylem. Transcripts of MdCOL11 noticeably accumulated at the ripening stage, concomitant with increases in the expressions of anthocyanin biosynthesis-related genes. In an in vitro treatment experiment, MdCOL11 was upregulated in an ultra-violet (UV)-B- and temperature-dependent manner, together with the inductions of anthocyanin biosynthesis-related genes and anthocyanin accumulation in apple peel. Furthermore, a dual-luciferase assay indicated that (1) MdCOL11 regulated the expression of MdMYBA and (2) MdCOL11 was a target of MdHY5. Taken together, our results suggest that MdCOL11 is involved in MdHY5-mediated signal transduction and regulates anthocyanin accumulation in apple peel, which sheds new light on anthocyanin accumulation in apples.

Direct Prediction of EPR Spectra from Lipid Bilayers: Understanding Structure and Dynamics in Biological Membranes.

PubMed

Catte, Andrea; White, Gaye F; Wilson, Mark R; Oganesyan, Vasily S

2018-06-02

Of the many biophysical techniques now being brought to bear on studies of membranes, electron paramagnetic resonance (EPR) of nitroxide spin probes was the first to provide information about both mobility and ordering in lipid membranes. Here, we report the first prediction of variable temperature EPR spectra of model lipid bilayers in the presence and absence of cholesterol from the results of large scale fully atomistic molecular dynamics (MD) simulations. Three types of structurally different spin probes were employed in order to study different parts of the bilayer. Our results demonstrate very good agreement with experiment and thus confirm the accuracy of the latest lipid force fields. The atomic resolution of the simulations allows the interpretation of the molecular motions and interactions in terms of their impact on the sensitive EPR line shapes. Direct versus indirect effects of cholesterol on the dynamics of spin probes are analysed. Given the complexity of structural organisation in lipid bilayers, the advantage of using a combined MD-EPR simulation approach is two-fold. Firstly, prediction of EPR line shapes directly from MD trajectories of actual phospholipid structures allows unambiguous interpretation of EPR spectra of biological membranes in terms of complex motions. Secondly, such an approach provides an ultimate test bed for the up-to-date MD simulation models employed in the studies of biological membranes, an area that currently attracts great attention. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The scope and variety of combined baccalaureate-MD programs in the United States.

PubMed

Eaglen, Robert H; Arnold, Louise; Girotti, Jorge A; Cosgrove, Ellen M; Green, Marianne M; Kollisch, Donald O; McBeth, Dani L; Penn, Mark A; Tracy, Sarah W

2012-11-01

The landscape of combined baccalaureate-MD programs has changed substantially in the last two decades but has not been documented in detail. The authors review the current state of these programs and discuss opportunities for future study of their evolving role and potential impact.In 2011, using a definition of baccalaureate-MD program built on prior research, the authors reviewed Association of American Medical Colleges sources and medical school Web sites to identify and characterize 81 active programs. In addition, they surveyed the 57 medical schools offering those programs; 31 schools with 39 programs responded. The resulting database inventories the number and distribution of programs; institutional affiliations; missions or goals; length; size; admissions criteria; curricula; and retention requirements.Since the inception of combined programs in 1961, their number and curricular length have increased. Pressures that spurred earlier programs remain evident in the goals of today's programs: attract talented high school or early college students, especially from diverse backgrounds; prepare physicians to meet societal needs; and offer an enriched premedical environment. Baccalaureate educational activities achieve program goals through special courses, medical experiences, community service, and learning communities tailored to students' needs. Admission and retention criteria are comparable to those of traditional medical schools.Combined baccalaureate-MD programs have evolved along several paths during the last half century and have enriched the baccalaureate experiences of medical students. Shifting expectations for the selection and education of future physicians warrant focused research on these programs to document their effectiveness in addressing those expectations.

Mediterranean diet pyramid today. Science and cultural updates.

PubMed

Bach-Faig, Anna; Berry, Elliot M; Lairon, Denis; Reguant, Joan; Trichopoulou, Antonia; Dernini, Sandro; Medina, F Xavier; Battino, Maurizio; Belahsen, Rekia; Miranda, Gemma; Serra-Majem, Lluís

2011-12-01

To present the Mediterranean diet (MD) pyramid: a lifestyle for today. A new graphic representation has been conceived as a simplified main frame to be adapted to the different nutritional and socio-economic contexts of the Mediterranean region. This review gathers updated recommendations considering the lifestyle, dietary, sociocultural, environmental and health challenges that the current Mediterranean populations are facing. Mediterranean region and its populations. Many innovations have arisen since previous graphical representations of the MD. First, the concept of composition of the 'main meals' is introduced to reinforce the plant-based core of the dietary pattern. Second, frugality and moderation is emphasised because of the major public health challenge of obesity. Third, qualitative cultural and lifestyle elements are taken into account, such as conviviality, culinary activities, physical activity and adequate rest, along with proportion and frequency recommendations of food consumption. These innovations are made without omitting other items associated with the production, selection, processing and consumption of foods, such as seasonality, biodiversity, and traditional, local and eco-friendly products. Adopting a healthy lifestyle and preserving cultural elements should be considered in order to acquire all the benefits from the MD and preserve this cultural heritage. Considering the acknowledgment of the MD as an Intangible Cultural Heritage of Humanity by UNESCO (2010), and taking into account its contribution to health and general well-being, we hope to contribute to a much better adherence to this healthy dietary pattern and its way of life with this new graphic representation.

Gene-by-social-environment interaction (GxSE) between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma-exposed women.

PubMed

Lowe, Sarah R; Pothen, John; Quinn, James W; Rundle, Andrew; Bradley, Bekh; Galea, Sandro; Ressler, Kerry J; Koenen, Karestan C

2015-11-15

Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women. Female participants (N=1361) were recruited from a public hospital, and completed measures of PTS and MD symptoms and provided DNA samples. Participants' home addresses were mapped onto 300 neighborhoods (2010 census tracts), and data on crime within neighborhoods was collected. Multilevel models detected a significant GxSE between rs2267735 and neighborhood crime for MD symptoms (p=.01). Having two copies of the risk (C) allele was associated with higher MD symptoms for participants living in high-crime neighborhoods. At least six limitations are noteworthy: (1) low statistical power; (2) use of self-report symptom inventories; (3) lack of information on symptom onset; (4) homogeneous sample from a single metropolitan area; (5) non-specific index of crime; and (6) use of census tracts to define neighborhoods. The results provide further evidence of GxSEs for psychiatric outcomes among trauma-exposed populations. Further investigations of genetic factors for trauma-related psychopathology should include careful assessments of the social environment. Copyright © 2015 Elsevier B.V. All rights reserved.

Gene-by-social-environment interaction (GxSE) between ADCYAP1R1 genotype and neighborhood crime predicts major depression symptoms in trauma-exposed women

PubMed Central

Lowe, Sarah R.; Pothen, John; Quinn, James W.; Rundle, Andrew; Bradley, Bekh; Galea, Sandro; Ressler, Kerry J.; Koenen, Karestan C.

2015-01-01

Background Few studies have explored interactions between genes and social environmental exposures (GxSEs) for trauma-related psychopathology, including symptoms of posttraumatic stress (PTS) and major depression (MD). The extant literature suggests the possibility of a GxSE between the rs2267735 variant of the ADCYAP1R1 gene and neighborhood crime. The current study aimed to explore this possibility among a predominantly African American sample of trauma-exposed women. Methods Female participants (N = 1361) were recruited from a public hospital, and completed measures of PTS and MD symptoms and provided DNA samples. Participants’ home addresses were mapped onto 300 neighborhoods (2010 census tracts), and data on crime within neighborhoods was collected. Results Multilevel models detected a significant GxSE between rs2267735 and neighborhood crime for MD symptoms (p = .01). Having two copies of the risk (C) allele was associated with higher MD symptoms for participants living in high-crime neighborhoods. Limitations At least six limitations are noteworthy: (1) low statistical power; (2) use of self-report symptom inventories; (3) lack of information on symptom onset; (4) homogeneous sample from a single metropolitan area; (5) non-specific index of crime; and (6) use of census tracts to define neighborhoods. Conclusions The results provide further evidence of GxSEs for psychiatric outcomes among trauma-exposed populations. Further investigations of genetic factors for trauma-related psychopathology should include careful assessments of the social environment. PMID:26334183

Silodosin is effective for treatment of LUTS in men with BPH: a systematic review

PubMed Central

Ding, Hui; Du, Wan; Hou, Zi-Zhen; Wang, Han-Zhang; Wang, Zhi-Ping

2013-01-01

The aim of this study was to systematically review the evidence on the efficacy and safety of silodosin treatments on lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) from randomized controlled trials. We searched PubMed (1966–December 2011), Embase (1974–December 2011) and the Cochrane Library Database (2011, Issue 12). The assessed outcome measures were the change from baseline for the International Prostate Symptom Score (IPSS), quality of life (QoL) score, peak urine maximum flow rate (Qmax), QoL related to urinary symptoms and adverse effects. Two authors independently assessed the study quality and extracted data. All data were analysed using RevMan 5.1. The meta-analysis included four randomized controlled trials with a total of 2504 patients. The study durations were each 12 weeks. At the follow-up end points, the pooled results showed that the change from baseline for the silodosin group was significantly higher than the placebo group for the IPSS, QoL score and Qmax(mean difference (MD)=−2.78, P<0.00001; MD=−0.42, P=0.004; MD=1.17, P<0.00001,respectively) and patients felt more satisfied with QoL related to urinary symptoms in the silodosin group than the placebo group. Ejaculation disorder was the most commonly reported adverse effect. The pooled results also showed that the silodosin group was superior to the 0.2 mg tamsulosin group with respect to the IPSS and QoL score (IPSS: MD=−1.14, P=0.02; QoL score: MD=−0.26, P=0.02) and inferior to the 0.2 mg tamsulosin group with respect to Qmax (MD=−0.85, P=0.01). In contrast, there was no significant difference in the incidence of ejaculation disorder and dizziness between the silodosin and 0.2 mg tamsulosin groups. The current meta-analysis suggested that silodosin is an effective therapy for LUTS in men with BPH and is not inferior to 0.2 mg tamsulosin. PMID:23223034

Risks associated with crack cocaine smoking among exotic dancers in Baltimore, MD.

PubMed

Sherman, Susan G; Reuben, Jacqueline; Chapman, Chris Serio; Lilleston, Pamela

2011-04-01

There is a dearth of research focusing on sex work in exotic dance clubs. We conducted a cross-sectional study to examine the prevalence and correlates of crack cocaine smoking among a sample of exotic dancers. The "block," a historical red-light district in downtown Baltimore, MD, is comprised of 30 adult-entertainment establishments. Between 01/09 and 08/09, we conducted a survey with exotic dancers (N=98). The survey explored demographic, and drug and sexual/drug risk behaviors. Bivariate and multivariate analysis was conducted using Poisson regression with robust variance estimates to examine correlates of current crack smoking. Crack cocaine smokers compared to non-crack cocaine smokers were significantly more likely to report: older age (29 vs. 23 years, respectively, p<0.0001); being White (79% vs. 50%, respectively, p=0.008); having been arrested (93% vs. 67%, respectively, p=0.008); daily alcohol consumption (36% vs. 17%, p=0.047); current heroin injection (57% vs. 13%, p<0.001); and current sex exchange (79% vs. 30%, p<0.001). In the presence of other variables, crack cocaine smokers compared to non-crack cocaine smokers were significantly older, more likely to report current heroin injection, and more likely to report current sex exchange. We found high levels of drug use and sexual risk behaviors as well as a number of risks behaviors associated with crack cocaine smoking among this very under-studied population. Targeted interventions are greatly needed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Clinical evaluation of Morgellons disease in a cohort of North American patients

PubMed Central

Fesler, Melissa C.; Middelveen, Marianne J.; Stricker, Raphael B.

2018-01-01

Morgellons disease (MD) is a dermatological condition characterized by aberrant production of keratin and collagen fibers in skin. Although infection with Borrelia burgdorferi, the causative agent of Lyme disease (LD), has been associated with MD, relatively few studies have hitherto provided epidemiological evidence regarding this association. A cohort of 1000 seropositive North American LD patients was evaluated for the presence of MD. Patients were diagnosed with MD based on detection of microscopic fibers in skin lesions or under unbroken skin. Demographic and clinical features of MD patients were analyzed, and laboratory testing for tickborne coinfections and other infectious agents, was performed. Subjective and objective features of MD were analyzed using statistical methods. Of 1000 seropositive LD patients, 60 (6%) were diagnosed with MD. Of these 60 patients, 75% were female and 78% presented in the late disseminated stage of MD. All 60 patients (100%) were seropositive for B. burgdorferi infection. Tickborne coinfections in these patients included Babesia spp (62%), Bartonella and Rickettsia (25% each), Ehrlichia (15%) and Anaplasma (10%). Helicobacter pylori was detected in 12% of MD patients. In all, 77% of MD patients had one or more coinfections. This study confirms recent findings that MD occurs in a limited subset of LD patients. The clinical and genetic determinants of MD in LD patients require further study. PMID:29774138

Clinical evaluation of Morgellons disease in a cohort of North American patients.

PubMed

Fesler, Melissa C; Middelveen, Marianne J; Stricker, Raphael B

2018-04-23

Morgellons disease (MD) is a dermatological condition characterized by aberrant production of keratin and collagen fibers in skin. Although infection with Borrelia burgdorferi , the causative agent of Lyme disease (LD), has been associated with MD, relatively few studies have hitherto provided epidemiological evidence regarding this association. A cohort of 1000 seropositive North American LD patients was evaluated for the presence of MD. Patients were diagnosed with MD based on detection of microscopic fibers in skin lesions or under unbroken skin. Demographic and clinical features of MD patients were analyzed, and laboratory testing for tickborne coinfections and other infectious agents, was performed. Subjective and objective features of MD were analyzed using statistical methods. Of 1000 seropositive LD patients, 60 (6%) were diagnosed with MD. Of these 60 patients, 75% were female and 78% presented in the late disseminated stage of MD. All 60 patients (100%) were seropositive for B. burgdorferi infection. Tickborne coinfections in these patients included Babesia spp (62%), Bartonella and Rickettsia (25% each), Ehrlichia (15%) and Anaplasma (10%). Helicobacter pylori was detected in 12% of MD patients. In all, 77% of MD patients had one or more coinfections. This study confirms recent findings that MD occurs in a limited subset of LD patients. The clinical and genetic determinants of MD in LD patients require further study.

Comprehensive Genomic Identification and Expression Analysis of the Phosphate Transporter (PHT) Gene Family in Apple

PubMed Central

Sun, Tingting; Li, Mingjun; Shao, Yun; Yu, Lingyan; Ma, Fengwang

2017-01-01

Elemental phosphorus (Pi) is essential to plant growth and development. The family of phosphate transporters (PHTs) mediates the uptake and translocation of Pi inside the plants. Members include five sub-cellular phosphate transporters that play different roles in Pi uptake and transport. We searched the Genome Database for Rosaceae and identified five clusters of phosphate transporters in apple (Malus domestica), including 37 putative genes. The MdPHT1 family contains 14 genes while MdPHT2 has two, MdPHT3 has seven, MdPHT4 has 11, and MdPHT5 has three. Our overview of this gene family focused on structure, chromosomal distribution and localization, phylogenies, and motifs. These genes displayed differential expression patterns in various tissues. For example, expression was high for MdPHT1;12, MdPHT3;6, and MdPHT3;7 in the roots, and was also increased in response to low-phosphorus conditions. In contrast, MdPHT4;1, MdPHT4;4, and MdPHT4;10 were expressed only in the leaves while transcript levels of MdPHT1;4, MdPHT1;12, and MdPHT5;3 were highest in flowers. In general, these 37 genes were regulated significantly in either roots or leaves in response to the imposition of phosphorus and/or drought stress. The results suggest that members of the PHT family function in plant adaptations to adverse growing environments. Our study will lay a foundation for better understanding the PHT family evolution and exploring genes of interest for genetic improvement in apple. PMID:28424713

Ubiquitination-Related MdBT Scaffold Proteins Target a bHLH Transcription Factor for Iron Homeostasis1[OPEN

PubMed Central

Zhao, Qiang; Wang, Qing-Jie; Wang, Xiao-Fei; You, Chun-Xiang

2016-01-01

Iron (Fe) homeostasis is crucial for plant growth and development. A network of basic helix-loop-helix (bHLH) transcription factors positively regulates Fe uptake during iron deficiency. However, their up-regulation or overexpression leads to Fe overload and reactive oxygen species generation, thereby damaging the plants. Here, we found that two BTB/TAZ proteins, MdBT1 and MdBT2, interact with the MbHLH104 protein in apple. In addition, the function of MdBT2 was characterized as a regulator of MdbHLH104 degradation via ubiquitination and the 26S proteasome pathway, thereby controlling the activity of plasma membrane H+-ATPases and the acquisition of iron. Furthermore, MdBT2 interacted with MdCUL3 proteins, which were required for the MdBT2-mediated ubiquitination modification of MdbHLH104 and its degradation. In sum, our findings demonstrate that MdBT proteins interact with MdCUL3 to bridge the formation of the MdBTsMdCUL3 complex, which negatively modulates the degradation of the MdbHLH104 protein in response to changes in Fe status to maintain iron homeostasis in plants. PMID:27660166

MdHIR proteins repress anthocyanin accumulation by interacting with the MdJAZ2 protein to inhibit its degradation in apples

PubMed Central

Chen, Ke-Qin; Zhao, Xian-Yan; An, Xiu-Hong; Tian, Yi; Liu, Dan-Dan; You, Chun-Xiang; Hao, Yu-Jin

2017-01-01

In higher plants, jasmonate ZIM-domain (JAZ) proteins negatively regulate the biosynthesis of anthocyanins by interacting with bHLH transcription factors. However, it is largely unknown if and how other regulators are involved in this process. In this study, the apple MdJAZ2 protein was characterized in regards to its function in the negative regulation of anthocyanin accumulation and peel coloration. MdJAZ2 was used as a bait to screen a cDNA library using the yeast two-hybrid method. The hypersensitive induced reaction (HIR) proteins, MdHIR2 and MdHIR4, were obtained from this yeast two-hybrid. The ZIM domain of MdJAZ2 and the PHB domain of the MdHIR proteins are necessary for their interactions. The interactions were further verified using an in vitro pull-down assay. Subsequently, immunoblotting assays demonstrated that MdHIR4 enhanced the stability of the MdJAZ2-GUS protein. Finally, a viral vector-based transformation method showed that MdHIR4 inhibited anthocyanin accumulation and fruit coloration in apple by modulating the expression of genes associated with anthocyanin biosynthesis. PMID:28317851

Increased COX-2 expression in epithelial and stromal cells of high mammographic density tissues and in a xenograft model of mammographic density.

PubMed

Chew, G L; Huo, C W; Huang, D; Hill, P; Cawson, J; Frazer, H; Hopper, J L; Haviv, I; Henderson, M A; Britt, K; Thompson, E W

2015-08-01

Mammographic density (MD) adjusted for age and body mass index is one of the strongest known risk factors for breast cancer. Given the high attributable risk of MD for breast cancer, chemoprevention with a safe and available agent that reduces MD and breast cancer risk would be beneficial. Cox-2 has been implicated in MD-related breast cancer risk, and was increased in stromal cells in high MD tissues in one study. Our study assessed differential Cox-2 expression in epithelial and stromal cells in paired samples of high and low MD human breast tissue, and in a validated xenograft biochamber model of MD. We also examined the effects of endocrine treatment upon Cox-2 expression in high and low MD tissues in the MD xenograft model. Paired high and low MD human breast tissue samples were immunostained for Cox-2, then assessed for differential expression and staining intensity in epithelial and stromal cells. High and low MD human breast tissues were separately maintained in biochambers in mice treated with Tamoxifen, oestrogen or placebo implants, then assessed for percentage Cox-2 staining in epithelial and stromal cells. Percentage Cox-2 staining was greater for both epithelial (p = 0.01) and stromal cells (p < 0.0001) of high compared with low MD breast tissues. In high MD biochamber tissues, percentage Cox-2 staining was greater in stromal cells of oestrogen-treated versus placebo-treated tissues (p = 0.05).

Molecular characterization of FLOWERING LOCUS T-like genes of apple (Malus x domestica Borkh.).

PubMed

Kotoda, Nobuhiro; Hayashi, Hidehiro; Suzuki, Motoko; Igarashi, Megumi; Hatsuyama, Yoshimichi; Kidou, Shin-Ichiro; Igasaki, Tomohiro; Nishiguchi, Mitsuru; Yano, Kanako; Shimizu, Tokurou; Takahashi, Sae; Iwanami, Hiroshi; Moriya, Shigeki; Abe, Kazuyuki

2010-04-01

The two FLOWERING LOCUS T (FT)-like genes of apple (Malus x domestica Borkh.), MdFT1 and MdFT2, have been isolated and characterized. MdFT1 and MdFT2 were mapped, respectively, on distinct linkage groups (LGs) with partial homoeology, LG 12 and LG 4. The expression pattern of MdFT1 and MdFT2 differed in that MdFT1 was expressed mainly in apical buds of fruit-bearing shoots in the adult phase, with little expression in the juvenile tissues, whereas MdFT2 was expressed mainly in reproductive organs, including flower buds and young fruit. On the other hand, both genes had the potential to induce early flowering since transgenic Arabidopsis, which ectopically expressed MdFT1 or MdFT2, flowered earlier than wild-type plants. Furthermore, overexpression of MdFT1 conferred precocious flowering in apple, with altered expression of other endogenous genes, such as MdMADS12. These results suggest that MdFT1 could function to promote flowering by altering the expression of those genes and that, at least, other genes may play an important role as well in the regulation of flowering in apple. The long juvenile period of fruit trees prevents early cropping and efficient breeding. Our findings will be useful information to unveil the molecular mechanism of flowering and to develop methods to shorten the juvenile period in various fruit trees, including apple.

Phenomenology of psychotic mood disorders: lifetime and major depressive episode features.

PubMed

Souery, Daniel; Zaninotto, Leonardo; Calati, Raffaella; Linotte, Sylvie; Sentissi, Othman; Amital, Daniela; Moser, Ulrike; Kasper, Siegfried; Zohar, Joseph; Mendlewicz, Julien; Serretti, Alessandro

2011-12-01

The nosological and clinical implications of psychotic features in the course of mood disorders have been widely debated. Currently, no specification exists for defining a subgroup of lifetime Psychotic Mood Disorder (PMD) patients. A total of 2178 patients were examined, including subjects with Bipolar Disorder (BP) type I (n=519) and II (n=207) and Major Depressive Disorder (n=1452). Patients were divided between PMD (n=645) and non-psychotic Mood Disorders (MD) (n=1533) by the lifetime presence of at least one mood episode with psychotic features. Subjects having a depressive episode at the time of assessment were also examined: HAM-D and YMRS scores were compared between MD and PMD subjects, both with and without current psychotic features. A diagnosis of BP-I, a higher familial load for BP, a higher number of mood episodes lifetime, and a higher prevalence of OCD and somatic comorbidities were all associated to PMD. A diagnosis of BP (OR=4.48) was the only significant predictor for psychosis. PMD with non-psychotic depression were apparently less severe than MD patients and had a lower rate of "non-responders" to AD treatment. Sub-threshold manic symptoms and suicidal risk were also more pronounced among PMD. The lack of information about number and polarity of previous psychotic mood episodes may be the major limitations of our study. BP diagnosis is the most significant predictor for psychosis in mood disorders. Non-psychotic mood episodes in PMD patients may be characterized by a distinctive symptom profile and, possibly, a different response to treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

Using Children's Literature to Decrease Moral Disengagement and Victimization among Elementary School Students

ERIC Educational Resources Information Center

Wang, Cixin; Goldberg, Taryn S.

2017-01-01

Previous research has suggested that moral disengagement is strongly associated with bullying and bystander behavior. The current study evaluated the effectiveness of a 5-week classroom-wide bullying intervention, "The Bullying Literature Project-Moral Disengagement Version (BLP-MD)", on moral disengagement and bullying among elementary…

76 FR 80448 - VASRD Forum-Improving VA's Disability Evaluation Criteria for Neurological Conditions and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-23

... to capture public comment and current medical science information from presentations made by subject matter experts. This Forum is scheduled for January 17-26, 2012. VA plans to use this information to... first-come, first-served basis. FOR FURTHER INFORMATION CONTACT: Nick Olmos-Lau, M.D., Regulation Staff...

77 FR 20611 - Notice of Intent To Request an Extension and Revision of a Currently Approved Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

... Service's (ARS) intention to seek approval to collect information in support of research and related... consideration. ADDRESSES: Address all comments concerning this notice to Jill Philpot, ARS Webmaster, 5601 Sunnyside Avenue, Beltsville, MD 20705. FOR FURTHER INFORMATION CONTACT: Contact Jill Philpot, ARS Webmaster...

Oscillations and Analogies: Thomas Young, MD, FRS, Genius.

ERIC Educational Resources Information Center

Martindale, Colin

2001-01-01

Thomas Young was a renowned genius in his time who did important work in many scientific disciplines. In today's specialized environment, scientists in each discipline do not appreciate his work. Despite his current obscurity, Young exemplifies traits found in a first-order genius (analogical thinking, high intelligence, hard work, wide interests,…

36 CFR 1225.26 - How do agencies change a disposition authority?

Code of Federal Regulations, 2012 CFR

2012-07-01

... (NWM), 8601 Adelphi Road, College Park, MD 20740-6001, phone number (301) 837-1738. NARA approval is... following, if applicable: (1) The SF 115 and item numbers to be superseded; (2) The General Records Schedules and item numbers that cover the records, if any; and (3) The current published records disposition...

36 CFR § 1225.26 - How do agencies change a disposition authority?

Code of Federal Regulations, 2013 CFR

2013-07-01

... (NWM), 8601 Adelphi Road, College Park, MD 20740-6001, phone number (301) 837-1738. NARA approval is... following, if applicable: (1) The SF 115 and item numbers to be superseded; (2) The General Records Schedules and item numbers that cover the records, if any; and (3) The current published records disposition...

36 CFR 1225.26 - How do agencies change a disposition authority?

Code of Federal Regulations, 2011 CFR

2011-07-01

... (NWM), 8601 Adelphi Road, College Park, MD 20740-6001, phone number (301) 837-1738. NARA approval is... following, if applicable: (1) The SF 115 and item numbers to be superseded; (2) The General Records Schedules and item numbers that cover the records, if any; and (3) The current published records disposition...

36 CFR 1225.26 - How do agencies change a disposition authority?

Code of Federal Regulations, 2014 CFR

2014-07-01

... (NWM), 8601 Adelphi Road, College Park, MD 20740-6001, phone number (301) 837-1738. NARA approval is... following, if applicable: (1) The SF 115 and item numbers to be superseded; (2) The General Records Schedules and item numbers that cover the records, if any; and (3) The current published records disposition...

75 FR 50707 - Drawbridge Operation Regulation; Curtis Creek, Baltimore, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-17

... double-leaf bascule drawbridge, has requested a temporary deviation from the current general operating... half of the draw spans to single-leaf operation. The drawbridge will operate as follows: (1) Closed to..., vessels openings will be provided if at least 48 hours advance notice is given; (2) Single leaf operation...

Postdoctoral Fellow | Center for Cancer Research

Cancer.gov

A post-doctoral fellowship is currently available for productive, highly-motivated, and energetic individuals in the Inflammation and Tumorigenesis Section of Dr. Yinling Hu at the NCI-Frederick campus.  A dynamic research environment and outstanding resources are available for enthusiastic individuals.  Requirements include a Ph.D., M.D., or equivalent degree and experience

Groundwater and surface water dynamics of Na and Cl in an urban stream: effects of road salts

EPA Science Inventory

AbstractRoad salts are a growing environmental and health concern in urban watersheds. We examined groundwater (GW) and surface water (SW) dynamics of Na and Cl in an urban stream, Minebank Run (MBR), MD. We observed an increasing salinity trend in this restored stream. Current b...

The AINTEGUMENTA genes, MdANT1 and MdANT2, are associated with the regulation of cell production during fruit growth in apple (Malus × domestica Borkh.)

PubMed Central

2012-01-01

Background Fruit growth in apple (Malus × domestica Borkh.) is mediated by cell production and expansion. Genes involved in regulating these processes and thereby fruit growth, are not well characterized. We hypothesized that the apple homolog(s) of AINTEGUMENTA (ANT), an APETALA2–repeat containing transcription factor, regulates cell production during fruit growth in apple. Results Two ANT genes, MdANT1 and MdANT2, were isolated from apple and their expression was studied during multiple stages of fruit development. MdANT1 and MdANT2 expression was high during early fruit growth coincident with the period of cell production, rapidly declined during exit from cell production, and remained low during the rest of fruit development. The effects of increase in carbohydrate availability during fruit growth were characterized. Increase in carbohydrate availability enhanced fruit growth largely through an increase in cell production. Expression of MdANT1 and MdANT2 increased sharply by up to around 5-fold in response to an increase in carbohydrate availability. Expression of the ANT genes was compared across two apple genotypes, ‘Gala’ and ‘Golden Delicious Smoothee’ (GS), which differ in the extent of fruit growth, largely due to differences in cell production. In comparison to ‘Gala’, the larger fruit-size genotype, GS, displayed higher levels and a longer duration of MdANT1 and MdANT2 expression. Expression of the ANTs and cell cycle genes in the fruit core and cortex tissues isolated using laser capture microdissection was studied. During early fruit growth, expression of the MdANTs was higher within the cortex, the tissue that constitutes the majority of the fruit. Additionally, MdANT1 and MdANT2 expression was positively correlated with that of A- and B-type CYCLINS, B-type CYCLIN-DEPENDENT-KINASES (CDKBs) and MdDEL1. Conclusions Multiple lines of evidence from this study suggest that MdANT1 and MdANT2 regulate cell production during fruit growth in apple. ANTs may coordinate the expression of cell proliferation genes and thereby affect the competence of cells for cell production during fruit growth. Together, data from this study implicate MdANT1 and MdANT2 in the regulation of fruit growth in apple. PMID:22731507

The AINTEGUMENTA genes, MdANT1 and MdANT2, are associated with the regulation of cell production during fruit growth in apple (Malus × domestica Borkh.).

PubMed

Dash, Madhumita; Malladi, Anish

2012-06-25

Fruit growth in apple (Malus × domestica Borkh.) is mediated by cell production and expansion. Genes involved in regulating these processes and thereby fruit growth, are not well characterized. We hypothesized that the apple homolog(s) of AINTEGUMENTA (ANT), an APETALA2-repeat containing transcription factor, regulates cell production during fruit growth in apple. Two ANT genes, MdANT1 and MdANT2, were isolated from apple and their expression was studied during multiple stages of fruit development. MdANT1 and MdANT2 expression was high during early fruit growth coincident with the period of cell production, rapidly declined during exit from cell production, and remained low during the rest of fruit development. The effects of increase in carbohydrate availability during fruit growth were characterized. Increase in carbohydrate availability enhanced fruit growth largely through an increase in cell production. Expression of MdANT1 and MdANT2 increased sharply by up to around 5-fold in response to an increase in carbohydrate availability. Expression of the ANT genes was compared across two apple genotypes, 'Gala' and 'Golden Delicious Smoothee' (GS), which differ in the extent of fruit growth, largely due to differences in cell production. In comparison to 'Gala', the larger fruit-size genotype, GS, displayed higher levels and a longer duration of MdANT1 and MdANT2 expression. Expression of the ANTs and cell cycle genes in the fruit core and cortex tissues isolated using laser capture microdissection was studied. During early fruit growth, expression of the MdANTs was higher within the cortex, the tissue that constitutes the majority of the fruit. Additionally, MdANT1 and MdANT2 expression was positively correlated with that of A- and B-type CYCLINS, B-type CYCLIN-DEPENDENT-KINASES (CDKBs) and MdDEL1. Multiple lines of evidence from this study suggest that MdANT1 and MdANT2 regulate cell production during fruit growth in apple. ANTs may coordinate the expression of cell proliferation genes and thereby affect the competence of cells for cell production during fruit growth. Together, data from this study implicate MdANT1 and MdANT2 in the regulation of fruit growth in apple.

A Putative Multiple-Demand System in the Macaque Brain.

PubMed

Mitchell, Daniel J; Bell, Andrew H; Buckley, Mark J; Mitchell, Anna S; Sallet, Jerome; Duncan, John

2016-08-17

In humans, cognitively demanding tasks of many types recruit common frontoparietal brain areas. Pervasive activation of this "multiple-demand" (MD) network suggests a core function in supporting goal-oriented behavior. A similar network might therefore be predicted in nonhuman primates that readily perform similar tasks after training. However, an MD network in nonhuman primates has not been described. Single-cell recordings from macaque frontal and parietal cortex show some similar properties to human MD fMRI responses (e.g., adaptive coding of task-relevant information). Invasive recordings, however, come from limited prespecified locations, so they do not delineate a macaque homolog of the MD system and their positioning could benefit from knowledge of where MD foci lie. Challenges of scanning behaving animals mean that few macaque fMRI studies specifically contrast levels of cognitive demand, so we sought to identify a macaque counterpart to the human MD system using fMRI connectivity in 35 rhesus macaques. Putative macaque MD regions, mapped from frontoparietal MD regions defined in humans, were found to be functionally connected under anesthesia. To further refine these regions, an iterative process was used to maximize their connectivity cross-validated across animals. Finally, whole-brain connectivity analyses identified voxels that were robustly connected to MD regions, revealing seven clusters across frontoparietal and insular cortex comparable to human MD regions and one unexpected cluster in the lateral fissure. The proposed macaque MD regions can be used to guide future electrophysiological investigation of MD neural coding and in task-based fMRI to test predictions of similar functional properties to human MD cortex. In humans, a frontoparietal "multiple-demand" (MD) brain network is recruited during a wide range of cognitively demanding tasks. Because this suggests a fundamental function, one might expect a similar network to exist in nonhuman primates, but this remains controversial. Here, we sought to identify a macaque counterpart to the human MD system using fMRI connectivity. Putative macaque MD regions were functionally connected under anesthesia and were further refined by iterative optimization. The result is a network including lateral frontal, dorsomedial frontal, and insular and inferior parietal regions closely similar to the human counterpart. The proposed macaque MD regions can be useful in guiding electrophysiological recordings or in task-based fMRI to test predictions of similar functional properties to human MD cortex. Copyright © 2016 Mitchell et al.

From laws of inference to protein folding dynamics.

PubMed

Tseng, Chih-Yuan; Yu, Chun-Ping; Lee, H C

2010-08-01

Protein folding dynamics is one of major issues constantly investigated in the study of protein functions. The molecular dynamic (MD) simulation with the replica exchange method (REM) is a common theoretical approach considered. Yet a trade-off in applying the REM is that the dynamics toward the native configuration in the simulations seems lost. In this work, we show that given REM-MD simulation results, protein folding dynamics can be directly derived from laws of inference. The applicability of the resulting approach, the entropic folding dynamics, is illustrated by investigating a well-studied Trp-cage peptide. Our results are qualitatively comparable with those from other studies. The current studies suggest that the incorporation of laws of inference and physics brings in a comprehensive perspective on exploring the protein folding dynamics.

MdHB1 down-regulation activates anthocyanin biosynthesis in the white-fleshed apple cultivar 'Granny Smith'.

PubMed

Jiang, Yonghua; Liu, Cuihua; Yan, Dan; Wen, Xiaohong; Liu, Yanli; Wang, Haojie; Dai, Jieyu; Zhang, Yujie; Liu, Yanfei; Zhou, Bin; Ren, Xiaolin

2017-02-01

Coloration in apple (Malus×domestica) flesh is mainly caused by the accumulation of anthocyanin. Anthocyanin is biosynthesized through the flavonoid pathway and regulated by MYB, bHLH, and WD40 transcription factors (TFs). Here, we report that the HD-Zip I TF MdHB1 was also involved in the regulation of anthocyanin accumulation. MdHB1 silencing caused the accumulation of anthocyanin in 'Granny Smith' flesh, whereas its overexpression reduced the flesh content of anthocyanin in 'Ballerina' (red-fleshed apple). Moreover, flowers of transgenic tobacco (Nicotiana tabacum 'NC89') overexpressing MdHB1 showed a remarkable reduction in pigmentation. Transient promoter activation assays and yeast one-hybrid results indicated that MdHB1 indirectly inhibited expression of the anthocyanin biosynthetic genes encoding dihydroflavonol-4-reductase (DFR) and UDP-glucose:flavonoid 3-O-glycosyltransferase (UFGT). Yeast two-hybrid and bimolecular fluorescence complementation determined that MdHB1 acted as a homodimer and could interact with MYB, bHLH, and WD40 in the cytoplasm, consistent with its cytoplasmic localization by green fluorescent protein fluorescence observations. Together, these results suggest that MdHB1 constrains MdMYB10, MdbHLH3, and MdTTG1 to the cytoplasm, and then represses the transcription of MdDFR and MdUFGT indirectly. When MdHB1 is silenced, these TFs are released to activate the expression of MdDFR and MdUFGT and also anthocyanin biosynthesis, resulting in red flesh in 'Granny Smith'. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Water consumption footprint and land requirements of large-scale alternative diesel and jet fuel production.

PubMed

Staples, Mark D; Olcay, Hakan; Malina, Robert; Trivedi, Parthsarathi; Pearlson, Matthew N; Strzepek, Kenneth; Paltsev, Sergey V; Wollersheim, Christoph; Barrett, Steven R H

2013-01-01

Middle distillate (MD) transportation fuels, including diesel and jet fuel, make up almost 30% of liquid fuel consumption in the United States. Alternative drop-in MD and biodiesel could potentially reduce dependence on crude oil and the greenhouse gas intensity of transportation. However, the water and land resource requirements of these novel fuel production technologies must be better understood. This analysis quantifies the lifecycle green and blue water consumption footprints of producing: MD from conventional crude oil; Fischer-Tropsch MD from natural gas and coal; fermentation and advanced fermentation MD from biomass; and hydroprocessed esters and fatty acids MD and biodiesel from oilseed crops, throughout the contiguous United States. We find that FT MD and alternative MD derived from rainfed biomass have lifecycle blue water consumption footprints of 1.6 to 20.1 Lwater/LMD, comparable to conventional MD, which ranges between 4.1 and 7.4 Lwater/LMD. Alternative MD derived from irrigated biomass has a lifecycle blue water consumption footprint potentially several orders of magnitude larger, between 2.7 and 22 600 Lwater/LMD. Alternative MD derived from biomass has a lifecycle green water consumption footprint between 1.1 and 19 200 Lwater/LMD. Results are disaggregated to characterize the relationship between geo-spatial location and lifecycle water consumption footprint. We also quantify the trade-offs between blue water consumption footprint and areal MD productivity, which ranges from 490 to 4200 LMD/ha, under assumptions of rainfed and irrigated biomass cultivation. Finally, we show that if biomass cultivation for alternative MD is irrigated, the ratio of the increase in areal MD productivity to the increase in blue water consumption footprint is a function of geo-spatial location and feedstock-to-fuel production pathway.

Prostate Cancer Research Training in Health Disparities for Undergraduates (PCaRT)

DTIC Science & Technology

2010-03-01

management Program Mentors Carlton Adams, M.D. LaMonica Stewart, Ph.D. Ben Ogunkua, M.D., Ph.D. Alphonse Pasipanodya, M.D. Jay Fowke, Ph.D., MPH...African-Americans Alphonse Pasipanodya, MD. (Primary Mentor) Flora A. M. Ukoli, MD., MPH. (Principal Investigator) Derrick Beech, M.D. (Co-PI...my goals is to be a successful black woman influencing and touching the lives of all those I come in contact with daily. Alphonse Pasipanodya

The Influence of Perceived Characteristics of Management Development Programs on Employee Outcomes

ERIC Educational Resources Information Center

Ardts, Joost C. A.; van der Velde, Mandy E. G.; Maurer, Todd J.

2010-01-01

Employees' perceptions of Management Development (MD) programs is the topic of this study. The purpose is to examine the influence of three important perceived characteristics of MD programs on relevant MD outcomes. The MD characteristics are: availability of role models, perceived control, and understanding the MD program. Outcomes are:…

relationship between diffusion tensor imaging findings and cognitive outcomes following adult traumatic brain injury: A meta-analysis.

PubMed

Wallace, E J; Mathias, J L; Ward, L

2018-05-24

Cognitive impairments are common following a traumatic brain injury (TBI) and frequently result from white matter (WM) damage. This damage can be quantified using diffusion tensor imaging (DTI), which measures the directionality (fractional anisotropy: FA) and amount (mean diffusivity/apparent diffusion coefficient: MD/ADC) of water diffusion in WM, with high FA and low MD/ADC thought to indicate greater WM integrity. However, the relationship between DTI and cognitive outcomes is currently unclear. The data from 20 studies that examined the relationship between WM integrity (measured using DTI) and cognition (categorised into seven domains) following mild-severe adult TBI were meta-analysed. Overall, high FA and low MD/ADC in most brain regions was associated with better cognitive performance, with memory and attention most strongly related to DTI findings. Specifically, memory and/or attention were very strongly related to DTI findings in the corpus callosum, fornix, internal capsule, arcuate and uncinate fasciculi. However, most findings were based on single studies and therefore await replication. Larger-scale, longitudinal studies are now needed to determine the predictive utility of DTI. Copyright © 2018. Published by Elsevier Ltd.

Selective Plasmonic Enhancement of Electric- and Magnetic-Dipole Radiations of Er Ions.

PubMed

Choi, Bongseok; Iwanaga, Masanobu; Sugimoto, Yoshimasa; Sakoda, Kazuaki; Miyazaki, Hideki T

2016-08-10

Lanthanoid series are unique in atomic elements. One reason is because they have 4f electronic states forbidding electric-dipole (ED) transitions in vacuum and another reason is because they are very useful in current-day optical technologies such as lasers and fiber-based telecommunications. Trivalent Er ions are well-known as a key atomic element supporting 1.5 μm band optical technologies and also as complex photoluminescence (PL) band deeply mixing ED and magnetic-dipole (MD) transitions. Here we show large and selective enhancement of ED and MD radiations up to 83- and 26-fold for a reference bulk state, respectively, in experiments employing plasmonic nanocavity arrays. We achieved the marked PL enhancement by use of an optimal design for electromagnetic (EM) local density of states (LDOS) and by Er-ion doping in deep subwavelength precision. We moreover clarify the quantitative contribution of ED and MD radiations to the PL band, and the magnetic Purcell effect in the PL-decay temporal measurement. This study experimentally demonstrates a new scheme of EM-LDOS engineering in plasmon-enhanced photonics, which will be a key technique to develop loss-compensated and active plasmonic devices.

Microdialysis Monitoring in Clinical Traumatic Brain Injury and Its Role in Neuroprotective Drug Development.

PubMed

Thelin, Eric Peter; Carpenter, Keri L H; Hutchinson, Peter J; Helmy, Adel

2017-03-01

Injuries to the central nervous system continue to be vast contributors to morbidity and mortality; specifically, traumatic brain injury (TBI) is the most common cause of death during the first four decades of life. Several modalities are used to monitor patients suffering from TBI in order to prevent detrimental secondary injuries. The microdialysis (MD) technique, introduced during the 1990s, presents the treating physician with a robust monitoring tool for brain chemistry in addition to conventional intracranial pressure monitoring. Nevertheless, some limitations remain, such as limited spatial resolution. Moreover, while there have been several attempts to develop new potential pharmacological therapies in TBI, there are currently no available drugs which have shown clinical efficacy that targets the underlying pathophysiology, despite various trials investigating a plethora of pharmaceuticals. Specifically in the brain, MD is able to demonstrate penetration of the drug through the blood-brain barrier into the brain extracellular space at potential site of action. In addition, the downstream effects of drug action can be monitored directly. In the future, clinical MD, together with other monitoring modalities, can identify specific pathological substrates which require tailored treatment strategies for patients suffering from TBI.

Effects of Tamoxifen and oestrogen on histology and radiographic density in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers.

PubMed

Chew, G L; Huo, C W; Huang, D; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M C; Hopper, J L; Britt, K; Henderson, M A; Haviv, I; Thompson, E W

2014-11-01

Mammographic density (MD) is a strong risk factor for breast cancer. It is altered by exogenous endocrine treatments, including hormone replacement therapy and Tamoxifen. Such agents also modify breast cancer (BC) risk. However, the biomolecular basis of how systemic endocrine therapy modifies MD and MD-associated BC risk is poorly understood. This study aims to determine whether our xenograft biochamber model can be used to study the effectiveness of therapies aimed at modulating MD, by examine the effects of Tamoxifen and oestrogen on histologic and radiographic changes in high and low MD tissues maintained within the biochamber model. High and low MD human tissues were precisely sampled under radiographic guidance from prophylactic mastectomy fresh specimens of high-risk women, then inserted into separate vascularized murine biochambers. The murine hosts were concurrently implanted with Tamoxifen, oestrogen or placebo pellets, and the high and low MD biochamber tissues maintained in the murine host environment for 3 months, before the high and low MD biochamber tissues were harvested for histologic and radiographic analyses. The radiographic density of high MD tissue maintained in murine biochambers was decreased in Tamoxifen-treated mice compared to oestrogen-treated mice (p = 0.02). Tamoxifen treatment of high MD tissue in SCID mice led to a decrease in stromal (p = 0.009), and an increase in adipose (p = 0.023) percent areas, compared to placebo-treated mice. No histologic or radiographic differences were observed in low MD biochamber tissue with any treatment. High MD biochamber tissues maintained in mice implanted with Tamoxifen, oestrogen or placebo pellets had dynamic and measurable histologic compositional and radiographic changes. This further validates the dynamic nature of the MD xenograft model, and suggests the biochamber model may be useful for assessing the underlying molecular pathways of Tamoxifen-reduced MD, and in testing of other pharmacologic interventions in a preclinical model of high MD.

Null mutation of the MdACS3 gene, coding for a ripening-specific 1-aminocyclopropane-1-carboxylate synthase, leads to long shelf life in apple fruit.

PubMed

Wang, Aide; Yamakake, Junko; Kudo, Hisayuki; Wakasa, Yuhya; Hatsuyama, Yoshimichi; Igarashi, Megumi; Kasai, Atsushi; Li, Tianzhong; Harada, Takeo

2009-09-01

Expression of MdACS1, coding for 1-aminocyclopropane-1-carboxylate synthase (ACS), parallels the level of ethylene production in ripening apple (Malus domestica) fruit. Here we show that expression of another ripening-specific ACS gene (MdACS3) precedes the initiation of MdACS1 expression by approximately 3 weeks; MdACS3 expression then gradually decreases as MdACS1 expression increases. Because MdACS3 expression continues in ripening fruit treated with 1-methylcyclopropene, its transcription appears to be regulated by a negative feedback mechanism. Three genes in the MdACS3 family (a, b, and c) were isolated from a genomic library, but two of them (MdACS3b and MdACS3c) possess a 333-bp transposon-like insertion in their 5' flanking region that may prevent transcription of these genes during ripening. A single nucleotide polymorphism in the coding region of MdACS3a results in an amino acid substitution (glycine-289 --> valine) in the active site that inactivates the enzyme. Furthermore, another null allele of MdACS3a, Mdacs3a, showing no ability to be transcribed, was found by DNA sequencing. Apple cultivars homozygous or heterozygous for both null allelotypes showed no or very low expression of ripening-related genes and maintained fruit firmness. These results suggest that MdACS3a plays a crucial role in regulation of fruit ripening in apple, and is a possible determinant of ethylene production and shelf life in apple fruit.

Chronic intraventricular administration of lysergic acid diethylamide (LSD) affects the sensitivity of cortical cells to monocular deprivation.

PubMed

McCall, M A; Tieman, D G; Hirsch, H V

1982-11-04

In kittens, but not in adult cats, depriving one eye of pattern vision by suturing the lids shut (monocular deprivation or MD) for one week reduces the proportion of binocular units in the visual cortex. A sensitivity of cortical units in adult cats to MD can be produced by infusing exogenous monoamines into the visual cortex. Since LSD interacts with monoamines, we have examined the effects of chronic administration of LSD on the sensitivity to MD for cortical cells in adult cats. Cats were assigned randomly to one of four conditions: MD/LSD, MD/No-LSD, No-MD/LSD, No-MD/No-LSD. An osmotic minipump delivered either LSD or the vehicle solution alone during a one-week period of MD. The animals showed no obvious anomalies during the administration of the drug. After one week the response properties of single units in area 17 of the visual cortex were studied without knowledge of the contents of the individual minipumps. With the exception of ocular dominance, the response properties of units recorded in all animals did not differ from normal. In the control animals (MD/No-LSD, No-MD/LSD, No-MD/No-LSD) the average proportion of binocular cells was 78%; similar to that observed for normal adult cats. However, in the experimental animals, which received LSD during the period of MD, only 52% of the cells were binocular. Our results suggest that chronic intraventricular administration of LSD affects either directly or indirectly the sensitivity of cortical neurons to MD.

Proposal and Testing of a Methodology for Evaluating an Occupational Health Program at a U.S. Army Installation

DTIC Science & Technology

1983-08-01

the literature for ten of the thirteen peptic ulcer diagnostic criteria most often cited in predeveloped listings compiled by various professional...Dershewitz, M.D., Richard A. Gross, M.D., and John W. Williamson, M.D., "Validating Audit Criteria: An Analytic Approach Illustrated by Peptic Ulcer ...A., M.D.; Gross, Richard A., M.D.; and Williamson, John W., M.D., "Validating Audit Criteria: An Analytic Approach Illustrated by Peptic Ulcer Disease

[Evaluation of three methods for forensic diatom test].

PubMed

Wang, Yuzhong; Zhao, Jian; Li, Peng; Hu, Sunlin; Wang, Huipin; Wang, Huijun; Liu, Chao

2015-03-01

To compare the efficacy of three methods for forensic diatom test, namely strong acid digestion-centrifuge enrichment-light microscopy (SD-CE-LM), microwave digestion-membrane filtration-automated scanning electron microscopy (MD-ME-SEM), and microwave digestion-membrane filtration-light microscopy (MD-MF-LM). Sixty samples were randomly divided into 3 groups for diatom test using three methods, and the sample preparation time, degree of digestion and recovery rate of diatoms were compared. The sample preparation time was the shortest with MD-MF-LM and the longest with SD-CE-LM (P<0.05). MD-ME-SEM and MD-MF-LM allowed more thorough tissue digestion than SD-CE-LM. MD-ME-SEM resulted in the highest total recovery rate of diatom, followed by MD-MF-LM and then by SD-CE-LM (P<0.05); the recover rate of different diatom species was the highest with MD-ME-SEM, followed by MD-MF-LM and SD-CE-LM (P<0.05). SD-CE-LM has a low recovery rate of diatoms especially for those with lengths shorter than 40 µm or densities less than 1/5. With a high recovery rate and accuracy in diatom test, MD-ME-SEM is suitable for diagnosis of suspected drowning cases. MD-MF-LM is highly efficient, sensitive and convenient for forensic diatom test.

SVP-like MADS Box Genes Control Dormancy and Budbreak in Apple

PubMed Central

Wu, Rongmei; Tomes, Sumathi; Karunairetnam, Sakuntala; Tustin, Stuart D.; Hellens, Roger P.; Allan, Andrew C.; Macknight, Richard C.; Varkonyi-Gasic, Erika

2017-01-01

The annual growth cycle of trees is the result of seasonal cues. The onset of winter triggers an endodormant state preventing bud growth and, once a chilling requirement is satisfied, these buds enter an ecodormant state and resume growing. MADS-box genes with similarity to Arabidopsis SHORT VEGETATIVE PHASE (SVP) [the SVP-like and DORMANCY ASSOCIATED MADS-BOX (DAM) genes] have been implicated in regulating flowering and growth-dormancy cycles in perennials. Here, we identified and characterized three DAM-like (MdDAMs) and two SHORT VEGETATIVE PHASE-like (MdSVPs) genes from apple (Malus × domestica ‘Royal Gala’). The expression of MdDAMa and MdDAMc indicated they may play a role in triggering autumn growth cessation. In contrast, the expression of MdDAMb, MdSVPa and MdSVPb suggested a role in maintaining bud dormancy. Consistent with this, ectopic expression of MdDAMb and MdSVPa in ‘Royal Gala’ apple plants resulted in delayed budbreak and architecture change due to constrained lateral shoot outgrowth, but normal flower and fruit development. The association of MdSVPa and MdSVPb expression with floral bud development in the low fruiting ‘Off’ trees of a biennial bearing cultivar ‘Sciros’ suggested the SVP genes might also play a role in floral meristem identity. PMID:28421103

ANA (Antinuclear Antibody Test)

MedlinePlus

... findarticles.com . Kavanaugh A, Tomar R, Reveille J, Solomon DH, Homburger HA. Guidelines for clinical use of ... Russell Tomar, MD, John Reveille, MD, Daniel H. Solomon, MD, MPH, and Henry A. Homburger, MD. Guidelines ...

Dynamic changes in high and low mammographic density human breast tissues maintained in murine tissue engineering chambers during various murine peripartum states and over time.

PubMed

Chew, G L; Huang, D; Huo, C W; Blick, T; Hill, P; Cawson, J; Frazer, H; Southey, M D; Hopper, J L; Henderson, M A; Haviv, I; Thompson, E W

2013-07-01

Mammographic density (MD) is a strong heritable risk factor for breast cancer, and may decrease with increasing parity. However, the biomolecular basis for MD-associated breast cancer remains unclear, and systemic hormonal effects on MD-associated risk is poorly understood. This study assessed the effect of murine peripartum states on high and low MD tissue maintained in a xenograft model of human MD. Method High and low MD human breast tissues were precisely sampled under radiographic guidance from prophylactic mastectomy specimens of women. The high and low MD tissues were maintained in separate vascularised biochambers in nulliparous or pregnant SCID mice for 4 weeks, or mice undergoing postpartum involution or lactation for three additional weeks. High and low MD biochamber material was harvested for histologic and radiographic comparisons during various murine peripartum states. High and low MD biochamber tissues in nulliparous mice were harvested at different timepoints for histologic and radiographic comparisons. Results High MD biochamber tissues had decreased stromal (p = 0.0027), increased adipose (p = 0.0003) and a trend to increased glandular tissue areas (p = 0.076) after murine postpartum involution. Stromal areas decreased (p = 0.042), while glandular (p = 0.001) and adipose areas (p = 0.009) increased in high MD biochamber tissues during lactation. A difference in radiographic density was observed in high (p = 0.0021) or low MD biochamber tissues (p = 0.004) between nulliparous, pregnant and involution groups. No differences in tissue composition were observed in high or low MD biochamber tissues maintained for different durations, although radiographic density increased over time. Conclusion High MD biochamber tissues had measurable histologic changes after postpartum involution or lactation. Alterations in radiographic density occurred in biochamber tissues between different peripartum states and over time. These findings demonstrate the dynamic nature of the human MD xenograft model, providing a platform for studying the biomolecular basis of MD-associated cancer risk.

Adsorption mechanism of physiologically active L-phenylalanine phosphonodipeptide analogues: Comparison of colloidal silver and macroscopic silver substrates

NASA Astrophysics Data System (ADS)

Podstawka, E.; Kudelski, A.; Proniewicz, L. M.

2007-11-01

Here we present SERS spectra of several L-phenylalanine (Phe) phosphonodipeptides, i.e., L-Phe- L-Ala-PO 3H 2 ( MD1), L-Phe- L-Va L-PO 3H 2 ( MD2), L-Phe-β-Ala-CH(OH)-PO 3H 2 ( MD3), L-Phe- L-Ala-CH(OH)-PO 3H 2 ( MD4), L-Ala-(3,4-dimethoxy)- L-Phe-PO 3H 2 ( MD5), and L-Ala-(3,4-dimethoxy)-(des-CH 2)- L-Phe-PO 3H 2 ( MD6), immobilized on electrochemically roughened silver electrodes. These spectra are analyzed by theoretical calculations using density functional theory (DFT) at the B3LYP level with 6-31++G∗∗ basis set. In addition, these spectra are compared with SERS spectra of these species adsorbed on a colloidal silver surface. We showed that on the macroscopic silver substrate, the Phe aromatic ring of MD3 and MD4 is oriented vertically, while for MD1 it almost "stands up" on this surface. In the other three cases, the Phe ring adopts a tilted orientation in regard to the substrate. We also find that the phosphonate (-PO32-), methyl/methane, or dimethoxy groups of MD1, MD2, MD3, MD5, and MD6 are involved in the interaction of these phosphonodipeptides with the electrochemically roughened surface. This phenomenon is clearly seen for -CH 2-/-CH 3/-OCH 3 moieties as well as for the PO32- group that adsorbs on the macroscopic silver substrates mainly via the P dbnd O fragment. We also showed that MD4 binds to the macroscopic silver substrate through the hydroxyl, amine, and phosphonate groups, while the methylene/methane moieties are remote from this surface. We found that studied phosphonodipeptides often adsorb differently on the macroscopic silver substrate and on the colloidal silver nanoparticles. For example, MD1 adopts an almost vertical orientation on the electrochemically roughened silver substrate and is tilted or close to flat on the silver nanoparticles.

75 FR 31835 - Environmental Impact Statement: Calvert and St. Mary's Counties, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-04

...: Calvert and St. Mary's Counties, MD AGENCY: Federal Highway Administration (FHWA), DOT. ACTION: Notice of... project in Calvert and St. Mary's Counties, Maryland (Federal Register Vol. 72, No. 203; FR Doc. 07-5190... replacement of MD 4 from MD 2 to MD 235 in Calvert and St. Mary's Counties, a distance of approximately 4.1...

Evaluation and Management of Patients with Inhalation Injury

DTIC Science & Technology

1990-12-01

PRUITT, Jr., M.D., WILLIAM G. CIOFFI, M.D., TAKESHI SHIMAZU, M.D. HISASHI IKEUCHI, M.D., AND ARTHUR D. MASON, Jr., M.D. D T CO ELECTE" Inhalation...215, 1988. Do you think that there is some common pathway here 22. Kimura , R., Traber, L., Herndon, D., et al: Ibuprofen reduces the where there is

Registration of cotton germplasm line md 10-5

USDA-ARS?s Scientific Manuscript database

MD 10-5 (Reg. No. ______, PI 675077) is a noncommercial breeding line of cotton (Gossypium hirsutum L.) released by the USDA-ARS at Stoneville, MS in 2015. MD 10-5 was selected in F4 progenies from a cross between MD 15 (PI 642769) and JJ 1145ne. MD 10-5 has a desirable combination between lint yi...

Parallel cascade selection molecular dynamics for efficient conformational sampling and free energy calculation of proteins

NASA Astrophysics Data System (ADS)

Kitao, Akio; Harada, Ryuhei; Nishihara, Yasutaka; Tran, Duy Phuoc

2016-12-01

Parallel Cascade Selection Molecular Dynamics (PaCS-MD) was proposed as an efficient conformational sampling method to investigate conformational transition pathway of proteins. In PaCS-MD, cycles of (i) selection of initial structures for multiple independent MD simulations and (ii) conformational sampling by independent MD simulations are repeated until the convergence of the sampling. The selection is conducted so that protein conformation gradually approaches a target. The selection of snapshots is a key to enhance conformational changes by increasing the probability of rare event occurrence. Since the procedure of PaCS-MD is simple, no modification of MD programs is required; the selections of initial structures and the restart of the next cycle in the MD simulations can be handled with relatively simple scripts with straightforward implementation. Trajectories generated by PaCS-MD were further analyzed by the Markov state model (MSM), which enables calculation of free energy landscape. The combination of PaCS-MD and MSM is reported in this work.

ProtoMD: A prototyping toolkit for multiscale molecular dynamics

NASA Astrophysics Data System (ADS)

Somogyi, Endre; Mansour, Andrew Abi; Ortoleva, Peter J.

2016-05-01

ProtoMD is a toolkit that facilitates the development of algorithms for multiscale molecular dynamics (MD) simulations. It is designed for multiscale methods which capture the dynamic transfer of information across multiple spatial scales, such as the atomic to the mesoscopic scale, via coevolving microscopic and coarse-grained (CG) variables. ProtoMD can be also be used to calibrate parameters needed in traditional CG-MD methods. The toolkit integrates 'GROMACS wrapper' to initiate MD simulations, and 'MDAnalysis' to analyze and manipulate trajectory files. It facilitates experimentation with a spectrum of coarse-grained variables, prototyping rare events (such as chemical reactions), or simulating nanocharacterization experiments such as terahertz spectroscopy, AFM, nanopore, and time-of-flight mass spectroscopy. ProtoMD is written in python and is freely available under the GNU General Public License from github.com/CTCNano/proto_md.

The medial dorsal thalamic nucleus and the medial prefrontal cortex of the rat function together to support associative recognition and recency but not item recognition.

PubMed

Cross, Laura; Brown, Malcolm W; Aggleton, John P; Warburton, E Clea

2012-12-21

In humans recognition memory deficits, a typical feature of diencephalic amnesia, have been tentatively linked to mediodorsal thalamic nucleus (MD) damage. Animal studies have occasionally investigated the role of the MD in single-item recognition, but have not systematically analyzed its involvement in other recognition memory processes. In Experiment 1 rats with bilateral excitotoxic lesions in the MD or the medial prefrontal cortex (mPFC) were tested in tasks that assessed single-item recognition (novel object preference), associative recognition memory (object-in-place), and recency discrimination (recency memory task). Experiment 2 examined the functional importance of the interactions between the MD and mPFC using disconnection techniques. Unilateral excitotoxic lesions were placed in both the MD and the mPFC in either the same (MD + mPFC Ipsi) or opposite hemispheres (MD + mPFC Contra group). Bilateral lesions in the MD or mPFC impaired object-in-place and recency memory tasks, but had no effect on novel object preference. In Experiment 2 the MD + mPFC Contra group was significantly impaired in the object-in-place and recency memory tasks compared with the MD + mPFC Ipsi group, but novel object preference was intact. Thus, connections between the MD and mPFC are critical for recognition memory when the discriminations involve associative or recency information. However, the rodent MD is not necessary for single-item recognition memory.

Physician self-disclosure in primary care visits: enough about you, what about me?

PubMed

McDaniel, Susan H; Beckman, Howard B; Morse, Diane S; Silberman, Jordan; Seaburn, David B; Epstein, Ronald M

2007-06-25

The value of physician self-disclosure (MD-SD) in creating successful patient-physician partnerships has not been demonstrated. To describe antecedents, delivery, and effects of MD-SD in primary care visits, we conducted a descriptive study using sequence analysis of transcripts of 113 unannounced, undetected, standardized patient visits to primary care physicians. Our main outcome measures were the number of MD-SDs per visit; number of visits with MD-SDs; word count; antecedents, timing, and effect of MD-SD on subsequent physician and patient communication; content and focus of MD-SD. The MD-SDs included discussion of personal emotions and experiences, families and/or relationships, professional descriptions, and personal experiences with the patient's diagnosis. Seventy-three MD-SDs were identified in 38 (34%) of 113 visits. Ten MD-SDs (14%) were a response to a patient question. Forty-four (60%) followed patient symptoms, family, or feelings; 29 (40%) were unrelated. Only 29 encounters (21%) returned to the patient topic preceding the disclosure. Most MD-SDs (n=62; 85%) were not considered useful to the patient by the research team. Eight MD-SDs (11%) were coded as disruptive. Practicing primary care physicians disclosed information about themselves or their families in 34% of new visits with unannounced, undetected, standardized patients. There was no evidence of positive effect of MD-SDs; some appeared disruptive. Primary care physicians should consider when self-disclosing whether other behaviors such as empathy might accomplish their goals more effectively.

Morgellons disease, illuminating an undefined illness: a case series.

PubMed

Harvey, William T; Bransfield, Robert C; Mercer, Dana E; Wright, Andrew J; Ricchi, Rebecca M; Leitao, Mary M

2009-07-01

This review of 25 consecutive patients with Morgellons disease (MD) was undertaken for two primary and extremely fundamental reasons. For semantic accuracy, there is only one "proven" MD patient: the child first given that label. The remainder of inclusive individuals adopted the label based on related descriptions from 1544 through 1884, an internet description quoted from Sir Thomas Browne (1674), or was given the label by practitioners using similar sources. Until now, there has been no formal characterization of MD from detailed examination of all body systems. Our second purpose was to differentiate MD from Delusions of Parasitosis (DP), another "informal" label that fit most of our MD patients. How we defined and how we treated these patients depended literally on factual data that would determine outcome. How they were labeled in one sense was irrelevant, except for the confusing conflict rampant in the medical community, possibly significantly skewing treatment outcomes. Clinical information was collected from 25 of 30 consecutive self-defined patients with Morgellons disease consisting of laboratory data, medical history and physical examination findings. Abnormalities were quantified and grouped by system, then compared and summarized, but the numbers were too small for more complex mathematical analysis. The quantification of physical and laboratory abnormalities allowed at least the creation of a practical clinical boundary, separating probable Morgellons from non-Morgellons patients. All the 25 patients studied meet the most commonly used DP definitions. These data suggest Morgellons disease can be characterized as a physical human illness with an often-related delusional component in adults. All medical histories support that behavioral aberrancies onset only after physical symptoms. The identified abnormalities include both immune deficiency and chronic inflammatory markers that correlate strongly with immune cytokine excess. The review of 251 current NLM DP references leads us to the possibility that Morgellons disease and DP are grossly truncated labels of the same illness but with the reversal of the cause-effect order. Further, the patients' data suggest that both illnesses have an infectious origin.

Apolipoprotein M T-778C polymorphism is associated with serum lipid levels and the risk of coronary artery disease in the Chinese population: a meta-analysis.

PubMed

Zhang, Zhi; Chu, Guang; Yin, Rui-Xing

2013-09-16

The apolipoprotein M (APOM) T-778C gene polymorphism has been associated with serum lipid levels and the risk of coronary artery disease (CAD), but the results are inconclusive. The purpose of this meta-analysis was to detect the association between the APOM T-778C polymorphism and serum lipid levels and the risk of CAD in the Chinese population. Databases of MEDLINE, EMBASE, the Cochrane Library and CNKI were systematically searched. Data were extracted using standardized methods. The association was assessed by mean difference (MD) with 95% confidence intervals (CI) or odds ratio (OR) with 95% CI. Ten studies with 4,413 patients were included in this meta-analysis. Pooled effects indicated that CT+CC group had higher levels of total cholesterol (TC) (MD:-0.36, 95% CI: -0.53 - -0.19, P < 0.0001) and low-density lipoprotein cholesterol (LDL-C) (MD: -0.08, 95% CI: -0.16 - -0.01, P = 0.03) than TT group. There was no difference in the levels of triglyceride (MD: 0.06, 95% CI: -0.04 - 0.15, P = 0.22) and high-density lipoprotein cholesterol (MD: 0.00, 95% CI: -0.03-0.03, P = 0.93) between TT and CT+CC groups. Pooled effects showed that CAD group had higher CT+CC genotype frequency than control group (OR: 1.97, 95% CI: 1.62-2.39, P < 0.00001; heterogeneity test x(2) = 2.96, P = 0.71, I(2) = 0%). The results of the current meta-analysis show that the CT+CC group has higher levels of TC and LDL-C than the TT group. Moreover, there is also a prominent association between APOM T-778C polymorphism and the risk of CAD in the Chinese population, the CT+CC genotype is associated with increased risk of CAD.

The Mediterranean diet improves hepatic steatosis and insulin sensitivity in individuals with non-alcoholic fatty liver disease.

PubMed

Ryan, Marno C; Itsiopoulos, Catherine; Thodis, Tania; Ward, Glenn; Trost, Nicholas; Hofferberth, Sophie; O'Dea, Kerin; Desmond, Paul V; Johnson, Nathan A; Wilson, Andrew M

2013-07-01

Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, cross-over 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic-euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance (1)H spectroscopy ((1)H-MRS). At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M=2.7 ± 1.0 mg/kg/min(-1)). Mean weight loss was not different between the two diets (p=0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/HCD: 39 ± 4% versus 7 ± 3%, as measured by (1)H-MRS (p=0.012). Insulin sensitivity improved with the MD, whereas after the LF/HCD there was no change (p=0.03 between diets). Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The effect of resistance training on clinical outcomes in heart failure: A systematic review and meta-analysis.

PubMed

Jewiss, D; Ostman, C; Smart, N A

2016-10-15

To quantify the change in effect sizes, for selected clinical outcome measures, in people with heart failure, from resistance exercise, either in isolation, or in combination with aerobic training. Most exercise training data in heart failure, relates to aerobic exercise, we sought to provide current evidence for the benefits of resistance training in this population. We conducted a MEDLINE search (1985 to May 1, 2016), for exercise based rehabilitation trials in heart failure, using search terms 'resistance training, combined training, left ventricular dysfunction, peak VO2, cardio-myopathy and systolic heart dysfunction'. The 27 included studies provided a total of 2321 participants, 1172 in an intervention and 1149 in either sedentary controls or aerobic exercise only groups, producing over 31,263 patient-hours of training. Mortality, hospitalization, resting blood pressure and Left ventricular fraction were all unchanged with resistance or combined aerobic and resistance training. Peak VO2 was improved in combined exercise vs. control MD of 1.43ml·kg(-1)·min(-1) (95% CI 0.63, 2.23, p=0.0004; and in resistance vs. control MD 3.99ml·kg(-1)·min(-1) (95% CI 1.47, 6.51, p=0.002). Quality of Life (MLwHFQ) was improved in combined vs. control MD -8.31 (95% CI -14.3, -2.33, p=0.006). Six-minute walk distance was improved combined exercise vs. control, MD 13.49m (95% CI 1.13, 25.84, p=0.03); and resistance vs. control MD 41.77m (95% CI 21.90, 61.64, p<0.0001): SMD 1.25 (95%CI 0.53, 1.98, p=0.0007). Resistance only or combined training improves peak VO2, quality of life and walking performance in heart failure patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

PubMed

Gupta, Arpana; Woodworth, Davis C; Ellingson, Benjamin M; Rapkin, Andrea J; Naliboff, Bruce; Kilpatrick, Lisa A; Stains, Jean; Masghati, Salome; Tillisch, Kirsten; Mayer, Emeran A; Labus, Jennifer S

2018-05-01

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

PubMed

Wiseman, S J; Bastin, M E; Hamilton, I F; Hunt, D; Ritchie, S J; Amft, E N; Thomson, S; Belch, J F F; Ralston, S H; Wardlaw, J M

2017-05-01

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

Measured and simulated electron thermal transport in the Madisom symmetric torus reversed field pinch

NASA Astrophysics Data System (ADS)

Rodrigue Mbombo, Brice

New high time resolution measurements of the evolution of the electron temperature profile through a sawtooth event in high current reversed-field pinch (RFP) discharges in the Madison Symmetric Torus (MST) have been made using the enhanced capabilities of the multipoint, multi-pulse Thomson scattering system. Using this and other data, the electron thermal diffusion chie determined and is found to vary by orders of magnitude over the course of the sawtooth cycle. This experimental data is compared directly to simulations run at experimentally relevant parameters. This includes zero beta, single fluid, nonlinear, resistive magnetohydrodynamic (MHD) simulations run with the aspect ratio, resistivity profile, and Lundquist number (S ˜ 4 x 106) of high current RFP discharges in MST. These simulations display MHD activity and sawtooth like behavior similar to that observed in the MST. This includes both the sawtooth period and the duration of the sawtooth crash. The radial shape of the magnetic mode amplitudes, scaled to match edge measurements made in MST, are then used to compute the expected level of thermal diffusion due to parallel losses along diffusing magnetic field lines, chiMD = upsilon∥Dmag. The evolution of the Dmag profile was determined for over 20 sawteeth so that the ensemble averaged evolution could be compared to the sawtooth ensembled data from MST. The resulting comparison to the measured chi e shows that chiMD is larger than chi e at most times. However, if electrons are trapped in a magnetic well, they cannot carry energy along the diffusing magnetic field lines, reducing the thermal transport. Accounting for trapped particles brings chi MD to within uncertainty of chie in the mid radius at most times throughout the sawtooth cycle. In the core, the measured chie is greater than chi MD leading up to and including the sawtooth crash, suggesting other transport mechanisms are important at these times. Additionally, in a simulation including pressure evolution, a striking agreement is found between the temperature fluctuations seen in the simulation and those previously measured in MST. This work supported by the US DOE and NSF.

Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations.

PubMed

Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

2015-07-01

β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 Å and 1.6 Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become a lead compound. Copyright © 2015 Elsevier Inc. All rights reserved.

The relationship between better-eye and integrated visual field mean deviation and visual disability.

PubMed

Arora, Karun S; Boland, Michael V; Friedman, David S; Jefferys, Joan L; West, Sheila K; Ramulu, Pradeep Y

2013-12-01

To determine the extent of difference between better-eye visual field (VF) mean deviation (MD) and integrated VF (IVF) MD among Salisbury Eye Evaluation (SEE) subjects and a larger group of glaucoma clinic subjects and to assess how those measures relate to objective and subjective measures of ability/performance in SEE subjects. Retrospective analysis of population- and clinic-based samples of adults. A total of 490 SEE and 7053 glaucoma clinic subjects with VF loss (MD ≤-3 decibels [dB] in at least 1 eye). Visual field testing was performed in each eye, and IVF MD was calculated. Differences between better-eye and IVF MD were calculated for SEE and clinic-based subjects. In SEE subjects with VF loss, models were constructed to compare the relative impact of better-eye and IVF MD on driving habits, mobility, self-reported vision-related function, and reading speed. Difference between better-eye and IVF MD and relationship of better-eye and IVF MD with performance measures. The median difference between better-eye and IVF MD was 0.41 dB (interquartile range [IQR], -0.21 to 1.04 dB) and 0.72 dB (IQR, 0.04-1.45 dB) for SEE subjects and clinic-based patients with glaucoma, respectively, with differences of ≥ 2 dB between the 2 MDs observed in 9% and 18% of the groups, respectively. Among SEE subjects with VF loss, both MDs demonstrated similar associations with multiple ability and performance metrics as judged by the presence/absence of a statistically significant association between the MD and the metric, the magnitude of observed associations (odds ratios, rate ratios, or regression coefficients associated with 5-dB decrements in MD), and the extent of variability in the metric explained by the model (R(2)). Similar associations of similar magnitude also were noted for the subgroup of subjects with glaucoma and subjects in whom better-eye and IVF MD differed by ≥ 2 dB. The IVF MD rarely differs from better-eye MD, and similar associations between VF loss and visual disability are obtained using either MD. Unlike better-eye MD, IVF measurements require extra software/calculation. As such, information from studies using better-eye MD can be more easily integrated into clinical decision-making, making better-eye MD a robust and meaningful method for reporting VF loss severity. Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Free Energy Calculation.

PubMed

Huang, Yu-Ming M; McCammon, J Andrew; Miao, Yinglong

2018-04-10

Through adding a harmonic boost potential to smooth the system potential energy surface, Gaussian accelerated molecular dynamics (GaMD) provides enhanced sampling and free energy calculation of biomolecules without the need of predefined reaction coordinates. This work continues to improve the acceleration power and energy reweighting of the GaMD by combining the GaMD with replica exchange algorithms. Two versions of replica exchange GaMD (rex-GaMD) are presented: force constant rex-GaMD and threshold energy rex-GaMD. During simulations of force constant rex-GaMD, the boost potential can be exchanged between replicas of different harmonic force constants with fixed threshold energy. However, the algorithm of threshold energy rex-GaMD tends to switch the threshold energy between lower and upper bounds for generating different levels of boost potential. Testing simulations on three model systems, including the alanine dipeptide, chignolin, and HIV protease, demonstrate that through continuous exchanges of the boost potential, the rex-GaMD simulations not only enhance the conformational transitions of the systems but also narrow down the distribution width of the applied boost potential for accurate energetic reweighting to recover biomolecular free energy profiles.

A CIPK protein kinase targets sucrose transporter MdSUT2.2 at Ser254 for phosphorylation to enhance salt tolerance.

PubMed

Ma, Qi-Jun; Sun, Mei-Hong; Kang, Hui; Lu, Jing; You, Chun-Xiang; Hao, Yu-Jin

2018-05-23

Soil salinity is one of the major abiotic stressors that negatively affect crop growth and yield. Salt stress can regulate antioxidants and the accumulation of osmoprotectants. In the study, a sucrose transporter MdSUT2.2 was identified in apple. Overexpression of MdSUT2.2 gene increased salt tolerance in the transgenic apple, compared with the WT control 'Gala'. In addition, it was found that protein MdSUT2.2 was phosphorylated at Ser 254 site in response to salt. A DUAL membrane yeast hybridization system through an apple cDNA library demonstrated that a protein kinase MdCIPK13 interacted with MdSUT2.2. A series of transgenic analysis in apple calli showed that MdCIPK13 was required for the salt-induced phosphorylation of MdSUT2.2 protein and enhanced its stability and transport activity. Finally, it was found that MdCIPK13 improved salt resistance in an MdSUT2.2-dependent manner. These findings had enriched our understanding of the molecular mechanisms underlying abiotic stress. This article is protected by copyright. All rights reserved.

Rapid exploration of configuration space with diffusion-map-directed molecular dynamics.

PubMed

Zheng, Wenwei; Rohrdanz, Mary A; Clementi, Cecilia

2013-10-24

The gap between the time scale of interesting behavior in macromolecular systems and that which our computational resources can afford often limits molecular dynamics (MD) from understanding experimental results and predicting what is inaccessible in experiments. In this paper, we introduce a new sampling scheme, named diffusion-map-directed MD (DM-d-MD), to rapidly explore molecular configuration space. The method uses a diffusion map to guide MD on the fly. DM-d-MD can be combined with other methods to reconstruct the equilibrium free energy, and here, we used umbrella sampling as an example. We present results from two systems: alanine dipeptide and alanine-12. In both systems, we gain tremendous speedup with respect to standard MD both in exploring the configuration space and reconstructing the equilibrium distribution. In particular, we obtain 3 orders of magnitude of speedup over standard MD in the exploration of the configurational space of alanine-12 at 300 K with DM-d-MD. The method is reaction coordinate free and minimally dependent on a priori knowledge of the system. We expect wide applications of DM-d-MD to other macromolecular systems in which equilibrium sampling is not affordable by standard MD.

Rapid Exploration of Configuration Space with Diffusion Map-directed-Molecular Dynamics

PubMed Central

Zheng, Wenwei; Rohrdanz, Mary A.; Clementi, Cecilia

2013-01-01

The gap between the timescale of interesting behavior in macromolecular systems and that which our computational resources can afford oftentimes limits Molecular Dynamics (MD) from understanding experimental results and predicting what is inaccessible in experiments. In this paper, we introduce a new sampling scheme, named Diffusion Map-directed-MD (DM-d-MD), to rapidly explore molecular configuration space. The method uses diffusion map to guide MD on the fly. DM-d-MD can be combined with other methods to reconstruct the equilibrium free energy, and here we used umbrella sampling as an example. We present results from two systems: alanine dipeptide and alanine-12. In both systems we gain tremendous speedup with respect to standard MD both in exploring the configuration space and reconstructing the equilibrium distribution. In particular, we obtain 3 orders of magnitude of speedup over standard MD in the exploration of the configurational space of alanine-12 at 300K with DM-d-MD. The method is reaction coordinate free and minimally dependent on a priori knowledge of the system. We expect wide applications of DM-d-MD to other macromolecular systems in which equilibrium sampling is not affordable by standard MD. PMID:23865517

Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice.

PubMed

Morovat, Alireza; Weerasinghe, Gayani; Nesbitt, Victoria; Hofer, Monika; Agnew, Thomas; Quaghebeur, Geralrine; Sergeant, Kate; Fratter, Carl; Guha, Nishan; Mirzazadeh, Mehdi; Poulton, Joanna

2017-08-21

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients' FGF-21 results were assessed by the use of age-adjusted z -scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance ( n = 32) and mtDNA rearrangements ( n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations ( n = 40) or mutations in other autosomal genes ( n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z -score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway.

Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice

PubMed Central

Weerasinghe, Gayani; Nesbitt, Victoria; Hofer, Monika; Agnew, Thomas; Quaghebeur, Geralrine; Sergeant, Kate; Guha, Nishan; Mirzazadeh, Mehdi; Poulton, Joanna

2017-01-01

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway. PMID:28825656

Molecular cloning and functional analysis of a blue light receptor gene MdCRY2 from apple (Malus domestica).

PubMed

Li, Yuan-Yuan; Mao, Ke; Zhao, Cheng; Zhao, Xian-Yan; Zhang, Rui-Fen; Zhang, Hua-Lei; Shu, Huai-Rui; Hao, Yu-Jin

2013-04-01

MdCRY2 was isolated from apple fruit skin, and its function was analyzed in MdCRY2 transgenic Arabidopsis. The interaction between MdCRY2 and AtCOP1 was found by yeast two-hybrid and BiFC assays. Cryptochromes are blue/ultraviolet-A (UV-A) light receptors involved in regulating various aspects of plant growth and development. Investigations of the structure and functions of cryptochromes in plants have largely focused on Arabidopsis (Arabidopsis thaliana), tomato (Solanum lycopersicum), pea (Pisum sativum), and rice (Oryza sativa). However, no data on the function of CRY2 are available in woody plants. In this study, we isolated a cryptochrome gene, MdCRY2, from apple (Malus domestica). The deduced amino acid sequences of MdCRY2 contain the conserved N-terminal photolyase-related domain and the flavin adenine dinucleotide (FAD) binding domain, as well as the C-terminal DQXVP-acidic-STAES (DAS) domain. Relationship analysis indicates that MdCRY2 shows the highest similarity to the strawberry FvCRY protein. The expression of MdCRY2 is induced by blue/UV-A light, which represents a 48-h circadian rhythm. To investigate the function of MdCRY2, we overexpressed the MdCRY2 gene in a cry2 mutant and wild type (WT) Arabidopsis, assessed the phenotypes of the resulting transgenic plants, and found that MdCRY2 functions to regulate hypocotyl elongation, root growth, flower initiation, and anthocyanin accumulation. Furthermore, we examined the interaction between MdCRY2 and AtCOP1 using a yeast two-hybrid assay and a bimolecular fluorescence complementation assay. These data provide functional evidence for a role of blue/UV-A light-induced MdCRY2 in controlling photomorphogenesis in apple.

Gaussian Accelerated Molecular Dynamics in NAMD

PubMed Central

2016-01-01

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for “unconstrained” enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules. PMID:28034310

Null Mutation of the MdACS3 Gene, Coding for a Ripening-Specific 1-Aminocyclopropane-1-Carboxylate Synthase, Leads to Long Shelf Life in Apple Fruit1[W][OA

PubMed Central

Wang, Aide; Yamakake, Junko; Kudo, Hisayuki; Wakasa, Yuhya; Hatsuyama, Yoshimichi; Igarashi, Megumi; Kasai, Atsushi; Li, Tianzhong; Harada, Takeo

2009-01-01

Expression of MdACS1, coding for 1-aminocyclopropane-1-carboxylate synthase (ACS), parallels the level of ethylene production in ripening apple (Malus domestica) fruit. Here we show that expression of another ripening-specific ACS gene (MdACS3) precedes the initiation of MdACS1 expression by approximately 3 weeks; MdACS3 expression then gradually decreases as MdACS1 expression increases. Because MdACS3 expression continues in ripening fruit treated with 1-methylcyclopropene, its transcription appears to be regulated by a negative feedback mechanism. Three genes in the MdACS3 family (a, b, and c) were isolated from a genomic library, but two of them (MdACS3b and MdACS3c) possess a 333-bp transposon-like insertion in their 5′ flanking region that may prevent transcription of these genes during ripening. A single nucleotide polymorphism in the coding region of MdACS3a results in an amino acid substitution (glycine-289 → valine) in the active site that inactivates the enzyme. Furthermore, another null allele of MdACS3a, Mdacs3a, showing no ability to be transcribed, was found by DNA sequencing. Apple cultivars homozygous or heterozygous for both null allelotypes showed no or very low expression of ripening-related genes and maintained fruit firmness. These results suggest that MdACS3a plays a crucial role in regulation of fruit ripening in apple, and is a possible determinant of ethylene production and shelf life in apple fruit. PMID:19587104

Trends in MD/PhD Graduates Entering Psychiatry: Assessing the Physician-Scientist Pipeline.

PubMed

Arbuckle, Melissa R; Luo, Sean X; Pincus, Harold Alan; Gordon, Joshua A; Chung, Joyce Y; Chavez, Mark; Oquendo, Maria A

2018-06-01

The goal of this study was to identify trends in MD/PhD graduates entering psychiatry, to compare these trends with other specialties, and to review strategies for enhancing the physician-scientist pipeline. Data on 226,588 medical students graduating from Liaison Committee on Medical Education accredited programs between 1999 and 2012 (6626 MD/PhDs) were used to evaluate the number, percentage, and proportion of MD/PhDs entering psychiatry in comparison with other specialties (neurology, neurosurgery, internal medicine, family medicine, and radiation oncology). Linear regression and multiple linear regression determined whether these values increased over time and varied by sex. Over 14 years, an average of 18 MD/PhDs (range 13-29) enrolled in psychiatry each year. The number of MD/PhDs going into psychiatry significantly increased, although these gains were modest (less than one additional MD/PhD per year). The proportion of students entering psychiatry who were MD/PhDs varied between 2.9 and 5.9 per 100 residents, with no significant change over time. There was also no change in the percentage of MD/PhDs entering psychiatry from among all MD/PhD graduates. The rate of increase in the number of MD/PhDs going into psychiatry did not differ significantly from other specialties except for family medicine, which is decreasing. The rate of MD/PhDs going into psychiatry was higher for women, suggesting closure of the sex gap in 17 years. Despite the increase in the number of MD/PhDs entering psychiatry, these numbers remain low. Expanding the cohort of physician-scientists dedicated to translational research in psychiatry will require a multipronged approach.

Analysis of the MdMYB1 gene sequence and development of new molecular markers related to apple skin color and fruit-bearing traits.

PubMed

Yuan, Kejun; Wang, Changjun; Wang, Jianghui; Xin, Li; Zhou, Guangfang; Li, Linguang; Shen, Guangning

2014-12-01

MdMYB1, a key transcription factor determining apple skin color, coordinately regulates genes in the anthocyanin pathway. In this study, we analyzed the MdMYB1 gene and its relationship to apple skin color and fruit-bearing traits to better understand this gene and its application to apple breeding. A previously reported MdMYB1 dCAPS marker failed to identify alleles of the MdMYB1 gene in 'Fuji', a very important apple cultivar. In this study, we revealed that the polymorphic site related to the MdMYB1 dCAPS marker is heterozygous in 'Fuji'. In addition, two new polymorphic sites related to apple skin color were identified in the MdMYB1 gene, with two new molecular markers accordingly developed. Testing of these markers in 'Fuji' and its progeny revealed that they could predict apple skin color and identify alleles of the MdMYB1 gene in this cultivar. Most interestingly, the allele MdMYB1-2 in 'Gala' apple and its hybrid plants was found to be related to the fruit-bearing trait, and the molecular marker Mb2 was able to identify the MdMYB1-2 allele. Our study is apparently the first to report a relationship between the MdMYB1 allele and the fruit-bearing trait in apple. More work is needed to determine whether and how the MdMYB1 gene or a gene linked to the MdMYB1-2 allele influences the flowering trait in perennial apple trees, and whether flowering in other plants is influenced by related genes.

Gaussian Accelerated Molecular Dynamics in NAMD.

PubMed

Pang, Yui Tik; Miao, Yinglong; Wang, Yi; McCammon, J Andrew

2017-01-10

Gaussian accelerated molecular dynamics (GaMD) is a recently developed enhanced sampling technique that provides efficient free energy calculations of biomolecules. Like the previous accelerated molecular dynamics (aMD), GaMD allows for "unconstrained" enhanced sampling without the need to set predefined collective variables and so is useful for studying complex biomolecular conformational changes such as protein folding and ligand binding. Furthermore, because the boost potential is constructed using a harmonic function that follows Gaussian distribution in GaMD, cumulant expansion to the second order can be applied to recover the original free energy profiles of proteins and other large biomolecules, which solves a long-standing energetic reweighting problem of the previous aMD method. Taken together, GaMD offers major advantages for both unconstrained enhanced sampling and free energy calculations of large biomolecules. Here, we have implemented GaMD in the NAMD package on top of the existing aMD feature and validated it on three model systems: alanine dipeptide, the chignolin fast-folding protein, and the M 3 muscarinic G protein-coupled receptor (GPCR). For alanine dipeptide, while conventional molecular dynamics (cMD) simulations performed for 30 ns are poorly converged, GaMD simulations of the same length yield free energy profiles that agree quantitatively with those of 1000 ns cMD simulation. Further GaMD simulations have captured folding of the chignolin and binding of the acetylcholine (ACh) endogenous agonist to the M 3 muscarinic receptor. The reweighted free energy profiles are used to characterize the protein folding and ligand binding pathways quantitatively. GaMD implemented in the scalable NAMD is widely applicable to enhanced sampling and free energy calculations of large biomolecules.

Quantitative Assessment of Molecular Dynamics Sampling for Flexible Systems.

PubMed

Nemec, Mike; Hoffmann, Daniel

2017-02-14

Molecular dynamics (MD) simulation is a natural method for the study of flexible molecules but at the same time is limited by the large size of the conformational space of these molecules. We ask by how much the MD sampling quality for flexible molecules can be improved by two means: the use of diverse sets of trajectories starting from different initial conformations to detect deviations between samples and sampling with enhanced methods such as accelerated MD (aMD) or scaled MD (sMD) that distort the energy landscape in controlled ways. To this end, we test the effects of these approaches on MD simulations of two flexible biomolecules in aqueous solution, Met-Enkephalin (5 amino acids) and HIV-1 gp120 V3 (a cycle of 35 amino acids). We assess the convergence of the sampling quantitatively with known, extensive measures of cluster number N c and cluster distribution entropy S c and with two new quantities, conformational overlap O conf and density overlap O dens , both conveniently ranging from 0 to 1. These new overlap measures quantify self-consistency of sampling in multitrajectory MD experiments, a necessary condition for converged sampling. A comprehensive assessment of sampling quality of MD experiments identifies the combination of diverse trajectory sets and aMD as the most efficient approach among those tested. However, analysis of O dens between conventional and aMD trajectories also reveals that we have not completely corrected aMD sampling for the distorted energy landscape. Moreover, for V3, the courses of N c and O dens indicate that much higher resources than those generally invested today will probably be needed to achieve convergence. The comparative analysis also shows that conventional MD simulations with insufficient sampling can be easily misinterpreted as being converged.

Expression of MdCAS1 and MdCAS2, encoding apple beta-cyanoalanine synthase homologs, is concomitantly induced during ripening and implicates MdCASs in the possible role of the cyanide detoxification in Fuji apple (Malus domestica Borkh.) fruits.

PubMed

Han, Sang Eun; Seo, Young Sam; Kim, Daeil; Sung, Soon-Kee; Kim, Woo Taek

2007-08-01

Fruit ripening involves complex biochemical and physiological changes. Ethylene is an essential hormone for the ripening of climacteric fruits. In the process of ethylene biosynthesis, cyanide (HCN), an extremely toxic compound, is produced as a co-product. Thus, most cyanide produced during fruit ripening should be detoxified rapidly by fruit cells. In higher plants, the key enzyme involved in the detoxification of HCN is beta-cyanoalanine synthase (beta-CAS). As little is known about the molecular function of beta-CAS genes in climacteric fruits, we identified two homologous genes, MdCAS1 and MdCAS2, encoding Fuji apple beta-CAS homologs. The structural features of the predicted polypeptides as well as an in vitro enzyme activity assay with bacterially expressed recombinant proteins indicated that MdCAS1 and MdCAS2 may indeed function as beta-CAS isozymes in apple fruits. RNA gel-blot studies revealed that both MdCAS1 and MdCAS2 mRNAs were coordinately induced during the ripening process of apple fruits in an expression pattern comparable with that of ACC oxidase and ethylene production. The MdCAS genes were also activated effectively by exogenous ethylene treatment and mechanical wounding. Thus, it seems like that, in ripening apple fruits, expression of MdCAS1 and MdCAS2 genes is intimately correlated with a climacteric ethylene production and ACC oxidase activity. In addition, beta-CAS enzyme activity was also enhanced as the fruit ripened, although this increase was not as dramatic as the mRNA induction pattern. Overall, these results suggest that MdCAS may play a role in cyanide detoxification in ripening apple fruits.

Gerstmann-Straussler-Scheinker Disease

MedlinePlus

... NIA) National Institutes of Health, DHHS 31 Center Drive, Rm. 5C27 MSC 2292 Bethesda MD Bethesda, MD ... NIA) National Institutes of Health, DHHS 31 Center Drive, Rm. 5C27 MSC 2292 Bethesda MD Bethesda, MD ...

Orthopaedic Surgery Residents and Program Directors Agree on How Time Is Currently Spent in Training and Targets for Improvement.

PubMed

Camp, Christopher L; Martin, John R; Karam, Matthew D; Ryssman, Daniel B; Turner, Norman S

2016-04-01

Although much attention has been paid to the role of deliberate practice as a means of achieving expert levels of performance in other medical specialties, little has been published regarding its role in maximizing orthopaedic surgery resident potential. As an initial step in this process, this study seeks to determine how residents and program directors (PDs) feel current time spent in training is allocated compared with a theoretical ideal distribution of time. According to residents and PDs, (1) how do resident responsibilities change by level of training as perceived and idealized by residents and PDs? (2) How do resident and PD perceptions of current and ideal time distributions compare with one another? (3) Do the current training structures described by residents and PDs differ from what they feel represents an ideal time allocation construct that maximizes the educational value of residency training? A survey was sent to orthopaedic surgery resident and PD members of the Midwest Orthopedic Surgical Skills Consortium asking how they felt residents' time spent in training was distributed across 10 domains and four operating room (OR) roles and what they felt would be an ideal distribution of that time. Responses were compared between residents and PDs and between current schedules and ideal schedules. Both residents and PDs agreed that time currently spent in training differs by postgraduate year with senior-level residents spending more time in the OR (33.7% ± 8.3% versus 17.9% ± 6.2% [interns] and 27.4% ± 10.2% [juniors] according to residents, p < 0.001; and 38.6% ± 8.1% versus 11.8% ± 6.4% [interns] and 26.1% ± 5.7% [juniors] according to PD, p < 0.001). The same holds true for their theoretical ideals. Residents and PDs agree on current resident time allocation across the 10 domains; however, they disagree on multiple components of the ideal program with residents desiring more time spent in the OR than what PDs prefer (residents 40.3% ± 10.3% versus PD 32.6% ± 14.6% [mean difference {MD}, 7.7; 95% confidence interval {CI}, 4.4, 11.0], p < 0.001). Residents would also prefer to have more time spent deliberately practicing surgical skills outside of the OR (current 1.8% ± 2.1% versus ideal 3.7% ± 3.2% [MD, -1.9; 95% CI, -.2.4 to -1.4], p < 0.001). Both residents and PDs want residents to spend less time completing paperwork (current 4.4% ± 4.1% versus ideal 0.8% ± 1.6% [MD, 3.6; 95% CI, 3.0-4.2], p < 0.001 for residents; and current 3.6% ± 4.1% versus ideal 1.5% ± 1.9% [MD, 2.1; 95% CI, 0.9-3.3], p < 0.001 for PDs). Residents and PDs seem to agree on how time is currently spent in residency training. Some differences of opinions continue to exist regarding how an ideal program should be structured; however, this work identifies a few potential targets for improvement that are agreed on by both residents and PDs. These areas include increasing OR time, finding opportunities for deliberate practice of surgical skills outside of the OR, and decreased clerical burden. This study may serve as a template to allow programs to continue to refine their educational models in an effort to achieve curricula that meet the desired goals of both learners and educators. Additionally, it is an initial step toward more objective identification of the optimal educational structure of an orthopaedic residency program.

Enhanced recovery after surgery and video-assisted thoracic surgery lobectomy: the Italian VATS Group**List of collaborators of the Italian ERAS Group: Jacopo Vannucci, MD (University of Perugia); Antonio D’Andrilli, MD (S. Andrea Hospital, Roma); Majed Refai, MD (Ospedali Riuniti, Ancona); Guendalina Graffigna, MD (Università Cattolica del Sacro Cuore, Milano); Stefano Lovadina, MD (Ospedali Riuniti, Trieste); Marzia Umari (Ospedali Riuniti, Trieste), Paolo Ferrari, MD (IRCCS ISMETT-UPMC, University of Pittsburgh, Palermo); Michele Zuliani, MD (Ospedali Riuniti, Trieste); Marco Taurchini, MD (Casa Sollievo della Sofferenza, San Giovanni Rotondo); Carlo Del Naja, MD (Casa Sollievo della Sofferenza, San Giovanni Rotondo); Domenico Massullo, MD (S. Andrea Hospital, Roma), Olha Putina, MD (ASST Mantova), Nicoletta Pia Ardò (University of Foggia). surgical protocol

PubMed Central

Viggiano, Domenico; Voltolini, Luca; Bertani, Alessandro; Bertolaccini, Luca; Crisci, Roberto; Droghetti, Andrea

2018-01-01

Enhanced recovery after surgery (ERAS®) is a strategy that seeks to reduce patients’ perioperative stress response, thereby reducing potential complications, decreasing hospital length of stay and enabling patients to return more quickly to their baseline functional status. The concept was introduced in the late 1990s and was first adopted in patients undergoing open colorectal surgery. Since then, the concept of ERAS has been adopted by multiple surgical specialties. The diffusion of video-assisted thoracic surgery lobectomy (VATS-L) sets also the surgical treatment of lung cancer as a new area for ERAS development. In this paper, we present the Italian VATS Group (www.vatsgroup.org) surgical protocol as part of the ERAS clinical pathway belonging to the VATS-L national database. PMID:29629203

Celastrol reverses palmitic acid (PA)-caused TLR4-MD2 activation-dependent insulin resistance via disrupting MD2-related cellular binding to PA.

PubMed

Zhang, Xue; Wang, Ying; Ge, Hui-Ya; Gu, Yi-Jun; Cao, Fan-Fan; Yang, Chun-Xin; Uzan, Georges; Peng, Bin; Zhang, Deng-Hai

2018-04-18

Elevated plasma statured fatty acids (FFAs) cause TLR4/MD2 activation-dependent inflammation and insulin tolerance, which account for the occurrence and development of obesity. It has been confirmed that statured palmitic acid (PA) (the most abundant FFA) could bind MD2 to cause cellular inflammation. The natural compound celastrol could improve obesity, which is suggested via inhibiting inflammation, yet the detailed mechanism for celastrol is still unclear. As celastrol is reported to directly target MD2, we thought disrupting the binding between FFAs and MD2 might be one of the ways for celastrol to inhibit FFAs-caused inflammation and insulin resistance. In this study, we found evidence to support our hypothesis: celastrol could reverse PA-caused TLR4/MD2 activation-dependent insulin resistance, as determined by glucose-lowering ability, cellular glucose uptake, insulin action-related proteins and TLR4/MD2/NF-κB activation. Bioinformatics and cellular experiments showed that both celastrol and PA could bind MD2, and that celastrol could expel PA from cells. Finally, celastrol could reverse high fat diet caused hyperglycemia and obesity, and liver NF-kB activations. Taking together, we proved that celastrol could reverses PA-caused TLR4-MD2 activation-dependent insulin resistance via disrupting PA binding to MD2. © 2018 Wiley Periodicals, Inc.

Collision-Induced Dissociation of Electrosprayed NaCl Clusters: Using Molecular Dynamics Simulations to Visualize Reaction Cascades in the Gas Phase

NASA Astrophysics Data System (ADS)

Schachel, Tilo D.; Metwally, Haidy; Popa, Vlad; Konermann, Lars

2016-11-01

Infusion of NaCl solutions into an electrospray ionization (ESI) source produces [Na( n+1)Cl n ]+ and other gaseous clusters. The n = 4, 13, 22 magic number species have cuboid ground state structures and exhibit elevated abundance in ESI mass spectra. Relatively few details are known regarding the mechanisms whereby these clusters undergo collision-induced dissociation (CID). The current study examines to what extent molecular dynamics (MD) simulations can be used to garner insights into the sequence of events taking place during CID. Experiments on singly charged clusters reveal that the loss of small neutrals is the dominant fragmentation pathway. MD simulations indicate that the clusters undergo extensive structural fluctuations prior to decomposition. Consistent with the experimentally observed behavior, most of the simulated dissociation events culminate in ejection of small neutrals ([NaCl] i , with i = 1, 2, 3). The MD data reveal that the prevalence of these dissociation channels is linked to the presence of short-lived intermediates where a relatively compact core structure carries a small [NaCl] i protrusion. The latter can separate from the parent cluster via cleavage of a single Na-Cl contact. Fragmentation events of this type are kinetically favored over other dissociation channels that would require the quasi-simultaneous rupture of multiple electrostatic contacts. The CID behavior of NaCl cluster ions bears interesting analogies to that of collisionally activated protein complexes. Overall, it appears that MD simulations represent a valuable tool for deciphering the dissociation of noncovalently bound systems in the gas phase.

Traversing the folding pathway of proteins using temperature-aided cascade molecular dynamics with conformation-dependent charges.

PubMed

Jani, Vinod; Sonavane, Uddhavesh; Joshi, Rajendra

2016-07-01

Protein folding is a multi-micro second time scale event and involves many conformational transitions. Crucial conformational transitions responsible for biological functions of biomolecules are difficult to capture using current state-of-the-art molecular dynamics (MD) simulations. Protein folding, being a stochastic process, witnesses these transitions as rare events. Many new methodologies have been proposed for observing these rare events. In this work, a temperature-aided cascade MD is proposed as a technique for studying the conformational transitions. Folding studies for Engrailed homeodomain and Immunoglobulin domain B of protein A have been carried out. Using this methodology, the unfolded structures with RMSD of 20 Å were folded to a structure with RMSD of 2 Å. Three sets of cascade MD runs were carried out using implicit solvation, explicit solvation, and charge updation scheme. In the charge updation scheme, charges based on the conformation obtained are calculated and are updated in the topology file. In all the simulations, the structure of 2 Å was reached within a few nanoseconds using these methods. Umbrella sampling has been performed using snapshots from the temperature-aided cascade MD simulation trajectory to build an entire conformational transition pathway. The advantage of the method is that the possible pathways for a particular reaction can be explored within a short duration of simulation time and the disadvantage is that the knowledge of the start and end state is required. The charge updation scheme adds the polarization effects in the force fields. This improves the electrostatic interaction among the atoms, which may help the protein to fold faster.

Evaluation of an automated knowledge-based textual summarization system for longitudinal clinical data, in the intensive care domain.

PubMed

Goldstein, Ayelet; Shahar, Yuval; Orenbuch, Efrat; Cohen, Matan J

2017-10-01

To examine the feasibility of the automated creation of meaningful free-text summaries of longitudinal clinical records, using a new general methodology that we had recently developed; and to assess the potential benefits to the clinical decision-making process of using such a method to generate draft letters that can be further manually enhanced by clinicians. We had previously developed a system, CliniText (CTXT), for automated summarization in free text of longitudinal medical records, using a clinical knowledge base. In the current study, we created an Intensive Care Unit (ICU) clinical knowledge base, assisted by two ICU clinical experts in an academic tertiary hospital. The CTXT system generated free-text summary letters from the data of 31 different patients, which were compared to the respective original physician-composed discharge letters. The main evaluation measures were (1) relative completeness, quantifying the data items missed by one of the letters but included by the other, and their importance; (2) quality parameters, such as readability; (3) functional performance, assessed by the time needed, by three clinicians reading each of the summaries, to answer five key questions, based on the discharge letter (e.g., "What are the patient's current respiratory requirements?"), and by the correctness of the clinicians' answers. Completeness: In 13/31 (42%) of the letters the number of important items missed in the CTXT-generated letter was actually less than or equal to the number of important items missed by the MD-composed letter. In each of the MD-composed letters, at least two important items that were mentioned by the CTXT system were missed (a mean of 7.2±5.74). In addition, the standard deviation in the number of missed items in the MD letters (STD=15.4) was much higher than the standard deviation in the CTXT-generated letters (STD=5.3). Quality: The MD-composed letters obtained a significantly better grade in three out of four measured parameters. However, the standard variation in the quality of the MD-composed letters was much greater than the standard variation in the quality of the CTXT-generated letters (STD=6.25 vs. STD=2.57, respectively). Functional evaluation: The clinicians answered the five questions on average 40% faster (p<0.001) when using the CTXT-generated letters than when using the MD-composed letters. In four out of the five questions the clinicians' correctness was equal to or significantly better (p<0.005) when using the CTXT-generated letters than when using the MD-composed letters. An automatic knowledge-based summarization system, such as the CTXT system, has the capability to model complex clinical domains, such as the ICU, and to support interpretation and summarization tasks such as the creation of a discharge summary letter. Based on the results, we suggest that the use of such systems could potentially enhance the standardization of the letters, significantly increase their completeness, and reduce the time to write the discharge summary. The results also suggest that using the resultant structured letters might reduce the decision time, and enhance the decision quality, of decisions made by other clinicians. Copyright © 2017 Elsevier B.V. All rights reserved.

77 FR 5201 - Drawbridge Operation Regulation; Bear Creek, Dundalk, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-02

... bridge opening to a 48-hour advance notice requirement for a bridge opening. Due to the lack of openings... this bridge has had fewer than 12 openings every year since 2008. The majority of these openings have... it difficult, logistically, to arrive at the bridge site for an opening within the current four hour...

Out-of-Hospital Combat Casualty Care in the Current War in Iraq

DTIC Science & Technology

2009-02-01

could not be cleared with available suction equipment (3). There were 10 instances of chitosan hemostatic dressing use (3% of wounded in action). A...Eagle: MAJ David Mathias, MD, CPT Tommy Laird, MPAS, EMPA-C, CPT Scott G. Sullivan, MPAS, PA-C, and CPT Anthony Freiler, PA-C. We also express our

New Consultant Joins Occupational Health Services’ Team | Poster

Cancer.gov

One of Occupational Health Services’ (OHS') most valuable resources is new medical consultant Anusha Belani, M.D., chief of epidemiology at Frederick Memorial Hospital (FMH). Belani graduated from the University of Delhi and received her medical degree from Lady Hardinge Medical College in 1979. She is currently the only physician in Frederick County who specializes in

Clinical Investigation Program Annual Progress Report

DTIC Science & Technology

1989-10-01

Investigators: Linda K. Kullama, Ph.D., Dr. Kenneth T. Nakamura,MD; Dr. Venkataraman Balaraman, MD, Wayne M. Ichimura, Biomedical Engineer. Department/Section...Investigators: John R. Claybaugh, Ph.D.; Kenneth T. Nakamura, MD; Dr. Venkataraman Balaraman, M.D. Department/Section: Clinical Investigation/Physiology Key...Pigs and Rats Principal ’Investigator: Linda K. Kullama, Ph.D.; John R. Claybaugh, Ph.D. Associate Investigators: Dr. Venkataraman Balaraman, M.D.; Dr

Clinical Investigation Program, Reports Control Symbol MED-300(R1), Fiscal Year 1988

DTIC Science & Technology

1988-10-01

Dr. Venkataraman Balaraman, M.D. Department/Section: Clinical Investigation Key Words: arginine vasopressin (AVP); vascular smooth muscle responses...Kullama, Ph.D. Associate Investigators: Dr. Venkataraman Balaraman, M.D.; Dr. Kenneth T. Nakamura, M.D.; John R. Claybaugh, Ph.D. Department/Section...Harrison Hassell, MC Associate Investigators: John R. Claybaugh, Ph.D.; Arnold Siemsen, MD; Jon Streltzer, MD Department/Section: Medicine/ Nephrology

33 CFR 334.180 - Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md.

Code of Federal Regulations, 2013 CFR

2013-07-01

.... Naval Mine Warfare Test Station, or of U.S. Naval Air Station property. A person in the water or a... areas, U.S. Naval Air Test Center, Patuxent River, Md. 334.180 Section 334.180 Navigation and Navigable... REGULATIONS § 334.180 Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md...

33 CFR 334.180 - Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md.

Code of Federal Regulations, 2014 CFR

2014-07-01

.... Naval Mine Warfare Test Station, or of U.S. Naval Air Station property. A person in the water or a... areas, U.S. Naval Air Test Center, Patuxent River, Md. 334.180 Section 334.180 Navigation and Navigable... REGULATIONS § 334.180 Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md...

33 CFR 334.180 - Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md.

Code of Federal Regulations, 2012 CFR

2012-07-01

.... Naval Mine Warfare Test Station, or of U.S. Naval Air Station property. A person in the water or a... areas, U.S. Naval Air Test Center, Patuxent River, Md. 334.180 Section 334.180 Navigation and Navigable... REGULATIONS § 334.180 Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md...

33 CFR 334.180 - Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md.

Code of Federal Regulations, 2011 CFR

2011-07-01

.... Naval Mine Warfare Test Station, or of U.S. Naval Air Station property. A person in the water or a... areas, U.S. Naval Air Test Center, Patuxent River, Md. 334.180 Section 334.180 Navigation and Navigable... REGULATIONS § 334.180 Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md...

33 CFR 334.180 - Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md.

Code of Federal Regulations, 2010 CFR

2010-07-01

.... Naval Mine Warfare Test Station, or of U.S. Naval Air Station property. A person in the water or a... areas, U.S. Naval Air Test Center, Patuxent River, Md. 334.180 Section 334.180 Navigation and Navigable... REGULATIONS § 334.180 Patuxent River, Md.; restricted areas, U.S. Naval Air Test Center, Patuxent River, Md...

Trapped in a Daydream: Daily Elevations in Maladaptive Daydreaming Are Associated With Daily Psychopathological Symptoms.

PubMed

Soffer-Dudek, Nirit; Somer, Eli

2018-01-01

Background: Maladaptive Daydreaming (MD) characterizes individuals who engage in vivid, fanciful daydreaming for hours on end, neglecting real-life relationships and responsibilities, resulting in clinical distress and functional impairment. Sufferers have embraced the term MD in cyber-communities devoted to this problem because it seemed to uniquely fit their experience and since existing diagnostic labels and their therapies seemed inadequate. However, scientific research in the field has been scarce, relying on cross-sectional or case study designs. Existing knowledge on MD suggests the involvement of dissociative and obsessive-compulsive symptoms, as well as positive reinforcement comparable to processes in addiction disorders. The present study aimed to rigorously explore factors that accompany MD employing a longitudinal daily-diary design, hypothesizing that temporal increases in MD will associate concurrently with, and will temporally precede, other symptoms and emotional changes. In addition, we aimed to explore which symptoms may act as precursors to increases in MD, in order to identify possible mechanisms bringing about daydreaming in these individuals. Methods: In a sample of 77 self-diagnosed individuals with MD we assessed relevant daily symptoms for 14 days, including MD, depression, general anxiety, social anxiety, obsessive-compulsive symptoms, and dissociation, as well as positive and negative emotion. Results: Increases in MD were strongly related to concurrent increases in all other symptoms and negative emotion, and to decreased positive emotion. Obsessive-compulsive symptoms, dissociation, and negative emotion also temporally followed MD. Obsessive-compulsive symptoms were the only consistent temporal antecedent of MD. Conclusions: MD and obsessive-compulsive symptoms coincided in what seems to be a vicious cycle; understanding possible shared mechanisms between these symptoms may inform our understanding of the etiology of MD. For example, Serotonin levels may possibly be involved in the development or maintenance of this condition. The findings may also provide clues as to potentially beneficial interventions for treating MD. For example, perhaps utilizing response prevention techniques may be useful for curbing or intercepting unwanted daydreaming. Future studies on MD should address its compulsory nature.

Apple fruit copper amine oxidase isoforms: peroxisomal MdAO1 prefers diamines as substrates, whereas extracellular MdAO2 exclusively utilizes monoamines.

PubMed

Zarei, Adel; Trobacher, Christopher P; Cooke, Alison R; Meyers, Ashley J; Hall, J Christopher; Shelp, Barry J

2015-01-01

4-Aminobutyrate (GABA) accumulates in apple fruit during controlled atmosphere storage. A potential source of GABA is the polyamine putrescine, which can be oxidized via copper-containing amine oxidase (CuAO), resulting in the production 4-aminobutanal/Δ(1)-pyrroline, with the consumption of O2 and release of H2O2 and ammonia. Five putative CuAO genes (MdAO genes) were cloned from apple (Malus domestica Borkh. cv. Empire) fruit, and the deduced amino acid sequences found to contain the active sites typically conserved in CuAOs. Genes encoding two of these enzymes, MdAO1 and MdAO2, were highly expressed in apple fruit and selected for further analysis. Amino acid sequence analysis predicted the presence of a C-terminal peroxisomal targeting signal 1 tripeptide in MdAO1 and an N-terminal signal peptide and N-glycosylation site in MdAO2. Transient expression of green fluorescent fusion proteins in Arabidopsis protoplasts or onion epidermal cells revealed a peroxisomal localization for MdAO1 and an extracellular localization for MdAO2. The enzymatic activities of purified recombinant MdAO1 and MdAO2 were measured continuously as H2O2 production using a coupled reaction. MdAO1 did not use monoamines or polyamines and displayed high catalytic efficiency for 1,3-diaminopropane, putrescine and cadaverine, whereas MdAO2 exclusively utilized aliphatic and aromatic monoamines, including 2-phenylethylamine and tyramine. Together, these results indicate that MdAO1 may contribute to GABA production via putrescine oxidation in the peroxisome of apple fruit under controlled atmosphere conditions. MdAO2 seems to be involved in deamination of 2-phenylethylamine, which is a step in the biosynthesis of 2-phenylethanol, a contributor to fruit flavor and flower fragrance. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Assessing the allelotypic effect of two aminocyclopropane carboxylic acid synthase-encoding genes MdACS1 and MdACS3a on fruit ethylene production and softening in Malus

PubMed Central

Dougherty, Laura; Zhu, Yuandi; Xu, Kenong

2016-01-01

Phytohormone ethylene largely determines apple fruit shelf life and storability. Previous studies demonstrated that MdACS1 and MdACS3a, which encode 1-aminocyclopropane-1-carboxylic acid synthases (ACS), are crucial in apple fruit ethylene production. MdACS1 is well-known to be intimately involved in the climacteric ethylene burst in fruit ripening, while MdACS3a has been regarded a main regulator for ethylene production transition from system 1 (during fruit development) to system 2 (during fruit ripening). However, MdACS3a was also shown to have limited roles in initiating the ripening process lately. To better assess their roles, fruit ethylene production and softening were evaluated at five time points during a 20-day post-harvest period in 97 Malus accessions and in 34 progeny from 2 controlled crosses. Allelotyping was accomplished using an existing marker (ACS1) for MdACS1 and two markers (CAPS866 and CAPS870) developed here to specifically detect the two null alleles (ACS3a-G289V and Mdacs3a) of MdACS3a. In total, 952 Malus accessions were allelotyped with the three markers. The major findings included: The effect of MdACS1 was significant on fruit ethylene production and softening while that of MdACS3a was less detectable; allele MdACS1–2 was significantly associated with low ethylene and slow softening; under the same background of the MdACS1 allelotypes, null allele Mdacs3a (not ACS3a-G289V) could confer a significant delay of ethylene peak; alleles MdACS1–2 and Mdacs3a (excluding ACS3a-G289V) were highly enriched in M. domestica and M. hybrid when compared with those in M. sieversii. These findings are of practical implications in developing apples of low and delayed ethylene profiles by utilizing the beneficial alleles MdACS1-2 and Mdacs3a. PMID:27231553

Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

PubMed Central

Rossignol, D A; Frye, R E

2012-01-01

A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B-vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD. PMID:21263444

A novel triazine ring compound (MD568) exerts in vivo and in vitro effects on lipid metabolism.

PubMed

Jia, Dan; Li, Ziwen; Gao, Ying; Feng, Yifan; Li, Weimin

2018-07-01

In this study, we investigated the toxicity and biological activity of a novel triazine ring compound named magnolol derivative 568 (MD568). The LD 50 of MD568 was determined in Sprague-Dawley (SD) rats by intraperitoneal injection. Treatment of high fat diet-induced obese rats with MD568 demonstrated that MD568 displayed significant anti-obesity effects. MD568 markedly reduced body weight, blood lipid contents, white adipose tissue (WAT) and liver mass in obese rats. In addition, MD568 modulated lesions in WAT through regulating PPAR-Ɣ, C/EBP-a, SREBP-1c and FABP-4 proteins in the liver through regulating PPAR-α, SREBP-1c and FABP-4. We also evaluated the effects of MD568 on the proliferation and differentiation of 3T3-L1 pre-adipocytes and investigated the underlying mechanism by microarray analysis. Results showed that MD568 has good inhibitory activity on lipogenesis and lipid accumulation in 3T3-L1 pre-adipocytes. The protein expression levels of the adipogenic transcription factors PPAR-Ɣ, C/EBP-a, SREBP-1c and FABP-4 were reduced by MD568. In addition, the gene expression of FAS and LDL was also significantly down-regulated by MD568. Microarray data enrichment analysis demonstrated that the underlying mechanism of action of MD568 may be related to its regulatory effects on genes associated with the biological processes or pathways in lipid metabolism. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Ionic Conductivity, Structural Deformation and Programmable Anisotropy of DNA Origami in Electric Field

PubMed Central

Li, Chen-Yu; Hemmig, Elisa A.; Kong, Jinglin; Yoo, Jejoong; Hernández-Ainsa, Silvia

2015-01-01

The DNA origami technique can enable functionalization of inorganic structures for single-molecule electric current recordings. Experiments have shown that several layers of DNA molecules—a DNA origami plate— placed on top of a solid-state nanopore is permeable to ions. Here, we report a comprehensive characterization of the ionic conductivity of DNA origami plates by means of all-atom molecular dynamics (MD) simulations and nanocapillary electric current recordings. Using the MD method, we characterize the ionic conductivity of several origami constructs, revealing the local distribution of ions, the distribution of the electrostatic potential and contribution of different molecular species to the current. The simulations determine the dependence of the ionic conductivity on the applied voltage, the number of DNA layers, the nucleotide content and the lattice type of the plates. We demonstrate that increasing the concentration of Mg2+ ions makes the origami plates more compact, reducing their conductivity. The conductance of a DNA origami plate on top of a solid-state nanopore is determined by the two competing effects: bending of the DNA origami plate that reduces the current and separation of the DNA origami layers that increases the current. The latter is produced by the electro-osmotic flow and is reversible at the time scale of a hundred nanoseconds. The conductance of a DNA origami object is found to depend on its orientation, reaching maximum when the electric field aligns with the direction of the DNA helices. Our work demonstrates feasibility of programming the electrical properties of a self-assembled nanoscale object using DNA. PMID:25623807

Ionic conductivity, structural deformation, and programmable anisotropy of DNA origami in electric field.

PubMed

Li, Chen-Yu; Hemmig, Elisa A; Kong, Jinglin; Yoo, Jejoong; Hernández-Ainsa, Silvia; Keyser, Ulrich F; Aksimentiev, Aleksei

2015-02-24

The DNA origami technique can enable functionalization of inorganic structures for single-molecule electric current recordings. Experiments have shown that several layers of DNA molecules, a DNA origami plate, placed on top of a solid-state nanopore is permeable to ions. Here, we report a comprehensive characterization of the ionic conductivity of DNA origami plates by means of all-atom molecular dynamics (MD) simulations and nanocapillary electric current recordings. Using the MD method, we characterize the ionic conductivity of several origami constructs, revealing the local distribution of ions, the distribution of the electrostatic potential and contribution of different molecular species to the current. The simulations determine the dependence of the ionic conductivity on the applied voltage, the number of DNA layers, the nucleotide content and the lattice type of the plates. We demonstrate that increasing the concentration of Mg(2+) ions makes the origami plates more compact, reducing their conductivity. The conductance of a DNA origami plate on top of a solid-state nanopore is determined by the two competing effects: bending of the DNA origami plate that reduces the current and separation of the DNA origami layers that increases the current. The latter is produced by the electro-osmotic flow and is reversible at the time scale of a hundred nanoseconds. The conductance of a DNA origami object is found to depend on its orientation, reaching maximum when the electric field aligns with the direction of the DNA helices. Our work demonstrates feasibility of programming the electrical properties of a self-assembled nanoscale object using DNA.

Gro2mat: a package to efficiently read gromacs output in MATLAB.

PubMed

Dien, Hung; Deane, Charlotte M; Knapp, Bernhard

2014-07-30

Molecular dynamics (MD) simulations are a state-of-the-art computational method used to investigate molecular interactions at atomic scale. Interaction processes out of experimental reach can be monitored using MD software, such as Gromacs. Here, we present the gro2mat package that allows fast and easy access to Gromacs output files from Matlab. Gro2mat enables direct parsing of the most common Gromacs output formats including the binary xtc-format. No openly available Matlab parser currently exists for this format. The xtc reader is orders of magnitudes faster than other available pdb/ascii workarounds. Gro2mat is especially useful for scientists with an interest in quick prototyping of new mathematical and statistical approaches for Gromacs trajectory analyses. © 2014 Wiley Periodicals, Inc. Copyright © 2014 Wiley Periodicals, Inc.

Registration of five upland cotton mutant germplasm lines with superior fiber length, strength, and uniformity

USDA-ARS?s Scientific Manuscript database

Mutant germplasm lines MD 15-Mut 13 (Reg. No. GP-1025, PI 681706), MD 15-Mut 31 (Reg. No. GP-1026, PI 681707), MD 15-Mut 61 (Reg. No. GP-1027, PI 681708), MD 15-Mut 89 (Reg. No. GP-1028, PI 681709), and MD 15-Mut 138 (Reg. No. GP-1029, PI 681710) are unique genotypes of upland cotton (Gossypium hirs...

VIEW IN OPPOSITE DIRECTION AS MD1351 AND MD1352. RAW MATERIAL ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

VIEW IN OPPOSITE DIRECTION AS MD-135-1 AND MD-135-2. RAW MATERIAL CONVEYOR AT LEFT DEPOSITS SHELL INTO MILLING MACHINE AT LOWER LEFT. ENGINE IS AT LOWER RIGHT AND RADIATOR AT LOWER CENTER. ROLLER SORTER IS AT TOP OF CONVEYOR. - F. & H. Benning Company Oyster Mill, 14430 Solomons Island Road (moved from 1014 Benning Road, Galesville, Anne Arundel County, Maryland), Solomons, Calvert County, MD

The bZIP transcription factor MdHY5 regulates anthocyanin accumulation and nitrate assimilation in apple.

PubMed

An, Jian-Ping; Qu, Feng-Jia; Yao, Ji-Fang; Wang, Xiao-Na; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2017-01-01

The basic leucine zipper (bZIP) transcription factor HY5 plays a multifaceted role in plant growth and development. Here the apple MdHY5 gene was cloned based on its homology with Arabidopsis HY5 . Expression analysis demonstrated that MdHY5 transcription was induced by light and abscisic acid treatments. Electrophoretic mobility shift assays and transient expression assays subsequently showed that MdHY5 positively regulated both its own transcription and that of MdMYB10 by binding to E-box and G-box motifs, respectively. Furthermore, we obtained transgenic apple calli that overexpressed the MdHY5 gene, and apple calli coloration assays showed that MdHY5 promoted anthocyanin accumulation by regulating expression of the MdMYB10 gene and downstream anthocyanin biosynthesis genes. In addition, the transcript levels of a series of nitrate reductase genes and nitrate uptake genes in both wild-type and transgenic apple calli were detected. In association with increased nitrate reductase activities and nitrate contents, the results indicated that MdHY5 might be an important regulator in nutrient assimilation. Taken together, these results indicate that MdHY5 plays a vital role in anthocyanin accumulation and nitrate assimilation in apple.

CAPTURE OF FREE-RANGING MULE DEER (ODOCOILEUS HEMIONUS) WITH A COMBINATION OF MEDETOMIDINE, AZAPERONE, AND ALFAXALONE.

PubMed

Mathieu, Amélie; Caulkett, Nigel; Stent, Patrick M; Schwantje, Helen M

2017-04-01

The combination of medetomidine, azaperone, and alfaxalone has been successfully used to anesthetize captive white-tailed deer ( Odocoileus virginianus ). This same combination was utilized to immobilize free-ranging female mule deer ( Odocoileus hemionus ; MD) in urban and nonurban environments (14 urban MD, 14 nonurban MD) in British Columbia, Canada. Physiologic data were collected to assess the safety and reliability of this drug combination under field conditions. Each deer received estimated dosages of 0.15 mg/kg medetomidine, 0.2 mg/kg azaperone, and 0.5 mg/kg alfaxalone intramuscularly via a remote darting system. Inductions were calm and rapid (mean time to sternal recumbency: urban MD, 6.4±2.2 min; nonurban MD, 8.2±4.1 min). Supplemental drugs were required to induce lateral recumbency in five deer, four of which had experienced initial dart failure (mean time to lateral recumbency: urban MD, 8.5±3.8 min; nonurban MD, 18.7±16.5 min). Recoveries were smooth and uneventful (time to standing: urban MD, 12.5±3.4 min; nonurban MD, 9.0±3.5 min) for all but one debilitated nonurban MD that died shortly after atipamezole administration (at five times the medetomidine dose). The major side effects of the combination were hypoxemia and hypercapnia. The combination of medetomidine, azaperone, and alfaxalone proved suitable for the immobilization of urban and nonurban free-ranging MD.

Angiotensin II induces kidney inflammatory injury and fibrosis through binding to myeloid differentiation protein-2 (MD2).

PubMed

Xu, Zheng; Li, Weixin; Han, Jibo; Zou, Chunpeng; Huang, Weijian; Yu, Weihui; Shan, Xiaoou; Lum, Hazel; Li, Xiaokun; Liang, Guang

2017-03-21

Growing evidence indicates that angiotensin II (Ang II), a potent biologically active product of RAS, is a key regulator of renal inflammation and fibrosis. In this study, we tested the hypothesis that Ang II induces renal inflammatory injury and fibrosis through interaction with myeloid differentiation protein-2 (MD2), the accessory protein of toll-like receptor 4 (TLR4) of the immune system. Results indicated that in MD2 -/- mice, the Ang II-induced renal fibrosis, inflammation and kidney dysfunction were significantly reduced compared to control Ang II-infused wild-type mice. Similarly, in the presence of small molecule MD2 specific inhibitor L6H21 or siRNA-MD2, the Ang II-induced increases of pro-fibrotic and pro-inflammatory molecules were prevented in tubular NRK-52E cells. MD2 blockade also inhibited activation of NF-κB and ERK. Moreover, MD2 blockade prevented the Ang II-stimulated formation of the MD2/TLR4/MyD88 signaling complex, as well as the increased surface binding of Ang II in NRK-52E cells. In addition, Ang II directly bound recombinant MD2 protein, rather than TLR4 protein. We conclude that MD2 is a significant contributor in the Ang II-induced kidney inflammatory injury in chronic renal diseases. Furthermore, MD2 inhibition could be a new and important therapeutic strategy for preventing progression of chronic renal diseases.

MdMYB1 Regulates Anthocyanin and Malate Accumulation by Directly Facilitating Their Transport into Vacuoles in Apples1[OPEN

PubMed Central

Hu, Da-Gang; Sun, Cui-Hui; Ma, Qi-Jun; You, Chun-Xiang; Hao, Yu-Jin

2016-01-01

Tonoplast transporters, including proton pumps and secondary transporters, are essential for plant cell function and for quality formation of fleshy fruits and ornamentals. Vacuolar transport of anthocyanins, malate, and other metabolites is directly or indirectly dependent on the H+-pumping activities of vacuolar H+-ATPase (VHA) and/or vacuolar H+-pyrophosphatase, but how these proton pumps are regulated in modulating vacuolar transport is largely unknown. Here, we report a transcription factor, MdMYB1, in apples that binds to the promoters of two genes encoding the B subunits of VHA, MdVHA-B1 and MdVHA-B2, to transcriptionally activate its expression, thereby enhancing VHA activity. A series of transgenic analyses in apples demonstrates that MdMYB1/10 controls cell pH and anthocyanin accumulation partially by regulating MdVHA-B1 and MdVHA-B2. Furthermore, several other direct target genes of MdMYB10 are identified, including MdVHA-E2, MdVHP1, MdMATE-LIKE1, and MdtDT, which are involved in H+-pumping or in the transport of anthocyanins and malates into vacuoles. Finally, we show that the mechanism by which MYB controls malate and anthocyanin accumulation in apples also operates in Arabidopsis (Arabidopsis thaliana). These findings provide novel insights into how MYB transcription factors directly modulate the vacuolar transport system in addition to anthocyanin biosynthesis, consequently controlling organ coloration and cell pH in plants. PMID:26637549

MdMYB1 Regulates Anthocyanin and Malate Accumulation by Directly Facilitating Their Transport into Vacuoles in Apples.

PubMed

Hu, Da-Gang; Sun, Cui-Hui; Ma, Qi-Jun; You, Chun-Xiang; Cheng, Lailiang; Hao, Yu-Jin

2016-03-01

Tonoplast transporters, including proton pumps and secondary transporters, are essential for plant cell function and for quality formation of fleshy fruits and ornamentals. Vacuolar transport of anthocyanins, malate, and other metabolites is directly or indirectly dependent on the H(+)-pumping activities of vacuolar H(+)-ATPase (VHA) and/or vacuolar H(+)-pyrophosphatase, but how these proton pumps are regulated in modulating vacuolar transport is largely unknown. Here, we report a transcription factor, MdMYB1, in apples that binds to the promoters of two genes encoding the B subunits of VHA, MdVHA-B1 and MdVHA-B2, to transcriptionally activate its expression, thereby enhancing VHA activity. A series of transgenic analyses in apples demonstrates that MdMYB1/10 controls cell pH and anthocyanin accumulation partially by regulating MdVHA-B1 and MdVHA-B2. Furthermore, several other direct target genes of MdMYB10 are identified, including MdVHA-E2, MdVHP1, MdMATE-LIKE1, and MdtDT, which are involved in H(+)-pumping or in the transport of anthocyanins and malates into vacuoles. Finally, we show that the mechanism by which MYB controls malate and anthocyanin accumulation in apples also operates in Arabidopsis (Arabidopsis thaliana). These findings provide novel insights into how MYB transcription factors directly modulate the vacuolar transport system in addition to anthocyanin biosynthesis, consequently controlling organ coloration and cell pH in plants. © 2016 American Society of Plant Biologists. All Rights Reserved.

Fouling-Resistant Membranes for Treating Concentrated Brines for Water Reuse in Advanced Energy Systems- Final Technical Report

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

Hendren, Zachary; Choi, Young Chul

The high total dissolved solids (TDS) levels in the wastewater quality generated from unconventional oil and gas development make the current state-of-the art approach to water treatment/disposal untenable. Our proposed membrane technology approach addresses the two major challenges associated with this water: 1) the membrane distillation process removes the high TDS content, which is often 8 times higher than that of seawater, and 2) our novel membrane coating prevents the formation of scale that would otherwise pose a significant operational hurdle. This is accomplished through next-generation electrically conductive membranes that mitigate fouling beyond what is currently possible, and allow formore » the flexibility to treat to the water to levels desirable for multiple reuse options, thus reducing fresh water withdrawal, all the way to direct disposal into the environment. The overall project objective was to demonstrate the efficacy of membrane distillation (MD) as a cost-savings technology to treat concentrated brines (such as, but not limited to, produced waters generated from fossil fuel extraction) that have high levels of TDS for beneficial water reuse in power production and other industrial operations as well as agricultural and municipal water uses. In addition, a novel fouling-resistant nanocomposite membrane was developed to reduce the need for chemicals to address membrane scaling due to the precipitation of divalent ions in high-TDS waters and improve overall MD performance via an electrically conductive membrane distillation process (ECMD). This anti-fouling membrane technology platform is based on incorporating carbon nanotubes (CNTs) into the surface layer of existing, commercially available MD membranes. The CNTs impart electrical conductivity to the membrane surface to prevent membrane scaling and fouling when an electrical potential is applied.« less

Genetic and environmental influences on last-year major depression in adulthood: a highly heritable stable liability but strong environmental effects on 1-year prevalence.

PubMed

Kendler, K S; Gardner, C O

2017-07-01

This study seeks to clarify the contribution of temporally stable and occasion-specific genetic and environmental influences on risk for major depression (MD). Our sample was 2153 members of female-female twin pairs from the Virginia Twin Registry. We examined four personal interview waves conducted over an 8-year period with MD in the last year defined by DSM-IV criteria. We fitted a structural equation model to the data using classic Mx. The model included genetic and environmental risk factors for a latent, stable vulnerability to MD and for episodes in each of the four waves. The best-fit model was simple and included genetic and unique environmental influences on the latent liability to MD and unique wave-specific environmental effects. The path from latent liability to MD in the last year was constant over time, moderate in magnitude (+0.65) and weaker than the impact of occasion-specific environmental effects (+0.76). Heritability of the latent stable liability to MD was much higher (78%) than that estimated for last-year MD (32%). Of the total unique environmental influences on MD, 13% reflected enduring consequences of earlier environmental insults, 17% diagnostic error and 70% wave-specific short-lived environmental stressors. Both genetic influences on MD and MD heritability are stable over middle adulthood. However, the largest influence on last-year MD is short-lived environmental effects. As predicted by genetic theory, the heritability of MD is increased substantially by measurement at multiple time points largely through the reduction of the effects of measurement error and short-term environmental risk factors.

Myeloid differentiation protein 2-dependent mechanisms in retinal ischemia-reperfusion injury

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

Ren, Luqing

Retinal ischemia-reperfusion (I/R) injury is a common pathological process in many eye disorders. Oxidative stress and inflammation play a role in retinal I/R injury. Recent studies show that toll-like receptor 4 (TLR4) is involved in initiating sterile inflammatory response in retinal I/R. However, the molecular mechanism by which TLR4 is activated is not known. In this study, we show that retinal I/R injury involves a co-receptor of TLR4, myeloid differentiation 2 (MD2). Inhibition of MD2 prevented cell death and preserved retinal function following retinal I/R injury. We confirmed these findings using MD2 knockout mice. Furthermore, we utilized human retinal pigmentmore » epithelial cells (ARPE-19 cells) to show that oxidative stress-induced cell death as well as inflammatory response are mediated through MD2. Inhibition of MD2 through a chemical inhibitor or knockdown prevented oxidative stress-induced cell death and expression of inflammatory cytokines. Oxidative stress was found to activate TLR4 in a MD2-dependent manner via increasing the expression of high mobility group box 1. In summary, our study shows that oxidative stress in retinal I/R injury can activate TLR4 signaling via MD2, resulting in induction of inflammatory genes and retinal damage. MD2 may represent an attractive therapeutic target for retinal I/R injury. - Highlights: • MD2 inhibition reduced retinal damage after I/R induction in mice. • TBHP induced TLR4/MD2 binding via increasing HMGB-1 expression. • TLR4/MD2 initiated inflammatory response via activation of MAPKs and NF-κB. • MD2 could be the therapeutic target for the treatment of retinal I/R.« less

Identification and expression analysis of the IPT and CKX gene families during axillary bud outgrowth in apple (Malus domestica Borkh.).

PubMed

Tan, Ming; Li, Guofang; Qi, Siyan; Liu, Xiaojie; Chen, Xilong; Ma, Juanjuan; Zhang, Dong; Han, Mingyu

2018-04-20

Cytokinins (CKs) play a crucial role in promoting axillary bud outgrowth and targeting the control of CK metabolism can be used to enhance branching in plants. CK levels are maintained mainly by CK biosynthesis (isopentenyl transferase, IPT) and degradation (dehydrogenase, CKX) genes in plants. A systematic study of the IPT and CKX gene families in apple, however, has not been conducted. In the present study, 12 MdIPTs and 12 MdCKXs were identified in the apple genome. Systematic phylogenetic, structural, and synteny analyses were performed. Expression analysis of these genes in different tissues was also assessed. MdIPT and MdCKX genes exhibit distinct expression patterns in different tissues. The response of MdIPT, MdCKX, and MdPIN1 genes to various treatments (6-BA, decapitation and Lovastatin, an inhibitor of CKs synthesis) that impact branching were also investigated. Results indicated that most of the MdIPT and MdCKX, and MdPIN1 genes were upregulated by 6-BA and decapitation treatment, but inhibited by Lovastatin, a compound that effectively suppresses axillary bud outgrowth induced by decapitation. These findings suggest that cytokinin biosynthesis is required for the activation of bud break and the export of auxin from buds in apple tree with intact primary shoot apex or decapitated apple tree. MdCKX8 and MdCKX10, however, exhibited little response to decapitation, but were significantly up-regulated by 6-BA and Lovastatin, a finding that warrants further investigation in order to understand their function in bud-outgrowth. Copyright © 2018 Elsevier B.V. All rights reserved.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities

PubMed Central

Gierach, Gretchen L.; Patel, Deesha A.; Pfeiffer, Ruth M.; Figueroa, Jonine D.; Linville, Laura; Papathomas, Daphne; Johnson, Jason M.; Chicoine, Rachael E.; Herschorn, Sally D.; Shepherd, John A.; Wang, Jeff; Malkov, Serghei; Vacek, Pamela M.; Weaver, Donald L.; Fan, Bo; Mahmoudzadeh, Amir Pasha; Palakal, Maya; Xiang, Jackie; Oh, Hannah; Horne, Hisani N.; Sprague, Brian L.; Hewitt, Stephen M.; Brinton, Louise A.; Sherman, Mark E.

2016-01-01

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLUs), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (peri-lesional). Three measures inversely related to TDLU involution (TDLU count/mm2, median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40–65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent peri-lesional MD (P-trend=0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P-trend<0.05) and absolute peri-lesional MD (P=0.003). Acini count was directly associated with absolute peri-lesional MD (P=0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P-trend≤0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in peri-lesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction. PMID:26645278

Damage Control Resuscitation: Directly Addressing the Early Coagulopathy of Trauma

DTIC Science & Technology

2007-02-01

FACS, Jay Johannigman, MD, FS, FACS, Peter Mahoney, FRCA, RAMC , Sumeru Mehta, MD, E. Darrin Cox, MD, FACS, Michael J. Gehrke, MD, Greg J. Beilman, MD...opportunity to formally evaluate the immediate and direct treatment of the coagulopathy of trauma is available. Submitted for publication September 22, 2006...the results were not evaluated in randomized human trials.33–35 Additionally, the potential benefits of mitigating ischemia-induced reperfusion injury

White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study.

PubMed

Bierer, Linda M; Ivanov, Iliyan; Carpenter, David M; Wong, Edmund W; Golier, Julia A; Tang, Cheuk Y; Yehuda, Rachel

2015-01-01

Gulf War veterans were exposed to environmental toxins not present in other combat theaters resulting in a unique biological signature that only partially resembles that seen in other combat veterans with PTSD. Thus it is important to determine if brain abnormalities seen in non-Gulf War veterans with PTSD are also present in Gulf War veterans. In this pilot study, diffusion tensor imaging (DTI) tractography was used to assess the ultra-structural integrity of fronto-limbic white matter connections in Gulf War veterans with and without PTSD. The effects of chronic multisymptom illness on DTI measures was also evaluated. Subjects were 20 previously studied Gulf War veterans on whom MRIs had been obtained. Mean diffusivity (MD) and fractional anisotropy (FA) were determined for left and right cingulum bundle by DTI tractography and compared in separate analyses for 12 veterans with, and 8 without PTSD. The effect of chronic multisymptom illness and it's interaction with PTSD, were similarly investigated using multivariate ACOVA. Partial correlations were used to test the associations of both DTI indices with PTSD severity and plasma cortisol, controlling for whole brain volume. Significantly lower MD was demonstrated in the right cingulum bundle among Gulf War veterans with PTSD. There were no significant differences in MD or FA in the left cingulum bundle. The presence of chronic multisymptom illness significantly attenuated the PTSD associated decrement in right cingulum MD. Clinician and self-rated PTSD symptom severity scores were significantly associated with reduced MD and increased FA in the right cingulum. Similar associations were observed for 8am plasma cortisol in a subset of participants. The preliminary findings indicate increased structural integrity - supporting enhanced connectivity - between right amygdala and anterior cingulate cortex in PTSD. This effect was strongest among Gulf War veterans without chronic multisymptom illness. The association of both MD and FA in the right cingulum with PTSD severity, and with heightened glucocorticoid responsivity, suggests that these DTI findings are a reflection of current PTSD illness expression. Although based on a small sample, these microstructural observations are consistent with a functional model suggesting increased amygdala responsivity in association with anterior cingulate modulation in PTSD. Copyright © 2014. Published by Elsevier Ltd.

D1-3: Marshfield Dictionary of Clinical and Translational Science (MD-CTS): An Online Reference for Clinical and Translational Science Terminology

PubMed Central

Finamore, Joe; Ray, William; Kadolph, Chris; Rastegar-Mojarad, Majid; Ye, Zhan; Jacqueline, Bohne; Tachinardi, Umberto; Mendonça, Eneida; Finnegan, Brian; Bartkowiak, Barbara; Weichelt, Bryan; Lin, Simon

2014-01-01

Background/Aims New terms are rapidly appearing in the literature and practice of clinical medicine and translational research. To catalog real-world usage of medical terms, we report the first construction of an online dictionary of clinical and translational medicinal terms, which are computationally generated in near real-time using a big data approach. This project is NIH CTSA-funded and developed by the Marshfield Clinic Research Foundation in conjunction with University of Wisconsin - Madison. Currently titled Marshfield Dictionary of Clinical and Translational Science (MD-CTS), this application is a Google-like word search tool. By entering a term into the search bar, MD-CTS will display that term’s definition, usage examples, contextual terms, related images, and ontological information. A prototype is available for public viewing at http://spellchecker.mfldclin.edu/. Methods We programmatically derived the lexicon for MD-CTS from scholarly communications by parsing through 15,156,745 MEDLINE abstracts and extracting all of the unique words found therein. We then ran this list through several filters in order to remove words that were not relevant for searching, such as common English words and numeric expressions. We then loaded the resulting 1,795,769 terms into SQL tables. Each term is cross-referenced with every occurrence in all abstracts in which it was found. Additional information is aggregated from Wiktionary, Bioportal, and Wikipedia in real-time and displayed on-screen. From this lexicon we created a supplemental dictionary resource (updated quarterly) to be used in Microsoft Office® products. Results We evaluated the utility of MD-CTS by creating a list of 100 words derived from recent clinical and translational medicine publications in the week of July 22, 2013. We then performed comparative searches for each term with Taber’s Cyclopedic Medical Dictionary, Stedman’s Medical Dictionary, Dorland’s Illustrated Medical Dictionary, Medical Subject Headings (MeSH), and MD-CTS. We compared our supplemental dictionary resource to OpenMedSpell for effectiveness in accuracy of term recognition. Conclusions In summary, we developed an online mobile and desktop reference, which comprehensively integrates Wiktionary (term information), Bioportal (ontological information), Wikipedia (related images), and Medline abstract information (term usage) for scientists and clinicians to browse in real-time. We also created a supplemental dictionary resource to be used in Microsoft Office® products.

MD-2 residues tyrosine 42, arginine 69, aspartic acid 122, and leucine 125 provide species specificity for lipid IVA.

PubMed

Meng, Jianmin; Drolet, Joshua R; Monks, Brian G; Golenbock, Douglas T

2010-09-03

Lipopolysaccharide (LPS) activates the innate immune response through the Toll-like receptor 4 (TLR4).MD-2 complex. A synthetic lipid A precursor, lipid IV(A), induces an innate immune response in mice but not in humans. Both TLR4 and MD-2 are required for the agonist activity of lipid IV(A) in mice, with TLR4 interacting through specific surface charges at the dimerization interface. In this study, we used site-directed mutagenesis to identify the MD-2 residues that determine lipid IV(A) species specificity. A single mutation of murine MD-2 at the hydrophobic pocket entrance, E122K, substantially reduced the response to lipid IV(A). Combining the murine MD-2 E122K with the murine TLR4 K367E/S386K/R434Q mutations completely abolished the response to lipid IV(A), effectively converting the murine cellular response to a human-like response. In human cells, however, simultaneous mutations of K122E, K125L, Y41F, and R69G on human MD-2 were required to promote a response to lipid IV(A). Combining the human MD-2 quadruple mutations with the human TLR4 E369K/Q436R mutations completely converted the human MD-2/human TLR4 receptor to a murine-like receptor. Because MD-2 residues 122 and 125 reside at the dimerization interface near the pocket entrance, surface charge differences here directly affect receptor dimerization. In comparison, residues 42 and 69 reside at the MD-2/TLR4 interaction surface opposite the dimerization interface. Surface charge differences there likely affect the binding angle and/or rigidity between MD-2 and TLR4, exerting an indirect influence on receptor dimerization and activation. Thus, surface charge differences at the two MD-2/TLR4 interfaces determine the species-specific activation of lipid IV(A).

Apple F-Box Protein MdMAX2 Regulates Plant Photomorphogenesis and Stress Response.

PubMed

An, Jian-Ping; Li, Rui; Qu, Feng-Jia; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2016-01-01

MAX2 (MORE AXILLARY GROWTH2) is involved in diverse physiological processes, including photomorphogenesis, the abiotic stress response, as well as karrikin and strigolactone signaling-mediated shoot branching. In this study, MdMAX2, an F-box protein that is a homolog of Arabidopsis MAX2, was identified and characterized. Overexpression of MdMAX2 in apple calli enhanced the accumulation of anthocyanin. Ectopic expression of MdMAX2 in Arabidopsis exhibited photomorphogenesis phenotypes, including increased anthocyanin content and decreased hypocotyl length. Further study indicated that MdMAX2 might promote plant photomorphogenesis by affecting the auxin signaling as well as other plant hormones. Transcripts of MdMAX2 were noticeably up-regulated in response to NaCl and Mannitol treatments. Moreover, compared with the wild-type, the MdMAX2 -overexpressing apple calli and Arabidopsis exhibited increased tolerance to salt and drought stresses. Taken together, these results suggest that MdMAX2 plays a positive regulatory role in plant photomorphogenesis and stress response.

An apple NAC transcription factor negatively regulates cold tolerance via CBF-dependent pathway.

PubMed

An, Jian-Ping; Li, Rui; Qu, Feng-Jia; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2018-02-01

Cold stress is an adverse stimulus that affects plant growth and development, and the C-repeat binding factor (CBF) cold-regulatory cascade has been regarded as a master regulator in the plant response to cold stress. Here, we showed that a NAC transcription factor modulated low-temperature tolerance. MdNAC029/MdNAP, an apple NAC gene was isolated and its role in regulating cold tolerance was investigated. MdNAC029 was responsive to low-temperature treatment, and over-expression of MdNAC029 reduced cold tolerance in apple calli and Arabidopsis. Furthermore, EMSA assays and transient expression assays demonstrated that MdNAC029 directly repressed the expression of MdCBF1 and MdCBF4 by binding to their promoters. Taken together, our data suggest that MdNAC029 functions as a negative regulator in regulating plant cold tolerance in a CBF-dependent manner, providing a deeper understanding of NAC transcription-factor-mediated cold tolerance. Copyright © 2017 Elsevier GmbH. All rights reserved.

MdHY5 positively regulates cold tolerance via CBF-dependent and CBF-independent pathways in apple.

PubMed

An, Jian-Ping; Yao, Ji-Fang; Wang, Xiao-Na; You, Chun-Xiang; Wang, Xiao-Fei; Hao, Yu-Jin

2017-11-01

Cold stress is a major external stimulator that affects crop quality and productivity. The CBF cold regulatory pathway has been regarded as a master regulator in the response to cold stress. In this study, we found that the apple bZIP transcription factor, MdHY5, was responsive to cold treatment both at the transcriptional and at the post-translational levels. Moreover, overexpression of MdHY5 enhanced cold tolerance in apple calli and Arabidopsis. Subsequently, EMSA assay and transient expression assay demonstrated that MdHY5 positively regulated the transcript of MdCBF1 by binding to G-Box motif of its promoter. Furthermore, MdHY5 also regulated the expression of CBF-independent cold-regulated genes. Taken together, our data suggest that MdHY5 positively modulates plant cold tolerance through CBF-dependent and CBF-independent pathways, providing a deeper understanding of MdHY5-regulated cold tolerance in apple. Copyright © 2017 Elsevier GmbH. All rights reserved.

Tutorial: Determination of thermal boundary resistance by molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Liang, Zhi; Hu, Ming

2018-05-01

Due to the high surface-to-volume ratio of nanostructured components in microelectronics and other advanced devices, the thermal resistance at material interfaces can strongly affect the overall thermal behavior in these devices. Therefore, the thermal boundary resistance, R, must be taken into account in the thermal analysis of nanoscale structures and devices. This article is a tutorial on the determination of R and the analysis of interfacial thermal transport via molecular dynamics (MD) simulations. In addition to reviewing the commonly used equilibrium and non-equilibrium MD models for the determination of R, we also discuss several MD simulation methods which can be used to understand interfacial thermal transport behavior. To illustrate how these MD models work for various interfaces, we will show several examples of MD simulation results on thermal transport across solid-solid, solid-liquid, and solid-gas interfaces. The advantages and drawbacks of a few other MD models such as approach-to-equilibrium MD and first-principles MD are also discussed.

Clinical features of and risk factors for major depression with history of postpartum episodes in Han Chinese women: A retrospective study.

PubMed

Yang, Fuzhong; Gardner, Charles O; Bigdeli, Tim; Gao, Jingfang; Zhang, Zhen; Tao, Ming; Liu, Ying; Li, Youhui; Wang, Gang; Shi, Jianguo; Gao, Chengge; Zhang, Kerang; Li, Kan; Wang, Xumei; Liu, Lanfen; Sun, Jing; Du, Bo; Shi, Shenxun; Zhang, Jingbei; Wu, Wenyuan; Wang, Xueyi; Shen, Jianhua; Liu, Tiebang; Gu, Danhua; Liang, Wei; Deng, Hong; Pan, Jiyang; Yang, Lijun; Jian, Hu; Jiang, Guoqin; Meng, Huaqing; Miao, Guodong; Li, Yi; Hu, Chunmei; Huang, Guoping; Zhang, Yutang; Chen, Yunchun; Ha, Baowei; Gao, Shu; Fang, Xiang; Mei, Qiyi; Hong, Xiaohong; Yang, Donglin; Liu, Tieqiao; Fengyu, Yu; Zhong, Hui; Sang, Hong; Chen, Guibing; Cai, Min; Song, Yan; Dong, Jicheng; Shen, Zhenmin; Zhang, Wei; Wang, Xiaoping; Pan, Runde; Liu, Xiaojuan; Li, Yi; Liu, Zhengrong; Zhang, Qiwen; Li, Gongying; Flint, Jonathan; Kendler, Kenneth S

2015-09-01

We sought to investigate the clinical features of and risk factors for recurrent major depression (MD) with history of postpartum episodes (PPD) in Han Chinese women and the differences between first-onset postpartum MD (MD that has its first lifetime depressive episode in the postpartum period) and first-onset non-postpartum MD (MD with history of PPD and has its first lifetime depressive episode in a period other than postpartum). Data were derived from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) study (N=6017 cases) and analyzed in two steps. We first examined the clinical features of and risk factors for MD patients with (N=981) or without (N=4410) a history of PPD. We then compared the differences between first-onset postpartum MD (N=583) and first-onset non-postpartum MD (N=398) in those with a history of PPD. Linear, logistic and multinomial logistic models were employed to measure the associations. A history of PPD was associated with more guilt feelings, greater psychiatric comorbidity, higher neuroticism, earlier onset and more chronicity (OR 0.2-2.8). Severe premenstrual symptoms (PMS) and more childbirths increased the risk of PPD, as did a family history of MD, childhood sexual abuse, stressful life events and lack of social support (OR 1.1-1.3). In the MD with history of PPD subsample, first-onset postpartum MD was associated with fewer recurrent major depressive episodes, less psychiatric comorbidity, lower neuroticism, less severe PMS and fewer disagreements with their husbands (OR 0.5-0.8), but more childbirths (OR 1.2). Data were obtained retrospectively through interview and recall bias may have affected the results. MD with history of PPD in Han Chinese women is typically chronic and severe, with particular risk factors including severe PMS and more childbirths. First-onset postpartum MD and first-onset non-postpartum MD can be partly differentiated by their clinical features and risk factors, but are not clearly distinctive. Copyright © 2015. Published by Elsevier B.V.

The effects of the mediterranean diet on biomarkers of vascular wall inflammation and plaque vulnerability in subjects with high risk for cardiovascular disease. A randomized trial.

PubMed

Casas, Rosa; Sacanella, Emilio; Urpí-Sardà, Mireia; Chiva-Blanch, Gemma; Ros, Emilio; Martínez-González, Miguel-Angel; Covas, Maria-Isabel; Salas-Salvadó, Jordi; Fiol, Miquel; Arós, Fernando; Estruch, Ramon

2014-01-01

Adherence to the Mediterranean diet (MD) is associated with reduced morbidity and mortality due to cardiovascular disease. However, how the MD exerts its effects is not fully known. To assess the 12-month effects of two enhanced MDs compared to a low-fat diet on inflammatory biomarkers related to atherosclerosis and plaque vulnerability in a subcohort of the PREDIMED (Prevención con Dieta Mediterránea) study. A total of 164 participants at high risk for cardiovascular disease were randomized into three diet groups: MD supplemented with 50mL/d of extra virgin olive oil (MD+EVOO) or 30 g/d of nuts (MD+Nuts) and a low-fat diet. Changes in classical cardiovascular risk factors, inflammatory biomarkers of atherosclerosis and plaque vulnerability were measured after 12 months of intervention. Compared to participants in the low-fat diet group, those receiving MD+EVOO and MD+Nuts showed a higher decrease in systolic (6mmHg) and diastolic (3mmHg) blood pressure (P = 0.02; both), as well as a reduction of 10% and 8% in LDL-cholesterol (P = 0.04), respectively. Patients in the MD+Nuts group showed a significant reduction of 34% in CD40 expression on monocyte surface compared to low-fat diet patients (P = 0.03). In addition, inflammatory biomarkers related to plaque instability such as C-reactive protein and interleukin-6 were reduced by 45% and 35% and 95% and 90% in the MD+EVOO and MD+Nuts groups, respectively (P<0.05; all) compared to the low-fat diet group. Likewise, sICAM and P-selectin were also reduced by 50% and 27%, respectively in the MD+EVOO group (P = 0.04) and P-selectin by 19% in MD+Nuts group (P = 0.04) compared to the low-fat diet group. Adherence to the MD is associated with an increase in serum markers of atheroma plaque stability which may explain, at least in part, the protective role of MD against ischemic heart disease. www.controlled-trials.com ISRCTN35739639.

Logistic model analysis of neurological findings in Minamata disease and the predicting index.

PubMed

Nakagawa, Masanori; Kodama, Tomoko; Akiba, Suminori; Arimura, Kimiyoshi; Wakamiya, Junji; Futatsuka, Makoto; Kitano, Takao; Osame, Mitsuhiro

2002-01-01

To establish a statistical diagnostic method to identify patients with Minamata disease (MD) considering factors of aging and sex, we analyzed the neurological findings in MD patients, inhabitants in a methylmercury polluted (MP) area, and inhabitants in a non-MP area. We compared the neurological findings in MD patients and inhabitants aged more than 40 years in the non-MP area. Based on the different frequencies of the neurological signs in the two groups, we devised the following formula to calculate the predicting index for MD: predicting index = 1/(1+e(-x)) x 100 (The value of x was calculated using the regression coefficients of each neurological finding obtained from logistic analysis. The index 100 indicated MD, and 0, non-MD). Using this method, we found that 100% of male and 98% of female patients with MD (95 cases) gave predicting indices higher than 95. Five percent of the aged inhabitants in the MP area (598 inhabitants) and 0.2% of those in the non-MP area (558 inhabitants) gave predicting indices of 50 or higher. Our statistical diagnostic method for MD was useful in distinguishing MD patients from healthy elders based on their neurological findings.

The Structural Basis for Lipid and Endotoxin Binding in RP105-MD-1, and Consequences for Regulation of Host Lipopolysaccharide Sensitivity.

PubMed

Ortiz-Suarez, Maite L; Bond, Peter J

2016-01-05

MD-1 is a member of the MD-2-related lipid-recognition (ML) family, and associates with RP105, a cell-surface protein that resembles Toll-like receptor 4 (TLR4). The RP105⋅MD-1 complex has been proposed to play a role in fine-tuning the innate immune response to endotoxin such as bacterial lipopolysaccharide (LPS) via TLR4⋅MD-2, but controversy surrounds its mechanism. We have used atomically detailed simulations to reveal the structural basis for ligand binding and consequent functional dynamics of MD-1 and the RP105 complex. We rationalize reports of endogenous phospholipid binding, by showing that they prevent collapse of the malleable MD-1 fold, before refining crystallographic models and uncovering likely binding modes for LPS analogs. Subsequent binding affinity calculations reveal that endotoxin specificity arises from the entropic cost of expanding the MD-1 cavity to accommodate bulky lipid tails, and support the role of MD-1 as a "sink" that sequesters endotoxin from TLR4 and stabilizes RP105/TLR4 interactions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Remains of abutments for Bridge No. 1575 at MD Rt. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Remains of abutments for Bridge No. 1575 at MD Rt. 51 in Spring Gap, Maryland, looking northeast. (Compare with HAER MD-115 photos taken 1988). - Western Maryland Railway, Cumberland Extension, Pearre to North Branch, from WM milepost 125 to 160, Pearre, Washington County, MD

Why do people google movement disorders? An infodemiological study of information seeking behaviors.

PubMed

Brigo, Francesco; Erro, Roberto

2016-05-01

Millions of people worldwide everyday search Google or Wikipedia to look for health-related information. Aim of this study was to evaluate and interpret web search queries for terms related to movement disorders (MD) in English-speaking countries and their changes over time. We analyzed information regarding the volume of online searches in Google and Wikipedia for the most common MD and their treatments. We determined the highest search volume peaks to identify possible relation with online news headlines. The volume of searches for some queries related to MD entered in Google enormously increased over time. Most queries were related to definition, subtypes, symptoms and treatment (mostly to adverse effects, or alternatively, to possible alternative treatments). The highest peaks of MD search queries were temporally related to news about celebrities suffering from MD, to specific mass-media events or to news concerning pharmaceutic companies or scientific discoveries on MD. An increasing number of people use Google and Wikipedia to look for terms related to MD to obtain information on definitions, causes and symptoms, possibly to aid initial self-diagnosis. MD information demand and the actual prevalence of different MDs do not travel together: web search volume may mirrors patients' fears and worries about some particular disorders perceived as more serious than others, or may be driven by release of news about celebrities suffering from MD, "breaking news" or specific mass-media events regarding MD.

Structural and functional analyses of genes encoding VQ proteins in apple.

PubMed

Dong, Qinglong; Zhao, Shuang; Duan, Dingyue; Tian, Yi; Wang, Yanpeng; Mao, Ke; Zhou, Zongshan; Ma, Fengwang

2018-07-01

Recent studies with Arabidopsis and soybean have shown that a class of valine-glutamine (VQ) motif-containing proteins interacts with some WRKY transcription factors. However, little is known about the evolution, structures, and functions of those proteins in apple. Here, we examined their features and identified 49 apple VQ genes. Our evolutional analysis revealed that the proteins could be clustered into nine groups together with their homologues in 33 species. Historically, the main characteristics of proteins in Groups I, V, VI, VII, IX, and X were thought to have been generated before the monocot-dicot split, whereas those in Groups II, III + IV, and VIII were generated after that split. In the structural analysis, apple MdVQ proteins appeared to bind only with Group I and IIc MdWRKY proteins. Meanwhile, MdVQ1, MdVQ10, MdVQ15, and MdVQ36 interacted with multiple MdVQ proteins to form heterodimers but MdVQ15 formed a homodimer. The functional analysis indicated that overexpression of some apple MdVQs in Arabidopsis and tobacco plants effected their vegetative and reproductive growth. These results provide important information about the characteristics of apple MdVQ genes and can serve as a solid foundation for further studies about the role of WRKY-VQ interactions in regulating apple developmental and defense mechanisms. Copyright © 2018 Elsevier B.V. All rights reserved.

Malaria, Moderate to Severe Anaemia, and Malarial Anaemia in Children at Presentation to Hospital in the Mount Cameroon Area: A Cross-Sectional Study

PubMed Central

Taiwe, Germain Sotoing

2016-01-01

Background. Malaria remains a major killer of children in Sub-Saharan Africa, while anaemia is a public health problem with significant morbidity and mortality. Examining the factors associated with moderate to severe anaemia (MdSA) and malarial anaemia as well as the haematological characteristics is essential. Methodology. Children (1–14 years) at presentation at the Regional Hospital Annex-Buea were examined clinically and blood samples were collected for malaria parasite detection and full blood count evaluation. Results. Plasmodium falciparum, anaemia, and malarial anaemia occurred in 33.8%, 62.0%, and 23.6% of the 216 children, respectively. Anaemia prevalence was significantly higher in malaria parasite positive children and those with fever than their respective counterparts. MdSA and moderate to severe malarial anaemia (MdSMA) were detected in 38.0% and 15.3% of the participants, respectively. The prevalence of MdSA was significantly higher in children whose household head had no formal education, resided in the lowland, or was febrile, while MdSMA was significantly higher in febrile children only. Children with MdSMA had significantly lower mean white blood cell, lymphocyte, and platelet counts while the mean granulocyte count was significantly higher. Conclusion. Being febrile was the only predictor of both MdSA and MdSMA. More haematological insult occurred in children with MdSMA compared to MdSA. PMID:27895939

The MdTFL1 gene of apple (Malus x domestica Borkh.) reduces vegetative growth and generation time.

PubMed

Flachowsky, Henryk; Szankowski, Iris; Waidmann, Sascha; Peil, Andreas; Tränkner, Conny; Hanke, Magda-Viola

2012-10-01

TFL1 is known as a floral repressor in Arabidopsis thaliana (L.) Heynh. In apple there are two TFL1 homologs, MdTFL1-1 and MdTFL1-2. The MdTFL1-1 gene was silenced in transgenic clones expressing a hairpin gene construct of a 323 bp fragment of MdTFL1-1. The hairpin gene construct was transferred to three different apple genotypes. Of 22 transgenic clones, 21 showed a significant reduction in MdTFL1-1 mRNA expression. Precocious flowering was obtained for 20 clones, which flowered already during in vitro cultivation. Nineteen clones could successfully be transferred to the greenhouse where 18 of them flowered within a few weeks followed by the death or at least a strongly inhibited vegetative growth of the plant. Most of the transgenic flowers developed abnormally. Results obtained on greenhouse-grown plants of the transgenic clones and transgenic seedlings clearly demonstrated the major role of MdTFL1 genes in maintaining the vegetative growth as prerequisite for a perennial lifecycle. It was shown that MdTFL1 dsRNAi promotes a life history similar to annual plants. Preliminary results obtained from grafting experiments with non-transgenic scions grafted onto MdTFL1 dsRNAi transgenic rootstocks indicated that the flower-inducing signal obtained after silencing of MdTFL1 genes seems not to be graft-transmissible.

Experience-enabled enhancement of adult visual cortex function.

PubMed

Tschetter, Wayne W; Alam, Nazia M; Yee, Christopher W; Gorz, Mario; Douglas, Robert M; Sagdullaev, Botir; Prusky, Glen T

2013-03-20

We previously reported in adult mice that visuomotor experience during monocular deprivation (MD) augmented enhancement of visual-cortex-dependent behavior through the non-deprived eye (NDE) during deprivation, and enabled enhanced function to persist after MD. We investigated the physiological substrates of this experience-enabled form of adult cortical plasticity by measuring visual behavior and visually evoked potentials (VEPs) in binocular visual cortex of the same mice before, during, and after MD. MD on its own potentiated VEPs contralateral to the NDE during MD and shifted ocular dominance (OD) in favor of the NDE in both hemispheres. Whereas we expected visuomotor experience during MD to augment these effects, instead enhanced responses contralateral to the NDE, and the OD shift ipsilateral to the NDE were attenuated. However, in the same animals, we measured NMDA receptor-dependent VEP potentiation ipsilateral to the NDE during MD, which persisted after MD. The results indicate that visuomotor experience during adult MD leads to enduring enhancement of behavioral function, not simply by amplifying MD-induced changes in cortical OD, but through an independent process of increasing NDE drive in ipsilateral visual cortex. Because the plasticity is resident in the mature visual cortex and selectively effects gain of visual behavior through experiential means, it may have the therapeutic potential to target and non-invasively treat eye- or visual-field-specific cortical impairment.

Comparison of mean deviation with AGIS and CIGTS scores in association with structural parameters in glaucomatous eyes.

PubMed

Naka, Maiko; Kanamori, Akiyasu; Tatsumi, Yasuko; Fujioka, Miyuki; Nagai-Kusuhara, Azusa; Nakamura, Makoto; Negi, Akira

2009-01-01

To evaluate which of the 3 clinically used visual field indices including mean deviation (MD), Advanced Glaucoma Intervention Study (AGIS) score, and Collaborative Initial Glaucoma Treatment Study (CIGTS) score are best in evaluating functional damage of glaucomatous optic neuropathy. In 213 glaucomatous eyes, peripapillary retinal nerve fiber layer thickness (RNFLT) and optic disc configuration were measured with Stratus optical coherence tomography and Heidelberg Retina Tomograph-2, respectively. Visual field was measured with standard automated perimetry 30-2. Correlations of the structural parameters compared with the 3 VF indices using second polynomial regression were calculated. In addition, these correlations were analyzed among eyes of 3 different stages of glaucoma, as defined by MD score (early, MD> or =-6 dB; moderate, -12 dB< or =MD<-6 dB; advanced, MD<-12 dB). Among structure-function relationships in all subjects, the highest correlation determination (R) was MD with RNFLT (=0.298). CIGTS score showed better R than MD or AGIS score with rim area, but these values were not higher than any R with RNFLT. In analyses of 3 groups depending on MD, statistically significant structure-function correlations were observed only in patients with an advanced stage. No clear difference was found among MD and AGIS/CIGTS scores in expressing functional damage of glaucomatous eyes. MD is suggested to be no worse than others in monitoring glaucoma in clinical setting.

Do word-problem features differentially affect problem difficulty as a function of students' mathematics difficulty with and without reading difficulty?

PubMed

Powell, Sarah R; Fuchs, Lynn S; Fuchs, Douglas; Cirino, Paul T; Fletcher, Jack M

2009-01-01

This study examined whether and, if so, how word-problem features differentially affect problem difficulty as a function of mathematics difficulty (MD) status: no MD (n = 109), MD only (n = 109), or MD in combination with reading difficulties (MDRD; n = 109). The problem features were problem type (total, difference, or change) and position of missing information in the number sentence representing the word problem (first, second, or third position). Students were assessed on 14 word problems near the beginning of third grade. Consistent with the hypothesis that mathematical cognition differs as a function of MD subtype, problem type affected problem difficulty differentially for MDRD versus MD-only students; however, the position of missing information in word problems did not. Implications for MD subtyping and for instruction are discussed.

Reconfigurable Flight Control System for a STOL (Short Take-Off and Landing) Aircraft Using Quantitative Feedback Theory.

DTIC Science & Technology

1984-12-01

XD2, XD3, XD4, XD5, XD6, XD7, XDS, 7M1, MA, MH, M0,MU, MDl,MD2, MD3, MD4, M5, MOS, MD7, MDS REAL CNB, CYB, CL, L, N DIMENSION AMAT(4,4), BMAT (4,S...NO, MU, ND1, MD2, ND3, MD4,ND5, MD6, ND7, NO REAL CNB, CYB, CL, L, N DIMENSION AMAT(4,4), BMAT (4,S)V DIMENSION DIRMAT(5, 5) ,DIRBMAT(5, SJ CHARACTER*3...INPUT MATRIX 8 C BMAT (l,1) - XO1 BMAT (1,2) - X02 BMAT (1,3) = XD3 BMAT (1,4) -XO4 SMAT(1,5) -XD5 BMAT (1,&) - XDG BMQT(1,7) = XD7 EMAT(I,8) - XDB BMAT (,1

The cold-induced basic helix-loop-helix transcription factor gene MdCIbHLH1 encodes an ICE-like protein in apple

PubMed Central

2012-01-01

Background Plant growth is greatly affected by low temperatures, and the expression of a number of genes is induced by cold stress. Although many genes in the cold signaling pathway have been identified in Arabidopsis, little is known about the transcription factors involved in the cold stress response in apple. Results Here, we show that the apple bHLH (basic helix-loop-helix) gene MdCIbHLH1 (Cold-Induced bHLH1), which encodes an ICE-like protein, was noticeably induced in response to cold stress. The MdCIbHLH1 protein specifically bound to the MYC recognition sequences in the AtCBF3 promoter, and MdCIbHLH1 overexpression enhanced cold tolerance in transgenic Arabidopsis. In addition, the MdCIbHLH1 protein bound to the promoters of MdCBF2 and favorably contributed to cold tolerance in transgenic apple plants by upregulating the expression of MdCBF2 through the CBF (C-repeat-binding factor) pathway. Our findings indicate that MdCIbHLH1 functions in stress tolerance in different species. For example, ectopic MdCIbHLH1 expression conferred enhanced chilling tolerance in transgenic tobacco. Finally, we observed that cold induces the degradation of the MdCIbHLH1 protein in apple and that this degradation was potentially mediated by ubiquitination and sumoylation. Conclusions Based on these findings, MdCIbHLH1 encodes a transcription factor that is important for the cold tolerance response in apple. PMID:22336381

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task

PubMed Central

Miller, Rikki L.A.

2017-01-01

Abstract The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior. PMID:29034318

Mediodorsal Thalamic Neurons Mirror the Activity of Medial Prefrontal Neurons Responding to Movement and Reinforcement during a Dynamic DNMTP Task.

PubMed

Miller, Rikki L A; Francoeur, Miranda J; Gibson, Brett M; Mair, Robert G

2017-01-01

The mediodorsal nucleus (MD) interacts with medial prefrontal cortex (mPFC) to support learning and adaptive decision-making. MD receives driver (layer 5) and modulatory (layer 6) projections from PFC and is the main source of driver thalamic projections to middle cortical layers of PFC. Little is known about the activity of MD neurons and their influence on PFC during decision-making. We recorded MD neurons in rats performing a dynamic delayed nonmatching to position (dDNMTP) task and compared results to a previous study of mPFC with the same task (Onos et al., 2016). Criterion event-related responses were observed for 22% (254/1179) of neurons recorded in MD, 237 (93%) of which exhibited activity consistent with mPFC response types. More MD than mPFC neurons exhibited responses related to movement (45% vs. 29%) and reinforcement (51% vs. 27%). MD had few responses related to lever presses, and none related to preparation or memory delay, which constituted 43% of event-related activity in mPFC. Comparison of averaged normalized population activity and population response times confirmed the broad similarity of common response types in MD and mPFC and revealed differences in the onset and offset of some response types. Our results show that MD represents information about actions and outcomes essential for decision-making during dDNMTP, consistent with evidence from lesion studies that MD supports reward-based learning and action-selection. These findings support the hypothesis that MD reinforces task-relevant neural activity in PFC that gives rise to adaptive behavior.

The knock-down of the expression of MdMLO19 reduces susceptibility to powdery mildew (Podosphaera leucotricha) in apple (Malus domestica).

PubMed

Pessina, Stefano; Angeli, Dario; Martens, Stefan; Visser, Richard G F; Bai, Yuling; Salamini, Francesco; Velasco, Riccardo; Schouten, Henk J; Malnoy, Mickael

2016-10-01

Varieties resistant to powdery mildew (PM; caused by Podosphaera leucotricha) are a major component of sustainable apple production. Resistance can be achieved by knocking-out susceptibility S-genes to be singled out among members of the MLO (Mildew Locus O) gene family. Candidates are MLO S-genes of phylogenetic clade V up-regulated upon PM inoculation, such as MdMLO11 and 19 (clade V) and MdMLO18 (clade VII). We report the knock-down through RNA interference of MdMLO11 and 19, as well as the complementation of resistance with MdMLO18 in the Arabidopsis thaliana triple mlo mutant Atmlo2/6/12. The knock-down of MdMLO19 reduced PM disease severity by 75%, whereas the knock-down of MdMLO11, alone or in combination with MdMLO19, did not result in any reduction or additional reduction of susceptibility compared with MdMLO19 alone. The test in A. thaliana excluded a role for MdMLO18 in PM susceptibility. Cell wall appositions (papillae) were present in both PM-resistant and PM-susceptible plants, but were larger in resistant lines. No obvious negative phenotype was observed in plants with mlo genes knocked down. Apparently, MdMLO19 plays the pivotal role in apple PM susceptibility and its knock-down induces a very significant level of resistance. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

Studies of the TLR4-associated protein MD-2 using yeast-display and mutational analyses

PubMed Central

Mattis, Daiva M.; Chervin, Adam; Ranoa, Diana; Kelley, Stacy; Tapping, Richard; Kranz, David M.

2015-01-01

Bacterial lipopolysaccharide (LPS) activates the innate immune system by forming a complex with myeloid differentiation factor 2 (MD-2) and Toll-like receptor 4 (TLR4), which is present on antigen presenting cells. MD-2 plays an essential role in this activation of the innate immune system as a member of the ternary complex, TLR4:MD-2:LPS. With the goal of further understanding the molecular details of the interaction of MD-2 with LPS and TLR4, and possibly toward engineering dominant negative regulators of the MD-2 protein, here we subjected MD-2 to a mutational analysis using yeast display. The approach included generation of site-directed alanine mutants, and ligand-driven selections of MD-2 mutant libraries. Our findings showed that: 1) proline mutations in the F119-K132 loop that binds LPS were strongly selected for enhanced yeast surface stability, 2) there was a preference for positive-charged side chains (R/K) at residue 120 for LPS binding, and negative-charged side chains (D/E) for TLR4 binding, 3) aromatic residues were strongly preferred at F119 and F121 for LPS binding, and 4) an MD-2 mutant (T84N/D101A/S118A/S120D/K122P) exhibited increased binding to TLR4 but decreased binding to LPS. These studies revealed the impact of specific residues and regions of MD-2 on the binding of LPS and TLR4, and they provide a framework for further directed evolution of the MD-2 protein. PMID:26320630

Species-Specific Activation of TLR4 by Hypoacylated Endotoxins Governed by Residues 82 and 122 of MD-2

PubMed Central

Oblak, Alja; Jerala, Roman

2014-01-01

The Toll-like receptor 4/MD-2 receptor complex recognizes endotoxin, a Gram-negative bacterial cell envelope component. Recognition of the most potent hexaacylated form of endotoxin is mediated by the sixth acyl chain that protrudes from the MD-2 hydrophobic pocket and bridges TLR4/MD-2 to the neighboring TLR4 ectodomain, driving receptor dimerization via hydrophobic interactions. In hypoacylated endotoxins all acyl chains could be accommodated within the binding pocket of the human hMD-2. Nevertheless, tetra- and pentaacylated endotoxins activate the TLR4/MD-2 receptor of several species. We observed that amino acid residues 82 and 122, located at the entrance to the endotoxin binding site of MD-2, have major influence on the species-specific endotoxin recognition. We show that substitution of hMD-2 residue V82 with an amino acid residue with a bulkier hydrophobic side chain enables activation of TLR4/MD-2 by pentaacylated and tetraacylated endotoxins. Interaction of the lipid A phosphate group with the amino acid residue 122 of MD-2 facilitates the appropriate positioning of the hypoacylated endotoxin. Moreover, mouse TLR4 contributes to the agonistic effect of pentaacylated msbB endotoxin. We propose a molecular model that explains how the molecular differences between the murine or equine MD-2, which both have sufficiently large hydrophobic pockets to accommodate all five or four acyl chains, influence the positioning of endotoxin so that one of the acyl chains remains outside the pocket and enables hydrophobic interactions with TLR4, leading to receptor activation. PMID:25203747

Species-specific activation of TLR4 by hypoacylated endotoxins governed by residues 82 and 122 of MD-2.

PubMed

Oblak, Alja; Jerala, Roman

2014-01-01

The Toll-like receptor 4/MD-2 receptor complex recognizes endotoxin, a Gram-negative bacterial cell envelope component. Recognition of the most potent hexaacylated form of endotoxin is mediated by the sixth acyl chain that protrudes from the MD-2 hydrophobic pocket and bridges TLR4/MD-2 to the neighboring TLR4 ectodomain, driving receptor dimerization via hydrophobic interactions. In hypoacylated endotoxins all acyl chains could be accommodated within the binding pocket of the human hMD-2. Nevertheless, tetra- and pentaacylated endotoxins activate the TLR4/MD-2 receptor of several species. We observed that amino acid residues 82 and 122, located at the entrance to the endotoxin binding site of MD-2, have major influence on the species-specific endotoxin recognition. We show that substitution of hMD-2 residue V82 with an amino acid residue with a bulkier hydrophobic side chain enables activation of TLR4/MD-2 by pentaacylated and tetraacylated endotoxins. Interaction of the lipid A phosphate group with the amino acid residue 122 of MD-2 facilitates the appropriate positioning of the hypoacylated endotoxin. Moreover, mouse TLR4 contributes to the agonistic effect of pentaacylated msbB endotoxin. We propose a molecular model that explains how the molecular differences between the murine or equine MD-2, which both have sufficiently large hydrophobic pockets to accommodate all five or four acyl chains, influence the positioning of endotoxin so that one of the acyl chains remains outside the pocket and enables hydrophobic interactions with TLR4, leading to receptor activation.

Linking the Regulatory and Reimbursement Processes for Medical Devices: The Need for Integrated Assessments.

PubMed

Ciani, Oriana; Wilcher, Britni; van Giessen, Anoukh; Taylor, Rod S

2017-02-01

Much criticism has been directed at the licencing requirements for medical devices (MDs) as they often result in a lack of robust evidence to inform health technology assessment (HTA) decisions. To better understand the current international decisional framework on MD technologies, we undertook three linked research studies: a review of the device regulatory procedures, a survey of current HTA practices and an empirical comparison of HTA reports of drugs versus MDs. Our review confirms that current device regulatory processes across the globe are substantially less stringent than drugs. As a result, international HTA agencies report that they face a number of challenges when assessing MDs, including reliance on suboptimal data to make clinical and cost-effectiveness decisions. Whilst many HTA agencies have adapted their processes and procedures to handle MD technology submissions, in our comparison of HTA reports we found little evidence of the application of methodologies that take account of device-specific issues, such as incremental development. Overall, our research reinforces the need for better linkage between licencing and HTA and the development and application of innovative HTA methodologies with the objective of securing faster patient access for those technologies that can be shown to represent good value for money. © 2017 The Authors. Health Economics Published by John Wiley & Sons, Ltd. © 2017 The Authors. Health Economics Published by John Wiley & Sons, Ltd.

75 FR 11563 - Jovencio L. Raneses, M.D.; Denial of Application

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-11

... DEPARTMENT OF JUSTICE Drug Enforcement Administration Jovencio L. Raneses, M.D.; Denial of... Enforcement Administration, issued an Order to Show Cause to Jovencio L. Raneses, M.D. (Respondent), of San... issued by the Medical Board of California. See In re Jovencio L. Raneses, M.D., Default Decision and...

76 FR 51424 - Satinder Dang, M.D.; Revocation of Registration

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-18

... DEPARTMENT OF JUSTICE Drug Enforcement Administration [Docket No. 10-4] Satinder Dang, M.D... Control, Drug Enforcement Administration, issued an Order to Show Cause to Satinder K. Dang, M.D....'' Id. (citing Harrell E. Robinson, M.D., 74 FR 61370, 61376-77 (2010)). The ALJ also found that...

77 FR 67673 - Fernando Valle, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-13

... DEPARTMENT OF JUSTICE Drug Enforcement Administration [Docket No. 12-56] Fernando Valle, M.D... Certificate of Registration Numbers FV1935595, FV2000711, and FV2000735, issued to Fernando Valle, M.D., be, and they hereby are, revoked. I further order that any pending applications of Fernando Valle, M.D...

Optimal Ozone Control with Inclusion of Spatiotemporal Marginal Damages and Electricity Demand.

PubMed

Mesbah, S Morteza; Hakami, Amir; Schott, Stephan

2015-07-07

Marginal damage (MD), or damage per ton of emission, is a policy metric used for effective pollution control and reducing the corresponding adverse health impacts. However, for a pollutant such as NOx, the MD varies by the time and location of the emissions, a complication that is not adequately accounted for in the currently implemented economic instruments. Policies accounting for MD information would aim to encourage emitters with large MDs to reduce their emissions. An optimization framework is implemented to account for NOx spatiotemporal MDs calculated through adjoint sensitivity analysis and to simulate power plants' behavior under emission and simplified electricity constraints. The results from a case study of U.S. power plants indicate that time-specific MDs are high around noon and low in the evening. Furthermore, an emissions reduction of about 40% and a net benefit of about $1200 million can be gained for this subset of power plants if a larger fraction of the electricity demand is supplied by power plants at low-damage times and in low-damage locations. The results also indicate that the consideration of temporal effects in NOx control policies results in a comparable net benefit to the consideration of spatial or spatiotemporal effects, thus providing a promising option for policy development.

Molecular dynamics simulation of dioxygen pathways through mini singlet oxygen generator (miniSOG), a genetically encoded marker and killer protein.

PubMed

Pietra, Francesco

2014-12-01

In this work, molecular dynamics (MD) simulations of the permeation of proteins by small gases of biological significance have been extended from gas carrier, sensor, and enzymatic proteins to genetically encoded tags and killer proteins. To this end, miniSOG was taken as an example of current high interest, using a biased form of MD, called random-acceleration MD. Various egress gates and binding pockets for dioxygen, as an indistinguishable mimic of singlet dioxygen, were found on both above and below the isoalloxazine plane of the flavin mononucleotide cofactor in miniSOG. Of such gates and binding pockets, those lying within two opposite cones, coaxial with a line normal to the isoalloxazine plane, and with the vertex at the center of such a plane are those most visited by the escaping gas molecule. Out of residues most capable of quenching (1) O2 , Y30, lying near the base of one such a cone, and H85, near the base of the opposite cone, are held to be most responsible for the reduced quantum yield of (1) O2 with folded miniSOG with respect to free flavin mononucleotide in solution. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

Acne conglobata in a long-term survivor with trisomy 13, accompanied by selective IgM deficiency.

PubMed

Inoue, Chiyoko N; Tanaka, Yoshiko; Tabata, Nobuko

2017-05-07

Trisomy 13 (T13) is a congenital chromosomal disorder that is usually fatal within 2 years of birth, and only a few patients have been reported to reach adolescence. Here, we report a male long-term survivor of T13, currently 15 years of age, with a several-year history of extensive acne conglobata (AC) with abscesses on the face and neck. Methicillin-resistant Staphylococcus aureus was consistently isolated from the pustular lesions. Serum IgM levels were extremely low at 10 mg/dl. There were no abnormalities in neutrophil and total B cell number, or in serum IgA and IgG levels. Increased CD8+ T cell counts and inversion of the CD4/CD8 ratio were observed repeatedly. The patient's clinical features and laboratory data support a diagnosis of selective IgM deficiency (SIgMD) with concurrent AC. Immunoglobulin replacement therapy elevated serum IgM levels to the normal range and reduced the severity of AC. We suggest that T13 may represent a syndromic disorder associated with multiple organ malformation and a risk of developing immunodeficiency involving SIgMD. Because pediatric SIgMD is rare and an immunological abnormality in T13 patients has not previously been reported, we describe the patient's clinical course. © 2017 Wiley Periodicals, Inc.

Sac surgery results as a function of preoperative distress level.

PubMed

Tyagi, Isha; Goyal, Amit; Syal, Rajan

2006-10-01

To evaluate the postoperative status of the patients after endolymphatic sac decompression (ESD) for intractable unilateral definite Ménière's disease (MD) using the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) 1995 criteria and to discuss the current status of ESD in the management of MD, especially after the wide use of intratympanic administration of gentamicin for the treatment of intractable MD. Retrospective questionnaire-based analysis. Thirty-nine patients who had undergone ESD between 1996 and May 2003 at Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, were evaluated via a set format according to AAO-HNS 1995 guidelines. Their preoperative and postoperative data were compared. We found significant improvement in functional level scales (FLSs) in 84.6%, Class A vertigo control in 82%, and improved disability outcome in 87% of cases after surgery at a median postoperative follow-up of 29 months. All the patients showing significant improvement in FLS were preoperatively in scale 4 or more, and all the patients whose treatment failed were in scale 3 or less. We recommend continued use of ESD in indicated patients. We found a positive relation between preoperative distress level of the patient and postoperative improvement in FLSs; any such relationship should be investigated with a larger sample.

Rehabilitative technology use among individuals with Duchenne/Becker muscular dystrophy.

PubMed

Pandya, Shree; Andrews, Jennifer; Campbell, Kim; Meaney, F John

2016-01-01

To document use of rehabilitative technology among individuals with Duchenne/Becker muscular dystrophy (DBMD) among sites of the Muscular Dystrophy Surveillance, Tracking, and Research network (MD STARnet). Data from 362 caregivers who participated in the MD STARnet caregiver interview between April 2006 and March 2012 (54.7% response rate) were analyzed to assess the type, frequency and duration of use of assistive technology. Caregiver reports of technology use by individuals with DBMD across five MD STARnet sites in the US demonstrated significant regional differences in the proportion of individuals who had ever used night splints (36.9%-73.0%), standers (3.1%-22.2%) and scooters (10.7%-54.5%). Among individuals who used night splints 59.7% stopped using them at a mean age of 10.3 years after a mean duration of 2.9 years in spite of the current recommendation to continue using them through the non-ambulatory phase. Results of this comprehensive survey document the frequency of assistive device use by individuals with DBMD in the USA and also provides data on differences across the sites. Further research is needed to understand the reasons for and the impact of these differences on clinical outcomes and health related quality of life of individuals with DBMD.

Chemical chaperone ameliorates pathological protein aggregation in plectin-deficient muscle

PubMed Central

Winter, Lilli; Staszewska, Ilona; Mihailovska, Eva; Fischer, Irmgard; Goldmann, Wolfgang H.; Schröder, Rolf; Wiche, Gerhard

2014-01-01

The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin-positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4-phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD. PMID:24487589

Phase II trial suggests new drug can shrink tumors in advanced ovarian cancer | Center for Cancer Research

Cancer.gov

In an ongoing phase II trial led by Jung-Min Lee, M.D., an Investigator in CCR’s Women’s Malignancies Branch, using the drug prexasertib led to decreases in tumor size in patients with advanced ovarian cancer, known as high-grade serious ovarian carcinoma, who currently have limited treatment options. Read more…

Hazardous Waste Minimization Assessment: Fort Meade, MD

DTIC Science & Technology

1991-01-01

Manual TSCA Toxic Substances Control Act TSDF T.xatment. Storage, and Disposal Facility USACERL U.S. Army Construction Engineering Research Laboratory...generation; and current methods of treatment, storage, and disposal, researchers conducted feasibility and economicanalyses of milnimizaion options...Bernard A. Donahue 7. PERFORMING ORGANIZATION NAME(S) ANO ADO ESS(ES) S. PERFORMING ORGANIZATION REPORT NUMBER U.S. Army Construction Engineering Research

78 FR 73739 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-09

...). SUMMARY: We propose to supersede Airworthiness Directives (ADs) 97-11- 07 and AD 99-18-23, which apply to all The Boeing Company Model MD-90- 30 airplanes. AD 97-11-07 and AD 99-18-23 currently require... for safe-life limited parts. Since we issued AD 97-11-07 and AD 99-18- 23, an analysis of data...

The 1993 Goddard Conference on Space Applications of Artificial Intelligence

NASA Technical Reports Server (NTRS)

Hostetter, Carl F. (Editor)

1993-01-01

This publication comprises the papers presented at the 1993 Goddard Conference on Space Applications of Artificial Intelligence held at the NASA/Goddard Space Flight Center, Greenbelt, MD on May 10-13, 1993. The purpose of this annual conference is to provide a forum in which current research and development directed at space applications of artificial intelligence can be presented and discussed.

Computation and analysis of the transverse current autocorrelation function, Ct(k,t), for small wave vectors: A molecular-dynamics study for a Lennard-Jones fluid

NASA Astrophysics Data System (ADS)

Vogelsang, R.; Hoheisel, C.

1987-02-01

Molecular-dynamics (MD) calculations are reported for three thermodynamic states of a Lennard-Jones fluid. Systems of 2048 particles and 105 integration steps were used. The transverse current autocorrelation function, Ct(k,t), has been determined for wave vectors of the range 0.5<||k||σ<1.5. Ct(k,t) was fitted by hydrodynamic-type functions. The fits returned k-dependent decay times and shear viscosities which showed a systematic behavior as a function of k. Extrapolation to the hydrodynamic region at k=0 gave shear viscosity coefficients in good agreement with direct Green-Kubo results obtained in previous work. The two-exponential model fit for the memory function proposed by other authors does not provide a reasonable description of the MD results, as the fit parameters show no systematic wave-vector dependence, although the Ct(k,t) functions are somewhat better fitted. Similarly, the semiempirical interpolation formula for the decay time based on the viscoelastic concept proposed by Akcasu and Daniels fails to reproduce the correct k dependence for the wavelength range investigated herein.

Sublattice parallel replica dynamics.

PubMed

Martínez, Enrique; Uberuaga, Blas P; Voter, Arthur F

2014-06-01

Exascale computing presents a challenge for the scientific community as new algorithms must be developed to take full advantage of the new computing paradigm. Atomistic simulation methods that offer full fidelity to the underlying potential, i.e., molecular dynamics (MD) and parallel replica dynamics, fail to use the whole machine speedup, leaving a region in time and sample size space that is unattainable with current algorithms. In this paper, we present an extension of the parallel replica dynamics algorithm [A. F. Voter, Phys. Rev. B 57, R13985 (1998)] by combining it with the synchronous sublattice approach of Shim and Amar [ and , Phys. Rev. B 71, 125432 (2005)], thereby exploiting event locality to improve the algorithm scalability. This algorithm is based on a domain decomposition in which events happen independently in different regions in the sample. We develop an analytical expression for the speedup given by this sublattice parallel replica dynamics algorithm and compare it with parallel MD and traditional parallel replica dynamics. We demonstrate how this algorithm, which introduces a slight additional approximation of event locality, enables the study of physical systems unreachable with traditional methodologies and promises to better utilize the resources of current high performance and future exascale computers.

A surgeon and a soldier--an interview with Booker King, MD, FACS. Interview by George Dawson.

PubMed

King, Booker

2005-05-01

Periodically, for the past two years, the editorial staff of the Journal of the National Association has attempted to-for history's sake--highlight physicians of color. In this vein, and in light of the current hostile activities in the Persian Gulf, we felt it important we our bring readers, in this issue, the background and views of an African-American physician/soldier who served in the Iraqi theater of operations during the initial combat. Notwithstanding the current political machinations regarding the legitimacy of the conflict, his story is both insightful and inspiring because, in the end, it is soldiers and their families who bear the psychological and physical burden of armed conflicts. Finally, because of the history of privation that persons of African ancestry have had to endure in these lands, we feel it important that we, in these times, tell our story, on our terms. And Dr. Booker's story is one we feel truly proud to present. This interview was conducted by George Dawson, MD. He serves as editor of the Art in Medicine, History and Health Tidbit sections of the Journal of the National Medical Association.

Progress on Numerical Modeling of the Dispersion of Ceramic Nanoparticles During Ultrasonic Processing and Solidification of Al-Based Nanocomposites

NASA Astrophysics Data System (ADS)

Zhang, Daojie; Nastac, Laurentiu

2016-12-01

In present study, 6061- and A356-based nano-composites are fabricated by using the ultrasonic stirring technology (UST) in a coreless induction furnace. SiC nanoparticles are used as the reinforcement. Nanoparticles are added into the molten metal and then dispersed by ultrasonic cavitation and acoustic streaming assisted by electromagnetic stirring. The applied UST parameters in the current experiments are used to validate a recently developed magneto-hydro-dynamics (MHD) model, which is capable of modeling the cavitation and nanoparticle dispersion during UST processing. The MHD model accounts for turbulent fluid flow, heat transfer and solidification, and electromagnetic field, as well as the complex interaction between the nanoparticles and both the molten and solidified alloys by using ANSYS Maxwell and ANSYS Fluent. Molecular dynamics (MD) simulations are conducted to analyze the complex interactions between the nanoparticle and the liquid/solid interface. The current modeling results demonstrate that a strong flow can disperse the nanoparticles relatively well during molten metal and solidification processes. MD simulation results prove that ultrafine particles (10 nm) will be engulfed by the solidification front instead of being pushed, which is beneficial for nano-dispersion.

Studies of Tissue Perfusion Failure at LAC+USCMC and the Incorporation of the Results into a National Trauma Database

DTIC Science & Technology

2005-04-01

Context Link] 29. Gibson JG, Seligman AM, Peacock WC, et al: The circulating red cell and plasma volume and the distribution of blood in large and...BS; Gandhi, Ashutosh BS; Chien, Li-Chien MD; Lu, Kevin MD; Martin, Matthew J. MD; Chan, Linda S. PhD; Demetriades, Demetrios MD, PhD; Ahmadpour...Physicians Outcome Prediction of Emergency Patients by Noninvasive Hemodynamic Monitoring* William C. Shoemaker, MD; Charles C. J. Wo, BS; Linda

Developmental Precursors of Moral Disengagement and the Role of Moral Disengagement in the Development of Antisocial Behavior

PubMed Central

Shaw, Daniel S.; Moilanen, Kristin L.

2010-01-01

The purpose of the study was to advance our understanding of the developmental precursors of Moral Disengagement (MD) and the role of MD in the development of antisocial behavior from early risk among an ethnically diverse sample of 187 low-income boys followed prospectively from ages 1.5 to 17. Results indicated associations between early rejecting parenting, neighborhood impoverishment, and child empathy and later MD. The link between some of these early constructs and later antisocial behavior was mediated by MD. Finally, in an exploratory path model both MD and biases in social information processing were found to mediate separate paths from early risk factors to later antisocial behavior. Results were partially consistent with the notion that adolescent MD was predicted by a combination of early family, neighborhood, and child risk factors, and that MD may be a mechanism underlying some boys' risk of antisocial behavior. PMID:19777337

Eating disorders and major depression: role of anger and personality.

PubMed

Giovanni, Abbate-Daga; Carla, Gramaglia; Enrica, Marzola; Federico, Amianto; Maria, Zuccolin; Secondo, Fassino

2011-01-01

This study aimed to evaluate comorbidity for MD in a large ED sample and both personality and anger as clinical characteristics of patients with ED and MD. We assessed 838 ED patients with psychiatric evaluations and psychometric questionnaires: Temperament and Character Inventory, Eating Disorder Inventory-2, Beck Depression Inventory, and State-Trait Anger Expression Inventory. 19.5% of ED patients were found to suffer from comorbid MD and 48.7% reported clinically significant depressive symptomatology: patients with Anorexia Binge-Purging and Bulimia Nervosa were more likely to be diagnosed with MD. Irritable mood was found in the 73% of patients with MD. High Harm Avoidance (HA) and low Self-Directedness (SD) predicted MD independently of severity of the ED symptomatology, several clinical variables, and ED diagnosis. Assessing both personality and depressive symptoms could be useful to provide effective treatments. Longitudinal studies are needed to investigate the pathogenetic role of HA and SD for ED and MD.

Nerve and muscle involvement in mitochondrial disorders: an electrophysiological study.

PubMed

Mancuso, Michelangelo; Piazza, Selina; Volpi, Leda; Orsucci, Daniele; Calsolaro, Valeria; Caldarazzo Ienco, Elena; Carlesi, Cecilia; Rocchi, Anna; Petrozzi, Lucia; Calabrese, Rosanna; Siciliano, Gabriele

2012-04-01

Involvement of the peripheral nervous system in mitochondrial disorders (MD) has been previously reported. However, the exact prevalence of peripheral neuropathy and/or myopathy in MD is still unclear. In order to evaluate the prevalence of neuropathy and myopathy in MD, we performed sensory and motor nerve conduction studies (NCS) and concentric needle electromyography (EMG) in 44 unselected MD patients. NCS were abnormal in 36.4% of cases, and were consistent with a sensori-motor axonal multineuropathy (multifocal neuropathy), mainly affecting the lower limbs. EMG evidence of myopathy was present in 54.5% of patients, again mainly affecting the lower limbs. Nerve and muscle involvement was frequently subclinical. Peripheral nerve and muscle involvement is common in MD patients. Our study supports the variability of the clinical expression of MD. Further studies are needed to better understand the molecular basis underlying the phenotypic variability among MD patients.

76 FR 48898 - Robert Leigh Kale, M.D., Decision and Order

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2013-02-04

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Multiscale molecular dynamics simulations of rotary motor proteins.

PubMed

Ekimoto, Toru; Ikeguchi, Mitsunori

2018-04-01

Protein functions require specific structures frequently coupled with conformational changes. The scale of the structural dynamics of proteins spans from the atomic to the molecular level. Theoretically, all-atom molecular dynamics (MD) simulation is a powerful tool to investigate protein dynamics because the MD simulation is capable of capturing conformational changes obeying the intrinsically structural features. However, to study long-timescale dynamics, efficient sampling techniques and coarse-grained (CG) approaches coupled with all-atom MD simulations, termed multiscale MD simulations, are required to overcome the timescale limitation in all-atom MD simulations. Here, we review two examples of rotary motor proteins examined using free energy landscape (FEL) analysis and CG-MD simulations. In the FEL analysis, FEL is calculated as a function of reaction coordinates, and the long-timescale dynamics corresponding to conformational changes is described as transitions on the FEL surface. Another approach is the utilization of the CG model, in which the CG parameters are tuned using the fluctuation matching methodology with all-atom MD simulations. The long-timespan dynamics is then elucidated straightforwardly by using CG-MD simulations.

Torsion of Meckel's Diverticulum in a Child

PubMed Central

Nose, Satoko; Okuyama, Hiroomi; Sasaki, Takashi; Nishimura, Mika

2013-01-01

Meckel's diverticulum (MD) is a common congenital anomaly of the gastrointestinal tract, the majority of cases of which are clinically silent. Patients with asymptomatic MD can unexpectedly develop acute abdominal pain. Making a diagnosis of MD is often difficult due to the lack of specific symptoms caused by this condition. Diagnostic laparotomy can be useful for making an accurate and prompt diagnosis of complicated MD. We herein describe a pediatric case of torsion of a MD in whom we performed laparoscopic-assisted emergency surgery. The patient was an 11-year-old male who developed sudden severe right lower abdominal pain. Clinical and laboratory findings were suggestive of appendicitis, however computed tomography scans showed a large cystic mass in the pelvis. Exploratory laparoscopy led to a diagnosis of torsion of a MD, and wedge resection of the gangrenous MD was performed through an umbilical port incision. The patient's postoperative course was uneventful. We conclude that diagnostic laparoscopy followed by laparoscopy-assisted Meckel's diverticulectomy via an umbilical incision is useful in the treatment of acute abdomen caused by MD. PMID:23466748

In silico characterization of binding mode of CCR8 inhibitor: homology modeling, docking and membrane based MD simulation study.

PubMed

Gadhe, Changdev G; Balupuri, Anand; Cho, Seung Joo

2015-01-01

Human CC-chemokine receptor 8 (CCR8) is a crucial drug target in asthma that belongs to G-protein-coupled receptor superfamily, which is characterized by seven transmembrane helices. To date, there is no X-ray crystal structure available for CCR8; this hampers active research on the target. Molecular basis of interaction mechanism of antagonist with CCR8 remains unclear. In order to provide binding site information and stable binding mode, we performed modeling, docking and molecular dynamics (MD) simulation of CCR8. Docking study of biaryl-ether-piperidine derivative (13C) was performed inside predefined CCR8 binding site to get the representative conformation of 13C. Further, MD simulations of receptor and complex (13C-CCR8) inside dipalmitoylphosphatidylcholine lipid bilayers were performed to explore the effect of lipids. Results analyses showed that the Gln91, Tyr94, Cys106, Val109, Tyr113, Cys183, Tyr184, Ser185, Lys195, Thr198, Asn199, Met202, Phe254, and Glu286 were conserved in both docking and MD simulations. This indicated possible role of these residues in CCR8 antagonism. However, experimental mutational studies on these identified residues could be effective to confirm their importance in CCR8 antagonism. Furthermore, calculated Coulombic interactions represented the crucial roles of Glu286, Lys195, and Tyr113 in CCR8 antagonism. Important residues identified in this study overlap with the previous non-peptide agonist (LMD-009) binding site. Though, the non-peptide agonist and currently studied inhibitor (13C) share common substructure, but they differ in their effects on CCR8. So, to get more insight into their agonist and antagonist effects, further side-by-side experimental studies on both agonist (LMD-009) and antagonist (13C) are suggested.

Mineral density volume gradients in normal and diseased human tissues

DOE PAGES

Djomehri, Sabra I.; Candell, Susan; Case, Thomas; ...

2015-04-09

Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-raymore » fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.« less

Newborn screening: A disease-changing intervention for glutaric aciduria type 1.

PubMed

Boy, Nikolas; Mengler, Katharina; Thimm, Eva; Schiergens, Katharina A; Marquardt, Thorsten; Weinhold, Natalie; Marquardt, Iris; Das, Anibh M; Freisinger, Peter; Grünert, Sarah C; Vossbeck, Judith; Steinfeld, Robert; Baumgartner, Matthias R; Beblo, Skadi; Dieckmann, Andrea; Näke, Andrea; Lindner, Martin; Heringer, Jana; Hoffmann, Georg F; Mühlhausen, Chris; Maier, Esther M; Ensenauer, Regina; Garbade, Sven F; Kölker, Stefan

2018-05-01

Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive. This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children. The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study. NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979. © 2018 American Neurological Association.

Chinese Herbal Medicine for Acute Mountain Sickness: A Systematic Review of Randomized Controlled Trials

PubMed Central

Wang, Jie; Xiong, Xingjiang; Xing, Yanwei; Liu, Zhen; Jiang, Wenrui; Huang, Junyi; Feng, Bo

2013-01-01

Objectives. We aimed to assess the current clinical evidence of Chinese herbal medicine for AMS. Methods. Seven electronic databases were searched until January 2013. We included randomized clinical trials testing Chinese herbal medicine against placebo, no drugs, Western drugs, or a combination of routine treatment drugs against routine treatment drugs. Study selection, data extraction, quality assessment, and data analyses were conducted according to Cochrane standards. Results. Nine randomized trials were included. The methodological quality of the included trials was evaluated as low. Two trials compared prescriptions of Chinese formula used alone with Western drugs. A meta-analysis showed a beneficial effect in decreasing the score of AMS (MD: −2.23 [−3.98, −0.49], P = 0.01). Only one trial compared prescriptions of Chinese formula used alone with no drugs. A meta-analysis showed a significant beneficial effect in decreasing the score of AMS (MD: −6.00 [−6.45, −5.55], P < 0.00001). Four trials compared Chinese formula used alone with placebo. A meta-analysis also showed a significant beneficial effect in decreasing the score of AMS (MD: −1.10 [−1.64, −0.55], P < 0.0001). Two trials compared the combination of Chinese formula plus routine treatment drugs with routine treatment drugs. A meta-analysis showed a beneficial effect in decreasing the score of AMS (MD: −5.99 [−11.11, −0.86], P = 0.02). Conclusions. No firm conclusion on the effectiveness and safety of Chinese herbal medicine for AMS can be made. More rigorous high-quality trials are required to generate a high level of evidence and to confirm the results. PMID:24454510

Mineral density volume gradients in normal and diseased human tissues

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

Djomehri, Sabra I.; Candell, Susan; Case, Thomas

Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-raymore » fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.« less

Mineral density volume gradients in normal and diseased human tissues.

PubMed

Djomehri, Sabra I; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W; Yun, Wenbing; Lau, S H; Webb, Samuel; Ho, Sunita P

2015-01-01

Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095 mg/cc, bone: 570-1415 mg/cc, cementum: 1240-1340 mg/cc, dentin: 1480-1590 mg/cc, cementum affected by periodontitis: 1100-1220 mg/cc, hypomineralized carious dentin: 345-1450 mg/cc, hypermineralized carious dentin: 1815-2740 mg/cc, and dental calculus: 1290-1770 mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations.

Blockade of opioid receptors in the medullary reticularis nucleus dorsalis, but not the rostral ventromedial medulla, prevents analgesia produced by diffuse noxious inhibitory control in rats with muscle inflammation.

PubMed

de Resende, Marcos A; Silva, Luis Felipe S; Sato, Karina; Arendt-Nielsen, Lars; Sluka, Kathleen A

2011-06-01

Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45 °C and 47 °C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD. The current study shows that DNIC activates opioid receptors in the MdD, but not the RVM, to produce analgesia. These data are important for understanding clinical studies on DNIC as well as for potential treatment of chronic pain patients. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Achilles and patellar tendinopathy display opposite changes in elastic properties: A shear wave elastography study.

PubMed

Coombes, B K; Tucker, K; Vicenzino, B; Vuvan, V; Mellor, R; Heales, L; Nordez, A; Hug, F

2018-03-01

To compare tendon elastic and structural properties of healthy individuals with those with Achilles or patellar tendinopathy. Sixty-seven participants (22 Achilles tendinopathy, 17 patellar tendinopathy, and 28 healthy controls) were recruited between March 2015 and March 2016. Shear wave velocity (SWV), an index of tissue elastic modulus, and tendon thickness were measured bilaterally at mid-tendon and insertional regions of Achilles and patellar tendons by an examiner blinded to group. Analysis of covariance, adjusted for age, body mass index, and sex was used to compare differences in tendon thickness and SWV between the two tendinopathy groups (relative to controls) and regions. Tendon thickness was included as a covariate for analysis of SWV. Compared to controls, participants with Achilles tendinopathy had lower SWV at the distal insertion (Mean difference MD; 95% CI: -1.56; -2.49 to -0.62 m/s; P < .001) and greater thickness at the mid-tendon (MD 0.19; 0.05-0.33 cm; P = .007). Compared to controls, participants with patellar tendinopathy had higher SWV at both regions (MD 1.25; 0.40-2.10 m/s; P = .005) and greater thickness proximally (MD 0.17; 0.06-0.29 cm; P = .003). Compared to controls, participants with Achilles and patellar tendinopathy displayed lower Achilles tendon elastic modulus and higher patellar tendon elastic modulus, respectively. More research is needed to explore whether maturation, aging, or chronic load underlie these findings and whether current management programs for Achilles and patellar tendinopathy need to be tailored to the tendon. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mineral Density Volume Gradients in Normal and Diseased Human Tissues

PubMed Central

Djomehri, Sabra I.; Candell, Susan; Case, Thomas; Browning, Alyssa; Marshall, Grayson W.; Yun, Wenbing; Lau, S. H.; Webb, Samuel; Ho, Sunita P.

2015-01-01

Clinical computed tomography provides a single mineral density (MD) value for heterogeneous calcified tissues containing early and late stage pathologic formations. The novel aspect of this study is that, it extends current quantitative methods of mapping mineral density gradients to three dimensions, discretizes early and late mineralized stages, identifies elemental distribution in discretized volumes, and correlates measured MD with respective calcium (Ca) to phosphorus (P) and Ca to zinc (Zn) elemental ratios. To accomplish this, MD variations identified using polychromatic radiation from a high resolution micro-computed tomography (micro-CT) benchtop unit were correlated with elemental mapping obtained from a microprobe X-ray fluorescence (XRF) using synchrotron monochromatic radiation. Digital segmentation of tomograms from normal and diseased tissues (N=5 per group; 40-60 year old males) contained significant mineral density variations (enamel: 2820-3095mg/cc, bone: 570-1415mg/cc, cementum: 1240-1340mg/cc, dentin: 1480-1590mg/cc, cementum affected by periodontitis: 1100-1220mg/cc, hypomineralized carious dentin: 345-1450mg/cc, hypermineralized carious dentin: 1815-2740mg/cc, and dental calculus: 1290-1770mg/cc). A plausible linear correlation between segmented MD volumes and elemental ratios within these volumes was established, and Ca/P ratios for dentin (1.49), hypomineralized dentin (0.32-0.46), cementum (1.51), and bone (1.68) were observed. Furthermore, varying Ca/Zn ratios were distinguished in adapted compared to normal tissues, such as in bone (855-2765) and in cementum (595-990), highlighting Zn as an influential element in prompting observed adaptive properties. Hence, results provide insights on mineral density gradients with elemental concentrations and elemental footprints that in turn could aid in elucidating mechanistic processes for pathologic formations. PMID:25856386

Stimulant treatment history predicts frontal-striatal structural connectivity in adolescents with attention-deficit/hyperactivity disorder.

PubMed

Schweren, L J S; Hartman, C A; Zwiers, M P; Heslenfeld, D J; Franke, B; Oosterlaan, J; Buitelaar, J K; Hoekstra, P J

2016-04-01

Diffusion tensor imaging (DTI) has revealed white matter abnormalities in individuals with attention-deficit/hyperactivity disorder (ADHD). Stimulant treatment may affect such abnormalities. The current study investigated associations between long-term stimulant treatment and white matter integrity within the frontal-striatal and mesolimbic pathways, in a large sample of children, adolescents and young adults with ADHD. Participants with ADHD (N=172; mean age 17, range 9-26) underwent diffusion-weighted MRI scanning, along with an age- and gendermatched group of 96 control participants. Five study-specific white matter tract masks (orbitofrontal-striatal, orbitofrontal-amygdalar, amygdalar-striatal, dorsolateral-prefrontal-striatal and medialprefrontal-striatal) were created. First we analyzed case-control differences in fractional anisotropy (FA) and mean diffusivity (MD) within each tract. Second, FA and MD in each tract was predicted from cumulative stimulant intake within the ADHD group. After correction for multiple testing, participants with ADHD showed reduced FA in the orbitofrontal-striatal pathway (p=0.010, effect size=0.269). Within the ADHD group, higher cumulative stimulant intake was associated with lower MD in the same pathway (p=0.011, effect size=-0.164), but not with FA. The association between stimulant treatment and orbitofrontal-striatal MD was of modest effect size. It fell short of significance after adding ADHD severity or ADHD type to the model (p=0.036 and p=0.094, respectively), while the effect size changed little. Our findings are compatible with stimulant treatment enhancing orbitofrontal-striatal white matter connectivity, and emphasize the importance of the orbitofrontal cortex and its connections in ADHD. Longitudinal studies including a drug-naïve baseline assessment are needed to distinguish between-subject variability in ADHD severity from treatment effects. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

High fidelity computational characterization of the mechanical response of thermally aged polycarbonate

NASA Astrophysics Data System (ADS)

Zhang, Zesheng; Zhang, Lili; Jasa, John; Li, Wenlong; Gazonas, George; Negahban, Mehrdad

2017-07-01

A representative all-atom molecular dynamics (MD) system of polycarbonate (PC) is built and conditioned to capture and predict the behaviours of PC in response to a broad range of thermo-mechanical loadings for various thermal aging. The PC system is constructed to have a distribution of molecular weights comparable to a widely used commercial PC (LEXAN 9034), and thermally conditioned to produce models for aged and unaged PC. The MD responses of these models are evaluated through comparisons to existing experimental results carried out at much lower loading rates, but done over a broad range of temperatures and loading modes. These experiments include monotonic extension/compression/shear, unilaterally and bilaterally confined compression, and load-reversal during shear. It is shown that the MD simulations show both qualitative and quantitative similarity with the experimental response. The quantitative similarity is evaluated by comparing the dilatational response under bilaterally confined compression, the shear flow viscosity and the equivalent yield stress. The consistency of the in silico response to real laboratory experiments strongly suggests that the current PC models are physically and mechanically relevant and potentially can be used to investigate thermo-mechanical response to loading conditions that would not easily be possible. These MD models may provide valuable insight into the molecular sources of certain observations, and could possibly offer new perspectives on how to develop constitutive models that are based on better understanding the response of PC under complex loadings. To this latter end, the models are used to predict the response of PC to complex loading modes that would normally be difficult to do or that include characteristics that would be difficult to measure. These include the responses of unaged and aged PC to unilaterally confined extension/compression, cyclic uniaxial/shear loadings, and saw-tooth extension/compression/shear.

Aspirin use is associated with lower mammographic density in a large screening cohort.

PubMed

Wood, Marie E; Sprague, Brian L; Oustimov, Andrew; Synnstvedt, Marie B; Cuke, Melissa; Conant, Emily F; Kontos, Despina

2017-04-01

Observational and biologic studies suggest that aspirin is a promising prevention therapy for breast cancer. However, clinical trials to date have not corroborated this evidence, potentially due to study design. We evaluated the effect of aspirin on mammographic density (MD), an established modifiable risk factor for breast cancer. Electronic medical records from the University of Pennsylvania were evaluated for women who underwent screening mammography, saw their primary care provider, and had a confirmed list of medications during 2012-2013. Logistic regression was performed to test for associations between clinically recorded MD and aspirin use, after adjusting for age, body mass index (BMI), and ethnicity. We identified 26,000 eligible women. Mean age was 57.3, mean BMI was 28.9 kg/m 2 , 41% were African American, and 19.7% reported current aspirin use. Aspirin users were significantly older and had higher BMI. There was an independent, inverse association between aspirin use and MD (P trend  < 0.001). Women with extremely dense breasts were less likely to be aspirin users than women with scattered fibroglandular density (OR 0.73; 95% CI 0.57-0.93). This association was stronger for younger women (P = 0.0002) and for African Americans (P = 0.011). The likelihood of having dense breasts decreased with aspirin dose (P trend  = 0.007), suggesting a dose response. We demonstrate an independent association between aspirin use and lower MD in a large, diverse screening cohort. This association was stronger for younger and African American women: two groups at greater risk for ER- breast cancer. These results contribute to the importance of investigating aspirin for breast cancer prevention.

Symptomatic Meckel's diverticulum in newborn: two interesting additional cases and review of literature.

PubMed

Bertozzi, Mirko; Melissa, Berardino; Radicioni, Maurizio; Magrini, Elisa; Appignani, Antonino

2013-09-01

This study aimed to review the literature about symptomatic Meckel's diverticulum (MD) in the neonatal period with 2 additional uncommon cases. The authors describe 2 interesting neonatal cases of symptomatic MD and analyze the literature on this topic, with particular reference to the prevalence of sex, age at presentation, most common signs and symptoms, treatment, histology, associated anomalies, and outcome. The first patient was a term newborn with bowel obstruction by a pseudocystic MD. The second patient was a preterm infant with double perforation of the MD and ileum. Literature search for published case reports and case series on this topic reveals only 18 cases of neonatal symptomatic MD. Males are more frequently involved than females, and even preterm infants may be affected. Bowel obstruction (58.3%) and pneumoperitoneum (33.3%) are the most frequent clinical manifestation. Acute inflammation of the MD is the prominent histopathological finding (75%), although it does not seem to be related with the presence of heterotopic tissue within the MD. Surgical treatment is essential. The association of neonatal symptomatic MD with other anomalies is exceptional but is otherwise life threatening despite surgery. Bowel obstruction and pneumoperitoneum are the most frequent clinical manifestations of symptomatic MD in the newborn. Surgery is required for a definitive diagnosis and successful outcome.

Characterization of three chalcone synthase-like genes from apple (Malus x domestica Borkh.).

PubMed

Yahyaa, Mosaab; Ali, Samah; Davidovich-Rikanati, Rachel; Ibdah, Muhammad; Shachtier, Alona; Eyal, Yoram; Lewinsohn, Efraim; Ibdah, Mwafaq

2017-08-01

Apple (Malus x domestica Brokh.) is a widely cultivated deciduous tree species of significant economic importance. Apple leaves accumulate high levels of flavonoids and dihydrochalcones, and their formation is dependent on enzymes of the chalcone synthase family. Three CHS genes were cloned from apple leaves and expressed in Escherichia coli. The encoded recombinant enzymes were purified and functionally characterized. In-vitro activity assays indicated that MdCHS1, MdCHS2 and MdCHS3 code for proteins exhibiting polyketide synthase activity that accepted either p-dihydrocoumaroyl-CoA, p-coumaroyl-CoA, or cinnamoyl-CoA as starter CoA substrates in the presence of malonyl-CoA, leading to production of phloretin, naringenin chalcone, and pinocembrin chalcone. MdCHS3 coded a chalcone-dihydrochalcone synthase enzyme with narrower substrate specificity than the previous ones. The apparent Km values of MdCHS3 for p-dihydrocoumaryl-CoA and p-coumaryl-CoA were both 5.0 μM. Expression analyses of MdCHS genes varied according to tissue type. MdCHS1, MdCHS2 and MdCHS3 expression levels were associated with the levels of phloretin accumulate in the respective tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

Incidental finding of carcinoid tumor on Meckel’s diverticulum: case report and literature review, should prophylactic resection be recommended?

PubMed Central

2014-01-01

Meckel’s diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract and is caused by incomplete obliteration of the vitelline duct during intrauterine life. MD affects less than 2% of the population. In most cases, MD is asymptomatic and the estimated average complication risk of MD carriers, which is inversely proportional to age, ranges between 2% and 4%. The most common MD-related complications are gastrointestinal bleeding, intestinal obstruction and acute phlogosis. Excision is mandatory in the case of symptomatic diverticula regardless of age, while surgical treatment for asymptomatic diverticula remains controversial. According to the majority of studies, the incidental finding of MD in children is an indication for surgical resection, while the management of adults is not yet unanimous. In this case report, we describe the prophylactic resection of an incidentally detected MD, which led to the removal of an occult mucosal carcinoid tumor. In literature, the association of MD and carcinoid tumor is reported as a rare finding. Even though the strategy for adult patients of an incidental finding of MD during surgery performed for other reasons divides the experts, we recommend prophylactic excision in order to avoid any further risk. PMID:24884768

Comorbidity between reading disability and math disability: concurrent psychopathology, functional impairment, and neuropsychological functioning.

PubMed

Willcutt, Erik G; Petrill, Stephen A; Wu, Sarah; Boada, Richard; Defries, John C; Olson, Richard K; Pennington, Bruce F

2013-01-01

Reading disability (RD) and math disability (MD) frequently co-occur, but the etiology of this comorbidity is not well understood. Groups with RD only (N = 241), MD only (N = 183), and RD + MD (N = 188) and a control group with neither disorder (N = 411) completed a battery of measures of internalizing and externalizing psychopathology, social and academic functioning, and 10 neuropsychological processes. Groups with RD only, MD only, and RD + MD were significantly impaired versus the control group on nearly all measures, and the group with RD + MD was more impaired than the groups with MD and RD alone on measures of internalizing psychopathology, academic functioning, and 7 of 10 neuropsychological constructs. Multiple regression analyses of the neuropsychological measures indicated that deficits in reading and math were associated with shared weaknesses in working memory, processing speed, and verbal comprehension. In contrast, reading difficulties were uniquely associated with weaknesses in phoneme awareness and naming speed, and math deficits were uniquely associated with weaknesses in set shifting. These results support multiple-deficit neuropsychological models of RD and MD and suggest that RD and MD are distinct but related disorders that co-occur because of shared neuropsychological weaknesses in working memory, processing speed, and verbal comprehension.

Extended phenotype and clinical subgroups in unilateral Meniere disease: A cross-sectional study with cluster analysis.

PubMed

Frejo, L; Martin-Sanz, E; Teggi, R; Trinidad, G; Soto-Varela, A; Santos-Perez, S; Manrique, R; Perez, N; Aran, I; Almeida-Branco, M S; Batuecas-Caletrio, A; Fraile, J; Espinosa-Sanchez, J M; Perez-Guillen, V; Perez-Garrigues, H; Oliva-Dominguez, M; Aleman, O; Benitez, J; Perez, P; Lopez-Escamez, J A

2017-12-01

To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. A cross-sectional study with a two-step cluster analysis. A tertiary referral multicenter study. Nine hundred and eighty-eight adult patients with unilateral MD. best predictors to define clinical subgroups with potential different aetiologies. We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials. © 2017 John Wiley & Sons Ltd.

Humanized TLR4/MD-2 mice reveal LPS recognition differentially impacts susceptibility to Yersinia pestis and Salmonella enterica.

PubMed

Hajjar, Adeline M; Ernst, Robert K; Fortuno, Edgardo S; Brasfield, Alicia S; Yam, Cathy S; Newlon, Lindsay A; Kollmann, Tobias R; Miller, Samuel I; Wilson, Christopher B

2012-01-01

Although lipopolysaccharide (LPS) stimulation through the Toll-like receptor (TLR)-4/MD-2 receptor complex activates host defense against Gram-negative bacterial pathogens, how species-specific differences in LPS recognition impact host defense remains undefined. Herein, we establish how temperature dependent shifts in the lipid A of Yersinia pestis LPS that differentially impact recognition by mouse versus human TLR4/MD-2 dictate infection susceptibility. When grown at 37°C, Y. pestis LPS is hypo-acylated and less stimulatory to human compared with murine TLR4/MD-2. By contrast, when grown at reduced temperatures, Y. pestis LPS is more acylated, and stimulates cells equally via human and mouse TLR4/MD-2. To investigate how these temperature dependent shifts in LPS impact infection susceptibility, transgenic mice expressing human rather than mouse TLR4/MD-2 were generated. We found the increased susceptibility to Y. pestis for "humanized" TLR4/MD-2 mice directly paralleled blunted inflammatory cytokine production in response to stimulation with purified LPS. By contrast, for other Gram-negative pathogens with highly acylated lipid A including Salmonella enterica or Escherichia coli, infection susceptibility and the response after stimulation with LPS were indistinguishable between mice expressing human or mouse TLR4/MD-2. Thus, Y. pestis exploits temperature-dependent shifts in LPS acylation to selectively evade recognition by human TLR4/MD-2 uncovered with "humanized" TLR4/MD-2 transgenic mice.

Identification of two novel mammographic density loci at 6Q25.1.

PubMed

Brand, Judith S; Li, Jingmei; Humphreys, Keith; Karlsson, Robert; Eriksson, Mikael; Ivansson, Emma; Hall, Per; Czene, Kamila

2015-06-03

Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci. Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account. Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10(-8) for percent MD and P = 8.7 × 10(-9) for absolute MD) and AREG (rs10034692, P = 6.7 × 10(-9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10(-9) for percent MD and P = 2.5 × 10(-8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10(-8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response. We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.

In silico analysis of the polygalacturonase inhibiting protein 1 from apple, Malus domestica.

PubMed

Matsaunyane, Lerato Bt; Oelofse, Dean; Dubery, Ian A

2015-03-11

The Malus domestica polygalacturonase inhibiting protein 1 (MdPGIP1) gene, encoding the M. domestica polygalacturonase inhibiting protein 1 (MdPGIP1), was isolated from the Granny Smith apple cultivar (GenBank accession no. DQ185063). The gene was used to transform tobacco and potato for enhanced resistance against fungal diseases. Analysis of the MdPGIP1 nucleotide sequence revealed that the gene comprises 993 nucleotides that encode a 330 amino acid polypeptide. In silico characterization of the MdPGIP1 polypeptide revealed domains typical of PGIP proteins, which include a 24 amino acid putative signal peptide, a potential cleavage site [Alanine-Leucine-Serine (ALS)] for the signal peptide, a 238 amino acid leucine-rich repeat (LRR) domain, a 46 amino acid N-terminal domain and a 22 amino acid C-terminal domain. The hydropathic evaluation of MdPGIP1 indicated a repetitive hydrophobic motif in the LRR domain and a hydrophilic surface area consistent with a globular protein. The typical consensus glycosylation sequence of Asn-X-Ser/Thr was identified in MdPGIP1, indicating potential N-linked glycosylation of MdPGIP1. The molecular mass of non-glycosylated MdPGIP1 was calculated as 36.615 kDa and the theoretical isoelectric point as 6.98. Furthermore, the secondary and tertiary structure of MdPGIP1 was modelled, and revealed that MdPGIP1 is a curved and elongated molecule that contains sheet B1, sheet B2 and 310-helices on its LRR domain. The overall properties of the MdPGIP1 protein is similar to that of the prototypical Phaseolus vulgaris PGIP 2 (PvPGIP2), and the detected differences supported its use in biotechnological applications as an inhibitor of targeted fungal polygalacturonases (PGs).

Towards fast, rigorous and efficient conformational sampling of biomolecules: Advances in accelerated molecular dynamics.

PubMed

Doshi, Urmi; Hamelberg, Donald

2015-05-01

Accelerated molecular dynamics (aMD) has been proven to be a powerful biasing method for enhanced sampling of biomolecular conformations on general-purpose computational platforms. Biologically important long timescale events that are beyond the reach of standard molecular dynamics can be accessed without losing the detailed atomistic description of the system in aMD. Over other biasing methods, aMD offers the advantages of tuning the level of acceleration to access the desired timescale without any advance knowledge of the reaction coordinate. Recent advances in the implementation of aMD and its applications to small peptides and biological macromolecules are reviewed here along with a brief account of all the aMD variants introduced in the last decade. In comparison to the original implementation of aMD, the recent variant in which all the rotatable dihedral angles are accelerated (RaMD) exhibits faster convergence rates and significant improvement in statistical accuracy of retrieved thermodynamic properties. RaMD in conjunction with accelerating diffusive degrees of freedom, i.e. dual boosting, has been rigorously tested for the most difficult conformational sampling problem, protein folding. It has been shown that RaMD with dual boosting is capable of efficiently sampling multiple folding and unfolding events in small fast folding proteins. RaMD with the dual boost approach opens exciting possibilities for sampling multiple timescales in biomolecules. While equilibrium properties can be recovered satisfactorily from aMD-based methods, directly obtaining dynamics and kinetic rates for larger systems presents a future challenge. This article is part of a Special Issue entitled Recent developments of molecular dynamics. Copyright © 2014 Elsevier B.V. All rights reserved.

Relationship between consecutive deterioration of mean deviation value and progression of visual field defect in open-angle glaucoma.

PubMed

Naito, Tomoko; Yoshikawa, Keiji; Mizoue, Shiro; Nanno, Mami; Kimura, Tairo; Suzumura, Hirotaka; Takeda, Ryuji; Shiraga, Fumio

2015-01-01

To analyze the relationship between consecutive deterioration of mean deviation (MD) value and glaucomatous visual field (VF) progression in open-angle glaucoma (OAG), including primary OAG and normal tension glaucoma. The subjects of the study were patients undergoing treatment for OAG who had performed VF tests at least 10 times with a Humphrey field analyzer (SITA standard, C30-2 program). The VF progression was defined by a significantly negative MD slope (MD slope worsening) at the final VF test during the follow-up period. The relationship between the MD slope worsening and the consecutive deterioration of MD value were retrospectively analyzed. A total of 165 eyes of 165 patients were included in the analysis. Significant progression of VF defects was observed in 72 eyes of 72 patients (43.6%), while no significant progression was evident in 93 eyes of 93 patients (56.4%). There was significant relationship between the frequency of consecutive deterioration of MD value and MD slope worsening (P<0.0001, Cochran-Armitage trend test). A significant association was observed for MD slope worsening in the eyes with three (odds ratio: 2.1, P=0.0224) and four (odds ratio: 3.6, P=0.0008) consecutive deterioration of MD value in multiple logistic regression analysis, but no significant association in the eyes with two consecutive deterioration (odds ratio: 1.1, P=0.8282). The eyes with VF progression had significantly lower intraocular pressure reduction rate (P<0.01). This retrospective study has shown that three or more consecutive deterioration of MD value might be a predictor to future significant MD slope worsening in OAG.

Past major depression and smoking cessation outcome: a systematic review and meta-analysis update

PubMed Central

Hitsman, Brian; Papandonatos, George D.; McChargue, Dennis E.; DeMott, Andrew; Herrera, María José; Spring, Bonnie; Borrelli, Belinda; Niaura, Raymond

2012-01-01

Aims To update our prior meta-analysis that showed past major depression (MD+) to be unrelated to smoking cessation outcome [Hitsman et al. J Consult Clin Psychol 2003; 71:657–63]. Methods Eligible trials included 14 from our original review and 28 identified through an updated systematic review (2000–2009). We coded for assessment of past MD, exclusion for recent MD episode (MDE; ≤6 months versus no exclusion), duration/modality of cognitive behavioral treatment (CBT; face-to-face versus self-help), and other factors. To minimize influence of experimental treatments that may selectively benefit MD+ smokers, we analyzed placebo/lowest intensity control arms only. Study-specific odds ratios (ORs) for the effect of past MD on short-term (≤3 months) and long-term (≥6 months) abstinence were estimated and combined using random effects. Two-way interaction models of past MD with study methodology and treatment factors were used to evaluate hypothesized moderators of the past MD-abstinence association. Results MD+ smokers had 17% lower odds of short-term abstinence (n=35, OR=0.83, 95% CI=0.72–0.95, p=0.009) and 19% lower odds of long-term abstinence (n=38, OR=0.81, 95% CI=0.67–0.97, p=0.023) than MD− smokers after excluding the sole study of varenicline because of its antidepressant properties. The association between past MD and abstinence was affected by methodological (recent MDE exclusion, type of MD assessment) and treatment (CBT modality) factors. Conclusions Past major depression has a modest adverse effect on abstinence during and after smoking cessation treatment. An increased focus on the identification of effective treatments or treatment adaptations that eliminate this disparity in smoking cessation for MD+ smokers is needed. PMID:23072580

Physician-directed software design: the role of utilization statistics and user input in enhancing HELP results review capabilities.

PubMed

Michael, P A

1993-01-01

The M.D. Rounds Report program was developed and implemented in June of 1992 as an adjunct to the HELP System at Rex Hospital. The program facilitates rapid access to information on allergies and current medications, laboratory results, radiology reports and therapist notes for a list of patients without physicians having to make additional menu or submenu selections. In planning for an upgrade of the program, utilization statistics and user feedback provided valuable information in terms of frequency of access, features used and unused, and the value of the program as a reporting tool in comparison to other online results reporting applications. A brief description of the functionality of the M.D. Rounds Report, evaluation of the program audit trail and user feedback, planned enhancements to the program, and a discussion of the prototyping and monitoring experience and the impact on future physician subsystem development will be presented.

Electronic effects in high-energy radiation damage in tungsten

DOE PAGES

Zarkadoula, Eva; Duffy, Dorothy M.; Nordlund, Kai; ...

2015-03-13

Even though the effects of the electronic excitations during high-energy radiation damage processes are not currently understood, it is shown that their role in the interaction of radiation with matter is important. We perform molecular dynamics simulations of high-energy collision cascades in bcc-tungsten using the coupled two-temperature molecular dynamics (2T-MD) model that incorporates both the effects of electronic stopping and electron–phonon interaction. We compare the combination of these effects on the induced damage with only the effect of electronic stopping, and conclude in several novel insights. In the 2T-MD model, the electron–phonon coupling results in less damage production in themore » molten region and in faster relaxation of the damage at short times. We show these two effects lead to a significantly smaller amount of the final damage at longer times.« less

Heat-sink free CW operation of injection microdisk lasers grown on Si substrate with emission wavelength beyond 1.3  μm.

PubMed

Kryzhanovskaya, Natalia; Moiseev, Eduard; Polubavkina, Yulia; Maximov, Mikhail; Kulagina, Marina; Troshkov, Sergey; Zadiranov, Yury; Guseva, Yulia; Lipovskii, Andrey; Tang, Mingchu; Liao, Mengya; Wu, Jiang; Chen, Siming; Liu, Huiyun; Zhukov, Alexey

2017-09-01

High-performance injection microdisk (MD) lasers grown on Si substrate are demonstrated for the first time, to the best of our knowledge. Continuous-wave (CW) lasing in microlasers with diameters from 14 to 30 μm is achieved at room temperature. The minimal threshold current density of 600  A/cm 2 (room temperature, CW regime, heatsink-free uncooled operation) is comparable to that of high-quality MD lasers on GaAs substrates. Microlasers on silicon emit in the wavelength range of 1320-1350 nm via the ground state transition of InAs/InGaAs/GaAs quantum dots. The high stability of the lasing wavelength (dλ/dI=0.1  nm/mA) and the low specific thermal resistance of 4×10 -3 °C×cm 2 /W are demonstrated.

Dietary Intervention Restored Menses in Female Athletes with Exercise-Associated Menstrual Dysfunction with Limited Impact on Bone and Muscle Health

PubMed Central

Cialdella-Kam, Lynn; Guebels, Charlotte P.; Maddalozzo, Gianni F.; Manore, Melinda M.

2014-01-01

Exercise-related menstrual dysfunction (ExMD) is associated with low energy availability (EA), decreased bone mineral density (BMD), and increased risk of musculoskeletal injury. We investigated whether a 6-month carbohydrate-protein (CHO-PRO) supplement (360 kcal/day, 54 g CHO/day, 20 g PRO/day) intervention would improve energy status and musculoskeletal health and restore menses in female athletes (n = 8) with ExMD. At pre/post-intervention, reproductive and thyroid hormones, bone health (BMD, bone mineral content, bone markers), muscle strength/power and protein metabolism markers, profile of mood state (POMS), and energy intake (EI)/energy expenditure (7 day food/activity records) were measured. Eumenorrheic athlete controls with normal menses (Eumen); n = 10) were measured at baseline. Multiple linear regressions were used to evaluate differences between groups and pre/post-intervention blocking on participants. Improvements in EI (+382 kcal/day; p = 0.12), EA (+417 kcal/day; p = 0.17) and energy balance (EB; +466 kcal/day; p = 0.14) were observed with the intervention but were not statistically significant. ExMD resumed menses (2.6 ± 2.2-months to first menses; 3.5 ± 1.9 cycles); one remaining anovulatory with menses. Female athletes with ExMD for >8 months took longer to resume menses/ovulation and had lower BMD (low spine (ExMD = 3; Eumen = 1); low hip (ExMD = 2)) than those with ExMD for <8 months; for 2 ExMD the intervention improved spinal BMD. POMS fatigue scores were 15% lower in ExMD vs. Eumen (p = 0.17); POMS depression scores improved by 8% in ExMD (p = 0.12). EI, EA, and EB were similar between groups, but the intervention (+360 kcal/day) improved energy status enough to reverse ExMD despite no statistically significant changes in EI. Similar baseline EA and EB between groups suggests that some ExMD athletes are more sensitive to EA and EB fluctuations. PMID:25090245

Dietary intervention restored menses in female athletes with exercise-associated menstrual dysfunction with limited impact on bone and muscle health.

PubMed

Cialdella-Kam, Lynn; Guebels, Charlotte P; Maddalozzo, Gianni F; Manore, Melinda M

2014-07-31

Exercise-related menstrual dysfunction (ExMD) is associated with low energy availability (EA), decreased bone mineral density (BMD), and increased risk of musculoskeletal injury. We investigated whether a 6-month carbohydrate-protein (CHO-PRO) supplement (360 kcal/day, 54 g CHO/day, 20 g PRO/day) intervention would improve energy status and musculoskeletal health and restore menses in female athletes (n = 8) with ExMD. At pre/post-intervention, reproductive and thyroid hormones, bone health (BMD, bone mineral content, bone markers), muscle strength/power and protein metabolism markers, profile of mood state (POMS), and energy intake (EI)/energy expenditure (7 day food/activity records) were measured. Eumenorrheic athlete controls with normal menses (Eumen); n = 10) were measured at baseline. Multiple linear regressions were used to evaluate differences between groups and pre/post-intervention blocking on participants. Improvements in EI (+382 kcal/day; p = 0.12), EA (+417 kcal/day; p = 0.17) and energy balance (EB; +466 kcal/day; p = 0.14) were observed with the intervention but were not statistically significant. ExMD resumed menses (2.6 ± 2.2-months to first menses; 3.5 ± 1.9 cycles); one remaining anovulatory with menses. Female athletes with ExMD for >8 months took longer to resume menses/ovulation and had lower BMD (low spine (ExMD = 3; Eumen = 1); low hip (ExMD = 2)) than those with ExMD for <8 months; for 2 ExMD the intervention improved spinal BMD. POMS fatigue scores were 15% lower in ExMD vs. Eumen (p = 0.17); POMS depression scores improved by 8% in ExMD (p = 0.12). EI, EA, and EB were similar between groups, but the intervention (+360 kcal/day) improved energy status enough to reverse ExMD despite no statistically significant changes in EI. Similar baseline EA and EB between groups suggests that some ExMD athletes are more sensitive to EA and EB fluctuations.

A novel gene, MdSSK1, as a component of the SCF complex rather than MdSBP1 can mediate the ubiquitination of S-RNase in apple.

PubMed

Yuan, Hui; Meng, Dong; Gu, Zhaoyu; Li, Wei; Wang, Aide; Yang, Qing; Zhu, Yuandi; Li, Tianzhong

2014-07-01

As a core factor in S-RNase-based gametophytic self-incompatibility (GSI), the SCF (SKP1-Cullin1-F-box-Rbx1) complex (including pollen determinant SLF, S-locus-F-box) functions as an E3 ubiquitin ligase on non-self S-RNase. The SCF complex is formed by SKP1 bridging between SLF, CUL1, and Rbx1; however, it is not known whether an SCF complex lacking SKP1 can mediate the ubiquitination of S-RNase. Three SKP1-like genes from pollen were cloned based on the structural features of the SLF-interacting-SKP1-like (SSK) gene and the 'Golden Delicious' apple genome. These genes have a motif of five amino acids following the standard 'WAFE' at the C terminal and, in addition, contain eight sheets and two helices. All three genes were expressed exclusively in pollen. In the yeast two-hybrid and pull-down assays only one was found to interact with MdSFBB and MdCUL1, suggesting it is the SLF-interacting SKP1-like gene in apple which was named MdSSK1. In vitro experiments using MdSSK1, S2-MdSFBB1 (S2-Malus domestica S-locus-F-box brother) and MdCUL1 proteins incubated with S 2-RNase and ubiquitin revealed that the SCF complex ubiquitinylates S-RNase in vitro, while MdSBP1 (Malus domestica S-RNase binding protein 1) could not functionally replace MdSSK1 in the SCF complex in ubiquitinylating S-RNase. According to the above experiments, MdSBP1 is probably the only factor responsible for recognition with S-RNase, while not a component of the SCF complex, and an SCF complex containing MdSSK1 is required for mediating the ubiquitination of S-RNase. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

PubMed Central

Barata, Teresa S.; Teo, Ian; Brocchini, Steve; Zloh, Mire; Shaunak, Sunil

2011-01-01

The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4′phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases. PMID:21738462

MdPIN1b encodes a putative auxin efflux carrier and has different expression patterns in BC and M9 apple rootstocks.

PubMed

Gan, Zengyu; Wang, Yi; Wu, Ting; Xu, Xuefeng; Zhang, Xinzhong; Han, Zhenhai

2018-03-01

Lower promoter activity is closely associated with lower MdPIN1b expression in the M9 interstem, which might contribute to the dwarfing effect in apple trees. Apple trees grafted onto dwarfing rootstock Malling 9 (M9) produce dwarfing tree architecture with high yield and widely applying in production. Previously, we have reported that in Malus 'Red Fuji' (RF) trees growing on M9 interstem and Baleng Crab (BC) rootstock, IAA content was relatively higher in bark tissue of M9 interstem than that in scion or rootstock. As IAA polar transportation largely depends on the PIN-FORMED (PIN) auxin efflux carrier. Herein, we identify two putative auxin efflux carrier genes in Malus genus, MdPIN1a and MdPIN1b, which were closely related to the AtPIN1. We found that MdPIN1b was expressed preferentially in BC and M9, and the expression of MdPIN1b was significantly lower in the phloem of M9 interstem than that in the scion and rootstock. The distinct expression of MdPIN1b and IAA content were concentrated in the cambium and adjacent xylem or phloem, and MdPIN1b protein was localized on cell plasma membrane in onion epidermal cells transiently expressing 35S:MdPIN1b-GFP fusion protein. Interestingly, an MdPIN1b mutant allele in the promoter region upstream of M9 exhibited decreased MdPIN1b expression compared to BC. MdPIN1b over-expressing interstem in tobacco exhibited increased polar auxin transport. It is proposed that natural allelic differences decreased promoter activity is closely associated with lower MdPIN1b expression in the M9 interstem, which might limit the basipetal transport of auxin, and in turn might contribute to the dwarfing effect. Taken together, these results reveal allelic variation underlying an important apple rootstock trait, and specifically a novel molecular genetic mechanism underlying dwarfing mechanism.

Unraveling the Molecular Mechanism of Benzothiophene and Benzofuran scaffold merged compounds binding to anti-apoptotic Myeloid cell leukemia 1.

PubMed

Marimuthu, Parthiban; Singaravelu, Kalaimathy

2018-05-10

Myeloid cell leukemia 1 (Mcl1), is an anti-apoptotic member of the Bcl-2 family proteins, has gained considerable importance due to its overexpression activity prevents the oncogenic cells to undergo apoptosis. This overexpression activity of Mcl1 eventually develops strong resistance to a wide variety of anticancer agents. Therefore, designing novel inhibitors with potentials to elicit higher binding affinity and specificity to inhibit Mcl1 activity is of greater importance. Thus, Mcl1 acts as an attractive cancer target. Despite recent experimental advancement in the identification and characterization of Benzothiophene and Benzofuran scaffold merged compounds the molecular mechanisms of their binding to Mcl1 are yet to be explored. The current study demonstrates an integrated approach -pharmacophore-based 3D-QSAR, docking, Molecular Dynamics (MD) simulation and free-energy estimation- to access the precise and comprehensive effects of current inhibitors targeting Mcl1 together with its known activity values. The pharmacophore -ANRRR.240- based 3D-QSAR model from the current study provided high confidence (R 2 =0.9154, Q 2 =0.8736, and RMSE=0.3533) values. Furthermore, the docking correctly predicted the binding mode of highly active compound 42. Additionally, the MD simulation for docked complex under explicit-solvent conditions together with free-energy estimation exhibited stable interaction and binding strength over the time period. Also, the decomposition analysis revealed potential energy contributing residues -M231, M250, V253, R265, L267, and F270- to the complex stability. Overall, the current investigation might serve as a valuable insight, either to (i) improve the binding affinity of the current compounds or (ii) discover new generation anti-cancer agents that can effectively downregulate Mcl1 activity.

77 FR 16929 - Safety Zones; Fireworks Displays within the Fifth Coast Guard District

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-23

...; Chesapeake Bay, Chesapeake Beach, MD; Potomac River, Charles County, MD; Potomac River, Charles County, MD...'' N, longitude 076[deg]26'07.6'' W and Patuxent River, Solomons Island, MD, centered at approximate position latitude 38[deg]19'21'' N, longitude 076[deg]27'55'' W. All coordinates for these safety zones...

76 FR 71369 - Robert G. Crummie, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-17

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Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-28

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Directory of Organizational Technical Report Acronym Codes (DOTRAC)

DTIC Science & Technology

1994-07-01

TM - Technical memo report........................................................... TMR- Technical news bulletin...BETHESDA 418182 MD DTRC- TM -12 DAVID TAYLOR RESEARCH CENTER BETHESDA 418631 MD SHIP SYSTEMS INTEGRATION DEPT DTRC- TM -14 DAVID TAYLOR RESEARCH CENTER...BETHESDA 419277 MD SHIP ELECTROMAGNETIC SIGNATURES DEPT DTRC- TM -15 DAVID TAYLOR RESEARCH CENTER BETHESDA 418173 MD SHIP HYDROMECHANICS DEPT DTRC- TM -16 DAVID

Applicability of effective fragment potential version 2 - Molecular dynamics (EFP2-MD) simulations for predicting excess properties of mixed solvents

NASA Astrophysics Data System (ADS)

Kuroki, Nahoko; Mori, Hirotoshi

2018-02-01

Effective fragment potential version 2 - molecular dynamics (EFP2-MD) simulations, where the EFP2 is a polarizable force field based on ab initio electronic structure calculations were applied to water-methanol binary mixture. Comparing EFP2s defined with (aug-)cc-pVXZ (X = D,T) basis sets, it was found that large sets are necessary to generate sufficiently accurate EFP2 for predicting mixture properties. It was shown that EFP2-MD could predict the excess molar volume. Since the computational cost of EFP2-MD are far less than ab initio MD, the results presented herein demonstrate that EFP2-MD is promising for predicting physicochemical properties of novel mixed solvents.

Toll-like receptor (TLR)-4 mediates anti-β2GPI/β2GPI-induced tissue factor expression in THP-1 cells

PubMed Central

Zhou, H; Yan, Y; Xu, G; Zhou, B; Wen, H; Guo, D; Zhou, F; Wang, H

2011-01-01

Our previous study demonstrated that annexin A2 (ANX2) on cell surface could function as a mediator and stimulate tissue factor (TF) expression of monocytes by anti-β2-glycoprotein I/β2-glycoprotein I complex (anti-β2GPI/β2GPI). However, ANX2 is not a transmembrane protein and lacks the intracellular signal transduction pathway. Growing evidence suggests that Toll-like receptor 4 (TLR-4) might act as an ‘adaptor’ for intracellular signal transduction in anti-β2GPI/β2GPI-induced TF expressing cells. In the current study, we investigated the roles of TLR-4 and its related molecules, myeloid differentiation protein 2 (MD-2) and myeloid differentiation factor 88 (MyD88), in anti-β2GPI/β2GPI-induced TF expressing human monocytic-derived THP-1 (human acute monocytic leukaemia) cells. The relationship of TLR-4 and ANX2 in this process was also explored. Along with TF, expression of TLR-4, MD-2 and MyD88 in THP-1 cells increased significantly when treated by anti-β2GPI (10 µg/ml)/β2GPI (100 µg/ml) complex. The addition of paclitaxel, which competes with the MD-2 ligand, could inhibit the effects of anti-β2GPI/β2GPI on TLR-4, MD-2, MyD88 and TF expression. Both ANX2 and TLR-4 in THP-1 cell lysates could bind to β2GPI that had been conjugated to a column (β2GPI-Affi-Gel). Furthermore, TLR-4, MD-2, MyD88 and TF expression was remarkably diminished in THP-1 cells infected with ANX2-specific RNA interference (RNAi) lentivirus (LV-RNAi-ANX2), in spite of treatment with a similar concentration of anti-β2GPI/β2GPI complex. These results indicate that TLR-4 and its signal transduction pathway contribute to anti-β2GPI/β2GPI-induced TF expression in THP-1 cells, and the effects of TLR-4 with ANX2 are tightly co-operative. PMID:21091668

Renal Autoregulation in Health and Disease

PubMed Central

Carlström, Mattias; Wilcox, Christopher S.; Arendshorst, William J.

2015-01-01

Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80–180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca2+]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca2+]i occurs predominantly by Ca2+ influx through L-type voltage-operated Ca2+ channels (VOCC). Increased [Ca2+]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca2+ from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca2+ sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study. PMID:25834230

Morgellons disease, illuminating an undefined illness: a case series

PubMed Central

2009-01-01

Introduction This review of 25 consecutive patients with Morgellons disease (MD) was undertaken for two primary and extremely fundamental reasons. For semantic accuracy, there is only one "proven" MD patient: the child first given that label. The remainder of inclusive individuals adopted the label based on related descriptions from 1544 through 1884, an internet description quoted from Sir Thomas Browne (1674), or was given the label by practitioners using similar sources. Until now, there has been no formal characterization of MD from detailed examination of all body systems. Our second purpose was to differentiate MD from Delusions of Parasitosis (DP), another "informal" label that fit most of our MD patients. How we defined and how we treated these patients depended literally on factual data that would determine outcome. How they were labeled in one sense was irrelevant, except for the confusing conflict rampant in the medical community, possibly significantly skewing treatment outcomes. Case presentation Clinical information was collected from 25 of 30 consecutive self-defined patients with Morgellons disease consisting of laboratory data, medical history and physical examination findings. Abnormalities were quantified and grouped by system, then compared and summarized, but the numbers were too small for more complex mathematical analysis. The quantification of physical and laboratory abnormalities allowed at least the creation of a practical clinical boundary, separating probable Morgellons from non-Morgellons patients. All the 25 patients studied meet the most commonly used DP definitions. Conclusions These data suggest Morgellons disease can be characterized as a physical human illness with an often-related delusional component in adults. All medical histories support that behavioral aberrancies onset only after physical symptoms. The identified abnormalities include both immune deficiency and chronic inflammatory markers that correlate strongly with immune cytokine excess. The review of 251 current NLM DP references leads us to the possibility that Morgellons disease and DP are grossly truncated labels of the same illness but with the reversal of the cause-effect order. Further, the patients' data suggest that both illnesses have an infectious origin. PMID:19830222

Probing the structure and function of biopolymer-carbon nanotube hybrids with molecular dynamics

NASA Astrophysics Data System (ADS)

Johnson, Robert R.

2009-12-01

Nanoscience deals with the characterization and manipulation of matter on the atomic/molecular size scale in order to deepen our understanding of condensed matter and develop revolutionary technology. Meeting the demands of the rapidly advancing nanotechnological frontier requires novel, multifunctional nanoscale materials. Among the most promising nanomaterials to fulfill this need are biopolymer-carbon nanotube hybrids (Bio-CNT). Bio-CNT consists of a single-walled carbon nanotube (CNT) coated with a self-assembled layer of biopolymers such as DNA or protein. Experiments have demonstrated that these nanomaterials possess a wide range of technologically useful properties with applications in nanoelectronics, medicine, homeland security, environmental safety and microbiology. However, a fundamental understanding of the self-assembly mechanics, structure and energetics of Bio-CNT is lacking. The objective of this thesis is to address this deficiency through molecular dynamics (MD) simulation, which provides an atomic-scale window into the behavior of this unique nanomaterial. MD shows that Bio-CNT composed of single-stranded DNA (ssDNA) self-assembles via the formation of high affinity contacts between DNA bases and the CNT sidewall. Calculation of the base-CNT binding free energy by thermodynamic integration reveals that these contacts result from the attractive pi--pi stacking interaction. Binding affinities follow the trend G > A > T > C. MD reveals that long ssDNA sequences are driven into a helical wrapping about CNT with a sub-10 nm pitch by electrostatic and torsional interactions in the backbone. A large-scale replica exchange molecular dynamics simulation reveals that ssDNA-CNT hybrids are disordered. At room temperature, ssDNA can reside in several low-energy conformations that contain a sequence-specific arrangement of bases detached from CNT surface. MD demonstrates that protein-CNT hybrids composed of the Coxsackie-adenovirus receptor are biologically active and function as a nanobiosensor with specific recognition of Knob proteins from the adenovirus capsid. Simulation also shows that the rigid CNT damps structural fluctuations in bound proteins, which may have important ramifications for biosensing devices composed of protein-CNT hybrids. These results expand current knowledge of Bio-CNT and demonstrate the effectiveness of MD for investigations of nanobiomolecular systems.

Potential of Mean Force Calculations of Solute Permeation Across UT-B and AQP1: A Comparison between Molecular Dynamics and 3D-RISM.

PubMed

Ariz-Extreme, Igor; Hub, Jochen S

2017-02-23

Membrane channels facilitate the efficient and selective flux of various solutes across biological membranes. A common approach to investigate the selectivity of a channel has been the calculation of potentials of mean force (PMFs) for solute permeation across the pore. PMFs have been frequently computed from molecular dynamics (MD) simulations, yet the three-dimensional reference interaction site model (3D-RISM) has been suggested as a computationally efficient alternative to MD. Whether the two methods yield comparable PMFs for solute permeation has remained unclear. In this study, we calculated potentials of mean force for water, ammonia, urea, molecular oxygen, and methanol across the urea transporter B (UT-B) and aquaporin-1 (AQP1), using 3D-RISM, as well as using MD simulations and umbrella sampling. To allow direct comparison between the PMFs from 3D-RISM and MD, we ensure that all PMFs refer to a well-defined reference area in the bulk or, equivalently, to a well-defined density of channels in the membrane. For PMFs of water permeation, we found reasonable agreement between the two methods, with differences of ≲3 kJ mol -1 . In contrast, we found stark discrepancies for the PMFs for all other solutes. Additional calculations confirm that discrepancies between MD and 3D-RISM are not explained by the choice for the closure relation, the definition the reaction coordinate (center of mass-based versus atomic site-based), details of the molecule force field, or fluctuations of the protein. Comparison of the PMFs suggests that 3D-RISM may underestimate effects from hydrophobic solute-channel interactions, thereby, for instance, missing the urea binding sites in UT-B. Furthermore, we speculate that the orientational averages inherent to 3D-RISM might lead to discrepancies in the narrow channel lumen. These findings suggest that current 3D-RISM solvers provide reasonable estimates for the PMF for water permeation, but that they are not suitable to study the selectivity of membrane channels with respect to uncharged nonwater solutes.

Auditory selective attention in adolescents with major depression: An event-related potential study.

PubMed

Greimel, E; Trinkl, M; Bartling, J; Bakos, S; Grossheinrich, N; Schulte-Körne, G

2015-02-01

Major depression (MD) is associated with deficits in selective attention. Previous studies in adults with MD using event-related potentials (ERPs) reported abnormalities in the neurophysiological correlates of auditory selective attention. However, it is yet unclear whether these findings can be generalized to MD in adolescence. Thus, the aim of the present ERP study was to explore the neural mechanisms of auditory selective attention in adolescents with MD. 24 male and female unmedicated adolescents with MD and 21 control subjects were included in the study. ERPs were collected during an auditory oddball paradigm. Depressive adolescents tended to show a longer N100 latency to target and non-target tones. Moreover, MD subjects showed a prolonged latency of the P200 component to targets. Across groups, longer P200 latency was associated with a decreased tendency of disinhibited behavior as assessed by a behavioral questionnaire. To be able to draw more precise conclusions about differences between the neural bases of selective attention in adolescents vs. adults with MD, future studies should include both age groups and apply the same experimental setting across all subjects. The study provides strong support for abnormalities in the neurophysiolgical bases of selective attention in adolecents with MD at early stages of auditory information processing. Absent group differences in later ERP components reflecting voluntary attentional processes stand in contrast to results reported in adults with MD and may suggest that adolescents with MD possess mechanisms to compensate for abnormalities in the early stages of selective attention. Copyright © 2014 Elsevier B.V. All rights reserved.

Behavior of visual field index in advanced glaucoma.

PubMed

Rao, Harsha L; Senthil, Sirisha; Choudhari, Nikhil S; Mandal, Anil K; Garudadri, Chandra S

2013-01-14

To evaluate the magnitude of Visual Field Index (VFI) change attributable to change in the estimation algorithm from the pattern deviation probability plot (PDPP) to the total deviation probability plot (TDPP) when the mean deviation (MD) crosses -20 decibels (dB). In a retrospective study, 37 stable glaucoma eyes in which MD of the VFs crossed -20 dB were identified. For each eye, a pair of VFs was selected so that one VF of the pair had a MD better than but close to -20 dB and the other had a MD worse than but again close to -20 dB. The change in VFI in the VF pairs and its associations with the number of points in probability plots with normal threshold sensitivities were evaluated. Similar pairs of VFs from 28 stable glaucoma eyes where the MD crossed -10 dB were chosen as controls. The change in VFI in VF pairs when the MD crossed 20 dB ranged from 3% to 33% (median: 15%), while the change when MD crossed -10 dB ranged from 1% to 8% (median: 4%). Difference in the number of points with normal threshold sensitivities in PDPP when MD was better than -20 dB compared to those in TDPP when MD crossed -20 dB significantly influenced the VFI change (R(2) = 0.65). Considering the eccentricity of these points further explained the VFI change (R(2) = 0.81). The decrease in VFI when MD crosses -20 dB can be highly variable. This has to be considered with the use of VFI in clinical and research settings.

Clinical Value of Vestibular Evoked Myogenic Potential in Assessing the Stage and Predicting the Hearing Results in Ménière's Disease.

PubMed

Kim, Min-Beom; Choi, Jeesun; Park, Ga Young; Cho, Yang-Sun; Hong, Sung Hwa; Chung, Won-Ho

2013-06-01

Our goal was to find the clinical value of cervical vestibular evoked myogenic potential (VEMP) in Ménière's disease (MD) and to evaluate whether the VEMP results can be useful in assessing the stage of MD. Furthermore, we tried to evaluate the clinical effectiveness of VEMP in predicting hearing outcomes. The amplitude, peak latency and interaural amplitude difference (IAD) ratio were obtained using cervical VEMP. The VEMP results of MD were compared with those of normal subjects, and the MD stages were compared with the IAD ratio. Finally, the hearing changes were analyzed according to their VEMP results. In clinically definite unilateral MD (n=41), the prevalence of cervical VEMP abnormality in the IAD ratio was 34.1%. When compared with normal subjects (n=33), the VEMP profile of MD patients showed a low amplitude and a similar latency. The mean IAD ratio in MD was 23%, which was significantly different from that of normal subjects (P=0.01). As the stage increased, the IAD ratio significantly increased (P=0.09). After stratification by initial hearing level, stage I and II subjects (hearing threshold, 0-40 dB) with an abnormal IAD ratio showed a decrease in hearing over time compared to those with a normal IAD ratio (P=0.08). VEMP parameters have an important clinical role in MD. Especially, the IAD ratio can be used to assess the stage of MD. An abnormal IAD ratio may be used as a predictor of poor hearing outcomes in subjects with early stage MD.

Mediodorsal thalamus hypofunction impairs flexible goal-directed behavior.

PubMed

Parnaudeau, Sébastien; Taylor, Kathleen; Bolkan, Scott S; Ward, Ryan D; Balsam, Peter D; Kellendonk, Christoph

2015-03-01

Cognitive inflexibility is a core symptom of several mental disorders including schizophrenia. Brain imaging studies in schizophrenia patients performing cognitive tasks have reported decreased activation of the mediodorsal thalamus (MD). Using a pharmacogenetic approach to model MD hypofunction, we recently showed that decreasing MD activity impairs reversal learning in mice. While this demonstrates causality between MD hypofunction and cognitive inflexibility, questions remain about the elementary cognitive processes that account for the deficit. Using the Designer Receptors Exclusively Activated by Designer Drugs system, we reversibly decreased MD activity during behavioral tasks assessing elementary cognitive processes inherent to flexible goal-directed behaviors, including extinction, contingency degradation, outcome devaluation, and Pavlovian-to-instrumental transfer (n = 134 mice). While MD hypofunction impaired reversal learning, it did not affect the ability to learn about nonrewarded cues or the ability to modulate action selection based on the outcome value. In contrast, decreasing MD activity delayed the ability to adapt to changes in the contingency between actions and their outcomes. In addition, while Pavlovian learning was not affected by MD hypofunction, decreasing MD activity during Pavlovian learning impaired the ability of conditioned stimuli to modulate instrumental behavior. Mediodorsal thalamus hypofunction causes cognitive inflexibility reflected by an impaired ability to adapt actions when their consequences change. Furthermore, it alters the encoding of environmental stimuli so that they cannot be properly utilized to guide behavior. Modulating MD activity could be a potential therapeutic strategy for promoting adaptive behavior in human subjects with cognitive inflexibility. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Comparative levels of excessive daytime sleepiness in common medical disorders.

PubMed

Stroe, Alice F; Roth, Thomas; Jefferson, Catherine; Hudgel, David W; Roehrs, Timothy; Moss, Kenneth; Drake, Christopher L

2010-10-01

Sleep restriction and sleep disorders are common causes of excessive daytime sleepiness (EDS). Medical disorders (MD) can also cause EDS, but previous studies have used non-standardized measures, selected samples, or have examined EDS in singular disorders. This study describes the relative degree of EDS associated with medical disorders to provide comparative data across a range of common medical conditions in a large unselected community-based sample. Responses of 2612 individuals (aged 18-65) were assessed after excluding those with suspected sleep disordered breathing, narcolepsy, and shift workers. Participants across a range of medical disorders were evaluated using the Epworth Sleepiness Scale (ESS) and patient reports of nocturnal sleep. Sixty-seven percent of the sample reported a MD. The prevalence of EDS (ESS>or=10) was 31.4% in individuals with MD and increased as a function of a number of MD (0 MD=29.4%, 1 MD=28.4%, 2 MD=31.0%, 3 MD=35.3%, 4 MD=38.4%). Disorders which were independent predictors of EDS were ulcers OR=2.21 (95% CI=1.35-3.61), migraines OR=1.36 (95% CI=1.08-1.72), and depression OR=1.46 (95% CI=1.16-1.83) after controlling for other conditions, age, gender, time in bed, caffeine, smoking and alcohol use. Participants with ulcers had the highest prevalence of sleepiness, 50.0%, as well as the highest level of problems falling asleep (40.8%) and awakenings during the night (62.5%). Individuals with ulcers, migraines, and depression have independent and clinically significant levels of EDS relative to other common MD.

RETROFIT COSTS FOR SO2 AND NOX CONTROL OPTIONS AT 200 COAL-FIRED PLANTS, VOLUME III - SITE SPECIFIC STUDIES FOR IN, KY, MA, MD, MI, MN

EPA Science Inventory

The report gives results of a study, the objective of which was to significantly improve engineering cost estimates currently being used to evaluate the economic effects of applying SO2 and NOx controls at 200 large SO2-emitting coal-fired utility plants. To accomplish the object...

A Distributed User Information System

DTIC Science & Technology

1990-03-01

NOE08 Department of Computer Science NOVO 8 1990 University of Maryland S College Park, MD 20742 D Abstract Current user information database technology ...Transactions on Computer Systems, May 1988. [So189] K. Sollins. A plan for internet directory services. Technical report, DDN Network Information Center...2424 A Distributed User Information System DTiC Steven D. Miller, Scott Carson, and Leo Mark DELECTE Institute for Advanced Computer Studies and

Aircraft Scheduled Structural Maintenance Programs: Current Philosophies and Methods in the United States and their Applicability to the Royal Australian Air Force

DTIC Science & Technology

1988-09-01

maintenance programs. They use "a dedicated age exploration technique and actuarial analyses (31:847)" to Justify any changes to programs. RAAF. The...A066593). 8. Coffin, M.D. and C.F. Tiffany. "New Air Force Requirements for Structural Safety, Durability and Life Management," AIAA/ ASME /SAE 16th

Seminal Plasma Proteins as Androgen Receptor Corregulators Promote Prostate Cancer Growth

DTIC Science & Technology

2015-10-01

functional analyses of semenogelins in pathological conditions have been reported and their roles in prostate cancer outgrowth remain uncertain. In...1Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Pathology and Laboratory... pathological conditions have been reported and their roles in prostate cancer growth remain uncertain. In the current study, we aim to determine the

Michael Griffin Senate Confirmation Hearing

NASA Image and Video Library

2005-04-12

U.S. Senator Barbara Mikulski, D-Md., left, talks with Michael Griffin as Senator Kay Bailey Hutchison, R-Tx., and Griffin's wife Rebecca look on prior to his testimony, Tuesday, April 12, 2005, at the Russell Senate Office Building in Washington. If confirmed, Griffin, who currently heads the space department at the Johns Hopkins University Applied Physics Laboratory will become NASA's 11th administrator. Photo Credit: (NASA/Renee Bouchard)

Direct push injection logging for high resolution characterization of low permeability zones

NASA Astrophysics Data System (ADS)

Liu, G.; Knobbe, S.; Butler, J. J., Jr.; Reboulet, E. C.; Borden, R. C.; Bohling, G.

2017-12-01

One of the grand challenges for groundwater protection and contaminated site remediation efforts is dealing with the slow, yet persistent, release of contaminants from low permeability zones. In zones of higher permeability, groundwater flow is relatively fast and contaminant transport can be more effectively affected by treatment activities. In the low permeability zones, however, groundwater flow and contaminant transport are slow and thus become largely insensitive to many in-situ treatment efforts. Clearly, for sites with low permeability zones, accurate depiction of the mass exchange between the low and higher permeability zones is critical for designing successful groundwater protection and remediation systems, which requires certain information such as the hydraulic conductivity (K) and porosity of the subsurface. The current generation of field methods is primarily developed for relatively permeable zones, and little work has been undertaken for characterizing zones of low permeability. For example, the direct push injection logging (DPIL) approach (e.g., Hydraulic Profiling Tool by Geoprobe) is commonly used for high resolution estimation of K over a range of 0.03 to 23 m/d. When K is below 0.03 m/d, the pressure responses from the current DPIL are generally too high for both the formation (potential formation alteration at high pressure) and measuring device (pressure exceeding the upper sensor limit). In this work, we modified the current DPIL tool by adding a low-flow pump and flowmeter so that injection logging can be performed with much reduced flow rates when K is low. Numerical simulations showed that the reduction in injection rates (reduced from 250 to 1 mL/min) allowed pressures to be measurable even when K was as low as 0.001 m/d. They also indicated that as the K decreased, the pore water pressure increase induced by probe advancement had a more significant impact on DPIL results. A new field DPIL profiling procedure was developed for reducing that impact. Our preliminary test results in both the lab and at a field site have demonstrated the promise of the modified DPIL approach as a practical method for characterizing low permeability zones.

Impacts of Mass-dimension and Area-dimension relationships on retrieval ice particle effective radius from radar and lidar measurements

NASA Astrophysics Data System (ADS)

Ham, S. H.; Kato, S.; Rose, F. G.

2016-12-01

In the retrieval of ice clouds from Radar and Lidar Measurements, mass-Dimension (m-D) and Area-Dimension (A-D) relationships are often used to describe nonspherical ice particle shapes. This study analytically investigates how the assumption of m-D and A-D relationships affects retrieval of ice effective radius. We use gamma and lognormal particle distributions and integrate optical parameters over the size distribution. The effective radius is expressed as a function of radar reflectivity factor, visible extinction coefficient, and parameters describing m-D and A-D relationships. The analytic expressions are used for converting effective radius retrieved from one set of m-D and A-D relationships into that with another set of m-D and A-D, including plates, solid columns, bullets, and mixture of different habits. The conversion method can be used for consistent radiative transfer simulation with cloud retrieval algorithms. In addition, when we want to merge cloud effective radii retrieved from different m-D and A-D, the conversion method can be efficiently used to remove undesired biases caused by m-D and A-D assumptions. Furthermore, the sensitivity of the effective radius to m-D and A-D relationships can be quantified by taking the first derivative of the effective radius with respect to parameters expressing the m-D and A-D relationships.

Functional identification and regulatory analysis of Δ6-fatty acid desaturase from the oleaginous fungus Mucor sp. EIM-10.

PubMed

Jiang, Xianzhang; Liu, Hongjiao; Niu, Yongchao; Qi, Feng; Zhang, Mingliang; Huang, Jianzhong

2017-03-01

To enlarge the diversity of the desaturases associated with PUFA biosynthesis and to better understand the transcriptional regulation of desaturases, a Δ 6 -desaturase gene (Md6) from Mucor sp. and its 5'-upstream sequence was functionally identified in Saccharomyces cerevisiae. Expression of the Δ 6 -fatty acid desaturase (Md6) in S. cerevisiae showed that Md6 could convert linolenic acid to γ-linolenic acid. Computational analysis of the promoter of Md6 suggested it contains several eukaryotic fundamental transcription regulatory elements. In vivo functional analysis of the promoter showed the 5'-upstream sequence of Md6 could initiate expression of GFP and Md6 itself in S. cerevisiae. A series deletion analysis of the promoter suggested that sequence between -919 to -784 bp (relative to start site) named as eMd6 is the key factor for high activity of Δ 6 -desaturase. The activity of Δ 6 -desaturase was increased by 2.8-fold and 2.5-fold when the eMd6 sequence was placed upstream of -434 with forward or reverse orientations respectively. To our best knowledge, the native promoter of Md6 from Mucor is the strongest promoter for Δ 6 -desaturase reported so far and the sequence between -919 to -784 bp is an enhancer for Δ 6 -desaturase activity.

Trypsin-sensitive modulation of intestinal epithelial MD-2 as mechanism of lipopolysaccharide tolerance.

PubMed

Cario, Elke; Golenbock, Douglas T; Visintin, Alberto; Rünzi, Michael; Gerken, Guido; Podolsky, Daniel K

2006-04-01

Intestinal epithelial cells (IEC) are constantly exposed to both high concentrations of the bacterial ligand LPS and the serine protease trypsin. MD-2, which contains multiple trypsin cleavage sites, is an essential accessory glycoprotein required for LPS recognition and signaling through TLR4. The aim of this study was to characterize the expression and subcellular distribution of intestinal epithelial MD-2 and to delineate potential functional interactions with trypsin and then alteration in inflammatory bowel disease (IBD). Although MD-2 protein expression was minimal in primary IEC of normal colonic or ileal mucosa, expression was significantly increased in IEC from patients with active IBD colitis, but not in ileal areas from patients with severe Crohn's disease. Endogenous MD-2 was predominantly retained in the calnexin-calreticulin cycle of the endoplasmic reticulum; only a small fraction was exported to the Golgi. MD-2 expression correlated inversely with trypsin activity. Biochemical evidence and in vitro experiments demonstrated that trypsin exposure resulted in extensive proteolysis of endogenous and soluble MD-2 protein, but not of TLR4 in IEC, and was associated with desensitization of IEC to LPS. In conclusion, the present study suggests that endoplasmic reticulum-associated MD-2 expression in IBD may be altered by ileal protease in inflammation, leading to impaired LPS recognition and hyporesponsiveness through MD-2 proteolysis in IEC, thus implying a physiologic mechanism that helps maintain LPS tolerance in the intestine.

Hard- and soft-tissue profiles of the midface region in patients with skeletal Class III malocclusion using cone-beam computed tomography multiplanar-reconstructed image analysis.

PubMed

Kim, Bomi; Lee, Hyung-Chul; Kim, Seong-Hun; Kim, Yongil; Son, Woosung; Kim, Seong Sik

2018-05-01

This study examined cone-beam computed tomography (CBCT)-derived multiplanar-reconstructed (MPR) cross-sections to clarify the salient characteristics of patients with skeletal class III malocclusion with midface deficiency (MD). The horizontal and sagittal plane intersection points were identified for middle-third facial analysis in 40 patients in the MD or normal (N) groups. MPR images acquired parallel to each horizontal plane were used for length and angular measurements. A comparison of the MD and N groups revealed significant differences in the zygoma prominence among female patients. The convex zygomatic area in the N group was larger than that in the MD group, and the inferior part of the midface in the N group was smaller than that in the MD group for both male and female patients. A significant difference was observed in the concave middle maxillary area among male patients. This study was conducted to demonstrate the difference between MD and normal face through MPR images derived from CBCT. Male patients in the MD group had a more flattened face than did those in the N group. Female patients in the MD group showed a concave-shaped lower section of the zygoma, which tended to have more severe MD. These findings indicate that orthognathic surgery to improve skeletal discrepancy requires different approaches in male and female patients.

Retrospective review of adverse incidents involving passengers seated in wheeled mobility devices while traveling in large accessible transit vehicles.

PubMed

Frost, Karen L; Bertocci, Gina

2010-04-01

Characterize wheeled mobility device (WhMD) adverse incidents on large accessible transit vehicles (LATVs) based on vehicle motion, WhMD activity during incident, incident scenario and injury. Retrospective records review. WhMD passengers traveling on LATVs while remaining seated in their. Adverse incidents characterized based on vehicle motion, WhMD activity during incident, and incident scenario. Injury characterized based on outcome, medical attention sought, vehicle activity, WhMD activity and incident scenario. 115 WhMD-related incident reports for years 2000-2005 were analyzed. Most incidents occurred when the LATV was stopped (73.9%), during ingress/egress (42.6%), and at the securement station (33.9%) when the LATV was moving. The combination of WhMD tipping and passenger falling (43.4%) occurred most frequently, and was 1.8 times more likely to occur during ingress/egress than at the securement station. One-third (33.6%) of all incidents resulted in injury, and injuries were equally distributed between ingress/egress (43.6%) and at the securement station (43.6%). WhMD users have a greater chance of incurring injury during ingress/egress than during transit. Research is needed to objectively assess real world transportation experiences of WhMD passengers, and to assess the adequacy of existing federal legislation/guidelines for accessible ramps used in public transportation. Copyright 2009 IPEM. Published by Elsevier Ltd. All rights reserved.

The influence of estradiol on muscle damage and leg strength after intense eccentric exercise.

PubMed

Minahan, Clare; Joyce, Sarah; Bulmer, Andrew C; Cronin, Neil; Sabapathy, Surendran

2015-07-01

To examine the influence of estradiol on muscle damage and leg strength after intense eccentric exercise. Eight men (MEN), eight normally menstruating women (WomenNM), and eight women using oral contraceptives (WomenOC) participated in this study. Subjects performed 240 maximal-effort bilateral eccentric contractions of the quadriceps muscle groups designed to elicit exercise-induced muscle damage (EiMD). Serum creatine kinase (CK), myoglobin (Mb), and fatty acid-binding protein (FABP) concentrations were measured before (pre-) EiMD, as well as 0, 6, 24, and 48 h post-EiMD. Peak isometric quadriceps torque (i.e., leg strength) was measured pre-EiMD, as well as 24 and 48 h post-EiMD. The increases in CK, Mb, and FABP concentrations from pre- to post-EiMD were greater in MEN (10-fold, 15-fold, and fourfold, respectively) and WomenOC (sevenfold, 11-fold, and ninefold) compared with WomenNM (five-, six-, and threefold; p < 0.05). The decline in leg strength was about 10 % pre- to 24 h post-EiMD in all groups and decreased a further 10-15 % by 48 h post-EiMD in the MEN and WomenOC only. Our findings suggest an important role of estradiol in blunting the muscle damage response to intense eccentric exercise and preserving muscle function after EiMD.

Identification of Rare Lewis Oligosaccharide Conformers in Aqueous Solution Using Enhanced Sampling Molecular Dynamics.

PubMed

Alibay, Irfan; Burusco, Kepa K; Bruce, Neil J; Bryce, Richard A

2018-03-08

Determining the conformations accessible to carbohydrate ligands in aqueous solution is important for understanding their biological action. In this work, we evaluate the conformational free-energy surfaces of Lewis oligosaccharides in explicit aqueous solvent using a multidimensional variant of the swarm-enhanced sampling molecular dynamics (msesMD) method; we compare with multi-microsecond unbiased MD simulations, umbrella sampling, and accelerated MD approaches. For the sialyl Lewis A tetrasaccharide, msesMD simulations in aqueous solution predict conformer landscapes in general agreement with the other biased methods and with triplicate unbiased 10 μs trajectories; these simulations find a predominance of closed conformer and a range of low-occupancy open forms. The msesMD simulations also suggest closed-to-open transitions in the tetrasaccharide are facilitated by changes in ring puckering of its GlcNAc residue away from the 4 C 1 form, in line with previous work. For sialyl Lewis X tetrasaccharide, msesMD simulations predict a minor population of an open form in solution corresponding to a rare lectin-bound pose observed crystallographically. Overall, from comparison with biased MD calculations, we find that triplicate 10 μs unbiased MD simulations may not be enough to fully sample glycan conformations in aqueous solution. However, the computational efficiency and intuitive approach of the msesMD method suggest potential for its application in glycomics as a tool for analysis of oligosaccharide conformation.

Preparing MD-PhD students for clinical rotations: navigating the interface between PhD and MD training.

PubMed

Goldberg, Charles; Insel, Paul A

2013-06-01

Many aspects of MD-PhD training are not optimally designed to prepare students for their future roles as translational clinician-scientists. The transition between PhD research efforts and clinical rotations is one hurdle that must be overcome. MD-PhD students have deficits in clinical skills compared with those of their MD-only colleagues at the time of this transition. Reimmersion programs (RPs) targeted to MD-PhD students have the potential to help them navigate this transition.The authors draw on their experience creating and implementing an RP that incorporates multiple types of activities (clinical exam review, objective structured clinical examination, and supervised practice in patient care settings) designed to enhance the participants' skills and readiness for clinical efforts. On the basis of this experience, they note that MD-PhD students' time away from the clinical environment negatively affects their clinical skills, causing them to feel underprepared for clinical rotations. The authors argue that participation in an RP can help students feel more comfortable speaking with and examining patients and decrease their anxiety regarding clinical encounters. The authors propose that RPs can have positive outcomes for improving the transition from PhD to clinical MD training in dual-degree programs. Identifying and addressing this and other transitions need to be considered to improve the educational experience of MD-PhD students.

An apple CIPK protein kinase targets a novel residue of AREB transcription factor for ABA-dependent phosphorylation.

PubMed

Ma, Qi-Jun; Sun, Mei-Hong; Lu, Jing; Liu, Ya-Jing; You, Chun-Xiang; Hao, Yu-Jin

2017-10-01

Phytohormone abscisic acid (ABA) regulates many important processes in plants. It is a major molecule facilitating signal transduction during the abiotic stress response. In this study, an ABA-inducible transcription factor gene, MdAREB2, was identified in apple. Transgenic analysis was performed to characterize its function in ABA sensitivity. Overexpression of the MdAREB2 gene increased ABA sensitivity in the transgenic apple compared with the wild-type (WT) control. In addition, it was found that the protein MdAREB2 was phosphorylated at a novel site Thr 411 in response to ABA. A yeast two-hybridization screen of an apple cDNA library demonstrated that a protein kinase, MdCIPK22, interacted with MdAREB2. Their interaction was further verified with Pull Down and Co-IP assays. A series of transgenic analyses in apple calli and plantlets showed that MdCIPK22 was required for ABA-induced phosphorylation at Thr 411 of the MdAREB2 protein and enhanced its stability and transcriptional activity. Finally, it was found that MdCIPK22 increased ABA sensitivity in an MdAREB2-dependent manner. Our findings indicate a novel phosphorylation site in CIPK-AREB regulatory module for the ABA signalling pathway, which would be helpful for researchers to identify the functions of uncharacterized homologs in the future. © 2017 John Wiley & Sons Ltd.

Visual experience and subsequent sleep induce sequential plastic changes in putative inhibitory and excitatory cortical neurons

PubMed Central

Aton, Sara J.; Broussard, Christopher; Dumoulin, Michelle; Seibt, Julie; Watson, Adam; Coleman, Tammi; Frank, Marcos G.

2013-01-01

Ocular dominance plasticity in the developing primary visual cortex is initiated by monocular deprivation (MD) and consolidated during subsequent sleep. To clarify how visual experience and sleep affect neuronal activity and plasticity, we continuously recorded extragranular visual cortex fast-spiking (FS) interneurons and putative principal (i.e., excitatory) neurons in freely behaving cats across periods of waking MD and post-MD sleep. Consistent with previous reports in mice, MD induces two related changes in FS interneurons: a response shift in favor of the closed eye and depression of firing. Spike-timing–dependent depression of open-eye–biased principal neuron inputs to FS interneurons may mediate these effects. During post-MD nonrapid eye movement sleep, principal neuron firing increases and becomes more phase-locked to slow wave and spindle oscillations. Ocular dominance (OD) shifts in favor of open-eye stimulation—evident only after post-MD sleep—are proportional to MD-induced changes in FS interneuron activity and to subsequent sleep-associated changes in principal neuron activity. OD shifts are greatest in principal neurons that fire 40–300 ms after neighboring FS interneurons during post-MD slow waves. Based on these data, we propose that MD-induced changes in FS interneurons play an instructive role in ocular dominance plasticity, causing disinhibition among open-eye–biased principal neurons, which drive plasticity throughout the visual cortex during subsequent sleep. PMID:23300282

Validity of the Medical College Admission Test for Predicting MD-PhD Student Outcomes

ERIC Educational Resources Information Center

Bills, James L.; VanHouten, Jacob; Grundy, Michelle M.; Chalkley, Roger; Dermody, Terence S.

2016-01-01

The Medical College Admission Test (MCAT) is a quantitative metric used by MD and MD-PhD programs to evaluate applicants for admission. This study assessed the validity of the MCAT in predicting training performance measures and career outcomes for MD-PhD students at a single institution. The study population consisted of 153 graduates of the…

Evaluation of Factors Affecting Vaccine Efficacy of Recombinant Marek's Disease Virus Lacking the Meq Oncogene in Chickens

USDA-ARS?s Scientific Manuscript database

We have previously reported that deletion of Meq gene from oncogenic rMd5 virus rendered it apathogenic for chickens. Here we examined multiple factors affecting Marek’s disease (MD) vaccine efficacy of this non-pathogenic recombinant Meq null rMd5 virus (rMd5deltaMeq). These factors included host g...

Accelerated molecular dynamics simulations of protein folding.

PubMed

Miao, Yinglong; Feixas, Ferran; Eun, Changsun; McCammon, J Andrew

2015-07-30

Folding of four fast-folding proteins, including chignolin, Trp-cage, villin headpiece and WW domain, was simulated via accelerated molecular dynamics (aMD). In comparison with hundred-of-microsecond timescale conventional molecular dynamics (cMD) simulations performed on the Anton supercomputer, aMD captured complete folding of the four proteins in significantly shorter simulation time. The folded protein conformations were found within 0.2-2.1 Å of the native NMR or X-ray crystal structures. Free energy profiles calculated through improved reweighting of the aMD simulations using cumulant expansion to the second-order are in good agreement with those obtained from cMD simulations. This allows us to identify distinct conformational states (e.g., unfolded and intermediate) other than the native structure and the protein folding energy barriers. Detailed analysis of protein secondary structures and local key residue interactions provided important insights into the protein folding pathways. Furthermore, the selections of force fields and aMD simulation parameters are discussed in detail. Our work shows usefulness and accuracy of aMD in studying protein folding, providing basic references in using aMD in future protein-folding studies. © 2015 Wiley Periodicals, Inc.

Transcription Factor AREB2 Is Involved in Soluble Sugar Accumulation by Activating Sugar Transporter and Amylase Genes.

PubMed

Ma, Qi-Jun; Sun, Mei-Hong; Lu, Jing; Liu, Ya-Jing; Hu, Da-Gang; Hao, Yu-Jin

2017-08-01

Sugars play important roles in plant growth and development, crop yield and quality, as well as responses to abiotic stresses. Abscisic acid (ABA) is a multifunctional hormone. However, the exact mechanism by which ABA regulates sugar accumulation is largely unknown in plants. Here, we tested the expression profile of several sugar transporter and amylase genes in response to ABA treatment. MdSUT2 and MdAREB2 were isolated and genetically transformed into apple ( Malus domestica ) to investigate their roles in ABA-induced sugar accumulation. The MdAREB2 transcription factor was found to bind to the promoters of the sugar transporter and amylase genes and activate their expression. Both MdAREB2 and MdSUT2 transgenic plants produced more soluble sugars than controls. Furthermore, MdAREB2 promoted the accumulation of sucrose and soluble sugars in an MdSUT2 -dependent manner. Our results demonstrate that the ABA-responsive transcription factor MdAREB2 directly activates the expression of amylase and sugar transporter genes to promote soluble sugar accumulation, suggesting a mechanism by which ABA regulates sugar accumulation in plants. © 2017 American Society of Plant Biologists. All Rights Reserved.

Understanding the link between feelings of mental defeat, self-efficacy and the experience of chronic pain.

PubMed

Hazeldine-Baker, Charlotte E; Salkovskis, Paul M; Osborn, Mike; Gauntlett-Gilbert, Jeremy

2018-05-01

'Mental defeat' (MD) has been identified among people with chronic pain as a type of self-processing related to social role and rank. Research has linked it to anxiety, pain interference and functional disability. The relationship between MD and other cognitive constructs, such as hopelessness and depression, remains poorly understood. This study considers the association between MD, pain symptomatology and self-efficacy in the context of other cognitive factors. In total, 59 participants completed a questionnaire pack assessing anxiety, depression, hopelessness, pain catastrophising and MD in order to examine the relationship with pain symptomatology and self-efficacy. Linear multiple regression analyses showed that anxiety was most strongly associated with pain symptomatology, accounting for 26% of the variance, while catastrophising showed the strongest association with sensory pain and MD the strongest association with affective pain. Finally, MD was found to be strongly associated with pain-related self-efficacy, accounting for 47% of the variance. This research has demonstrated the potential importance of assessing MD in chronic pain patients, suggesting that targeting these cognitions during interventions and therapy could be valuable. Furthermore, the study indicates that MD differs from related cognitive constructs involved in pain, such as depression, hopelessness and catastrophising.

Fractions Learning in Children With Mathematics Difficulties.

PubMed

Tian, Jing; Siegler, Robert S

Learning fractions is difficult for children in general and especially difficult for children with mathematics difficulties (MD). Recent research on developmental and individual differences in fraction knowledge of children with MD and typically achieving (TA) children has demonstrated that U.S. children with MD start middle school behind their TA peers in fraction understanding and fall further behind during middle school. In contrast, Chinese children, who like the MD children in the United States score in the bottom one third of the distribution in their country, possess reasonably good fraction understanding. We interpret these findings within the framework of the integrated theory of numerical development. By emphasizing the importance of fraction magnitude knowledge for numerical understanding in general, the theory proved useful for understanding differences in fraction knowledge between MD and TA children and for understanding how knowledge can be improved. Several interventions demonstrated the possibility of improving fraction magnitude knowledge and producing benefits that generalize to fraction arithmetic learning among children with MD. The reasonably good fraction understanding of Chinese children with MD and several successful interventions with U.S. students provide hope for the improvement of fraction knowledge among American children with MD.

Vestibular syncope: A disorder associated with drop attack in Ménière's disease.

PubMed

Pyykkö, Ilmari; Manchaiah, Vinaya; Zou, Jing; Levo, Hilla; Kentala, Erna

2018-04-01

Experiments in humans and animals indicate that vestibular influx through vestibular sympathetic reflex is an important and vital part of the regulatory system of circulation. The otolith organ adjusts the circulatory responses through the vestibular sympathetic reflex during an upright stance and may trigger a vasovagal attack of syncope. The aim of the present study was to evaluate the prevalence and association of syncope attacks among patients with Ménière's disease (MD). Vestibular syncope was defined as a sudden and transient loss of consciousness, which subsides spontaneously in people with vestibular disorders and without localizing neurological deficit. During clinical interactions, we encountered 5 patients with syncope during a Tumarkin attack of MD. Thereafter we evaluated data from 952 patients collected with a questionnaire from the Finnish Ménière Association (FMA). The data contained case histories with special attention to Tumarkin attacks, participation restriction, migraines, and syncope attacks. The mean age of the subjects participating in the study was 60.6 years (range 25-75 years). The duration of the disease was on average 9.8 years (range 0.5-35 years). In the current study sample, attacks of syncope were reported by 38 patients (4%) in association with the vertigo attack. Syncope was associated with Tumarkin attacks (X 2 =16.7, p<0.001), migraine (X 2 =7.4, p<0.011), history of ischemic heart disease (X 2 =6.0, p<0.025), and history of cerebrovascular disease (X 2 =11.7, p<0.004). Duration of MD was correlated with syncope. Syncope was provoked by physical strain and environmental pressure, and was associated with impairment of the visual field (i.e., visual blurring). In logistic regression analysis, syncope was significantly associated with Tumarkin attacks (odds ratio 3.2), migraines (odds ratio 2.3) and nausea (odds ratio 1.3). The attack of syncope was experienced as frightening, and general health related quality of life (HRQoL) was significantly worsened. Also, the patients suffered more from fatigue. The current study indicates that patients with MD who suffer from Tumarkin attacks can suffer from syncope. It confirms the role of the otolith organ in controlling the circulatory homeostasis of the body. The actions are mediated through the vestibular sympathetic reflex. Copyright © 2017 Elsevier B.V. All rights reserved.

Differentiating the levels of risk for muscle dysmorphia among Hungarian male weightlifters: a factor mixture modeling approach.

PubMed

Babusa, Bernadett; Czeglédi, Edit; Túry, Ferenc; Mayville, Stephen B; Urbán, Róbert

2015-01-01

Muscle dysmorphia (MD) is a body image disturbance characterized by a pathological preoccupation with muscularity. The study aimed to differentiate the levels of risk for MD among weightlifters and to define a tentative cut-off score for the Muscle Appearance Satisfaction Scale (MASS) for the identification of high risk MD cases. Hungarian male weightlifters (n=304) completed the MASS, the Exercise Addiction Inventory, and specific exercise and body image related questions. For the differentiation of MD, factor mixture modeling was performed, resulting in three independent groups: low-, moderate-, and high risk MD groups. The estimated prevalence of high risk MD in this sample of weightlifters was 15.1%. To determine a cut-off score for the MASS, sensitivity and specificity analyses were performed and a cut-off point of 63 was suggested. The proposed cut-off score for the MASS can be useful for the early detection of high risk MD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Correlates of muscle dysmorphia symptomatology in natural bodybuilders: Distinguishing factors in the pursuit of hyper-muscularity.

PubMed

Mitchell, Lachlan; Murray, Stuart B; Hoon, Matthew; Hackett, Daniel; Prvan, Tania; O'Connor, Helen

2017-09-01

Muscle dysmorphia (MD) is characterized by the pathological pursuit of muscularity and leanness, which includes eating- and exercise-related practices. The aim of this cross-sectional study was to identify correlations of MD symptomatology in natural bodybuilders. An online survey assessing diet, supplementation and training practices, and MD and eating disorder symptoms was completed by male bodybuilders with recent experience competing in a drug-tested competition. Sixty participants (age 29.6±7.1 years) completed the survey. Eating disorder scores (β=.298), rate of pre-competition weight loss (β=.307) and number of competitions (β=-.257) were significant predictors of MD. The association between the EAT-26 and MDDI underscores the salience of disordered eating pathology in presentations of MD. Supporting this, greater rate of pre-competition weight loss, which may reflect disordered eating practices, is also associated with MD symptomatology. The inverse association of competition experience suggests novice bodybuilders may display increased MD symptomatology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of Fact Retrieval Tutoring on Third-Grade Students with Math Difficulties with and without Reading Difficulties.

PubMed

Powell, Sarah R; Fuchs, Lynn S; Fuchs, Douglas; Cirino, Paul T; Fletcher, Jack M

2009-01-01

The purpose of this study was to assess the efficacy of fact retrieval tutoring as a function of math difficulty (MD) subtype, that is, whether students have MD alone (MD-only) or have concurrent difficulty with math and reading (MDRD). Third graders (n = 139) at two sites were randomly assigned, blocking by site and MD subtype, to four tutoring conditions: fact retrieval practice, conceptual fact retrieval instruction with practice, procedural computation/estimation instruction, and control (no tutoring). Tutoring occurred for 45 sessions over 15weeks for 15-25 minutes per session. Results provided evidence of an interaction between tutoring condition and MD subtype status for assessment of fact retrieval. For MD-only students, students in both fact retrieval conditions achieved comparably and outperformed MD-only students in the control group as well as those in the procedural computation/estimation instruction group. By contrast, for MDRD students, there were no significant differences among intervention conditions.

Effects of Fact Retrieval Tutoring on Third-Grade Students with Math Difficulties with and without Reading Difficulties

PubMed Central

Powell, Sarah R.; Fuchs, Lynn S.; Fuchs, Douglas; Cirino, Paul T.; Fletcher, Jack M.

2009-01-01

The purpose of this study was to assess the efficacy of fact retrieval tutoring as a function of math difficulty (MD) subtype, that is, whether students have MD alone (MD-only) or have concurrent difficulty with math and reading (MDRD). Third graders (n = 139) at two sites were randomly assigned, blocking by site and MD subtype, to four tutoring conditions: fact retrieval practice, conceptual fact retrieval instruction with practice, procedural computation/estimation instruction, and control (no tutoring). Tutoring occurred for 45 sessions over 15weeks for 15–25 minutes per session. Results provided evidence of an interaction between tutoring condition and MD subtype status for assessment of fact retrieval. For MD-only students, students in both fact retrieval conditions achieved comparably and outperformed MD-only students in the control group as well as those in the procedural computation/estimation instruction group. By contrast, for MDRD students, there were no significant differences among intervention conditions. PMID:19448840

Eating Disorders and Major Depression: Role of Anger and Personality

PubMed Central

Giovanni, Abbate-Daga; Carla, Gramaglia; Enrica, Marzola; Federico, Amianto; Maria, Zuccolin; Secondo, Fassino

2011-01-01

This study aimed to evaluate comorbidity for MD in a large ED sample and both personality and anger as clinical characteristics of patients with ED and MD. We assessed 838 ED patients with psychiatric evaluations and psychometric questionnaires: Temperament and Character Inventory, Eating Disorder Inventory-2, Beck Depression Inventory, and State-Trait Anger Expression Inventory. 19.5% of ED patients were found to suffer from comorbid MD and 48.7% reported clinically significant depressive symptomatology: patients with Anorexia Binge-Purging and Bulimia Nervosa were more likely to be diagnosed with MD. Irritable mood was found in the 73% of patients with MD. High Harm Avoidance (HA) and low Self-Directedness (SD) predicted MD independently of severity of the ED symptomatology, several clinical variables, and ED diagnosis. Assessing both personality and depressive symptoms could be useful to provide effective treatments. Longitudinal studies are needed to investigate the pathogenetic role of HA and SD for ED and MD. PMID:21977317

Five-year growth trajectories of kindergarten children with learning difficulties in mathematics.

PubMed

Morgan, Paul L; Farkas, George; Qiong Wu

2009-01-01

The investigators used data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K) to estimate whether and to what extent the timing and persistence of mathematics difficulties (MD) in kindergarten predicted children's first through fifth grade math growth trajectories. Results indicated that children persistently displaying MD (i.e., those experiencing MD in both fall and spring of kindergarten) had the lowest subsequent growth rates, children with MD in spring only had the second-lowest growth rates, and children with MD in the fall only (and who had thus recovered from their MD by the spring of kindergarten) had the next-lowest growth rates. The children who did not have MD in either fall or spring of kindergarten had the highest growth rates. These results were observed prior to and after statistical control for additional variables. They indicate that measuring the timing and persistence of kindergarten children's mathematics learning difficulties may help identify those most at risk for failing to become mathematically proficient during elementary school.

The severity of Minamata disease declined in 25 years: temporal profile of the neurological findings analyzed by multiple logistic regression model.

PubMed

Uchino, Makoto; Hirano, Teruyuki; Satoh, Hiroshi; Arimura, Kimiyoshi; Nakagawa, Masanori; Wakamiya, Jyunji

2005-01-01

Minamata disease (MD) was caused by ingestion of seafood from the methylmercury-contaminated areas. Although 50 years have passed since the discovery of MD, there have been only a few studies on the temporal profile of neurological findings in certified MD patients. Thus, we evaluated changes in neurological symptoms and signs of MD using discriminants by multiple logistic regression analysis. The severity of predictive index declined in 25 years in most of the patients. Only a few patients showed aggravation of neurological findings, which was due to complications such as spino-cerebellar degeneration. Patients with chronic MD aged over 45 years had several concomitant diseases so that their clinical pictures were complicated. It was difficult to differentiate chronic MD using statistically established discriminants based on sensory disturbance alone. In conclusion, the severity of MD declined in 25 years along with the modification by age-related concomitant disorders.

New Developments in the Embedded Statistical Coupling Method: Atomistic/Continuum Crack Propagation

NASA Technical Reports Server (NTRS)

Saether, E.; Yamakov, V.; Glaessgen, E.

2008-01-01

A concurrent multiscale modeling methodology that embeds a molecular dynamics (MD) region within a finite element (FEM) domain has been enhanced. The concurrent MD-FEM coupling methodology uses statistical averaging of the deformation of the atomistic MD domain to provide interface displacement boundary conditions to the surrounding continuum FEM region, which, in turn, generates interface reaction forces that are applied as piecewise constant traction boundary conditions to the MD domain. The enhancement is based on the addition of molecular dynamics-based cohesive zone model (CZM) elements near the MD-FEM interface. The CZM elements are a continuum interpretation of the traction-displacement relationships taken from MD simulations using Cohesive Zone Volume Elements (CZVE). The addition of CZM elements to the concurrent MD-FEM analysis provides a consistent set of atomistically-based cohesive properties within the finite element region near the growing crack. Another set of CZVEs are then used to extract revised CZM relationships from the enhanced embedded statistical coupling method (ESCM) simulation of an edge crack under uniaxial loading.

Coarse-Grained MD Simulations and Protein-Protein Interactions: The Cohesin-Dockerin System.

PubMed

Hall, Benjamin A; Sansom, Mark S P

2009-09-08

Coarse-grained molecular dynamics (CG-MD) may be applied as part of a multiscale modeling approach to protein-protein interactions. The cohesin-dockerin interaction provides a valuable test system for evaluation of the use of CG-MD, as structural (X-ray) data indicate a dual binding mode for the cohesin-dockerin pair. CG-MD simulations (of 5 μs duration) of the association of cohesin and dockerin identify two distinct binding modes, which resemble those observed in X-ray structures. For each binding mode, ca. 80% of interfacial residues are predicted correctly. Furthermore, each of the binding modes identified by CG-MD is conformationally stable when converted to an atomistic model and used as the basis of a conventional atomistic MD simulation of duration 20 ns.

Hypnosis in the Treatment of Major Depression: An Analysis of Heart Rate Variability.

PubMed

Chen, Xiuwen; Yang, Rongqian; Ge, Lulu; Luo, Jie; Lv, Ruixue

2017-01-01

Hypnosis is an adjuvant treatment of major depression (MD). Heart rate variability (HRV) can assess the autonomic nervous system, which is associated with MD, and HRV is decreased in MD patients. There is a lack of research on HRV changes before, during, and after the use of hypnosis in MD patients. A total of 21 MD patients participated in this study, and 5-minute electrocardiograms were recorded before, during, and after hypnosis. Compared with the prehypnotic condition, HRV parameters significantly (p < .01) increased in the hypnotic and posthypnotic conditions. The results suggest that hypnosis treatment should bring some functional improvement to the autonomic nervous system. HRV is potentially a useful tool that quantifies the physiological impact of hypnosis treatment in MD patients.

Using collective variables to drive molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Fiorin, Giacomo; Klein, Michael L.; Hénin, Jérôme

2013-12-01

A software framework is introduced that facilitates the application of biasing algorithms to collective variables of the type commonly employed to drive massively parallel molecular dynamics (MD) simulations. The modular framework that is presented enables one to combine existing collective variables into new ones, and combine any chosen collective variable with available biasing methods. The latter include the classic time-dependent biases referred to as steered MD and targeted MD, the temperature-accelerated MD algorithm, as well as the adaptive free-energy biases called metadynamics and adaptive biasing force. The present modular software is extensible, and portable between commonly used MD simulation engines.

hamlet, a binary genetic switch between single- and multiple- dendrite neuron morphology.

PubMed

Moore, Adrian W; Jan, Lily Yeh; Jan, Yuh Nung

2002-08-23

The dendritic morphology of neurons determines the number and type of inputs they receive. In the Drosophila peripheral nervous system (PNS), the external sensory (ES) neurons have a single nonbranched dendrite, whereas the lineally related multidendritic (MD) neurons have extensively branched dendritic arbors. We report that hamlet is a binary genetic switch between these contrasting morphological types. In hamlet mutants, ES neurons are converted to an MD fate, whereas ectopic hamlet expression in MD precursors results in transformation of MD neurons into ES neurons. Moreover, hamlet expression induced in MD neurons undergoing dendrite outgrowth drastically reduces arbor branching.

Impact of business infrastructure on financial metrics in departments of surgery.

PubMed

Wai, Philip Y; O'Hern, Tim; Andersen, Dave O; Kuo, Marissa C; Weber, Cynthia E; Talbot, Lindsay J; Kuo, Paul C

2012-10-01

In the current environment, pressure is ever increasing to maximize financial performance in surgery departments. Factors such as physician extenders, billing and collection, payor mix, contracting, incentives from the Centers for Medicare and Medicaid Services, and administrative incentives may greatly influence financial performance. However, despite a plethora of information from the University HealthSystem Consortium and the Association of American Medical Colleges, best-practice information for business infrastructure is lacking. To obtain a sampling of current practices, we conducted a survey of departments of surgery. An anonymous 30-question survey addressing demographics, productivity, revenue and expense profile, payor mix, physician extender and staff personnel, billing and collections methodology, and financial performance was distributed among members of the Society of Surgical Chairs via SurveyMonkey. This was approved by the Loyola Institutional Research Board. Multivariate linear regression analyses and t tests/rank-sum tests were performed, as appropriate. Data are presented as mean ± SEM. A total of 25 (19%) departments responded; 14 were integrated with the hospital/health system, and 11 were integrated with the medical school. In 60% (n = 15), the main hospital had 500 to 1,000 beds; 48% (n = 12) had >4 hospitals in their system. For FY10, MD clinical full-time equivalents (FTEs) were 49 ± 10; total work relative value units (wRVUs) were 320 ± 8 k; and total billed cases were 43 ± 16 k. A total of 23 of 25 used physician-extenders with an average of 18 ± 5 per department and in 22 of 23, the physician extenders billed. On average, there were 18 ± 6 clinical-support staff, 25 ± 11 front-office staff, and 13 ± 3 back-office support staff FTEs. Among these FTEs, there were 16 ± 5 devoted to business operations (billing, coding, denial/claims management, financial oversight). Collections/wRVUs were $60 ± 3 (range, 39-80). Regression modeling demonstrated that total wRVUs were determined by the number of MD FTEs (P = .01), number of physician extenders (P = .01), number of front-office staff (P = .01), number of back-office staff (P = .02), and number of total business staff (P = .01). Collections/wRVUs were predicted by number of hospitals (P = .04), number of MD FTEs (P = .03), number of physician extenders (P = .01), and number of cases/total business staff (P = .02). Interestingly, wRVUs/MD was predicted by number of MD FTEs (P = .01) but were not greatly impacted by numbers of clinical or business support staff. In 4 of 25, the billing and coding staff were incentivized and had a Collections/wRVU = 64 ± 5 whereas nonincentivized staff had collections/wRVU = 59 ± 3. (P = NS) Also, %Accounts receivable >90 days (15% vs 25%) were not substantially different. Only 48% (12/25) have departments have recouped Centers for Medicare and Medicaid dollars for Physician Quality Reporting Initiative, Meaningful Use, Patient-Centered Medical Homes, or other Accountable Care-like programs. One-half (13) of the departments had both an inpatient and outpatient electronic medical record. Finally, on a scale of 1-10 (10 = highest), the average level of satisfaction with billing and collections processes was 6. Our results indicate that the physician extender, clinical support staff, and business staff environment can impact surgeon productivity, and there is opportunity for improvement. Determining best practices for ratios of support staff/MD and optimizing the role of electronic medical record in workflow and billing/collections are critical in the current environment. Our pilot study requires extension across more institutions for validation. Copyright © 2012 Mosby, Inc. All rights reserved.

[Relationship between visual field index and visual field morphological stages of glaucoma and their diagnostic value].

PubMed

Hou, X R; Qin, J Y; Ren, Z Q

2017-02-11

Objective: To investigate the rationality of visual field morphological stages of glaucoma, its relationship with visual field index and their diagnostic value. Methods: Retrospective series case study. Two hundred and seventy-four glaucoma patients and 100 normal control received visual field examination by Humphrey perimeter using standard automatic perimetry (SAP) program from March 2014 to September 2014. Glaucoma patients were graded into four stages according to characteristic morphological damage of visual field, distribution of mean defect (MD) and visual field index (VFI) of each stage were plotted and receiver operation characteristic curve (ROC) was used to explore its correlation with MD and VFI. The diagnostic value of MD and VFI was also compared. For the comparison of general data of subjects, categorical variables were compared using χ(2) test, numerical variables were compared using F test. MD and VFI were compared using ANOVA among stages according to visual field, followed by multiple comparisons using LSD method. The correlation between MD and VFI and different stages according to visual field defined their diagnostic value, and compared using area under the curve (AUC) of ROC. Results: No characteristic visual field damage was found in normal control group, and MD and VFI was (-0.06±1.24) dB and (99.15±0.76)%, respectively. Glaucomatous visual field damage was graded into early, medium, late and end stage according to morphological characteristic. MD for each stage were (-2.83±2.00) dB, (-9.70±3.68) dB, (-18.46±2.90) dB, and (-27.96±2.76) dB, respectively. VFI for each stage were (93.84±3.61)%, (75.16±10.85)%, (49.36±11.26)% and (17.65±10.59)%, respectively. MD and VFI of each stage of glaucomatous group and normal control group were all significantly different ( F= 1 165.53 and P <0.01 for MD; F= 1 028.04 and P <0.01 for VFI). AUC of ROC was A(MD)=0.91 and Se(MD)=0.01 (95% confident interval was 0.89-0.94) for MD, and A(VFI)=0.97, Se(VFI)=0.01 (95% confident interval was 0.94-0.10) for VFI. So, AUC(VFI)>AUC(MD) ( P< 0.05). Conclusions: It is feasible and rational of glaucomatous visual field damage to be graded into early, medium, late and end stage using Humphrey perimeter. Distribution of MD and VFI for each stage was relatively concentrative. Both MD and VFI were useful for grading glaucomatous visual field damage with preference for VFI. (Chin J Ophthalmol, 2017, 53: 92-97) .

Properties of acid gels made from sodium caseinate-maltodextrin conjugates prepared by a wet heating method.

PubMed

Zhang, Shuwen; Gong, Yuansheng; Khanal, Som; Lu, Yanjie; Lucey, John A

2017-11-01

Covalent attachment of polysaccharides to proteins (conjugation) via the Maillard reaction has been extensively studied. Conjugation can lead to a significant improvement in protein functionality (e.g., solubility, emulsification, and heat stability). Caseins have previously been successfully conjugated with maltodextrin (Md), but the effect on the detailed acid gelation properties has not been examined. We studied the effect of conjugating sodium caseinate (NaCN) with 3 different sized Md samples via the Maillard reaction in aqueous solutions. The Md samples had dextrose equivalents of 4 to 7, 9 to 12, and 20 to 23 for Md40, Md100, and Md200, respectively. The conjugation reaction was performed in mixtures with 5% NaCN and 5% Md, which were heated at 90°C for 10 h. The degree of conjugation was estimated from the reduction in free amino groups as well as color changes. Sodium dodecyl sulfate-PAGE analysis was performed to confirm conjugation by employing staining of both protein and carbohydrate bands. The molar mass of samples was determined by size-exclusion chromatography coupled with multi-angle laser light scattering. After the conjugation reaction, samples were then gelled by the addition of 0.63% (wt/vol) glucono-δ-lactone at 30°C, such that samples reached pH 4.6 after about 13 h. The rheological properties of samples during acidification was monitored by small-strain dynamic oscillatory rheology. The microstructure of acid gels at pH 4.6 was examined by fluorescence microscopy. Conjugation resulted in a loss of 10.8, 8.8, and 11.9% of the available amino groups in the protein for the NaCN-Md40 conjugates (C40), NaCN-Md100 conjugates (C100), and NaCN-Md100 conjugates (C200), respectively. With a decrease in the size of the type of Md, an increase occurred in the molar mass of the resultant conjugate. The weight average molar masses of NaCN-Md samples were 340, 368, and 425 kDa for the conjugates C40, C100, and C200, respectively. Addition of Md to NaCN dispersion resulted in slightly shorter acid gelation times even without the conjugation reaction. The storage modulus (G') of acid gels was significantly lower in conjugated samples compared with the corresponding (unreacted) mixtures of Md and NaCN. The sample with the lowest G' value at pH 4.6 was the C40 conjugate. Fluorescence microscopy showed that gels made by conjugates had slightly larger pores. These results indicate that conjugation of casein modified its acid gelation properties, presumably by the Md polysaccharide moiety hindering aggregation and rearrangements of the casein network. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Muscular Dystrophy: Data and Statistics

MedlinePlus

... For… Media Policy Makers MD STARnet Data and Statistics Recommend on Facebook Tweet Share Compartir Expand All Collapse All The following data and statistics come from MD STARnet. Data from the MD ...

An unusual plant triterpene synthase with predominant α-amyrin-producing activity identified by characterizing oxidosqualene cyclases from Malus × domestica.

PubMed

Brendolise, Cyril; Yauk, Yar-Khing; Eberhard, Ellen D; Wang, Mindy; Chagne, David; Andre, Christelle; Greenwood, David R; Beuning, Lesley L

2011-07-01

The pentacyclic triterpenes, in particular ursolic acid and oleanolic acid and their derivatives, exist abundantly in the plant kingdom, where they are well known for their anti-inflammatory, antitumour and antimicrobial properties. α-Amyrin and β-amyrin are the precursors of ursolic and oleanolic acids, respectively, formed by concerted cyclization of squalene epoxide by a complex synthase reaction. We identified three full-length expressed sequence tag sequences in cDNA libraries constructed from apple (Malus × domestica 'Royal Gala') that were likely to encode triterpene synthases. Two of these expressed sequence tag sequences were essentially identical (> 99% amino acid similarity; MdOSC1 and MdOSC3). MdOSC1 and MdOSC2 were expressed by transient expression in Nicotiana benthamiana leaves and by expression in the yeast Pichia methanolica. The resulting products were analysed by GC and GC-MS. MdOSC1 was shown to be a mixed amyrin synthase (a 5 : 1 ratio of α-amyrin to β-amyrin). MdOSC1 is the only triterpene synthase so far identified in which the level of α-amyrin produced is > 80% of the total product and is, therefore, primarily an α-amyrin synthase. No product was evident for MdOSC2 when expressed either transiently or in yeast, suggesting that this putative triterpene synthase is either encoded by a pseudogene or does not express well in these systems. Transcript expression analysis in Royal Gala indicated that the genes are mostly expressed in apple peel, and that the MdOSC2 expression level was much lower than that of MdOSC1 and MdOSC3 in all the tissues tested. Amyrin content analysis was undertaken by LC-MS, and demonstrated that levels and ratios differ between tissues, but that the true consequence of synthase activity is reflected in the ursolic/oleanolic acid content and in further triterpenoids derived from them. Phylogenetic analysis placed the three triterpene synthase sequences with other triterpene synthases that encoded either α-amyrin and/or β-amyrin synthase. MdOSC1 and MdOSC3 clustered with the multifunctional triterpene synthases, whereas MdOSC2 was most similar to the β-amyrin synthases. © 2011 The New Zealand Institute for Plant and Food Research Limited. Journal compilation © 2011 FEBS.

Host Genetics and Vaccine Efficacy: Global gene expression differentiation induced by vaccine and MDV in MD resistant and susceptible chickens based on Next-Gen RNA-Seq reads

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a herpesvirus-induced disease of poultry and it continues to threaten the poultry industry worldwide as MD virus (MDV) evolves to escalate the virulence of field strains. MD has been primarily controlled by vaccination and management measures. This study aimed to compare the ...

78 FR 32556 - Safety Zone; 2013 Ocean City Air Show, Atlantic Ocean; Ocean City, MD

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-31

...-AA00 Safety Zone; 2013 Ocean City Air Show, Atlantic Ocean; Ocean City, MD AGENCY: Coast Guard, DHS... navigable waters of the Atlantic Ocean in the vicinity of Ocean City, MD to support the Ocean City Air Show... June 9, 2013, Ocean City, MD will host an air show event between Talbot Street and 33rd Street over the...

Comparison of sediment and nutrient export and runoff characteristics from watersheds with centralized versus distributed stormwater management

USGS Publications Warehouse

Hopkins, Kristina G.; Loperfido, J.V.; Craig, Laura S.; Noe, Gregory; Hogan, Dianna

2017-01-01

Stormwater control measures (SCMs) are used to retain stormwater and pollutants. SCMs have traditionally been installed in a centralized manner using detention to mitigate peak flows. Recently, distributed SCM networks that treat runoff near the source have been increasingly utilized. The aim of this study was to evaluate differences among watersheds that vary in SCM arrangement by assessing differences in baseflow nutrient (NOx-N and PO4−) concentrations and fluxes, stormflow export of suspended sediments and particulate phosphorus (PP), and runoff characteristics. A paired watershed approach was used to compare export between 2004 and 2016 from one forested watershed (For-MD), one suburban watershed with centralized SCMs (Cent-MD), and one suburban watershed with distributed SCMs (Dist-MD). Results indicated baseflow nitrate (NOx-N) concentrations typically exceeded 1 mg-N/L in all watersheds and were highest in Dist-MD. Over the last 10 years in Dist-MD, nitrate concentrations in both stream baseflow and in a groundwater well declined as land use shifted from agriculture to suburban. Baseflow nitrate export temporarily increased during the construction phase of SCM development in Dist-MD. This temporary pulse of nitrate may be attributed to the conversion of sediment control facilities to SCMs and increased subsurface flushing as infiltration SCMs came on line. During storm flow, Dist-MD tended to have less runoff and lower maximum specific discharge than Cent-MD for small events (<1.3 cm), but runoff responses became increasingly similar to Cent-MD with increasing precipitation (>1.3 cm). Mass export estimated during paired storm events indicated Dist-MD exported 30% less sediment and 31% more PP than Cent-MD. For large precipitation events, export of sediment and PP was similar among all three watersheds. Results suggest that distributed SCMs can reduce runoff and sediment loads during small rain events compared to centralized SCMs, but these differences become less evident for large events when peak discharge likely leads to substantial bank erosion.

Enhanced configurational sampling with hybrid non-equilibrium molecular dynamics-Monte Carlo propagator

NASA Astrophysics Data System (ADS)

Suh, Donghyuk; Radak, Brian K.; Chipot, Christophe; Roux, Benoît

2018-01-01

Molecular dynamics (MD) trajectories based on classical equations of motion can be used to sample the configurational space of complex molecular systems. However, brute-force MD often converges slowly due to the ruggedness of the underlying potential energy surface. Several schemes have been proposed to address this problem by effectively smoothing the potential energy surface. However, in order to recover the proper Boltzmann equilibrium probability distribution, these approaches must then rely on statistical reweighting techniques or generate the simulations within a Hamiltonian tempering replica-exchange scheme. The present work puts forth a novel hybrid sampling propagator combining Metropolis-Hastings Monte Carlo (MC) with proposed moves generated by non-equilibrium MD (neMD). This hybrid neMD-MC propagator comprises three elementary elements: (i) an atomic system is dynamically propagated for some period of time using standard equilibrium MD on the correct potential energy surface; (ii) the system is then propagated for a brief period of time during what is referred to as a "boosting phase," via a time-dependent Hamiltonian that is evolved toward the perturbed potential energy surface and then back to the correct potential energy surface; (iii) the resulting configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-end momentum reversal prescription is used at the end of the neMD trajectories to guarantee that the hybrid neMD-MC sampling propagator obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The hybrid neMD-MC sampling propagator is designed and implemented to enhance the sampling by relying on the accelerated MD and solute tempering schemes. It is also combined with the adaptive biased force sampling algorithm to examine. Illustrative tests with specific biomolecular systems indicate that the method can yield a significant speedup.

Enhanced configurational sampling with hybrid non-equilibrium molecular dynamics-Monte Carlo propagator.

PubMed

Suh, Donghyuk; Radak, Brian K; Chipot, Christophe; Roux, Benoît

2018-01-07

Molecular dynamics (MD) trajectories based on classical equations of motion can be used to sample the configurational space of complex molecular systems. However, brute-force MD often converges slowly due to the ruggedness of the underlying potential energy surface. Several schemes have been proposed to address this problem by effectively smoothing the potential energy surface. However, in order to recover the proper Boltzmann equilibrium probability distribution, these approaches must then rely on statistical reweighting techniques or generate the simulations within a Hamiltonian tempering replica-exchange scheme. The present work puts forth a novel hybrid sampling propagator combining Metropolis-Hastings Monte Carlo (MC) with proposed moves generated by non-equilibrium MD (neMD). This hybrid neMD-MC propagator comprises three elementary elements: (i) an atomic system is dynamically propagated for some period of time using standard equilibrium MD on the correct potential energy surface; (ii) the system is then propagated for a brief period of time during what is referred to as a "boosting phase," via a time-dependent Hamiltonian that is evolved toward the perturbed potential energy surface and then back to the correct potential energy surface; (iii) the resulting configuration at the end of the neMD trajectory is then accepted or rejected according to a Metropolis criterion before returning to step 1. A symmetric two-end momentum reversal prescription is used at the end of the neMD trajectories to guarantee that the hybrid neMD-MC sampling propagator obeys microscopic detailed balance and rigorously yields the equilibrium Boltzmann distribution. The hybrid neMD-MC sampling propagator is designed and implemented to enhance the sampling by relying on the accelerated MD and solute tempering schemes. It is also combined with the adaptive biased force sampling algorithm to examine. Illustrative tests with specific biomolecular systems indicate that the method can yield a significant speedup.

Efficient hybrid non-equilibrium molecular dynamics--Monte Carlo simulations with symmetric momentum reversal.

PubMed

Chen, Yunjie; Roux, Benoît

2014-09-21

Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory ("one-end momentum reversal"). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory ("symmetric two-ends momentum reversal"), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.

Efficient hybrid non-equilibrium molecular dynamics - Monte Carlo simulations with symmetric momentum reversal

NASA Astrophysics Data System (ADS)

Chen, Yunjie; Roux, Benoît

2014-09-01

Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory ("one-end momentum reversal"). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory ("symmetric two-ends momentum reversal"), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.