11-Step Total Synthesis of Araiosamines

PubMed Central

2016-01-01

A concise route to a small family of exotic marine alkaloids known as the araiosamines has been developed, and their absolute configuration has been assigned. The dense array of functionality, high polarity, and rich stereochemistry coupled with equilibrating topologies present an unusual challenge for chemical synthesis and an opportunity for innovation. Key steps involve the use of a new reagent for guanidine installation, a remarkably selective C–H functionalization, and a surprisingly simple final step that intersects a presumed biosynthetic intermediate. Synthetic araiosamines were shown to exhibit potency against Gram-positive and -negative bacteria despite a contrary report of no activity. PMID:27748593

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489.

PubMed

Geddis, Stephen M; Carro, Laura; Hodgkinson, James T; Spring, David R

2016-12-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald-Hartwig amination and a final acid-catalysed 1,3-allylic-alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.

One-Pot Two-Step Multicomponent Process of Indole and Other Nitrogenous Heterocycles or Amines toward α-Oxo-acetamidines.

PubMed

Martinez-Ariza, Guillermo; McConnell, Nicholas; Hulme, Christopher

2016-04-15

A cesium carbonate promoted three-component reaction of N-H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.

The Course Development Plan: Macro-Level Decisions and Micro-Level Processes

ERIC Educational Resources Information Center

Franker, Karen; James, Dennis

2016-01-01

A key step in distance learning project management is the creation of a course development plan. The plan should account for decisions related to materials, curriculum, delivery methods, staffing, technology applications, resources, reporting lines, and project management--issues that may require administrator involvement and support, particularly…

Excellence in Schooling: Effective Styles for Effective Schools.

ERIC Educational Resources Information Center

Georgiades, William D. H.

School principals are an important factor in the improvement of American schools. Key findings of two studies show that principals are the most significant people in the educational change process. Outlined are seven important steps involved in the process of instructional improvement that will take place only if committed and knowledgeable…

Girls and Computer Technology: Barrier or Key?

ERIC Educational Resources Information Center

Gipson, Joella

1997-01-01

Discusses the disparity in numbers of girls and boys taking math, science, and computer classes in elementary and secondary schools, and examines steps being taken to better prepare girls, especially minority girls, for an increasingly technical society. A program in Michigan is described that involved a school and business partnership. (LRW)

Facilitating telemedicine project sustainability in medically underserved areas: a healthcare provider participant perspective.

PubMed

Paul, David L; McDaniel, Reuben R

2016-04-26

Very few telemedicine projects in medically underserved areas have been sustained over time. This research furthers understanding of telemedicine service sustainability by examining teleconsultation projects from the perspective of healthcare providers. Drivers influencing healthcare providers' continued participation in teleconsultation projects and how projects can be designed to effectively and efficiently address these drivers is examined. Case studies of fourteen teleconsultation projects that were part of two health sciences center (HSC) based telemedicine networks was utilized. Semi-structured interviews of 60 key informants (clinicians, administrators, and IT professionals) involved in teleconsultation projects were the primary data collection method. Two key drivers influenced providers' continued participation. First was severe time constraints. Second was remote site healthcare providers' (RSHCPs) sense of professional isolation. Two design steps to address these were identified. One involved implementing relatively simple technology and process solutions to make participation convenient. The more critical and difficult design step focused on designing teleconsultation projects for collaborative, active learning. This learning empowered participating RSHCPs by leveraging HSC specialists' expertise. In order to increase sustainability the fundamental purpose of teleconsultation projects needs to be re-conceptualized. Doing so requires HSC specialists and RSHCPs to assume new roles and highlights the importance of trust. By implementing these design steps, healthcare delivery in medically underserved areas can be positively impacted.

High-volume workflow management in the ITN/FBI system

NASA Astrophysics Data System (ADS)

Paulson, Thomas L.

1997-02-01

The Identification Tasking and Networking (ITN) Federal Bureau of Investigation system will manage the processing of more than 70,000 submissions per day. The workflow manager controls the routing of each submission through a combination of automated and manual processing steps whose exact sequence is dynamically determined by the results at each step. For most submissions, one or more of the steps involve the visual comparison of fingerprint images. The ITN workflow manager is implemented within a scaleable client/server architecture. The paper describes the key aspects of the ITN workflow manager design which allow the high volume of daily processing to be successfully accomplished.

Implementing Immediate Postpartum Long-Acting Reversible Contraception Programs.

PubMed

Hofler, Lisa G; Cordes, Sarah; Cwiak, Carrie A; Goedken, Peggy; Jamieson, Denise J; Kottke, Melissa

2017-01-01

To understand the most important steps required to implement immediate postpartum long-acting reversible contraception (LARC) programs in different Georgia hospitals and the barriers to implementing such a program. This was a qualitative study. We interviewed 32 key personnel from 10 Georgia hospitals working to establish immediate postpartum LARC programs. Data were analyzed using directed qualitative content analysis principles. We used the Stages of Implementation to organize participant-identified key steps for immediate postpartum LARC into an implementation guide. We compared this guide to hospitals' implementation experiences. At the completion of the study, LARC was available for immediate postpartum placement at 7 of 10 study hospitals. Participants identified common themes for the implementation experience: team member identification and ongoing communication, payer preparedness challenges, interdependent department-specific tasks, and piloting with continuing improvements. Participants expressed a need for anticipatory guidance throughout the process. Key first steps to immediate postpartum LARC program implementation were identifying project champions, creating an implementation team that included all relevant departments, obtaining financial reassurance, and ensuring hospital administration awareness of the project. Potential barriers included lack of knowledge about immediate postpartum LARC, financial concerns, and competing clinical and administrative priorities. Hospitals that were successful at implementing immediate postpartum LARC programs did so by prioritizing clear communication and multidisciplinary teamwork. Although the implementation guide reflects a comprehensive assessment of the steps to implementing immediate postpartum LARC programs, not all hospitals required every step to succeed. Hospital teams report that implementing immediate postpartum LARC programs involves multiple departments and a number of important steps to consider. A stage-based approach to implementation, and a standardized guide detailing these steps, may provide the necessary structure for the complex process of implementing immediate postpartum LARC programs in the hospital setting.

Preparing Every Teacher to Reach English Learners: A Practical Guide for Teacher Educators

ERIC Educational Resources Information Center

Nutta, Joyce W., Ed.; Mokhtari, Kouider, Ed.; Strebel, Carine, Ed.

2012-01-01

"Preparing Every Teacher to Reach English Learners" presents a practical, flexible model for infusing English learner (EL) instruction into teacher education courses. The editors outline the key steps involved in this approach--winning faculty support, assessing needs, and developing capacity--and share strategies for avoiding pitfalls. The…

Case Management of Adolescents with Chronic Disease.

ERIC Educational Resources Information Center

Lankard, Bettina A.

This training guide presents a model for optimum delivery of the primary duties, tasks, and steps required in the comprehensive case management of adolescents with chronic disease. Using a team approach to coordinated health care, the guide involves the patient and family as key members of the care team along with the physician, nurse, dietitian,…

Biogenesis of ER subdomains containing DGAT2, an enzyme involved in industrial oil biosynthesis

USDA-ARS?s Scientific Manuscript database

Diacylglycerol acyltransferases (DGATs) are enzymes that catalyze the committed step in triacylglycerol (TAG) biosynthesis by transferring a fatty acyl group from the acyl-CoA pool to the sn-3 position of diacylglycerol. The substrate specificity and overall activity of these enzymes play a key role...

3D-QSAR Study of Steroidal and Azaheterocyclic Human Aromatase Inhibitors using Quantitative Profile of Protein-Ligand Interactions

EPA Science Inventory

Aromatase is a member of the cytochrome P450 superfamily responsible for a key step in the biosynthesis of estrogens. As estrogens are involved in the control of important reproduction-related processes, including sexual differentiation and maturation, aromatase is a potential ta...

Genes related to antioxidant metabolism are involved in Methylobacterium mesophilicum-soybean interaction.

PubMed

Araújo, Welington Luiz; Santos, Daiene Souza; Dini-Andreote, Francisco; Salgueiro-Londoño, Jennifer Katherine; Camargo-Neves, Aline Aparecida; Andreote, Fernando Dini; Dourado, Manuella Nóbrega

2015-10-01

The genus Methylobacterium is composed of pink-pigmented methylotrophic bacterial species that are widespread in natural environments, such as soils, stream water and plants. When in association with plants, this genus colonizes the host plant epiphytically and/or endophytically. This association is known to promote plant growth, induce plant systemic resistance and inhibit plant infection by phytopathogens. In the present study, we focused on evaluating the colonization of soybean seedling-roots by Methylobacterium mesophilicum strain SR1.6/6. We focused on the identification of the key genes involved in the initial step of soybean colonization by methylotrophic bacteria, which includes the plant exudate recognition and adaptation by planktonic bacteria. Visualization by scanning electron microscopy revealed that M. mesophilicum SR1.6/6 colonizes soybean roots surface effectively at 48 h after inoculation, suggesting a mechanism for root recognition and adaptation before this period. The colonization proceeds by the development of a mature biofilm on roots at 96 h after inoculation. Transcriptomic analysis of the planktonic bacteria (with plant) revealed the expression of several genes involved in membrane transport, thus confirming an initial metabolic activation of bacterial responses when in the presence of plant root exudates. Moreover, antioxidant genes were mostly expressed during the interaction with the plant exudates. Further evaluation of stress- and methylotrophic-related genes expression by qPCR showed that glutathione peroxidase and glutathione synthetase genes were up-regulated during the Methylobacterium-soybean interaction. These findings support that glutathione (GSH) is potentially a key molecule involved in cellular detoxification during plant root colonization. In addition to methylotrophic metabolism, antioxidant genes, mainly glutathione-related genes, play a key role during soybean exudate recognition and adaptation, the first step in bacterial colonization.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489

PubMed Central

Geddis, Stephen M.; Carro, Laura; Hodgkinson, James T.

2016-01-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid‐catalysed 1,3‐allylic‐alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported. PMID:28111524

Mechanism and the origins of stereospecificity in copper-catalyzed ring expansion of vinyl oxiranes: a traceless dual transition-metal-mediated process.

PubMed

Mustard, Thomas J L; Mack, Daniel J; Njardarson, Jon T; Cheong, Paul Ha-Yeon

2013-01-30

Density functional theory computations of the Cu-catalyzed ring expansion of vinyloxiranes is mediated by a traceless dual Cu(I)-catalyst mechanism. Overall, the reaction involves a monomeric Cu(I)-catalyst, but a single key step, the Cu migration, requires two Cu(I)-catalysts for the transformation. This dual-Cu step is found to be a true double Cu(I) transition state rather than a single Cu(I) transition state in the presence of an adventitious, spectator Cu(I). Both Cu(I) catalysts are involved in the bond forming and breaking process. The single Cu(I) transition state is not a stationary point on the potential energy surface. Interestingly, the reductive elimination is rate-determining for the major diastereomeric product, while the Cu(I) migration step is rate-determining for the minor. Thus, while the reaction requires dual Cu(I) activation to proceed, kinetically, the presence of the dual-Cu(I) step is untraceable. The diastereospecificity of this reaction is controlled by the Cu migration step. Suprafacial migration is favored over antarafacial migration due to the distorted Cu π-allyl in the latter.

A novel glucuronosyltransferase has an unprecedented ability to catalyse continuous two-step glucuronosylation of glycyrrhetinic acid to yield glycyrrhizin.

PubMed

Xu, Guojie; Cai, Wei; Gao, Wei; Liu, Chunsheng

2016-10-01

Glycyrrhizin is an important bioactive compound that is used clinically to treat chronic hepatitis and is also used as a sweetener world-wide. However, the key UDP-dependent glucuronosyltransferases (UGATs) involved in the biosynthesis of glycyrrhizin remain unknown. To discover unknown UGATs, we fully annotated potential UGATs from Glycyrrhiza uralensis using deep transcriptome sequencing. The catalytic functions of candidate UGATs were determined by an in vitro enzyme assay. Systematically screening 434 potential UGATs, we unexpectedly found one unique GuUGAT that was able to catalyse the glucuronosylation of glycyrrhetinic acid to directly yield glycyrrhizin via continuous two-step glucuronosylation. Expression analysis further confirmed the key role of GuUGAT in the biosynthesis of glycyrrhizin. Site-directed mutagenesis revealed that Gln-352 may be important for the initial step of glucuronosylation, and His-22, Trp-370, Glu-375 and Gln-392 may be important residues for the second step of glucuronosylation. Notably, the ability of GuUGAT to catalyse a continuous two-step glucuronosylation reaction was determined to be unprecedented among known glycosyltransferases of bioactive plant natural products. Our findings increase the understanding of traditional glycosyltransferases and pave the way for the complete biosynthesis of glycyrrhizin. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes.

PubMed

Lence, Emilio; van der Kamp, Marc W; González-Bello, Concepción; Mulholland, Adrian J

2018-05-16

Type II dehydroquinase enzymes (DHQ2), recognized targets for antibiotic drug discovery, show significantly different activities dependent on the species: DHQ2 from Mycobacterium tuberculosis (MtDHQ2) and Helicobacter pylori (HpDHQ2) show a 50-fold difference in catalytic efficiency. Revealing the determinants of this activity difference is important for our understanding of biological catalysis and further offers the potential to contribute to tailoring specificity in drug design. Molecular dynamics simulations using a quantum mechanics/molecular mechanics potential, with correlated ab initio single point corrections, identify and quantify the subtle determinants of the experimentally observed difference in efficiency. The rate-determining step involves the formation of an enolate intermediate: more efficient stabilization of the enolate and transition state of the key step in MtDHQ2, mainly by the essential residues Tyr24 and Arg19, makes it more efficient than HpDHQ2. Further, a water molecule, which is absent in MtDHQ2 but involved in generation of the catalytic Tyr22 tyrosinate in HpDHQ2, was found to destabilize both the transition state and the enolate intermediate. The quantification of the contribution of key residues and water molecules in the rate-determining step of the mechanism also leads to improved understanding of higher potencies and specificity of known inhibitors, which should aid ongoing inhibitor design.

The Synthesis of Quinolone Natural Products from Pseudonocardia sp.

PubMed Central

Salvaggio, Flavia; Hodgkinson, James T.; Carro, Laura; Geddis, Stephen M.; Galloway, Warren R. J. D.; Welch, Martin

2015-01-01

Abstract The synthesis of four quinolone natural products from the actinomycete Pseudonocardia sp. is reported. The key step involved a sp2–sp3 Suzuki–Miyaura reaction between a common boronic ester lateral chain and various functionalised quinolone cores. The quinolones slowed growth of E. coli and S. aureus by inducing extended lag phases.

Molecular underpinnings of neurodegenerative disorders: striatal-enriched protein tyrosine phosphatase signaling and synaptic plasticity

PubMed Central

Lombroso, Paul J.; Ogren, Marilee; Kurup, Pradeep; Nairn, Angus C.

2016-01-01

This commentary focuses on potential molecular mechanisms related to the dysfunctional synaptic plasticity that is associated with neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Specifically, we focus on the role of striatal-enriched protein tyrosine phosphatase (STEP) in modulating synaptic function in these illnesses. STEP affects neuronal communication by opposing synaptic strengthening and does so by dephosphorylating several key substrates known to control synaptic signaling and plasticity. STEP levels are elevated in brains from patients with Alzheimer’s and Parkinson’s disease. Studies in model systems have found that high levels of STEP result in internalization of glutamate receptors as well as inactivation of ERK1/2, Fyn, Pyk2, and other STEP substrates necessary for the development of synaptic strengthening. We discuss the search for inhibitors of STEP activity that may offer potential treatments for neurocognitive disorders that are characterized by increased STEP activity. Future studies are needed to examine the mechanisms of differential and region-specific changes in STEP expression pattern, as such knowledge could lead to targeted therapies for disorders involving disrupted STEP activity. PMID:29098072

From micronutrient recommendations to policy: consumer and stakeholder involvement.

PubMed

Timotijevic, L; Raats, M M; Barnett, J; Brown, K; Shepherd, R; Fernandez, L; Dömölki, L; Ruprich, J; Sonne, A-M; Hermoso, M; Koletzko, B; Frost-Andersen, L; Timmer, A

2010-06-01

To achieve the nutritional goals stipulated by micronutrient recommendations, greater attention must be paid to the behavioural routes to such nutritional outcomes. Coopting stakeholders and consumers into decisions regarding micronutrient recommendations is an important step towards achieving a greater link between micronutrient recommendations and behaviour. This study aims to examine the rationale and processes associated with consumer and stakeholder involvement in setting micronutrient recommendations across Europe. Using the contacts established through the Eurreca network of excellence (commissioned by the European Commission), the research involved in-depth desk research of key documents and communication channels linked to the process of setting micronutrient recommendations across seven countries: the United Kingdom, Norway, Denmark, Germany, Spain, the Czech Republic and Hungary. Stakeholder engagement is recognized by most countries as an important aspect of the process of setting micronutrient recommendations and their translation into policy, although there is notable variation in the extent to which this has been achieved across the seven countries and its effect on final decisions. Stakeholders were not involved at the outset of the process ('framing' of the problem) in any of the countries, and there was no evidence of consumer involvement and open public fora. Some of the key explanatory factors for diversity in the degree of involvement include historical sociopolitical context; the extent to which food and nutrition are key policy agenda; and the relative power of stakeholders in influencing food and nutrition policy.

Mechanistic insights into the decomposition of fructose to hydroxy methyl furfural in neutral and acidic environments using high-level quantum chemical methods.

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

Assary, R. S.; Redfern, P. C.; Greeley, J.

2011-03-28

Efficient catalytic chemical transformation of fructose to hydroxy methyl furfural (HMF) is one of the key steps for attaining industrial level conversion of biomass to useful chemicals. We report an investigation of the reaction mechanisms for the decomposition of fructose to HMF in both neutral and acidic environments at the Gaussian-4 level of theory including calculation of enthalpies, free energies, and effective solvation interactions. In neutral water solvent, the transformation of fructose to HMF involves a four step reaction sequence with four transition states. The effective activation energy relative to fructose in neutral water at 298 K is very large,more » about 74 kcal/mol, so that transformation in neutral media around this temperature is unlikely. In contrast, the computed potential energy surface is much more favorable for the transformation in acidic media at 498 K, as the effective activation barrier is about 39 kcal/mol. The transformation in acidic media is a much more complex mechanism involving dehydration and hydrogen transfer steps, which are more favorable when protonated intermediates are involved.« less

Mechanistic Insights into the Decomposition of Fructose to Hydroxy Methyl Furfural in Neutral and Acidic Environments Using High-Level Quantum Chemical Methods

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

Assary, Rajeev S.; Redfern, Paul C.; Greeley, Jeffrey P.

2011-04-21

Efficient catalytic chemical transformation of fructose to hydroxy methyl furfural (HMF) is one of the key steps for attaining industrial level conversion of biomass to useful chemicals. We report an investigation of the reaction mechanisms for the decomposition of fructose to HMF in both neutral and acidic environments at the Gaussian-4 level of theory including calculation of enthalpies, free energies, and effective solvation interactions. In neutral water solvent, the transformation of fructose to HMF involves a four step reaction sequence with four transition states. The effective activation energy relative to fructose in neutral water at 298 K is very large,more » about 74 kcal/mol, so that transformation in neutral media around this temperature is unlikely. In contrast, the computed potential energy surface is much more favorable for the transformation in acidic media at 498 K, as the effective activation barrier is about 39 kcal/mol. The transformation in acidic media is a much more complex mechanism involving dehydration and hydrogen transfer steps, which are more favorable when protonated intermediates are involved.« less

Mechanistic Insights into the Decomposition of Fructose to Hydroxy Methyl Furfural in Neutral and Acidic Environments Using High-Level Quantum Chemical Methods

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

Assary, Rajeev S.; Redfern, Paul C.; Greeley, Jeffrey

2011-03-28

Efficient catalytic chemical transformation of fructose to hydroxy methyl furfural (HMF) is one of the key steps for attaining industrial level conversion of biomass to useful chemicals. We report an investigation of the reaction mechanisms for the decomposition of fructose to HMF in both neutral and acidic environments at the Gaussian-4 level of theory including calculation of enthalpies, free energies, and effective solvation interactions. In neutral water solvent, the transformation of fructose to HMF involves a four step reaction sequence with four transition states. The effective activation energy relative to fructose in neutral water at 298 K is very large,more » about 74 kcal/mol, so that transformation in neutral media around this temperature is unlikely. In contrast, the computed potential energy surface is much more favorable for the transformation in acidic media at 498 K, as the effective activation barrier is about 39 kcal/mol. The transformation in acidic media is a much more complex mechanism involving dehydration and hydrogen transfer steps, which are more favorable when protonated intermediates are involved.« less

Melatonin: a universal time messenger.

PubMed

Erren, Thomas C; Reiter, Russel J

2015-01-01

Temporal organization plays a key role in humans, and presumably all species on Earth. A core building block of the chronobiological architecture is the master clock, located in the suprachi asmatic nuclei [SCN], which organizes "when" things happen in sub-cellular biochemistry, cells, organs and organisms, including humans. Conceptually, time messenging should follow a 5 step-cascade. While abundant evidence suggests how steps 1 through 4 work, step 5 of "how is central time information transmitted througout the body?" awaits elucidation. Step 1: Light provides information on environmental (external) time; Step 2: Ocular interfaces between light and biological (internal) time are intrinsically photosensitive retinal ganglion cells [ipRGS] and rods and cones; Step 3: Via the retinohypothalamic tract external time information reaches the light-dependent master clock in the brain, viz the SCN; Step 4: The SCN translate environmental time information into biological time and distribute this information to numerous brain structures via a melanopsin-based network. Step 5: Melatonin, we propose, transmits, or is a messenger of, internal time information to all parts of the body to allow temporal organization which is orchestrated by the SCN. Key reasons why we expect melatonin to have such role include: First, melatonin, as the chemical expression of darkness, is centrally involved in time- and timing-related processes such as encoding clock and calendar information in the brain; Second, melatonin travels throughout the body without limits and is thus a ubiquitous molecule. The chemial conservation of melatonin in all tested species could make this molecule a candidate for a universal time messenger, possibly constituting a legacy of an all-embracing evolutionary history.

Writing an academic essay: a practical guide for nurses.

PubMed

Booth, Y

Writing academic essays can be a major hurdle and source of anxiety for many students. Fears and misconceptions relating to this kind of writing can be dispelled if the task is approached in a logical and systematic manner. This article outlines the key steps involved in successfully completing an essay and provides some practical tips to facilitate critical and analytical writing. These steps are: analysing the task; exploring the subject; planning the essay; writing the account; and revising the drafts. Although this process is challenging, academic writing is a means of developing both personally and professionally.

Eight-step method to build the clinical content of an evidence-based care pathway: the case for COPD exacerbation

PubMed Central

2012-01-01

Background Optimization of the clinical care process by integration of evidence-based knowledge is one of the active components in care pathways. When studying the impact of a care pathway by using a cluster-randomized design, standardization of the care pathway intervention is crucial. This methodology paper describes the development of the clinical content of an evidence-based care pathway for in-hospital management of chronic obstructive pulmonary disease (COPD) exacerbation in the context of a cluster-randomized controlled trial (cRCT) on care pathway effectiveness. Methods The clinical content of a care pathway for COPD exacerbation was developed based on recognized process design and guideline development methods. Subsequently, based on the COPD case study, a generalized eight-step method was designed to support the development of the clinical content of an evidence-based care pathway. Results A set of 38 evidence-based key interventions and a set of 24 process and 15 outcome indicators were developed in eight different steps. Nine Belgian multidisciplinary teams piloted both the set of key interventions and indicators. The key intervention set was judged by the teams as being valid and clinically applicable. In addition, the pilot study showed that the indicators were feasible for the involved clinicians and patients. Conclusions The set of 38 key interventions and the set of process and outcome indicators were found to be appropriate for the development and standardization of the clinical content of the COPD care pathway in the context of a cRCT on pathway effectiveness. The developed eight-step method may facilitate multidisciplinary teams caring for other patient populations in designing the clinical content of their future care pathways. PMID:23190552

Removing Barriers to High School Completion--Technical Report. System Improvement and Reporting.

ERIC Educational Resources Information Center

Alberta Learning, Edmonton.

The ability of every student to successfully complete high school is fundamental to continued success and quality of life. As such, Alberta Learning's 2000-2003 Business Plan has set a target for improving high school completion by 19-year-old students from 70% to 75%. A key step to achieving this target has involved completing a study of barriers…

Enantioselective modular synthesis of cyclohexenones: total syntheses of (+)-crypto- and (+)-infectocaryone.

PubMed

Franck, Géraldine; Brödner, Kerstin; Helmchen, Günter

2010-09-03

A modular synthesis of cyclohexenones is described and applied to the first enantioselective total syntheses of (+)-crypto- and (+)-infectocaryone. Key steps in the synthesis of cyclohexenones are an iridium-catalyzed allylic alkylation, nucleophilic allylation, and ring-closing metathesis. On the way to (+)-cryptocaryone, a catch and release strategy involving an iodolactonization/elimination and a regioselective C-acylation were used.

Orthodontic-orthognathic interventions in orthognathic surgical cases: “Paper surgery” and “model surgery” concepts in surgical orthodontics

PubMed Central

Gandedkar, Narayan H.; Chng, Chai Kiat; Yeow, Vincent Kok Leng

2016-01-01

Thorough planning and execution is the key for successful treatment of dentofacial deformity involving surgical orthodontics. Presurgical planning (paper surgery and model surgery) are the most essential prerequisites of orthognathic surgery, and orthodontist is the one who carries out this procedure by evaluating diagnostic aids such as crucial clinical findings and radiographic assessments. However, literature pertaining to step-by-step orthognathic surgical guidelines is limited. Hence, this article makes an attempt to provide an insight and nuances involved in the planning and execution. The diagnostic information revealed from clinical findings and radiographic assessments is integrated in the “paper surgery” to establish “surgical-plan.” Furthermore, the “paper surgery” is emulated in “model surgery” such that surgical bite-wafers are created, which aid surgeon to preview the final outcome and make surgical movements that are deemed essential for the desired skeletal and dental outcomes. Skeletal complexities are corrected by performing “paper surgery” and an occlusion is set up during “model surgery” for the fabrication of surgical bite-wafers. Further, orthodontics is carried out for the proper settling and finishing of occlusion. Article describes the nuances involved in the treatment of Class III skeletal deformity individuals treated with orthognathic surgical approach and illustrates orthodontic-orthognathic step-by-step procedures from “treatment planning” to “execution” for successful management of aforementioned dentofacial deformity. PMID:27630506

Moves Management for physician fundraising in a capital campaign.

PubMed

Lehner, Larry K

2005-01-01

Hospitals are turning to philanthropy as a significant source of funding for capital programs, and physicians are a key resource. Through their own giving and their community-wide influence, physicians provide a high return on capital campaign investment. By adapting Moves Management, the premier method for prospecting and cultivation, development officers can achieve a high rate of participation by the hospital's physicians and, through them, attain increased community giving. Moves Management is defined as a process that involves managing a series of steps (moves) with identified prospects (the 10 percent who can give 90 percent). The number and type of steps depend upon the individual involved, such that each prospect is moved from attention to interest to desire to action and then back to interest until he or she has given everything he/she will or can to the organization.

A mixed-methods research approach to the review of competency standards for orthotist/prosthetists in Australia.

PubMed

Ash, Susan; O'Connor, Jackie; Anderson, Sarah; Ridgewell, Emily; Clarke, Leigh

2015-06-01

The requirement for an allied health workforce is expanding as the global burden of disease increases internationally. To safely meet the demand for an expanded workforce of orthotist/prosthetists in Australia, competency based standards, which are up-to-date and evidence-based, are required. The aims of this study were to determine the minimum level for entry into the orthotic/prosthetic profession; to develop entry level competency standards for the profession; and to validate the developed entry-level competency standards within the profession nationally, using an evidence-based approach. A mixed-methods research design was applied, using a three-step sequential exploratory design, where step 1 involved collecting and analyzing qualitative data from two focus groups; step 2 involved exploratory instrument development and testing, developing the draft competency standards; and step 3 involved quantitative data collection and analysis - a Delphi survey. In stage 1 (steps 1 and 2), the two focus groups - an expert and a recent graduate group of Australian orthotist/prosthetists - were led by an experienced facilitator, to identify gaps in the current competency standards and then to outline a key purpose, and work roles and tasks for the profession. The resulting domains and activities of the first draft of the competency standards were synthesized using thematic analysis. In stage 2 (step 3), the draft-competency standards were circulated to a purposive sample of the membership of the Australian Orthotic Prosthetic Association, using three rounds of Delphi survey. A project reference group of orthotist/prosthetists reviewed the results of both stages. In stage 1, the expert (n = 10) and the new graduate (n = 8) groups separately identified work roles and tasks, which formed the initial draft of the competency standards. Further drafts were refined and performance criteria added by the project reference group, resulting in the final draft-competency standards. In stage 2, the final draft-competency standards were circulated to 56 members (n = 44 final round) of the Association, who agreed on the key purpose, 6 domains, 18 activities, and 68 performance criteria of the final competency standards. This study outlines a rigorous and evidence-based mixed-methods approach for developing and endorsing professional competency standards, which is representative of the views of the profession of orthotist/prosthetists.

Sequential enzymatic epoxidation involved in polyether lasalocid biosynthesis.

PubMed

Minami, Atsushi; Shimaya, Mayu; Suzuki, Gaku; Migita, Akira; Shinde, Sandip S; Sato, Kyohei; Watanabe, Kenji; Tamura, Tomohiro; Oguri, Hiroki; Oikawa, Hideaki

2012-05-02

Enantioselective epoxidation followed by regioselective epoxide opening reaction are the key processes in construction of the polyether skeleton. Recent genetic analysis of ionophore polyether biosynthetic gene clusters suggested that flavin-containing monooxygenases (FMOs) could be involved in the oxidation steps. In vivo and in vitro analyses of Lsd18, an FMO involved in the biosynthesis of polyether lasalocid, using simple olefin or truncated diene of a putative substrate as substrate mimics demonstrated that enantioselective epoxidation affords natural type mono- or bis-epoxide in a stepwise manner. These findings allow us to figure out enzymatic polyether construction in lasalocid biosynthesis. © 2012 American Chemical Society

Extraocular muscle regeneration in zebrafish requires late signals from Insulin-like growth factors.

PubMed

Saera-Vila, Alfonso; Louie, Ke'ale W; Sha, Cuilee; Kelly, Ryan M; Kish, Phillip E; Kahana, Alon

2018-01-01

Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.

Human telomerase: biogenesis, trafficking, recruitment, and activation.

PubMed

Schmidt, Jens C; Cech, Thomas R

2015-06-01

Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. © 2015 Schmidt and Cech Published by Cold Spring Harbor Laboratory Press.

The "Motor" in Implicit Motor Sequence Learning: A Foot-stepping Serial Reaction Time Task.

PubMed

Du, Yue; Clark, Jane E

2018-05-03

This protocol describes a modified serial reaction time (SRT) task used to study implicit motor sequence learning. Unlike the classic SRT task that involves finger-pressing movements while sitting, the modified SRT task requires participants to step with both feet while maintaining a standing posture. This stepping task necessitates whole body actions that impose postural challenges. The foot-stepping task complements the classic SRT task in several ways. The foot-stepping SRT task is a better proxy for the daily activities that require ongoing postural control, and thus may help us better understand sequence learning in real-life situations. In addition, response time serves as an indicator of sequence learning in the classic SRT task, but it is unclear whether response time, reaction time (RT) representing mental process, or movement time (MT) reflecting the movement itself, is a key player in motor sequence learning. The foot-stepping SRT task allows researchers to disentangle response time into RT and MT, which may clarify how motor planning and movement execution are involved in sequence learning. Lastly, postural control and cognition are interactively related, but little is known about how postural control interacts with learning motor sequences. With a motion capture system, the movement of the whole body (e.g., the center of mass (COM)) can be recorded. Such measures allow us to reveal the dynamic processes underlying discrete responses measured by RT and MT, and may aid in elucidating the relationship between postural control and the explicit and implicit processes involved in sequence learning. Details of the experimental set-up, procedure, and data processing are described. The representative data are adopted from one of our previous studies. Results are related to response time, RT, and MT, as well as the relationship between the anticipatory postural response and the explicit processes involved in implicit motor sequence learning.

Development of a Mass Casualty Triage Performance Assessment Tool

DTIC Science & Technology

2015-02-01

mass casualty triage and interviews with members of the unit, the triage assessment development involved three steps: (1) identification of key...Unlimited c. THIS PAGE Unlimited Unlimited Unclassified 35 19b. TELEPHONE NUMBER (include area code ) i Technical...in this report was initiated by ARI-FHRU to develop a prototype measure of performance for one of the three collective tasks identified in the

Therapeutic Implications for Striatal-Enriched Protein Tyrosine Phosphatase (STEP) in Neuropsychiatric Disorders

PubMed Central

Goebel-Goody, Susan M.; Baum, Matthew; Paspalas, Constantinos D.; Fernandez, Stephanie M.; Carty, Niki C.; Kurup, Pradeep

2012-01-01

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the Src family tyrosine kinase Fyn, N-methyl-d-aspartate receptors (NMDARs), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders. PMID:22090472

"Extracting" the key fragment in ETS-10 crystallization and its application in AM-6 assembly.

PubMed

Guo, Meiling; Feng, Zhaochi; Li, Guanna; Hofmann, Jan P; Pidko, Evgeny A; Magusin, Pieter C M M; Guo, Qiang; Weckhuysen, Bert M; Hensen, Emiel J M; Fan, Fengtao; Li, Can

2012-09-17

The mechanism of crystallization of microporous titanosilicate ETS-10 was investigated by Raman spectroscopy combined with (29)Si magic-angle spinning (MAS) NMR spectroscopy, DFT calculations, and SEM imaging. The formation of three-membered ring species is shown to be the key step in the hydrothermal synthesis of ETS-10. They are formed by means of a complex process that involves the interaction of silicate species in the reaction mixture, which promotes the dissolution of TiO(2) particles. These insights into the mechanism of ETS-10 growth led to the successful development of a new synthesis route to the vanadosilicate AM-6 that involves the use of intermediates that contain three-membered ring species as an initiator. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Research activities to improve the utilization of antibiotics in Africa.

PubMed

Massele, Amos; Tiroyakgosi, Celda; Matome, Matshediso; Desta, Abayneh; Muller, Arno; Paramadhas, Bene D Anand; Malone, Brighid; Kurusa, Gobuiwang; Didimalang, Thatayaone; Moyo, Mosana; Godman, Brian

2017-02-01

There is a need to improve the rational use of antibiotics across continents including Africa. This has resulted in initiatives in Botswana including treatment guidelines and the instigation of Antibiotic Stewardship Programs (ASPs). The next steps involve a greater understanding of current antibiotic utilization and resistance patterns (AMR). This resulted in a 2-day meeting involving key stakeholders principally from Botswana to discuss key issues including AMR rates as well as ASPs in both the public and private sectors. Following this, the findings will be used to plan future studies across Africa including point prevalence studies. The findings will be presented in July 2016 at the next Medicines Utilization Research in Africa meeting will ideally serve as a basis for planning future pertinent interventional studies to enhance the rational use of antibiotics in Botswana and wider.

Development of a standardized training course for laparoscopic procedures using Delphi methodology.

PubMed

Bethlehem, Martijn S; Kramp, Kelvin H; van Det, Marc J; ten Cate Hoedemaker, Henk O; Veeger, Nicolaas J G M; Pierie, Jean Pierre E N

2014-01-01

Content, evaluation, and certification of laparoscopic skills and procedure training lack uniformity among different hospitals in The Netherlands. Within the process of developing a new regional laparoscopic training curriculum, a uniform and transferrable curriculum was constructed for a series of laparoscopic procedures. The aim of this study was to determine regional expert consensus regarding the key steps for laparoscopic appendectomy and cholecystectomy using Delphi methodology. Lists of suggested key steps for laparoscopic appendectomy and cholecystectomy were created using surgical textbooks, available guidelines, and local practice. A total of 22 experts, working for teaching hospitals throughout the region, were asked to rate the suggested key steps for both procedures on a Likert scale from 1-5. Consensus was reached with Crohnbach's α ≥ 0.90. Of the 22 experts, 21 completed and returned the survey (95%). Data analysis already showed consensus after the first round of Delphi on the key steps for laparoscopic appendectomy (Crohnbach's α = 0.92) and laparoscopic cholecystectomy (Crohnbach's α = 0.90). After the second round, 15 proposed key steps for laparoscopic appendectomy and 30 proposed key steps for laparoscopic cholecystectomy were rated as important (≥4 by at least 80% of the expert panel). These key steps were used for the further development of the training curriculum. By using the Delphi methodology, regional consensus was reached on the key steps for laparoscopic appendectomy and cholecystectomy. These key steps are going to be used for standardized training and evaluation purposes in a new regional laparoscopic curriculum. Copyright © 2014 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

A longitudinal study of the comparative efficacy of Women for Sobriety, LifeRing, SMART Recovery, and 12-step groups for those with AUD.

PubMed

Zemore, Sarah E; Lui, Camillia; Mericle, Amy; Hemberg, Jordana; Kaskutas, Lee Ann

2018-05-01

Despite the effectiveness of 12-step groups, most people reporting a prior alcohol use disorder (AUD) do not sustain involvement in such groups at beneficial levels. This highlights the need for research on other mutual help groups that address alcohol problems and may attract those who avoid 12-step groups. The current study addresses this need, offering outcome data from the first longitudinal, comparative study of 12-step groups and their alternatives: The Peer ALlternatives for Addiction (PAL) Study. Adults with a lifetime AUD were surveyed at baseline (N=647), 6months (81% response rate) and 12months (83% response rate). Members of the largest known secular mutual help alternatives, namely Women for Sobriety (WFS), LifeRing, and SMART, were recruited in collaboration with group directors; current 12-step attendees were recruited from an online meeting hub. Online surveys assessed demographic and clinical variables; mutual help involvement; and alcohol and drug use and severity. Analyses involved multivariate logistic GEEs separately modelling alcohol abstinence, alcohol problems, and total abstinence across 6 and 12months. Key predictors were baseline primary group affiliation (PGA); primary group involvement (PGI) at both baseline and 6months; and the interaction between baseline PGA and 6-month PGI. The critical effects of interest were the interactions, expressing whether associations between changes in PGI from baseline to 6months and substance use outcomes differed by primary group. None of the interactions between baseline PGA and 6-month PGI were significant, suggesting no differences in the efficacy of WFS, LifeRing, or SMART, vs. 12-step groups. Nevertheless, some PGA main effects emerged. Compared to 12-step members, those identifying SMART as their primary group at baseline fared worse across outcomes, and those affiliating with LifeRing showed lower odds of total abstinence. Still, these effects became nonsignificant when controlling for baseline alcohol recovery goal, suggesting that any group differences may be explained by selection of those with weaker abstinence motivation into LifeRing and (especially) SMART. This study makes a valuable contribution in view of the extremely limited evidence on mutual help alternatives. Results tentatively suggest that WFS, LifeRing, and SMART are as effective as 12-step groups for those with AUDs, and that this population has the best odds of success when committing to lifetime total abstinence. An optimal care plan may thus involve facilitating involvement in a broad array of mutual help groups and supporting abstinence motivation. Copyright © 2018 Elsevier Inc. All rights reserved.

Synthesis of the Strychnos Alkaloid (-)-Strychnopivotine and Confirmation of its Absolute Configuration.

PubMed

Maertens, Gaëtan; Canesi, Sylvain

2016-05-17

The first enantioselective synthesis of (-)-strychnopivotine from a known and inexpensive phenol has been achieved in 15 steps. The strategy is based on a new diastereoselective aza-Michael-enol-ether cascade desymmetrization of a dienone, guided by a removable lactic acid-derived chiral auxiliary. Synthesis involves a phenol dearomatization, a conjugated silicon addition, a stereoselective double reductive amination, and two Heck-type carbopalladations as key steps. The absolute configuration of the natural compound, which, to date, has been uncertain, was confirmed by using circular dichroism (CD) spectroscopy and X-ray analyses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

O–O bond formation in ruthenium-catalyzed water oxidation: single-site nucleophilic attack vs. O–O radical coupling

DOE PAGES

Shaffer, David W.; Xie, Yan; Concepcion, Javier J.

2017-09-01

In this review we discuss at the mechanistic level the different steps involved in water oxidation catalysis with ruthenium-based molecular catalysts. We have chosen to focus on ruthenium-based catalysts to provide a more coherent discussion and because of the availability of detailed mechanistic studies for these systems but many of the aspects presented in this review are applicable to other systems as well. The water oxidation cycle has been divided in four major steps: water oxidative activation, O–O bond formation, oxidative activation of peroxide intermediates, and O 2 evolution. A significant portion of the review is dedicated to the O–Omore » bond formation step as the key step in water oxidation catalysis. As a result, the two main pathways to accomplish this step, single-site water nucleophilic attack and O–O radical coupling, are discussed in detail and compared in terms of their potential use in photoelectrochemical cells for solar fuels generation.« less

O–O bond formation in ruthenium-catalyzed water oxidation: single-site nucleophilic attack vs. O–O radical coupling

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

Shaffer, David W.; Xie, Yan; Concepcion, Javier J.

In this review we discuss at the mechanistic level the different steps involved in water oxidation catalysis with ruthenium-based molecular catalysts. We have chosen to focus on ruthenium-based catalysts to provide a more coherent discussion and because of the availability of detailed mechanistic studies for these systems but many of the aspects presented in this review are applicable to other systems as well. The water oxidation cycle has been divided in four major steps: water oxidative activation, O–O bond formation, oxidative activation of peroxide intermediates, and O 2 evolution. A significant portion of the review is dedicated to the O–Omore » bond formation step as the key step in water oxidation catalysis. As a result, the two main pathways to accomplish this step, single-site water nucleophilic attack and O–O radical coupling, are discussed in detail and compared in terms of their potential use in photoelectrochemical cells for solar fuels generation.« less

O-O bond formation in ruthenium-catalyzed water oxidation: single-site nucleophilic attack vs. O-O radical coupling.

PubMed

Shaffer, David W; Xie, Yan; Concepcion, Javier J

2017-10-16

In this review we discuss at the mechanistic level the different steps involved in water oxidation catalysis with ruthenium-based molecular catalysts. We have chosen to focus on ruthenium-based catalysts to provide a more coherent discussion and because of the availability of detailed mechanistic studies for these systems but many of the aspects presented in this review are applicable to other systems as well. The water oxidation cycle has been divided in four major steps: water oxidative activation, O-O bond formation, oxidative activation of peroxide intermediates, and O 2 evolution. A significant portion of the review is dedicated to the O-O bond formation step as the key step in water oxidation catalysis. The two main pathways to accomplish this step, single-site water nucleophilic attack and O-O radical coupling, are discussed in detail and compared in terms of their potential use in photoelectrochemical cells for solar fuels generation.

Understanding Proximal-Distal Economic Projections of the Benefits of Childhood Preventive Interventions

PubMed Central

Slade, Eric P.; Becker, Kimberly D.

2014-01-01

This paper discusses the steps and decisions involved in proximal-distal economic modeling, in which social, behavioral, and academic outcomes data for children may be used to inform projections of the economic consequences of interventions. Economic projections based on proximal-distal modeling techniques may be used in cost-benefit analyses when information is unavailable for certain long term outcomes data in adulthood or to build entire cost-benefit analyses. Although examples of proximal-distal economic analyses of preventive interventions exist in policy reports prepared for governmental agencies, such analyses have rarely been completed in conjunction with research trials. The modeling decisions on which these prediction models are based are often opaque to policymakers and other end-users. This paper aims to illuminate some of the key steps and considerations involved in constructing proximal-distal prediction models and to provide examples and suggestions that may help guide future proximal-distal analyses. PMID:24337979

STEPS: A NARRATIVE ACCOUNT OF A GABAPENTIN SEEDING TRIAL

PubMed Central

Krumholz, Samuel D.; Egilman, David S.; Ross, Joseph S.

2012-01-01

Background Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. Methods We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing v. Pfizer and Franklin v. Warner-Lambert, the majority of which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial, in order to identify key themes related to the trial’s conduct and determine the extent of marketing involvement in its planning and implementation. Results Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company’s marketing plans. Documents demonstrated that several external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in two published papers. Conclusions The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation. PMID:21709111

Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial.

PubMed

Krumholz, Samuel D; Egilman, David S; Ross, Joseph S

2011-06-27

Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices, and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert, most which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial in order to identify key themes related to the trial's conduct and determine the extent of marketing involvement in its planning and implementation. Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles. The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation.

SNARE-mediated membrane fusion in autophagy

PubMed Central

Wang, Yongyao; Li, Linsen; Hou, Chen; Lai, Ying; Long, Jiangang; Liu, Jiankang; Zhong, Qing; Diao, Jiajie

2016-01-01

Autophagy, a conserved self-eating process for the bulk degradation of cytoplasmic materials, involves double-membrane autophagosomes formed when an isolation membrane emerges and their direct fusion with lysosomes for degradation. For the early biogenesis of autophagosomes and their later degradation in lysosomes, membrane fusion is necessary, although different sets of genes and autophagy-related proteins involved in distinct fusion steps have been reported. To clarify the molecular mechanism of membrane fusion in autophagy, to not only expand current knowledge of autophagy, but also benefit human health, this review discusses key findings that elucidate the unique membrane dynamics of autophagy. PMID:27422330

What Is Happening when the Blue Bottle Bleaches: An Investigation of the Methylene Blue-Catalyzed Air Oxidation of Glucose

ERIC Educational Resources Information Center

Anderson, Laurens; Wittkopp, Stacy M.; Painter, Christopher J.; Liegel, Jessica J.; Schreiner, Rodney; Bell, Jerry A.; Shakhashiri, Bassam Z.

2012-01-01

An investigation of the Blue Bottle Experiment, a well-known lecture demonstration reaction involving the dye-catalyzed air oxidation of a reducing sugar in alkaline solution, has delineated the sequence of reactions leading to the bleaching of the dye, the regeneration of color, and so forth. Enolization of the sugar is proposed as a key step in…

Retrovirus Integration: Some Assembly Required?

PubMed

Ali, Ibraheem; Conrad, Ryan J; Ott, Melanie

2016-12-14

Integration is a key feature of the retroviral life cycle. This process involves packaging of the viral genome into chromatin, which is often assumed to occur as a post-integration step. In this issue of Cell Host & Microbe, Wang and colleagues (Wang et al., 2016) show that chromatinization occurs before integration, raising new questions about the role of histones in retroviral integration and transcription. Copyright © 2016. Published by Elsevier Inc.

Convergent Synthesis and Structural Confirmation of Phellodonin and Sarcodonin ε

PubMed Central

Usui, Ippei; Lin, David W.; Masuda, Takeshi

2013-01-01

The first synthesis of members of the sarcodonin family, phellodonin and sarcodonin ε, is reported herein. This verifies that the unprecedented and seemingly unstable N,N-dioxide-containing benzodioxazine framework can be constructed in the laboratory, and lends further support to the proposed structures. The key step in the synthesis involves a biomimetic hetero-Diels–Alder reaction between a pyrazine N-oxide and an ortho-quinone. PMID:23577748

Revealing the Gag Itinerary: How HIV is Transmitted One Cell at a Time | Center for Cancer Research

Cancer.gov

Although person-to-person transmission of HIV has been well understood for years, researchers are still trying to figure out exactly how the virus moves from one cell to another. Researchers have delineated the steps and key players involved in the generation of HIV particles inside infected (host) cells. However, the precise location of virus assembly inside these cells and

The Nine-Step Minnesota Grading System for Eyebank Eyes With Age Related Macular Degeneration: A Systematic Approach to Study Disease Stages.

PubMed

Olsen, Timothy W; Liao, Albert; Robinson, Hershonna S; Palejwala, Neal V; Sprehe, Nicholas

2017-10-01

To refine the Minnesota Grading System (MGS) using definitions from the Age-Related Eye Disease Studies (AREDS) into a nine-step grading scale (MGS-9). A nine-step grading scale descriptive analysis using three key phenotypic features (total drusen area, increased, and decreased pigmentation) of human eyebank eyes that were graded according to definitions from the AREDS criteria in order to harmonize studies of disease progression for research involving human tissue. From 2005 through February 2017, we have analyzed 1159 human eyes, procured from two eyebanks. Each macula was imaged using high-resolution, stereoscopic color fundus photography with both direct- and transillumination. Fundus images were digitally overlaid with a grading template and triangulated for foveal centration. We documented and stratified risk for each globe by applying the AREDS nine-step grading scale to the key clinical features from the MGS-9. We found a good distribution within the MGS categories (1-9) with few level eight globes. Eyes were processed within 12.1 ± 6.3, hours from the time of death through imaging, dissection, and freezing or fixation. Applying the MGS-9 to 331 pairs (662 eyes were simultaneously graded), 84% were within one-grading step and 93% within two steps of the fellow eye. We also document reticular pseudodrusen, basal laminar drusen, and pattern dystrophy. The MGS nine-step grading scale enables researchers using human tissue to refine the risk assessment of donor tissue. This analysis will harmonize results among researchers when grading human tissue using MGS criteria. Most importantly, the MGS-9 links directly to the known risk for progression from the AREDS.

Application of linker technique to trap transiently interacting protein complexes for structural studies

PubMed Central

Reddy Chichili, Vishnu Priyanka; Kumar, Veerendra; Sivaraman, J.

2016-01-01

Protein-protein interactions are key events controlling several biological processes. We have developed and employed a method to trap transiently interacting protein complexes for structural studies using glycine-rich linkers to fuse interacting partners, one of which is unstructured. Initial steps involve isothermal titration calorimetry to identify the minimum binding region of the unstructured protein in its interaction with its stable binding partner. This is followed by computational analysis to identify the approximate site of the interaction and to design an appropriate linker length. Subsequently, fused constructs are generated and characterized using size exclusion chromatography and dynamic light scattering experiments. The structure of the chimeric protein is then solved by crystallization, and validated both in vitro and in vivo by substituting key interacting residues of the full length, unlinked proteins with alanine. This protocol offers the opportunity to study crucial and currently unattainable transient protein interactions involved in various biological processes. PMID:26985443

Procedural key steps in laparoscopic colorectal surgery, consensus through Delphi methodology.

PubMed

Dijkstra, Frederieke A; Bosker, Robbert J I; Veeger, Nicolaas J G M; van Det, Marc J; Pierie, Jean Pierre E N

2015-09-01

While several procedural training curricula in laparoscopic colorectal surgery have been validated and published, none have focused on dividing surgical procedures into well-identified segments, which can be trained and assessed separately. This enables the surgeon and resident to focus on a specific segment, or combination of segments, of a procedure. Furthermore, it will provide a consistent and uniform method of training for residents rotating through different teaching hospitals. The goal of this study was to determine consensus on the key steps of laparoscopic right hemicolectomy and laparoscopic sigmoid colectomy among experts in our University Medical Center and affiliated hospitals. This will form the basis for the INVEST video-assisted side-by-side training curriculum. The Delphi method was used for determining consensus on key steps of both procedures. A list of 31 steps for laparoscopic right hemicolectomy and 37 steps for laparoscopic sigmoid colectomy was compiled from textbooks and national and international guidelines. In an online questionnaire, 22 experts in 12 hospitals within our teaching region were invited to rate all steps on a Likert scale on importance for the procedure. Consensus was reached in two rounds. Sixteen experts agreed to participate. Of these 16 experts, 14 (88%) completed the questionnaire for both procedures. Of the 14 who completed the first round, 13 (93%) completed the second round. Cronbach's alpha was 0.79 for the right hemicolectomy and 0.91 for the sigmoid colectomy, showing high internal consistency between the experts. For the right hemicolectomy, 25 key steps were established; for the sigmoid colectomy, 24 key steps were established. Expert consensus on the key steps for laparoscopic right hemicolectomy and laparoscopic sigmoid colectomy was reached. These key steps will form the basis for a video-assisted teaching curriculum.

Classic fungal natural products in the genomic age: the molecular legacy of Harold Raistrick.

PubMed

Schor, Raissa; Cox, Russell

2018-03-01

Covering: 1893 to 2017Harold Raistrick was involved in the discovery of many of the most important classes of fungal metabolites during the 20th century. This review focusses on how these discoveries led to developments in isotopic labelling, biomimetic chemistry and the discovery, analysis and exploitation of biosynthetic gene clusters for major classes of fungal metabolites including: alternariol; geodin and metabolites of the emodin pathway; maleidrides; citrinin and the azaphilones; dehydrocurvularin; mycophenolic acid; and the tropolones. Key recent advances in the molecular understanding of these important pathways, including the discovery of biosynthetic gene clusters, the investigation of the molecular and chemical aspects of key biosynthetic steps, and the reengineering of key components of the pathways are reviewed and compared. Finally, discussion of key relationships between metabolites and pathways and the most important recent advances and opportunities for future research directions are given.

Description of the Baudet Surgical Technique and Introduction of a Systematic Method for Training Surgeons to Perform Male-to-Female Sex Reassignment Surgery.

PubMed

Leclère, Franck Marie; Casoli, Vincent; Baudet, Jacques; Weigert, Romain

2015-12-01

Male-to-female sex reassignment surgery involves three main procedures, namely, clitoroplasty, new urethral meatoplasty and vaginopoiesis. Herein we describe the key steps of our surgical technique. Male-to-female sex reassignment surgery includes the following 14 key steps which are documented in this article: (1) patient installation and draping, (2) urethral catheter placement, (3) scrotal incision and vaginal cavity formation, (4) bilateral orchidectomy, (5) penile skin inversion, (6) dismembering of the urethra from the corpora, (7) neoclitoris formation, (8) neoclitoris refinement, (9) neovaginalphallic cylinder formation, (10) fixation of the neoclitoris, (11) neovaginalphallic cylinder insertion, (12) contouring of the labia majora and positioning the neoclitoris and urethra, (13) tie-over dressing and (14) compression dressing. The size and position of the neoclitoris, position of the urethra, adequacy of the neovaginal cavity, position and tension on the triangular flap, size of the neo labia minora, size of the labia majora, symmetry and ease of intromission are important factors when considering the immediate results of the surgery. We present our learning process of graduated responsibility for optimisation of these results. We describe our postoperative care and the possible complications. Herein, we have described the 14 steps of the Baudet technique for male-to-female sex reassignment surgery which include clitoroplasty, new urethral meatoplasty and vaginopoiesis. The review of each key stage of the procedure represents the first step of our global teaching process. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Transmission electron microscopy of amyloid fibrils.

PubMed

Gras, Sally L; Waddington, Lynne J; Goldie, Kenneth N

2011-01-01

Transmission Electron Microscopy of negatively stained and cryo-prepared specimens allows amyloid fibrils to be visualised at high resolution in a dried or a hydrated state, and is an essential method for characterising the morphology of fibrils and pre-fibrillar species. We outline the key steps involved in the preparation and observation of samples using negative staining and cryo-electron preservation. We also discuss methods to measure fibril characteristics, such as fibril width, from electron micrographs.

The A, C, G, and T of Genome Assembly.

PubMed

Wajid, Bilal; Sohail, Muhammad U; Ekti, Ali R; Serpedin, Erchin

2016-01-01

Genome assembly in its two decades of history has produced significant research, in terms of both biotechnology and computational biology. This contribution delineates sequencing platforms and their characteristics, examines key steps involved in filtering and processing raw data, explains assembly frameworks, and discusses quality statistics for the assessment of the assembled sequence. Furthermore, the paper explores recent Ubuntu-based software environments oriented towards genome assembly as well as some avenues for future research.

Effects of acute alcohol intoxication on automated processing: evidence from the double-step paradigm.

PubMed

Vorstius, Christian; Radach, Ralph; Lang, Alan R

2012-02-01

Reflexive and voluntary levels of processing have been studied extensively with respect to possible impairments due to alcohol intoxication. This study examined alcohol effects at the 'automated' level of processing essential to many complex visual processing tasks (e.g., reading, visual search) that involve ongoing modifications or reprogramming of well-practiced routines. Data from 30 participants (16 male) were collected in two counterbalanced sessions (alcohol vs. no-alcohol control; mean breath alcohol concentration = 68 mg/dL vs. 0 mg/dL). Eye movements were recorded during a double-step task where 75% of trials involved two target stimuli in rapid succession (inter-stimulus interval [ISI]=40, 70, or 100 ms) so that they could elicit two distinct saccades or eye movements (double steps). On 25% of trials a single target appeared. Results indicated that saccade latencies were longer under alcohol. In addition, the proportion of single-step responses and the mean saccade amplitude (length) of primary saccades decreased significantly with increasing ISI. The key novel finding, however, was that the reprogramming time needed to cancel the first saccade and adjust saccade amplitude was extended significantly by alcohol. The additional time made available by prolonged latencies due to alcohol was not utilized by the saccade programming system to decrease the number of two-step responses. These results represent the first demonstration of specific alcohol-induced programming deficits at the automated level of oculomotor processing.

Total synthesis of (±)-antroquinonol d.

PubMed

Sulake, Rohidas S; Jiang, Yan-Feng; Lin, Hsiao-Han; Chen, Chinpiao

2014-11-21

Total synthesis of (±)-antroquinonol D, which is isolated from very expensive and rarely found Antrodia camphorata and which has potential anticancer properties, was achieved from 4-methoxyphenol. In addition, a Michael addition to dimethoxy cyclohexadienones was studied. The main step involved chelation and substrate-controlled diastereoselective reduction of cyclohexenone and lactonization. Lactone synthesis facilitated the diastereoselective reduction of ketone, which help control the desired stereochemistry at the crucial stereogenic center in the natural product. Other key reactions in the synthesis involved a Michael addition of dimethyl malonate on cyclohexadienone, dihydroxylation, and Wittig olefination. A sesquiterpene side chain was synthesized through coupling with geranyl phenyl sulfide and Bouveault-Blanc reduction.

SNARE-mediated membrane fusion in autophagy.

PubMed

Wang, Yongyao; Li, Linsen; Hou, Chen; Lai, Ying; Long, Jiangang; Liu, Jiankang; Zhong, Qing; Diao, Jiajie

2016-12-01

Autophagy, a conserved self-eating process for the bulk degradation of cytoplasmic materials, involves double-membrane autophagosomes formed when an isolation membrane emerges and their direct fusion with lysosomes for degradation. For the early biogenesis of autophagosomes and their later degradation in lysosomes, membrane fusion is necessary, although different sets of genes and autophagy-related proteins involved in distinct fusion steps have been reported. To clarify the molecular mechanism of membrane fusion in autophagy, to not only expand current knowledge of autophagy, but also benefit human health, this review discusses key findings that elucidate the unique membrane dynamics of autophagy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Synthetic studies of the zoanthamine alkaloids: the total syntheses of norzoanthamine and zoanthamine.

PubMed

Yoshimura, Fumihiko; Sasaki, Minoru; Hattori, Izumi; Komatsu, Kei; Sakai, Mio; Tanino, Keiji; Miyashita, Masaaki

2009-07-06

The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely, norzoanthamine (1) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic drug, while zoanthamine (2) has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. Their distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of norzoanthamine (1) and zoanthamine (2) in full detail, which involve stereoselective synthesis of the requisite triene (18) for an intramolecular Diels-Alder reaction via the sequential three-component coupling reactions, the key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of norzoanthamine (1) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively.

Architectural programming for the workplace and the careplace.

PubMed

Easter, James G

2002-01-01

Sensitive planning and architectural design will impact long-term costs and daily operations. At the same time, the quality of the total environment has a direct impact on the patient, the family and the staff. These needs should be carefully balanced with the emotions of the patient, the care partner (parent, husband, wife or guardian) and those of the clinical team (physicians, nurses and staff). This article addresses the first step in the process; the master plan and then focuses in detail on one aspect of the architectural work referred to as architectural programming. The key to the process is selecting the best team of consultants, following the steps carefully, involving the client at every appropriate milestone along the way and asking the right questions. With this experienced team on board; following the proper steps, listening carefully to the answers and observing the daily process one can expect a successful product.

[Progress in the study on mammalian diacylgycerol acyltransgerase (DGAT) gene and its biological function].

PubMed

Wang, Yan; Xu, Heng-Yong; Zhu, Qing

2007-10-01

Diacylglycerol acyltransferase (DGAT; EC 2.3.1.20) is a microsomal enzyme that plays a central role in the metabolism of cellular glycerolipids. DGAT catalyzes the final step in triacylglycerol (TAG) biosynthesis by converting diacylgycerol (DAG) and fatty acyl-coenzyme A (CoA) into triacylglycero1. DGAT plays a fundamental role in the metabolism of cellular diacylglycerol and is important in higher eukaryotes for physiologic processes involving triacylglycerol metabolism such as intestinal fat absorption, lipoprotein assembly, adipose tissue formation, and lactation. Therefore, DGAT is not only an key factor for control triglycerides and fatty acids, but also may play a key modulatory role in animal fat deposition.

The A, C, G, and T of Genome Assembly

PubMed Central

Wajid, Bilal; Sohail, Muhammad U.; Ekti, Ali R.; Serpedin, Erchin

2016-01-01

Genome assembly in its two decades of history has produced significant research, in terms of both biotechnology and computational biology. This contribution delineates sequencing platforms and their characteristics, examines key steps involved in filtering and processing raw data, explains assembly frameworks, and discusses quality statistics for the assessment of the assembled sequence. Furthermore, the paper explores recent Ubuntu-based software environments oriented towards genome assembly as well as some avenues for future research. PMID:27247941

Ugi 4-CR Synthesis of γ- and δ-Lactams providing new access to diverse enzyme interactions, a PDB analysis.

PubMed

Boltjes, André; Liao, George P; Zhao, Ting; Herdtweck, Eberhardt; Dömling, Alexander

2014-07-01

A three step synthesis of N -unsubstituted tetrazolo γ- and δ-lactams involving a key Ugi-4CR is presented. The compounds, otherwise difficult to access, are conveniently synthesized in overall good yields by our route. PDB analysis of the N -unsubstituted γ- and δ-lactam fragment reveals a strongly tri-directional hydrogen bond donor acceptor interaction with the amino acids of the binding sites.

Computational investigation of rearrangements in huisgen cycloadducts of azolium N-dicyanomethanide 1,3-dipoles with alkynes: a mechanistic panoply.

PubMed

Burke, Luke A; Butler, Richard N

2009-08-07

The reaction surfaces leading to rearrangements and ring expansions of azapentalene cycloadducts of imidazolo- and triazolodicyanomethanide 1,3-dipoles with alkynes are studied with the B3LYP DFT method using the 6-31G(d) and 6-311+G(2d,p) basis sets. The surprisingly complex surface involves (1) consecutive but not combined pericyclic steps, a coarctate TS, and pseudopericyclic mechanisms, (2) anchimerically assisted H-atom transfer competing effectively with concerted symmetry-allowed sigmatropic steps, and (3) azolium methanide zwitterions and ketenimines as key intermediates. The azolium methanide is identified as the intermediate detected previously in a variable-temperature NMR experiment that converted the unstable cycloadduct to product imine.

Mechanical, thermal and morphological characterization of polycarbonate/oxidized carbon nanofiber composites produced with a lean 2-step manufacturing process.

PubMed

Lively, Brooks; Kumar, Sandeep; Tian, Liu; Li, Bin; Zhong, Wei-Hong

2011-05-01

In this study we report the advantages of a 2-step method that incorporates an additional process pre-conditioning step for rapid and precise blending of the constituents prior to the commonly used melt compounding method for preparing polycarbonate/oxidized carbon nanofiber composites. This additional step (equivalent to a manufacturing cell) involves the formation of a highly concentrated solid nano-nectar of polycarbonate/carbon nanofiber composite using a solution mixing process followed by melt mixing with pure polycarbonate. This combined method yields excellent dispersion and improved mechanical and thermal properties as compared to the 1-step melt mixing method. The test results indicated that inclusion of carbon nanofibers into composites via the 2-step method resulted in dramatically reduced ( 48% lower) coefficient of thermal expansion compared to that of pure polycarbonate and 30% lower than that from the 1-step processing, at the same loading of 1.0 wt%. Improvements were also found in dynamic mechanical analysis and flexural mechanical properties. The 2-step approach is more precise and leads to better dispersion, higher quality, consistency, and improved performance in critical application areas. It is also consistent with Lean Manufacturing principles in which manufacturing cells are linked together using less of the key resources and creates a smoother production flow. Therefore, this 2-step process can be more attractive for industry.

Striatal-enriched Tyrosine Protein Phosphatase (STEP) in the Mechanisms of Depressive Disorders.

PubMed

Kulikova, Elizabeth; Kulikov, Alexander

2017-08-30

Striatal-enriched tyrosine protein phosphatase (STEP) is expressed mainly in the brain. Its dysregulation is associated with Alzheimer's and Huntington's diseases, schizophrenia, fragile X syndrome, drug abuse and stroke/ischemia. However, an association between STEP and depressive disorders is still obscure. The review discusses the theoretical foundations and experimental facts concerning possible relationship between STEP dysregulation and depression risk. STEP dephosphorylates and inactivates several key neuronal signaling proteins such as extracellular signal-regulating kinase 1 and 2 (ERK1/2), stress activated protein kinases p38, the Src family tyrosine kinases Fyn, Pyk2, NMDA and AMPA glutamate receptors. The inactivation of these proteins decreases the expression of brain derived neurotrophic factor (BDNF) necessary for neurogenesis and neuronal survival. The deficit of BDNF results in progressive degeneration of neurons in the hippocampus and cortex and increases depression risk. At the same time, a STEP inhibitor, 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153), increases BDNF expression in the hippocampus and attenuated the depressivelike behavior in mice. Thus, STEP is involved in the mechanism of depressive disorders and it is a promising molecular target for atypical antidepressant drugs of new generation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Acetogenesis and the Wood-Ljungdahl Pathway of CO2 Fixation

PubMed Central

Ragsdale, Stephen W.; Pierce, Elizabeth

2008-01-01

I. Summary Conceptually, the simplest way to synthesize an organic molecule is to construct it one carbon at a time. The Wood-Ljungdahl pathway of CO2 fixation involves this type of stepwise process. The biochemical events that underlie the condensation of two one-carbon units to form the two-carbon compound, acetate, have intrigued chemists, biochemists, and microbiologists for many decades. We begin this review with a description of the biology of acetogenesis. Then, we provide a short history of the important discoveries that have led to the identification of the key components and steps of this usual mechanism of CO and CO2 fixation. In this historical perspective, we have included reflections that hopefully will sketch the landscape of the controversies, hypotheses, and opinions that led to the key experiments and discoveries. We then describe the properties of the genes and enzymes involved in the pathway and conclude with a section describing some major questions that remain unanswered. PMID:18801467

Revisit, revamp and revitalize your business plan: Part 4.

PubMed

Waldron, David

2011-01-01

A best practice for all imaging leaders working on a management development program should be to invest enough time to complete a detailed planthatsetsgoals, objectives, step targets, landmarks, and a timetable for their achievements. Keys to success for a management development program include no surprises, active participation, and preparation by both the facilitator and the managers involved. A successful management team will have trained staff and lean processes mapped and documented, as well as be comfortable in a coaching, delegating, and consensus management style.

Resolving the Gordian Knot: Srs2 Strips Intermediates Formed during Homologous Recombination.

PubMed

Ghodke, Harshad; Lewis, Jacob S; van Oijen, Antoine M

2018-03-01

Cells use a suite of specialized enzymes to repair chromosomal double-strand breaks (DSBs). Two recent studies describe how single-molecule fluorescence imaging techniques are used in the direct visualization of some of the key molecular steps involved. De Tullio et al. and Kaniecki et al. watch individual Srs2 helicase molecules disrupt repair intermediates formed by RPA, Rad51, and Rad52 on DNA during homologous recombination. Copyright © 2017 Elsevier Ltd. All rights reserved.

Enantioselective Syntheses of (−)-Alloyohimbane and (−)-Yohimbane by an Efficient Enzymatic Desymmetrization Process

PubMed Central

Ghosh, Arun K.; Sarkar, Anindya

2016-01-01

Enantioselective syntheses of (−)-alloyohimbane and (−)-yohimbane was accomplished in a convergent manner. The key step involved a modified mild protocol for the enantioselective enzymatic desymmetrization of meso-diacetate. The protocol provided convenient access to an optically active monoacetate in multi-gram scale in high enantiomeric purity. This monoacetate was converted to (−)-alloyohimbane. Reductive amination of the derived aldehyde causes the isomerization leading to the trans-product and allows the synthesis of (−)-yohimbane. PMID:28757804

Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins.

PubMed

Bischoff, Matthias; Sippel, Claudia; Bracher, Andreas; Hausch, Felix

2014-10-17

A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp(3)-sp(2) Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode.

An enantioselective enzymatic desymmetrization route to hexahydro-4H-furopyranol, a high-affinity ligand for HIV-1 protease inhibitors.

PubMed

Ghosh, Arun K; Sarkar, Anindya

2017-08-16

An enantioselective synthesis of ( 3 a S , 4S , 7 a R )-hexahydro-4 H -furo[2,3- b ]pyran-4-ol, a high-affinity nonpeptide ligand for a variety of potent HIV-1 protease inhibitors is described. The key steps involved a highly enantioselective enzymatic desymmetrization of meso -diacetate, an efficient transacetalization, and a highly diastereoselective reduction of a ketone. This route is amenable to large-scale synthesis using readily available starting materials.

Theorising and testing environmental pathways to behaviour change: natural experimental study of the perception and use of new infrastructure to promote walking and cycling in local communities

PubMed Central

Panter, Jenna; Ogilvie, David

2015-01-01

Objective Some studies have assessed the effectiveness of environmental interventions to promote physical activity, but few have examined how such interventions work. We investigated the environmental mechanisms linking an infrastructural intervention with behaviour change. Design Natural experimental study. Setting Three UK municipalities (Southampton, Cardiff and Kenilworth). Participants Adults living within 5 km of new walking and cycling infrastructure. Intervention Construction or improvement of walking and cycling routes. Exposure to the intervention was defined in terms of residential proximity. Outcome measures Questionnaires at baseline and 2-year follow-up assessed perceptions of the supportiveness of the environment, use of the new infrastructure, and walking and cycling behaviours. Analysis proceeded via factor analysis of perceptions of the physical environment (step 1) and regression analysis to identify plausible pathways involving physical and social environmental mediators and refine the intervention theory (step 2) to a final path analysis to test the model (step 3). Results Participants who lived near and used the new routes reported improvements in their perceptions of provision and safety. However, path analysis (step 3, n=967) showed that the effects of the intervention on changes in time spent walking and cycling were largely (90%) explained by a simple causal pathway involving use of the new routes, and other pathways involving changes in environmental cognitions explained only a small proportion of the effect. Conclusions Physical improvement of the environment itself was the key to the effectiveness of the intervention, and seeking to change people's perceptions may be of limited value. Studies of how interventions lead to population behaviour change should complement those concerned with estimating their effects in supporting valid causal inference. PMID:26338837

Multicomponent synthesis of 4,4-dimethyl sterol analogues and their effect on eukaryotic cells.

PubMed

Alonso, Fernando; Cirigliano, Adriana M; Dávola, María Eugenia; Cabrera, Gabriela M; García Liñares, Guadalupe E; Labriola, Carlos; Barquero, Andrea A; Ramírez, Javier A

2014-06-01

Most sterols, such as cholesterol and ergosterol, become functional only after the removal of the two methyl groups at C-4 from their biosynthetic precursors. Nevertheless, some findings suggest that 4,4-dimethyl sterols might be involved in specific physiological processes. In this paper we present the synthesis of a collection of analogues of 4,4-dimethyl sterols with a diamide side chain and a preliminary analysis of their in vitro activity on selected biological systems. The key step for the synthesis involves an Ugi condensation, a versatile multicomponent reaction. Some of the new compounds showed antifungal and cytotoxic activity. Copyright © 2014 Elsevier Inc. All rights reserved.

The autumn effect: timing of physical dormancy break in seeds of two winter annual species of Geraniaceae by a stepwise process

PubMed Central

Gama-Arachchige, N. S.; Baskin, J. M.; Geneve, R. L.; Baskin, C. C.

2012-01-01

Background and Aims The involvement of two steps in the physical dormancy (PY)-breaking process previously has been demonstrated in seeds of Fabaceae and Convolvulaceae. Even though there is a claim for a moisture-controlled stepwise PY-breaking in some species of Geraniaceae, no study has evaluated the role of temperature in the PY-breaking process in this family. The aim of this study was to determine whether a temperature-controlled stepwise PY-breaking process occurs in seeds of the winter annuals Geranium carolinianum and G. dissectum. Methods Seeds of G. carolinianum and G. dissectum were stored under different temperature regimes to test the effect of storage temperature on PY-break. The role of temperature and moisture regimes in regulating PY-break was investigated by treatments simulating natural conditions. Greenhouse (non-heated) experiments on seed germination and burial experiments (outdoors) were carried out to determine the PY-breaking behaviour in the natural habitat. Key Results Irrespective of moisture conditions, sensitivity to the PY-breaking step in seeds of G. carolinianum was induced at temperatures ≥20 °C, and exposure to temperatures ≤20 °C made the sensitive seeds permeable. Sensitivity of seeds increased with time. In G. dissectum, PY-break occurred at temperatures ≥20 °C in a single step under constant wet or dry conditions and in two steps under alternate wet–dry conditions if seeds were initially kept wet. Conclusions Timing of seed germination with the onset of autumn can be explained by PY-breaking processes involving (a) two temperature-dependent steps in G. carolinianum and (b) one or two moisture-dependent step(s) along with the inability to germinate under high temperatures in G. dissectum. Geraniaceae is the third of 18 families with PY in which a two-step PY-breaking process has been demonstrated. PMID:22684684

Analysis of repair and PCNA complex formation induced by ionizing radiation in human fibroblast cell lines.

PubMed

Karmakar, P; Balajee, A S; Natarajan, A T

2001-05-01

Proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerase delta and epsilon, is involved in both DNA replication and repair. Previous studies in vitro have demonstrated the requirement of PCNA in the resynthesis step of nucleotide excision repair (NER) and base excision repair (BER). Using a native chromatin template isolated under near physiological conditions, we have analysed the involvement of PCNA in the BER pathway in different NER defective human cell lines. The repair sites and PCNA were visualized by indirect immunolabelling followed by fluorescence microscopy. The results indicate that exposure to X-rays triggers the induction of PCNA in all the three human fibroblast cell lines studied, namely normal, xeroderma pigmentosum group A (XP-A) and Cockayne syndrome group B (CS-B). In all the cell lines, induction of PCNA and repair patches occurred in a dose- and time-dependent fashion. Induction of repair patches in NER-deficient XP-A cells suggests that the X-ray-induced lesions are largely repaired via the BER pathway involving PCNA as one of the key components of this pathway. X-ray-induced repair synthesis was greatly inhibited by treatment of cells with DNA polymerase inhibitors aphidicolin and cytosine arabinoside. Interestingly, inhibition of repair resynthesis did not affect the intensity of PCNA staining in X-irradiated cells indicating that the PCNA may be required for the BER pathway at a step preceding the resynthesis step.

Mechanism of Oxidation of Ethane to Ethanol at Iron(IV)-Oxo Sites in Magnesium-Diluted Fe2(dobdc).

PubMed

Verma, Pragya; Vogiatzis, Konstantinos D; Planas, Nora; Borycz, Joshua; Xiao, Dianne J; Long, Jeffrey R; Gagliardi, Laura; Truhlar, Donald G

2015-05-06

The catalytic properties of the metal-organic framework Fe2(dobdc), containing open Fe(II) sites, include hydroxylation of phenol by pure Fe2(dobdc) and hydroxylation of ethane by its magnesium-diluted analogue, Fe0.1Mg1.9(dobdc). In earlier work, the latter reaction was proposed to occur through a redox mechanism involving the generation of an iron(IV)-oxo species, which is an intermediate that is also observed or postulated (depending on the case) in some heme and nonheme enzymes and their model complexes. In the present work, we present a detailed mechanism by which the catalytic material, Fe0.1Mg1.9(dobdc), activates the strong C-H bonds of ethane. Kohn-Sham density functional and multireference wave function calculations have been performed to characterize the electronic structure of key species. We show that the catalytic nonheme-Fe hydroxylation of the strong C-H bond of ethane proceeds by a quintet single-state σ-attack pathway after the formation of highly reactive iron-oxo intermediate. The mechanistic pathway involves three key transition states, with the highest activation barrier for the transfer of oxygen from N2O to the Fe(II) center. The uncatalyzed reaction, where nitrous oxide directly oxidizes ethane to ethanol is found to have an activation barrier of 280 kJ/mol, in contrast to 82 kJ/mol for the slowest step in the iron(IV)-oxo catalytic mechanism. The energetics of the C-H bond activation steps of ethane and methane are also compared. Dehydrogenation and dissociation pathways that can compete with the formation of ethanol were shown to involve higher barriers than the hydroxylation pathway.

Tackling wicked problems in infection prevention and control: a guideline for co-creation with stakeholders.

PubMed

van Woezik, Anne F G; Braakman-Jansen, Louise M A; Kulyk, Olga; Siemons, Liseth; van Gemert-Pijnen, Julia E W C

2016-01-01

Infection prevention and control can be seen as a wicked public health problem as there is no consensus regarding problem definition and solution, multiple stakeholders with different needs and values are involved, and there is no clear end-point of the problem-solving process. Co-creation with stakeholders has been proposed as a suitable strategy to tackle wicked problems, yet little information and no clear step-by-step guide exist on how to do this. The objectives of this study were to develop a guideline to assist developers in tackling wicked problems using co-creation with stakeholders, and to apply this guideline to practice with an example case in the field of infection prevention and control. A mixed-method approach consisting of the integration of both quantitative and qualitative research was used. Relevant stakeholders from the veterinary, human health, and public health sectors were identified using a literature scan, expert recommendations, and snowball sampling. The stakeholder salience approach was used to select key stakeholders based on 3 attributes: power, legitimacy, and urgency. Key values of stakeholders (N = 20) were derived by qualitative semi-structured interviews and quantitatively weighted and prioritized using an online survey. Our method showed that stakeholder identification and analysis are prerequisites for understanding the complex stakeholder network that characterizes wicked problems. A total of 73 stakeholders were identified of which 36 were selected as potential key stakeholders, and only one was seen as a definite stakeholder. In addition, deriving key stakeholder values is a necessity to gain insights into different problem definitions, solutions and needs stakeholders have regarding the wicked problem. Based on the methods used, we developed a step-by-step guideline for co-creation with stakeholders when tackling wicked problems. The mixed-methods guideline presented here provides a systematic, transparent method to identify, analyze, and co-create with stakeholders, and to recognize and prioritize their values, problem definitions, and solutions in the context of wicked problems. This guideline consists of a general framework and although it was applied in an eHealth context, may be relevant outside of eHealth as well.

NADPH: Protochlorophyllide Oxidoreductase-Structure, Catalytic Function, and Role in Prolamellar Body Formation and Morphogenesis

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

Timko, Michael P

2013-02-01

The biosynthesis of chlorophyll is a critical biochemical step in the development of photosynthetic vascular plants and green algae. From photosynthetic bacteria (cyanobacteria) to algae, non-vascular plants, gymnosperms and vascular plants, mechanisms have evolved for protochlorophyllide reduction a key step in chlorophyll synthesis. Protochlorophyllide reduction is carried out by both a light-dependent (POR) and light-independent (LIPOR) mechanisms. NADPH: protochlorophyllide oxidoreductase (EC 1.3.1.33, abbreviated POR) catalyzes the light-dependent reduction of protochlorophyllide (PChlide) to chlorophyllide (Chlide). In contrast, a light-independent protochlorophyllide reductase (LIPOR) involves three plastid gene products (chlL, chlN, and chlB) and several nuclear factors. Our work focused on characterization ofmore » both the POR and LIPOR catalyzed processes.« less

STAKEHOLDER INVOLVEMENT THROUGHOUT HEALTH TECHNOLOGY ASSESSMENT: AN EXAMPLE FROM PALLIATIVE CARE.

PubMed

Brereton, Louise; Wahlster, Philip; Mozygemba, Kati; Lysdahl, Kristin Bakke; Burns, Jake; Polus, Stephanie; Tummers, Marcia; Refolo, Pietro; Sacchini, Dario; Leppert, Wojciech; Chilcott, James; Ingleton, Christine; Gardiner, Clare; Goyder, Elizabeth

2017-01-01

Internationally, funders require stakeholder involvement throughout health technology assessment (HTA). We report successes, challenges, and lessons learned from extensive stakeholder involvement throughout a palliative care case study that demonstrates new concepts and methods for HTA. A 5-step "INTEGRATE-HTA Model" developed within the INTEGRATE-HTA project guided the case study. Using convenience or purposive sampling or directly / indirectly identifying and approaching individuals / groups, stakeholders participated in qualitative research or consultation meetings. During scoping, 132 stakeholders, aged ≥ 18 years in seven countries (England, Italy, Germany, The Netherlands, Norway, Lithuania, and Poland), highlighted key issues in palliative care that assisted identification of the intervention and comparator. Subsequently stakeholders in four countries participated in face-face, telephone and / or video Skype meetings to inform evidence collection and / or review assessment results. An applicability assessment to identify contextual and implementation barriers and enablers for the case study findings involved twelve professionals in the three countries. Finally, thirteen stakeholders participated in a mock decision-making meeting in England. Views about the best methods of stakeholder involvement vary internationally. Stakeholders make valuable contributions in all stages of HTA; assisting decision making about interventions, comparators, research questions; providing evidence and insights into findings, gap analyses and applicability assessments. Key challenges exist regarding inclusivity, time, and resource use. Stakeholder involvement is feasible and worthwhile throughout HTA, sometimes providing unique insights. Various methods can be used to include stakeholders, although challenges exist. Recognition of stakeholder expertise and further guidance about stakeholder consultation methods is needed.

48 CFR 3036.104-90 - Authority for one-step turn-key design-build contracting for the United States Coast Guard (USCG).

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Authority for one-step... General 3036.104-90 Authority for one-step turn-key design-build contracting for the United States Coast Guard (USCG). The Head of the Contracting Activity (HCA) of the U.S. Coast Guard may use one-step turn...

Unraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNA.

PubMed

Dans, Pablo Daniel; Faustino, Ignacio; Battistini, Federica; Zakrzewska, Krystyna; Lavery, Richard; Orozco, Modesto

2014-10-01

We have made a detailed study of one of the most surprising sources of polymorphism in B-DNA: the high twist/low twist (HT/LT) conformational change in the d(CpG) base pair step. Using extensive computations, complemented with database analysis, we were able to characterize the twist polymorphism in the d(CpG) step in all the possible tetranucleotide environment. We found that twist polymorphism is coupled with BI/BII transitions, and, quite surprisingly, with slide polymorphism in the neighboring step. Unexpectedly, the penetration of cations into the minor groove of the d(CpG) step seems to be the key element in promoting twist transitions. The tetranucleotide environment also plays an important role in the sequence-dependent d(CpG) polymorphism. In this connection, we have detected a previously unexplored intramolecular C-H···O hydrogen bond interaction that stabilizes the low twist state when 3'-purines flank the d(CpG) step. This work explains a coupled mechanism involving several apparently uncorrelated conformational transitions that has only been partially inferred by earlier experimental or theoretical studies. Our results provide a complete description of twist polymorphism in d(CpG) steps and a detailed picture of the molecular choreography associated with this conformational change. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity*

PubMed Central

Xu, Jian; Kurup, Pradeep; Bartos, Jason A.; Patriarchi, Tommaso; Hell, Johannes W.; Lombroso, Paul J.

2012-01-01

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family and is highly expressed in brain and hematopoietic cells. Pyk2 plays diverse functions in cells, including the regulation of cell adhesion, migration, and cytoskeletal reorganization. In the brain, it is involved in the induction of long term potentiation through regulation of N-methyl-d-aspartate receptor trafficking. This occurs through the phosphorylation and activation of Src family tyrosine kinase members, such as Fyn, that phosphorylate GluN2B at Tyr1472. Phosphorylation at this site leads to exocytosis of GluN1-GluN2B receptors to synaptic membranes. Pyk2 activity is modulated by phosphorylation at several critical tyrosine sites, including Tyr402. In this study, we report that Pyk2 is a substrate of striatal-enriched protein-tyrosine phosphatase (STEP). STEP binds to and dephosphorylates Pyk2 at Tyr402. STEP KO mice showed enhanced phosphorylation of Pyk2 at Tyr402 and of the Pyk2 substrates paxillin and ASAP1. Functional studies indicated that STEP opposes Pyk2 activation after KCl depolarization of cortical slices and blocks Pyk2 translocation to postsynaptic densities, a key step required for Pyk2 activation and function. This is the first study to identify Pyk2 as a substrate for STEP. PMID:22544749

Modelling uveal melanoma

PubMed Central

Foss, A.; Cree, I.; Dolin, P.; Hungerford, J.

1999-01-01

BACKGROUND/AIM—There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease.
METHODS—Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease.
RESULTS—The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease.
CONCLUSIONS—There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes—namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

 PMID:10216060

Characterization of ent-kaurene synthase and kaurene oxidase involved in gibberellin biosynthesis from Scoparia dulcis.

PubMed

Yamamura, Yoshimi; Taguchi, Yukari; Ichitani, Kei; Umebara, Io; Ohshita, Ayako; Kurosaki, Fumiya; Lee, Jung-Bum

2018-03-01

Gibberellins (GAs) are ubiquitous diterpenoids in higher plants, whereas some higher plants produce unique species-specific diterpenoids. In GA biosynthesis, ent-kaurene synthase (KS) and ent-kaurene oxidase (KO) are key players which catalyze early step(s) of the cyclization and oxidation reactions. We have studied the functional characterization of gene products of a KS (SdKS) and two KOs (SdKO1 and SdKO2) involved in GA biosynthesis in Scoparia dulcis. Using an in vivo heterologous expression system of Escherichia coli, we found that SdKS catalyzed a cyclization reaction from ent-CPP to ent-kaurene and that the SdKOs oxidized ent-kaurene to ent-kaurenoic acid after modification of the N-terminal region for adaptation to the E. coli expression system. The real-time PCR results showed that the SdKS, SdKO1 and SdKO2 genes were mainly expressed in the root and lateral root systems, which are elongating tissues. Based on these results, we suggest that these three genes may be responsible for the metabolism of GAs in S. dulcis.

A numerical method for computing unsteady 2-D boundary layer flows

NASA Technical Reports Server (NTRS)

Krainer, Andreas

1988-01-01

A numerical method for computing unsteady two-dimensional boundary layers in incompressible laminar and turbulent flows is described and applied to a single airfoil changing its incidence angle in time. The solution procedure adopts a first order panel method with a simple wake model to solve for the inviscid part of the flow, and an implicit finite difference method for the viscous part of the flow. Both procedures integrate in time in a step-by-step fashion, in the course of which each step involves the solution of the elliptic Laplace equation and the solution of the parabolic boundary layer equations. The Reynolds shear stress term of the boundary layer equations is modeled by an algebraic eddy viscosity closure. The location of transition is predicted by an empirical data correlation originating from Michel. Since transition and turbulence modeling are key factors in the prediction of viscous flows, their accuracy will be of dominant influence to the overall results.

Video Completion in Digital Stabilization Task Using Pseudo-Panoramic Technique

NASA Astrophysics Data System (ADS)

Favorskaya, M. N.; Buryachenko, V. V.; Zotin, A. G.; Pakhirka, A. I.

2017-05-01

Video completion is a necessary stage after stabilization of a non-stationary video sequence, if it is desirable to make the resolution of the stabilized frames equalled the resolution of the original frames. Usually the cropped stabilized frames lose 10-20% of area that means the worse visibility of the reconstructed scenes. The extension of a view of field may appear due to the pan-tilt-zoom unwanted camera movement. Our approach deals with a preparing of pseudo-panoramic key frame during a stabilization stage as a pre-processing step for the following inpainting. It is based on a multi-layered representation of each frame including the background and objects, moving differently. The proposed algorithm involves four steps, such as the background completion, local motion inpainting, local warping, and seamless blending. Our experiments show that a necessity of a seamless stitching occurs often than a local warping step. Therefore, a seamless blending was investigated in details including four main categories, such as feathering-based, pyramid-based, gradient-based, and optimal seam-based blending.

Characterization of Developer Application Methods Used in Fluorescent Penetrant Inspection

NASA Astrophysics Data System (ADS)

Brasche, L. J. H.; Lopez, R.; Eisenmann, D.

2006-03-01

Fluorescent penetrant inspection (FPI) is the most widely used inspection method for aviation components seeing use for production as well as an inservice inspection applications. FPI is a multiple step process requiring attention to the process parameters for each step in order to enable a successful inspection. A multiyear program is underway to evaluate the most important factors affecting the performance of FPI, to determine whether existing industry specifications adequately address control of the process parameters, and to provide the needed engineering data to the public domain. The final step prior to the inspection is the application of developer with typical aviation inspections involving the use of dry powder (form d) usually applied using either a pressure wand or dust storm chamber. Results from several typical dust storm chambers and wand applications have shown less than optimal performance. Measurements of indication brightness and recording of the UVA image, and in some cases, formal probability of detection (POD) studies were used to assess the developer application methods. Key conclusions and initial recommendations are provided.

A practical guide to assessing clinical decision-making skills using the key features approach.

PubMed

Farmer, Elizabeth A; Page, Gordon

2005-12-01

This paper in the series on professional assessment provides a practical guide to writing key features problems (KFPs). Key features problems test clinical decision-making skills in written or computer-based formats. They are based on the concept of critical steps or 'key features' in decision making and represent an advance on the older, less reliable patient management problem (PMP) formats. The practical steps in writing these problems are discussed and illustrated by examples. Steps include assembling problem-writing groups, selecting a suitable clinical scenario or problem and defining its key features, writing the questions, selecting question response formats, preparing scoring keys, reviewing item quality and item banking. The KFP format provides educators with a flexible approach to testing clinical decision-making skills with demonstrated validity and reliability when constructed according to the guidelines provided.

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides†

PubMed Central

Hein, Jason E.

2011-01-01

Copper-catalyzed azide–alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(i) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science. PMID:20309487

Phased implementation of spaced clinic visits for stable HIV-positive patients in Rwanda to support Treat All.

PubMed

Nsanzimana, Sabin; Remera, Eric; Ribakare, Muhayimpundu; Burns, Tracy; Dludlu, Sibongile; Mills, Edward J; Condo, Jeanine; Bucher, Heiner C; Ford, Nathan

2017-07-21

In 2016, Rwanda implemented "Treat All," requiring the national HIV programme to increase antiretroviral (ART) treatment coverage to all people living with HIV. Approximately half of the 164,262 patients on ART have been on treatment for more than five years, and long-term retention of patients in care is an increasing concern. To address these challenges, the Ministry of Health has introduced a differentiated service delivery approach to reduce the frequency of clinical visits and medication dispensing for eligible patients. This article draws on key policy documents and the views of technical experts involved in policy development to describe the process of implementation of differentiated service delivery in Rwanda. Implementation of differentiated service delivery followed a phased approach to ensure that all steps are clearly defined and agreed by all partners. Key steps included: definition of scope, including defining which patients were eligible for transition to the new model; definition of the key model components; preparation for patient enrolment; considerations for special patient groups; engagement of implementing partners; securing political and financial support; forecasting drug supply; revision, dissemination and implementation of ART guidelines; and monitoring and evaluation. Based on the outcomes of the evaluation of the new service delivery model, the Ministry of Health will review and strategically reduce costs to the national HIV program and to the patient by exploring and implementing adjustments to the service delivery model.

Cytoplasmic dynein binding, run length, and velocity are guided by long-range electrostatic interactions

PubMed Central

Li, Lin; Alper, Joshua; Alexov, Emil

2016-01-01

Dyneins are important molecular motors involved in many essential biological processes, including cargo transport along microtubules, mitosis, and in cilia. Dynein motility involves the coupling of microtubule binding and unbinding to a change in the configuration of the linker domain induced by ATP hydrolysis, which occur some 25 nm apart. This leaves the accuracy of dynein stepping relatively inaccurate and susceptible to thermal noise. Using multi-scale modeling with a computational focusing technique, we demonstrate that the microtubule forms an electrostatic funnel that guides the dynein’s microtubule binding domain (MTBD) as it finally docks to the precise, keyed binding location on the microtubule. Furthermore, we demonstrate that electrostatic component of the MTBD’s binding free energy is linearly correlated with the velocity and run length of dynein, and we use this linearity to predict the effect of mutating each glutamic and aspartic acid located in MTBD domain to alanine. Lastly, we show that the binding of dynein to the microtubule is associated with conformational changes involving several helices, and we localize flexible hinge points within the stalk helices. Taken all together, we demonstrate that long range electrostatic interactions bring a level of precision to an otherwise noisy dynein stepping process. PMID:27531742

Telomere biology: Rationale for diagnostics and therapeutics in cancer

PubMed Central

Rousseau, Philippe; Autexier, Chantal

2015-01-01

The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and understanding to position the different aspects of telomere biology and dysfunction as diagnostic, preventive and curative tools in the field of cancer. PMID:26291128

Palladium(II)-Catalyzed Annulation between ortho-Alkenylphenols and Allenes. Key Role of the Metal Geometry in Determining the Reaction Outcome.

PubMed

Casanova, Noelia; Del Rio, Karina P; García-Fandiño, Rebeca; Mascareñas, José L; Gulías, Moisés

2016-05-06

2-Alkenylphenols react with allenes, upon treatment with catalytic amounts of Pd(II) and Cu(II), to give benzoxepine products in high yields and with very good regio- and diastereoselectivities. This contrasts with the results obtained with Rh catalysts, which provided chromene-like products through a pathway involving a β-hydrogen elimination step. Computational studies suggest that the square planar geometry of the palladium is critical to favor the reductive elimination process required for the formation of the oxepine products.

FIBER OPTICS: Role of point defects in the photosensitivity of hydrogen-loaded phosphosilicate glass

NASA Astrophysics Data System (ADS)

Larionov, Yu V.

2010-08-01

It is shown that point defect modifications in hydrogen-loaded phosphosilicate glass (PSG) do not play a central role in determining its photosensitivity. Photochemical reactions that involve a two-step point defect modification and pre-exposure effect are incapable of accounting for photoinduced refractive index changes. It seems likely that a key role in UV-induced refractive index modifications is played by structural changes in the PSG network. Experimental data are presented that demonstrate intricate network rearrangement dynamics during UV exposure of PSG.

Nitrosation of amides involves a pseudopericyclic 1,3-sigmatropic rearrangement.

PubMed

Birney, David M

2004-03-04

Two possible pathways for the nitrosation of formamide and N-methyl formamide by nitrosonium ion (NO(+)) have been investigated at the B3LYP/6-31G(d,p) level. The key steps are pseudopericyclic 1,3-sigmatropic rearrangements to give the observed N-nitrosamides. The transition structures (8a and 8b) are close to planar on the amide moiety and have remarkably low barriers of only 6.6 and 4.8 kcal/mol from the lowest energy conformations of 6a and 6b, respectively. [reaction: see text

Telomere biology: Rationale for diagnostics and therapeutics in cancer.

PubMed

Rousseau, Philippe; Autexier, Chantal

2015-01-01

The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and understanding to position the different aspects of telomere biology and dysfunction as diagnostic, preventive and curative tools in the field of cancer.

Infusing Reliability Techniques into Software Safety Analysis

NASA Technical Reports Server (NTRS)

Shi, Ying

2015-01-01

Software safety analysis for a large software intensive system is always a challenge. Software safety practitioners need to ensure that software related hazards are completely identified, controlled, and tracked. This paper discusses in detail how to incorporate the traditional reliability techniques into the entire software safety analysis process. In addition, this paper addresses how information can be effectively shared between the various practitioners involved in the software safety analyses. The author has successfully applied the approach to several aerospace applications. Examples are provided to illustrate the key steps of the proposed approach.

Revealing the Gag Itinerary: How HIV is Transmitted One Cell at a Time | Center for Cancer Research

Cancer.gov

Although person-to-person transmission of HIV has been well understood for years, researchers are still trying to figure out exactly how the virus moves from one cell to another. Researchers have delineated the steps and key players involved in the generation of HIV particles inside infected (host) cells. However, the precise location of virus assembly inside these cells and the route the virus takes to reach the cell surface before it is released to infect other cells are still matters of heated debate.

Dopamine is a key regulator in the signalling pathway underlying predator-induced defences in Daphnia

PubMed Central

Weiss, Linda C.; Leese, Florian; Laforsch, Christian; Tollrian, Ralph

2015-01-01

The waterflea Daphnia is a model to investigate the genetic basis of phenotypic plasticity resulting from one differentially expressed genome. Daphnia develops adaptive phenotypes (e.g. morphological defences) thwarting predators, based on chemical predator cue perception. To understand the genomic basis of phenotypic plasticity, the description of the precedent cellular and neuronal mechanisms is fundamental. However, key regulators remain unknown. All neuronal and endocrine stimulants were able to modulate but not induce defences, indicating a pathway of interlinked steps. A candidate able to link neuronal with endocrine responses is the multi-functional amine dopamine. We here tested its involvement in trait formation in Daphnia pulex and Daphnia longicephala using an induction assay composed of predator cues combined with dopaminergic and cholinergic stimulants. The mere application of both stimulants was sufficient to induce morphological defences. We determined dopamine localization in cells found in close association with the defensive trait. These cells serve as centres controlling divergent morphologies. As a mitogen and sclerotization agent, we anticipate that dopamine is involved in proliferation and structural formation of morphological defences. Furthermore, dopamine pathways appear to be interconnected with endocrine pathways, and control juvenile hormone and ecdysone levels. In conclusion, dopamine is suggested as a key regulator of phenotypic plasticity. PMID:26423840

STAKEHOLDER INVOLVEMENT IN THE HEALTH TECHNOLOGY ASSESSMENT PROCESS IN LATIN AMERICA.

PubMed

Pichon-Riviere, Andres; Soto, Natalie; Augustovski, Federico; Sampietro-Colom, Laura

2018-06-11

Latin American countries are taking important steps to expand and strengthen universal health coverage, and health technology assessment (HTA) has an increasingly prominent role in this process. Participation of all relevant stakeholders has become a priority in this effort. Key issues in this area were discussed during the 2017 Latin American Health Technology Assessment International (HTAi) Policy Forum. The Forum included forty-one participants from Latin American HTA agencies; public, social security, and private insurance sectors; and the pharmaceutical and medical device industry. A background paper and presentations by invited experts and Forum members supported discussions. This study presents a summary of these discussions. Stakeholder involvement in HTA remains inconsistently implemented in the region and few countries have established formal processes. Participants agreed that stakeholder involvement is key to improve the HTA process, but the form and timing of such improvements must be adapted to local contexts. The legitimization of both HTA and decision-making processes was identified as one of the main reasons to promote stakeholder involvement; but to be successful, the entire system of assessment and decision making must be properly staffed and organized, and certain basic conditions must be met, including transparency in the HTA process and a clear link between HTA and decision making. Participants suggested a need for establishing clear rules of participation in HTA that would protect HTA producers and decision makers from potentially distorting external influences. Such rules and mechanisms could help foster trust and credibility among stakeholders, supporting actual involvement in HTA processes.

Monoterpenol Oxidative Metabolism: Role in Plant Adaptation and Potential Applications

PubMed Central

Ilc, Tina; Parage, Claire; Boachon, Benoît; Navrot, Nicolas; Werck-Reichhart, Danièle

2016-01-01

Plants use monoterpenols as precursors for the production of functionally and structurally diverse molecules, which are key players in interactions with other organisms such as pollinators, flower visitors, herbivores, fungal, or microbial pathogens. For humans, many of these monoterpenol derivatives are economically important because of their pharmaceutical, nutraceutical, flavor, or fragrance applications. The biosynthesis of these derivatives is to a large extent catalyzed by enzymes from the cytochrome P450 superfamily. Here we review the knowledge on monoterpenol oxidative metabolism in plants with special focus on recent elucidations of oxidation steps leading to diverse linalool and geraniol derivatives. We evaluate the common features between oxidation pathways of these two monoterpenols, such as involvement of the CYP76 family, and highlight the differences. Finally, we discuss the missing steps and other open questions in the biosynthesis of oxygenated monoterpenol derivatives. PMID:27200002

Decoration of Chondroitin Polysaccharide with Threonine: Synthesis, Conformational Study, and Ice-Recrystallization Inhibition Activity.

PubMed

Laezza, Antonio; Casillo, Angela; Cosconati, Sandro; Biggs, Caroline I; Fabozzi, Antonio; Paduano, Luigi; Iadonisi, Alfonso; Novellino, Ettore; Gibson, Matthew I; Randazzo, Antonio; Corsaro, Maria M; Bedini, Emiliano

2017-08-14

Several threonine (Thr)- and alanine (Ala)-rich antifreeze glycoproteins (AFGPs) and polysaccharides act in nature as ice recrystallization inhibitors. Among them, the Thr-decorated capsular polysaccharide (CPS) from the cold-adapted Colwellia psychrerythraea 34H bacterium was recently investigated for its cryoprotectant activity. A semisynthetic mimic thereof was here prepared from microbial sourced chondroitin through a four-step strategy, involving a partial protection of the chondroitin polysaccharide as a key step for gaining an unprecedented quantitative amidation of its glucuronic acid units. In-depth NMR and computational analysis suggested a fairly linear conformation for the semisynthetic polysaccharide, for which the antifreeze activity by a quantitative ice recrystallization inhibition assay was measured. We compared the structure-activity relationships for the Thr-derivatized chondroitin and the natural Thr-decorated CPS from C. psychrerythraea.

Supramolecular water oxidation with Ru-bda-based catalysts.

PubMed

Richmond, Craig J; Matheu, Roc; Poater, Albert; Falivene, Laura; Benet-Buchholz, Jordi; Sala, Xavier; Cavallo, Luigi; Llobet, Antoni

2014-12-22

Extremely slow and extremely fast new water oxidation catalysts based on the Ru-bda (bda=2,2'-bipyridine-6,6'-dicarboxylate) systems are reported with turnover frequencies in the range of 1 and 900 cycles s(-1) , respectively. Detailed analyses of the main factors involved in the water oxidation reaction have been carried out and are based on a combination of reactivity tests, electrochemical experiments, and DFT calculations. These analyses give a convergent interpretation that generates a solid understanding of the main factors involved in the water oxidation reaction, which in turn allows the design of catalysts with very low energy barriers in all the steps involved in the water oxidation catalytic cycle. We show that for this type of system π-stacking interactions are the key factors that influence reactivity and by adequately controlling them we can generate exceptionally fast water oxidation catalysts. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Surgical education to improve the quality of patient care: the role of practice-based learning and improvement.

PubMed

Sachdeva, Ajit K

2007-11-01

Health care is going through immense change, and concerns regarding the quality of patient care and patient safety continue to be expressed in many national forums. A variety of stakeholders are demanding greater accountability from the health care profession. Education is key to supporting surgeons' efforts to provide high-quality patient care during these challenging times. Educational programs for surgeons should be founded on principles of continuous professional development (CPD) and practice-based learning and improvement (PBLI). CPD focuses on the specific needs of individual surgeons and involves lifelong learning throughout a surgeon's career. It needs to form the basis of PBLI efforts. PBLI involves a cycle of four steps--identifying areas for improvement, engaging in learning, applying new knowledge and skills to practice, and checking for improvement. Ongoing involvement in PBLI activities to address specific learning needs should positively impact a surgeon's practice and improve outcomes of surgical care.

Sustainable fisheries management: Pacific salmon

USGS Publications Warehouse

Knudsen, E. Eric; Steward, Cleveland R.; MacDonald, Donald; Williams, Jack E.; Reiser, Dudley W.

1999-01-01

What has happened to the salmon resource in the Pacific Northwest? Who is responsible and what can be done to reverse the decline in salmon populations? The responsibly falls on everyone involved - fishermen, resource managers and concerned citizens alike - to take the steps necessary to ensure that salmon populations make a full recovery.This collection of papers examines the state of the salmon fisheries in the Pacific Northwest. They cover existing methods and supply model approaches for alternative solutions. The editors stress the importance of input from and cooperation with all parties involved to create a viable solution. Grass roots education and participation is the key to public support - and ultimately the success - of whatever management solutions are developed.A unique and valuable scientific publication, Sustainable Fisheries Management: Pacific Salmon clearly articulates the current state of the Pacific salmon resource, describes the key features of its management, and provides important guidance on how we can make the transition towards sustainable fisheries. The solutions presented in this book provide the basis of a strategy for sustainable fisheries, requiring society and governmental agencies to establish a shared vision, common policies, and a process for collaborative management.

Transport and pharmacodynamics of albitiazolium, an antimalarial drug candidate

PubMed Central

Wein, S; Maynadier, M; Bordat, Y; Perez, J; Maheshwari, S; Bette-Bobillo, P; Tran Van Ba, C; Penarete-Vargas, D; Fraisse, L; Cerdan, R; Vial, H

2012-01-01

BACKGROUND AND PURPOSE Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis. EXPERIMENTAL APPROACH We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis. KEY RESULTS Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC. CONCLUSIONS AND IMPLICATIONS Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug. PMID:22471905

Using the "customer service framework" to successfully implement patient- and family-centered care.

PubMed

Rangachari, Pavani; Bhat, Anita; Seol, Yoon-Ho

2011-01-01

Despite the growing momentum toward patient- and family-centered care at the federal policy level, the organizational literature remains divided on its effectiveness, especially in regard to its key dimension of involving patients and families in treatment decisions and safety practices. Although some have argued for the universal adoption of patient involvement, others have questioned both the effectiveness and feasibility of patient involvement. In this article, we apply a well-established theoretical perspective, that is, the Service Quality Model (SQM) (also known as the "customer service framework") to the health care context, to reconcile the debate related to patient involvement. The application helps support the case for universal adoption of patient involvement and also question the arguments against it. A key contribution of the SQM lies in highlighting a set of fundamental service quality determinants emanating from basic consumer service needs. It also provides a simple framework for understanding how gaps between consumer expectations and management perceptions of those expectations can affect the gap between "expected" and "perceived" service quality from a consumer's perspective. Simultaneously, the SQM also outlines "management requirements" for the successful implementation of a customer service strategy. Applying the SQM to the health care context therefore, in addition to reconciling the debate on patient involvement, helps identify specific steps health care managers could take to successfully implement patient- and family-centered care. Correspondingly, the application also provides insights into strategies for the successful implementation of policy recommendations related to patient- and family-centered care in health care organizations.

Social impact assessments: Developing a consolidated conceptual framework

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

Arce-Gomez, Antonio, E-mail: aarcegomez@swin.edu.au; Donovan, Jerome D., E-mail: jdonovan@swin.edu.au; Bedggood, Rowan E., E-mail: rbedggood@swin.edu.au

Social Impact Assessments (SIAs) have played an increasingly important role in the conduct of planned interventions, providing proponents the capacity to assess and manage the social consequences of their activities. Whilst the SIA field has experienced significant conceptual and practical development over the last decade, efforts at consolidating this within one framework have been limited. In this paper, we incorporate this new knowledge by redeveloping and thus updating the SIA procedural framework developed by Interorganizational Committee on Guidelines and Principles for Social Impact Assessment. In doing so, this updated procedural framework has attempted to incorporate current ‘best practice’ that focusesmore » on participatory approaches to undertaking an SIA. This involved making adaptions to two steps, expansions to five steps, integration of a stronger participatory approach to six steps, and the development of a new step, Management and Evaluation reflecting moves towards ex-post use of SIA processes. It is hoped that this consolidation of the literature of a decade's worth of key findings in SIA research will lead to further efforts towards a meta-evaluation of SIA literature and a platform from which newer developments may be further investigated.« less

Human Mission to Europa and Titan - Why Not? Executive Summary

NASA Technical Reports Server (NTRS)

Finarelli, Margaret G.

2005-01-01

Outline a step-by-step Development Plan of the key barriers and their solutions to enable human exploration of the outer solar system. Secondary: Perform a case study which supports and emphasizes the key elements of the Development Plan.

Photodamage: all signs lead to actinic keratosis and early squamous cell carcinoma.

PubMed

Wei, Jerry; Kok, Lai Fong; Byrne, Scott N; Halliday, Gary M

2015-01-01

Ultraviolet (UV) radiation is likely to drive the initiation and progression of skin cancer from actinic keratosis to squamous cell carcinoma. Signs of photodamage occur at multiple steps. UV radiation damages many cellular constituents, including lipids, proteins and DNA, all of which are likely to contribute to UV-induced skin cancer. Two biological events culminating from photodamage are mutations in the genes critical to the control of cell division, differentiation and invasion and immunosuppression. DNA photodamage, if unrepaired prior to cell division, can result in the incorporation of an incorrect nucleotide into newly synthesised DNA. Mutations in critical genes contribute to carcinogenesis. Photodamage to proteins such as those involved in DNA repair or proteins or lipids involved in cellular signalling can interfere with this repair process and contribute to mutagenesis. Mutations in key genes, including TP53, BRM, PTCH1, and HRAS, contribute to skin carcinogenesis. UV also damages immunity. Photodamage to DNA and signalling lipids as well as other molecular changes are detrimental to the key cells that regulate immunity. Photodamaged dendritic cells and altered responses by mast cells lead to the activation of T and B regulatory cells that suppress immunity to the protein products of UV-mutated genes. This stops the immune response from its protective function of destroying mutated cells, enabling the transformed cells to progress to skin cancer. UV appears to play a pivotal role at each of these steps, and therefore, signs of photodamage point to the development of skin cancer. © 2015 S. Karger AG, Basel.

Transgenic approaches to altering carbon and nitrogen partitioning in whole plants: assessing the potential to improve crop yields and nutritional quality

DOE PAGES

Yadav, Umesh P.; Ayre, Brian G.; Bush, Daniel R.

2015-04-22

The principal components of plant productivity and nutritional value, from the standpoint of modern agriculture, are the acquisition and partitioning of organic carbon (C) and nitrogen (N) compounds among the various organs of the plant. The flow of essential organic nutrients among the plant organ systems is mediated by its complex vascular system, and is driven by a series of transport steps including export from sites of primary assimilation, transport into and out of the phloem and xylem, and transport into the various import-dependent organs. Manipulating C and N partitioning to enhance yield of harvested organs is evident in themore » earliest crop domestication events and continues to be a goal for modern plant biology. Research on the biochemistry, molecular and cellular biology, and physiology of C and N partitioning has now matured to an extent that strategic manipulation of these transport systems through biotechnology are being attempted to improve movement from source to sink tissues in general, but also to target partitioning to specific organs. These nascent efforts are demonstrating the potential of applied biomass targeting but are also identifying interactions between essential nutrients that require further basic research. In this review, we summarize the key transport steps involved in C and N partitioning, and discuss various transgenic approaches for directly manipulating key C and N transporters involved. In addition, we propose several experiments that could enhance biomass accumulation in targeted organs while simultaneously testing current partitioning models.« less

Transgenic approaches to altering carbon and nitrogen partitioning in whole plants: assessing the potential to improve crop yields and nutritional quality

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

Yadav, Umesh P.; Ayre, Brian G.; Bush, Daniel R.

The principal components of plant productivity and nutritional value, from the standpoint of modern agriculture, are the acquisition and partitioning of organic carbon (C) and nitrogen (N) compounds among the various organs of the plant. The flow of essential organic nutrients among the plant organ systems is mediated by its complex vascular system, and is driven by a series of transport steps including export from sites of primary assimilation, transport into and out of the phloem and xylem, and transport into the various import-dependent organs. Manipulating C and N partitioning to enhance yield of harvested organs is evident in themore » earliest crop domestication events and continues to be a goal for modern plant biology. Research on the biochemistry, molecular and cellular biology, and physiology of C and N partitioning has now matured to an extent that strategic manipulation of these transport systems through biotechnology are being attempted to improve movement from source to sink tissues in general, but also to target partitioning to specific organs. These nascent efforts are demonstrating the potential of applied biomass targeting but are also identifying interactions between essential nutrients that require further basic research. In this review, we summarize the key transport steps involved in C and N partitioning, and discuss various transgenic approaches for directly manipulating key C and N transporters involved. In addition, we propose several experiments that could enhance biomass accumulation in targeted organs while simultaneously testing current partitioning models.« less

Value of Collaboration With Standardized Patients and Patient Facilitators in Enhancing Reflection During the Process of Building a Simulation.

PubMed

Stanley, Claire; Lindsay, Sally; Parker, Kathryn; Kawamura, Anne; Samad Zubairi, Mohammad

2018-05-09

We previously reported that experienced clinicians find the process of collectively building and participating in simulations provide (1) a unique reflective opportunity; (2) a venue to identify different perspectives through discussion and action in a group; and (3) a safe environment for learning. No studies have assessed the value of collaborating with standardized patients (SPs) and patient facilitators (PFs) in the process. In this work, we describe this collaboration in building a simulation and the key elements that facilitate reflection. Three simulation scenarios surrounding communication were built by teams of clinicians, a PF, and SPs. Six build sessions were audio recorded, transcribed, and thematically analyzed through an iterative process to (1) describe the steps of building a simulation scenario and (2) identify the key elements involved in the collaboration. The five main steps to build a simulation scenario were (1) storytelling and reflection; (2) defining objectives and brainstorming ideas; (3) building a stem and creating a template; (4) refining the scenario with feedback from SPs; and (5) mock run-throughs with follow-up discussion. During these steps, the PF shared personal insights, challenging participants to reflect deeper to better understand and consider the patient's perspective. The SPs provided unique outside perspective to the group. In addition, the interaction between the SPs and the PF helped refine character roles. A collaborative approach incorporating feedback from PFs and SPs to create a simulation scenario is a valuable method to enhance reflective practice for clinicians.

Theorising and testing environmental pathways to behaviour change: natural experimental study of the perception and use of new infrastructure to promote walking and cycling in local communities.

PubMed

Panter, Jenna; Ogilvie, David

2015-09-03

Some studies have assessed the effectiveness of environmental interventions to promote physical activity, but few have examined how such interventions work. We investigated the environmental mechanisms linking an infrastructural intervention with behaviour change. Natural experimental study. Three UK municipalities (Southampton, Cardiff and Kenilworth). Adults living within 5 km of new walking and cycling infrastructure. Construction or improvement of walking and cycling routes. Exposure to the intervention was defined in terms of residential proximity. Questionnaires at baseline and 2-year follow-up assessed perceptions of the supportiveness of the environment, use of the new infrastructure, and walking and cycling behaviours. Analysis proceeded via factor analysis of perceptions of the physical environment (step 1) and regression analysis to identify plausible pathways involving physical and social environmental mediators and refine the intervention theory (step 2) to a final path analysis to test the model (step 3). Participants who lived near and used the new routes reported improvements in their perceptions of provision and safety. However, path analysis (step 3, n=967) showed that the effects of the intervention on changes in time spent walking and cycling were largely (90%) explained by a simple causal pathway involving use of the new routes, and other pathways involving changes in environmental cognitions explained only a small proportion of the effect. Physical improvement of the environment itself was the key to the effectiveness of the intervention, and seeking to change people's perceptions may be of limited value. Studies of how interventions lead to population behaviour change should complement those concerned with estimating their effects in supporting valid causal inference. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

DNA topology and transcription

PubMed Central

Kouzine, Fedor; Levens, David; Baranello, Laura

2014-01-01

Chromatin is a complex assembly that compacts DNA inside the nucleus while providing the necessary level of accessibility to regulatory factors conscripted by cellular signaling systems. In this superstructure, DNA is the subject of mechanical forces applied by variety of molecular motors. Rather than being a rigid stick, DNA possesses dynamic structural variability that could be harnessed during critical steps of genome functioning. The strong relationship between DNA structure and key genomic processes necessitates the study of physical constrains acting on the double helix. Here we provide insight into the source, dynamics, and biology of DNA topological domains in the eukaryotic cells and summarize their possible involvement in gene transcription. We emphasize recent studies that might inspire and impact future experiments on the involvement of DNA topology in cellular functions. PMID:24755522

Salt-induced aggregation of lysozyme: Implications for crystal growth

NASA Technical Reports Server (NTRS)

Wilson, Lori J.

1994-01-01

Crystallization of proteins is a prerequisite for structural analysis by x-ray crystallography. While improvements in protein crystals have been obtained in microgravity onboard the U.S. Space Shuttle, attempts to improve the crystal growth process both on the ground and in space have been limited by our lack of understanding of the mechanisms involved. Almost all proteins are crystallized with the aid of a precipitating agent. Many of the common precipitating agents are inorganic salts. An understanding of the role of salts on the aggregation of protein monomers is the key to the elucidation of the mechanisms involved in protein crystallization. In order for crystallization to occur individual molecules must self-associate into aggregates. Detection and characterization of aggregates in supersaturated protein solutions is the first step in understanding salt-induced crystallization.

Learning science as a potential new source of understanding and improvement for continuing education and continuing professional development.

PubMed

Van Hoof, Thomas J; Doyle, Terrence J

2018-01-15

Learning science is an emerging interdisciplinary field that offers educators key insights about what happens in the brain when learning occurs. In addition to explanations about the learning process, which includes memory and involves different parts of the brain, learning science offers effective strategies to inform the planning and implementation of activities and programs in continuing education and continuing professional development. This article provides a brief description of learning, including the three key steps of encoding, consolidation and retrieval. The article also introduces four major learning-science strategies, known as distributed learning, retrieval practice, interleaving, and elaboration, which share the importance of considerable practice. Finally, the article describes how learning science aligns with the general findings from the most recent synthesis of systematic reviews about the effectiveness of continuing medical education.

[How to produce a video to promote HIV testing in men who have sex with men?].

PubMed

Menacho, Luis A; Blas, Magaly M

2015-01-01

The aim of the study was to describe the process of designing and producing a video to promote HIV testing in Peruvian men who have sex with men (MSM). The process involved the following steps: identification of the theories of behavior change; identifying key messages and video features; developing a script that would captivate the target audience; working with an experienced production company; and piloting the video. A video with everyday situations of risk associated with HIV infection was the one preferred by participants. Key messages identified, and theoretical constructs models chosen were used to create the video scenes. Participants identified with the main, 9 minute video which they considered to be clear and dynamic. It is necessary to work with the target population to design a video according to their preferences.

Multiple Criteria Decision Analysis for Health Care Decision Making--Emerging Good Practices: Report 2 of the ISPOR MCDA Emerging Good Practices Task Force.

PubMed

Marsh, Kevin; IJzerman, Maarten; Thokala, Praveen; Baltussen, Rob; Boysen, Meindert; Kaló, Zoltán; Lönngren, Thomas; Mussen, Filip; Peacock, Stuart; Watkins, John; Devlin, Nancy

2016-01-01

Health care decisions are complex and involve confronting trade-offs between multiple, often conflicting objectives. Using structured, explicit approaches to decisions involving multiple criteria can improve the quality of decision making. A set of techniques, known under the collective heading, multiple criteria decision analysis (MCDA), are useful for this purpose. In 2014, ISPOR established an Emerging Good Practices Task Force. The task force's first report defined MCDA, provided examples of its use in health care, described the key steps, and provided an overview of the principal methods of MCDA. This second task force report provides emerging good-practice guidance on the implementation of MCDA to support health care decisions. The report includes: a checklist to support the design, implementation and review of an MCDA; guidance to support the implementation of the checklist; the order in which the steps should be implemented; illustrates how to incorporate budget constraints into an MCDA; provides an overview of the skills and resources, including available software, required to implement MCDA; and future research directions. Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Methoxypyrazines biosynthesis and metabolism in grape: A review.

PubMed

Lei, Yujuan; Xie, Sha; Guan, Xueqiang; Song, Changzheng; Zhang, Zhenwen; Meng, Jiangfei

2018-04-15

This review summarizes research on the discovery, biosynthesis, accumulation, transport, and metabolism of 3-alkyl-2-methoxypyrazines (MPs) in grape. The MPs are a family of potent volatile compounds distributed throughout biological kingdoms. These compounds impart herbaceous/green/vegetal sensory attributes to certain varieties of wine. Generally, high levels of MPs in wine are derived mainly from the corresponding grapes. Although two pathways for MPs biosynthesis have been proposed, only the final step and the enzymes that catalyze it has been confirmed in grape, and the metabolic intermediates and key enzymes involved in other steps are still unknown. The limited understanding of MPs metabolism has restricted research on these compounds, and some empirical results cannot be explained by the current knowledge of MPs metabolism. This review provides insights into research on MPs biosynthesis and metabolism, and proposes directions for further research on this important class of flavour/odour compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

High-throughput measurement of recombination rates and genetic interference in Saccharomyces cerevisiae.

PubMed

Raffoux, Xavier; Bourge, Mickael; Dumas, Fabrice; Martin, Olivier C; Falque, Matthieu

2018-06-01

Allelic recombination owing to meiotic crossovers is a major driver of genome evolution, as well as a key player for the selection of high-performing genotypes in economically important species. Therefore, we developed a high-throughput and low-cost method to measure recombination rates and crossover patterning (including interference) in large populations of the budding yeast Saccharomyces cerevisiae. Recombination and interference were analysed by flow cytometry, which allows time-consuming steps such as tetrad microdissection or spore growth to be avoided. Moreover, our method can also be used to compare recombination in wild-type vs. mutant individuals or in different environmental conditions, even if the changes in recombination rates are small. Furthermore, meiotic mutants often present recombination and/or pairing defects affecting spore viability but our method does not involve growth steps and thus avoids filtering out non-viable spores. Copyright © 2018 John Wiley & Sons, Ltd.

Promotion and advocacy for improved complementary feeding: can we apply the lessons learned from breastfeeding?

PubMed

Piwoz, Ellen G; Huffman, Sandra L; Quinn, Victoria J

2003-03-01

Although many successes have been achieved in promoting breastfeeding, this has not been the case for complementary feeding. Some successes in promoting complementary feeding at the community level have been documented, but few of these efforts have expanded to a larger scale and become sustained. To discover the reasons for this difference, the key factors for the successful promotion of breastfeeding on a large scale were examined and compared with the efforts made in complementary feeding. These factors include definition and rationale, policy support, funding, advocacy, private-sector involvement, availability and use of monitoring data, integration of research into action, and the existence of a well-articulated series of steps for successful implementation. The lessons learned from the promotion of breastfeeding should be applied to complementary feeding, and the new Global Strategy for Infant and Young Child Feeding provides an excellent first step in this process.

Religiosity and Participation in Mutual-Aid Support Groups for Addiction

PubMed Central

Atkins, Randolph G.; Hawdon, James E.

2007-01-01

Mutual-aid support groups play a vital role in substance abuse treatment in the United States. A national survey of mutual-aid support groups for addiction was conducted to identify key differences between participants in recovery groups. Survey data indicate that active involvement in support groups significantly improves one's chances of remaining clean and sober, regardless of the group in which one participates. Respondents whose individual beliefs better matched those of their primary support groups showed greater levels of group participation, resulting in better outcomes as measured by increased number of days clean and sober. Religious respondents were more likely to participate in 12-Step groups and Women for Sobriety. Non-religious respondents were significantly less likely to participate in 12-Step groups. Religiosity had little impact on SMART Recovery participation, but actually decreased participation in SOS. These results have important implications for treatment planning and matching individuals to appropriate support groups. PMID:17889302

Standardized Competencies for Parenteral Nutrition Order Review and Parenteral Nutrition Preparation, Including Compounding: The ASPEN Model.

PubMed

Boullata, Joseph I; Holcombe, Beverly; Sacks, Gordon; Gervasio, Jane; Adams, Stephen C; Christensen, Michael; Durfee, Sharon; Ayers, Phil; Marshall, Neil; Guenter, Peggi

2016-08-01

Parenteral nutrition (PN) is a high-alert medication with a complex drug use process. Key steps in the process include the review of each PN prescription followed by the preparation of the formulation. The preparation step includes compounding the PN or activating a standardized commercially available PN product. The verification and review, as well as preparation of this complex therapy, require competency that may be determined by using a standardized process for pharmacists and for pharmacy technicians involved with PN. An American Society for Parenteral and Enteral Nutrition (ASPEN) standardized model for PN order review and PN preparation competencies is proposed based on a competency framework, the ASPEN-published interdisciplinary core competencies, safe practice recommendations, and clinical guidelines, and is intended for institutions and agencies to use with their staff. © 2016 American Society for Parenteral and Enteral Nutrition.

Water oxidation chemistry of photosystem II.

PubMed Central

Vrettos, John S; Brudvig, Gary W

2002-01-01

The O(2)-evolving complex of photosystem II catalyses the light-driven four-electron oxidation of water to dioxygen in photosynthesis. In this article, the steps leading to photosynthetic O(2) evolution are discussed. Emphasis is given to the proton-coupled electron-transfer steps involved in oxidation of the manganese cluster by oxidized tyrosine Z (Y(*)(Z)), the function of Ca(2+) and the mechanism by which water is activated for formation of an O-O bond. Based on a consideration of the biophysical studies of photosystem II and inorganic manganese model chemistry, a mechanism for photosynthetic O(2) evolution is presented in which the O-O bond-forming step occurs via nucleophilic attack on an electron-deficient Mn(V)=O species by a calcium-bound water molecule. The proposed mechanism includes specific roles for the tetranuclear manganese cluster, calcium, chloride, Y(Z) and His190 of the D1 polypeptide. Recent studies of the ion selectivity of the calcium site in the O(2)-evolving complex and of a functional inorganic manganese model system that test key aspects of this mechanism are also discussed. PMID:12437878

Diels-Alder and Stille Coupling Approach for the Short Protecting-Group-Free Synthesis of Mycophenolic Acid, Its Phenylsulfenyl and Phenylselenyl Analogues, and Reactive Oxygen Species (ROS) Probing Capacity in Water.

PubMed

Halle, Mahesh B; Yudhistira, Tesla; Lee, Woo-Hyun; Mulay, Sandip V; Churchill, David G

2018-06-15

A short, protecting-group-free synthesis is achieved. The synthesis is step-efficient and general. A Diels-Alder and Stille cross-coupling approach includes key transformations, allowing for a competitive synthesis which involves a rare halophenol Stille cross-coupling study. The phenylselenyl and phenylsulfenyl analogues were prepared as novel compounds in good overall yield. The applicability of one of the intermediates as a potential probe for reactive oxygen species (ROS) in water is investigated.

Collaborative problem solving with a total quality model.

PubMed

Volden, C M; Monnig, R

1993-01-01

A collaborative problem-solving system committed to the interests of those involved complies with the teachings of the total quality management movement in health care. Deming espoused that any quality system must become an integral part of routine activities. A process that is used consistently in dealing with problems, issues, or conflicts provides a mechanism for accomplishing total quality improvement. The collaborative problem-solving process described here results in quality decision-making. This model incorporates Ishikawa's cause-and-effect (fishbone) diagram, Moore's key causes of conflict, and the steps of the University of North Dakota Conflict Resolution Center's collaborative problem solving model.

RNA polymerase II transcriptional fidelity control and its functional interplay with DNA modifications

PubMed Central

Xu, Liang; Wang, Wei; Chong, Jenny; Shin, Ji Hyun; Xu, Jun; Wang, Dong

2016-01-01

Accurate genetic information transfer is essential for life. As a key enzyme involved in the first step of gene expression, RNA polymerase II (Pol II) must maintain high transcriptional fidelity while it reads along DNA template and synthesizes RNA transcript in a stepwise manner during transcription elongation. DNA lesions or modifications may lead to significant changes in transcriptional fidelity or transcription elongation dynamics. In this review, we will summarize recent progress towards understanding the molecular basis of RNA Pol II transcriptional fidelity control and impacts of DNA lesions and modifications on Pol II transcription elongation. PMID:26392149

Insight into the SEA amide thioester equilibrium. Application to the synthesis of thioesters at neutral pH.

PubMed

Pira, S L; El Mahdi, O; Raibaut, L; Drobecq, H; Dheur, J; Boll, E; Melnyk, O

2016-07-26

The bis(2-sulfanylethyl)amide (SEA) N,S-acyl shift thioester surrogate has found a variety of useful applications in the field of protein total synthesis. Here we present novel insights into the SEA amide/thioester equilibrium in water which is an essential step in any reaction involving the thioester surrogate properties of the SEA group. We also show that the SEA amide thioester equilibrium can be efficiently displaced at neutral pH for accessing peptide alkylthioesters, i.e. the key components of the native chemical ligation (NCL) reaction.

Health care consumerism movement takes a step forward.

PubMed

Thompson, Michael; Cutler, Charles M

2010-01-01

One of the contributing factors to both the increase in health care costs and the backlash to managed care was the lack of consumer awareness of the cost of health care service, the effect of health care costs on profits and wages, and the need to engage consumers more actively as consumers in health care decisions. This article reviews the birth of the health care consumerism movement and identifies gaps in health care consumerism today. The authors reveal some of the keys to building a sustainable health care consumerism framework, which involves enlisting consumers as well as other stakeholders.

Facile reductive amination of aldehydes with electron-deficient anilines by acyloxyborohydrides in TFA: application to a diazaindoline scale-up.

PubMed

Boros, Eric E; Thompson, James B; Katamreddy, Subba R; Carpenter, Andrew J

2009-05-01

A scale-up of diazaindoline 1 was achieved in four stages and 32% overall yield. The key step involved rapid reductive amination of aldehyde 8 with aniline 5 by sodium triacetoxyborohydride (STAB-H) and TFA followed by ring closure of intermediate amine 9 to compound 1 in the same pot. These reaction conditions were also applied to facile reductive aminations with anilines known to have little reactivity under STAB-H/AcOH conditions. Spectral data supported the tris(trifluoroacetoxy)borohydride anion (16) as the active reducing agent.

Heteromultimetallic catalysis for sustainable organic syntheses.

PubMed

Lorion, Mélanie M; Maindan, Karan; Kapdi, Anant R; Ackermann, Lutz

2017-12-07

Fully complementary bimetallic catalysis has been identified as an increasingly powerful tool for molecular transformations, which was largely inspired by early examples of sequential catalytic transformations. Thus, energy-efficient one-pot reactions involving different metal catalysts orchestrated in concert constitute an attractive alternative to multi-step protocols, with major recent progress through the elegant ligand design in heterobimetallic catalysis as well as sustainable photo-induced C-H transformations, among others. This review provides a critical assessment of the state of the art in heterobimetallic catalysis for sustainable organic syntheses (SOS), highlighting key advances and representative examples until summer 2017.

Understanding the real risks of changing employee benefit plans.

PubMed

Kane, Jon; St Amour, Jeffrey

2005-01-01

In an environment of constant change, corporations are looking to alter employee benefits programs to make them more responsive to employee and business needs. A complete risk assessment process is the key to preparing for changes to employee benefits programs by providing employers with an analysis of cost savings against the potential negative ramifications of change. This article outlines the steps involved in a complete review of risk assessment. It then discusses how employers can develop successful change management communication strategies if, after conducting a risk assessment, employers decide to move forward with alterations to their employee benefits programs.

Legionnaire's Disease: Cardiac Manifestations.

PubMed

Brusch, John L

2017-03-01

Most cardiac infections with Legionella are secondary to bacteremias arising from a pulmonary focus. Other possible sites of origin are infected sternotomy wounds or equipment contaminated by Legionella spp. Legionella endocarditis is truly a "stealth" infection, with almost no hallmarks of bacterial endocarditis. The key step in making the diagnosis of Legionella endocarditis is for the physician to be aware of the clinical causes of culture-negative infective endocarditis and to include Legionella cardiac involvement in this differential. Many times the issue of endocarditis arises only on examination of resected valvular material. Copyright © 2016 Elsevier Inc. All rights reserved.

Post-processing techniques to enhance reliability of assignment algorithm based performance measures : [technical summary].

DOT National Transportation Integrated Search

2011-01-01

Travel demand modeling plays a key role in the transportation system planning and evaluation process. The four-step sequential travel demand model is the most widely used technique in practice. Traffic assignment is the key step in the conventional f...

High-throughput process development: I. Process chromatography.

PubMed

Rathore, Anurag S; Bhambure, Rahul

2014-01-01

Chromatographic separation serves as "a workhorse" for downstream process development and plays a key role in removal of product-related, host cell-related, and process-related impurities. Complex and poorly characterized raw materials and feed material, low feed concentration, product instability, and poor mechanistic understanding of the processes are some of the critical challenges that are faced during development of a chromatographic step. Traditional process development is performed as trial-and-error-based evaluation and often leads to a suboptimal process. High-throughput process development (HTPD) platform involves an integration of miniaturization, automation, and parallelization and provides a systematic approach for time- and resource-efficient chromatography process development. Creation of such platforms requires integration of mechanistic knowledge of the process with various statistical tools for data analysis. The relevance of such a platform is high in view of the constraints with respect to time and resources that the biopharma industry faces today. This protocol describes the steps involved in performing HTPD of process chromatography step. It described operation of a commercially available device (PreDictor™ plates from GE Healthcare). This device is available in 96-well format with 2 or 6 μL well size. We also discuss the challenges that one faces when performing such experiments as well as possible solutions to alleviate them. Besides describing the operation of the device, the protocol also presents an approach for statistical analysis of the data that is gathered from such a platform. A case study involving use of the protocol for examining ion-exchange chromatography of granulocyte colony-stimulating factor (GCSF), a therapeutic product, is briefly discussed. This is intended to demonstrate the usefulness of this protocol in generating data that is representative of the data obtained at the traditional lab scale. The agreement in the data is indeed very significant (regression coefficient 0.93). We think that this protocol will be of significant value to those involved in performing high-throughput process development of process chromatography.

Gain-of-function mutations in beet DODA2 identify key residues for betalain pigment evolution.

PubMed

Bean, Alexander; Sunnadeniya, Rasika; Akhavan, Neda; Campbell, Annabelle; Brown, Matthew; Lloyd, Alan

2018-05-13

The key enzymatic step in betalain biosynthesis involves conversion of l-3,4-dihydroxyphenylalanine (l-DOPA) to betalamic acid. One class of enzymes capable of this is 3,4-dihydroxyphenylalanine 4,5-dioxygenase (DODA). In betalain-producing species, multiple paralogs of this gene are maintained. This study demonstrates which paralogs function in the betalain pathway and determines the residue changes required to evolve a betalain-nonfunctional DODA into a betalain-functional DODA. Functionalities of two pairs of DODAs were tested by expression in beets, Arabidopsis and yeast, and gene silencing was performed by virus-induced gene silencing. Site-directed mutagenesis identified amino acid residues essential for betalamic acid production. Beta vulgaris and Mirabilis jalapa both possess a DODA1 lineage that functions in the betalain pathway and at least one other lineage, DODA2, that does not. Site-directed mutagenesis resulted in betalain biosynthesis by a previously nonfunctional DODA, revealing key residues required for evolution of the betalain pathway. Divergent functionality of DODA paralogs, one clade involved in betalain biosynthesis but others not, is present in various Caryophyllales species. A minimum of seven amino acid residue changes conferred betalain enzymatic activity to a betalain-nonfunctional DODA paralog, providing insight into the evolution of the betalain pigment pathway in plants. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

The roles of SSU processome components and surveillance factors in the initial processing of human ribosomal RNA

PubMed Central

Sloan, Katherine E.; Bohnsack, Markus T.; Schneider, Claudia; Watkins, Nicholas J.

2014-01-01

During eukaryotic ribosome biogenesis, three of the mature ribosomal (r)RNAs are released from a single precursor transcript (pre-rRNA) by an ordered series of endonucleolytic cleavages and exonucleolytic processing steps. Production of the 18S rRNA requires the removal of the 5′ external transcribed spacer (5′ETS) by endonucleolytic cleavages at sites A0 and A1/site 1. In metazoans, an additional cleavage in the 5′ETS, at site A′, upstream of A0, has also been reported. Here, we have investigated how A′ processing is coordinated with assembly of the early preribosomal complex. We find that only the tUTP (UTP-A) complex is critical for A′ cleavage, while components of the bUTP (UTP-B) and U3 snoRNP are important, but not essential, for efficient processing at this site. All other factors involved in the early stages of 18S rRNA processing that were tested here function downstream from this processing step. Interestingly, we show that the RNA surveillance factors XRN2 and MTR4 are also involved in A′ cleavage in humans. A′ cleavage is largely bypassed when XRN2 is depleted, and we also discover that A′ cleavage is not always the initial processing event in all cell types. Together, our data suggest that A′ cleavage is not a prerequisite for downstream pre-rRNA processing steps and may, in fact, represent a quality control step for initial pre-rRNA transcripts. Furthermore, we show that components of the RNA surveillance machinery, including the exosome and TRAMP complexes, also play key roles in the recycling of excised spacer fragments and degradation of aberrant pre-rRNAs in human cells. PMID:24550520

The Multigrid-Mask Numerical Method for Solution of Incompressible Navier-Stokes Equations

NASA Technical Reports Server (NTRS)

Ku, Hwar-Ching; Popel, Aleksander S.

1996-01-01

A multigrid-mask method for solution of incompressible Navier-Stokes equations in primitive variable form has been developed. The main objective is to apply this method in conjunction with the pseudospectral element method solving flow past multiple objects. There are two key steps involved in calculating flow past multiple objects. The first step utilizes only Cartesian grid points. This homogeneous or mask method step permits flow into the interior rectangular elements contained in objects, but with the restriction that the velocity for those Cartesian elements within and on the surface of an object should be small or zero. This step easily produces an approximate flow field on Cartesian grid points covering the entire flow field. The second or heterogeneous step corrects the approximate flow field to account for the actual shape of the objects by solving the flow field based on the local coordinates surrounding each object and adapted to it. The noise occurring in data communication between the global (low frequency) coordinates and the local (high frequency) coordinates is eliminated by the multigrid method when the Schwarz Alternating Procedure (SAP) is implemented. Two dimensional flow past circular and elliptic cylinders will be presented to demonstrate the versatility of the proposed method. An interesting phenomenon is found that when the second elliptic cylinder is placed in the wake of the first elliptic cylinder a traction force results in a negative drag coefficient.

Crystal structure of norcoclaurine-6-O-methyltransferase, a key rate-limiting step in the synthesis of benzylisoquinoline alkaloids.

PubMed

Robin, Adeline Y; Giustini, Cécile; Graindorge, Matthieu; Matringe, Michel; Dumas, Renaud

2016-09-01

Growing pharmaceutical interest in benzylisoquinoline alkaloids (BIA) coupled with their chemical complexity make metabolic engineering of microbes to create alternative platforms of production an increasingly attractive proposition. However, precise knowledge of rate-limiting enzymes and negative feedback inhibition by end-products of BIA metabolism is of paramount importance for this emerging field of synthetic biology. In this work we report the structural characterization of (S)-norcoclaurine-6-O-methyltransferase (6OMT), a key rate-limiting step enzyme involved in the synthesis of reticuline, the final intermediate to be shared between the different end-products of BIA metabolism, such as morphine, papaverine, berberine and sanguinarine. Four different crystal structures of the enzyme from Thalictrum flavum (Tf 6OMT) were solved: the apoenzyme, the complex with S-adenosyl-l-homocysteine (SAH), the complexe with SAH and the substrate and the complex with SAH and a feedback inhibitor, sanguinarine. The Tf 6OMT structural study provides a molecular understanding of its substrate specificity, active site structure and reaction mechanism. This study also clarifies the inhibition of Tf 6OMT by previously suggested feedback inhibitors. It reveals its high and time-dependent sensitivity toward sanguinarine. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Optimization and quality control of genome-wide Hi-C library preparation.

PubMed

Zhang, Xiang-Yuan; He, Chao; Ye, Bing-Yu; Xie, De-Jian; Shi, Ming-Lei; Zhang, Yan; Shen, Wen-Long; Li, Ping; Zhao, Zhi-Hu

2017-09-20

Highest-throughput chromosome conformation capture (Hi-C) is one of the key assays for genome- wide chromatin interaction studies. It is a time-consuming process that involves many steps and many different kinds of reagents, consumables, and equipments. At present, the reproducibility is unsatisfactory. By optimizing the key steps of the Hi-C experiment, such as crosslinking, pretreatment of digestion, inactivation of restriction enzyme, and in situ ligation etc., we established a robust Hi-C procedure and prepared two biological replicates of Hi-C libraries from the GM12878 cells. After preliminary quality control by Sanger sequencing, the two replicates were high-throughput sequenced. The bioinformatics analysis of the raw sequencing data revealed the mapping-ability and pair-mate rate of the raw data were around 90% and 72%, respectively. Additionally, after removal of self-circular ligations and dangling-end products, more than 96% of the valid pairs were reached. Genome-wide interactome profiling shows clear topological associated domains (TADs), which is consistent with previous reports. Further correlation analysis showed that the two biological replicates strongly correlate with each other in terms of both bin coverage and all bin pairs. All these results indicated that the optimized Hi-C procedure is robust and stable, which will be very helpful for the wide applications of the Hi-C assay.

The Role of Quantum Decoherence in FRET.

PubMed

Nelson, Philip C

2018-02-16

Resonance energy transfer has become an indispensable experimental tool for single-molecule and single-cell biophysics. Its physical underpinnings, however, are subtle: it involves a discrete jump of excitation from one molecule to another, and so we regard it as a strongly quantum-mechanical process. And yet its kinetics differ from what many of us were taught about two-state quantum systems, quantum superpositions of the states do not seem to arise, and so on. Although J. R. Oppenheimer and T. Förster navigated these subtleties successfully, it remains hard to find an elementary derivation in modern language. The key step involves acknowledging quantum decoherence. Appreciating that aspect can be helpful when we attempt to extend our understanding to situations in which Förster's original analysis is not applicable. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Don't break a leg: running birds from quail to ostrich prioritise leg safety and economy on uneven terrain.

PubMed

Birn-Jeffery, Aleksandra V; Hubicki, Christian M; Blum, Yvonne; Renjewski, Daniel; Hurst, Jonathan W; Daley, Monica A

2014-11-01

Cursorial ground birds are paragons of bipedal running that span a 500-fold mass range from quail to ostrich. Here we investigate the task-level control priorities of cursorial birds by analysing how they negotiate single-step obstacles that create a conflict between body stability (attenuating deviations in body motion) and consistent leg force-length dynamics (for economy and leg safety). We also test the hypothesis that control priorities shift between body stability and leg safety with increasing body size, reflecting use of active control to overcome size-related challenges. Weight-support demands lead to a shift towards straighter legs and stiffer steady gait with increasing body size, but it remains unknown whether non-steady locomotor priorities diverge with size. We found that all measured species used a consistent obstacle negotiation strategy, involving unsteady body dynamics to minimise fluctuations in leg posture and loading across multiple steps, not directly prioritising body stability. Peak leg forces remained remarkably consistent across obstacle terrain, within 0.35 body weights of level running for obstacle heights from 0.1 to 0.5 times leg length. All species used similar stance leg actuation patterns, involving asymmetric force-length trajectories and posture-dependent actuation to add or remove energy depending on landing conditions. We present a simple stance leg model that explains key features of avian bipedal locomotion, and suggests economy as a key priority on both level and uneven terrain. We suggest that running ground birds target the closely coupled priorities of economy and leg safety as the direct imperatives of control, with adequate stability achieved through appropriately tuned intrinsic dynamics. © 2014. Published by The Company of Biologists Ltd.

Don't break a leg: running birds from quail to ostrich prioritise leg safety and economy on uneven terrain

PubMed Central

Birn-Jeffery, Aleksandra V.; Hubicki, Christian M.; Blum, Yvonne; Renjewski, Daniel; Hurst, Jonathan W.; Daley, Monica A.

2014-01-01

Cursorial ground birds are paragons of bipedal running that span a 500-fold mass range from quail to ostrich. Here we investigate the task-level control priorities of cursorial birds by analysing how they negotiate single-step obstacles that create a conflict between body stability (attenuating deviations in body motion) and consistent leg force–length dynamics (for economy and leg safety). We also test the hypothesis that control priorities shift between body stability and leg safety with increasing body size, reflecting use of active control to overcome size-related challenges. Weight-support demands lead to a shift towards straighter legs and stiffer steady gait with increasing body size, but it remains unknown whether non-steady locomotor priorities diverge with size. We found that all measured species used a consistent obstacle negotiation strategy, involving unsteady body dynamics to minimise fluctuations in leg posture and loading across multiple steps, not directly prioritising body stability. Peak leg forces remained remarkably consistent across obstacle terrain, within 0.35 body weights of level running for obstacle heights from 0.1 to 0.5 times leg length. All species used similar stance leg actuation patterns, involving asymmetric force–length trajectories and posture-dependent actuation to add or remove energy depending on landing conditions. We present a simple stance leg model that explains key features of avian bipedal locomotion, and suggests economy as a key priority on both level and uneven terrain. We suggest that running ground birds target the closely coupled priorities of economy and leg safety as the direct imperatives of control, with adequate stability achieved through appropriately tuned intrinsic dynamics. PMID:25355848

The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts.

PubMed

Peinado, Héctor; Lavotshkin, Simon; Lyden, David

2011-04-01

Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Antiretroviral procurement and supply chain management.

PubMed

Ripin, David J; Jamieson, David; Meyers, Amy; Warty, Umesh; Dain, Mary; Khamsi, Cyril

2014-01-01

Procurement, the country-level process of ordering antiretrovirals (ARVs), and supply chain management, the mechanism by which they are delivered to health-care facilities, are critical processes required to move ARVs from manufacturers to patients. To provide a glimpse into the ARV procurement and supply chain, the following pages provide an overview of the primary stakeholders, principal operating models, and policies and regulations involved in ARV procurement. Also presented are key challenges that need to be addressed to ensure that the supply chain is not a barrier to the goal of universal coverage. This article will cover the steps necessary to order and distribute ARVs, including different models of delivery, key stakeholders involved, strategic considerations that vary depending on context and policies affecting them. The single drug examples given illustrate the complications inherent in fragmented supply and demand-driven models of procurement and supply chain management, and suggest tools for navigating these hurdles that will ultimately result in more secure and reliable ARV provision. Understanding the dynamics of ARV supply chain is important for the global health community, both to ensure full and efficient treatment of persons living with HIV as well as to inform the supply chain decisions for other public health products.

'Team up against TB': promoting involvement in Thibela TB, a trial of community-wide tuberculosis preventive therapy.

PubMed

Grant, Alison D; Coetzee, Leonie; Fielding, Katherine L; Lewis, James J; Ntshele, Smanga; Luttig, Mariëtha M; Mngadi, Kathryn T; Muller, Dorothy; Popane, Flora; Mdluli, John; Mngadi, Nkosinathi; Sefuthi, Clement; Clark, David A; Churchyard, Gavin

2010-11-01

To describe a programme of community education and mobilization to promote uptake in a cluster-randomized trial of tuberculosis preventive therapy offered to all members of intervention clusters. Gold mines in South Africa, where tuberculosis incidence is extremely high, despite conventional control measures. All employees in intervention clusters (mine shaft and associated hostel) were invited to enrol. Cumulative enrolment in the study in intervention clusters. Key steps in communicating information relevant to the study included extensive consultation with key stakeholders; working with a communication company to develop a project 'brand'; developing a communication strategy tailored to each intervention site; and involving actors from a popular television comedy series to help inform communities about the study. One-to-one communications used peer educators along with study staff, and participant advisory groups facilitated two-way communication between study staff and participants. By contrast, treatment 'buddies' and text messaging to promote adherence proved less successful. Mean cumulative enrolment in the first four intervention clusters was 61.9%, increasing to 83.0% in the final four clusters. A tailored communication strategy can facilitate a high level of enrolment in a community health intervention.

Hybrid strategy for increasing fusion performance and stagnation pressure in x-ray driven inertially confined fusion implosions on the NIF

NASA Astrophysics Data System (ADS)

Hurricane, O. A.; Callahan, D. A.; Edwards, M. J.; Casey, D.; Doeppner, T.; Hohenberger, M.; Hinkel, D.; Berzak Hopkins, L.; Le Pape, S.; MacLaren, S.; Masse, L.; Thomas, C.; Zylstra, A.

2017-10-01

Post NIC (2012), more stable and lower convergence implosions were developed and used as part of a `basecamp' strategy to identify obstacles to further performance. From 2013-2015 by probing away from a conservative working implosion in-steps towards conditions of higher velocity and compression, `Fuel Gain' and alpha-heating were obtained. In the process, performance cliffs unrelated to `mix' were identified the most impactful of which were symmetry control of the implosion and hydro seeded by engineering features. From 2015-2017 we focused on mitigating poor symmetry control and engineering improvements on fill-tubes and capsule mounting techniques. The results were more efficient implosions that can obtain the same performance levels as the earlier implosions, but with less laser energy. Presently, the best of these implosions is poised to step into a burning plasma state. Here, we describe the next step in our strategy that involves using the data we've acquired across parameter space to make a step to the largest symmetric implosions that can be fielded on NIF with the energy available. We describe the key principles that form the foundation of this approach. Performed under the auspices of U.S. Dept. of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

Implementing an intravenous insulin protocol in your practice: practical advice to overcome clinical, administrative, and financial barriers.

PubMed

Kelly, Janet L; Hirsch, Irl B; Furnary, Anthony P

2006-01-01

Diabetes mellitus is the fourth most common comorbid condition among hospitalized patients, and 30% of patients undergoing open-heart surgery have diabetes. The link between hyperglycemia and poor outcome has been well described, and large clinical trials have shown that aggressive control of blood glucose with an insulin infusion can improve these outcomes. The barriers to implementing an insulin infusion protocol are numerous, despite the fact that doing so is paramount to clinical success. Barriers include safety concerns, such as fear of hypoglycemia, insufficient nursing staff to patient ratios, lack of administrative and physician support, various system and procedural issues, and resistance to change. Key steps to overcome the barriers include building support with multidisciplinary champions, involving key staff, educating staff, and administrators of the clinical and economic benefits of improving glycemic control, setting realistic goals, selecting a validated insulin infusion protocol, and internally marketing the success of the protocol.

Synthesis of a basket-shaped C56H38 hydrocarbon as a precursor toward an end-cap template for carbon [6,6]nanotubes.

PubMed

Cui, Hu; Akhmedov, Novruz G; Petersen, Jeffrey L; Wang, Kung K

2010-03-19

A basket-shaped C(56)H(38) hydrocarbon (3) possessing a 30-carbon difluorenonaphthacenyl core that can be mapped onto the surface of C(78) was synthesized from 4-bromo-1-indanone. The first stage of the synthesis involved the preparation of tetraketone 10 as a key intermediate. The use of cascade cyclization reactions of benzannulated enyne-allenes as key features in the next stage of the synthetic sequence provides an efficient route to 3 from 4-bromo-1-indanone in 12 steps. The all-cis relationship among the methyl groups and the methine hydrogens causes the two benzofluorenyl units in 3 to be in an essentially perpendicular orientation to each other. Hydrocarbon 3 and its derivatives could serve as attractive precursors leading to a geodesic C(68)H(26) end-cap template for carbon [6,6]nanotubes.

School Climate Improvement Action Guide for District Leaders. School Climate Improvement Resource Package

ERIC Educational Resources Information Center

National Center on Safe Supportive Learning Environments, 2017

2017-01-01

Improving school climate takes time and commitment from a variety of people in a variety of roles. This document outlines key action steps that district leaders--including superintendents, assistant superintendents, directors of student support services, or others--can take to support school climate improvements. Key action steps are provided for…

Your company's secret change agents.

PubMed

Pascale, Richard Tanner; Sternin, Jerry

2005-05-01

Organizational change has traditionally come about through top-down initiatives such as hiring experts or importing best-of-breed practices. Such methods usually result in companywide rollouts of templates mandated from on high. These do little to get people excited. But within every organization, there are a few individuals who find unique ways to look at problems that seem impossible to solve. Although these change agents start out with the same tools and access to resources as their peers, they are able to see solutions where others do not. They find a way to bridge the divide between what is happening and what is possible. These positive deviants are the key, the authors believe, to a better way of creating organizational change. Your company can make the most of their methods by following six steps. In Step 1, Make the group the guru, the members of the community are engaged in the process of their own evolution. Step 2, Reframe through facts, entails restating the problem in a way that opens minds to new possibilities. Step 3, Make it safe to learn, involves creating an environment that supports innovative ideas. In Step 4, Make the problem concrete, the community combats abstraction by stating uncomfortable truths. In Step 5, Leverage social proof, the community looks to the larger society for examples of solutions that have worked in parallel situations. In Step 6, Confound the immune defense response, solutions are introduced organically from within the group in a way that promotes acceptance. Throughout the steps, the leader must suspend his or her traditional role in favor of more facilitatory practices. The positive-deviance approach has unearthed solutions to such complicated and diverse problems as malnutrition in Mali and human trafficking in East Java. This methodology can help solve even the most extreme dilemmas.

ATP analogues at a glance.

PubMed

Bagshaw, C

2001-02-01

ATP has long been known to play a central role in the energetics of cells both in transduction mechanisms and in metabolic pathways, and is involved in regulation of enzyme, channel and receptor activities. Numerous ATP analogues have been synthesised to probe the role of ATP in biosystems (Yount, 1975; Jameson and Eccleston, 1997; Bagshaw, 1998). In general, two contrasting strategies are employed. Modifications may be introduced deliberately to change the properties of ATP (e.g. making it non-hydrolysable) so as to perturb the chemical steps involved in its action. Typically these involve modification of the phosphate chain. Alternatively, derivatives (e.g. fluorescent probes) are designed to report on the action of ATP but have a minimal effect on its properties. ATP-utilising systems vary enormously in their specificity; so what acts as a good analogue in one case may be very poor in another. The accompanying poster shows a representative selection of derivatives that have been synthesised and summarises their key properties.

Exploiting genomic data to identify proteins involved in abalone reproduction.

PubMed

Mendoza-Porras, Omar; Botwright, Natasha A; McWilliam, Sean M; Cook, Mathew T; Harris, James O; Wijffels, Gene; Colgrave, Michelle L

2014-08-28

Aside from their critical role in reproduction, abalone gonads serve as an indicator of sexual maturity and energy balance, two key considerations for effective abalone culture. Temperate abalone farmers face issues with tank restocking with highly marketable abalone owing to inefficient spawning induction methods. The identification of key proteins in sexually mature abalone will serve as the foundation for a greater understanding of reproductive biology. Addressing this knowledge gap is the first step towards improving abalone aquaculture methods. Proteomic profiling of female and male gonads of greenlip abalone, Haliotis laevigata, was undertaken using liquid chromatography-mass spectrometry. Owing to the incomplete nature of abalone protein databases, in addition to searching against two publicly available databases, a custom database comprising genomic data was used. Overall, 162 and 110 proteins were identified in females and males respectively with 40 proteins common to both sexes. For proteins involved in sexual maturation, sperm and egg structure, motility, acrosomal reaction and fertilization, 23 were identified only in females, 18 only in males and 6 were common. Gene ontology analysis revealed clear differences between the female and male protein profiles reflecting a higher rate of protein synthesis in the ovary and higher metabolic activity in the testis. A comprehensive mass spectrometry-based analysis was performed to profile the abalone gonad proteome providing the foundation for future studies of reproduction in abalone. Key proteins involved in both reproduction and energy balance were identified. Genomic resources were utilised to build a database of molluscan proteins yielding >60% more protein identifications than in a standard workflow employing public protein databases. Copyright © 2014 Elsevier B.V. All rights reserved.

School Climate Improvement Action Guide for Instructional Staff. School Climate Improvement Resource Package

ERIC Educational Resources Information Center

National Center on Safe Supportive Learning Environments, 2017

2017-01-01

Improving school climate takes time and commitment from a variety of people in a variety of roles. This document outlines key action steps that instructional staff--including teachers, paraprofessionals, and others in the classroom who provide instruction or assistance--can take to support school climate improvements. Key action steps are provided…

School Climate Improvement Action Guide for School Leaders. School Climate Improvement Resource Package

ERIC Educational Resources Information Center

National Center on Safe Supportive Learning Environments, 2017

2017-01-01

Improving school climate takes time and commitment from a variety of people in a variety of roles. This document outlines key action steps that school leaders--including principals, assistant/vice principals, and building leaders--can take to support school climate improvements. Key action steps are provided for the following strategies: (1)…

School Climate Improvement Action Guide for Working with Students. School Climate Improvement Resource Package

ERIC Educational Resources Information Center

National Center on Safe Supportive Learning Environments, 2017

2017-01-01

Improving school climate takes time and commitment from a variety of people in a variety of roles. This document outlines key action steps to engage students in the school climate improvement process. Key action steps are provided for the following strategies: (1) Participate in planning for school climate improvements; (2) Engage stakeholders in…

Approaches to Children’s Exposure Assessment: Case Study with Diethylhexylphthalate (DEHP)

PubMed Central

Ginsberg, Gary; Ginsberg, Justine; Foos, Brenda

2016-01-01

Children’s exposure assessment is a key input into epidemiology studies, risk assessment and source apportionment. The goals of this article are to describe a methodology for children’s exposure assessment that can be used for these purposes and to apply the methodology to source apportionment for the case study chemical, diethylhexylphthalate (DEHP). A key feature is the comparison of total (aggregate) exposure calculated via a pathways approach to that derived from a biomonitoring approach. The 4-step methodology and its results for DEHP are: (1) Prioritization of life stages and exposure pathways, with pregnancy, breast-fed infants, and toddlers the focus of the case study and pathways selected that are relevant to these groups; (2) Estimation of pathway-specific exposures by life stage wherein diet was found to be the largest contributor for pregnant women, breast milk and mouthing behavior for the nursing infant and diet, house dust, and mouthing for toddlers; (3) Comparison of aggregate exposure by pathways vs biomonitoring-based approaches wherein good concordance was found for toddlers and pregnant women providing confidence in the exposure assessment; (4) Source apportionment in which DEHP presence in foods, children’s products, consumer products and the built environment are discussed with respect to early life mouthing, house dust and dietary exposure. A potential fifth step of the method involves the calculation of exposure doses for risk assessment which is described but outside the scope for the current case study. In summary, the methodology has been used to synthesize the available information to identify key sources of early life exposure to DEHP. PMID:27376320

"Nailing" the management of the ingrown great toenail.

PubMed

Block, Stan L

2014-11-01

"Nailing" the management of the severely ingrown great toenail, commonly encountered in the adolescent population, is an important tool in the pediatrician's armamentarium. I have found great toenail removal to be worthwhile, with straightforward indications; and quite rewarding for my patients in terms of time, convenience, and costs. The key to the procedure is to keep it simple. Four basic vital steps are involved: (1) operative permit and explanation; (2) performing a careful complete digital nerve block; (3) removing the entire toenail; and, importantly, (4) performing a partial chemical matricectomy--with readily available silver nitrate sticks--to prevent frequent recurrences. Copyright 2014, SLACK Incorporated.

Convergent evolution of morphogenetic processes in fungi

PubMed Central

Malagnac, Fabienne; Bidard, Frédérique; Lalucque, Hervé; Brun, Sylvain; Lambou, Karine; Lebrun, Marc-Henri

2008-01-01

Convergent evolution of trophic life style and morphological characters are very common in the fungal kingdom. Recently, we have shown that the same molecular machinery containing a tetraspanin and a NADPH oxidase has been recruited in two different fungal species for the same purpose (exiting from a melanized re-enforced cell at a focal weakened point), but at different stages of their development (ascospore germination and appressorium mediated penetration). Although this molecular machinery is required at these key developmental steps, it is also likely involved in specialized cellular functions at other stages of fungal development, as shown here for nutrient acquisition by Podospora anserina. PMID:19704887

Concise Syntheses of bis-Strychnos Alkaloids (-)-Sungucine, (-)-Isosungucine, and (-)-Strychnogucine B from (-)-Strychnine.

PubMed

Zhao, Senzhi; Teijaro, Christiana N; Chen, Heng; Sirasani, Gopal; Vaddypally, Shivaiah; Zdilla, Michael J; Dobereiner, Graham E; Andrade, Rodrigo B

2016-08-08

The first chemical syntheses of complex, bis-Strychnos alkaloids (-)-sungucine (1), (-)-isosungucine (2), and (-)-strychnogucine B (3) from (-)-strychnine (4) is reported. Key steps included (1) the Polonovski-Potier activation of strychnine N-oxide; (2) a biomimetic Mannich coupling to forge the signature C23-C5' bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH3 CN-mediated reduction to fashion the ethylidene moieties in 1-3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simple Backdoors on RSA Modulus by Using RSA Vulnerability

NASA Astrophysics Data System (ADS)

Sun, Hung-Min; Wu, Mu-En; Yang, Cheng-Ta

This investigation proposes two methods for embedding backdoors in the RSA modulus N=pq rather than in the public exponent e. This strategy not only permits manufacturers to embed backdoors in an RSA system, but also allows users to choose any desired public exponent, such as e=216+1, to ensure efficient encryption. This work utilizes lattice attack and exhaustive attack to embed backdoors in two proposed methods, called RSASBLT and RSASBES, respectively. Both approaches involve straightforward steps, making their running time roughly the same as that of normal RSA key-generation time, implying that no one can detect the backdoor by observing time imparity.

Properties of language networks and language systems. Comment on "Approaching human language with complex networks" by Cong and Liu

NASA Astrophysics Data System (ADS)

Yu, Shuiyuan; Xu, Chunshan

2014-12-01

Language is generally considered a defining feature of human beings, a key medium for interpersonal communication, a fundamental tool for human thinking and an important vehicle for culture transmission. For the anthropoids to evolve into human being, the emergence of linguistic system is a vital step. Then, how can language serve functions so complicated and so important? To answer this question, it is necessary to probe into a central topic in linguistics: the structure of language, which has been inevitably involved in various fields of linguistic research-the functions of languages, the evolution of languages, the typology of languages, etc.

Phosphate Tether-Mediated Approach to the Formal Total Synthesis of (-)-Salicylihalamides A and B

PubMed Central

Chegondi, Rambabu; Tan, Mary M. L.; Hanson, Paul R.

2011-01-01

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4-steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol. PMID:21504150

Multi-Step Time Series Forecasting with an Ensemble of Varied Length Mixture Models.

PubMed

Ouyang, Yicun; Yin, Hujun

2018-05-01

Many real-world problems require modeling and forecasting of time series, such as weather temperature, electricity demand, stock prices and foreign exchange (FX) rates. Often, the tasks involve predicting over a long-term period, e.g. several weeks or months. Most existing time series models are inheritably for one-step prediction, that is, predicting one time point ahead. Multi-step or long-term prediction is difficult and challenging due to the lack of information and uncertainty or error accumulation. The main existing approaches, iterative and independent, either use one-step model recursively or treat the multi-step task as an independent model. They generally perform poorly in practical applications. In this paper, as an extension of the self-organizing mixture autoregressive (AR) model, the varied length mixture (VLM) models are proposed to model and forecast time series over multi-steps. The key idea is to preserve the dependencies between the time points within the prediction horizon. Training data are segmented to various lengths corresponding to various forecasting horizons, and the VLM models are trained in a self-organizing fashion on these segments to capture these dependencies in its component AR models of various predicting horizons. The VLM models form a probabilistic mixture of these varied length models. A combination of short and long VLM models and an ensemble of them are proposed to further enhance the prediction performance. The effectiveness of the proposed methods and their marked improvements over the existing methods are demonstrated through a number of experiments on synthetic data, real-world FX rates and weather temperatures.

The substitution reaction of (CNC)Fe-2N₂ with CO.

PubMed

Liu, Hongyan; Liu, Shuangshuang; Zhang, Xiang

2013-06-01

The substitution mechanism of two N₂ ligands in (CNC)Fe-2N₂ replaced by CO was studied theoretically at the B3LYP/LACVP* level. Both SN1 and SN₂ mechanisms were considered. The calculated results for the gas phase suggested that: 1) in SN1 mechanism, N₂ elimination, which involves S₀-T₁ PESs crossing, is the rate control step for both substitution stages. The barrier heights are 9.7 kcal mol(-1) and 13.05 kcal mol(-1), respectively. 2) In SN2 mechanism, the calculated barrier heights on LS PES are respectively 13.7 and 19.83 kcal mol(-1) for the two substitution steps, but S₀-T₁ PESs crossing lowers the two barriers to 10.7 and 15.7 kcal mol(-1), respectively. 3) Inclusion of solvation effect of THF by PCM model, the relative energies of all the key species (including minima, transition states and S₀-T₁ crossing points) do not have great difference from their gas phase relative energies. Considering that for each substitution step, SN1 barrier heights is slightly smaller than SN2 barrier, SN1 mechanism seems to be slightly preferable to SN2 mechanism.

Portable Raman monitoring of modern cleaning and consolidation operations of artworks on mineral supports.

PubMed

Martínez-Arkarazo, I; Sarmiento, A; Maguregui, M; Castro, K; Madariaga, J M

2010-08-01

Any restoration performed on cultural heritage artworks must guarantee a low impact on the treated surfaces. Although completely risk-free methods do not exist, the use of tailor-made procedures and the continuous monitoring by portable instrumentation is surely one of the best approaches to conduct a modern restoration process. In this work, a portable Raman monitoring, combined sometimes with spectroscopic techniques providing the elemental composition, is the key analysis technique in the three-step restoration protocol proposed: (a) in situ analysis of the surface to be treated (original composition and degradation products/pollutants) and the cleaning agents used as extractants, (b) the thermodynamic study of the species involved in the treatment in order to design a suitable restoration method and (c) application and monitoring of the treatment. Two cleaning operations based on new technologies were studied and applied to two artworks on mineral supports: a wall painting affected by nitrate impact, and a black crusted stone (chalk) altarpiece. Raman bands of nitrate and gypsum, respectively, decreased after the step-by-step operations in each case, which helped restorers to decide when the treatment was concluded, thus avoiding any further damage to the treated surface of the artworks.

Embodied Cognition is Not What you Think it is

PubMed Central

Wilson, Andrew D.; Golonka, Sabrina

2013-01-01

The most exciting hypothesis in cognitive science right now is the theory that cognition is embodied. Like all good ideas in cognitive science, however, embodiment immediately came to mean six different things. The most common definitions involve the straight-forward claim that “states of the body modify states of the mind.” However, the implications of embodiment are actually much more radical than this. If cognition can span the brain, body, and the environment, then the “states of mind” of disembodied cognitive science won’t exist to be modified. Cognition will instead be an extended system assembled from a broad array of resources. Taking embodiment seriously therefore requires both new methods and theory. Here we outline four key steps that research programs should follow in order to fully engage with the implications of embodiment. The first step is to conduct a task analysis, which characterizes from a first person perspective the specific task that a perceiving-acting cognitive agent is faced with. The second step is to identify the task-relevant resources the agent has access to in order to solve the task. These resources can span brain, body, and environment. The third step is to identify how the agent can assemble these resources into a system capable of solving the problem at hand. The last step is to test the agent’s performance to confirm that agent is actually using the solution identified in step 3. We explore these steps in more detail with reference to two useful examples (the outfielder problem and the A-not-B error), and introduce how to apply this analysis to the thorny question of language use. Embodied cognition is more than we think it is, and we have the tools we need to realize its full potential. PMID:23408669

Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis.

PubMed

Munshi, Tulika; Gupta, Antima; Evangelopoulos, Dimitrios; Guzman, Juan David; Gibbons, Simon; Keep, Nicholas H; Bhakta, Sanjib

2013-01-01

ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthetic pathway. In line with the previous findings on the regulation of mycobacterial MurD and corynebacterial MurC synthetases via phosphorylation, we found that all of the Mur synthetases interacted with the Ser/Thr protein kinases, PknA and PknB. In addition, we critically analyzed the interaction network of all of the Mur synthetases with proteins involved in cell division and cell wall PG biosynthesis to re-evaluate the importance of these key enzymes as novel therapeutic targets in anti-tubercular drug discovery.

Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis

PubMed Central

Munshi, Tulika; Gupta, Antima; Evangelopoulos, Dimitrios; Guzman, Juan David; Gibbons, Simon; Keep, Nicholas H.; Bhakta, Sanjib

2013-01-01

ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthetic pathway. In line with the previous findings on the regulation of mycobacterial MurD and corynebacterial MurC synthetases via phosphorylation, we found that all of the Mur synthetases interacted with the Ser/Thr protein kinases, PknA and PknB. In addition, we critically analyzed the interaction network of all of the Mur synthetases with proteins involved in cell division and cell wall PG biosynthesis to re-evaluate the importance of these key enzymes as novel therapeutic targets in anti-tubercular drug discovery. PMID:23555903

How to write a surgical clinical research protocol: literature review and practical guide.

PubMed

Rosenthal, Rachel; Schäfer, Juliane; Briel, Matthias; Bucher, Heiner C; Oertli, Daniel; Dell-Kuster, Salome

2014-02-01

The study protocol is the core document of every clinical research project. Clinical research in studies involving surgical interventions presents some specific challenges, which need to be accounted for and described in the study protocol. The aim of this review is to provide a practical guide for developing a clinical study protocol for surgical interventions with a focus on methodologic issues. On the basis of an in-depth literature search of methodologic literature and on some cardinal published surgical trials and observational studies, the authors provides a 10-step guide for developing a clinical study protocol in surgery. This practical guide outlines key methodologic issues important when planning an ethically and scientifically sound research project involving surgical interventions, with the ultimate goal of providing high-level evidence relevant for health care decision making in surgery. Copyright © 2014 Elsevier Inc. All rights reserved.

Hybrid method for moving interface problems with application to the Hele-Shaw flow

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

Hou, T.Y.; Li, Zhilin; Osher, S.

In this paper, a hybrid approach which combines the immersed interface method with the level set approach is presented. The fast version of the immersed interface method is used to solve the differential equations whose solutions and their derivatives may be discontinuous across the interfaces due to the discontinuity of the coefficients or/and singular sources along the interfaces. The moving interfaces then are updated using the newly developed fast level set formulation which involves computation only inside some small tubes containing the interfaces. This method combines the advantage of the two approaches and gives a second-order Eulerian discretization for interfacemore » problems. Several key steps in the implementation are addressed in detail. This new approach is then applied to Hele-Shaw flow, an unstable flow involving two fluids with very different viscosity. 40 refs., 10 figs., 3 tabs.« less

Clinical research data sharing: what an open science world means for researchers involved in evidence synthesis.

PubMed

Ross, Joseph S

2016-09-20

The International Committee of Medical Journal Editors (ICMJE) recently announced a bold step forward to require data generated by interventional clinical trials that are published in its member journals to be responsibly shared with external investigators. The movement toward a clinical research culture that supports data sharing has important implications for the design, conduct, and reporting of systematic reviews and meta-analyses. While data sharing is likely to enhance the science of evidence synthesis, facilitating the identification and inclusion of all relevant research, it will also pose key challenges, such as requiring broader search strategies and more thorough scrutiny of identified research. Furthermore, the adoption of data sharing initiatives by the clinical research community should challenge the community of researchers involved in evidence synthesis to follow suit, including the widespread adoption of systematic review registration, results reporting, and data sharing, to promote transparency and enhance the integrity of the research process.

The Extracellular δ-Domain is Essential for the Formation of CD81 Tetraspanin Webs

PubMed Central

Homsi, Yahya; Schloetel, Jan-Gero; Scheffer, Konstanze D.; Schmidt, Thomas H.; Destainville, Nicolas; Florin, Luise; Lang, Thorsten

2014-01-01

CD81 is a ubiquitously expressed member of the tetraspanin family. It forms large molecular platforms, so-called tetraspanin webs that play physiological roles in a variety of cellular functions and are involved in viral and parasite infections. We have investigated which part of the CD81 molecule is required for the formation of domains in the cell membranes of T-cells and hepatocytes. Surprisingly, we find that large CD81 platforms assemble via the short extracellular δ-domain, independent from a strong primary partner binding and from weak interactions mediated by palmitoylation. The δ-domain is also essential for the platforms to function during viral entry. We propose that, instead of stable binary interactions, CD81 interactions via the small δ-domain, possibly involving a dimerization step, play the key role in organizing CD81 into large tetraspanin webs and controlling its function. PMID:24988345

On the complexity of search for keys in quantum cryptography

NASA Astrophysics Data System (ADS)

Molotkov, S. N.

2016-03-01

The trace distance is used as a security criterion in proofs of security of keys in quantum cryptography. Some authors doubted that this criterion can be reduced to criteria used in classical cryptography. The following question has been answered in this work. Let a quantum cryptography system provide an ɛ-secure key such that ½‖ρ XE - ρ U ⊗ ρ E ‖1 < ɛ, which will be repeatedly used in classical encryption algorithms. To what extent does the ɛ-secure key reduce the number of search steps (guesswork) as compared to the use of ideal keys? A direct relation has been demonstrated between the complexity of the complete consideration of keys, which is one of the main security criteria in classical systems, and the trace distance used in quantum cryptography. Bounds for the minimum and maximum numbers of search steps for the determination of the actual key have been presented.

Increased metastatic potential of tumor cells in von Willebrand factor-deficient mice.

PubMed

Terraube, V; Pendu, R; Baruch, D; Gebbink, M F B G; Meyer, D; Lenting, P J; Denis, C V

2006-03-01

The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet-tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis. To investigate whether VWF is involved in metastasis development. In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells. In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis. These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated.

A comparison of African American and Caucasian stimulant users in 12-step facilitation treatment

PubMed Central

Peavy, K. Michelle; Garrett, Sharon; Doyle, Suzanne; Donovan, Dennis

2017-01-01

Engagement in 12-step meetings and activities has been shown to be a powerful aid to recovery from substance use disorders. However, only limited attention has been given to ethnic and racial differences in attitudes toward 12-step and involvement. This study utilized data from a large multisite trial testing the effectiveness of a 12-step facilitation therapy with stimulant-dependent treatment seekers. We compared baseline differences and treatment outcomes between African American and Caucasian participants. A select few baseline differences were found (i.e., African Americans reported higher levels of spirituality than Caucasians; African American participants indicated more perceived benefits of 12-step involvement; Caucasians were more likely to endorse future involvement in 12-step). There were no outcome differences (e.g., substance use outcomes, 12-step meeting attendance). The tested intervention produced similar outcomes for both groups, indicating that it may be useful across racial categories. PMID:27294812

A comparison of African American and Caucasian stimulant users in 12-step facilitation treatment.

PubMed

Peavy, K Michelle; Garrett, Sharon; Doyle, Suzanne; Donovan, Dennis

2017-01-01

Engagement in 12-step meetings and activities has been shown to be a powerful aid to recovery from substance use disorders. However, only limited attention has been given to ethnic and racial differences in attitudes toward 12-step and involvement. This study utilized data from a large multisite trial testing the effectiveness of a 12-step facilitation therapy with stimulant-dependent treatment seekers. We compared baseline differences and treatment outcomes between African American and Caucasian participants. A select few baseline differences were found (i.e., African Americans reported higher levels of spirituality than Caucasians; African American participants indicated more perceived benefits of 12-step involvement; Caucasians were more likely to endorse future involvement in 12-step). There were no outcome differences (e.g., substance use outcomes, 12-step meeting attendance). The tested intervention produced similar outcomes for both groups, indicating that it may be useful across racial categories.

Army Independent Risk Assessment Guidebook

DTIC Science & Technology

2014-04-01

17 5.4.2 Step 2: Gather relevant technology and alternative information............... 17 5.4.3 Step 3: Secure SME support for readiness...level assessment. ................... 17 5.4.4 Step 4: SMEs assess TRL, IRL, and MRL for each technology. .............. 17 5.4.5 Step 5: Identify...technical risks, risk ratings, and mitigations. .................. 20 5.4.6 Step 6: SMEs identify key technologies

Developing a workbook to support the contextualisation of global health systems guidance: a case study identifying steps and critical factors for success in this process at WHO.

PubMed

Alvarez, Elizabeth; Lavis, John N; Brouwers, Melissa; Schwartz, Lisa

2018-03-02

Global guidance can help countries strengthen their health systems to deliver effective interventions to their populations. However, to have an impact, guidance needs to be contextualised or adapted to local settings; this process includes consideration of health system arrangements and political system factors. To date, methods to support contextualisation do not exist. In response, a workbook was designed to provide specific methods and strategies to enable the contextualisation of WHO's 'Optimizing health worker roles to improve maternal and newborn health' (OptimizeMNH) guidance at the national or subnational level. The objective of this study was to describe the process of developing the workbook and identify key steps of the development process, barriers that arose and facilitators that helped overcome some of these barriers. A qualitative single case study design was carried out. Interviews, documents and a reflexive journal were used. Constant comparison and an edit-style of organisation were used during data analysis to develop concepts, themes, subthemes and relationships among them. Thirteen interviews were conducted and 52 documents were reviewed. Three main steps were identified in the process of developing the workbook for health systems guidance contextualisation, namely (1) determining the need for and gaining approval to develop the workbook, (2) developing the workbook (taking on the task, creating the structure of the workbook, operationalising its components, undergoing approval processes and editing it), and (3) implementing the workbook both at the WHO level and at the national/subnational level. Five barriers and/or facilitators emerged relevant to each step, namely (1) having well-placed and credible champions, (2) creating and capitalising on opportunities, (3) finding the right language to engage various actors and obtain buy-in, (4) obtaining and maintaining meaningful buy-in, and (5) ensuring access to resources. Understanding the key steps and the critical factors involved in the process of developing the workbook could help in the planning of similar and other tools aimed to support the implementation of WHO guidance. A plan for dissemination and implementation needs to be addressed during the preparation of these tools.

Are there dynamical effects in enzyme catalysis? Some thoughts concerning the enzymatic chemical step.

PubMed

Tuñón, Iñaki; Laage, Damien; Hynes, James T

2015-09-15

We offer some thoughts on the much debated issue of dynamical effects in enzyme catalysis, and more specifically on their potential role in the acceleration of the chemical step. Since the term 'dynamics' has been used with different meanings, we find it useful to first return to the Transition State Theory rate constant, its assumptions and the choices it involves, and detail the various sources of deviations from it due to dynamics (or not). We suggest that much can be learned about the key current questions for enzyme catalysis from prior extensive studies of dynamical and other effects in the case of reactions in solution. We analyze dynamical effects both in the neighborhood of the transition state and far from it, together with the situation when quantum nuclear motion is central to the reaction, and we illustrate our discussion with various examples of enzymatic reactions. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Dynamic cholesteric liquid crystal superstructures photoaligned by one-step polarization holography

NASA Astrophysics Data System (ADS)

Li, Sen-Sen; Shen, Yuan; Chang, Zhen-Ni; Li, Wen-Song; Xu, Yan-Chao; Fan, Xing-Yu; Chen, Lu-Jian

2017-12-01

A convenient approach to modulate the fingerprint textures of methyl red (MR) doped cholesteric liquid crystals by asymmetric photoalignment in the green-light waveband is presented, resulting in the generation of voltage-controllable helical superstructures. The interaction between the MR molecules and the incident light polarization determines the initial twisted planar geometry, providing a multivariant control over the stripe directions of fingerprint textures by applying a proper electric field. The key factors for precise manipulation of fingerprint stripes in a predictable and rewritable manner are analyzed theoretically and investigated experimentally, which involves the alignment asymmetry, the ratio of cell gap to natural pitch length, and the chirality of chiral dopant. Dynamic periodic fingerprint textures in shapes of dashed curve and dashed line are further demonstrated by utilizing a facile one-step polarization holography process using two beams with orthogonal circular and orthogonal linear polarizations, respectively. It is believed that the practical approach described in this study would enrich the research contents of self-assembled hierarchical superstructures using soft liquid crystal building blocks.

Strategies for Efficient Charge Separation and Transfer in Artificial Photosynthesis of Solar Fuels.

PubMed

Xu, Yuxing; Li, Ailong; Yao, Tingting; Ma, Changtong; Zhang, Xianwen; Shah, Jafar Hussain; Han, Hongxian

2017-11-23

Converting sunlight to solar fuels by artificial photosynthesis is an innovative science and technology for renewable energy. Light harvesting, photogenerated charge separation and transfer (CST), and catalytic reactions are the three primary steps in the processes involved in the conversion of solar energy to chemical energy (SE-CE). Among the processes, CST is the key "energy pump and delivery" step in determining the overall solar-energy conversion efficiency. Efficient CST is always high priority in designing and assembling artificial photosynthesis systems for solar-fuel production. This Review not only introduces the fundamental strategies for CST but also the combinatory application of these strategies to five types of the most-investigated semiconductor-based artificial photosynthesis systems: particulate, Z-scheme, hybrid, photoelectrochemical, and photovoltaics-assisted systems. We show that artificial photosynthesis systems with high SE-CE efficiency can be rationally designed and constructed through combinatory application of these strategies, setting a promising blueprint for the future of solar fuels. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inter vs. intraglycosidic acetal linkages control sulfation pattern in semi-synthetic chondroitin sulfate.

PubMed

Laezza, Antonio; De Castro, Cristina; Parrilli, Michelangelo; Bedini, Emiliano

2014-11-04

Microbial-sourced unsulfated chondroitin could be converted into chondroitin sulfate (CS) polysaccharide by a multi-step strategy relying upon benzylidenation and acetylation reactions as key-steps for its regioselective protection. By conducting the two reactions one- or two-pots, CSs with different sulfation patterns could be obtained at the end of the semi-synthesis. In particular, a CS polysaccharide possessing sulfate groups randomly distributed between positions 4 and 6 of N-acetyl-galactosamine (GalNAc) units could be obtained through the two-pots route, whereas the one-pot pathway allowed an additional sulfation at position 3 of some glucuronic acid (GlcA) units. This difference was ascribed to the stabilization of a labile interglycosidic benzylidene acetal involving positions O-3 and O-6 of some GlcA and GalNAc, respectively, when the benzylidene-acetylation reactions were conducted in a one-pot fashion. Isolation and characterization of a polysaccharide intermediate showing interglycosidic acetal moieties was accomplished. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dispersive shock waves in systems with nonlocal dispersion of Benjamin-Ono type

NASA Astrophysics Data System (ADS)

El, G. A.; Nguyen, L. T. K.; Smyth, N. F.

2018-04-01

We develop a general approach to the description of dispersive shock waves (DSWs) for a class of nonlinear wave equations with a nonlocal Benjamin-Ono type dispersion term involving the Hilbert transform. Integrability of the governing equation is not a pre-requisite for the application of this method which represents a modification of the DSW fitting method previously developed for dispersive-hydrodynamic systems of Korteweg-de Vries (KdV) type (i.e. reducible to the KdV equation in the weakly nonlinear, long wave, unidirectional approximation). The developed method is applied to the Calogero-Sutherland dispersive hydrodynamics for which the classification of all solution types arising from the Riemann step problem is constructed and the key physical parameters (DSW edge speeds, lead soliton amplitude, intermediate shelf level) of all but one solution type are obtained in terms of the initial step data. The analytical results are shown to be in excellent agreement with results of direct numerical simulations.

SPIKES: a framework for breaking bad news to patients with cancer.

PubMed

Kaplan, Marcelle

2010-08-01

SPIKES is an acronym for presenting distressing information in an organized manner to patients and families. The SPIKES protocol provides a step-wise framework for difficult discussions such as when cancer recurs or when palliative or hospice care is indicated. Each letter represents a phase in the six-step sequence. S stands for setting, P for perception, I for invitation or information, K for knowledge, E for empathy, and S for summarize or strategize. Breaking bad news is a complex communication task, but following the SPIKES protocol can help ease the distress felt by the patient who is receiving the news and the healthcare professional who is breaking the news. Key components of the SPIKES strategy include demonstrating empathy, acknowledging and validating the patient's feelings, exploring the patient's understanding and acceptance of the bad news, and providing information about possible interventions. Having a plan of action provides structure for this difficult discussion and helps support all involved.

Deconvolutions based on singular value decomposition and the pseudoinverse: a guide for beginners.

PubMed

Hendler, R W; Shrager, R I

1994-01-01

Singular value decomposition (SVD) is deeply rooted in the theory of linear algebra, and because of this is not readily understood by a large group of researchers who could profit from its application. In this paper, we discuss the subject on a level that should be understandable to scientists who are not well versed in linear algebra. However, because it is necessary that certain key concepts in linear algebra be appreciated in order to comprehend what is accomplished by SVD, we present the section, 'Bare basics of linear algebra'. This is followed by a discussion of the theory of SVD. Next we present step-by-step examples to illustrate how SVD is applied to deconvolute a titration involving a mixture of three pH indicators. One noiseless case is presented as well as two cases where either a fixed or varying noise level is present. Finally, we discuss additional deconvolutions of mixed spectra based on the use of the pseudoinverse.

The use of emergency manuals in perioperative crisis management: a cautious approach.

PubMed

Szabo, Ashley; August, David A; Klainer, Suzanne; Miller, Andrew D; Kaye, Alan D; Raemer, Daniel B; Urman, Richard D

2015-01-01

When an unexpected perioperative crisis arises, simulation studies have suggested that the use of an emergency manual (EM) may offset the large cognitive load involved in crisis management, facilitating the efficient performance of key steps in treatment. However, little is known about how well EMs will translate into actual practice and what is required to use them optimally. While EMs are a promising tool in the management of perioperative critical events, more research is needed to define best practices and their limitations. In the interim, cautious use of these cognitive aids is recommended, especially when the diagnosis is not straightforward, falls "in between" sections of the EM, or falls outside of the EM itself. Further research should focus on the efficacy of EMs as measured by the percentage of critical steps correctly performed by their users in scenarios that do not closely mirror one of the listed EM scenarios from the beginning or as the situation evolves.

A cross-sectional survey of supports for evidence-informed decision-making in healthcare organisations: a research protocol.

PubMed

Ouimet, Mathieu; Lavis, John N; Léon, Grégory; Ellen, Moriah E; Bédard, Pierre-Olivier; Grimshaw, Jeremy M; Gagnon, Marie-Pierre

2014-10-09

This protocol builds on the development of a) a framework that identified the various supports (i.e. positions, activities, interventions) that a healthcare organisation or health system can implement for evidence-informed decision-making (EIDM) and b) a qualitative study that showed the current mix of supports that some Canadian healthcare organisations have in place and the ones that are perceived to facilitate the use of research evidence in decision-making. Based on these findings, we developed a web survey to collect cross-sectional data about the specific supports that regional health authorities and hospitals in two Canadian provinces (Ontario and Quebec) have in place to facilitate EIDM. This paper describes the methods for a cross-sectional web survey among 32 regional health authorities and 253 hospitals in the provinces of Quebec and Ontario (Canada) to collect data on the current mix of organisational supports that these organisations have in place to facilitate evidence-informed decision-making. The data will be obtained through a two-step survey design: a 10-min survey among CEOs to identify key units and individuals in regard to our objectives (step 1) and a 20-min survey among managers of the key units identified in step 1 to collect information about the activities performed by their unit regarding the acquisition, assessment, adaptation and/or dissemination of research evidence in decision-making (step 2). The study will target three types of informants: CEOs, library/documentation centre managers and all other key managers whose unit is involved in the acquisition, assessment, adaptation/packaging and/or dissemination of research evidence in decision-making. We developed an innovative data collection system to increase the likelihood that only the best-informed respondent available answers each survey question. The reporting of the results will be done using descriptive statistics of supports by organisation type and by province. This study will be the first to collect and report large-scale cross-sectional data on the current mix of supports health system organisations in the two most populous Canadian provinces have in place for evidence-informed decision-making. The study will also provide useful information to researchers on how to collect organisation-level data with reduced risk of self-reporting bias.

A Selection Method That Succeeds!

ERIC Educational Resources Information Center

Weitman, Catheryn J.

Provided a structural selection method is carried out, it is possible to find quality early childhood personnel. The hiring process involves five definite steps, each of which establishes a base for the next. A needs assessment formulating basic minimal qualifications is the first step. The second step involves review of current job descriptions…

48 CFR 3036.104-90 - Authority for one-step turn-key design-build contracting for the United States Coast Guard (USCG).

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 7 2014-10-01 2014-10-01 false Authority for one-step turn-key design-build contracting for the United States Coast Guard (USCG). 3036.104-90 Section 3036.104-90 Federal Acquisition Regulations System DEPARTMENT OF HOMELAND SECURITY, HOMELAND SECURITY ACQUISITION REGULATION (HSAR) SPECIAL CATEGORIES OF...

Synthesis of natural urolithin M6, a galloflavin mimetic, as a potential inhibitor of lactate dehydrogenase A.

PubMed

Rupiani, Sebastiano; Guidotti, Laura; Manerba, Marcella; Di Ianni, Lorenza; Giacomini, Elisa; Falchi, Federico; Di Stefano, Giuseppina; Roberti, Marinella; Recanatini, Maurizio

2016-11-22

Glycolysis is the main route for energy production in tumors. LDH-A is a key enzyme of this process and its inhibition represents an attractive strategy to hamper cancer cell metabolism. Galloflavin is a reliable LDH-A inhibitor as previously identified by us; however, its poor physicochemical properties and chemical tractability render it unsuitable for further development. Therefore, a rational design was undertaken with the aim to reproduce the pharmacophore of galloflavin on simpler, potentially more soluble and synthetic accessible scaffolds. Following a process of structural simplification, natural urolithin M6 (UM6), which is an ellagitannin metabolite produced by gut microbiota, was identified as a putative galloflavin mimetic. In the present study, the synthesis of UM6 is described for the first time. An efficient synthetic pathway has been developed, which involved five steps from readily accessible starting materials. The key reaction steps, a Suzuki coupling and an intramolecular C-H oxygenation, have been optimized to improve the synthetic feasibility and provide the best conditions in terms of reaction time and yield. Moreover, this route would be suitable to obtain other analogs for SAR studies. Preliminary biological tests revealed that UM6 was able to smoothly reproduce the behavior of galloflavin, confirming that our approach was successful in providing a new and accessible structure in the search for new LDH-A inhibitors.

31P and 13C NMR analyses of the energy metabolism of the thermophilic anaerobe Clostridium thermocellum.

PubMed

Tolman, C J; Kanodia, S; Roberts, M F

1987-08-15

The energy metabolism of an anaerobic obligate thermophile, Clostridium thermocellum, has been examined as a function of incubation temperature using 31P NMR spectroscopy. Specifically investigated were the generation and availability of ATP as a function of temperature, activation energies for key processes in energy metabolism including formation of a pH gradient across the cell membrane, transport of key nutrients, and initial steps in glycolysis, and the existence of a membrane phase transition in the intact organism. Cells generate ATP via glycolysis at all temperatures examined; hence, limitation of the energy supply is not directly responsible for the lack of growth of this organism at low temperatures. Estimations of activation energies show a distinct hierarchy in the ATP-utilizing reactions examined. Conservation of ATP hydrolysis energy as delta pH has the lowest activation energy (less than or equal to 4 kcal/mol), two transport processes exhibit 10 kcal/mol activation energies, and early phosphorylation steps in glycolysis have significantly higher activation energies (approximately 25 kcal/mol). Neither the membrane-bound ATPase responsible for formation of the pH gradient nor the permease involved in phosphate transport shows evidence of a change in behavior around the phase transition temperature determined for extracted lipids of C. thermocellum. Line widths of inorganic phosphate do show a break in behavior around 35-40 degrees C. Possible explanations for this behavior are discussed.

Keeping a Step Ahead: formative phase of a workplace intervention trial to prevent obesity.

PubMed

Zapka, Jane; Lemon, Stephenie C; Estabrook, Barbara B; Jolicoeur, Denise G

2007-11-01

Ecological interventions hold promise for promoting overweight and obesity prevention in worksites. Given the paucity of evaluative research in the hospital worksite setting, considerable formative work is required for successful implementation and evaluation. This paper describes the formative phases of Step Ahead, a site-randomized controlled trial of a multilevel intervention that promotes physical activity and healthy eating in six hospitals in central Massachusetts. The purpose of the formative research phase was to increase the feasibility, effectiveness, and likelihood of sustainability of the intervention. The Step Ahead ecological intervention approach targets change at the organization, interpersonal work environment, and individual levels. The intervention was developed using fundamental steps of intervention mapping and important tenets of participatory research. Formative research methods were used to engage leadership support and assistance and to develop an intervention plan that is both theoretically and practically grounded. This report uses observational data, program minutes and reports, and process tracking data. Leadership involvement (key informant interviews and advisory boards), employee focus groups and advisory boards, and quantitative environmental assessments cultivated participation and support. Determining multiple foci of change and designing measurable objectives and generic assessment tools to document progress are complex challenges encountered in planning phases. Multilevel trials in diverse organizations require flexibility and balance of theory application and practice-based perspectives to affect impact and outcome objectives. Formative research is an essential component.

Development of a fluorescence in situ hybridization protocol for the identification of micro-organisms associated with wastewater particles and flocs.

PubMed

Ormeci, Banu; Linden, Karl G

2008-11-01

Fluorescence in situ hybridization (FISH) provides a unique tool to study micro-organisms associated with particles and flocs. FISH enables visual examination of micro-organisms while they are structurally intact and associated with particles. However, application of FISH to wastewater and sludge samples presents a specific set of problems. Wastewater samples generate high background fluorescence due to their organic and inorganic content making it difficult to differentiate a probe-conferred signal from naturally fluorescing particles with reasonable certainty. Furthermore, some of the FISH steps involve harsh treatment of samples, and are likely to disrupt the floc structure. This study developed a FISH protocol for studying micro-organisms that are associated with particles and flocs. The results indicate that choice of a proper fluorochrome and labeling technique is a key step in reducing the background fluorescence and non-specific binding, and increasing the intensity of the probe signal. Compared to other fluorochromes tested, CY3 worked very well and enabled the observation of particles and debris in red and probe signal from microbes in yellow. Fixation, hybridization, and washing steps disturbed the floc structure and particle-microbe association. Modifications to these steps were necessary, and were achieved by replacing centrifugation with filtration and employment of nylon filters. Microscope slides generated excellent quality images, but polycarbonate membrane filters performed better in preserving the floc structure.

[Audits across state borders for medical consulting agencies within the German healthcare insurance system].

PubMed

Schneider, T; Sommerfeld, W; Möller, J

2003-06-01

The Medizinischer Dienst der Krankenversicherung (MDK) is a non-profit medical consulting organisation serving the German Healthcare Insurance System. Despite its uniform commission throughout Germany, organisation and structure differ considerably between Provincial States which is reflected by differing results. A common nationwide system of key figures and indicators aims at analysing results and learning from one another. Development of an audit concept for analysing key figures and indicators within the MDK aiming at quality improvement. Development of a system of key figures and indicators covering five spheres (products, staff, costs, data analysis, structure). Analysis by means of audits carried out across provincial state borders in five steps (audit manual, training of auditors, visitation, audit report, repetition audit). The system of key figures and indicators assures relevant and comparable data. Audit manual, training of auditors, visitation, and audit report meet the needs of all people and institutions involved. Preparation of auditors as well as openness, and flow of information within audited organisations offer areas for improvement. There is as yet no assessment of the cost-benefit ratio of audits. The concept presented in this article consists of two parts: A system of key figures and indicators as well as a concept for audits. The concept is suitable for a) generating and analysing relevant key figures and indicators for each MDK, and b) providing information for benchmarking between different MDK. Further development of the concept to a comprehensive management concept is necessary.

Optimization and planning of operating theatre activities: an original definition of pathways and process modeling.

PubMed

Barbagallo, Simone; Corradi, Luca; de Ville de Goyet, Jean; Iannucci, Marina; Porro, Ivan; Rosso, Nicola; Tanfani, Elena; Testi, Angela

2015-05-17

The Operating Room (OR) is a key resource of all major hospitals, but it also accounts for up 40% of resource costs. Improving cost effectiveness, while maintaining a quality of care, is a universal objective. These goals imply an optimization of planning and a scheduling of the activities involved. This is highly challenging due to the inherent variable and unpredictable nature of surgery. A Business Process Modeling Notation (BPMN 2.0) was used for the representation of the "OR Process" (being defined as the sequence of all of the elementary steps between "patient ready for surgery" to "patient operated upon") as a general pathway ("path"). The path was then both further standardized as much as possible and, at the same time, keeping all of the key-elements that would allow one to address or define the other steps of planning, and the inherent and wide variability in terms of patient specificity. The path was used to schedule OR activity, room-by-room, and day-by-day, feeding the process from a "waiting list database" and using a mathematical optimization model with the objective of ending up in an optimized planning. The OR process was defined with special attention paid to flows, timing and resource involvement. Standardization involved a dynamics operation and defined an expected operating time for each operation. The optimization model has been implemented and tested on real clinical data. The comparison of the results reported with the real data, shows that by using the optimization model, allows for the scheduling of about 30% more patients than in actual practice, as well as to better exploit the OR efficiency, increasing the average operating room utilization rate up to 20%. The optimization of OR activity planning is essential in order to manage the hospital's waiting list. Optimal planning is facilitated by defining the operation as a standard pathway where all variables are taken into account. By allowing a precise scheduling, it feeds the process of planning and, further up-stream, the management of a waiting list in an interactive and bi-directional dynamic process.

Notes from the field: the economic value chain in disease management organizations.

PubMed

Fetterolf, Donald

2006-12-01

The disease management (DM) "value chain" is composed of a linear series of steps that include operational milestones in the development of knowledge, each stage evolving from the preceding one. As an adaptation of Michael Porter's "value chain" model, the process flow in DM moves along the following path: (1) data/information technology, (2) information generation, (3) analysis, (4) assessment/recommendations, (5) actionable customer plan, and (6) program assessment/reassessment. Each of these stages is managed as a major line of product operations within a DM company or health plan. Metrics around each of the key production variables create benchmark milestones, ongoing management insight into program effectiveness, and potential drivers for activity-based cost accounting pricing models. The value chain process must remain robust from early entry of data and information into the system, through the final presentation and recommendations for our clients if the program is to be effective. For individuals involved in the evaluation or review of DM programs, this framework is an excellent method to visualize the key components and sequence in the process. The value chain model is an excellent way to establish the value of a formal DM program and to create a consultancy relationship with a client involved in purchasing these complex services.

Strychnine inhibits inflammatory angiogenesis in mice via down regulation of VEGF, TNF-α and TGF-β.

PubMed

Saraswati, Sarita; Agarwal, S S

2013-05-01

Strychnine is known to possess anti-inflammatory and antitumour activity, but its roles in tumour angiogenesis, the key step involved in tumour growth and metastasis, and the involved molecular mechanism are still unknown. We aimed to investigate the effects of strychnine on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and strychnine (0.25, and 0.5 mg/kg/day) was given through installed cannulas for 9 days. The implants collected at day 9 postimplantation were processed for the assessment of haemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG) and collagen used as indexes for angiogenesis, neutrophil and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic and fibrogenic cytokines were also determined. Strychnine treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF)-α and transforming growth factor (TGF-β). A regulatory function of strychnine on multiple parameters of main components of inflammatory angiogenesis has been revealed giving insight into the potential therapeutic underlying the actions of strychnine. Copyright © 2013 Elsevier Inc. All rights reserved.

Key enzymes of the retinoid (visual) cycle in vertebrate retina

PubMed Central

Kiser, Philip D.; Golczak, Marcin; Maeda, Akiko; Palczewski, Krzysztof

2011-01-01

A major goal in vision research over the past few decades has been to understand the molecular details of retinoid processing within the retinoid (visual) cycle. This includes the consequences of side reactions that result from delayed all-trans-retinal clearance and condensation with phospholipids that characterize a variety of serious retinal diseases. Knowledge of the basic retinoid biochemistry involved in these diseases is essential for development of effective therapeutics. Photoisomerization of the 11-cis-retinal chromophore of rhodopsin triggers a complex set of metabolic transformations collectively termed phototransduction that ultimately lead to light perception. Continuity of vision depends on continuous conversion of all-trans-retinal back to the 11-cis-retinal isomer. This process takes place in a series of reactions known as the retinoid cycle, which occur in photoreceptor and RPE cells. All-trans-retinal, the initial substrate of this cycle, is a chemically reactive aldehyde that can form toxic conjugates with proteins and lipids. Therefore, much experimental effort has been devoted to elucidate molecular mechanisms of the retinoid cycle and all-trans-retinal-mediated retinal degeneration, resulting in delineation of many key steps involved in regenerating 11-cis-retinal. Three particularly important reactions are catalyzed by enzymes broadly classified as acyltransferases, short-chain dehydrogenases/reductases and carotenoid/retinoid isomerases/oxygenases. PMID:21447403

CPSF30 at the Interface of Alternative Polyadenylation and Cellular Signaling in Plants

PubMed Central

Chakrabarti, Manohar; Hunt, Arthur G.

2015-01-01

Post-transcriptional processing, involving cleavage of precursor messenger RNA (pre mRNA), and further incorporation of poly(A) tail to the 3' end is a key step in the expression of genetic information. Alternative polyadenylation (APA) serves as an important check point for the regulation of gene expression. Recent studies have shown widespread prevalence of APA in diverse systems. A considerable amount of research has been done in characterizing different subunits of so-called Cleavage and Polyadenylation Specificity Factor (CPSF). In plants, CPSF30, an ortholog of the 30 kD subunit of mammalian CPSF is a key polyadenylation factor. CPSF30 in the model plant Arabidopsis thaliana was reported to possess unique biochemical properties. It was also demonstrated that poly(A) site choice in a vast majority of genes in Arabidopsis are CPSF30 dependent, suggesting a pivotal role of this gene in APA and subsequent regulation of gene expression. There are also indications of this gene being involved in oxidative stress and defense responses and in cellular signaling, suggesting a role of CPSF30 in connecting physiological processes and APA. This review will summarize the biochemical features of CPSF30, its role in regulating APA, and possible links with cellular signaling and stress response modules. PMID:26061761

Voluntary stepping behavior under single- and dual-task conditions in chronic stroke survivors: A comparison between the involved and uninvolved legs.

PubMed

Melzer, Itshak; Goldring, Melissa; Melzer, Yehudit; Green, Elad; Tzedek, Irit

2010-12-01

If balance is lost, quick step execution can prevent falls. Research has shown that speed of voluntary stepping was able to predict future falls in old adults. The aim of the study was to investigate voluntary stepping behavior, as well as to compare timing and leg push-off force-time relation parameters of involved and uninvolved legs in stroke survivors during single- and dual-task conditions. We also aimed to compare timing and leg push-off force-time relation parameters between stroke survivors and healthy individuals in both task conditions. Ten stroke survivors performed a voluntary step execution test with their involved and uninvolved legs under two conditions: while focusing only on the stepping task and while a separate attention-demanding task was performed simultaneously. Temporal parameters related to the step time were measured including the duration of the step initiation phase, the preparatory phase, the swing phase, and the total step time. In addition, force-time parameters representing the push-off power during stepping were calculated from ground reaction data and compared with 10 healthy controls. The involved legs of stroke survivors had a significantly slower stepping time than uninvolved legs due to increased swing phase duration during both single- and dual-task conditions. For dual compared to single task, the stepping time increased significantly due to a significant increase in the duration of step initiation. In general, the force time parameters were significantly different in both legs of stroke survivors as compared to healthy controls, with no significant effect of dual compared with single-task conditions in both groups. The inability of stroke survivors to swing the involved leg quickly may be the most significant factor contributing to the large number of falls to the paretic side. The results suggest that stroke survivors were unable to rapidly produce muscle force in fast actions. This may be the mechanism of delayed execution of a fast step when balance is lost, thus increasing the likelihood of falls in stroke survivors. Copyright © 2010 Elsevier Ltd. All rights reserved.

An Anti-Inflammatory Role of VEGFR2/Src Kinase Inhibitor in Herpes Simplex Virus 1-Induced Immunopathology▿

PubMed Central

Sharma, Shalini; Mulik, Sachin; Kumar, Naveen; Suryawanshi, Amol; Rouse, Barry T.

2011-01-01

Corneal neovascularization represents a key step in the blinding inflammatory stromal keratitis (SK) lesion caused by ocular infection with herpes simplex virus (HSV). In this report, we describe a novel approach for limiting the angiogenesis caused by HSV infection of the mouse eye. We show that topical or systemic administration of the Src kinase inhibitor (TG100572) that inhibits downstream molecules involved in the vascular endothelial growth factor (VEGF) signaling pathway resulted in markedly diminished levels of HSV-induced angiogenesis and significantly reduced the severity of SK lesions. Multiple mechanisms were involved in the inhibitory effects. These included blockade of IL-8/CXCL1 involved in inflammatory cells recruitment that are a source of VEGF, diminished cellular infiltration in the cornea, and reduced proliferation and migration of CD4+ T cells into the corneas. As multiple angiogenic factors (VEGF and basic fibroblast growth factor [bFGF]) play a role in promoting angiogenesis during SK and since Src kinases are involved in signaling by many of them, the use of Src kinase inhibition represents a promising way of limiting the severity of SK lesions the most common cause of infectious blindness in the Western world. PMID:21471229

A highly sensitive and accurate gene expression analysis by sequencing ("bead-seq") for a single cell.

PubMed

Matsunaga, Hiroko; Goto, Mari; Arikawa, Koji; Shirai, Masataka; Tsunoda, Hiroyuki; Huang, Huan; Kambara, Hideki

2015-02-15

Analyses of gene expressions in single cells are important for understanding detailed biological phenomena. Here, a highly sensitive and accurate method by sequencing (called "bead-seq") to obtain a whole gene expression profile for a single cell is proposed. A key feature of the method is to use a complementary DNA (cDNA) library on magnetic beads, which enables adding washing steps to remove residual reagents in a sample preparation process. By adding the washing steps, the next steps can be carried out under the optimal conditions without losing cDNAs. Error sources were carefully evaluated to conclude that the first several steps were the key steps. It is demonstrated that bead-seq is superior to the conventional methods for single-cell gene expression analyses in terms of reproducibility, quantitative accuracy, and biases caused during sample preparation and sequencing processes. Copyright © 2014 Elsevier Inc. All rights reserved.

Convergent evolution of morphogenetic processes in fungi: Role of tetraspanins and NADPH oxidases 2 in plant pathogens and saprobes.

PubMed

Malagnac, Fabienne; Bidard, Frédérique; Lalucque, Hervé; Brun, Sylvain; Lambou, Karine; Lebrun, Marc-Henri; Silar, Philippe

2008-01-01

Convergent evolution of trophic life style and morphological characters are very common in the fungal kingdom. Recently, we have shown that the same molecular machinery containing a tetraspanin and a NADPH oxidase has been recruited in two different fungal species for the same purpose (exiting from a melanized re-enforced cell at a focal weakened point), but at different stages of their development (ascospore germination and appressorium mediated penetration). Although this molecular machinery is required at these key developmental steps, it is also likely involved in specialized cellular functions at other stages of fungal development, as shown here for nutrient acquisition by Podospora anserina.

Educational Video Recording and Editing for The Hand Surgeon

PubMed Central

Rehim, Shady A.; Chung, Kevin C.

2016-01-01

Digital video recordings are increasingly used across various medical and surgical disciplines including hand surgery for documentation of patient care, resident education, scientific presentations and publications. In recent years, the introduction of sophisticated computer hardware and software technology has simplified the process of digital video production and improved means of disseminating large digital data files. However, the creation of high quality surgical video footage requires basic understanding of key technical considerations, together with creativity and sound aesthetic judgment of the videographer. In this article we outline the practical steps involved with equipment preparation, video recording, editing and archiving as well as guidance for the choice of suitable hardware and software equipment. PMID:25911212

Metal Transport across Biomembranes: Emerging Models for a Distinct Chemistry*

PubMed Central

Argüello, José M.; Raimunda, Daniel; González-Guerrero, Manuel

2012-01-01

Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models. PMID:22389499

Metal transport across biomembranes: emerging models for a distinct chemistry.

PubMed

Argüello, José M; Raimunda, Daniel; González-Guerrero, Manuel

2012-04-20

Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models.

Method of producing monolithic ceramic cross-flow filter

DOEpatents

Larsen, D.A.; Bacchi, D.P.; Connors, T.F.; Collins, E.L. III

1998-02-10

Ceramic filter of various configuration have been used to filter particulates from hot gases exhausted from coal-fired systems. Prior ceramic cross-flow filters have been favored over other types, but those previously have been assemblies of parts somehow fastened together and consequently subject often to distortion or delamination on exposure hot gas in normal use. The present new monolithic, seamless, cross-flow ceramic filters, being of one-piece construction, are not prone to such failure. Further, these new products are made by a novel casting process which involves the key steps of demolding the ceramic filter green body so that none of the fragile inner walls of the filter is cracked or broken. 2 figs.

Method of producing monolithic ceramic cross-flow filter

DOEpatents

Larsen, David A.; Bacchi, David P.; Connors, Timothy F.; Collins, III, Edwin L.

1998-01-01

Ceramic filter of various configuration have been used to filter particulates from hot gases exhausted from coal-fired systems. Prior ceramic cross-flow filters have been favored over other types, but those previously horn have been assemblies of parts somehow fastened together and consequently subject often to distortion or delamination on exposure hot gas in normal use. The present new monolithic, seamless, cross-flow ceramic filters, being of one-piece construction, are not prone to such failure. Further, these new products are made by novel casting process which involves the key steps of demolding the ceramic filter green body so that none of the fragile inner walls of the filter is cracked or broken.

A novel and efficient samarium iodide-mediated synthesis of neoflavonoids (4-arycloumarins)

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

Nagasawa, Kazuo; Ryohke, Hirosi; Ohnishi, Makoto

1995-12-31

Bioactive 4-arylcoumarins (4-aryl-2H-1-benzopyran-2-ones) have been recently isolated from the plants belonging to the families like Leguminosae, Guttiferae, and Compositae, some of which are still used as the traditional folk medicine. Despite many methods reported so far, there appears to be of limited success or of no success in some cases (II{sub b-g}) and, therefore, a simpler and more reliable one remains to be highly desired. Thus, a new and sterling protocol is now presented for the synthesis of neoflavonoids, which involves the intramolecular Reformatsky-type reaction via a one electron transfer process with samarium diiodide as a key step.

Protein mass spectra data analysis for clinical biomarker discovery: a global review.

PubMed

Roy, Pascal; Truntzer, Caroline; Maucort-Boulch, Delphine; Jouve, Thomas; Molinari, Nicolas

2011-03-01

The identification of new diagnostic or prognostic biomarkers is one of the main aims of clinical cancer research. In recent years there has been a growing interest in using high throughput technologies for the detection of such biomarkers. In particular, mass spectrometry appears as an exciting tool with great potential. However, to extract any benefit from the massive potential of clinical proteomic studies, appropriate methods, improvement and validation are required. To better understand the key statistical points involved with such studies, this review presents the main data analysis steps of protein mass spectra data analysis, from the pre-processing of the data to the identification and validation of biomarkers.

Refined and Microlocal Kakeya-Nikodym Bounds of Eigenfunctions in Higher Dimensions

NASA Astrophysics Data System (ADS)

Blair, Matthew D.; Sogge, Christopher D.

2017-12-01

We prove a Kakeya-Nikodym bound on eigenfunctions and quasimodes, which sharpens a result of the authors (Blair and Sogge in Anal PDE 8:747-764, 2015) and extends it to higher dimensions. As in the prior work, the key intermediate step is to prove a microlocal version of these estimates, which involves a phase space decomposition of these modes that is essentially invariant under the bicharacteristic/geodesic flow. In a companion paper (Blair and Sogge in J Differ Geom, 2015), it will be seen that these sharpened estimates yield improved L q ( M) bounds on eigenfunctions in the presence of nonpositive curvature when {2 < q < 2(d+1)/d-1}.

Cytochrome P450-mediated metabolism of vitamin D

PubMed Central

Jones, Glenville; Prosser, David E.; Kaufmann, Martin

2014-01-01

The vitamin D signal transduction system involves a series of cytochrome P450-containing sterol hydroxylases to generate and degrade the active hormone, 1α,25-dihydroxyvitamin D3, which serves as a ligand for the vitamin D receptor-mediated transcriptional gene expression described in companion articles in this review series. This review updates our current knowledge of the specific anabolic cytochrome P450s involved in 25- and 1α-hydroxylation, as well as the catabolic cytochrome P450 involved in 24- and 23-hydroxylation steps, which are believed to initiate inactivation of the vitamin D molecule. We focus on the biochemical properties of these enzymes; key residues in their active sites derived from crystal structures and mutagenesis studies; the physiological roles of these enzymes as determined by animal knockout studies and human genetic diseases; and the regulation of these different cytochrome P450s by extracellular ions and peptide modulators. We highlight the importance of these cytochrome P450s in the pathogenesis of kidney disease, metabolic bone disease, and hyperproliferative diseases, such as psoriasis and cancer; as well as explore potential future developments in the field. PMID:23564710

Probing Complex Free-Radical Reaction Pathways of Fuel Model Compounds

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

Buchanan III, A C; Kidder, Michelle; Beste, Ariana

2012-01-01

Fossil (e.g. coal) and renewable (e.g. woody biomass) organic energy resources have received considerable attention as possible sources of liquid transportation fuels and commodity chemicals. Knowledge of the reactivity of these complex materials has been advanced through fundamental studies of organic compounds that model constituent substructures. In particular, an improved understanding of thermochemical reaction pathways involving free-radical intermediates has arisen from detailed experimental kinetic studies and, more recently, advanced computational investigations. In this presentation, we will discuss our recent investigations of the fundamental pyrolysis pathways of model compounds that represent key substructures in the lignin component of woody biomass withmore » a focus on molecules representative of the dominant beta-O-4 aryl ether linkages. Additional mechanistic insights gleaned from DFT calculations on the kinetics of key elementary reaction steps will also be presented, as well as a few thoughts on the significant contributions of Jim Franz to this area of free radical chemistry.« less

Bicarbonate transporters in corals point towards a key step in the evolution of cnidarian calcification.

PubMed

Zoccola, Didier; Ganot, Philippe; Bertucci, Anthony; Caminiti-Segonds, Natacha; Techer, Nathalie; Voolstra, Christian R; Aranda, Manuel; Tambutté, Eric; Allemand, Denis; Casey, Joseph R; Tambutté, Sylvie

2015-06-04

The bicarbonate ion (HCO3(-)) is involved in two major physiological processes in corals, biomineralization and photosynthesis, yet no molecular data on bicarbonate transporters are available. Here, we characterized plasma membrane-type HCO3(-) transporters in the scleractinian coral Stylophora pistillata. Eight solute carrier (SLC) genes were found in the genome: five homologs of mammalian-type SLC4 family members, and three of mammalian-type SLC26 family members. Using relative expression analysis and immunostaining, we analyzed the cellular distribution of these transporters and conducted phylogenetic analyses to determine the extent of conservation among cnidarian model organisms. Our data suggest that the SLC4γ isoform is specific to scleractinian corals and responsible for supplying HCO3(-) to the site of calcification. Taken together, SLC4γ appears to be one of the key genes for skeleton building in corals, which bears profound implications for our understanding of coral biomineralization and the evolution of scleractinian corals within cnidarians.

Integrin Beta 1 Suppresses Multilayering of a Simple Epithelium

PubMed Central

Chen, Jichao; Krasnow, Mark A.

2012-01-01

Epithelia are classified as either simple, a single cell layer thick, or stratified (multilayered). Stratified epithelia arise from simple epithelia during development, and transcription factor p63 functions as a key positive regulator of epidermal stratification. Here we show that deletion of integrin beta 1 (Itgb1) in the developing mouse airway epithelium abrogates airway branching and converts this monolayer epithelium into a multilayer epithelium with more than 10 extra layers. Mutant lung epithelial cells change mitotic spindle orientation to seed outer layers, and cells in different layers become molecularly and functionally distinct, hallmarks of normal stratification. However, mutant lung epithelial cells do not activate p63 and do not switch to the stratified keratin profile of epidermal cells. These data, together with previous data implicating Itgb1 in regulation of epidermal stratification, suggest that the simple-versus-stratified developmental decision may involve not only stratification inducers like p63 but suppressors like Itgb1 that prevent simple epithelia from inappropriately activating key steps in the stratification program. PMID:23285215

Structural aspects of denitrifying enzymes.

PubMed

Moura, I; Moura, J J

2001-04-01

The reduction of nitrate to nitrogen gas via nitrite, nitric oxide and nitrous oxide is the metabolic pathway usually known as denitrification, a key step in the nitrogen cycle. As observed for other elemental cycles, a battery of enzymes are utilized, namely the reductases for nitrate, nitrite, nitric oxide and nitrous oxide, as well as multiple electron donors that interact with these enzymes, in order to carry out the stepwise reactions that involve key intermediates. Because of the importance of this pathway (of parallel importance to the nitrogen-fixation pathway), efforts are underway to understand the structures of the participating enzymes and to uncover mechanistic aspects. Three-dimensional structures have been solved for the majority of these enzymes in the past few years, revealing the architecture of the active metal sites as well as global structural aspects, and possible mechanistic aspects. In addition, the recognition of specific electron-transfer partners raises important questions regarding specific electron-transfer pathways, partner recognition and control of metabolism.

Considerations for sustainable influenza vaccine production in developing countries.

PubMed

Nannei, Claudia; Chadwick, Christopher; Fatima, Hiba; Goldin, Shoshanna; Grubo, Myriam; Ganim, Alexandra

2016-10-26

Through its Global Action Plan for Influenza Vaccines (GAP), the World Health Organization (WHO) in collaboration with the United States Department of Health and Human Services has produced a checklist to support policy-makers and influenza vaccine manufacturers in identifying key technological, political, financial, and logistical issues affecting the sustainability of influenza vaccine production. This checklist highlights actions in five key areas that are beneficial for establishing successful local vaccine manufacturing. These five areas comprise: (1) the policy environment and health-care systems; (2) surveillance systems and influenza evidence; (3) product development and manufacturing; (4) product approval and regulation; and (5) communication to support influenza vaccination. Incorporating the checklist into national vaccine production programmes has identified the policy gaps and next steps for countries involved in GAP's Technology Transfer Initiative. Lessons learnt from country experiences provide context and insight that complement the checklist's goal of simplifying the complexities of influenza prevention, preparedness, and vaccine manufacturing. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Correlation analysis between residual displacement and hip function after reconstruction of acetabular fractures].

PubMed

Ma, Kunlong; Fang, Yue; Luan, Fujun; Tu, Chongqi; Yang, Tianfu

2012-03-01

To investigate the relationships between residual displacement of weight-bearing and non weight-bearing zones (gap displacement and step displacement) and hip function by analyzing the CT images after reconstruction of acetabular fractures. The CT measures and clinical outcome were retrospectively analyzed from 48 patients with displaced acetabular fracture between June 2004 and June 2009. All patients were treated by open reduction and internal fixation, and were followed up 24 to 72 months (mean, 36 months); all fractures healed after operation. The residual displacement involved the weight-bearing zone in 30 cases (weight-bearing group), and involved the non weight-bearing zone in 18 cases (non weight-bearing group). The clinical outcomes were evaluated by Merle d'Aubigné-Postel criteria, and the reduction of articular surface by CT images, including the maximums of two indexes (gap displacement and step displacement). All the data were analyzed in accordance with the Spearman rank correlation coefficient analysis. There was strong negative correlation between the hip function and the residual displacement values in weight-bearing group (r(s) = -0.722, P = 0.001). But there was no correlation between the hip function and the residual displacement values in non weight-bearing group (r(s) = 0.481, P = 0.059). The results of clinical follow-up were similar to the correlation analysis results. In weight-bearing group, the hip function had strong negative correlation with step displacement (r(s) = 0.825, P = 0.002), but it had no correlation with gap displacement (r(s) = 0.577, P = 0.134). In patients with acetabular fracture, the hip function has correlation not only with the extent of the residual displacement but also with the location of the residual displacement, so the residual displacement of weight-bearing zone is a key factor to affect the hip function. In patients with residual displacement in weight-bearing zone, the bigger the step displacement is, the worse the hip function is.

Allosteric activation transitions in enzymes and biomolecular motors: insights from atomistic and coarse-grained simulations.

PubMed

Daily, Michael D; Yu, Haibo; Phillips, George N; Cui, Qiang

2013-01-01

The chemical step in enzymes is usually preceded by a kinetically distinct activation step that involves large-scale conformational transitions. In "simple" enzymes this step corresponds to the closure of the active site; in more complex enzymes, such as biomolecular motors, the activation step is more complex and may involve interactions with other biomolecules. These activation transitions are essential to the function of enzymes and perturbations in the scale and/or rate of these transitions are implicated in various serious human diseases; incorporating key flexibilities into engineered enzymes is also considered a major remaining challenge in rational enzyme design. Therefore it is important to understand the underlying mechanism of these transitions. This is a significant challenge to both experimental and computational studies because of the allosteric and multi-scale nature of such transitions. Using our recent studies of two enzyme systems, myosin and adenylate kinase (AK), we discuss how atomistic and coarse-grained simulations can be used to provide insights into the mechanism of activation transitions in realistic systems. Collectively, the results suggest that although many allosteric transitions can be viewed as domain displacements mediated by flexible hinges, there are additional complexities and various deviations. For example, although our studies do not find any evidence for "cracking" in AK, our results do underline the contribution of intra-domain properties (e.g., dihedral flexibility) to the rate of the transition. The study of mechanochemical coupling in myosin highlights that local changes important to chemistry require stabilization from more extensive structural changes; in this sense, more global structural transitions are needed to activate the chemistry in the active site. These discussions further emphasize the importance of better understanding factors that control the degree of co-operativity for allosteric transitions, again hinting at the intimate connection between protein stability and functional flexibility. Finally, a number of topics of considerable future interest are briefly discussed.

Simulation methods with extended stability for stiff biochemical Kinetics.

PubMed

Rué, Pau; Villà-Freixa, Jordi; Burrage, Kevin

2010-08-11

With increasing computer power, simulating the dynamics of complex systems in chemistry and biology is becoming increasingly routine. The modelling of individual reactions in (bio)chemical systems involves a large number of random events that can be simulated by the stochastic simulation algorithm (SSA). The key quantity is the step size, or waiting time, tau, whose value inversely depends on the size of the propensities of the different channel reactions and which needs to be re-evaluated after every firing event. Such a discrete event simulation may be extremely expensive, in particular for stiff systems where tau can be very short due to the fast kinetics of some of the channel reactions. Several alternative methods have been put forward to increase the integration step size. The so-called tau-leap approach takes a larger step size by allowing all the reactions to fire, from a Poisson or Binomial distribution, within that step. Although the expected value for the different species in the reactive system is maintained with respect to more precise methods, the variance at steady state can suffer from large errors as tau grows. In this paper we extend Poisson tau-leap methods to a general class of Runge-Kutta (RK) tau-leap methods. We show that with the proper selection of the coefficients, the variance of the extended tau-leap can be well-behaved, leading to significantly larger step sizes. The benefit of adapting the extended method to the use of RK frameworks is clear in terms of speed of calculation, as the number of evaluations of the Poisson distribution is still one set per time step, as in the original tau-leap method. The approach paves the way to explore new multiscale methods to simulate (bio)chemical systems.

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa.

PubMed

Hermo, Louis; Pelletier, R-Marc; Cyr, Daniel G; Smith, Charles E

2010-04-01

Spermiogenesis is a long process whereby haploid spermatids derived from the meiotic divisions of spermatocytes undergo metamorphosis into spermatozoa. It is subdivided into distinct steps with 19 being identified in rats, 16 in mouse and 8 in humans. Spermiogenesis extends over 22.7 days in rats and 21.6 days in humans. In this part, we review several key events that take place during the development of spermatids from a structural and functional point of view. During early spermiogenesis, the Golgi apparatus forms the acrosome, a lysosome-like membrane bound organelle involved in fertilization. The endoplasmic reticulum undergoes several topographical and structural modifications including the formation of the radial body and annulate lamellae. The chromatoid body is fully developed and undergoes structural and functional modifications at this time. It is suspected to be involved in RNA storing and processing. The shape of the spermatid head undergoes extensive structural changes that are species-specific, and the nuclear chromatin becomes compacted to accommodate the stream-lined appearance of the sperm head. Microtubules become organized to form a curtain or manchette that associates with spermatids at specific steps of their development. It is involved in maintenance of the sperm head shape and trafficking of proteins in the spermatid cytoplasm. During spermiogenesis, many genes/proteins have been implicated in the diverse dynamic events occurring at this time of development of germ cells and the absence of some of these have been shown to result in subfertility or infertility. Copyright 2009 Wiley-Liss, Inc.

Cryptosystem based on two-step phase-shifting interferometry and the RSA public-key encryption algorithm

NASA Astrophysics Data System (ADS)

Meng, X. F.; Peng, X.; Cai, L. Z.; Li, A. M.; Gao, Z.; Wang, Y. R.

2009-08-01

A hybrid cryptosystem is proposed, in which one image is encrypted to two interferograms with the aid of double random-phase encoding (DRPE) and two-step phase-shifting interferometry (2-PSI), then three pairs of public-private keys are utilized to encode and decode the session keys (geometrical parameters, the second random-phase mask) and interferograms. In the stage of decryption, the ciphered image can be decrypted by wavefront reconstruction, inverse Fresnel diffraction, and real amplitude normalization. This approach can successfully solve the problem of key management and dispatch, resulting in increased security strength. The feasibility of the proposed cryptosystem and its robustness against some types of attack are verified and analyzed by computer simulations.

Collaborative Behavioral Management for Drug-Involved Parolees: Rationale and Design of the Step'n Out Study

ERIC Educational Resources Information Center

Friedmann, Peter D.; Katz, Elizabeth C.; Rhodes, Anne G.; Taxman, Faye S.; O'Connell, Daniel J.; Frisman, Linda K.; Burdon, William M.; Fletcher, Bennett W.; Litt, Mark D.; Clarke, Jennifer; Martin, Steven S.

2008-01-01

This article describes the rationale, study design, and implementation for the Step'n Out study of the Criminal Justice Drug Abuse Treatment Studies. Step'n Out tests the relative effectiveness of collaborative behavioral management of drug-involved parolees. Collaborative behavioral management integrates the roles of parole officers and treatment…

The Arabidopsis transcription factor AtTCP15 regulates endoreduplication by modulating expression of key cell-cycle genes.

PubMed

Li, Zi-Yu; Li, Bin; Dong, Ai-Wu

2012-01-01

Plant cells frequently undergo endoreduplication, a modified cell cycle in which genome is repeatedly replicated without cytokinesis. As the key step to achieve final size and function for cells, endoreduplication is prevalent during plant development. However, mechanisms to control the balance between endoreduplication and mitotic cell division are still poorly understood. Here, we show that the Arabidopsis TCP (CINCINNATA-like TEOSINTE BRANCHED1-CYCLOIDEA-PCF)-family transcription factor gene AtTCP15 is expressed in trichomes, as well as in rapidly dividing and vascular tissues. Expression of AtTCP15SRDX, AtTCP15 fused with a SRDX repressor domain, induces extra endoreduplication in trichomes and cotyledon cells in transgenic Arabidopsis. On the contrary, overexpression of AtTCP15 suppresses endoreduplication in trichomes and other examined cells. Misregulation of AtTCP15 affects the expression of several important genes involved in cell-cycle regulation. AtTCP15 protein binds directly to the promoter regions of CYCA2;3 and RETINOBLASTOMA-RELATED (RBR) genes, which play key roles in endoreduplication. Taken together, AtTCP15 plays an important role in regulating endoreduplication during Arabidopsis development.

Overcoming the rate-distance limit of quantum key distribution without quantum repeaters.

PubMed

Lucamarini, M; Yuan, Z L; Dynes, J F; Shields, A J

2018-05-01

Quantum key distribution (QKD) 1,2 allows two distant parties to share encryption keys with security based on physical laws. Experimentally, QKD has been implemented via optical means, achieving key rates of 1.26 megabits per second over 50 kilometres of standard optical fibre 3 and of 1.16 bits per hour over 404 kilometres of ultralow-loss fibre in a measurement-device-independent configuration 4 . Increasing the bit rate and range of QKD is a formidable, but important, challenge. A related target, which is currently considered to be unfeasible without quantum repeaters 5-7 , is overcoming the fundamental rate-distance limit of QKD 8 . This limit defines the maximum possible secret key rate that two parties can distil at a given distance using QKD and is quantified by the secret-key capacity of the quantum channel 9 that connects the parties. Here we introduce an alternative scheme for QKD whereby pairs of phase-randomized optical fields are first generated at two distant locations and then combined at a central measuring station. Fields imparted with the same random phase are 'twins' and can be used to distil a quantum key. The key rate of this twin-field QKD exhibits the same dependence on distance as does a quantum repeater, scaling with the square-root of the channel transmittance, irrespective of who (malicious or otherwise) is in control of the measuring station. However, unlike schemes that involve quantum repeaters, ours is feasible with current technology and presents manageable levels of noise even on 550 kilometres of standard optical fibre. This scheme is a promising step towards overcoming the rate-distance limit of QKD and greatly extending the range of secure quantum communications.

Step-by-step mechanism of DNA damage recognition by human 8-oxoguanine DNA glycosylase.

PubMed

Kuznetsova, Alexandra A; Kuznetsov, Nikita A; Ishchenko, Alexander A; Saparbaev, Murat K; Fedorova, Olga S

2014-01-01

Extensive structural studies of human DNA glycosylase hOGG1 have revealed essential conformational changes of the enzyme. However, at present there is little information about the time scale of the rearrangements of the protein structure as well as the dynamic behavior of individual amino acids. Using pre-steady-state kinetic analysis with Trp and 2-aminopurine fluorescence detection the conformational dynamics of hOGG1 wild-type (WT) and mutants Y203W, Y203A, H270W, F45W, F319W and K249Q as well as DNA-substrates was examined. The roles of catalytically important amino acids F45, Y203, K249, H270, and F319 in the hOGG1 enzymatic pathway and their involvement in the step-by-step mechanism of oxidative DNA lesion recognition and catalysis were elucidated. The results show that Tyr-203 participates in the initial steps of the lesion site recognition. The interaction of the His-270 residue with the oxoG base plays a key role in the insertion of the damaged base into the active site. Lys-249 participates not only in the catalytic stages but also in the processes of local duplex distortion and flipping out of the oxoG residue. Non-damaged DNA does not form a stable complex with hOGG1, although a complex with a flipped out guanine base can be formed transiently. The kinetic data obtained in this study significantly improves our understanding of the molecular mechanism of lesion recognition by hOGG1. © 2013.

Collaborative Behavioral Management for Drug-Involved Parolees: Rationale and Design of the Step'n Out Study

PubMed Central

FRIEDMANN, PETER D.; KATZ, ELIZABETH C.; RHODES, ANNE G.; TAXMAN, FAYE S.; O'CONNELL, DANIEL J.; FRISMAN, LINDA K.; BURDON, WILLIAM M.; FLETCHER, BENNETT W.; LITT, MARK D.; CLARKE, JENNIFER; MARTIN, STEVEN S.

2009-01-01

This article describes the rationale, study design, and implementation for the Step'n Out study of the Criminal Justice Drug Abuse Treatment Studies. Step'n Out tests the relative effectiveness of collaborative behavioral management of drug-involved parolees. Collaborative behavioral management integrates the roles of parole officers and treatment counselors to provide role induction counseling, contract for pro-social behavior, and deliver contingent reinforcement of behaviors consistent with treatment objectives. The Step'n Out study will randomize 450 drug-involved parolees to collaborative behavioral management or usual parole. Follow-up at 3-and 9-months will assess primary outcomes of rearrest, crime and drug use. If collaborative behavioral management is effective, its wider adoption could improve the outcomes of community reentry of drug-involved ex-offenders. PMID:19809591

Method for exponentiating in cryptographic systems

DOEpatents

Brickell, Ernest F.; Gordon, Daniel M.; McCurley, Kevin S.

1994-01-01

An improved cryptographic method utilizing exponentiation is provided which has the advantage of reducing the number of multiplications required to determine the legitimacy of a message or user. The basic method comprises the steps of selecting a key from a preapproved group of integer keys g; exponentiating the key by an integer value e, where e represents a digital signature, to generate a value g.sup.e ; transmitting the value g.sup.e to a remote facility by a communications network; receiving the value g.sup.e at the remote facility; and verifying the digital signature as originating from the legitimate user. The exponentiating step comprises the steps of initializing a plurality of memory locations with a plurality of values g.sup.xi ; computi The United States Government has rights in this invention pursuant to Contract No. DE-AC04-76DP00789 between the Department of Energy and AT&T Company.

Some Key Factors in Policy Implementation.

ERIC Educational Resources Information Center

Rowen, Henry

Business policy texts identify numerous steps that make up the policy implementation process for private firms. On the surface, these steps also appear applicable to the implementation of public policies. However, the problems of carrying out these implementing steps in the public sector are significantly different than in the private sector due…

Determinants of 12-step group affiliation and moderators of the affiliation-abstinence relationship.

PubMed

Timko, Christine; Billow, Rachel; DeBenedetti, Anna

2006-06-28

This study examined characteristics of substance use disorder (SUD) outpatients at intake to treatment (N=345) that were associated with more 12-step group attendance and involvement, Steps worked, and acceptance of 12-step philosophy at a 6-month follow-up (N=281, 81.4%). Patient characteristics covered the domains of sociodemographics, SUD severity, personal functioning, and previous help received. Distinguishing baseline characteristics of patients who attended more 12-step group meetings during follow-up were being less-educated, more engaged in religious practices, and more extroverted and interpersonally competent, and having had more previous 12-step group exposure. These patient characteristics were generally similar to those associated with more 12-step meeting involvement and philosophy acceptance. More 12-step meeting attendance and involvement were related to abstinence at 6 months. Associations of attendance with abstinence were stronger among patients who were younger, white, less-educated, unstably employed, less religious, and less interpersonally skilled. These patients may have had fewer available social resources and so benefitted more from the fellowship and support for abstinence that 12-step group members often provide. We suggest methods by which treatment providers may encourage 12-step group affiliation among patients likely to benefit from it on substance use outcomes.

Oxidative and Nitrosative Stress in the Metastatic Microenvironment

PubMed Central

Ortega, Ángel L.; Mena, Salvador; Estrela, José M.

2010-01-01

Metastases that are resistant to conventional therapies are the main cause of most cancer-related deaths in humans. Tumor cell heterogeneity, which associates with genomic and phenotypic instability, represents a major problem for cancer therapy. Additional factors, such as the attack of immune cells or organ-specific microenvironments, also influence metastatic cell behavior and the response to therapy. Interaction of cancer and endothelial cells in capillary beds, involving mechanical contact and transient adhesion, is a critical step in the initiation of metastasis. This interaction initiates a cascade of activation pathways that involves cytokines, growth factors, bioactive lipids and reactive oxygen and nitrogen species (ROS and RNS) produced by either the cancer cell or the endothelium. Vascular endothelium-derived NO and H2O2 are cytotoxic for the cancer cells, but also help to identify some critical molecular targets that appear essential for survival of invasive metastatic cell subsets. Surviving cancer cells that extravasate and start colonization of an organ or tissue can still be attacked by macrophages and be influenced by specific intraorgan microenvironment conditions. At all steps; from the primary tumor until colonization of a distant organ; metastatic cells undergo a dynamic process of constant adaptations that may lead to the survival of highly resistant malignant cell subsets. In this sequence of molecular events both ROS and RNS play key roles. PMID:24281071

Comparing the energy landscapes for native folding and aggregation of PrP

PubMed Central

Dee, Derek R.; Woodside, Michael T.

2016-01-01

ABSTRACT Protein sequences are evolved to encode generally one folded structure, out of a nearly infinite array of possible folds. Underlying this code is a funneled free energy landscape that guides folding to the native conformation. Protein misfolding and aggregation are also a manifestation of free-energy landscapes. The detailed mechanisms of these processes are poorly understood, but often involve rare, transient species and a variety of different pathways. The inherent complexity of misfolding has hampered efforts to measure aggregation pathways and the underlying energy landscape, especially using traditional methods where ensemble averaging obscures important rare and transient events. We recently studied the misfolding and aggregation of prion protein by examining 2 monomers tethered in close proximity as a dimer, showing how the steps leading to the formation of a stable aggregated state can be resolved in the single-molecule limit and the underlying energy landscape thereby reconstructed. This approach allows a more quantitative comparison of native folding versus misfolding, including fundamental differences in the dynamics for misfolding. By identifying key steps and interactions leading to misfolding, it should help to identify potential drug targets. Here we describe the importance of characterizing free-energy landscapes for aggregation and the challenges involved in doing so, and we discuss how single-molecule studies can help test proposed structural models for PrP aggregates. PMID:27191683

(-)-Menthol biosynthesis and molecular genetics

NASA Astrophysics Data System (ADS)

Croteau, Rodney B.; Davis, Edward M.; Ringer, Kerry L.; Wildung, Mark R.

2005-12-01

(-)-Menthol is the most familiar of the monoterpenes as both a pure natural product and as the principal and characteristic constituent of the essential oil of peppermint ( Mentha x piperita). In this paper, we review the biosynthesis and molecular genetics of (-)-menthol production in peppermint. In Mentha species, essential oil biosynthesis and storage is restricted to the peltate glandular trichomes (oil glands) on the aerial surfaces of the plant. A mechanical method for the isolation of metabolically functional oil glands, has provided a system for precursor feeding studies to elucidate pathway steps, as well as a highly enriched source of the relevant biosynthetic enzymes and of their corresponding transcripts with which cDNA libraries have been constructed to permit cloning and characterization of key structural genes. The biosynthesis of (-)-menthol from primary metabolism requires eight enzymatic steps, and involves the formation and subsequent cyclization of the universal monoterpene precursor geranyl diphosphate to the parent olefin (-)-(4 S)-limonene as the first committed reaction of the sequence. Following hydroxylation at C3, a series of four redox transformations and an isomerization occur in a general “allylic oxidation-conjugate reduction” scheme that installs three chiral centers on the substituted cyclohexanoid ring to yield (-)-(1 R, 3 R, 4 S)-menthol. The properties of each enzyme and gene of menthol biosynthesis are described, as are their probable evolutionary origins in primary metabolism. The organization of menthol biosynthesis is complex in involving four subcellular compartments, and regulation of the pathway appears to reside largely at the level of gene expression. Genetic engineering to up-regulate a flux-limiting step and down-regulate a side route reaction has led to improvement in the composition and yield of peppermint oil.

Processing and properties of carbon nanofibers reinforced epoxy powder composites

NASA Astrophysics Data System (ADS)

Palencia, C.; Mazo, M. A.; Nistal, A.; Rubio, F.; Rubio, J.; Oteo, J. L.

2011-11-01

Commercially available CNFs (diameter 30-300 nm) have been used to develop both bulk and coating epoxy nanocomposites by using a solvent-free epoxy matrix powder. Processing of both types of materials has been carried out by a double-step process consisting in an initial physical premix of all components followed by three consecutive extrusions. The extruded pellets were grinded into powder and sieved. Carbon nanofibers powder coatings were obtained by electrostatic painting of the extruded powder followed by a curing process based in a thermal treatment at 200 °C for 25 min. On the other hand, for obtaining bulk carbon nanofibers epoxy composites, a thermal curing process involving several steps was needed. Gloss and mechanical properties of both nanocomposite coatings and bulk nanocomposites were improved as a result of the processing process. FE-SEM fracture surface microphotographs corroborate these results. It has been assessed the key role played by the dispersion of CNFs in the matrix, and the highly important step that is the processing and curing of the nanocomposites. A processing stage consisted in three consecutive extrusions has reached to nanocomposites free of entanglements neither agglomerates. This process leads to nanocomposite coatings of enhanced properties, as it has been evidenced through gloss and mechanical properties. A dispersion limit of 1% has been determined for the studied system in which a given dispersion has been achieved, as the bending mechanical properties have been increased around 25% compared with the pristine epoxy resin. It has been also demonstrated the importance of the thickness in the nanocomposite, as it involves the curing stage. The complex curing treatment carried out in the case of bulk nanocomposites has reached to reagglomeration of CNFs.

Business Modeling to Implement an eHealth Portal for Infection Control: A Reflection on Co-Creation With Stakeholders.

PubMed

van Limburg, Maarten; Wentzel, Jobke; Sanderman, Robbert; van Gemert-Pijnen, Lisette

2015-08-13

It is acknowledged that the success and uptake of eHealth improve with the involvement of users and stakeholders to make technology reflect their needs. Involving stakeholders in implementation research is thus a crucial element in developing eHealth technology. Business modeling is an approach to guide implementation research for eHealth. Stakeholders are involved in business modeling by identifying relevant stakeholders, conducting value co-creation dialogs, and co-creating a business model. Because implementation activities are often underestimated as a crucial step while developing eHealth, comprehensive and applicable approaches geared toward business modeling in eHealth are scarce. This paper demonstrates the potential of several stakeholder-oriented analysis methods and their practical application was demonstrated using Infectionmanager as an example case. In this paper, we aim to demonstrate how business modeling, with the focus on stakeholder involvement, is used to co-create an eHealth implementation. We divided business modeling in 4 main research steps. As part of stakeholder identification, we performed literature scans, expert recommendations, and snowball sampling (Step 1). For stakeholder analyzes, we performed "basic stakeholder analysis," stakeholder salience, and ranking/analytic hierarchy process (Step 2). For value co-creation dialogs, we performed a process analysis and stakeholder interviews based on the business model canvas (Step 3). Finally, for business model generation, we combined all findings into the business model canvas (Step 4). Based on the applied methods, we synthesized a step-by-step guide for business modeling with stakeholder-oriented analysis methods that we consider suitable for implementing eHealth. The step-by-step guide for business modeling with stakeholder involvement enables eHealth researchers to apply a systematic and multidisciplinary, co-creative approach for implementing eHealth. Business modeling becomes an active part in the entire development process of eHealth and starts an early focus on implementation, in which stakeholders help to co-create the basis necessary for a satisfying success and uptake of the eHealth technology.

Mutations in Four Glycosyl Hydrolases Reveal a Highly Coordinated Pathway for Rhodopsin Biosynthesis and N-Glycan Trimming in Drosophila melanogaster

PubMed Central

Rosenbaum, Erica E.; Vasiljevic, Eva; Brehm, Kimberley S.; Colley, Nansi Jo

2014-01-01

As newly synthesized glycoproteins move through the secretory pathway, the asparagine-linked glycan (N-glycan) undergoes extensive modifications involving the sequential removal and addition of sugar residues. These modifications are critical for the proper assembly, quality control and transport of glycoproteins during biosynthesis. The importance of N-glycosylation is illustrated by a growing list of diseases that result from defects in the biosynthesis and processing of N-linked glycans. The major rhodopsin in Drosophila melanogaster photoreceptors, Rh1, is highly unique among glycoproteins, as the N-glycan appears to be completely removed during Rh1 biosynthesis and maturation. However, much of the deglycosylation pathway for Rh1 remains unknown. To elucidate the key steps in Rh1 deglycosylation in vivo, we characterized mutant alleles of four Drosophila glycosyl hydrolases, namely α-mannosidase-II (α-Man-II), α-mannosidase-IIb (α-Man-IIb), a β-N-acetylglucosaminidase called fused lobes (Fdl), and hexosaminidase 1 (Hexo1). We have demonstrated that these four enzymes play essential and unique roles in a highly coordinated pathway for oligosaccharide trimming during Rh1 biosynthesis. Our results reveal that α-Man-II and α-Man-IIb are not isozymes like their mammalian counterparts, but rather function at distinct stages in Rh1 maturation. Also of significance, our results indicate that Hexo1 has a biosynthetic role in N-glycan processing during Rh1 maturation. This is unexpected given that in humans, the hexosaminidases are typically lysosomal enzymes involved in N-glycan catabolism with no known roles in protein biosynthesis. Here, we present a genetic dissection of glycoprotein processing in Drosophila and unveil key steps in N-glycan trimming during Rh1 biosynthesis. Taken together, our results provide fundamental advances towards understanding the complex and highly regulated pathway of N-glycosylation in vivo and reveal novel insights into the functions of glycosyl hydrolases in the secretory pathway. PMID:24785692

AgMIP: Next Generation Models and Assessments

NASA Astrophysics Data System (ADS)

Rosenzweig, C.

2014-12-01

Next steps in developing next-generation crop models fall into several categories: significant improvements in simulation of important crop processes and responses to stress; extension from simplified crop models to complex cropping systems models; and scaling up from site-based models to landscape, national, continental, and global scales. Crop processes that require major leaps in understanding and simulation in order to narrow uncertainties around how crops will respond to changing atmospheric conditions include genetics; carbon, temperature, water, and nitrogen; ozone; and nutrition. The field of crop modeling has been built on a single crop-by-crop approach. It is now time to create a new paradigm, moving from 'crop' to 'cropping system.' A first step is to set up the simulation technology so that modelers can rapidly incorporate multiple crops within fields, and multiple crops over time. Then the response of these more complex cropping systems can be tested under different sustainable intensification management strategies utilizing the updated simulation environments. Model improvements for diseases, pests, and weeds include developing process-based models for important diseases, frameworks for coupling air-borne diseases to crop models, gathering significantly more data on crop impacts, and enabling the evaluation of pest management strategies. Most smallholder farming in the world involves integrated crop-livestock systems that cannot be represented by crop modeling alone. Thus, next-generation cropping system models need to include key linkages to livestock. Livestock linkages to be incorporated include growth and productivity models for grasslands and rangelands as well as the usual annual crops. There are several approaches for scaling up, including use of gridded models and development of simpler quasi-empirical models for landscape-scale analysis. On the assessment side, AgMIP is leading a community process for coordinated contributions to IPCC AR6 that involves the key modeling groups from around the world including North America, Europe, South America, Sub-Saharan Africa, South Asia, East Asia, and Australia and Oceania. This community process will lead to mutually agreed protocols for coordinated global and regional assessments.

Stereoselective Total Synthesis of (±)-5- epi-Cyanthiwigin I via an Intramolecular Pauson-Khand Reaction as the Key Step.

PubMed

Chang, Yuanyuan; Shi, Linlin; Huang, Jun; Shi, Lili; Zhang, Zichun; Hao, Hong-Dong; Gong, Jianxian; Yang, Zhen

2018-05-09

A convenient approach to the construction of the 5-6-7 tricarbocyclic fused core structure of cyanthiwigins via a Co-mediated Pauson-Khand reaction as a key step has been developed. The cyathane core intermediate obtained by this strategy was used in the concise synthesis of (±)-5- epi-cyanthiwigin I. The developed chemistry paves the way for the total synthesis of structurally diverse cyanthiwigins.

Tracking problem solving by multivariate pattern analysis and Hidden Markov Model algorithms.

PubMed

Anderson, John R

2012-03-01

Multivariate pattern analysis can be combined with Hidden Markov Model algorithms to track the second-by-second thinking as people solve complex problems. Two applications of this methodology are illustrated with a data set taken from children as they interacted with an intelligent tutoring system for algebra. The first "mind reading" application involves using fMRI activity to track what students are doing as they solve a sequence of algebra problems. The methodology achieves considerable accuracy at determining both what problem-solving step the students are taking and whether they are performing that step correctly. The second "model discovery" application involves using statistical model evaluation to determine how many substates are involved in performing a step of algebraic problem solving. This research indicates that different steps involve different numbers of substates and these substates are associated with different fluency in algebra problem solving. Copyright © 2011 Elsevier Ltd. All rights reserved.

KEEPING A STEP AHEAD - FORMATIVE PHASE OF A WORKPLACE INTERVENTION TRIAL TO PREVENT OBESITY

PubMed Central

Zapka, Jane; Lemon, Stephenie C.; Estabrook, Barbara B.; Jolicoeur, Denise G.

2008-01-01

Background Ecological interventions hold promise for promoting overweight and obesity prevention in worksites. Given the paucity of evaluative research in the hospital worksite setting, considerable formative work is required for successful implementation and evaluation. Purpose This paper describes the formative phases of Step Ahead, a site-randomized controlled trial of a multi-level intervention that promotes physical activity and healthy eating in 6 hospitals in central Massachusetts. The purpose of the formative research phase was to increase the feasibility, effectiveness and likelihood of sustainability of the intervention. Design and Procedures The Step Ahead ecological intervention approach targets change at the organization, the interpersonal work environment and the individual levels. The intervention was developed using fundamental steps of intervention mapping and important tenets of participatory research. Formative research methods were used to engage leadership support and assistance and to develop an intervention plan that is both theoretically and practically grounded. This report uses observational data, program minutes and reports, and process tracking data. Developmental Strategies and Observations Leadership involvement (key informant interviews and advisory boards), employee focus groups and advisory boards, and quantitative environmental assessments cultivated participation and support. Determining multiple foci of change and designing measurable objectives and generic assessment tools to document progress are complex challenges encountered in planning phases. Lessons Learned Multi-level trials in diverse organizations require flexibility and balance of theory application and practice-based perspectives to affect impact and outcome objectives. Formative research is an essential component. PMID:18073339

Skeletal muscle plasticity induced by seasonal acclimatization in carp involves differential expression of rRNA and molecules that epigenetically regulate its synthesis.

PubMed

Fuentes, Eduardo N; Zuloaga, Rodrigo; Nardocci, Gino; Fernandez de la Reguera, Catalina; Simonet, Nicolas; Fumeron, Robinson; Valdes, Juan Antonio; Molina, Alfredo; Alvarez, Marco

2014-01-01

Ribosomal biogenesis controls cellular growth in living organisms, with the rate-limiting step of this process being the transcription of ribosomal DNA (rDNA). Considering that epigenetic mechanisms allow an organism to respond to environmental changes, the expression in muscle of several molecules that regulate epigenetic rRNA synthesis, as well as rDNA transcription, were evaluated during the seasonal acclimatization of the carp. First, the nucleotide sequences encoding the components forming the NoRC (ttf-I, tip5) and eNoSC (sirt1, nml, suv39h1), two chromatin remodeling complexes that silence rRNA synthesis, as well as the sequence of ubf1, a key regulator of rDNA transcription, were obtained. Subsequently the transcriptional regulation of the aforementioned molecules, and other key molecules involved in rRNA synthesis (mh2a1, mh2a2, h2a.z, h2a.z.7, nuc, p80), was assessed. The carp sequences for TTF-I, TIP5, SIRT1, NML, SUV39H1, and UBF1 showed a high conservation of domains and key amino acids in comparison with other fish and higher vertebrates. The mRNA contents in muscle for ttf-I, tip5, sirt1, nml, suv39h1, mh2a1, mh2a.z, and nuc were up-regulated during winter in comparison with summer, whereas the mRNA levels of mh2a2, ubf1, and p80 were down-regulated. Also, the contents of molecules involved in processing the rRNA (snoRNAs) and pRNA, a stabilizer of NoRC complex, were analyzed, finding that these non-coding RNAs were not affected by seasonal acclimatization. These results suggest that variations in the expression of rRNA and the molecules that epigenetically regulate its synthesis are contributing to the muscle plasticity induced by seasonal acclimatization in carp. Copyright © 2014 Elsevier Inc. All rights reserved.

Osteopontin-c mediates the upregulation of androgen responsive genes in LNCaP cells through PI3K/Akt and androgen receptor signaling.

PubMed

Tilli, Tatiana Martins; Ferreira, Luciana Bueno; Gimba, Etel Rodrigues Pereira

2015-04-01

Androgen receptor (AR) signaling is a key pathway modulating prostate cancer (PCa) progression. Several steps in this pathway have been investigated in order to propose novel treatment strategies for advanced PCa. Total osteopontin (OPN) has been described as a biomarker for PCa, in addition to its role in activating the progression of this tumor. Based on the known effects of the OPNc splice variant on PCa progression, the present study investigated whether this isoform can also modulate AR signaling. In order to test this, an in vitro model was used in which LNCaP cells were cultured in the presence of conditioned medium (CM) secreted by PCa cells overexpressing OPNc (OPNc-CM). The activation of AR signaling was evaluated by measuring the expression levels of AR-responsive genes (ARGs) using quantitative polymerase chain reaction and specific oligonucleotides. The data demonstrated that all nine tested ARGs ( Fgf8 , TMPRSS2 , Greb1 , Cdk2 , Ndrg1 , Cdk1 , Pmepa1 , Psa and Ar ) are significantly upregulated in response to OPNc-CM compared with LNCaP cells cultured in CM secreted by control cells transfected with empty expression vector. The specific involvement of OPNc was demonstrated by depleting OPNc from OPNc-CM using an anti-OPNc neutralizing antibody. In addition, by using a phosphoinositide 3-kinase (PI3K)-specific inhibitor and AR antagonists, such as flutamide and bicalutamide, it was also observed that upregulation of ARGs in response to OPNc-CM involves PI3K signaling and depends on the AR. In conclusion, these data indicated that OPNc is able to activate AR signaling through the PI3K pathway and the AR. These data further corroborate our previous data, revealing the OPNc splice variant to be a key molecule that is able to modulate key signaling pathways involved in PCa progression.

Osteopontin-c mediates the upregulation of androgen responsive genes in LNCaP cells through PI3K/Akt and androgen receptor signaling

PubMed Central

TILLI, TATIANA MARTINS; FERREIRA, LUCIANA BUENO; GIMBA, ETEL RODRIGUES PEREIRA

2015-01-01

Androgen receptor (AR) signaling is a key pathway modulating prostate cancer (PCa) progression. Several steps in this pathway have been investigated in order to propose novel treatment strategies for advanced PCa. Total osteopontin (OPN) has been described as a biomarker for PCa, in addition to its role in activating the progression of this tumor. Based on the known effects of the OPNc splice variant on PCa progression, the present study investigated whether this isoform can also modulate AR signaling. In order to test this, an in vitro model was used in which LNCaP cells were cultured in the presence of conditioned medium (CM) secreted by PCa cells overexpressing OPNc (OPNc-CM). The activation of AR signaling was evaluated by measuring the expression levels of AR-responsive genes (ARGs) using quantitative polymerase chain reaction and specific oligonucleotides. The data demonstrated that all nine tested ARGs (Fgf8, TMPRSS2, Greb1, Cdk2, Ndrg1, Cdk1, Pmepa1, Psa and Ar) are significantly upregulated in response to OPNc-CM compared with LNCaP cells cultured in CM secreted by control cells transfected with empty expression vector. The specific involvement of OPNc was demonstrated by depleting OPNc from OPNc-CM using an anti-OPNc neutralizing antibody. In addition, by using a phosphoinositide 3-kinase (PI3K)-specific inhibitor and AR antagonists, such as flutamide and bicalutamide, it was also observed that upregulation of ARGs in response to OPNc-CM involves PI3K signaling and depends on the AR. In conclusion, these data indicated that OPNc is able to activate AR signaling through the PI3K pathway and the AR. These data further corroborate our previous data, revealing the OPNc splice variant to be a key molecule that is able to modulate key signaling pathways involved in PCa progression. PMID:25789054

Stannous Fluoride Effects on Gene Expression of Streptococcus mutans and Actinomyces viscosus.

PubMed

Shi, Y; Li, R; White, D J; Biesbrock, A R

2018-02-01

A genome-wide transcriptional analysis was performed to elucidate the bacterial cellular response of Streptococcus mutans and Actinomyces viscosus to NaF and SnF 2 . The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of SnF 2 were predetermined before microarray study. Gene expression profiling microarray experiments were carried out in the absence (control) and presence (experimental) of 10 ppm and 100 ppm Sn 2+ (in the form of SnF 2 ) and fluoride controls for 10-min exposures (4 biological replicates/treatment). These Sn 2+ levels and treatment time were chosen because they have been shown to slow bacterial growth of S. mutans (10 ppm) and A. viscosus (100 ppm) without affecting cell viability. All data generated by microarray experiments were analyzed with bioinformatics tools by applying the following criteria: 1) a q value should be ≤0.05, and 2) an absolute fold change in transcript level should be ≥1.5. Microarray results showed SnF 2 significantly inhibited several genes encoding enzymes of the galactose pathway upon a 10-min exposure versus a negative control: lacA and lacB (A and B subunits of the galactose-6-P isomerase), lacC (tagatose-6-P kinase), lacD (tagatose-1,6-bP adolase), galK (galactokinase), galT (galactose-1-phosphate uridylyltransferase), and galE (UDP-glucose 4-epimerase). A gene fruK encoding fructose-1-phosphate kinase in the fructose pathway was also significantly inhibited. Several genes encoding fructose/mannose-specific enzyme IIABC components in the phosphotransferase system (PTS) were also downregulated, as was ldh encoding lactate dehydrogenase, a key enzyme involved in lactic acid synthesis. SnF 2 downregulated the transcription of most key enzyme genes involved in the galactose pathway and also suppressed several key genes involved in the PTS, which transports sugars into the cell in the first step of glycolysis.

12-step affiliation and attendance following treatment for comorbid substance dependence and depression: a latent growth curve mediation model.

PubMed

Worley, Matthew J; Tate, Susan R; McQuaid, John R; Granholm, Eric L; Brown, Sandra A

2013-01-01

Among substance-dependent individuals, comorbid major depressive disorder (MDD) is associated with greater severity and poorer treatment outcomes, but little research has examined mediators of posttreatment substance use outcomes within this population. Using latent growth curve models, the authors tested relationships between individual rates of change in 12-step involvement and substance use, utilizing posttreatment follow-up data from a trial of group Twelve-Step Facilitation (TSF) and integrated cognitive-behavioral therapy (ICBT) for veterans with substance dependence and MDD. Although TSF patients were higher on 12-step affiliation and meeting attendance at end-of-treatment as compared with ICBT, they also experienced significantly greater reductions in these variables during the year following treatment, ending at similar levels as ICBT. Veterans in TSF also had significantly greater increases in drinking frequency during follow-up, and this group difference was mediated by their greater reductions in 12-step affiliation and meeting attendance. Patients with comorbid depression appear to have difficulty sustaining high levels of 12-step involvement after the conclusion of formal 12-step interventions, which predicts poorer drinking outcomes over time. Modifications to TSF and other formal 12-step protocols or continued therapeutic contact may be necessary to sustain 12-step involvement and reduced drinking for patients with substance dependence and MDD.

Response of a rice paddy soil methanogen to syntrophic growth as revealed by transcriptional analyses.

PubMed

Liu, Pengfei; Yang, Yanxiang; Lü, Zhe; Lu, Yahai

2014-08-01

Members of Methanocellales are widespread in paddy field soils and play the key role in methane production. These methanogens feature largely in these organisms’ adaptation to low H2 and syntrophic growth with anaerobic fatty acid oxidizers. The adaptive mechanisms, however, remain unknown. In the present study, we determined the transcripts of 21 genes involved in the key steps of methanogenesis and acetate assimilation of Methanocella conradii HZ254, a strain recently isolated from paddy field soil. M. conradii was grown in monoculture and syntrophically with Pelotomaculum thermopropionicum (a propionate syntroph) or Syntrophothermus lipocalidus (a butyrate syntroph). Comparison of the relative transcript abundances showed that three hydrogenase-encoding genes and all methanogenesis-related genes tested were upregulated in cocultures relative to monoculture. The genes encoding formylmethanofuran dehydrogenase (Fwd), heterodisulfide reductase (Hdr), and the membrane-bound energy-converting hydrogenase (Ech) were the most upregulated among the evaluated genes. The expression of the formate dehydrogenase (Fdh)-encoding gene also was significantly upregulated. In contrast, an acetate assimilation gene was downregulated in cocultures. The genes coding for Fwd, Hdr, and the D subunit of F420-nonreducing hydrogenase (Mvh) form a large predicted transcription unit; therefore, the Mvh/Hdr/Fwd complex, capable of mediating the electron bifurcation and connecting the first and last steps of methanogenesis, was predicted to be formed in M. conradii. We propose that Methanocella methanogens cope with low H2 and syntrophic growth by (i) stabilizing the Mvh/Hdr/Fwd complex and (ii) activating formatedependent methanogenesis.

Involving Practicing Scientists in K-12 Science Teacher Professional Development

NASA Astrophysics Data System (ADS)

Bertram, K. B.

2011-12-01

The Science Teacher Education Program (STEP) offered a unique framework for creating professional development courses focused on Arctic research from 2006-2009. Under the STEP framework, science, technology, engineering, and math (STEM) training was delivered by teams of practicing Arctic researchers in partnership with master teachers with 20+ years experience teaching STEM content in K-12 classrooms. Courses based on the framework were offered to educators across Alaska. STEP offered in-person summer-intensive institutes and follow-on audio-conferenced field-test courses during the academic year, supplemented by online scientist mentorship for teachers. During STEP courses, teams of scientists offered in-depth STEM content instruction at the graduate level for teachers of all grade levels. STEP graduate-level training culminated in the translation of information and data learned from Arctic scientists into standard-aligned lessons designed for immediate use in K-12 classrooms. This presentation will focus on research that explored the question: To what degree was scientist involvement beneficial to teacher training and to what degree was STEP scientist involvement beneficial to scientist instructors? Data sources reveal consistently high levels of ongoing (4 year) scientist and teacher participation; high STEM content learning outcomes for teachers; high STEM content learning outcomes for students; high ratings of STEP courses by scientists and teachers; and a discussion of the reasons scientists indicate they benefited from STEP involvement. Analyses of open-ended comments by teachers and scientists support and clarify these findings. A grounded theory approach was used to analyze teacher and scientist qualitative feedback. Comments were coded and patterns analyzed in three databases. The vast majority of teacher open-ended comments indicate that STEP involvement improved K-12 STEM classroom instruction, and the vast majority of scientist open-ended comments focus on the benefits scientists received from networking with K-12 teachers. The classroom lessons resulting from STEP have been so popular among teachers, the Alaska Department of Education and Early Development recently contracted with the PI to create a website that will make the STEP database open to teachers across Alaska. When the Alaska Department of Education and Early Development launched the new website in August 2011, the name of the STEP program was changed to the Alaska K-12 Science Curricular Initiative (AKSCI). The STEP courses serving as the foundation to the new AKSCI site are located under the "History" tab of the new website.

Antisense targeting of 3' end elements involved in DUX4 mRNA processing is an efficient therapeutic strategy for facioscapulohumeral dystrophy: a new gene-silencing approach.

PubMed

Marsollier, Anne-Charlotte; Ciszewski, Lukasz; Mariot, Virginie; Popplewell, Linda; Voit, Thomas; Dickson, George; Dumonceaux, Julie

2016-04-15

Defects in mRNA 3'end formation have been described to alter transcription termination, transport of the mRNA from the nucleus to the cytoplasm, stability of the mRNA and translation efficiency. Therefore, inhibition of polyadenylation may lead to gene silencing. Here, we choose facioscapulohumeral dystrophy (FSHD) as a model to determine whether or not targeting key 3' end elements involved in mRNA processing using antisense oligonucleotide drugs can be used as a strategy for gene silencing within a potentially therapeutic context. FSHD is a gain-of-function disease characterized by the aberrant expression of the Double homeobox 4 (DUX4) transcription factor leading to altered pathogenic deregulation of multiple genes in muscles. Here, we demonstrate that targeting either the mRNA polyadenylation signal and/or cleavage site is an efficient strategy to down-regulate DUX4 expression and to decrease the abnormally high-pathological expression of genes downstream of DUX4. We conclude that targeting key functional 3' end elements involved in pre-mRNA to mRNA maturation with antisense drugs can lead to efficient gene silencing and is thus a potentially effective therapeutic strategy for at least FSHD. Moreover, polyadenylation is a crucial step in the maturation of almost all eukaryotic mRNAs, and thus all mRNAs are virtually eligible for this antisense-mediated knockdown strategy. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part II: Background to a research strategy.

PubMed

Bragge, P; Piccenna, L; Middleton, J; Williams, S; Creasey, G; Dunlop, S; Brown, D; Gruen, R

2015-10-01

Literature review/semi-structured interviews. To develop a spinal cord injury (SCI) research strategy for Australia and New Zealand. Australia. The National Trauma Research Institute Forum approach of structured evidence review and stakeholder consultation was employed. This involved gathering from published literature and stakeholder consultation the information necessary to properly consider the challenge, and synthesising this into a briefing document. A research strategy 'roadmap' was developed to define the major steps and key planning questions to consider; next, evidence from published SCI research strategy initiatives was synthesised with information from four one-on-one semi-structured interviews with key SCI research stakeholders to create a research strategy framework, articulating six key themes and associated activities for consideration. These resources, combined with a review of SCI prioritisation literature, were used to generate a list of draft principles for discussion in a structured stakeholder dialogue meeting. The research strategy roadmap and framework informed discussion at a structured stakeholder dialogue meeting of 23 participants representing key SCI research constituencies, results of which are published in a companion paper. These resources could also be of value in other research strategy or planning exercises. This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand Spinal Cord Injury Network.

NADPH-generating systems in bacteria and archaea

PubMed Central

Spaans, Sebastiaan K.; Weusthuis, Ruud A.; van der Oost, John; Kengen, Servé W. M.

2015-01-01

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms. It provides the reducing power that drives numerous anabolic reactions, including those responsible for the biosynthesis of all major cell components and many products in biotechnology. The efficient synthesis of many of these products, however, is limited by the rate of NADPH regeneration. Hence, a thorough understanding of the reactions involved in the generation of NADPH is required to increase its turnover through rational strain improvement. Traditionally, the main engineering targets for increasing NADPH availability have included the dehydrogenase reactions of the oxidative pentose phosphate pathway and the isocitrate dehydrogenase step of the tricarboxylic acid (TCA) cycle. However, the importance of alternative NADPH-generating reactions has recently become evident. In the current review, the major canonical and non-canonical reactions involved in the production and regeneration of NADPH in prokaryotes are described, and their key enzymes are discussed. In addition, an overview of how different enzymes have been applied to increase NADPH availability and thereby enhance productivity is provided. PMID:26284036

Experimental and computational fluid dynamic studies of mixing for complex oral health products

NASA Astrophysics Data System (ADS)

Garcia, Marti Cortada; Mazzei, Luca; Angeli, Panagiota

2015-11-01

Mixing high viscous non-Newtonian fluids is common in the consumer health industry. Sometimes this process is empirical and involves many pilot plants trials which are product specific. The first step to study the mixing process is to build on knowledge on the rheology of the fluids involved. In this research a systematic approach is used to validate the rheology of two liquids: glycerol and a gel formed by polyethylene glycol and carbopol. Initially, the constitutive equation is determined which relates the viscosity of the fluids with temperature, shear rate, and concentration. The key variable for the validation is the power required for mixing, which can be obtained both from CFD and experimentally using a stirred tank and impeller of well-defined geometries at different impeller speeds. A good agreement between the two values indicates a successful validation of the rheology and allows the CFD model to be used for the study of mixing in the complex vessel geometries and increased sizes encountered during scale up.

Increasing minority enrollment utilizing dental admissions workshop strategies.

PubMed

Price, Shelia S; Crout, Richard J; Mitchell, Dennis A; Brunson, W David; Wearden, Stanley

2008-11-01

Oral Health in America, the landmark U.S. surgeon general's report, inextricably connects oral health disparities with poor access to oral care by vulnerable populations. Furthermore, the report associates an insufficiently diverse dental workforce with oral health disparities among some minority groups. Successful strategies to curtail oral health disparities and remedy work-force issues require collaboration among all involved in dental education. As gatekeepers to dental programs, admissions committees are significant stakeholders in diversifying the dental workforce. The purpose of this article is to demonstrate that a workshop on diversity in admissions can modify the perceptions of individuals involved in the student recruitment and admissions processes and lead to increased matriculation of underrepresented minority students. Emerging from the workshop were key concepts and action steps for promoting a holistic review of dental applicants. Results since implementing the workshop recommendations have been positive, with underrepresented minority dental student acceptances increasing sixfold. The workshop was cosponsored by the Robert Wood Johnson Foundation and facilitated by two nationally recognized dental educators.

Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy.

PubMed

Yamamoto, Guilherme L; Baratela, Wagner A R; Almeida, Tatiana F; Lazar, Monize; Afonso, Clara L; Oyamada, Maria K; Suzuki, Lisa; Oliveira, Luiz A N; Ramos, Ester S; Kim, Chong A; Passos-Bueno, Maria Rita; Bertola, Débora R

2014-01-02

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Carbon dioxide hydrogenation on Ni(110).

PubMed

Vesselli, Erik; De Rogatis, Loredana; Ding, Xunlei; Baraldi, Alessandro; Savio, Letizia; Vattuone, Luca; Rocca, Mario; Fornasiero, Paolo; Peressi, Maria; Baldereschi, Alfonso; Rosei, Renzo; Comelli, Giovanni

2008-08-27

We demonstrate that the key step for the reaction of CO 2 with hydrogen on Ni(110) is a change of the activated molecule coordination to the metal surface. At 90 K, CO 2 is negatively charged and chemically bonded via the carbon atom. When the temperature is increased and H approaches, the H-CO 2 complex flips and binds to the surface through the two oxygen atoms, while H binds to the carbon atom, thus yielding formate. We provide the atomic-level description of this process by means of conventional ultrahigh vacuum surface science techniques combined with density functional theory calculations and corroborated by high pressure reactivity tests. Knowledge about the details of the mechanisms involved in this reaction can yield a deeper comprehension of heterogeneous catalytic organic synthesis processes involving carbon dioxide as a reactant. We show why on Ni the CO 2 hydrogenation barrier is remarkably smaller than that on the common Cu metal-based catalyst. Our results provide a possible interpretation of the observed high catalytic activity of NiCu alloys.

Culture models of human mammary epithelial cell transformation

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

Stampfer, Martha R.; Yaswen, Paul

2000-11-10

Human pre-malignant breast diseases, particularly ductal carcinoma in situ (DCIS)3 already display several of the aberrant phenotypes found in primary breast cancers, including chromosomal abnormalities, telomerase activity, inactivation of the p53 gene and overexpression of some oncogenes. Efforts to model early breast carcinogenesis in human cell cultures have largely involved studies in vitro transformation of normal finite lifespan human mammary epithelial cells (HMEC) to immortality and malignancy. We present a model of HMEC immortal transformation consistent with the know in vivo data. This model includes a recently described, presumably epigenetic process, termed conversion, which occurs in cells that have overcomemore » stringent replicative senescence and are thus able to maintain proliferation with critically short telomeres. The conversion process involves reactivation of telomerase activity, and acquisition of good uniform growth in the absence and presence of TFGB. We propose th at overcoming the proliferative constraints set by senescence, and undergoing conversion, represent key rate-limiting steps in human breast carcinogenesis, and occur during early stage breast cancer progression.« less

A functional network involved in the recycling of nucleocytoplasmic pre-60S factors

PubMed Central

Lebreton, Alice; Saveanu, Cosmin; Decourty, Laurence; Rain, Jean-Christophe; Jacquier, Alain; Fromont-Racine, Micheline

2006-01-01

Eukaryotic pre-ribosomes go through cytoplasmic maturation steps before entering translation. The nucleocytoplasmic proteins participating in these late stages of maturation are reimported to the nucleus. In this study, we describe a functional network focused on Rei1/Ybr267w, a strictly cytoplasmic pre-60S factor indirectly involved in nuclear 27S pre-ribosomal RNA processing. In the absence of Rei1, the nuclear import of at least three other pre-60S factors is impaired. The accumulation in the cytoplasm of a small complex formed by the association of Arx1 with a novel factor, Alb1/Yjl122w, inhibits the release of the putative antiassociation factor Tif6 from the premature large ribosomal subunits and its recycling to the nucleus. We propose a model in which Rei1 is a key factor for the coordinated dissociation and recycling of the last pre-60S factors before newly synthesized large ribosomal subunits enter translation. PMID:16651379

Clinical Oncology Society of Australia position statement on the use of complementary and alternative medicine by cancer patients.

PubMed

Braun, Lesley; Harris, Jessica; Katris, Paul; Cain, Michael; Dhillon, Haryana; Koczwara, Bogda; Olver, Ian; Robotin, Monica

2014-12-01

Health professionals involved in the clinical management of cancer are becoming increasingly aware that their patients use complementary and alternative medicine (CAM). As cancer incidence and survival rates increase, use of CAM is also likely to increase. This paper outlines the position of the Clinical Oncology Society of Australia (COSA) on the use of CAM by cancer patients and provides guidance for health professionals involved with the treatment of cancer patients who are using or wish to use CAM. Key definitions and common communication scenarios are presented along with evidence-based recommended steps for health professionals when discussing CAM use. COSA encourages health professionals to focus on open discussion with their patients regarding CAM, to become familiar with reputable resources for CAM information, to discuss with patients the concept of evidence-based medicine, to recognize limitations to their knowledge of CAM and seek further advice when necessary, and to be respectful of the patients' right to autonomy. © 2014 Wiley Publishing Asia Pty Ltd.

Electride support boosts nitrogen dissociation over ruthenium catalyst and shifts the bottleneck in ammonia synthesis

DOE PAGES

Kitano, Masaaki; Kanbara, Shinji; Inoue, Yasunori; ...

2015-03-30

We actively sough novel approaches to efficient ammonia synthesis at an ambient pressure so as to reduce the cost of ammonia production and to allow for compact production facilities. It is accepted that the key is the development of a high-performance catalyst that significantly enhances dissociation of the nitrogen-nitrogen triple bond, which is generally considered a rate-determining step. Here we examine the kinetics of nitrogen and hydrogen isotope exchange and hydrogen adsorption/desorption reactions for a recently discovered efficient catalyst for ammonia synthesis --ruthenium-loaded 12CaO∙7AI 2O 3 electride (Ru/C12A7:more » $$\\bar{e}$$ )--and find that the rate controlling step of ammonia synthesis over Ru/C12A7:$$\\bar{e}$$ is not dissociation of the nitrogen-nitrogen triple bond but the subsequent formation of N-H n species. A mechanism of ammonia synthesis involving reversible storage and release of hydrogen atoms on the Ru/C12A7:$$\\bar{e}$$ surface is proposed on the basis of observed hydrogen adsorption/desorption kinetics.« less

Electride support boosts nitrogen dissociation over ruthenium catalyst and shifts the bottleneck in ammonia synthesis

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

Kitano, Masaaki; Kanbara, Shinji; Inoue, Yasunori

We actively sough novel approaches to efficient ammonia synthesis at an ambient pressure so as to reduce the cost of ammonia production and to allow for compact production facilities. It is accepted that the key is the development of a high-performance catalyst that significantly enhances dissociation of the nitrogen-nitrogen triple bond, which is generally considered a rate-determining step. Here we examine the kinetics of nitrogen and hydrogen isotope exchange and hydrogen adsorption/desorption reactions for a recently discovered efficient catalyst for ammonia synthesis --ruthenium-loaded 12CaO∙7AI 2O 3 electride (Ru/C12A7:more » $$\\bar{e}$$ )--and find that the rate controlling step of ammonia synthesis over Ru/C12A7:$$\\bar{e}$$ is not dissociation of the nitrogen-nitrogen triple bond but the subsequent formation of N-H n species. A mechanism of ammonia synthesis involving reversible storage and release of hydrogen atoms on the Ru/C12A7:$$\\bar{e}$$ surface is proposed on the basis of observed hydrogen adsorption/desorption kinetics.« less

Oxidative desulfurization-fluorination of thioethers. Application for the synthesis of fluorinated nitrogen containing building blocks.

PubMed

Hugenberg, Verena; Fröhlich, Roland; Haufe, Günter

2010-12-21

An oxidative desulfurization-fluorination protocol has been used to synthesize (2S)-2-(difluoromethyl)-N-tosylpyrrolidine (6a) and (2S)-2-(trifluoromethyl)-N-tosylpyrrolidine (7a) from the (2S)-prolinol-derived (2S)-2-(4-chlorophenylthiomethyl)-N-tosylpyrrolidine (9) or (2S)-2-(dithian-2-yl)-N-tosylpyrrolidine (5). Efforts to prepare 3,3-difluoroalanine similarly from an N-protected S-aryl-cysteine ester 17 gave only traces of the target compound 18. Instead, an unique N-(α,α-difluorobenzyl)-N-α',α'-dibromoglycine ester 19 was formed by an unprecedented sequence of reaction steps. A plausible mechanism is suggested involving a sulfur-assisted deoxygenation-difluorination of an imino oxygen and a haloform reaction like carbon-carbon bond fission as key-steps. Efforts to prepare (2S)-2-(fluoromethyl)-N-tosylpyrrolidine (12) from (2S)-N-tosylprolinol (3) by treatment with Fluolead™ (1-tert-butyl-4-trifluorosulfanyl-3,5-dimethylbenzene) gave only 5% of the target compound, but 95% of (3R)-3-fluoro-N-tosylpiperidine (11a) by ring enlargement.

Legislation and refusal of blood transfusion by a minor Jehovah-Witness in Belgium.

PubMed

Deneyer, M; Matthys, D; Ramet, J; Michel, L; Holsters, D; Vandenplas, Y

2011-01-01

The refusal of blood transfusion by Jehovah's Witnesses in critical situations constitutes an ethical and juridical dilemma. The refusal to receive blood products by Jehovah's Witnesses is based on biblical verses. Recurring arguments to sustain this refusal regard the right to self-determination and the right to freedom of faith. If minors are involved, the problem is rendered even more difficult as the parental authority over young children needs to be taken into account. When adolescents are concerned, the situation if even more ambiguous since adolescents might be considered as mature enough to provide autonomous consent. On the basis of three cases, the most frequent bottlenecks that can come up in paediatric emergency services are highlighted: (1) the refusal of a blood transfusion by the parents of a young child; (2) the refusal by an adolescent and (3) prior refusal based on a "No Blood"-document. Regarding minors, the law on patients' rights in Belgium contains safety mechanisms concerning the preservation of physical integrity. Therefore, a key responsibility has been assigned to the physician. A step-by-step plan and a synoptic diagram are presented.

Coexpression of β-D-galactosidase and L-arabinose isomerase in the production of D-tagatose: a functional sweetener.

PubMed

Zhan, Yijing; Xu, Zheng; Li, Sha; Liu, Xiaoliu; Xu, Lu; Feng, Xiaohai; Xu, Hong

2014-03-19

The functional sweetener, d-tagatose, is commonly transformed from galactose by l-arabinose isomerase. To make use of a much cheaper starting material, lactose, hydrolization, and isomerization are required to take place collaboratively. Therefore, a single-step method involving β-d-galactosidase was explored for d-tagatose production. The two vital genes, β-d-galactosidase gene (lacZ) and l-arabinose isomerase mutant gene (araA') were extracted separately from Escherichia coli strains and incorporated into E. coli simultaneously. This gave us E. coli-ZY, a recombinant producing strain capable of coexpressing the two key enzymes. The resulted cells exhibited maximum d-tagatose producing activity at 34 °C and pH 6.5 and in the presence of borate, 10 mM Fe(2+), and 1 mM Mn(2+). Further monitoring showed that the recombinant cells could hydrolyze more than 95% lactose and convert 43% d-galactose into d-tagatose. This research has verified the feasibility of single-step d-tagatose fermentation, thereby laying down the foundation for industrial usage of lactose.

Actin and Endocytosis in Budding Yeast

PubMed Central

Goode, Bruce L.; Eskin, Julian A.; Wendland, Beverly

2015-01-01

Endocytosis, the process whereby the plasma membrane invaginates to form vesicles, is essential for bringing many substances into the cell and for membrane turnover. The mechanism driving clathrin-mediated endocytosis (CME) involves > 50 different protein components assembling at a single location on the plasma membrane in a temporally ordered and hierarchal pathway. These proteins perform precisely choreographed steps that promote receptor recognition and clustering, membrane remodeling, and force-generating actin-filament assembly and turnover to drive membrane invagination and vesicle scission. Many critical aspects of the CME mechanism are conserved from yeast to mammals and were first elucidated in yeast, demonstrating that it is a powerful system for studying endocytosis. In this review, we describe our current mechanistic understanding of each step in the process of yeast CME, and the essential roles played by actin polymerization at these sites, while providing a historical perspective of how the landscape has changed since the preceding version of the YeastBook was published 17 years ago (1997). Finally, we discuss the key unresolved issues and where future studies might be headed. PMID:25657349

Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl and Methyl (S)-3-(Oxiran-2-yl)propanoates from Renewable Levoglucosenone: An Access to Enantiopure (S)-Dairy Lactone.

PubMed

Peru, Aurélien A M; Flourat, Amandine L; Gunawan, Christian; Raverty, Warwick; Jevric, Martyn; Greatrex, Ben W; Allais, Florent

2016-07-29

Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S)-1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo-enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3-(oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value-added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO.

A statistical approach to optimizing concrete mixture design.

PubMed

Ahmad, Shamsad; Alghamdi, Saeid A

2014-01-01

A step-by-step statistical approach is proposed to obtain optimum proportioning of concrete mixtures using the data obtained through a statistically planned experimental program. The utility of the proposed approach for optimizing the design of concrete mixture is illustrated considering a typical case in which trial mixtures were considered according to a full factorial experiment design involving three factors and their three levels (3(3)). A total of 27 concrete mixtures with three replicates (81 specimens) were considered by varying the levels of key factors affecting compressive strength of concrete, namely, water/cementitious materials ratio (0.38, 0.43, and 0.48), cementitious materials content (350, 375, and 400 kg/m(3)), and fine/total aggregate ratio (0.35, 0.40, and 0.45). The experimental data were utilized to carry out analysis of variance (ANOVA) and to develop a polynomial regression model for compressive strength in terms of the three design factors considered in this study. The developed statistical model was used to show how optimization of concrete mixtures can be carried out with different possible options.

A Statistical Approach to Optimizing Concrete Mixture Design

PubMed Central

Alghamdi, Saeid A.

2014-01-01

A step-by-step statistical approach is proposed to obtain optimum proportioning of concrete mixtures using the data obtained through a statistically planned experimental program. The utility of the proposed approach for optimizing the design of concrete mixture is illustrated considering a typical case in which trial mixtures were considered according to a full factorial experiment design involving three factors and their three levels (33). A total of 27 concrete mixtures with three replicates (81 specimens) were considered by varying the levels of key factors affecting compressive strength of concrete, namely, water/cementitious materials ratio (0.38, 0.43, and 0.48), cementitious materials content (350, 375, and 400 kg/m3), and fine/total aggregate ratio (0.35, 0.40, and 0.45). The experimental data were utilized to carry out analysis of variance (ANOVA) and to develop a polynomial regression model for compressive strength in terms of the three design factors considered in this study. The developed statistical model was used to show how optimization of concrete mixtures can be carried out with different possible options. PMID:24688405

Key process parameters involved in the treatment of olive mill wastewater by membrane bioreactor.

PubMed

Jaouad, Y; Villain-Gambier, M; Mandi, L; Marrot, B; Ouazzani, N

2018-04-18

The Olive Mill Wastewater (OMWW) biodegradation in an external ceramic membrane bioreactor (MBR) was investigated with a starting acclimation step with a Ultrafiltration (UF) membrane (150 kDa) and no sludge discharge in order to develop a specific biomass adapted to OMWW biodegradation. After acclimation step, UF was replaced by an Microfiltration (MF) membrane (0.1 µm). Sludge Retention Time (SRT) was set around 25 days and Food to Microorganisms ratio (F/M) was fixed at 0.2 kg COD  kg MLVSS -1  d -1 . At stable state, removal of the main phenolic compounds (hydroxytyrosol and tyrosol) and Chemical Oxygen Demand (COD) were successfully reached (95% both). Considered as a predominant fouling factor, but never quantified in MBR treated OMWW, Soluble Microbial Products (SMP) proteins, polysaccharides and humic substances concentrations were determined (80, 110 and 360 mg L -1 respectively). At the same time, fouling was easily managed due to favourable hydraulic conditions of external ceramic MBR. Therefore, OMWW could be efficiently and durably treated by an MF MBR process under adapted operating parameters.

Undertaking clinical audit, with reference to a Prescribing Observatory for Mental Health audit of lithium monitoring.

PubMed

Paton, Carol; Barnes, Thomas R E

2014-06-01

Audit is an important tool for quality improvement. The collection of data on clinical performance against evidence-based and clinically relevant standards, which are considered by clinicians to be realistic in routine practice, can usefully prompt reflective practice and the implementation of change. Evidence of participation in clinical audit is required to achieve intended learning outcomes for trainees in psychiatry and revalidation for those who are members of the Royal College of Psychiatrists. This article addresses some of the practical steps involved in conducting an audit project, and, to illustrate key points, draws on lessons learnt from a national, audit-based, quality improvement programme of lithium prescribing and monitoring conducted through the Prescribing Observatory for Mental Health.

Extreme-Scale De Novo Genome Assembly

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

Georganas, Evangelos; Hofmeyr, Steven; Egan, Rob

De novo whole genome assembly reconstructs genomic sequence from short, overlapping, and potentially erroneous DNA segments and is one of the most important computations in modern genomics. This work presents HipMER, a high-quality end-to-end de novo assembler designed for extreme scale analysis, via efficient parallelization of the Meraculous code. Genome assembly software has many components, each of which stresses different components of a computer system. This chapter explains the computational challenges involved in each step of the HipMer pipeline, the key distributed data structures, and communication costs in detail. We present performance results of assembling the human genome and themore » large hexaploid wheat genome on large supercomputers up to tens of thousands of cores.« less

Total Synthesis and Biological Evaluation of 22-Hydroxyacuminatine

PubMed Central

Xiao, Xiangshu; Antony, Smitha; Pommier, Yves; Cushman, Mark

2008-01-01

A total synthesis of 22-hydroxyacuminatine, a cytotoxic alkaloid isolated from Camptotheca acuminata, is reported. The key step in the synthesis involves the reaction of 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline with a brominated phthalide to generate a substituted pentacyclic 12H-5,11a-diazadibenzo[b,h]fluoren-11-one intermediate. Despite its structural resemblance to camptothecin and luotonin A, a biological evaluation of 22-hydroxyacuminatine in a topoisomerase I-deficient cell line P388/CPT45 has confirmed that the observed cytotoxicity is not due to topoisomerase I inhibition. This result is consistent with the hypothesis that π-π stacking is more important than hydrogen bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex. PMID:16480276

Mass Spectrometry: A Technique of Many Faces

PubMed Central

Olshina, Maya A.; Sharon, Michal

2016-01-01

Protein complexes form the critical foundation for a wide range of biological process, however understanding the intricate details of their activities is often challenging. In this review we describe how mass spectrometry plays a key role in the analysis of protein assemblies and the cellular pathways which they are involved in. Specifically, we discuss how the versatility of mass spectrometric approaches provides unprecedented information on multiple levels. We demonstrate this on the ubiquitin-proteasome proteolytic pathway, a process that is responsible for protein turnover. We follow the various steps of this degradation route and illustrate the different mass spectrometry workflows that were applied for elucidating molecular information. Overall, this review aims to stimulate the integrated use of multiple mass spectrometry approaches for analyzing complex biological systems. PMID:28100928

Separation of actinides from lanthanides utilizing molten salt electrorefining

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

Grimmett, D.L.; Fusselman, S.P.; Roy, J.J.

1996-10-01

TRUMP-S (TRansUranic Management through Pyropartitioning Separation) is a pyrochemical process being developed to separate actinides form fission products in nuclear waste. A key process step involving molten salt electrorefining to separate actinides from lanthanides has been studied on a laboratory scale. Electrorefining of U, Np, Pu, Am, and lanthanide mixtures from molten cadmium at 450 C to a solid cathode utilizing a molten chloride electrolyte resulted in > 99% removal of actinides from the molten cadmium and salt phases. Removal of the last few percent of actinides is accompanied by lowered cathodic current efficiency and some lanthanide codeposition. Actinide/lanthanide separationmore » ratios on the cathode are ordered U > Np > Pu > Am and are consistent with predictions based on equilibrium potentials.« less

Fast and calibration free determination of first order reaction kinetics in API synthesis using in-situ ATR-FTIR.

PubMed

Rehbein, Moritz C; Husmann, Sascha; Lechner, Christian; Kunick, Conrad; Scholl, Stephan

2018-05-01

In early stages of drug development only sparse amounts of the key substances are available, which is problematic for the determination of important process data like reaction kinetics. Therefore, it is important to perform experiments as economically as possible, especially in regards to limiting compounds. Here we demonstrate the use of a temperature step experiment enabling the determination of complete reaction kinetics in a single non-isothermal experiment. In contrast to the traditionally used HPLC, the method takes advantage of the high measuring rate and the low amount of labor involved in using in-situ ATR-FTIR to determine time-dependent concentration-equivalent data. Copyright © 2017 Elsevier B.V. All rights reserved.

Total synthesis and biological activity of the proposed structure of phaeosphaeride A.

PubMed

Chatzimpaloglou, Anthoula; Yavropoulou, Maria P; Rooij, Karien E; Biedermann, Ralf; Mueller, Uwe; Kaskel, Stefan; Sarli, Vasiliki

2012-11-02

The total synthesis of the structure assigned to the natural product phaeosphaeride A 1a was accomplished. The key steps involve the addition of vinyllithium reagent 7 to the acetonide-protected aldehyde 8 to access the carbon backbone of 1a, the introduction of the methoxylamino group followed by intramolecular hetero-Michael cyclization, and methanol elimination to form the dihydropyran ring. In this study, both enantiomers of 1a were synthesized and tested for biological activity. Preliminary results showed that (6R,7R,8R)-1a and (6S,7S,8S)-1a inhibit STAT3-dependent transcriptional activity in a dose-dependent manner and exhibit antiproliferative properties in breast (MDA-MB-231) and pancreatic (PANC-1) cancer cells.

High-Throughput Method of Whole-Brain Sectioning, Using the Tape-Transfer Technique.

PubMed

Pinskiy, Vadim; Jones, Jamie; Tolpygo, Alexander S; Franciotti, Neil; Weber, Kevin; Mitra, Partha P

2015-01-01

Cryostat sectioning is a popular but labor-intensive method for preparing histological brain sections. We have developed a modification of the commercially available CryoJane tape collection method that significantly improves the ease of collection and the final quality of the tissue sections. The key modification involves an array of UVLEDs to achieve uniform polymerization of the glass slide and robust adhesion between the section and slide. This report presents system components and detailed procedural steps, and provides examples of end results; that is, 20 μm mouse brain sections that have been successfully processed for routine Nissl, myelin staining, DAB histochemistry, and fluorescence. The method is also suitable for larger brains, such as rat and monkey.

High-Throughput Method of Whole-Brain Sectioning, Using the Tape-Transfer Technique

PubMed Central

Pinskiy, Vadim; Jones, Jamie; Tolpygo, Alexander S.; Franciotti, Neil; Weber, Kevin; Mitra, Partha P.

2015-01-01

Cryostat sectioning is a popular but labor-intensive method for preparing histological brain sections. We have developed a modification of the commercially available CryoJane tape collection method that significantly improves the ease of collection and the final quality of the tissue sections. The key modification involves an array of UVLEDs to achieve uniform polymerization of the glass slide and robust adhesion between the section and slide. This report presents system components and detailed procedural steps, and provides examples of end results; that is, 20μm mouse brain sections that have been successfully processed for routine Nissl, myelin staining, DAB histochemistry, and fluorescence. The method is also suitable for larger brains, such as rat and monkey. PMID:26181725

Wood formation in Angiosperms.

PubMed

Déjardin, Annabelle; Laurans, Françoise; Arnaud, Dominique; Breton, Christian; Pilate, Gilles; Leplé, Jean-Charles

2010-04-01

Wood formation is a complex biological process, involving five major developmental steps, including (1) cell division from a secondary meristem called the vascular cambium, (2) cell expansion (cell elongation and radial enlargement), (3) secondary cell wall deposition, (4) programmed cell death, and (5) heartwood formation. Thanks to the development of genomic studies in woody species, as well as genetic engineering, recent progress has been made in the understanding of the molecular mechanisms underlying wood formation. In this review, we will focus on two different aspects, the lignification process and the control of microfibril angle in the cell wall of wood fibres, as they are both key features of wood material properties. Copyright (c) 2010 Académie des sciences. Published by Elsevier SAS. All rights reserved.

Design and Processing of a Novel Chaos-Based Stepped Frequency Synthesized Wideband Radar Signal.

PubMed

Zeng, Tao; Chang, Shaoqiang; Fan, Huayu; Liu, Quanhua

2018-03-26

The linear stepped frequency and linear frequency shift keying (FSK) signal has been widely used in radar systems. However, such linear modulation signals suffer from the range-Doppler coupling that degrades radar multi-target resolution. Moreover, the fixed frequency-hopping or frequency-coded sequence can be easily predicted by the interception receiver in the electronic countermeasures (ECM) environments, which limits radar anti-jamming performance. In addition, the single FSK modulation reduces the radar low probability of intercept (LPI) performance, for it cannot achieve a large time-bandwidth product. To solve such problems, we propose a novel chaos-based stepped frequency (CSF) synthesized wideband signal in this paper. The signal introduces chaotic frequency hopping between the coherent stepped frequency pulses, and adopts a chaotic frequency shift keying (CFSK) and phase shift keying (PSK) composited coded modulation in a subpulse, called CSF-CFSK/PSK. Correspondingly, the processing method for the signal has been proposed. According to our theoretical analyses and the simulations, the proposed signal and processing method achieve better multi-target resolution and LPI performance. Furthermore, flexible modulation is able to increase the robustness against identification of the interception receiver and improve the anti-jamming performance of the radar.

Planning a graduate programme in public health nutrition for experienced nutrition professionals.

PubMed

Fox, Ann; Beyers, Joanne

2011-08-01

Public health renewal in Canada has highlighted the need for development and expansion of the public health nutrition workforce, particularly in northern and rural communities. The purpose of the present paper is to describe the planning of a more accessible graduate programme for experienced nutrition professionals. The planning effort was challenged by a short timeframe between programme approval and implementation and required intense collaboration with stakeholders and students. The programme planning model developed by The Health Communication Unit (THCU) at the Centre for Health Promotion was used to guide the process. This six-step model was familiar to key stakeholders and involved pre-planning, conducting a situational assessment, establishing goals and objectives, developing strategies and outcome indicators, and monitoring feedback. Resource constraints, short timelines and debates around distance education options presented challenges that were overcome by conducting a thorough needs assessment, creating an advisory committee, engaging key stakeholders in the planning process, and building on existing resources. Extensive involvement of the first cohort of students in ongoing planning and evaluation was particularly helpful in informing the evolution of the programme. The THCU planning model provided a useful framework for stakeholder collaboration and for planning and implementing the new graduate programme in public health nutrition. Preliminary data suggest that graduates are benefiting from their educational experiences through career enhancement opportunities. The evaluation strategies built into the programme design will be useful in informing ongoing programme development.

Deciphering the Structural Requirements of Nucleoside Bisubstrate Analogues for Inhibition of MbtA in Mycobacterium tuberculosis: A FB-QSAR Study and Combinatorial Library Generation for Identifying Potential Hits.

PubMed

Maganti, Lakshmi; Das, Sanjit Kumar; Mascarenhas, Nahren Manuel; Ghoshal, Nanda

2011-10-01

The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade. Inhibitors of aryl acid adenylating enzyme known as MbtA, involved in siderophore biosynthesis in Mycobacterium tuberculosis, are being explored as potential antitubercular agents. The ability to identify fragments that interact with a biological target is a key step in fragment based drug design (FBDD). To expand the boundaries of quantitative structure activity relationship (QSAR) paradigm, we have proposed a Fragment Based QSAR methodology, referred here in as FB-QSAR, for deciphering the structural requirements of a series of nucleoside bisubstrate analogs for inhibition of MbtA, a key enzyme involved in siderophore biosynthetic pathway. For the development of FB-QSAR models, statistical techniques such as stepwise multiple linear regression (SMLR), genetic function approximation (GFA) and GFAspline were used. The predictive ability of the generated models was validated using different statistical metrics, and similarity-based coverage estimation was carried out to define applicability boundaries. To aid the creation of novel antituberculosis compounds, a bioisosteric database was enumerated using the combichem approach endorsed mining in a lead-like chemical space. The generated library was screened using an integrated in-silico approach and potential hits identified. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular Insights Into Development and Virulence Determinants of Aspergilli: A Proteomic Perspective

PubMed Central

Shankar, Jata; Tiwari, Shraddha; Shishodia, Sonia K.; Gangwar, Manali; Hoda, Shanu; Thakur, Raman; Vijayaraghavan, Pooja

2018-01-01

Aspergillus species are the major cause of health concern worldwide in immunocompromised individuals. Opportunistic Aspergilli cause invasive to allergic aspergillosis, whereas non-infectious Aspergilli have contributed to understand the biology of eukaryotic organisms and serve as a model organism. Morphotypes of Aspergilli such as conidia or mycelia/hyphae helped them to survive in favorable or unfavorable environmental conditions. These morphotypes contribute to virulence, pathogenicity and invasion into hosts by excreting proteins, enzymes or toxins. Morphological transition of Aspergillus species has been a critical step to infect host or to colonize on food products. Thus, we reviewed proteins from Aspergilli to understand the biological processes, biochemical, and cellular pathways that are involved in transition and morphogenesis. We majorly analyzed proteomic studies on A. fumigatus, A. flavus, A. terreus, and A. niger to gain insight into mechanisms involved in the transition from conidia to mycelia along with the role of secondary metabolites. Proteome analysis of morphotypes of Aspergilli provided information on key biological pathways required to exit conidial dormancy, consortia of virulent factors and mycotoxins during the transition. The application of proteomic approaches has uncovered the biological processes during development as well as intermediates of secondary metabolite biosynthesis pathway. We listed key proteins/ enzymes or toxins at different morphological types of Aspergillus that could be applicable in discovery of novel therapeutic targets or metabolite based diagnostic markers. PMID:29896454

Molecular Insights Into Development and Virulence Determinants of Aspergilli: A Proteomic Perspective.

PubMed

Shankar, Jata; Tiwari, Shraddha; Shishodia, Sonia K; Gangwar, Manali; Hoda, Shanu; Thakur, Raman; Vijayaraghavan, Pooja

2018-01-01

Aspergillus species are the major cause of health concern worldwide in immunocompromised individuals. Opportunistic Aspergilli cause invasive to allergic aspergillosis, whereas non-infectious Aspergilli have contributed to understand the biology of eukaryotic organisms and serve as a model organism. Morphotypes of Aspergilli such as conidia or mycelia/hyphae helped them to survive in favorable or unfavorable environmental conditions. These morphotypes contribute to virulence, pathogenicity and invasion into hosts by excreting proteins, enzymes or toxins. Morphological transition of Aspergillus species has been a critical step to infect host or to colonize on food products. Thus, we reviewed proteins from Aspergilli to understand the biological processes, biochemical, and cellular pathways that are involved in transition and morphogenesis. We majorly analyzed proteomic studies on A. fumigatus, A. flavus, A. terreus , and A. niger to gain insight into mechanisms involved in the transition from conidia to mycelia along with the role of secondary metabolites. Proteome analysis of morphotypes of Aspergilli provided information on key biological pathways required to exit conidial dormancy, consortia of virulent factors and mycotoxins during the transition. The application of proteomic approaches has uncovered the biological processes during development as well as intermediates of secondary metabolite biosynthesis pathway. We listed key proteins/ enzymes or toxins at different morphological types of Aspergillus that could be applicable in discovery of novel therapeutic targets or metabolite based diagnostic markers.

Physical principles of filamentous protein self-assembly kinetics

NASA Astrophysics Data System (ADS)

Michaels, Thomas C. T.; Liu, Lucie X.; Meisl, Georg; Knowles, Tuomas P. J.

2017-04-01

The polymerization of proteins and peptides into filamentous supramolecular structures is an elementary form of self-organization of key importance to the functioning biological systems, as in the case of actin biofilaments that compose the cellular cytoskeleton. Aberrant filamentous protein self-assembly, however, is associated with undesired effects and severe clinical disorders, such as Alzheimer’s and Parkinson’s diseases, which, at the molecular level, are associated with the formation of certain forms of filamentous protein aggregates known as amyloids. Moreover, due to their unique physicochemical properties, protein filaments are finding extensive applications as biomaterials for nanotechnology. With all these different factors at play, the field of filamentous protein self-assembly has experienced tremendous activity in recent years. A key question in this area has been to elucidate the microscopic mechanisms through which filamentous aggregates emerge from dispersed proteins with the goal of uncovering the underlying physical principles. With the latest developments in the mathematical modeling of protein aggregation kinetics as well as the improvement of the available experimental techniques it is now possible to tackle many of these complex systems and carry out detailed analyses of the underlying microscopic steps involved in protein filament formation. In this paper, we review some classical and modern kinetic theories of protein filament formation, highlighting their use as a general strategy for quantifying the molecular-level mechanisms and transition states involved in these processes.

Biocatalytic conversion of methane to methanol as a key step for development of methane-based biorefineries.

PubMed

Hwang, In Yeub; Lee, Seung Hwan; Choi, Yoo Seong; Park, Si Jae; Na, Jeong Geol; Chang, In Seop; Kim, Choongik; Kim, Hyun Cheol; Kim, Yong Hwan; Lee, Jin Won; Lee, Eun Yeol

2014-12-28

Methane is considered as a next-generation carbon feedstock owing to the vast reserves of natural and shale gas. Methane can be converted to methanol by various methods, which in turn can be used as a starting chemical for the production of value-added chemicals using existing chemical conversion processes. Methane monooxygenase is the key enzyme that catalyzes the addition of oxygen to methane. Methanotrophic bacteria can transform methane to methanol by inhibiting methanol dehydrogenase. In this paper, we review the recent progress made on the biocatalytic conversion of methane to methanol as a key step for methane-based refinery systems and discuss future prospects for this technology.

Key Elements of Observing Practice: A Data Wise DVD and Facilitator's Guide

ERIC Educational Resources Information Center

Boudett, Kathryn Parker; City, Elizabeth A.; Russell, Marcia K.

2010-01-01

Based on the bestselling book "Data Wise: A Step-by-Step Guide to Using Assessment Results to Improve Teaching and Learning", and its companion volume, "Data Wise in Action", this DVD and Facilitator's Guide offer insight into one of the most challenging steps in capturing data about school performance: observing and analyzing instructional…

Key Steps in the Special Review Process

EPA Pesticide Factsheets

EPA uses this process when it has reason to believe that the use of a pesticide may result in unreasonable adverse effects on people or the environment. Steps include comprehensive risk and benefit analyses and multiple Position Documents.

Business Modeling to Implement an eHealth Portal for Infection Control: A Reflection on Co-Creation With Stakeholders

PubMed Central

Wentzel, Jobke; Sanderman, Robbert; van Gemert-Pijnen, Lisette

2015-01-01

Background It is acknowledged that the success and uptake of eHealth improve with the involvement of users and stakeholders to make technology reflect their needs. Involving stakeholders in implementation research is thus a crucial element in developing eHealth technology. Business modeling is an approach to guide implementation research for eHealth. Stakeholders are involved in business modeling by identifying relevant stakeholders, conducting value co-creation dialogs, and co-creating a business model. Because implementation activities are often underestimated as a crucial step while developing eHealth, comprehensive and applicable approaches geared toward business modeling in eHealth are scarce. Objective This paper demonstrates the potential of several stakeholder-oriented analysis methods and their practical application was demonstrated using Infectionmanager as an example case. In this paper, we aim to demonstrate how business modeling, with the focus on stakeholder involvement, is used to co-create an eHealth implementation. Methods We divided business modeling in 4 main research steps. As part of stakeholder identification, we performed literature scans, expert recommendations, and snowball sampling (Step 1). For stakeholder analyzes, we performed “basic stakeholder analysis,” stakeholder salience, and ranking/analytic hierarchy process (Step 2). For value co-creation dialogs, we performed a process analysis and stakeholder interviews based on the business model canvas (Step 3). Finally, for business model generation, we combined all findings into the business model canvas (Step 4). Results Based on the applied methods, we synthesized a step-by-step guide for business modeling with stakeholder-oriented analysis methods that we consider suitable for implementing eHealth. Conclusions The step-by-step guide for business modeling with stakeholder involvement enables eHealth researchers to apply a systematic and multidisciplinary, co-creative approach for implementing eHealth. Business modeling becomes an active part in the entire development process of eHealth and starts an early focus on implementation, in which stakeholders help to co-create the basis necessary for a satisfying success and uptake of the eHealth technology. PMID:26272510

Predictive Variables of Half-Marathon Performance for Male Runners

PubMed Central

Gómez-Molina, Josué; Ogueta-Alday, Ana; Camara, Jesus; Stickley, Christoper; Rodríguez-Marroyo, José A.; García-López, Juan

2017-01-01

The aims of this study were to establish and validate various predictive equations of half-marathon performance. Seventy-eight half-marathon male runners participated in two different phases. Phase 1 (n = 48) was used to establish the equations for estimating half-marathon performance, and Phase 2 (n = 30) to validate these equations. Apart from half-marathon performance, training-related and anthropometric variables were recorded, and an incremental test on a treadmill was performed, in which physiological (VO2max, speed at the anaerobic threshold, peak speed) and biomechanical variables (contact and flight times, step length and step rate) were registered. In Phase 1, half-marathon performance could be predicted to 90.3% by variables related to training and anthropometry (Equation 1), 94.9% by physiological variables (Equation 2), 93.7% by biomechanical parameters (Equation 3) and 96.2% by a general equation (Equation 4). Using these equations, in Phase 2 the predicted time was significantly correlated with performance (r = 0.78, 0.92, 0.90 and 0.95, respectively). The proposed equations and their validation showed a high prediction of half-marathon performance in long distance male runners, considered from different approaches. Furthermore, they improved the prediction performance of previous studies, which makes them a highly practical application in the field of training and performance. Key points The present study obtained four equations involving anthropometric, training, physiological and biomechanical variables to estimate half-marathon performance. These equations were validated in a different population, demonstrating narrows ranges of prediction than previous studies and also their consistency. As a novelty, some biomechanical variables (i.e. step length and step rate at RCT, and maximal step length) have been related to half-marathon performance. PMID:28630571

Optimizing identification and management of COPD patients – reviewing the role of the community pharmacist

PubMed Central

van Boven, Job F. M.; Maguire, Terence; Goyal, Pankaj; Altman, Pablo

2016-01-01

The aim of this paper was to propose key steps for community pharmacist integration into a patient care pathway for chronic obstructive pulmonary disease (COPD) management. A literature search was conducted to identify publications focusing on the role of the community pharmacist in identification and management of COPD. The literature search highlighted evidence supporting an important role for pharmacists at each of the four key steps in the patient care pathway for COPD management. Step 1 (primary prevention): pharmacists are ideally placed to provide information on disease awareness and risk prevention campaigns, and to encourage lifestyle interventions, including smoking cessation. Step 2 (early detection/case finding): pharmacists are often the first point of contact between the patient and the healthcare system and can therefore play an important role in the early identification of patients with COPD. Step 3 (management and ongoing support): pharmacists can assist patients by providing advice and education on dosage, inhaler technique, treatment expectations and the importance of adherence, and by supporting self‐management, including recognition and treatment of COPD exacerbations. Step 4 (review and follow‐up): pharmacists can play an important role in monitoring adherence and ongoing inhaler technique in patients with COPD. In summary, pharmacists are ideally positioned to play a vital role in all key stages of an integrated COPD patient care pathway from early disease detection to the support of management plans, including advice and counselling regarding medications, inhaler technique and treatment adherence. Areas requiring additional consideration include pharmacist training, increasing awareness of the pharmacist role, administration and reimbursement, and increasing physician–pharmacist collaboration. PMID:27510273

Employing Simulation to Evaluate Designs: The APEX Approach

NASA Technical Reports Server (NTRS)

Freed, Michael A.; Shafto, Michael G.; Remington, Roger W.; Null, Cynthia H. (Technical Monitor)

1998-01-01

The key innovations of APEX are its integrated approaches to task analysis, procedure definition, and intelligent, resource-constrained multi-tasking. This paper presents a step-by-step description of how APEX is used, from scenario development through trace analysis.

Roles of Inflammation, Oxidative Stress, and Vascular Dysfunction in Hypertension

PubMed Central

Dinh, Quynh N.; Drummond, Grant R.; Sobey, Christopher G.

2014-01-01

Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Approximately 90% of hypertension cases are classified as essential hypertension, where the precise cause is unknown. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood. The purpose of this review is to describe evidence from human and animal studies that inflammation leads to the development of hypertension, as well as the evidence for involvement of oxidative stress and endothelial dysfunction—both thought to be key steps in the development of hypertension. Other potential proinflammatory conditions that contribute to hypertension—such as activation of the sympathetic nervous system, aging, and elevated aldosterone—are also discussed. Finally, we consider the potential benefit of anti-inflammatory drugs and statins for antihypertensive therapy. The evidence reviewed suggests that inflammation can lead to the development of hypertension and that oxidative stress and endothelial dysfunction are involved in the inflammatory cascade. Aging and aldosterone may also both be involved in inflammation and hypertension. Hence, in the absence of serious side effects, anti-inflammatory drugs could potentially be used to treat hypertension in the future. PMID:25136585

A First Step in Learning Analytics: Pre-Processing Low-Level Alice Logging Data of Middle School Students

ERIC Educational Resources Information Center

Werner, Linda; McDowell, Charlie; Denner, Jill

2013-01-01

Educational data mining can miss or misidentify key findings about student learning without a transparent process of analyzing the data. This paper describes the first steps in the process of using low-level logging data to understand how middle school students used Alice, an initial programming environment. We describe the steps that were…

Probing the transcriptome of Aconitum carmichaelii reveals the candidate genes associated with the biosynthesis of the toxic aconitine-type C19-diterpenoid alkaloids.

PubMed

Zhao, Dake; Shen, Yong; Shi, Yana; Shi, Xingqiao; Qiao, Qin; Zi, Shuhui; Zhao, Erqiang; Yu, Diqiu; Kennelly, Edward J

2018-05-11

Aconitum carmichaelii has long been used as a traditional Chinese medicine, and its processed lateral roots are known commonly as fuzi. Aconitine-type C 19 -diterpenoid alkaloids accumulating in the lateral roots are some of the main toxicants of this species, yet their biosynthesis remains largely unresolved. As a first step towards understanding the biosynthesis of aconitine-type C 19 -diterpenoid alkaloids, we performed de novo transcriptome assembly and analysis of rootstocks and leaf tissues of Aconitum carmichaelii by next-generation sequencing. A total of 525 unigene candidates were identified as involved in the formation of C 19 -diterpenoid alkaloids, including those encoding enzymes in the early steps of diterpenoid alkaloids scaffold biosynthetic pathway, such as ent-copalyl diphosphate synthases, ent-kaurene synthases, kaurene oxidases, cyclases, and key aminotransferases. Furthermore, candidates responsible for decorating of diterpenoid alkaloid skeletons were discovered from transcriptome sequencing of fuzi, such as monooxygenases, methyltransferase, and BAHD acyltransferases. In addition, 645 differentially expressed genes encoding transcription factors potentially related to diterpenoid alkaloids accumulation underground were documented. Subsequent modular domain structure phylogenetics and differential expression analysis led to the identification of BAHD acyltransferases possibly involved in the formation of acetyl and benzoyl esters of diterpenoid alkaloids, associated with the acute toxicity of fuzi. The transcriptome data provide the foundation for future research into the molecular basis for aconitine-type C 19 -diterpenoid alkaloids biosynthesis in A. carmichaelii. Copyright © 2018. Published by Elsevier Ltd.

Medicago truncatula CYP716A12 Is a Multifunctional Oxidase Involved in the Biosynthesis of Hemolytic Saponins[W

PubMed Central

Carelli, Maria; Biazzi, Elisa; Panara, Francesco; Tava, Aldo; Scaramelli, Laura; Porceddu, Andrea; Graham, Neil; Odoardi, Miriam; Piano, Efisio; Arcioni, Sergio; May, Sean; Scotti, Carla; Calderini, Ornella

2011-01-01

Saponins, a group of glycosidic compounds present in several plant species, have aglycone moieties that are formed using triterpenoid or steroidal skeletons. In spite of their importance as antimicrobial compounds and their possible benefits for human health, knowledge of the genetic control of saponin biosynthesis is still poorly understood. In the Medicago genus, the hemolytic activity of saponins is related to the nature of their aglycone moieties. We have identified a cytochrome P450 gene (CYP716A12) involved in saponin synthesis in Medicago truncatula using a combined genetic and biochemical approach. Genetic loss-of-function analysis and complementation studies showed that CYP716A12 is responsible for an early step in the saponin biosynthetic pathway. Mutants in CYP716A12 were unable to produce hemolytic saponins and only synthetized soyasaponins, and were thus named lacking hemolytic activity (lha). In vitro enzymatic activity assays indicate that CYP716A12 catalyzes the oxidation of β-amyrin and erythrodiol at the C-28 position, yielding oleanolic acid. Transcriptome changes in the lha mutant showed a modulation in the main steps of triterpenic saponin biosynthetic pathway: squalene cyclization, β-amyrin oxidation, and glycosylation. The analysis of CYP716A12 expression in planta is reported together with the sapogenin content in different tissues and stages. This article provides evidence for CYP716A12 being a key gene in hemolytic saponin biosynthesis. PMID:21821776

Physiological Characterization and Comparative Transcriptome Analysis of White and Green Leaves of Ananas comosus var. bracteatus

PubMed Central

Li, Xia; Kanakala, Surapathrudu; He, Yehua; Zhong, Xiaolan; Yu, Sanmiao; Li, Ruixue; Sun, Lingxia; Ma, Jun

2017-01-01

Leaf coloration is one of the most important and attractive characteristics of Ananas comosus var. bracteatus. The chimeric character is not stable during the in vitro tissue culturing. Many regenerated plants lost economic values for the loss of the chimeric character of leaves. In order to reveal the molecular mechanisms involved in the albino phenotype of the leaf cells, the physiological and transcriptional differences between complete white (CWh) and green (CGr) leaf cells of A. comosus var. bracteatus were analyzed. A total of 1,431 differentially expressed unigenes (DEGs) in CGr and CWh leaves were identified using RNA-seq. A comparison to the COG, GO and KEGG annotations revealed DEGs involved in chlorophyll biosynthesis, chloroplast development and photosynthesis. Furthermore, the measurement of main precursors of chlorophyll in the CWh leaves confirmed that the rate-limiting step in chlorophyll biosynthesis, and thus the cause of the albino phenotype of the white cells, was the conversion of pyrrole porphobilinogen (PBG) to uroporphyrinogen III (Uro III). The enzyme activity of porphobilinogen deaminase (PBGD) and uroporporphyrinogn III synthase (UROS), which catalyze the transition of PBG to Uro III, was significantly decreased in the CWh leaves. Our data showed the transcriptional differences between the CWh and CGr plants and characterized key steps in chlorophyll biosynthesis of the CWh leaves. These results contribute to our understanding of the mechanisms and regulation of pigment biosynthesis in the CWh leaf cells of A. comosus var. bracteatus. PMID:28095462

Physiological Characterization and Comparative Transcriptome Analysis of White and Green Leaves of Ananas comosus var. bracteatus.

PubMed

Li, Xia; Kanakala, Surapathrudu; He, Yehua; Zhong, Xiaolan; Yu, Sanmiao; Li, Ruixue; Sun, Lingxia; Ma, Jun

2017-01-01

Leaf coloration is one of the most important and attractive characteristics of Ananas comosus var. bracteatus. The chimeric character is not stable during the in vitro tissue culturing. Many regenerated plants lost economic values for the loss of the chimeric character of leaves. In order to reveal the molecular mechanisms involved in the albino phenotype of the leaf cells, the physiological and transcriptional differences between complete white (CWh) and green (CGr) leaf cells of A. comosus var. bracteatus were analyzed. A total of 1,431 differentially expressed unigenes (DEGs) in CGr and CWh leaves were identified using RNA-seq. A comparison to the COG, GO and KEGG annotations revealed DEGs involved in chlorophyll biosynthesis, chloroplast development and photosynthesis. Furthermore, the measurement of main precursors of chlorophyll in the CWh leaves confirmed that the rate-limiting step in chlorophyll biosynthesis, and thus the cause of the albino phenotype of the white cells, was the conversion of pyrrole porphobilinogen (PBG) to uroporphyrinogen III (Uro III). The enzyme activity of porphobilinogen deaminase (PBGD) and uroporporphyrinogn III synthase (UROS), which catalyze the transition of PBG to Uro III, was significantly decreased in the CWh leaves. Our data showed the transcriptional differences between the CWh and CGr plants and characterized key steps in chlorophyll biosynthesis of the CWh leaves. These results contribute to our understanding of the mechanisms and regulation of pigment biosynthesis in the CWh leaf cells of A. comosus var. bracteatus.

Picosecond laser micro/nano surface texturing of nickel for superhydrophobicity

NASA Astrophysics Data System (ADS)

Wang, X. C.; Wang, B.; Xie, H.; Zheng, H. Y.; Lam, Y. C.

2018-03-01

A single step direct picosecond laser texturing process was demonstrated to be able to obtain a superhydrophobic surface on a nickel substrate, a key material for mold fabrication in the manufacture of various devices, including polymeric microfluidic devices. A two-scale hierarchical surface structure of regular 2D array micro-bumps with nano-ripples was produced on a nickel surface. The laser textured surface initially showed superhydrophilicity with almost complete wetting of the structured surface just after laser treatment, then quickly changed to nearly superhydrophobic with a water contact angle (WCA) of 140° in less than 1 d, and finally became superhydrophobic with a WCA of more than 150° and a contact angle hysteresis (CAH) of less than 5°. The mechanism involved in the process is discussed in terms of surface morphology and surface chemistry. The ultra-fast laser induced NiO catalytic effect was thought to play a key role in modifying the surface chemistry so as to lower the surface energy. The developed process has the potential to improve the performance of nickel mold in the fabrication of microfluidic devices.

"Speaking the dialect": understanding public discourse in the aftermath of an HIV vaccine trial shutdown.

PubMed

Newman, Peter A; Logie, Carmen; James, Llana; Charles, Tamicka; Maxwell, John; Salam, Khaled; Woodford, Michael

2011-09-01

We investigated how persons from key populations at higher risk of HIV exposure interpreted the process and outcomes of the Step Study HIV-1 vaccine trial, which was terminated early, and implications for willingness to participate in and community support for HIV vaccine research. We used qualitative methods and a community-based approach in 9 focus groups (n = 72) among ethnically and sexually diverse populations and 6 semistructured key informant interviews in Ontario, Canada, in 2007 to 2008. Participants construed social meaning from complex clinical and biomedical phenomena. Social representations and mental models emerged in fears of vaccine-induced infection, conceptualizations of unfair recruitment practices and increased risk behaviors among trial participants, and questioning of informed consent. Narratives of altruism and the common good demonstrated support for future trials. Public discourse on HIV vaccine trials is a productive means of interpreting complex clinical trial processes and outcomes in the context of existing beliefs and experiences regarding HIV vaccines, medical research, and historical disenfranchisement. Strategic engagement with social representations and mental models may promote meaningful community involvement in biomedical HIV prevention research.

Determination of protein carbonyls in plasma, cell extracts, tissue homogenates, isolated proteins: Focus on sample preparation and derivatization conditions

PubMed Central

Weber, Daniela; Davies, Michael J.; Grune, Tilman

2015-01-01

Protein oxidation is involved in regulatory physiological events as well as in damage to tissues and is thought to play a key role in the pathophysiology of diseases and in the aging process. Protein-bound carbonyls represent a marker of global protein oxidation, as they are generated by multiple different reactive oxygen species in blood, tissues and cells. Sample preparation and stabilization are key steps in the accurate quantification of oxidation-related products and examination of physiological/pathological processes. This review therefore focuses on the sample preparation processes used in the most relevant methods to detect protein carbonyls after derivatization with 2,4-dinitrophenylhydrazine with an emphasis on measurement in plasma, cells, organ homogenates, isolated proteins and organelles. Sample preparation, derivatization conditions and protein handling are presented for the spectrophotometric and HPLC method as well as for immunoblotting and ELISA. An extensive overview covering these methods in previously published articles is given for researchers who plan to measure protein carbonyls in different samples. PMID:26141921

Determination of protein carbonyls in plasma, cell extracts, tissue homogenates, isolated proteins: Focus on sample preparation and derivatization conditions.

PubMed

Weber, Daniela; Davies, Michael J; Grune, Tilman

2015-08-01

Protein oxidation is involved in regulatory physiological events as well as in damage to tissues and is thought to play a key role in the pathophysiology of diseases and in the aging process. Protein-bound carbonyls represent a marker of global protein oxidation, as they are generated by multiple different reactive oxygen species in blood, tissues and cells. Sample preparation and stabilization are key steps in the accurate quantification of oxidation-related products and examination of physiological/pathological processes. This review therefore focuses on the sample preparation processes used in the most relevant methods to detect protein carbonyls after derivatization with 2,4-dinitrophenylhydrazine with an emphasis on measurement in plasma, cells, organ homogenates, isolated proteins and organelles. Sample preparation, derivatization conditions and protein handling are presented for the spectrophotometric and HPLC method as well as for immunoblotting and ELISA. An extensive overview covering these methods in previously published articles is given for researchers who plan to measure protein carbonyls in different samples. © 2015 Published by Elsevier Ltd.

Regulating the ethylene response of a plant by modulation of F-box proteins

DOEpatents

Guo, Hongwei [Beijing, CN; Ecker, Joseph R [Carlsbad, CA

2014-01-07

The relationship between F-box proteins and proteins invovled in the ethylene response in plants is described. In particular, F-box proteins may bind to proteins involved in the ethylene response and target them for degradation by the ubiquitin/proteasome pathway. The transcription factor EIN3 is a key transcription factor mediating ethylne-regulated gene expression and morphological responses. EIN3 is degraded through a ubiquitin/proteasome pathway mediated by F-box proteins EBF1 and EBF2. The link between F-box proteins and the ethylene response is a key step in modulating or regulating the response of a plant to ethylene. Described herein are transgenic plants having an altered sensitivity to ethylene, and methods for making transgenic plant haing an althered sensitivity to ethylene by modulating the level of activity of F-box proteins. Methods of altering the ethylene response in a plant by modulating the activity or expression of an F-box protein are described. Also described are methods of identifying compounds that modulate the ethylene response in plants by modulating the level of F-box protein expression or activity.

Single-molecule comparison of DNA Pol I activity with native and analog nucleotides

NASA Astrophysics Data System (ADS)

Gul, Osman; Olsen, Tivoli; Choi, Yongki; Corso, Brad; Weiss, Gregory; Collins, Philip

2014-03-01

DNA polymerases are critical enzymes for DNA replication, and because of their complex catalytic cycle they are excellent targets for investigation by single-molecule experimental techniques. Recently, we studied the Klenow fragment (KF) of DNA polymerase I using a label-free, electronic technique involving single KF molecules attached to carbon nanotube transistors. The electronic technique allowed long-duration monitoring of a single KF molecule while processing thousands of template strands. Processivity of up to 42 nucleotide bases was directly observed, and statistical analysis of the recordings determined key kinetic parameters for the enzyme's open and closed conformations. Subsequently, we have used the same technique to compare the incorporation of canonical nucleotides like dATP to analogs like 1-thio-2'-dATP. The analog had almost no affect on duration of the closed conformation, during which the nucleotide is incorporated. On the other hand, the analog increased the rate-limiting duration of the open conformation by almost 40%. We propose that the thiolated analog interferes with KF's recognition and binding, two key steps that determine its ensemble turnover rate.

Six steps to an effective denials management program.

PubMed

Robertson, Brian; Doré, Alexander

2005-09-01

The following six steps can help you manage denials management issues in your organization: Create standard definitions of denial types. Establish a denial hierarchy. Establish a centralized denial database. Develop key performance indicators. Build responsibility matrices. Measure, monitor, and take action.

11-Step Total Synthesis of (−)-Maoecrystal V

PubMed Central

2016-01-01

An expedient, practical, and enantioselective route to the highly congested ent-kaurane diterpene maoecrystal V is presented. This route, which has been several years in the making, is loosely modeled after a key pinacol shift in the proposed biosynthesis. Only 11 steps, many of which are strategic in that they build key skeletal bonds and incorporate critical functionalities, are required to access (−)-maoecrystal V. Several unique and unexpected maneuvers are featured in this potentially scalable pathway. Reevaluation of the biological activity calls into question the initial exuberance surrounding this natural product. PMID:27457680

Lean Information Management: Criteria For Selecting Key Performance Indicators At Shop Floor

NASA Astrophysics Data System (ADS)

Iuga, Maria Virginia; Kifor, Claudiu Vasile; Rosca, Liviu-Ion

2015-07-01

Most successful organizations worldwide use key performance indicators as an important part of their corporate strategy in order to forecast, measure and plan their businesses. Performance metrics vary in their purpose, definition and content. Therefore, the way organizations select what they think are the optimal indicators for their businesses varies from company to company, sometimes even from department to department. This study aims to answer the question of what is the most suitable way to define and select key performance indicators. More than that, it identifies the right criteria to select key performance indicators at shop floor level. This paper contributes to prior research by analysing and comparing previously researched selection criteria and proposes an original six-criteria-model, which caters towards choosing the most adequate KPIs. Furthermore, the authors take the research a step further by further steps to closed research gaps within this field of study.

Mother Involvement as an Influence on Father Involvement with Early Adolescents

PubMed Central

Pleck, Joseph H.; Hofferth, Sandra L.

2009-01-01

This study hypothesized that father involvement is influenced by mothers' level of involvement as well as by marital conflict, mothers' work hours, and fathers' status as biological or step father. The analysis also tested hypotheses about mother involvement as a potential mediator of the effects of marital conflict and maternal work hours on father involvement, and hypotheses about factors influencing mother involvement. Children aged 10-14 from the NLSY79 who resided with their biological or step father and with their mother reported on each parent's involvement with them. As hypothesized, father involvement was predicted by mother involvement, and the reciprocal influence was not significant. Father involvement was associated with low marital conflict and being a biological father. Mothers' involvement partially mediated the effects of marital conflict on father involvement. If the mediating role of maternal involvement is not taken into account, the effect of marital conflict on father involvement is overestimated. PMID:21776195

Cooperative catalytic methoxycarbonylation of alkenes: uncovering the role of palladium complexes with hemilabile ligands† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc02964k

PubMed Central

Dong, Kaiwu; Sang, Rui; Wei, Zhihong; Liu, Jie; Dühren, Ricarda; Spannenberg, Anke; Jiao, Haijun; Neumann, Helfried; Jackstell, Ralf; Franke, Robert

2018-01-01

Mechanistic studies of the catalyst [Pd2(dba)3/1,1′-bis(tert-butyl(pyridin-2-yl)phosphanyl)ferrocene, L2] for olefin alkoxycarbonylation reactions are described. X-ray crystallography reveals the coordination of the pyridyl nitrogen atom in L2 to the palladium center of the catalytic intermediates. DFT calculations on the elementary steps of the industrially relevant carbonylation of ethylene (the Lucite α-process) indicate that the protonated pyridyl moiety is formed immediately, which facilitates the formation of the active palladium hydride complex. The insertion of ethylene and CO into this intermediate leads to the corresponding palladium acyl species, which is kinetically reversible. Notably, this key species is stabilized by the hemilabile coordination of the pyridyl nitrogen atom in L2. The rate-determining alcoholysis of the acyl palladium complex is substantially facilitated by metal–ligand cooperation. Specifically, the deprotonation of the alcohol by the built-in base of the ligand allows a facile intramolecular nucleophilic attack on the acyl palladium species concertedly. Kinetic measurements support this mechanistic proposal and show that the rate of the carbonylation step is zero-order dependent on ethylene and CO. Comparing CH3OD and CH3OH as nucleophiles suggests the involvement of (de)protonation in the rate-determining step. PMID:29732128

Electron transfer precedes ATP hydrolysis during nitrogenase catalysis

PubMed Central

Duval, Simon; Danyal, Karamatullah; Shaw, Sudipta; Lytle, Anna K.; Dean, Dennis R.; Hoffman, Brian M.; Antony, Edwin; Seefeldt, Lance C.

2013-01-01

The biological reduction of N2 to NH3 catalyzed by Mo-dependent nitrogenase requires at least eight rounds of a complex cycle of events associated with ATP-driven electron transfer (ET) from the Fe protein to the catalytic MoFe protein, with each ET coupled to the hydrolysis of two ATP molecules. Although steps within this cycle have been studied for decades, the nature of the coupling between ATP hydrolysis and ET, in particular the order of ET and ATP hydrolysis, has been elusive. Here, we have measured first-order rate constants for each key step in the reaction sequence, including direct measurement of the ATP hydrolysis rate constant: kATP = 70 s−1, 25 °C. Comparison of the rate constants establishes that the reaction sequence involves four sequential steps: (i) conformationally gated ET (kET = 140 s−1, 25 °C), (ii) ATP hydrolysis (kATP = 70 s−1, 25 °C), (iii) Phosphate release (kPi = 16 s−1, 25 °C), and (iv) Fe protein dissociation from the MoFe protein (kdiss = 6 s−1, 25 °C). These findings allow completion of the thermodynamic cycle undergone by the Fe protein, showing that the energy of ATP binding and protein–protein association drive ET, with subsequent ATP hydrolysis and Pi release causing dissociation of the complex between the Feox(ADP)2 protein and the reduced MoFe protein. PMID:24062462

Mutant selection in the self-incompatible plant radish (Raphanus sativus L. var. sativus) using two-step TILLING

PubMed Central

Kohzuma, Kaori; Chiba, Motoko; Nagano, Soichiro; Anai, Toyoaki; Ueda, Miki U.; Oguchi, Riichi; Shirai, Kazumasa; Hanada, Kousuke; Hikosaka, Kouki; Fujii, Nobuharu

2017-01-01

Radish (Raphanus sativus L. var. sativus), a widely cultivated root vegetable crop, possesses a large sink organ (the root), implying that photosynthetic activity in radish can be enhanced by altering both the source and sink capacity of the plant. However, since radish is a self-incompatible plant, improved mutation-breeding strategies are needed for this crop. TILLING (Targeting Induced Local Lesions IN Genomes) is a powerful method used for reverse genetics. In this study, we developed a new TILLING strategy involving a two-step mutant selection process for mutagenized radish plants: the first selection is performed to identify a BC1M1 line, that is, progenies of M1 plants crossed with wild-type, and the second step is performed to identify BC1M1 individuals with mutations. We focused on Rubisco as a target, since Rubisco is the most abundant plant protein and a key photosynthetic enzyme. We found that the radish genome contains six RBCS genes and one pseudogene encoding small Rubisco subunits. We screened 955 EMS-induced BC1M1 lines using our newly developed TILLING strategy and obtained six mutant lines for the six RsRBCS genes, encoding proteins with four different types of amino acid substitutions. Finally, we selected a homozygous mutant and subjected it to physiological measurements. PMID:28744180

The demonstration of a theory-based approach to the design of localized patient safety interventions

PubMed Central

2013-01-01

Background There is evidence of unsafe care in healthcare systems globally. Interventions to implement recommended practice often have modest and variable effects. Ideally, selecting and adapting interventions according to local contexts should enhance effects. However, the means by which this can happen is seldom systematic, based on theory, or made transparent. This work aimed to demonstrate the applicability, feasibility, and acceptability of a theoretical domains framework implementation (TDFI) approach for co-designing patient safety interventions. Methods We worked with three hospitals to support the implementation of evidence-based guidance to reduce the risk of feeding into misplaced nasogastric feeding tubes. Our stepped process, informed by the TDF and key principles from implementation literature, entailed: involving stakeholders; identifying target behaviors; identifying local factors (barriers and levers) affecting behavior change using a TDF-based questionnaire; working with stakeholders to generate specific local strategies to address key barriers; and supporting stakeholders to implement strategies. Exit interviews and audit data collection were undertaken to assess the feasibility and acceptability of this approach. Results Following audit and discussion, implementation teams for each Trust identified the process of checking the positioning of nasogastric tubes prior to feeding as the key behavior to target. Questionnaire results indicated differences in key barriers between organizations. Focus groups generated innovative, generalizable, and adaptable strategies for overcoming barriers, such as awareness events, screensavers, equipment modifications, and interactive learning resources. Exit interviews identified themes relating to the benefits, challenges, and sustainability of this approach. Time trend audit data were collected for 301 patients over an 18-month period for one Trust, suggesting clinically significant improved use of pH and documentation of practice following the intervention. Conclusions The TDF is a feasible and acceptable framework to guide the implementation of patient safety interventions. The stepped TDFI approach engages healthcare professionals and facilitates contextualization in identifying the target behavior, eliciting local barriers, and selecting strategies to address those barriers. This approach may be of use to implementation teams and policy makers, although our promising findings confirm the need for a more rigorous evaluation; a balanced block evaluation is currently underway. PMID:24131864

Semantic Structures of One-Step Word Problems Involving Multiplication or Division.

ERIC Educational Resources Information Center

Schmidt, Siegbert; Weiser, Werner

1995-01-01

Proposes a four-category classification of semantic structures of one-step word problems involving multiplication and division: forming the n-th multiple of measures, combinatorial multiplication, composition of operators, and multiplication by formula. This classification is compatible with semantic structures of addition and subtraction word…

Analysing UK clinicians' understanding of cognitive symptoms in major depression: A survey of primary care physicians and psychiatrists.

PubMed

McAllister-Williams, R Hamish; Bones, Kate; Goodwin, Guy M; Harrison, John; Katona, Cornelius; Rasmussen, Jill; Strong, Sarah; Young, Allan H

2017-01-01

Cognitive dysfunction occurs in depression and can persist into remission. It impacts on patient functioning but remains largely unrecognised, unmonitored and untreated. We explored understanding of cognitive dysfunction in depression among UK clinicians. A multi-step consultation process. Step 1: a multi-stakeholder steering committee identified key themes of burden, detection and management of cognitive dysfunction in depression, and developed statements on each to explore understanding and degree of agreement among clinicians. Step 2: 100 general practitioners (GPs) and 100 psychiatrists indicated their level of agreement with these statements. Step 3: the steering committee reviewed responses and highlighted priority areas for future education and research. There was agreement that clinicians are not fully aware of cognitive dysfunction in depression. Views of the relationship between cognitive dysfunction and other depressive symptom severities was not consistent with the literature. In particular, there was a lack of recognition that some cognitive dysfunction can persist into remission. There was understandable uncertainty around treatment options, given the current limited evidence base. However, it was recognised that cognitive dysfunction is an area of unmet need and that there is a lack of objective tests of cognition appropriate for depressed patients that can be easily implemented in the clinic. Respondents are likely to be 'led' by the direction of the statements they reviewed. The study did not involve patients and carers. UK clinicians should undergo training regarding cognitive dysfunction in depression, and further research is needed into its assessment, treatment and monitoring. Copyright © 2016 Elsevier B.V. All rights reserved.

Global research priorities for interpersonal violence prevention: a modified Delphi study.

PubMed

Mikton, Christopher R; Tanaka, Masako; Tomlinson, Mark; Streiner, David L; Tonmyr, Lil; Lee, Bandy X; Fisher, Jane; Hegadoren, Kathy; Pim, Joam Evans; Wang, Shr-Jie Sharlenna; MacMillan, Harriet L

2017-01-01

To establish global research priorities for interpersonal violence prevention using a systematic approach. Research priorities were identified in a three-round process involving two surveys. In round 1, 95 global experts in violence prevention proposed research questions to be ranked in round 2. Questions were collated and organized according to the four-step public health approach to violence prevention. In round 2, 280 international experts ranked the importance of research in the four steps, and the various substeps, of the public health approach. In round 3, 131 international experts ranked the importance of detailed research questions on the public health step awarded the highest priority in round 2. In round 2, "developing, implementing and evaluating interventions" was the step of the public health approach awarded the highest priority for four of the six types of violence considered (i.e. child maltreatment, intimate partner violence, armed violence and sexual violence) but not for youth violence or elder abuse. In contrast, "scaling up interventions and evaluating their cost-effectiveness" was ranked lowest for all types of violence. In round 3, research into "developing, implementing and evaluating interventions" that addressed parenting or laws to regulate the use of firearms was awarded the highest priority. The key limitations of the study were response and attrition rates among survey respondents. However, these rates were in line with similar priority-setting exercises. These findings suggest it is premature to scale up violence prevention interventions. Developing and evaluating smaller-scale interventions should be the funding priority.

Global research priorities for interpersonal violence prevention: a modified Delphi study

PubMed Central

Tanaka, Masako; Tomlinson, Mark; Streiner, David L; Tonmyr, Lil; Lee, Bandy X; Fisher, Jane; Hegadoren, Kathy; Pim, Joam Evans; Wang, Shr-Jie Sharlenna; MacMillan, Harriet L

2017-01-01

Abstract Objective To establish global research priorities for interpersonal violence prevention using a systematic approach. Methods Research priorities were identified in a three-round process involving two surveys. In round 1, 95 global experts in violence prevention proposed research questions to be ranked in round 2. Questions were collated and organized according to the four-step public health approach to violence prevention. In round 2, 280 international experts ranked the importance of research in the four steps, and the various substeps, of the public health approach. In round 3, 131 international experts ranked the importance of detailed research questions on the public health step awarded the highest priority in round 2. Findings In round 2, “developing, implementing and evaluating interventions” was the step of the public health approach awarded the highest priority for four of the six types of violence considered (i.e. child maltreatment, intimate partner violence, armed violence and sexual violence) but not for youth violence or elder abuse. In contrast, “scaling up interventions and evaluating their cost–effectiveness” was ranked lowest for all types of violence. In round 3, research into “developing, implementing and evaluating interventions” that addressed parenting or laws to regulate the use of firearms was awarded the highest priority. The key limitations of the study were response and attrition rates among survey respondents. However, these rates were in line with similar priority-setting exercises. Conclusion These findings suggest it is premature to scale up violence prevention interventions. Developing and evaluating smaller-scale interventions should be the funding priority. PMID:28053363

Grandparenting and adolescent adjustment in two-parent biological, lone-parent, and step-families.

PubMed

Attar-Schwartz, Shalhevet; Tan, Jo-Pei; Buchanan, Ann; Flouri, Eirini; Griggs, Julia

2009-02-01

There is limited research on the links between grandparenting and adolescents' well-being, especially from the perspective of the adolescents. The study examined whether grandparent involvement varied in two-parent biological, lone-parent, and step-families and whether this had a different contribution to the emotional and behavioral adjustment of adolescents across different family structures. The study is based on a sample of 1,515 secondary school students (ages 11-16 years) from England and Wales who completed a structured questionnaire. Findings of hierarchical regression analyses showed that among the whole sample, greater grandparent involvement was associated with fewer emotional problems (p < .01) and with more prosocial behavior (p < .001). In addition, while there were no differences in the level of grandparent involvement across the different family structures, grandparent involvement was more strongly associated with reduced adjustment difficulties among adolescents from lone-parent and step-families than those from two-parent biological families. A possible implication is that the positive role of grandparent involvement in lone-parent and step- families should be more emphasized in family psychology. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

A METHOD FOR DETERMINING THE COMPATIBILITY OF HAZARDOUS WASTES

EPA Science Inventory

This report describes a method for determining the compatibility of the binary combinations of hazardous wastes. The method consists of two main parts, namely: (1) the step-by-step compatibility analysis procedures, and (2) the hazardous wastes compatibility chart. The key elemen...

Keys to a Safe, Secure School.

ERIC Educational Resources Information Center

Kennedy, Mike

2002-01-01

Outlines 10 steps that school administrators can take to make their schools safer and more secure for students and staff. These steps encompass crime prevention through environmental design, crisis planning, entrances, lighting, police presence, prevention programs, rapport with students, smaller schools, technology implementation, and staff…

Interactive Exploration and Analysis of Large-Scale Simulations Using Topology-Based Data Segmentation.

PubMed

Bremer, Peer-Timo; Weber, Gunther; Tierny, Julien; Pascucci, Valerio; Day, Marcus S; Bell, John B

2011-09-01

Large-scale simulations are increasingly being used to study complex scientific and engineering phenomena. As a result, advanced visualization and data analysis are also becoming an integral part of the scientific process. Often, a key step in extracting insight from these large simulations involves the definition, extraction, and evaluation of features in the space and time coordinates of the solution. However, in many applications, these features involve a range of parameters and decisions that will affect the quality and direction of the analysis. Examples include particular level sets of a specific scalar field, or local inequalities between derived quantities. A critical step in the analysis is to understand how these arbitrary parameters/decisions impact the statistical properties of the features, since such a characterization will help to evaluate the conclusions of the analysis as a whole. We present a new topological framework that in a single-pass extracts and encodes entire families of possible features definitions as well as their statistical properties. For each time step we construct a hierarchical merge tree a highly compact, yet flexible feature representation. While this data structure is more than two orders of magnitude smaller than the raw simulation data it allows us to extract a set of features for any given parameter selection in a postprocessing step. Furthermore, we augment the trees with additional attributes making it possible to gather a large number of useful global, local, as well as conditional statistic that would otherwise be extremely difficult to compile. We also use this representation to create tracking graphs that describe the temporal evolution of the features over time. Our system provides a linked-view interface to explore the time-evolution of the graph interactively alongside the segmentation, thus making it possible to perform extensive data analysis in a very efficient manner. We demonstrate our framework by extracting and analyzing burning cells from a large-scale turbulent combustion simulation. In particular, we show how the statistical analysis enabled by our techniques provides new insight into the combustion process.

AGPase: its role in crop productivity with emphasis on heat tolerance in cereals.

PubMed

Saripalli, Gautam; Gupta, Pushpendra Kumar

2015-10-01

AGPase, a key enzyme of starch biosynthetic pathway, has a significant role in crop productivity. Thermotolerant variants of AGPase in cereals may be used for developing cultivars, which may enhance productivity under heat stress. Improvement of crop productivity has always been the major goal of plant breeders to meet the global demand for food. However, crop productivity itself is influenced in a large measure by a number of abiotic stresses including heat, which causes major losses in crop productivity. In cereals, crop productivity in terms of grain yield mainly depends upon the seed starch content so that starch biosynthesis and the enzymes involved in this process have been a major area of investigation for plant physiologists and plant breeders alike. Considerable work has been done on AGPase and its role in crop productivity, particularly under heat stress, because this enzyme is one of the major enzymes, which catalyses the rate-limiting first committed key enzymatic step of starch biosynthesis. Keeping the above in view, this review focuses on the basic features of AGPase including its structure, regulatory mechanisms involving allosteric regulators, its sub-cellular localization and its genetics. Major emphasis, however, has been laid on the genetics of AGPases and its manipulation for developing high yielding cultivars that will have comparable productivity under heat stress. Some important thermotolerant variants of AGPase, which mainly involve specific amino acid substitutions, have been highlighted, and the prospects of using these thermotolerant variants of AGPase in developing cultivars for heat prone areas have been discussed. The review also includes a brief account on transgenics for AGPase, which have been developed for basic studies and crop improvement.

Deciphering the ubiquitin-mediated pathway in apicomplexan parasites: a potential strategy to interfere with parasite virulence.

PubMed

Ponts, Nadia; Yang, Jianfeng; Chung, Duk-Won Doug; Prudhomme, Jacques; Girke, Thomas; Horrocks, Paul; Le Roch, Karine G

2008-06-11

Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders. Here we describe the use of an HMM search of functional Pfam domains found in the key components of the ubiquitin-mediated pathway necessary to activate and reversibly modify target proteins in eight apicomplexan parasitic protozoa for which complete or late-stage genome projects exist. In parallel, the same search was conducted on five model organisms, single-celled and metazoans, to generate data to validate both the search parameters employed and aid paralog classification in Apicomplexa. For each of the 13 species investigated, a set of proteins predicted to be involved in the ubiquitylation pathway has been identified and demonstrates increasing component members of the ubiquitylation pathway correlating with organism and genome complexity. Sequence homology and domain architecture analyses facilitated prediction of apicomplexan-specific protein function, particularly those involved in regulating cell division during these parasite's complex life cycles. This study provides a comprehensive analysis of proteins predicted to be involved in the apicomplexan ubiquitin-mediated pathway. Given the importance of such pathway in a wide variety of cellular processes, our data is a key step in elucidating the biological networks that, in part, direct the pathogenicity of these parasites resulting in a massive impact on global health. Moreover, apicomplexan-specific adaptations of the ubiquitylation pathway may represent new therapeutic targets for much needed drugs against apicomplexan parasites.

Predictors of round window accessibility for adult cochlear implantation based on pre-operative CT scan: a prospective observational study.

PubMed

Park, Edward; Amoodi, Hosam; Kuthubutheen, Jafri; Chen, Joseph M; Nedzelski, Julian M; Lin, Vincent Y W

2015-05-28

Cochlear implantation has become a mainstream treatment option for patients with severe to profound sensorineural hearing loss. During cochlear implant, there are key surgical steps which are influenced by anatomical variations between each patient. The aim of this study is to determine if there are potential predictors of difficulties that may be encountered during the cortical mastoidectomy, facial recess approach and round window access in cochlear implant surgery based upon pre-operative temporal bone CT scan. Fifty seven patients undergoing unilateral cochlear implantation were analyzed. Difficulty with 1) cortical mastoidectomy, 2) facial recess approach, and 3) round window access were scored intra-operatively by the surgeon in a blinded fashion (1 = "easy", 2 = "moderate", 3 = "difficult"). Pre-operative temporal bone CT scans were analyzed for 1) degree of mastoid aeration; 2) location of the sigmoid sinus; 3) height of the tegmen; 4) the presence of air cells in the facial recess, and 5) degree of round window bony overhang. Poor mastoid aeration and lower tegmen position, but not the location of sigmoid sinus, are associated with greater difficulty with the cortical mastoidectomy. Presence of an air cell around the facial nerve was predictive of easier facial recess access. However, the degree of round window bony overhang was not predictive of difficulty associated with round window access. Certain parameters on the pre-operative temporal bone CT scan may be useful in predicting potential difficulties encountered during the key steps involved in cochlear implant surgery.

Freedom of Information Act Requests: Six Keys to Handling Them

DTIC Science & Technology

2016-01-01

Defense AT&L: January–February 2016 50 Freedom of Information Act Requests Six Keys to Handling Them Michael A. Rodgers Rodgers is a professor of...crucial mission tasks. Understanding and using the six steps and keys provided above will free you from FOIA-induced distractions. The author can be contacted at michael.rodgers@dau.mil.

One-time pad, complexity of verification of keys, and practical security of quantum cryptography

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

Molotkov, S. N., E-mail: sergei.molotkov@gmail.com

2016-11-15

A direct relation between the complexity of the complete verification of keys, which is one of the main criteria of security in classical systems, and a trace distance used in quantum cryptography is demonstrated. Bounds for the minimum and maximum numbers of verification steps required to determine the actual key are obtained.

Community Participation on an Urban Sanitation Program: a Comparative Study

NASA Astrophysics Data System (ADS)

Rini Dwi Ari, Ismu; Nyoman Suluh Wijaya, I.; Dewanto, Aditya

2018-05-01

Sanitation development becomes one aspect, particularly the sixth pillar, of Sustainable Development Goals that aims at ensuring the access to water and sanitation for all. The success of the sanitation program will bring about significant changes in the human life. However, it is necessary to consider community involvement in the development program in all of the steps holistically – planning, implementation, operation and maintenance. This research scrutinizes the key factors of successful urban sanitation development programs in Talangagung sub-district as compared to Ardirejo sub-district in Kepanjen district in Malang regency, Indonesia. Through field observation in the two-research areas, and questionnaire survey distributed to to104 heads of households in Talangagung sub-district and 84 heads of households in Ardirejo sub-district, an evaluation on the suitability of the program as well as the social capital measurement was conducted. The result of estimation illustrates that Talangagung sub-district has higher score than Adirejo sub-district, which respectively 470 and 340 for the whole steps of the development. Then, the study continued with the social capital measurement using three indices of social network analysis – covering rate of participation, density and centrality. In general, the rate of participation and density of the residents involved in the urban sanitation program development in Talangagung sub-district was higher value than in Ardirejo sub-district. However, the residents’ participation in the development process tends to decrease from the planning – implementation – operation/maintenance. It is predicted that the low participation in the third step – operation/maintenance, is due to the lack of understanding of the whole participants, since the information is exclusively understood by the organizing committee. In other words, there is asymmetrical information occurring between the organizing committee and the residents. For the centrality, this research utilized three indices of the centrality covering degree – closeness – betweenness centrality. The estimation result at planning step draws that there are 21 central actors in Talangagung, wherein 8 of them are the committee members and 13 of them are regular residents. Meanwhile, in Ardirejo sub-disctrict, there are 5 central actors, but all of them are committee members. In the implementation step, there are 10 central actors, consisting of 7 committee members and 3 residents in Talangagung sub-district. Meanwhile, in Ardirejo sub-district, there are 7 central actors and all of them are the committee members. Finally, at the operation/maintenance step, there is no central actor for both sub-districts.

Optimizing identification and management of COPD patients - reviewing the role of the community pharmacist.

PubMed

van der Molen, Thys; van Boven, Job F M; Maguire, Terence; Goyal, Pankaj; Altman, Pablo

2017-01-01

The aim of this paper was to propose key steps for community pharmacist integration into a patient care pathway for chronic obstructive pulmonary disease (COPD) management. A literature search was conducted to identify publications focusing on the role of the community pharmacist in identification and management of COPD. The literature search highlighted evidence supporting an important role for pharmacists at each of the four key steps in the patient care pathway for COPD management. Step 1 (primary prevention): pharmacists are ideally placed to provide information on disease awareness and risk prevention campaigns, and to encourage lifestyle interventions, including smoking cessation. Step 2 (early detection/case finding): pharmacists are often the first point of contact between the patient and the healthcare system and can therefore play an important role in the early identification of patients with COPD. Step 3 (management and ongoing support): pharmacists can assist patients by providing advice and education on dosage, inhaler technique, treatment expectations and the importance of adherence, and by supporting self-management, including recognition and treatment of COPD exacerbations. Step 4 (review and follow-up): pharmacists can play an important role in monitoring adherence and ongoing inhaler technique in patients with COPD. In summary, pharmacists are ideally positioned to play a vital role in all key stages of an integrated COPD patient care pathway from early disease detection to the support of management plans, including advice and counselling regarding medications, inhaler technique and treatment adherence. Areas requiring additional consideration include pharmacist training, increasing awareness of the pharmacist role, administration and reimbursement, and increasing physician-pharmacist collaboration. © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Synthesis of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, amines and aldehydes.

PubMed

Xiang, Jinbao; Geng, Chao; Yi, Lang; Dang, Qun; Bai, Xu

2011-11-01

A practical strategy was developed for the preparation of highly substituted 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones from 4,6-dichloro-5-formylpyrimidine, primary amines, and aldehydes. The key step for this synthesis entails a cyclization reaction involving an intramolecular amide addition to an iminium intermediate formed in situ from 4-amino-pyrimidine-5-carboxamide 2 and aldehydes to form the pyrimido[4,5-d]pyrimidine core with a strategically placed 5-Cl group for further derivatization. The utility of this methodology was demonstrated through the preparation of a 27-membered library of representative 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones in moderate to good yields.

Synthesis of Benzo[a]carbazoles and an Indolo[2,3-a]carbazole from 3-Aryltetramic Acids.

PubMed

Truax, Nathanyal J; Banales Mejia, Fernando; Kwansare, Deborah O; Lafferty, Megan M; Kean, Maeve H; Pelkey, Erin T

2016-08-05

A simple and flexible approach to 3-pyrrolin-2-one fused carbazoles is disclosed. The key step involves the BF3-mediated electrophilic substitution of indoles with N-alkyl-substituted 3-aryltetramic acids, which provides access to indole-substituted 3-pyrrolin-2-ones. Scholl-type oxidative cyclizations of these materials led to the formation of the corresponding 3-pyrrolin-2-one-fused benzo[a]carbazoles and indolo[2,3-a]carbazoles. This work represents the first synthesis of the benzo[a]pyrrolo[3,4-c]carbazol-3(8H)-one ring system, while the indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one ring system is found in a number of biologically active compounds including the protein kinase C (PKC) inhibitor, staurosporine.

Total synthesis and structural revision of the marine macrolide neopeltolide.

PubMed

Custar, Daniel W; Zabawa, Thomas P; Scheidt, Karl A

2008-01-23

The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (1H, 13C, HRMS, IR, NOESY, [alpha]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.

Lipid rafts in T cell signalling and disease

PubMed Central

Jury, Elizabeth C.; Flores-Borja, Fabian; Kabouridis, Panagiotis S.

2007-01-01

Lipid rafts is a blanket term used to describe distinct areas in the plasma membrane rich in certain lipids and proteins and which are thought to perform diverse functions. A large number of studies report on lipid rafts having a key role in receptor signalling and activation of lymphocytes. In T cells, lipid raft involvement was demonstrated in the early steps during T cell receptor (TCR) stimulation. Interestingly, recent evidence has shown that signalling in these domains differs in T cells isolated from patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we discuss these findings and explore the potential of lipid rafts as targets for the development of a new class of agents to downmodulate immune responses and for the treatment of autoimmune diseases. PMID:17890113

Cooperative Light-Activated Iodine and Photoredox Catalysis for the Amination of Csp3 -H Bonds.

PubMed

Becker, Peter; Duhamel, Thomas; Stein, Christopher J; Reiher, Markus; Muñiz, Kilian

2017-06-26

An unprecedented method that makes use of the cooperative interplay between molecular iodine and photoredox catalysis has been developed for dual light-activated intramolecular benzylic C-H amination. Iodine serves as the catalyst for the formation of a new C-N bond by activating a remote Csp3 -H bond (1,5-HAT process) under visible-light irradiation while the organic photoredox catalyst TPT effects the reoxidation of the molecular iodine catalyst. To explain the compatibility of the two involved photochemical steps, the key N-I bond activation was elucidated by computational methods. The new cooperative catalysis has important implications for the combination of non-metallic main-group catalysis with photocatalysis. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Textual data in psychiatry: reasoning by analogy to quantitative principles.

PubMed

Yang, Suzanne; Mulvey, Edward P; Falissard, Bruno

2012-08-01

Personal meaning in subjective experience is a key element in the treatment of persons with mental disorders. Open-response speech samples would appear to be suitable for studying this type of subjective experience, but there are still important challenges in using language as data. Scientific principles involved in sample size calculation, validity, and reliability may be applicable, by analogy, to data collected in the form of words. We describe a rationale for including computer-assisted techniques as one step of a qualitative analysis procedure that includes manual reading. Clarification of a framework for including language as data in psychiatric research may allow us to more effectively bridge biological and psychometric research with clinical practice, a setting where the patient's clinical "data" are, in large part, conveyed in words.

A Two-Step Approach for Producing an Ultrafine-Grain Structure in Cu-30Zn Brass (Postprint)

DTIC Science & Technology

2015-08-13

crystallization anneal at 400 °C (0.55Tm, where Tm is the melting point ) for times ranging from 1 min to 10 hours, followed by water quenching; an additional...200 words) A two-step approach involving cryogenic rolling and subsequent recrystallization annealing was developed to produce an ultrafine-grain...b s t r a c t A two-step approach involving cryogenic rolling and subsequent recrystallization annealing was devel- oped to produce an ultrafine

Molecular water oxidation mechanisms followed by transition metals: state of the art.

PubMed

Sala, Xavier; Maji, Somnath; Bofill, Roger; García-Antón, Jordi; Escriche, Lluís; Llobet, Antoni

2014-02-18

One clean alternative to fossil fuels would be to split water using sunlight. However, to achieve this goal, researchers still need to fully understand and control several key chemical reactions. One of them is the catalytic oxidation of water to molecular oxygen, which also occurs at the oxygen evolving center of photosystem II in green plants and algae. Despite its importance for biology and renewable energy, the mechanism of this reaction is not fully understood. Transition metal water oxidation catalysts in homogeneous media offer a superb platform for researchers to investigate and extract the crucial information to describe the different steps involved in this complex reaction accurately. The mechanistic information extracted at a molecular level allows researchers to understand both the factors that govern this reaction and the ones that derail the system to cause decomposition. As a result, rugged and efficient water oxidation catalysts with potential technological applications can be developed. In this Account, we discuss the current mechanistic understanding of the water oxidation reaction catalyzed by transition metals in the homogeneous phase, based on work developed in our laboratories and complemented by research from other groups. Rather than reviewing all of the catalysts described to date, we focus systematically on the several key elements and their rationale from molecules studied in homogeneous media. We organize these catalysts based on how the crucial oxygen-oxygen bond step takes place, whether via a water nucleophilic attack or via the interaction of two M-O units, rather than based on the nuclearity of the water oxidation catalysts. Furthermore we have used DFT methodology to characterize key intermediates and transition states. The combination of both theory and experiments has allowed us to get a complete view of the water oxidation cycle for the different catalysts studied. Finally, we also describe the various deactivation pathways for these catalysts.

Permeability and kinetic coefficients for mesoscale BCF surface step dynamics: Discrete two-dimensional deposition-diffusion equation analysis

DOE PAGES

Zhao, Renjie; Evans, James W.; Oliveira, Tiago J.

2016-04-08

Here, a discrete version of deposition-diffusion equations appropriate for description of step flow on a vicinal surface is analyzed for a two-dimensional grid of adsorption sites representing the stepped surface and explicitly incorporating kinks along the step edges. Model energetics and kinetics appropriately account for binding of adatoms at steps and kinks, distinct terrace and edge diffusion rates, and possible additional barriers for attachment to steps. Analysis of adatom attachment fluxes as well as limiting values of adatom densities at step edges for nonuniform deposition scenarios allows determination of both permeability and kinetic coefficients. Behavior of these quantities is assessedmore » as a function of key system parameters including kink density, step attachment barriers, and the step edge diffusion rate.« less

Permeability and kinetic coefficients for mesoscale BCF surface step dynamics: Discrete two-dimensional deposition-diffusion equation analysis

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

Zhao, Renjie; Evans, James W.; Oliveira, Tiago J.

Here, a discrete version of deposition-diffusion equations appropriate for description of step flow on a vicinal surface is analyzed for a two-dimensional grid of adsorption sites representing the stepped surface and explicitly incorporating kinks along the step edges. Model energetics and kinetics appropriately account for binding of adatoms at steps and kinks, distinct terrace and edge diffusion rates, and possible additional barriers for attachment to steps. Analysis of adatom attachment fluxes as well as limiting values of adatom densities at step edges for nonuniform deposition scenarios allows determination of both permeability and kinetic coefficients. Behavior of these quantities is assessedmore » as a function of key system parameters including kink density, step attachment barriers, and the step edge diffusion rate.« less

Oxidative stress induced oligomerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61

PubMed Central

Deb, Ishani; Poddar, Ranjana; Paul, Surojit

2011-01-01

The neuron-specific tyrosine phosphatase STEP (STriatal Enriched Phosphatase) is emerging as an important mediator of glutamatergic transmission in the brain. STEP is also thought to be involved in the etiology of neurodegenerative disorders that are linked to oxidative stress such as Alzheimer's disease and cerebral ischemia. However the mechanism by which oxidative stress can modulate STEP activity is still unclear. In the present study we have investigated whether dimerization may play a role in regulating the activity of STEP. Our findings show that STEP61, the membrane associated isoform, can undergo homodimerization under basal conditions in neurons. Dimerization of STEP61 involves intermolecular disulfide bond formation between two cysteine residues (Cys 65 and Cys 76 respectively) present in the hydrophobic region at the N-terminus specific to STEP61. Oxidative stress-induced by hydrogen peroxide leads to a significant increase in the formation of dimers and higher order oligomers of STEP61. Using two substrates, para-nitrophenylphosphate and ERK MAPK we further demonstrate that oligomerization leads to a significant reduction in its enzymatic activity. PMID:21198639

Parents Are Lifesavers. A Handbook for Parent Involvement in Schools.

ERIC Educational Resources Information Center

Batey, Carol S.

Practical and well-defined solutions are presented to build effective and long-lasting partnerships among parents, educators, and community members for the improvement of schools. A step-by-step model is presented, with an outline to guide anyone attempting to involve parents in their children's schools. Chapter 1, "My Journey to Parent…

Guidelines for conducting TMDL consultations on selenium

Treesearch

Dennis A. Lemly

2000-01-01

This report was prepared to provide Environmental Contaminants Specialists in the U.S. Fish and Wildlife Service (Service) with a step-by-step procedure for consultations involving Total Maximum Daily Loads (TMDL's) for selenium. The need for this information stems from recent actions taken by the U.S. Environmental Protection Agency (EPA) that will involve the...

Teachers as Child Advocates: A Continuum of Involvement.

ERIC Educational Resources Information Center

Lindamood, Judy B.

1995-01-01

Describes the steps to increasing levels of teacher involvement in child advocacy. Steps range from "dreamer" with a vision of a better condition, to "volunteer" who gives time and energy without compensation, to "fighter" who uses conflict and dissension to achieve goals. Suggests that this simple continuum encourages teachers to become involved…

Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes.

PubMed

Martin, David B C; Nguyen, Lucas Q; Vanderwal, Christopher D

2012-01-06

A full account of the development of the base-mediated intramolecular Diels-Alder cycloadditions of tryptamine-derived Zincke aldehydes is described. This important complexity-generating transformation provides the tetracyclic core of many indole monoterpene alkaloids in only three steps from commercially available starting materials and played a key role in short syntheses of norfluorocurarine (five steps), dehydrodesacetylretuline (six steps), valparicine (seven steps), and strychnine (six steps). Reasonable mechanistic possibilities for this reaction, a surprisingly facile dimerization of the products, and an unexpected cycloreversion to regenerate Zincke aldehydes under specific conditions are also discussed.

Step by Step to Smoke-Free Schools.

ERIC Educational Resources Information Center

VanSciver, James H.; Roberts, H. Earl

1989-01-01

This ERIC digest discusses ways of effectively banning smoking in schools so that controversies do not continue after implementation of the policy. By advocating a process approach, the document cites steps taken by the Lake Forest School Board to prohibit smoking in and around school grounds. Step one involved committee planning involving…

The effects of continuing care on emerging adult outcomes following residential addiction treatment.

PubMed

Bergman, Brandon G; Hoeppner, Bettina B; Nelson, Lindsay M; Slaymaker, Valerie; Kelly, John F

2015-08-01

Professional continuing care services enhance recovery rates among adults and adolescents, though less is known about emerging adults (18-25 years old). Despite benefit shown from emerging adults' participation in 12-step mutual-help organizations (MHOs), it is unclear whether participation offers benefit independent of professional continuing care services. Greater knowledge in this area would inform clinical referral and linkage efforts. Emerging adults (N=284; 74% male; 95% Caucasian) were assessed during the year after residential treatment on outpatient sessions per week, percent days in residential treatment and residing in a sober living environment, substance use disorder (SUD) medication use, active 12-step MHO involvement (e.g., having a sponsor, completing step work, contact with members outside meetings), and continuous abstinence (dichotomized yes/no). One generalized estimating equation (GEE) model tested the unique effect of each professional service on abstinence, and, in a separate GEE model, the unique effect of 12-step MHO involvement on abstinence over and above professional services, independent of individual covariates. Apart from SUD medication, all professional continuing care services were significantly associated with abstinence over and above individual factors. In the more comprehensive model, relative to zero 12-step MHO activities, odds of abstinence were 1.3 times greater if patients were involved in one activity, and 3.2 times greater if involved in five activities (lowest mean number of activities in the sample across all follow-ups). Both active involvement in 12-step MHOs and recovery-supportive, professional services that link patients with these community-based resources may enhance outcomes for emerging adults after residential treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Development and Pilot Testing of 24/7 In-Ambulance Telemedicine for Acute Stroke: Prehospital Stroke Study at the Universitair Ziekenhuis Brussel-Project.

PubMed

Valenzuela Espinoza, Alexis; Van Hooff, Robbert-Jan; De Smedt, Ann; Moens, Maarten; Yperzeele, Laetitia; Nieboer, Koenraad; Hubloue, Ives; de Keyser, Jacques; Convents, Andre; Fernandez Tellez, Helio; Dupont, Alain; Putman, Koen; Brouns, Raf

2016-01-01

In-ambulance telemedicine is a recently developed and a promising approach to improve emergency care. We implemented the first ever 24/7 in-ambulance telemedicine service for acute stroke. We report on our experiences with the development and pilot testing of the Prehospital Stroke Study at the Universitair Ziekenhuis Brussel (PreSSUB) to facilitate a wider spread of the knowledge regarding this technique. Successful execution of the project involved the development and validation of a novel stroke scale, design and creation of specific hardware and software solutions, execution of field tests for mobile internet connectivity, design of new care processes and information flows, recurrent training of all professional caregivers involved in acute stroke management, extensive testing on healthy volunteers, organisation of a 24/7 teleconsultation service by trained stroke experts and 24/7 technical support, and resolution of several legal issues. In all, it took 41 months of research and development to confirm the safety, technical feasibility, reliability, and user acceptance of the PreSSUB approach. Stroke-specific key information can be collected safely and reliably before and during ambulance transportation and can adequately be communicated with the inhospital team awaiting the patient. This paper portrays the key steps required and the lessons learned for successful implementation of a 24/7 expert telemedicine service supporting patients with acute stroke during ambulance transportation to the hospital. © 2016 S. Karger AG, Basel.

Molecular characterization of the enzymes involved in the degradation of a brominated aromatic herbicide.

PubMed

Chen, Kai; Huang, Linglong; Xu, Changfeng; Liu, Xiaomei; He, Jian; Zinder, Stephen H; Li, Shunpeng; Jiang, Jiandong

2013-09-01

Dehalogenation is the key step in the degradation of halogenated aromatics, while reductive dehalogenation is originally thought to rarely occur in aerobes. In this study, an aerobic strain of Comamonas sp. 7D-2 was shown to degrade the brominated aromatic herbicide bromoxynil completely and release two equivalents of bromides under aerobic conditions. The enzymes involved in the degradation of bromoxynil to 4-carboxy-2-hydroxymuconate-6-semialdehyde, including nitrilase, reductive dehalogenase (BhbA), 4-hydroxybenzoate 3-monooxygenase and protocatechuate 4,5-dioxygenase, were molecularly characterized. The novel dehalogenase BhbA was shown to be a complex of a respiration-linked reductive dehalogenase (RdhA) domain and a NAD(P)H-dependent oxidoreductase domain and to have key features of anaerobic respiratory RdhAs, including two predicted binding motifs for [4Fe-4S] clusters and a close association with a hydrophobic membrane protein (BhbB). BhbB was confirmed to anchor BhbA to the membrane. BhbA was partially purified and found to use NAD(P)H as electron donors. Full-length bhbA homologues were found almost exclusively in marine aerobic proteobacteria, suggesting that reductive dehalogenation occurs extensively in aerobes and that bhbA is horizontally transferred from marine microorganisms. The discovery of a functional reductive dehalogenase and ring-cleavage oxygenases in an aerobe opens up possibilities for basic research as well as the potential application for bioremediation. © 2013 John Wiley & Sons Ltd.

Nuclear Power System Architecture and Safety Study- Feasibility of Launch Pad Explosion Simulation using Radios

NASA Astrophysics Data System (ADS)

Destefanis, Stefano; Tracino, Emanuele; Giraudo, Martina

2014-06-01

During a mission involving a spacecraft using nuclear power sources (NPS), the consequences to the population induced by an accident has to be taken into account carefully.Part of the study (led by AREVA, with TAS-I as one of the involved parties) was devoted to "Worst Case Scenario Consolidation". In particular, one of the activities carried out by TAS-I had the aim of characterizing the accidental environment (explosion on launch pad or during launch) and consolidate the requirements given as input in the study. The resulting requirements became inputs for Nuclear Power Source container design.To do so, TAS-I did first an overview of the available technical literature (mostly developed in the frame of NASA Mercury / Apollo program), to identify the key parameters to be used for analytical assessment (blast pressure wave, fragments size, speed and distribution, TNT equivalent of liquid propellant).Then, a simplified Radioss model was setup, to verify both the cards needed for blast / fragment impact analysis and the consistency between preliminary results and available technical literature (Radioss is commonly used to design mine - resistant vehicles, by simulating the effect of blasts onto structural elements, and it is used in TAS-I for several types of analysis, including land impact, water impact and fluid - structure interaction).The obtained results (albeit produced by a very simplified model) are encouraging, showing that the analytical tool and the selected key parameters represent a step in the right direction.

From Diapers to Dating. A Parent's Guide to Raising Sexually Healthy Children.

ERIC Educational Resources Information Center

Haffner, Debra W.

This step-by-step program for raising sexually healthy children helps parents provide accurate information and communicate their own values to their children. Chapter 1, "The Basics"; includes "Sexually Healthy Families"; "The Key: Finding Teachable Moments"; and "Guidelines for Communication." Chapter 2,…

Nurse-led clinics: 10 essential steps to setting up a service.

PubMed

Hatchett, Richard

This article outlines 10 key steps for practitioners to consider when setting up and running a nurse-led clinic. It lays emphasis on careful planning, professional development and the need to audit and evaluate the service to ensure the clinic is measurably effective.

Unraveling the early molecular and physiological mechanisms involved in response to phenanthrene exposure.

PubMed

Dumas, Anne-Sophie; Taconnat, Ludivine; Barbas, Evangelos; Rigaill, Guillem; Catrice, Olivier; Bernard, Delphine; Benamar, Abdelilah; Macherel, David; El Amrani, Abdelhak; Berthomé, Richard

2016-10-21

Higher plants have to cope with increasing concentrations of pollutants of both natural and anthropogenic origin. Given their capacity to concentrate and metabolize various compounds including pollutants, plants can be used to treat environmental problems - a process called phytoremediation. However, the molecular mechanisms underlying the stabilization, the extraction, the accumulation and partial or complete degradation of pollutants by plants remain poorly understood. Here, we determined the molecular events involved in the early plant response to phenanthrene, used as a model of polycyclic aromatic hydrocarbons. A transcriptomic and a metabolic analysis strongly suggest that energy availability is the crucial limiting factor leading to high and rapid transcriptional reprogramming that can ultimately lead to death. We show that the accumulation of phenanthrene in leaves inhibits electron transfer and photosynthesis within a few minutes, probably disrupting energy transformation. This kinetic analysis improved the resolution of the transcriptome in the initial plant response to phenanthrene, identifying genes that are involved in primary processes set up to sense and detoxify this pollutant but also in molecular mechanisms used by the plant to cope with such harmful stress. The identification of first events involved in plant response to phenanthrene is a key step in the selection of candidates for further functional characterization, with the prospect of engineering efficient ecological detoxification systems for polycyclic aromatic hydrocarbons.

Post-processing procedure for industrial quantum key distribution systems

NASA Astrophysics Data System (ADS)

Kiktenko, Evgeny; Trushechkin, Anton; Kurochkin, Yury; Fedorov, Aleksey

2016-08-01

We present algorithmic solutions aimed on post-processing procedure for industrial quantum key distribution systems with hardware sifting. The main steps of the procedure are error correction, parameter estimation, and privacy amplification. Authentication of classical public communication channel is also considered.

An in vivo genetic screen for genes involved in spliced leader trans-splicing indicates a crucial role for continuous de novo spliced leader RNP assembly.

PubMed

Philippe, Lucas; Pandarakalam, George C; Fasimoye, Rotimi; Harrison, Neale; Connolly, Bernadette; Pettitt, Jonathan; Müller, Berndt

2017-08-21

Spliced leader (SL) trans-splicing is a critical element of gene expression in a number of eukaryotic groups. This process is arguably best understood in nematodes, where biochemical and molecular studies in Caenorhabditis elegans and Ascaris suum have identified key steps and factors involved. Despite this, the precise details of SL trans-splicing have yet to be elucidated. In part, this is because the systematic identification of the molecules involved has not previously been possible due to the lack of a specific phenotype associated with defects in this process. We present here a novel GFP-based reporter assay that can monitor SL1 trans-splicing in living C. elegans. Using this assay, we have identified mutants in sna-1 that are defective in SL trans-splicing, and demonstrate that reducing function of SNA-1, SNA-2 and SUT-1, proteins that associate with SL1 RNA and related SmY RNAs, impairs SL trans-splicing. We further demonstrate that the Sm proteins and pICln, SMN and Gemin5, which are involved in small nuclear ribonucleoprotein assembly, have an important role in SL trans-splicing. Taken together these results provide the first in vivo evidence for proteins involved in SL trans-splicing, and indicate that continuous replacement of SL ribonucleoproteins consumed during trans-splicing reactions is essential for effective trans-splicing. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

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

Colman, Joan; Rice, Glenn E., E-mail: rice.glenn@epa.gov; Wright, J. Michael

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmentalmore » effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.« less

Canopy1, a positive feedback regulator of FGF signaling, controls progenitor cell clustering during Kupffer's vesicle organogenesis

PubMed Central

Matsui, Takaaki; Thitamadee, Siripong; Murata, Tomoko; Kakinuma, Hisaya; Nabetani, Takuji; Hirabayashi, Yoshio; Hirate, Yoshikazu; Okamoto, Hitoshi; Bessho, Yasumasa

2011-01-01

The assembly of progenitor cells is a crucial step for organ formation during vertebrate development. Kupffer's vesicle (KV), a key organ required for the left–right asymmetric body plan in zebrafish, is generated from a cluster of ∼20 dorsal forerunner cells (DFCs). Although several genes are known to be involved in KV formation, how DFC clustering is regulated and how cluster formation then contributes to KV formation remain unclear. Here we show that positive feedback regulation of FGF signaling by Canopy1 (Cnpy1) controls DFC clustering. Cnpy1 positively regulates FGF signals within DFCs, which in turn promote Cadherin1-mediated cell adhesion between adjacent DFCs to sustain cell cluster formation. When this FGF positive feedback loop is disrupted, the DFC cluster fails to form, eventually leading to KV malformation and defects in the establishment of laterality. Our results therefore uncover both a previously unidentified role of FGF signaling during vertebrate organogenesis and a regulatory mechanism underlying cell cluster formation, which is an indispensable step for formation of a functional KV and establishment of the left–right asymmetric body plan. PMID:21628557

NET-VISA, a Bayesian method next-generation automatic association software. Latest developments and operational assessment.

NASA Astrophysics Data System (ADS)

Le Bras, Ronan; Kushida, Noriyuki; Mialle, Pierrick; Tomuta, Elena; Arora, Nimar

2017-04-01

The Preparatory Commission for the Comprehensive Nuclear-Test-Ban Treaty Organization (CTBTO) has been developing a Bayesian method and software to perform the key step of automatic association of seismological, hydroacoustic, and infrasound (SHI) parametric data. In our preliminary testing in the CTBTO, NET_VISA shows much better performance than its currently operating automatic association module, with a rate for automatic events matching the analyst-reviewed events increased by 10%, signifying that the percentage of missed events is lowered by 40%. Initial tests involving analysts also showed that the new software will complete the automatic bulletins of the CTBTO by adding previously missed events. Because products by the CTBTO are also widely distributed to its member States as well as throughout the seismological community, the introduction of a new technology must be carried out carefully, and the first step of operational integration is to first use NET-VISA results within the interactive analysts' software so that the analysts can check the robustness of the Bayesian approach. We report on the latest results both on the progress for automatic processing and for the initial introduction of NET-VISA results in the analyst review process

Radio Astronomy on and Around the Moon

NASA Astrophysics Data System (ADS)

Falcke, Heino; Klein Wolt, Mark; Ping, Jinsong; Chen, Linjie

2018-06-01

The exploration of remote places on other planets has now become a major goal in current space flight scenarios. On the other hand, astronomers have always sought the most remote and isolated sites to place their observatories and to make their most precise and most breath taking discoveries. Especially for radio astronomy, lunar exploration offers a complete new window to the universe. The polar region and the far-side of the moon are acknowledged as unique locations for a low-frequency radio telescope providing scientific data at wavelengths that cannot be obtained from the Earth nor from single satellites. Scientific areas to be covered range from radio surveys, to solar-system studies, exo-planet detection, and astroparticle physics. The key science area, however, is the detection and measurement of cosmological 21 cm hydrogen emission from the still unexplored dark ages of the universe. Developing a lunar radio facility can happen in steps and may involve small satellites, rover-based radio antennas, of free- flying constellations around the moon. A first such step could be the Netherlands-Chinese Long Wavelength Explorer (NCLE), which is supposed to be launched in 2018 as part of the ChangE’4 mission to the moon-earth L2 point.

A multi-step chromatographic strategy to purify three fungal endo-β-glucanases.

PubMed

McCarthy, Tracey; Tuohy, Maria G

2011-01-01

Fungi and fungal enzymes have traditionally occupied a central role in biotechnology. Understanding the biochemical properties of the variety of enzymes produced by these eukaryotes has been an area of research interest for decades and again more recently due to global interest in greener bio-production technologies. Purification of an individual enzyme allows its unique biochemical and functional properties to be determined, can provide key information as to the role of individual biocatalysts within a complex enzyme system, and can inform both protein engineering and enzyme production strategies in the development of novel green technologies based on fungal biocatalysts. Many enzymes of current biotechnological interest are secreted by fungi into the extracellular culture medium. These crude enzyme mixtures are typically complex, multi-component, and generally also contain other non-enzymatic proteins and secondary metabolites. In this chapter, we describe a multi-step chromatographic strategy required to isolate three new endo-β-glucanases (denoted EG V, EG VI, and EG VII) with activity against cereal mixed-linkage β-glucans from the thermophilic fungus Talaromyces emersonii. This work also illustrates the challenges frequently involved in isolating individual extracellular fungal proteins in general.

Changes in melatonin levels in transgenic 'Micro-Tom' tomato overexpressing ovine AANAT and ovine HIOMT genes.

PubMed

Wang, Lin; Zhao, Yu; Reiter, Russel J; He, Changjiu; Liu, Guoshi; Lei, Qiong; Zuo, Bixiao; Zheng, Xiao Dong; Li, Qingtian; Kong, Jin

2014-03-01

In animals, the melatonin biosynthesis pathway has been well defined after the isolation and identification of the four key genes that are involved in the conversion of tryptophan to melatonin. In plants, there are special alternative catalyzing steps, and plant genes share very low homology with the animal genes. It was of interest to examine the phenotype of transgenic Micro-Tom tomato plants overexpressing the homologous sheep oAANAT and oHIOMT genes responsible for the last two steps of melatonin synthesis. The oAANAT transgenic plants have higher melatonin levels and lower indoleacetic acid (IAA) contents than control due to the competition for tryptophan, the same precursor for both melatonin and IAA. Therefore, the oAANAT lines lose the 'apical dominance' inferring that melatonin likely lacks auxin activity. The significantly higher melatonin content in oHIOMT lines than oAANAT lines provides new proof for the important role of ASMT in plant melatonin synthesis. In addition, the enhanced drought tolerance of oHIOMT lines will also be an important contribution for plant engineering. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[Metabolic engineering of edible plant oils].

PubMed

Yue, Ai-Qin; Sun, Xi-Ping; Li, Run-Zhi

2007-12-01

Plant seed oil is the major source of many fatty acids for human nutrition, and also one of industrial feedstocks. Recent advances in understanding of the basic biochemistry of seed oil biosynthesis, coupled with cloning of the genes encoding the enzymes involved in fatty acid modification and oil accumulation, have set the stage for the metabolic engineering of oilseed crops that produce "designer" plant seed oils with the improved nutritional values for human being. In this review we provide an overview of seed oil biosynthesis/regulation and highlight the key enzymatic steps that are targets for gene manipulation. The strategies of metabolic engineering of fatty acids in oilseeds, including overexpression or suppression of genes encoding single or multi-step biosynthetic pathways and assembling the complete pathway for the synthesis of long-chain polyunsaturated fatty acids (e.g. arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid) are described in detail. The current "bottlenecks" in using common oilseeds as "bioreactors" for commercial production of high-value fatty acids are analyzed. It is also discussed that the future research focuses of oilseed metabolic engineering and the prospects in creating renewable sources and promoting the sustainable development of human society and economy.

Targeting innate immunity for neurodegenerative disorders of the central nervous system.

PubMed

Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco; Ginhoux, Florent; Holmes, Clive; Lamb, Bruce; Landreth, Gary; Lee, Daniel C; Low, Donovan; Lynch, Marina A; Monsonego, Alon; O'Banion, M Kerry; Pekny, Milos; Puschmann, Till; Russek-Blum, Niva; Sandusky, Leslie A; Selenica, Maj-Linda B; Takata, Kazuyuki; Teeling, Jessica; Town, Terrence; Van Eldik, Linda J

2016-09-01

Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. © 2016 International Society for Neurochemistry.

Construction and analysis of lncRNA-lncRNA synergistic networks to reveal clinically relevant lncRNAs in cancer.

PubMed

Li, Yongsheng; Chen, Juan; Zhang, Jinwen; Wang, Zishan; Shao, Tingting; Jiang, Chunjie; Xu, Juan; Li, Xia

2015-09-22

Long non-coding RNAs (lncRNAs) play key roles in diverse biological processes. Moreover, the development and progression of cancer often involves the combined actions of several lncRNAs. Here we propose a multi-step method for constructing lncRNA-lncRNA functional synergistic networks (LFSNs) through co-regulation of functional modules having three features: common coexpressed genes of lncRNA pairs, enrichment in the same functional category and close proximity within protein interaction networks. Applied to three cancers, we constructed cancer-specific LFSNs and found that they exhibit a scale free and modular architecture. In addition, cancer-associated lncRNAs tend to be hubs and are enriched within modules. Although there is little synergistic pairing of lncRNAs across cancers, lncRNA pairs involved in the same cancer hallmarks by regulating same or different biological processes. Finally, we identify prognostic biomarkers within cancer lncRNA expression datasets using modules derived from LFSNs. In summary, this proof-of-principle study indicates synergistic lncRNA pairs can be identified through integrative analysis of genome-wide expression data sets and functional information.

The Consequences of Surface Confinement on Free Radical Chemistry

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

Birtt, P.F.; Buchanan, A.C., III

1999-08-22

Mass transport limitations impact the thermochemical processing of fossil and renewable energy resources, which involves the breakdown of cross-linked, macromolecular networks. To Investigate the molecular level details of the consequences of molecular confinement on high temperature (275-500°C) free-radical reaction pathways, we have been examining the pyrolysis of model compounds attached to the surface of non-porous silica nanoparticles through a thermally robust Si-O-C aryl, tetha. Pyrolysis of silica-immobilized diphenylalkanes and related ethers have been studied in detail and compared with the corresponding behavior in fluid phases. The diffusional constraints can lead to reduced rates of radical termination on the surface, andmore » enhancement of neophyl-like rearrangements, cyclization-dehydrogenation pathways, and ipso- aromatic substitutions. Furthermore, studies of two-component surfaces have revealed the importance of a radical relay mechanism involving rapid serial hydrogen transfer steps resulting from the molecular pre-organization on the low fractal dimension silica surface. Key findings are reviewed in this paper, and the implications of these results for fuel processing are described.« less

The role of materials in global competitiveness

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

NONE

A symposium on global competitiveness was sponsored by ASM`s Advisory Technical Awareness Council during Materials Week in Cleveland last October. Carpenter Technology`s approach to internationalization and diversification involves three steps: internationalization of core businesses, diversification into engineered products, and focused research and development. Aluminum`s potential was the basis of the Audi-Alcoa relationship, and the result was a true breakthrough: a spaceframe structure designed to integrate every component surface as a structural entity, featuring straight and curved extruded sections joined by complex diecast nodes at key intersections and connection points. Through the support of research and development, many federal departments andmore » agencies have long been involved directly or indirectly in the support of civilian as well as defense industries. New copper alloys and fabrication techniques are enhancing global competitiveness, based largely on copper`s natural advantages of conductivity and corrosion resistance. The heavy equipment industry is a major transformer and user of steel, rubber, aluminum, welding consumables and equipment; glass, plastics, microprocessors and electronics; machine tools, and energy. It comprises the construction, farming, mining, and powertrain equipment manufacturers.« less

Live Cell Imaging Confocal Microscopy Analysis of HBV Myr-PreS1 Peptide Binding and Uptake in NTCP-GFP Expressing HepG2 Cells.

PubMed

König, Alexander; Glebe, Dieter

2017-01-01

To obtain basic knowledge about specific molecular mechanisms involved in the entry of pathogens into cells is the basis for establishing pharmacologic substances blocking initial viral binding, infection, and subsequent viral spread. Lack of information about key cellular factors involved in the initial steps of HBV infection has hampered the characterization of HBV binding and entry for decades. However, recently, the liver-specific sodium-dependent taurocholate cotransporting polypeptide (NTCP) has been discovered as a functional receptor for HBV and HDV, thus opening the field for new concepts of basic binding and entry of HBV and HDV. Here, we describe practical issues of a basic in vitro assay system to examine kinetics and mechanisms of receptor-dependent HBV binding, uptake, and intracellular trafficking by live-cell imaging confocal microscopy. The assay system is comprised of HepG2 cells expressing a NTCP-GFP fusion-protein and chemically synthesized, fluorophore-labeled part of HBV surface protein, spanning the first N-terminal 48 amino acids of preS1 of the large hepatitis B virus surface protein.

High-solid Anaerobic Co-digestion of Sewage Sludge and Cattle Manure: The Effects of Volatile Solid Ratio and pH

PubMed Central

Dai, Xiaohu; Chen, Yang; Zhang, Dong; Yi, Jing

2016-01-01

High-solid anaerobic digestion is an attractive solution to the problem of sewage sludge disposal. One method that can be used to enhance the production of volatile fatty acids (VFAs) and the generation of methane from anaerobic digestion involves combining an alkaline pretreatment step with the synergistic effects of sewage sludge and cattle manure co-digestion, which improves the activity of key enzymes and microorganisms in the anaerobic co-digestion system to promote the digestion of organic waste. In this study, we describe an efficient strategy that involves adjusting the volatile solid (VS) ratio (sewage sludge/cattle manure: 3/7) and initial pH (9.0) to improve VFA production and methane generation from the co-digestion of sludge and manure. The experimental results indicate that the maximum VFA production was 98.33 g/kg-TS (total solid) at the optimal conditions. Furthermore, methane generation in a long-term semi-continuously operated reactor (at a VS ratio of 3/7 and pH of 9.0) was greater than 120.0 L/kg-TS. PMID:27725704

New high-efficiency silicon solar cells

NASA Technical Reports Server (NTRS)

Daud, T.; Crotty, G. T.

1985-01-01

A design for silicon solar cells was investigated as an approach to increasing the cell open-circuit voltage and efficiency for flat-plate terrestrial photovoltaic applications. This deviates from past designs, where either the entire front surface of the cell is covered by a planar junction or the surface is textured before junction formation, which results in an even greater (up to 70%) junction area. The heavily doped front region and the junction space charge region are potential areas of high recombination for generated and injected minority carriers. The design presented reduces junction area by spreading equidiameter dot junctions across the surface of the cell, spaced about a diffusion length or less from each other. Various dot diameters and spacings allowed variations in total junction area. A simplified analysis was done to obtain a first-order design optimization. Efficiencies of up to 19% can be obtained. Cell fabrication involved extra masking steps for selective junction diffusion, and made surface passivation a key element in obtaining good collection. It also involved photolithography, with line widths down to microns. A method is demonstrated for achieving potentially high open-circuit voltages and solar-cell efficiencies.

High-solid Anaerobic Co-digestion of Sewage Sludge and Cattle Manure: The Effects of Volatile Solid Ratio and pH

NASA Astrophysics Data System (ADS)

Dai, Xiaohu; Chen, Yang; Zhang, Dong; Yi, Jing

2016-10-01

High-solid anaerobic digestion is an attractive solution to the problem of sewage sludge disposal. One method that can be used to enhance the production of volatile fatty acids (VFAs) and the generation of methane from anaerobic digestion involves combining an alkaline pretreatment step with the synergistic effects of sewage sludge and cattle manure co-digestion, which improves the activity of key enzymes and microorganisms in the anaerobic co-digestion system to promote the digestion of organic waste. In this study, we describe an efficient strategy that involves adjusting the volatile solid (VS) ratio (sewage sludge/cattle manure: 3/7) and initial pH (9.0) to improve VFA production and methane generation from the co-digestion of sludge and manure. The experimental results indicate that the maximum VFA production was 98.33 g/kg-TS (total solid) at the optimal conditions. Furthermore, methane generation in a long-term semi-continuously operated reactor (at a VS ratio of 3/7 and pH of 9.0) was greater than 120.0 L/kg-TS.

Bacterial cell-wall recycling

PubMed Central

Johnson, Jarrod W.; Fisher, Jed F.; Mobashery, Shahriar

2012-01-01

Many Gram-negative and Gram-positive bacteria recycle a significant proportion of the peptidoglycan components of their cell walls during their growth and septation. In many—and quite possibly all—bacteria, the peptidoglycan fragments are recovered and recycled. While cell-wall recycling is beneficial for the recovery of resources, it also serves as a mechanism to detect cell-wall–targeting antibiotics and to regulate resistance mechanisms. In several Gram-negative pathogens, anhydro-MurNAc-peptide cell-wall fragments regulate AmpC β-lactamase induction. In some Gram-positive organisms, short peptides derived from the cell wall regulate the induction of both β-lactamase and β-lactam-resistant penicillin-binding proteins. The involvement of peptidoglycan recycling with resistance regulation suggests that inhibitors of the enzymes involved in the recycling might synergize with cell-wall-targeted antibiotics. Indeed, such inhibitors improve the potency of β-lactams in vitro against inducible AmpC β-lactamase-producing bacteria. We describe the key steps of cell-wall remodeling and recycling, the regulation of resistance mechanisms by cell-wall recycling, and recent advances toward the discovery of cell-wall recycling inhibitors. PMID:23163477

Gold-Catalyzed Formal C-C Bond Insertion Reaction of 2-Aryl-2-diazoesters with 1,3-Diketones.

PubMed

Ren, Yuan-Yuan; Chen, Mo; Li, Ke; Zhu, Shou-Fei

2018-06-29

The transition-metal-catalyzed formal C-C bond insertion reaction of diazo compounds with monocarbonyl compounds is well established, but the related reaction of 1,3-diketones instead gives C-H bond insertion products. Herein, we report a protocol for a gold-catalyzed formal C-C bond insertion reaction of 2-aryl-2-diazoesters with 1,3-diketones, which provides efficient access to polycarbonyl compounds with an all-carbon quaternary center. The aryl ester moiety plays a crucial role in the unusual chemoselectivity, and the addition of a Brønsted acid to the reaction mixture improves the yield of the C-C bond insertion product. A reaction mechanism involving cyclopropanation of a gold carbenoid with an enolate and ring-opening of the resulting donor-acceptor-type cyclopropane intermediate is proposed. This mechanism differs from that of the traditional Lewis-acid-catalyzed C-C bond insertion reaction of diazo compounds with monocarbonyl compounds, which involves a rearrangement of a zwitterion intermediate as a key step. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Child Sexual Abuse Prevention: How to Take the First Steps.

ERIC Educational Resources Information Center

Anderson, Cordelia

This booklet provides advice and guidelines for persons interested in developing and implementing child sexual abuse prevention programs. Eight steps to child sexual abuse prevention are outlined. Step 1 involves recognition that child sexual abuse can be prevented, and provides facts to use when discussing sexual abuse. Step 2 highlights ways of…

A Dynamic Pathway for Stone-Wales Bond Rotation on Carbon Nanotubes through Diamond-Like Bonds

NASA Technical Reports Server (NTRS)

Wei, Chen-Yu; Srivastava, Deepak; Cho, Kyeong-Jae; Menon, Madhu

2003-01-01

A new lower energy barrier with a two-step pathway of Stone-Wales (SW) ,ond rotation on carbon nanotubes (CNTs) is found through molecular dynamics (MD) simulations of CNTs under tension. The first step involves going over to a stable sp3-like metastable configuration with half rotated and partially tilted C-C bond. The second step involves going over to the fully rotated C-C bond with the formation of a SW defect in the nanotube. The energy barrier for this two-step dynamic pathway is significantly lower than the previously known static barrier for in-plane rotation of the C-C bond on a tensile strained (> 4%) CNT.

Boric acid reversibly inhibits the second step of pre-mRNA splicing.

PubMed

Shomron, Noam; Ast, Gil

2003-09-25

Several approaches have been used to identify the factors involved in mRNA splicing. None of them, however, comprises a straightforward reversible method for inhibiting the second step of splicing using an external reagent other than a chelator. This investigation demonstrates that the addition of boric acid to an in vitro pre-mRNA splicing reaction causes a dose-dependent reversible inhibition effect on the second step of splicing. The mechanism of action does not involve chelation of several metal ions; hindrance of 3' splice-site; or binding to hSlu7. This study presents a novel method for specific reversible inhibition of the second step of pre-mRNA splicing.

The role of public-private partnerships in addressing the biomedical innovation challenge.

PubMed

Said, Maya; Zerhouni, Elias

2014-11-01

Without a step change in the productivity of pharmaceutical research and development, it will be difficult to tackle the public health challenges facing societies worldwide. Public–private partnerships could play a key role in achieving this step change, but they need to be well designed and led.

Essentials of Millon Inventories Assessment. Essentials of Psychological Assessment Series.

ERIC Educational Resources Information Center

Strack, Stephen

This step-by-step reference guide to the five key Millon personality inventories includes vital information about each of the tests, including information on psychometric characteristics, special populations, assets-limitations, reliability-validity, and interpretation. The tests are: the Millon Clinical Multiaxial Inventory III (MCMI-III); the…

Strategic Marketing: The President's Perspective.

ERIC Educational Resources Information Center

Pappas, Richard J.; Shaink, M. Richard

1994-01-01

Provides a step-by-step guide to developing a college marketing plan. Identifying a target market and determining an appropriate mix of promotional strategies are considered key to the process. Highlights the college president's role in the marketing process, indicating that, although the president is the chief marketer, all employees must be…

The Mentor Kit. A Step-by-Step Guide To Creating an Effective Mentor Program in Your School [and] Reproducible Forms To Accompany the Mentor Program in Your School.

ERIC Educational Resources Information Center

Nash, Diane; Treffinger, Don

Mentorships, the art of a creatively productive person teaching, counseling, and inspiring a student with similar interests, can be the result of circumstance or they can be the result of mentorship programs engineered in the academic world. Data collected from over 25 different academic models of mentorship have been distilled into 7 key steps to…

Involvement of α-, γ- and δ-Tocopherol Isomers from
Pumpkin (Cucurbita pepo L.) Seed Oil or Oil Mixtures in
the Biphasic DPPH˙ Disappearance Kinetics

PubMed Central

Broznić, Dalibor; Milin, Čedomila

2016-01-01

Summary The antioxidant activity of three types of pumpkin seed oil or oil mixtures (cold- -pressed, produced from roasted seed paste and salad) produced in the northern part of Croatia and the kinetics of their behaviour as free radical scavengers were investigated using DPPH˙. In addition, the involvement of oil tocopherol isomers (α-, γ- and δ-) in different steps of DPPH˙ disappearance and their impact on the rate of reaction were analysed. The kinetics of DPPH˙ disappearance is a two-step process. In the first step, rapid disappearance of DPPH˙ occurs during the first 11 min of the reaction, depending on the oil type, followed by a slower decline in the second step. To describe DPPH˙ disappearance kinetics, six mathematical models (mono- and biphasic) were tested. Our findings showed that γ- and δ-tocopherols affected DPPH˙ disappearance during the first step, and α-tocopherol in the second step of the reaction. Moreover, α-tocopherol demonstrated 30 times higher antioxidant activity than γ- and δ-tocopherols. The results indicated the biphasic double-exponential behaviour of DPPH˙ disappearance in oil samples, due to the complexity of reactions that involve different tocopherol isomers and proceed through different chemical pathways. PMID:27904410

Involvement of α-, γ- and δ-Tocopherol Isomers from
Pumpkin (Cucurbita pepo L.) Seed Oil or Oil Mixtures in
the Biphasic DPPH˙ Disappearance Kinetics.

PubMed

Broznić, Dalibor; Jurešić, Gordana Čanadi; Milin, Čedomila

2016-06-01

The antioxidant activity of three types of pumpkin seed oil or oil mixtures (cold- -pressed, produced from roasted seed paste and salad) produced in the northern part of Croatia and the kinetics of their behaviour as free radical scavengers were investigated using DPPH˙. In addition, the involvement of oil tocopherol isomers (α-, γ- and δ-) in different steps of DPPH˙ disappearance and their impact on the rate of reaction were analysed. The kinetics of DPPH˙ disappearance is a two-step process. In the first step, rapid disappearance of DPPH˙ occurs during the first 11 min of the reaction, depending on the oil type, followed by a slower decline in the second step. To describe DPPH˙ disappearance kinetics, six mathematical models (mono- and biphasic) were tested. Our findings showed that γ- and δ-tocopherols affected DPPH˙ disappearance during the first step, and α-tocopherol in the second step of the reaction. Moreover, α-tocopherol demonstrated 30 times higher antioxidant activity than γ- and δ-tocopherols. The results indicated the biphasic double-exponential behaviour of DPPH˙ disappearance in oil samples, due to the complexity of reactions that involve different tocopherol isomers and proceed through different chemical pathways.

Eating and drinking interventions for people at risk of lacking decision-making capacity: who decides and how?

PubMed

Clarke, Gemma; Galbraith, Sarah; Woodward, Jeremy; Holland, Anthony; Barclay, Stephen

2015-06-11

Some people with progressive neurological diseases find they need additional support with eating and drinking at mealtimes, and may require artificial nutrition and hydration. Decisions concerning artificial nutrition and hydration at the end of life are ethically complex, particularly if the individual lacks decision-making capacity. Decisions may concern issues of life and death: weighing the potential for increasing morbidity and prolonging suffering, with potentially shortening life. When individuals lack decision-making capacity, the standard processes of obtaining informed consent for medical interventions are disrupted. Increasingly multi-professional groups are being utilised to make difficult ethical decisions within healthcare. This paper reports upon a service evaluation which examined decision-making within a UK hospital Feeding Issues Multi-Professional Team. A three month observation of a hospital-based multi-professional team concerning feeding issues, and a one year examination of their records. The key research questions are: a) How are decisions made concerning artificial nutrition for individuals at risk of lacking decision-making capacity? b) What are the key decision-making factors that are balanced? c) Who is involved in the decision-making process? Decision-making was not a singular decision, but rather involved many different steps. Discussions involving relatives and other clinicians, often took place outside of meetings. Topics of discussion varied but the outcome relied upon balancing the information along four interdependent axes: (1) Risks, burdens and benefits; (2) Treatment goals; (3) Normative ethical values; (4) Interested parties. Decision-making was a dynamic ongoing process with many people involved. The multiple points of decision-making, and the number of people involved with the decision-making process, mean the question of 'who decides' cannot be fully answered. There is a potential for anonymity of multiple decision-makers to arise. Decisions in real world clinical practice may not fit precisely into a model of decision-making. The findings from this service evaluation illustrate that within multi-professional team decision-making; decisions may contain elements of both substituted and supported decision-making, and may be better represented as existing upon a continuum.

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

PubMed

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

2007-09-15

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

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

PubMed

Desai, Kashappa Goud; Obayashi, Hirokazu; Colandene, James D; Nesta, Douglas P

2018-03-28

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Protein Kinase A Regulates Molecular Chaperone Transcription and Protein Aggregation

PubMed Central

Prince, Thomas; Calderwood, Stuart K.

2011-01-01

Heat shock factor 1 (HSF1) regulates one of the major pathways of protein quality control and is essential for deterrence of protein-folding disorders, particularly in neuronal cells. However, HSF1 activity declines with age, a change that may open the door to progression of neurodegenerative disorders such as Huntington's disease. We have investigated mechanisms of HSF1 regulation that may become compromised with age. HSF1 binds stably to the catalytic domain of protein kinase A (PKAcα) and becomes phosphorylated on at least one regulatory serine residue (S320). We show here that PKA is essential for effective transcription of HSP genes by HSF1. PKA triggers a cascade involving HSF1 binding to the histone acetylase p300 and positive translation elongation factor 1 (p-TEFb) and phosphorylation of the c-terminal domain of RNA polymerase II, a key mechanism in the downstream steps of HSF1-mediated transcription. This cascade appears to play a key role in protein quality control in neuronal cells expressing aggregation-prone proteins with long poly-glutamine (poly-Q) tracts. Such proteins formed inclusion bodies that could be resolved by HSF1 activation during heat shock. Resolution of the inclusions was inhibited by knockdown of HSF1, PKAcα, or the pTEFb component CDK9, indicating a key role for the HSF1-PKA cascade in protein quality control. PMID:22216146

Multiple Criteria Decision Analysis for Health Care Decision Making--An Introduction: Report 1 of the ISPOR MCDA Emerging Good Practices Task Force.

PubMed

Thokala, Praveen; Devlin, Nancy; Marsh, Kevin; Baltussen, Rob; Boysen, Meindert; Kalo, Zoltan; Longrenn, Thomas; Mussen, Filip; Peacock, Stuart; Watkins, John; Ijzerman, Maarten

2016-01-01

Health care decisions are complex and involve confronting trade-offs between multiple, often conflicting, objectives. Using structured, explicit approaches to decisions involving multiple criteria can improve the quality of decision making and a set of techniques, known under the collective heading multiple criteria decision analysis (MCDA), are useful for this purpose. MCDA methods are widely used in other sectors, and recently there has been an increase in health care applications. In 2014, ISPOR established an MCDA Emerging Good Practices Task Force. It was charged with establishing a common definition for MCDA in health care decision making and developing good practice guidelines for conducting MCDA to aid health care decision making. This initial ISPOR MCDA task force report provides an introduction to MCDA - it defines MCDA; provides examples of its use in different kinds of decision making in health care (including benefit risk analysis, health technology assessment, resource allocation, portfolio decision analysis, shared patient clinician decision making and prioritizing patients' access to services); provides an overview of the principal methods of MCDA; and describes the key steps involved. Upon reviewing this report, readers should have a solid overview of MCDA methods and their potential for supporting health care decision making. Copyright © 2016. Published by Elsevier Inc.

Implementation of a standardized handoff protocol for post-operative admissions to the surgical intensive care unit.

PubMed

Mukhopadhyay, Dhriti; Wiggins-Dohlvik, Katie C; MrDutt, Mary M; Hamaker, Jeffrey S; Machen, Graham L; Davis, Matthew L; Regner, Justin L; Smith, Randall W; Ciceri, David P; Shake, Jay G

2018-01-01

The transfer of critically ill patients from the operating room (OR) to the surgical intensive care unit (SICU) involves handoffs between multiple providers. Incomplete handoffs lead to poor communication, a major contributor to sentinel events. Our aim was to determine whether handoff standardization led to improvements in caregiver involvement and communication. A prospective intervention study was designed to observe thirty one patient handoffs from OR to SICU for 49 critical parameters including caregiver presence, peri-operative details, and time required to complete key steps. Following a six month implementation period, thirty one handoffs were observed to determine improvement. A significant improvement in presence of physician providers including intensivists and surgeons was observed (p = 0.0004 and p < 0.0001, respectively). Critical details were communicated more consistently, including procedure performed (p = 0.0048), complications (p < 0.0001), difficult airways (p < 0.0001), ventilator settings (p < 0.0001) and pressor requirements (p = 0.0134). Conversely, handoff duration did not increase significantly (p = 0.22). Implementation of a standardized protocol for handoffs between OR and SICU significantly improved caregiver involvement and reduced information omission without affecting provider time commitment. Copyright © 2017 Elsevier Inc. All rights reserved.

Dual Functions of the Trans-2-Enoyl-CoA Reductase TER in the Sphingosine 1-Phosphate Metabolic Pathway and in Fatty Acid Elongation*

PubMed Central

Wakashima, Takeshi; Abe, Kensuke; Kihara, Akio

2014-01-01

The sphingolipid metabolite sphingosine 1-phosphate (S1P) functions as a lipid mediator and as a key intermediate of the sole sphingolipid to glycerophospholipid metabolic pathway (S1P metabolic pathway). In this pathway, S1P is converted to palmitoyl-CoA through 4 reactions, then incorporated mainly into glycerophospholipids. Although most of the genes responsible for the S1P metabolic pathway have been identified, the gene encoding the trans-2-enoyl-CoA reductase, responsible for the saturation step (conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA) remains unidentified. In the present study, we show that TER is the missing gene in mammals using analyses involving yeast cells, deleting the TER homolog TSC13, and TER-knockdown HeLa cells. TER is known to be involved in the production of very long-chain fatty acids (VLCFAs). A significant proportion of the saturated and monounsaturated VLCFAs are used for sphingolipid synthesis. Therefore, TER is involved in both the production of VLCFAs used in the fatty acid moiety of sphingolipids as well as in the degradation of the sphingosine moiety of sphingolipids via S1P. PMID:25049234

Cygnus Performance in Subcritical Experiments

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

G. Corrow, M. Hansen, D. Henderson, S. Lutz, C. Mitton, et al.

2008-02-01

The Cygnus Dual Beam Radiographic Facility consists of two identical radiographic sources with the following specifications: 4-rad dose at 1 m, 1-mm spot size, 50-ns pulse length, 2.25-MeV endpoint energy. The facility is located in an underground tunnel complex at the Nevada Test Site. Here SubCritical Experiments (SCEs) are performed to study the dynamic properties of plutonium. The Cygnus sources were developed as a primary diagnostic for these tests. Since SCEs are single-shot, high-value events - reliability and reproducibility are key issues. Enhanced reliability involves minimization of failure modes through design, inspection, and testing. Many unique hardware and operational featuresmore » were incorporated into Cygnus to insure reliability. Enhanced reproducibility involves normalization of shot-to-shot output also through design, inspection, and testing. The first SCE to utilize Cygnus, Armando, was executed on May 25, 2004. A year later, April - May 2005, calibrations using a plutonium step wedge were performed. The results from this series were used for more precise interpretation of the Armando data. In the period February - May 2007 Cygnus was fielded on Thermos, which is a series of small-sample plutonium shots using a one-dimensional geometry. Pulsed power research generally dictates frequent change in hardware configuration. Conversely, SCE applications have typically required constant machine settings. Therefore, while operating during the past four years we have accumulated a large database for evaluation of machine performance under highly consistent operating conditions. Through analysis of this database Cygnus reliability and reproducibility on Armando, Step Wedge, and Thermos is presented.« less

Obstacle stepping involves spinal anticipatory activity associated with quadrupedal limb coordination.

PubMed

Michel, J; van Hedel, H J A; Dietz, V

2008-04-01

Obstacle avoidance steps are associated with a facilitation of spinal reflexes in leg muscles. Here we have examined the involvement of both leg and arm muscles. Subjects walking with reduced vision on a treadmill were acoustically informed about an approaching obstacle and received feedback about task performance. Reflex responses evoked by tibial nerve stimulation were observed in all arm and leg muscles examined in this study. They were enhanced before the execution of obstacle avoidance compared with normal steps and showed an exponential adaptation in contralateral arm flexor muscles corresponding to the improvement of task performance. This enhancement was absent when the body was partially supported during the task. During the execution of obstacle steps, electromyographic activity in the arm muscles mimicked the preceding reflex behaviour with respect to enhancement and adaptation. Our results demonstrate an anticipatory quadrupedal limb coordination with an involvement of proximal arm muscles in the acquisition and performance of this precision locomotor task. This is presumably achieved by an up-regulated activity of coupled cervico-thoracal interneuronal circuits.

Differential Effects of Monovalent Cations and Anions on Key Nanoparticle Attributes

EPA Science Inventory

Understanding the key particle attributes such as particle size, size distribution and surface charge of both the nano- and micron-sized particles is the first step in drug formulation as such attributes are known to directly influence several characteristics of drugs including d...

Surgical anatomy of medial open-wedge high tibial osteotomy: crucial steps and pitfalls.

PubMed

Madry, Henning; Goebel, Lars; Hoffmann, Alexander; Dück, Klaus; Gerich, Torsten; Seil, Romain; Tschernig, Thomas; Pape, Dietrich

2017-12-01

To give an overview of the basic knowledge of the functional surgical anatomy of the proximal lower leg and the popliteal region relevant to medial high tibial osteotomy (HTO) as key anatomical structures in spatial relation to the popliteal region and the proximal tibiofibular joint are usually not directly visible and thus escape a direct inspection. The surgical anatomy of the human proximal lower leg and its relevance for HTO are illustrated with a special emphasis on the individual steps of the operation involving creation of the osteotomy planes and plate fixation. The posteriorly located popliteal neurovascular bundle, but also lateral structures such as the peroneal nerve, the head of the fibula and the lateral collateral ligament must be protected from the instruments used for osteotomy. Neither positioning the knee joint in flexion, nor the posterior thin muscle layer of the popliteal muscle offers adequate protection of the popliteal neurovascular bundle when performing the osteotomy. Tactile feedback through a loss-of-resistance when the opposite cortex is perforated is only possible when sawing and drilling is performed in a pounding fashion. Kirschner wires with a proximal thread, therefore, always need to be introduced under fluoroscopic control. Due to anatomy of the tibial head, the tibial slope may increase inadvertently. Enhanced surgical knowledge of anatomical structures that are at a potential risk during the different steps of osteotomy or plate fixation will help to avoid possible injuries. Expert opinion, Level V.

Methodology and Natural Product Syntehsis: (A) Novel Glycosyl Donors; (B) N-Sulfinyl Metallodienamines and Their Application to the Total Synthesis of (-)-Albocycline

NASA Astrophysics Data System (ADS)

Chatare, Vijay K.

My research involved in two different areas, development of novel glycosylation methodology and scope in oligosaccharide synthesis. A new scaffold for antibiotic development targeting the bacterial cell wall: Total synthesis of Albocycline and its analogs to see the mechanism of action in cell wall biosynthesis. Developed novel gem-dimethyl analogs of Fraser-Reid's NPGs from 3,3-dimethyl 4-pentenol and 2,2-dimethyl 4-pentenol. These donors are stable toward acidic and basic conditions, which makes them step-efficient when compared to other glycosylating agents. The scope and reactivity of 3,3-dimethyl 4-pentenyl glycosides of glucose, mannose, galactose, and N-acetylglucosamine have been studied extensively for oligosaccharide synthesis. The donors are readily prepared from commercial starting materials and both glycosylation and hydrolysis yields are in the synthetically useful in oligosaccharide synthesis. NSMD methodology introduced a key step in albocycline synthesis, where (-)-albocycline has great biological activity against "superbug" methicillin-resistant Staphylococcus aureus (MRSA). We hypothesize that albocycline inhibits the first committed step in bacterial cell wall biosynthesis. We have successfully completed two generation syntheses of albocycline. Vinylogous aldol on the left-handed fragment, aldehyde to get selectively up alcohol at the C-8 position using Davis-Ellman sulfinylimine chemistry and then oxidation with Davis oxaziridine to access requisite stereochemistry at C-4 alcohol followed by Horner-Wadsworth-Emmons to access seco-acid. Finally, a Keck macrolactonization reaction provided access to desired (-)-Albocycline.

Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII produced in a human cell-line.

PubMed

Winge, Stefan; Yderland, Louise; Kannicht, Christoph; Hermans, Pim; Adema, Simon; Schmidt, Torben; Gilljam, Gustav; Linhult, Martin; Tiemeyer, Maya; Belyanskaya, Larisa; Walter, Olaf

2015-11-01

Human-cl rhFVIII (Nuwiq®), a new generation recombinant factor VIII (rFVIII), is the first rFVIII produced in a human cell-line approved by the European Medicines Agency. To describe the development, upscaling and process validation for industrial-scale human-cl rhFVIII purification. The purification process involves one centrifugation, two filtration, five chromatography columns and two dedicated pathogen clearance steps (solvent/detergent treatment and 20 nm nanofiltration). The key purification step uses an affinity resin (VIIISelect) with high specificity for FVIII, removing essentially all host-cell proteins with >80% product recovery. The production-scale multi-step purification process efficiently removes process- and product-related impurities and results in a high-purity rhFVIII product, with an overall yield of ∼50%. Specific activity of the final product was >9000 IU/mg, and the ratio between active FVIII and total FVIII protein present was >0.9. The entire production process is free of animal-derived products. Leaching of potential harmful compounds from chromatography resins and all pathogens tested were below the limit of quantification in the final product. Human-cl rhFVIII can be produced at 500 L bioreactor scale, maintaining high purity and recoveries. The innovative purification process ensures a high-purity and high-quality human-cl rhFVIII product with a high pathogen safety margin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Fail-safe transcription termination: Because one is never enough.

PubMed

Lemay, Jean-François; Bachand, François

2015-01-01

Termination of RNA polymerase II (RNAPII) transcription is a fundamental step of gene expression that involves the release of the nascent transcript and dissociation of RNAPII from the DNA template. As transcription termination is intimately linked to RNA 3' end processing, termination pathways have a key decisive influence on the fate of the transcribed RNA. Quite remarkably, when reaching the 3' end of genes, a substantial fraction of RNAPII fail to terminate transcription, requiring the contribution of alternative or "fail-safe" mechanisms of termination to release the polymerase. This point of view covers redundant mechanisms of transcription termination and how they relate to conventional termination models. In particular, we expand on recent findings that propose a reverse torpedo model of termination, in which the 3'5' exonucleolytic activity of the RNA exosome targets transcription events associated with paused and backtracked RNAPII.

An assessment of NASA master directory/catalog interoperability for interdisciplinary study of the global water cycle

NASA Technical Reports Server (NTRS)

Peuquet, Donna J.

1991-01-01

The most important issue facing science is understanding global change; the causes, the processes involved and their consequences. The key to success in this massive Earth science research effort will depend on efficient identification and access to the most data available across the atmospheric, oceanographic, and land sciences. Current mechanisms used by earth scientists for accessing these data fall far short of meeting this need. Scientists must as a result frequently rely on a priori knowledge and informal person to person networks to find relevant data. The Master Directory/Catalog Interoperability Program (MC/CI) undertaken by NASA is an important step in overcoming these problems. The stated goal of the MD project is to enable researchers to efficiently identify, locate, and obtain access to space and Earth science data.

Multilayer multiferroic composites with imperfect interfaces

NASA Astrophysics Data System (ADS)

Kuo, Hsin-Yi; Wu, Tien-Jung; Pan, Ernian

2018-07-01

We study the macroscopic behaviors of multilayered multiferroic composites with interface imperfections by a direct micromechanical approach. Both generalized interface stress type and generalized linear spring type imperfect interfaces are considered. Concise matrix expressions of the overall behaviors of the layered piezoelectric–piezomagnetic composite with contact imperfection are presented. The key step is to observe that the two types of imperfect interface conditions are equivalent to the perfect ones due to the laminated geometry. Numerical calculations are demonstrated for BaTiO3–CoFe2O4 multilayer media, and are shown in good agreement with the more involved interphase model. Furthermore, it is observed that the interface imperfection would reduce the magnitude of the magnetoelectric voltage coefficients as compared to the corresponding perfect interface case. This feature is opposite to that predicted and observed in the corresponding cylindrical composites.

Neural and hybrid modeling: an alternative route to efficiently predict the behavior of biotechnological processes aimed at biofuels obtainment.

PubMed

Curcio, Stefano; Saraceno, Alessandra; Calabrò, Vincenza; Iorio, Gabriele

2014-01-01

The present paper was aimed at showing that advanced modeling techniques, based either on artificial neural networks or on hybrid systems, might efficiently predict the behavior of two biotechnological processes designed for the obtainment of second-generation biofuels from waste biomasses. In particular, the enzymatic transesterification of waste-oil glycerides, the key step for the obtainment of biodiesel, and the anaerobic digestion of agroindustry wastes to produce biogas were modeled. It was proved that the proposed modeling approaches provided very accurate predictions of systems behavior. Both neural network and hybrid modeling definitely represented a valid alternative to traditional theoretical models, especially when comprehensive knowledge of the metabolic pathways, of the true kinetic mechanisms, and of the transport phenomena involved in biotechnological processes was difficult to be achieved.

Neural and Hybrid Modeling: An Alternative Route to Efficiently Predict the Behavior of Biotechnological Processes Aimed at Biofuels Obtainment

PubMed Central

Saraceno, Alessandra; Calabrò, Vincenza; Iorio, Gabriele

2014-01-01

The present paper was aimed at showing that advanced modeling techniques, based either on artificial neural networks or on hybrid systems, might efficiently predict the behavior of two biotechnological processes designed for the obtainment of second-generation biofuels from waste biomasses. In particular, the enzymatic transesterification of waste-oil glycerides, the key step for the obtainment of biodiesel, and the anaerobic digestion of agroindustry wastes to produce biogas were modeled. It was proved that the proposed modeling approaches provided very accurate predictions of systems behavior. Both neural network and hybrid modeling definitely represented a valid alternative to traditional theoretical models, especially when comprehensive knowledge of the metabolic pathways, of the true kinetic mechanisms, and of the transport phenomena involved in biotechnological processes was difficult to be achieved. PMID:24516363

Video requirements for remote medical diagnosis

NASA Technical Reports Server (NTRS)

Davis, J. G.

1974-01-01

Minimal television system requirements for medical telediagnosis were studied. The experiment was conducted with the aid of a simulated telemedicine system. The first step involved making high quality videotape recordings of actual medical examinations conducted by a skilled nurse under the direction of a physician watching on closed circuit television. These recordings formed the baseline for the study. Next, these videotape recordings were electronically degraded to simulate television systems of less than broadcast quality. Finally, the baseline and degraded video recordings were shown (via a statistically randomized procedure) to a large number of physicians who attempted to reach a correct medical diagnosis and to visually recognize key physical signs for each patient. By careful scoring and analysis of the results of these viewings, the pictorial and diagnostic limitations as a function of technical video characteristics were to be defined.

Chiral poly-rare earth metal complexes in asymmetric catalysis

PubMed Central

Shibasaki, Masakatsu

2006-01-01

Asymmetric catalysis is a powerful component of modern synthetic organic chemistry. To further broaden the scope and utility of asymmetric catalysis, new basic concepts for the design of asymmetric catalysts are crucial. Because most chemical reactions involve bond-formation between two substrates or moieties, high enantioselectivity and catalyst activity should be realized if an asymmetric catalyst can activate two reacting substrates simultaneously at defined positions. Thus, we proposed the concept of bifunctional asymmetric catalysis, which led us to the design of new asymmetric catalysts containing two functionalities (e.g. a Lewis acid and a Brønsted base or a Lewis acid and a Lewis base). These catalysts demonstrated broad reaction applicability with excellent substrate generality. Using our catalytic asymmetric reactions as keys steps, efficient total syntheses of pharmaceuticals and their biologically active lead natural products were achieved. PMID:25792774

Atom Tunneling in the Hydroxylation Process of Taurine/α-Ketoglutarate Dioxygenase Identified by Quantum Mechanics/Molecular Mechanics Simulations.

PubMed

Álvarez-Barcia, Sonia; Kästner, Johannes

2017-06-01

Taurine/α-ketoglutarate dioxygenase is one of the most studied α-ketoglutarate-dependent dioxygenases (αKGDs), involved in several biotechnological applications. We investigated the key step in the catalytic cycle of the αKGDs, the hydrogen transfer process, by a quantum mechanics/molecular mechanics approach (B3LYP/CHARMM22). Analysis of the charge and spin densities during the reaction demonstrates that a concerted mechanism takes place, where the H atom transfer happens simultaneously with the electron transfer from taurine to the Fe═O cofactor. We found the quantum tunneling of the hydrogen atom to increase the rate constant by a factor of 40 at 5 °C. As a consequence, a quite high kinetic isotope effect close to 60 is obtained, which is consistent with the experimental value.

Does stress induce (para)sex? Implications for Candida albicans evolution.

PubMed

Berman, Judith; Hadany, Lilach

2012-05-01

Theory predicts that stress is a key factor in explaining the evolutionary role of sex in facultatively sexual organisms, including microorganisms. Organisms capable of reproducing both sexually and asexually are expected to mate more frequently when stressed, and such stress-induced mating is predicted to facilitate adaptation. Here, we propose that stress has an analogous effect on the parasexual cycle in Candida albicans, which involves alternation of generations between diploid and tetraploid cells. The parasexual cycle can generate high levels of diversity, including aneuploidy, yet it apparently occurs only rarely in nature. We review the evidence that stress facilitates four major steps in the parasexual cycle and suggest that parasex occurs much more frequently under stress conditions. This may explain both the evolutionary significance of parasex and its apparent rarity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Prediction (early recognition) of emerging flu strain clusters

NASA Astrophysics Data System (ADS)

Li, X.; Phillips, J. C.

2017-08-01

Early detection of incipient dominant influenza strains is one of the key steps in the design and manufacture of an effective annual influenza vaccine. Here we report the most current results for pandemic H3N2 flu vaccine design. A 2006 model of dimensional reduction (compaction) of viral mutational complexity derives two-dimensional Cartesian mutational maps (2DMM) that exhibit an emergent dominant strain as a small and distinct cluster of as few as 10 strains. We show that recent extensions of this model can detect incipient strains one year or more in advance of their dominance in the human population. Our structural interpretation of our unexpectedly rich 2DMM involves sialic acid, and is based on nearly 6000 strains in a series of recent 3-year time windows. Vaccine effectiveness is predicted best by analyzing dominant mutational epitopes.

Tissue tropisms in group A streptococcal infections.

PubMed

Bessen, Debra E; Lizano, Sergio

2010-04-01

Group A Streptococcus (GAS) is a human-specific pathogen that is highly prevalent throughout the world. The vast majority of GAS infections lead to a mild disease involving the epithelial surfaces of either the throat or skin. The concept of distinct sets of 'throat' and 'skin' strains of GAS has long been conceived. From an ecological standpoint, the epithelium of the throat and skin are important because it is where the organism is most successful in reproducing and transmitting to new hosts. This article examines key features of the epidemiology, population biology and molecular pathogenesis that underlie the tissue site preferences for infection exhibited by GAS, with an emphasis on work from our laboratory on skin tropisms. Recombinational replacement with orthologous gene forms, following interspecies transfer, appears to be an important genetic step leading up to the exploitation of new niches by GAS.

Synthesis of ω-Oxo Amino Acids and trans-5-Substituted Proline Derivatives Using Cross-Metathesis of Unsaturated Amino Acids.

PubMed

Salih, Nabaz; Adams, Harry; Jackson, Richard F W

2016-09-16

A range of 7-oxo, 8-oxo, and 9-oxo amino acids, analogues of 8-oxo-2-aminodecanoic acid, one of the key components of the cyclic tetrapeptide apicidin, have been prepared by a three-step process involving copper-catalyzed allylation of serine-, aspartic acid-, and glutamic acid-derived organozinc reagents, followed by cross-metathesis of the resulting terminal alkenes with unsaturated ketones and hydrogenation. The intermediate 7-oxo-5-enones underwent a highly diastereoselective (dr ≥96:4) acid-catalyzed aza-Michael reaction to give trans-2,5-disubstituted pyrrolidines, 5-substituted proline derivatives. The aza-Michael reaction was first observed when the starting enones were allowed to stand in solution in deuterochloroform but can be efficiently promoted by catalytic amounts of dry HCl.

Criteria for the selection of a solid phase to be used in immunoassays.

PubMed

Delagneau, J F; Masseyeff, R

1990-01-01

Heterogeneous immunoassays are very sensitive and only limited in terms of performance by non specific binding. They require separation of free from bound fractions and concomitant use of a solid phase coated with an immunoreactive component (i.e. immunosorbent). The improvement of these key immunosorbents is crucial and involves a great deal of expertise and capabilities. Specifications differ according to procedure (e.g. capture or competitive assay). Each routinely used solid phase, such as polystyrene wells, porous membrane or dispersible microbeads, presents specific performance characteristics, advantages, and drawbacks. Among the tasks to be implemented are optimization of the spatial orientation of immunological reagents, selection of the surface neutral hydrophilic support, acceleration of reactions by increasing the reactive surface area of the supports, streamlining and simplification of procedural steps. These various aspects are abundantly described and emphasized here.

Efficient Control Law Simulation for Multiple Mobile Robots

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

Driessen, B.J.; Feddema, J.T.; Kotulski, J.D.

1998-10-06

In this paper we consider the problem of simulating simple control laws involving large numbers of mobile robots. Such simulation can be computationally prohibitive if the number of robots is large enough, say 1 million, due to the 0(N2 ) cost of each time step. This work therefore uses hierarchical tree-based methods for calculating the control law. These tree-based approaches have O(NlogN) cost per time step, thus allowing for efficient simulation involving a large number of robots. For concreteness, a decentralized control law which involves only the distance and bearing to the closest neighbor robot will be considered. The timemore » to calculate the control law for each robot at each time step is demonstrated to be O(logN).« less

A short and efficient synthesis of the pharmacological research tool GW501516 for the peroxisome proliferator-activated receptor delta.

PubMed

Wei, Zhi-Liang; Kozikowski, Alan P

2003-11-14

The most potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonist GW501516 (1) was synthesized in 4 steps and 78% overall yield starting from o-cresol by using a one-pot regiocontrolled dialkylation of mercaptophenol 5 as the key step.

A Miniature Wastewater Cleaning Plant to Demonstrate Primary Treatment in the Classroom

ERIC Educational Resources Information Center

Ne´el, Bastien; Cardoso, Catia; Perret, Didier; Bakker, Eric

2015-01-01

A small-scale wastewater cleaning plant is described that includes the key physical pretreatment steps followed by the chemical treatment of mud by flocculation. Water, clay particles, and riverside deposits mimicked odorless wastewater. After a demonstration of the optimization step, the flocculation process was carried out with iron(III)…

Strengthening the revenue cycle: a 4-step method for optimizing payment.

PubMed

Clark, Jonathan J

2008-10-01

Four steps for enhancing the revenue cycle to ensure optimal payment are: *Establish key performance indicator dashboards in each department that compare current with targeted performance; *Create proper organizational structures for each department; *Ensure that high-performing leaders are hired in all management and supervisory positions; *Implement efficient processes in underperforming operations.

First Steps to School Readiness: South Carolina's Response to At-Risk Early Childhood Population.

ERIC Educational Resources Information Center

Buford, Rhonda; Stegelin, Dolores A.

2003-01-01

Describes South Carolina's new state early childhood program, First Steps to School Readiness. Includes a profile of the state's at-risk child population, noting poverty and education risk indicators, and describing key program components. The article discusses program oversight, local program partnerships, program funding mechanisms, and local…

Implementation of Competency-Based Pharmacy Education (CBPE)

PubMed Central

Koster, Andries; Schalekamp, Tom; Meijerman, Irma

2017-01-01

Implementation of competency-based pharmacy education (CBPE) is a time-consuming, complicated process, which requires agreement on the tasks of a pharmacist, commitment, institutional stability, and a goal-directed developmental perspective of all stakeholders involved. In this article the main steps in the development of a fully-developed competency-based pharmacy curriculum (bachelor, master) are described and tips are given for a successful implementation. After the choice for entering into CBPE is made and a competency framework is adopted (step 1), intended learning outcomes are defined (step 2), followed by analyzing the required developmental trajectory (step 3) and the selection of appropriate assessment methods (step 4). Designing the teaching-learning environment involves the selection of learning activities, student experiences, and instructional methods (step 5). Finally, an iterative process of evaluation and adjustment of individual courses, and the curriculum as a whole, is entered (step 6). Successful implementation of CBPE requires a system of effective quality management and continuous professional development as a teacher. In this article suggestions for the organization of CBPE and references to more detailed literature are given, hoping to facilitate the implementation of CBPE. PMID:28970422

Going To The Field: Immersing Student Researchers in Coupled Human-Natural Systems

NASA Astrophysics Data System (ADS)

Weissmann, G. S.; Ibarra, R.

2014-12-01

Taking students into the field can offer a rich, grounded understanding of a particular environment and of a particular scientific approach to attaining a desired observation. Going into the field immerses students into coupled human-natural systems, which introduces two key elements to teaching: experiential learning and socio-cultural context. While these elements can greatly enrich student learning, instructors have to take extra steps to scaffold this learning. This scaffolding can present physical scientists with a challenge: how to reconcile views that such pedagogical activities are 'extraneous'/not central to the pursuit of physical science. Here we offer perspectives as an anthropologist and as an environmental scientist on the value of a diverse pedagogical approach to conducting field studies involving students. Insights drawn from facilitating a range of field experiences (e.g., short-term study abroad, service-learning and independent/supervised research both home and abroad) will be shared regarding approaches to scaffolding student learning. We will focus on an approach that the scholarship of teaching and learning has long shown to be effective - what can be called a "wrap-around" approach to the field: preparation before, support during, and reflection afterward. Of these steps, the post-trip reflection on the experience is a key, and often under-utilized, strategy, and suggestions as to why this are offered. This approach not only helps students understand better the course content, but it also helps them understand the role that socio-cultural context plays in shaping both the research and in the state of the environment. We illustrate these different dimensions of the field experience with examples from our courses.

Friction of atomically stepped surfaces

NASA Astrophysics Data System (ADS)

Dikken, R. J.; Thijsse, B. J.; Nicola, L.

2017-03-01

The friction behavior of atomically stepped metal surfaces under contact loading is studied using molecular dynamics simulations. While real rough metal surfaces involve roughness at multiple length scales, the focus of this paper is on understanding friction of the smallest scale of roughness: atomic steps. To this end, periodic stepped Al surfaces with different step geometry are brought into contact and sheared at room temperature. Contact stress that continuously tries to build up during loading, is released with fluctuating stress drops during sliding, according to the typical stick-slip behavior. Stress release occurs not only through local slip, but also by means of step motion. The steps move along the contact, concurrently resulting in normal migration of the contact. The direction of migration depends on the sign of the step, i.e., its orientation with respect to the shearing direction. If the steps are of equal sign, there is a net migration of the entire contact accompanied by significant vacancy generation at room temperature. The stick-slip behavior of the stepped contacts is found to have all the characteristic of a self-organized critical state, with statistics dictated by step density. For the studied step geometries, frictional sliding is found to involve significant atomic rearrangement through which the contact roughness is drastically changed. This leads for certain step configurations to a marked transition from jerky sliding motion to smooth sliding, making the final friction stress approximately similar to that of a flat contact.

Which ecological determinants influence Australian children's fruit and vegetable consumption?

PubMed

Godrich, Stephanie L; Davies, Christina R; Darby, Jill; Devine, Amanda

2018-04-01

This study investigated determinants of fruit and vegetable (F&V) consumption among regional and remote Western Australian (WA) children, using an Ecological Model of Health Behaviour. Semi-structured interviews were conducted with 20 key informants (Health Workers, Food Supply Workers, and School/Youth Workers) purposively sampled from across regional and remote WA. Interviews were transcribed, analysed thematically using QSR-NVivo 10 software, and embedded within an Ecological Model of Health Behaviour to demonstrate the multiple levels of influence on health. Key determinants of F&V consumption at the intrapersonal level included attitude and food literacy among children. Key interpersonal level determinants included role modelling and parental food literacy. Institutional determinants included health service provision, school nutrition education and food skill programs. F&V availability, community networks and health-promoting spaces were key themes affecting families at the community level. The public policy level influencer included implementation of a store policy within local food outlets. Study findings suggested participatory programs with an emphasis on parental involvement and role modelling could increase F&V intake among children living in regional and remote areas; while school curriculum linkages were essential for school-based programs. Policy makers should consider further investment in school food literacy programs and family programs that are delivered collaboratively. Further, support of local food supply options and support for healthy food policies in food outlets are critical next steps. This study contributes new knowledge to build the evidence base and facilitate the development of targeted strategies to increase consumption of F&V among children living in regional and remote areas.

Factors that influence career progression among postdoctoral clinical academics: a scoping review of the literature

PubMed Central

Ranieri, Veronica; Barratt, Helen; Fulop, Naomi; Rees, Geraint

2016-01-01

Background The future of academic medicine is uncertain. Concerns regarding the future availability of qualified and willing trainee clinical academics have been raised worldwide. Of significant concern is our failure to retain postdoctoral trainee clinical academics, who are likely to be our next generation of leaders in scientific discovery. Objectives To review the literature about factors that may influence postdoctoral career progression in early career clinical academics. Design This study employed a scoping review method. Three reviewers separately assessed whether the articles found fit the inclusion criteria. Data sources PubMed, Scopus, Web of Science and Google Scholar (1991–2015). Article selection The review encompassed a broad search of English language studies published anytime up to November 2015. All articles were eligible for inclusion, including research papers employing either quantitative or qualitative methods, as well as editorials and other summary articles. Data extraction Data extracted from included publications were charted according to author(s), sample population, study design, key findings, country of origin and year of publication. Results Our review identified 6 key influences: intrinsic motivation, work–life balance, inclusiveness, work environment, mentorship and availability of funding. It also detected significant gaps within the literature about these influences. Conclusions Three key steps are proposed to help support postdoctoral trainee clinical academics. These focus on ensuring that researchers feel encouraged in their workplace, involved in collaborative dialogue with key stakeholders and able to access reliable information regarding their chosen career pathway. Finally, we highlight recommendations for future research. PMID:27798036

Angle comparison using an autocollimator

NASA Astrophysics Data System (ADS)

Geckeler, Ralf D.; Just, Andreas; Vasilev, Valentin; Prieto, Emilio; Dvorácek, František; Zelenika, Slobodan; Przybylska, Joanna; Duta, Alexandru; Victorov, Ilya; Pisani, Marco; Saraiva, Fernanda; Salgado, Jose-Antonio; Gao, Sitian; Anusorn, Tonmueanwai; Leng Tan, Siew; Cox, Peter; Watanabe, Tsukasa; Lewis, Andrew; Chaudhary, K. P.; Thalmann, Ruedi; Banreti, Edit; Nurul, Alfiyati; Fira, Roman; Yandayan, Tanfer; Chekirda, Konstantin; Bergmans, Rob; Lassila, Antti

2018-01-01

Autocollimators are versatile optical devices for the contactless measurement of the tilt angles of reflecting surfaces. An international key comparison (KC) on autocollimator calibration, EURAMET.L-K3.2009, was initiated by the European Association of National Metrology Institutes (EURAMET) to provide information on the capabilities in this field. The Physikalisch-Technische Bundesanstalt (PTB) acted as the pilot laboratory, with a total of 25 international participants from EURAMET and from the Asia Pacific Metrology Programme (APMP) providing measurements. This KC was the first one to utilise a high-resolution electronic autocollimator as a standard. In contrast to KCs in angle metrology which usually involve the full plane angle, it focused on relatively small angular ranges (+/-10 arcsec and +/-1000 arcsec) and step sizes (10 arcsec and 0.1 arcsec, respectively). This document represents the approved final report on the results of the KC. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCL, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

“Speaking the Dialect”: Understanding Public Discourse in the Aftermath of an HIV Vaccine Trial Shutdown

PubMed Central

Logie, Carmen; James, LLana; Charles, Tamicka; Maxwell, John; Salam, Khaled; Woodford, Michael

2011-01-01

Objectives. We investigated how persons from key populations at higher risk of HIV exposure interpreted the process and outcomes of the Step Study HIV-1 vaccine trial, which was terminated early, and implications for willingness to participate in and community support for HIV vaccine research. Methods. We used qualitative methods and a community-based approach in 9 focus groups (n = 72) among ethnically and sexually diverse populations and 6 semistructured key informant interviews in Ontario, Canada, in 2007 to 2008. Results. Participants construed social meaning from complex clinical and biomedical phenomena. Social representations and mental models emerged in fears of vaccine-induced infection, conceptualizations of unfair recruitment practices and increased risk behaviors among trial participants, and questioning of informed consent. Narratives of altruism and the common good demonstrated support for future trials. Conclusions. Public discourse on HIV vaccine trials is a productive means of interpreting complex clinical trial processes and outcomes in the context of existing beliefs and experiences regarding HIV vaccines, medical research, and historical disenfranchisement. Strategic engagement with social representations and mental models may promote meaningful community involvement in biomedical HIV prevention research. PMID:21778490

Crystallization and X-ray diffraction analysis of salicylate synthase, a chorismate-utilizing enyme involved in siderophore biosynthesis

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

Parsons, James F., E-mail: parsonsj@umbi.umd.edu; Shi, Katherine; Calabrese, Kelly

2006-03-01

Salicylate synthase, which catalyzes the first step in the synthesis of the siderophore yersiniabactin, has been crystallized. Diffraction data have been collected to 2.5 Å. Bacteria have evolved elaborate schemes that help them thrive in environments where free iron is severely limited. Siderophores such as yersiniabactin are small iron-scavenging molecules that are deployed by bacteria during iron starvation. Several studies have linked siderophore production and virulence. Yersiniabactin, produced by several Enterobacteriaceae, is derived from the key metabolic intermediate chorismic acid via its conversion to salicylate by salicylate synthase. Crystals of salicylate synthase from the uropathogen Escherichia coli CFT073 have beenmore » grown by vapour diffusion using polyethylene glycol as the precipitant. The monoclinic (P2{sub 1}) crystals diffract to 2.5 Å. The unit-cell parameters are a = 57.27, b = 164.07, c = 59.04 Å, β = 108.8°. The solvent content of the crystals is 54% and there are two molecules of the 434-amino-acid protein in the asymmetric unit. It is anticipated that the structure will reveal key details about the reaction mechanism and the evolution of salicylate synthase.« less

Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction.

PubMed

Pettersson, Mariell; Quant, Maria; Min, Jaeki; Iconaru, Luigi; Kriwacki, Richard W; Waddell, M Brett; Guy, R Kiplin; Luthman, Kristina; Grøtli, Morten

2015-01-01

The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein-protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay.

Design, Synthesis and Evaluation of 2,5-Diketopiperazines as Inhibitors of the MDM2-p53 Interaction

PubMed Central

Pettersson, Mariell; Quant, Maria; Min, Jaeki; Iconaru, Luigi; Kriwacki, Richard W.; Waddell, M. Brett; Guy, R. Kiplin; Luthman, Kristina; Grøtli, Morten

2015-01-01

The transcription factor p53 is the main tumour suppressor in cells and many cancer types have p53 mutations resulting in a loss of its function. In tumours that retain wild-type p53 function, p53 activity is down-regulated by MDM2 (human murine double minute 2) via a direct protein—protein interaction. We have designed and synthesised two series of 2,5-diketopiperazines as inhibitors of the MDM2-p53 interaction. The first set was designed to directly mimic the α-helical region of the p53 peptide, containing key residues in the i, i+4 and i+7 positions of a natural α-helix. Conformational analysis indicated that 1,3,6-trisubstituted 2,5-diketopiperazines were able to place substituents in the same spatial orientation as an α-helix template. The key step of the synthesis involved the cyclisation of substituted dipeptides. The other set of tetrasubstituted 2,5-diketopiperazines were designed based on structure-based docking studies and the Ugi multicomponent reaction was used for the synthesis. This latter set comprised the most potent inhibitors which displayed micromolar IC50-values in a biochemical fluorescence polarisation assay. PMID:26427060

Study of AMPK-Regulated Metabolic Fluxes in Neurons Using the Seahorse XFe Analyzer.

PubMed

Marinangeli, Claudia; Kluza, Jérome; Marchetti, Philippe; Buée, Luc; Vingtdeux, Valérie

2018-01-01

AMP-activated protein kinase (AMPK) is the intracellular master energy sensor and metabolic regulator. AMPK is involved in cell energy homeostasis through the regulation of glycolytic flux and mitochondrial biogenesis. Interestingly, metabolic dysfunctions and AMPK deregulations are observed in many neurodegenerative diseases, including Alzheimer's. While these deregulations could play a key role in the development of these diseases, the study of metabolic fluxes has remained quite challenging and time-consuming. In this chapter, we describe the Seahorse XFe respirometry assay as a fundamental experimental tool to investigate the role of AMPK in controlling and modulating cell metabolic fluxes in living and intact differentiated primary neurons. The Seahorse XFe respirometry assay allows the real-time monitoring of glycolytic flux and mitochondrial respiration from different kind of cells, tissues, and isolated mitochondria. Here, we specify a protocol optimized for primary neuronal cells using several energy substrates such as glucose, pyruvate, lactate, glutamine, and ketone bodies. Nevertheless, this protocol can easily be adapted to monitor metabolic fluxes from other types of cells, tissues, or isolated mitochondria by taking into account the notes proposed for each key step of this assay.

Evidence-based decision-making 7: Knowledge translation.

PubMed

Manns, Braden J

2015-01-01

There is a significant gap between what is known and what is implemented by key stakeholders in practice (the evidence to practice gap). The primary purpose of knowledge translation is to address this gap, bridging evidence to clinical practice. The knowledge to action cycle is one framework for knowledge translation that integrates policy-makers throughout the research cycle. The knowledge to action cycle begins with the identification of a problem (usually a gap in care provision). After identification of the problem, knowledge creation is undertaken, depicted at the center of the cycle as a funnel. Knowledge inquiry is at the wide end of the funnel, and moving down the funnel, the primary data is synthesized into knowledge products in the form of educational materials, guidelines, decision aids, or clinical pathways. The remaining components of the knowledge to action cycle refer to the action of applying the knowledge that has been created. This includes adapting knowledge to local context, assessing barriers to knowledge use, selecting, tailoring implementing interventions, monitoring knowledge use, evaluating outcomes, and sustaining knowledge use. Each of these steps is connected by bidirectional arrows and ideally involves healthcare decision-makers and key stakeholders at each transition.

Identifying key areas for active interprofessional learning partnerships: A facilitated dialogue.

PubMed

Steven, Kathryn; Angus, Allyson; Breckenridge, Jenna; Davey, Peter; Tully, Vicki; Muir, Fiona

2016-11-01

Student and service user involvement is recognised as an important factor in creating interprofessional education (IPE) opportunities. We used a team-based learning approach to bring together undergraduate health professional students, early career professionals (ECPs), public partners, volunteers, and carers to explore learning partnerships. Influenced by evaluative inquiry, this qualitative study used a free text response to allow participants to give their own opinion. A total of 153 participants (50 public partners and 103 students and professionals representing 11 healthcare professions) took part. Participants were divided into mixed groups of six (n = 25) and asked to identify areas where students, professionals, and public could work together to improve health professional education. Each group documented their discussions by summarising agreed areas and next steps. Responses were collected and transcribed for inductive content analysis. Seven key themes (areas for joint working) were identified: communication, public as partners, standards of conduct, IPE, quality improvement, education, and learning environments. The team-based learning format enabled undergraduate and postgraduate health professionals to achieve consensus with public partners on areas for IPE and collaboration. Some of our results may be context-specific but the approach is generalisable to other areas.

An Alternative Pathway for Formononetin Biosynthesis in Pueraria lobata

PubMed Central

Li, Jia; Li, Changfu; Gou, Junbo; Wang, Xin; Fan, Rongyan; Zhang, Yansheng

2016-01-01

The O-methylation is an important tailing process in Pueraria lobata isoflavone metabolism, but the molecular mechanism governing it remains not elucidated. This manuscript describes the mining of key O-methyltransferases (OMTs) involved in the process. Using our previously constructed P. lobata transcriptome, the OMT candidates were searched, extensively analyzed, and their functions were investigated by expression in yeast, Escherichia coli, or Glycine max hairy roots. Here, we report the identification of the key OMT gene responsible for formononetin production in P. lobata (designated as PlOMT9). PlOMT9 primarily functions as an isoflavone-specific 4′-O-methyltransferase, although it shows high sequence identities with isoflavone 7-O-methyltransferases. Moreover, unlike the previously reported OMTs that catalyze the 4′-O-methylation for formononetin biosynthesis at the isoflavanone stage, PlOMT9 performs this modifying step at the isoflavone level, using daidzein rather than 2,7,4′-trihydroxy-isoflavanone as the substrate. Gene expression analyses and metabolite profiling supported its proposed roles in P. lobata. Using the system of transgenic G. max hairy roots, the role of PlOMT9 in the biosynthesis of formononetin was further demonstrated in vivo. PMID:27379141

An Alternative Pathway for Formononetin Biosynthesis in Pueraria lobata.

PubMed

Li, Jia; Li, Changfu; Gou, Junbo; Wang, Xin; Fan, Rongyan; Zhang, Yansheng

2016-01-01

The O-methylation is an important tailing process in Pueraria lobata isoflavone metabolism, but the molecular mechanism governing it remains not elucidated. This manuscript describes the mining of key O-methyltransferases (OMTs) involved in the process. Using our previously constructed P. lobata transcriptome, the OMT candidates were searched, extensively analyzed, and their functions were investigated by expression in yeast, Escherichia coli, or Glycine max hairy roots. Here, we report the identification of the key OMT gene responsible for formononetin production in P. lobata (designated as PlOMT9). PlOMT9 primarily functions as an isoflavone-specific 4'-O-methyltransferase, although it shows high sequence identities with isoflavone 7-O-methyltransferases. Moreover, unlike the previously reported OMTs that catalyze the 4'-O-methylation for formononetin biosynthesis at the isoflavanone stage, PlOMT9 performs this modifying step at the isoflavone level, using daidzein rather than 2,7,4'-trihydroxy-isoflavanone as the substrate. Gene expression analyses and metabolite profiling supported its proposed roles in P. lobata. Using the system of transgenic G. max hairy roots, the role of PlOMT9 in the biosynthesis of formononetin was further demonstrated in vivo.

Remote Access to the PXRR Macromolecular Crystallography Facilities at the NSLS

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

Soares, A.S.; Schneider, D. K.; Skinner, J. M.

2008-09-01

The most recent surge of innovations that have simplified and streamlined the process of determining macromolecular structures by crystallography owes much to the efforts of the structural genomics community. However, this was only the last step in a long evolution that saw the metamorphosis of crystallography from an heroic effort that involved years of dedication and skill into a straightforward measurement that is occasionally almost trivial. Many of the steps in this remarkable odyssey involved reducing the physical labor that is demanded of experimenters in the field. Other steps reduced the technical expertise required for conducting those experiments.

Remote Access to the PXRR Macromolecular Crystallography Facilities at the NSLS

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

A Soares; D Schneider; J Skinner

2011-12-31

The most recent surge of innovations that have simplified and streamlined the process of determining macromolecular structures by crystallography owes much to the efforts of the structural genomics community. However, this was only the last step in a long evolution that saw the metamorphosis of crystallography from an heroic effort that involved years of dedication and skill into a straightforward measurement that is occasionally almost trivial. Many of the steps in this remarkable odyssey involved reducing the physical labor that is demanded of experimenters in the field. Other steps reduced the technical expertise required for conducting those experiments.

Using Key Performance Indicators to Drive Strategic Decision Making.

ERIC Educational Resources Information Center

Dolence, Michael G.; Norris, Donald M.

1994-01-01

A nine-step method for defining and pursuing key performance indicators (KPIs), derived from a strategic planning process, is outlined, and its applications at the University of Northern Colorado and Illinois Benedictine College are described and tabulated. A chart summarizes current and projected KPIs for Illinois Benedictine College for each…

Twenty-six key research questions in urban stream ecology: an assessment of the state of the science

EPA Science Inventory

Although urban streams have been the focus of much research activity in recent years, there remain many unanswered questions about the mechanisms driving the “urban stream syndrome.” Identification of these key research questions is an important step toward effective, efficient ...

The space program's impact on society

NASA Astrophysics Data System (ADS)

Toffler, Alvin

In terms of human evolution, when viewed from 500 or 1000 years from now, today's primitive, still faltering steps beyond the Earth will be recognized as the most important human project of our era, matched only by what is going on in computers and biology. In this paper the social effects of space activity are addressed at three different levels: key social institutions, key social groups, and key social processes.

Theoretical analysis of the effects of light intensity on the photocorrosion of semiconductor electrodes

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

Benito, R.M.; Nozik, A.J.

1985-07-18

A kinetic model was developed to describe the effects of light intensity on the photocorrosion of n-type semiconductor electrodes. The model is an extension of previous work by Gomes and co-workers that includes the possibility of multiple steps for the oxidation reaction of the reducing agent in the electrolyte. Six cases are considered where the semiconductor decomposition reaction is multistep (each step involves a hole); the oxidation reaction of the reducing agent is multistep (each step after the first involves a hole or a chemical intermediate), and the first steps of the competing oxidation reactions are reversible or irreversible. Itmore » was found, contrary to previous results, that the photostability of semiconductor electrodes could increase with increased light intensity if the desired oxidation reaction of the reducing agent in the electrolyte was multistep with the first step being reversible. 14 references, 5 figures, 1 table.« less

Facilitating Involvement in Alcoholics Anonymous During Outpatient Treatment: A Randomized Clinical Trial

PubMed Central

Walitzer, Kimberly S.; Dermen, Kurt H.; Barrick, Christopher

2009-01-01

AIM This study evaluated two strategies to facilitate involvement in Alcoholics Anonymous (AA) – a 12-step-based directive approach and a motivational enhancement approach – during skills-focused individual treatment. DESIGN Randomized controlled trial with assessments at baseline, end of treatment, and 3, 6, 9, and 12 months after treatment. PARTICIPANTS, SETTING, and INTERVENTION 169 alcoholic outpatients (57 women) randomly assigned to one of three conditions: a directive approach to facilitating AA, a motivational enhancement approach to facilitating AA, or treatment as usual with no special emphasis on AA. MEASUREMENTS Self-report of AA meeting attendance and involvement, alcohol consumption (percent days abstinent, percent days heavy drinking), and negative alcohol consequences. FINDINGS Participants exposed to the 12-step directive condition for facilitating AA involvement reported more AA meeting attendance, more evidence of active involvement in AA, and a higher percent days abstinent relative to participants in the treatment-as-usual comparison group. Evidence suggested also that the effect of the directive strategy on abstinent days was partially mediated through AA involvement. The motivational enhancement approach to facilitating AA had no effect on outcome measures. CONCLUSIONS These results suggest that treatment providers can use a 12-step-based directive approach to effectively facilitate involvement in AA and thereby improve client outcome. PMID:19207347

The Move to Field Based Teacher Education: A Practical Guide for Field Hands. Teacher Education Forum; Volume 4, Number 14.

ERIC Educational Resources Information Center

Rockwood, Stacy F.

This paper outlines the procedures used at the University of Cincinnati for establishing a field based elementary teacher education program in the form of a field guide. The first step involves a meeting with university faculty to discuss the implications of such a program. Step two involves meeting with the elementary school principal and selling…

Reducing Medical Admissions into Hospital through Optimising Medicines (REMAIN HOME) Study: protocol for a stepped-wedge, cluster-randomised trial

PubMed Central

Foot, Holly; Freeman, Christopher; Hemming, Karla; Scott, Ian; Coombes, Ian D; Williams, Ian D; Connelly, Luke; Whitty, Jennifer A; Sturman, Nancy; Kirsa, Sue; Nicholson, Caroline; Russell, Grant; Kirkpatrick, Carl; Cottrell, Neil

2017-01-01

Introduction A model of general practitioner (GP) and pharmacist collaboration in primary care may be an effective strategy to reduce medication-related problems and provide better support to patients after discharge. The aim of this study is to investigate whether a model of structured pharmacist and GP care reduces hospital readmissions in high-risk patients. Methods and analysis This protocol details a stepped-wedge, cluster-randomised trial that will recruit participants over 9 months with a 12-month follow-up. There will be 14 clusters each representing a different general practice medical centre. A total of 2240 participants will be recruited from hospital who attend an enrolled medical centre, take five or more long-term medicines or whose reason for admission was related to heart failure or chronic obstructive pulmonary disease. The intervention is a multifaceted service, involving a pharmacist integrated into a medical centre to assist patients after hospitalisation. Participants will meet with the practice pharmacist and their GP after discharge to review and reconcile their medicines and discuss changes made in hospital. The pharmacist will follow-up with the participant and liaise with other health professionals involved in the participant’s care. The control will be usual care, which usually involves a patient self-organising a visit to their GP after hospital discharge. The primary outcome is the rate of unplanned, all-cause hospital readmissions over 12 months, which will be analysed using a mixed effects Poisson regression model with a random effect for cluster and a fixed effect to account for any temporal trend. A cost analysis will be undertaken to compare the healthcare costs associated with the intervention to those of usual care. Ethics and dissemination The study has received ethical approval (HREC/16/QRBW/410). The study findings will be disseminated through peer-reviewed publications, conferences and reports to key stakeholders. Trial registration number ACTRN12616001627448 PMID:28408545

Predictors of 12-Step Attendance and Participation for Individuals With Stimulant Use Disorders.

PubMed

Hatch-Maillette, Mary; Wells, Elizabeth A; Doyle, Suzanne R; Brigham, Gregory S; Daley, Dennis; DiCenzo, Jessica; Donovan, Dennis; Garrett, Sharon; Horigian, Viviana E; Jenkins, Lindsay; Killeen, Therese; Owens, Mandy; Perl, Harold I

2016-09-01

Few studies have examined the effectiveness of 12-step peer recovery support programs with drug use disorders, especially stimulant use, and it is difficult to know how outcomes related to 12-step attendance and participation generalize to individuals with non-alcohol substance use disorders (SUDs). A clinical trial of 12-step facilitation (N=471) focusing on individuals with cocaine or methamphetamine use disorders allowed examination of four questions: Q1) To what extent do treatment-seeking stimulant users use 12-step programs and, which ones? Q2) Do factors previously found to predict 12-step participation among those with alcohol use disorders also predict participation among stimulant users? Q3) What specific baseline "12-step readiness" factors predict subsequent 12-step participation and attendance? And Q4) Does stimulant drug of choice differentially predict 12-step participation and attendance? The four outcomes variables, attendance, speaking, duties at 12-step meetings, and other peer recovery support activities, were not related to baseline demographic or substance problem history or severity. Drug of choice was associated with differential days of Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) attendance among those who reported attending, and cocaine users reported more days of attending AA or NA at 1-, 3- and 6-month follow-ups than did methamphetamine users. Pre-randomization measures of perceived benefit of 12-step groups predicted 12-step attendance at 3- and 6-month follow-ups. Pre-randomization 12-step attendance significantly predicted number of other self-help activities at end-of-treatment, 3- and 6-month follow-ups. Pre-randomization perceived benefit and problem severity both predicted number of self-help activities at end-of-treatment and 3-month follow-up. Pre-randomization perceived barriers to 12-step groups were negatively associated with self-help activities at end-of-treatment and 3-month follow-up. Whether or not one participated in any duties was predicted at all time points by pre-randomization involvement in self-help activities. The primary finding of this study is one of continuity: prior attendance and active involvement with 12-step programs were the main signs pointing to future involvement. Limitations and recommendations are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Predictors of 12-Step Attendance and Participation for Individuals with Stimulant Use Disorders

PubMed Central

Hatch-Maillette, Mary; Wells, Elizabeth A.; Doyle, Suzanne R.; Brigham, Gregory S.; Daley, Dennis; DiCenzo, Jessica; Donovan, Dennis; Garrett, Sharon; Horigian, Viviana E.; Jenkins, Lindsay; Killeen, Therese; Owens, Mandy; Perl, Harold I.

2017-01-01

Objective Few studies have examined the effectiveness of 12-step peer recovery support programs with drug use disorders, especially stimulant use, and it is difficult to know how outcomes related to 12-step attendance and participation generalize to individuals with non-alcohol substance use disorders (SUDs). Method A clinical trial of 12-step facilitation (N=471) focusing on individuals with cocaine or methamphetamine use disorders allowed examination of four questions: Q1) To what extent do treatment-seeking stimulant users use 12-step programs and, which ones? Q2) Do factors previously found to predict 12-step participation among those with alcohol use disorders also predict participation among stimulant users? Q3) What specific baseline “12-step readiness” factors predict subsequent 12-step participation and attendance? And Q4) Does stimulant drug of choice differentially predict 12-step participation and attendance? Results The four outcomes variables, Attendance, Speaking, Duties at 12-step meetings, and other peer recovery support Activities, were not related to baseline demographic or substance problem history or severity. Drug of choice was associated with differential days of Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) attendance among those who reported attending, and cocaine users reported more days of attending AA or NA at 1-, 3- and 6-month follow-ups than did methamphetamine users. Pre-randomization measures of Perceived Benefit of 12-step groups predicted 12-step Attendance at 3- and 6-month follow-ups. Pre-randomization 12-step Attendance significantly predicted number of other Self-Help Activities at end-of-treatment, 3- and 6-month follow-ups. Pre-randomization Perceived Benefit and problem severity both predicted number of Self-Help Activities at end-of-treatment and 3-month follow-up. Pre-randomization Perceived Barriers to 12-step groups were negatively associated with Self-Help Activities at end-of-treatment and 3-month follow-up. Whether or not one participated in any Duties was predicted at all time points by pre-randomization involvement in Self-Help Activities. Conclusions The primary finding of this study is one of continuity: prior attendance and active involvement with 12-step programs were the main signs pointing to future involvement. Limitations and Recommendations are discussed. PMID:27431050

Preprocessing and Analysis of LC-MS-Based Proteomic Data

PubMed Central

Tsai, Tsung-Heng; Wang, Minkun; Ressom, Habtom W.

2016-01-01

Liquid chromatography coupled with mass spectrometry (LC-MS) has been widely used for profiling protein expression levels. This chapter is focused on LC-MS data preprocessing, which is a crucial step in the analysis of LC-MS based proteomics. We provide a high-level overview, highlight associated challenges, and present a step-by-step example for analysis of data from LC-MS based untargeted proteomic study. Furthermore, key procedures and relevant issues with the subsequent analysis by multiple reaction monitoring (MRM) are discussed. PMID:26519169

Hospital cost accounting: implementing the system successfully.

PubMed

Burik, D; Duvall, T J

1985-05-01

To successfully implement a cost accounting system, certain key steps should be undertaken. These steps include developing and installing software; developing cost center budgets and inter-cost center allocations; developing service item standard costs; generating cost center level and patient level standard cost reports and reconciling these costs to actual costs; generating product line profitability reports and reconciling these reports to the financial statements; and providing ad hoc reporting capabilities. By following these steps, potential problems in the implementation process can be anticipated and avoided.

Novel Syntrophic Populations Dominate an Ammonia-Tolerant Methanogenic Microbiome.

PubMed

Frank, J A; Arntzen, M Ø; Sun, L; Hagen, L H; McHardy, A C; Horn, S J; Eijsink, V G H; Schnürer, A; Pope, P B

2016-01-01

Biogas reactors operating with protein-rich substrates have high methane potential and industrial value; however, they are highly susceptible to process failure because of the accumulation of ammonia. High ammonia levels cause a decline in acetate-utilizing methanogens and instead promote the conversion of acetate via a two-step mechanism involving syntrophic acetate oxidation (SAO) to H 2 and CO 2 , followed by hydrogenotrophic methanogenesis. Despite the key role of syntrophic acetate-oxidizing bacteria (SAOB), only a few culturable representatives have been characterized. Here we show that the microbiome of a commercial, ammonia-tolerant biogas reactor harbors a deeply branched, uncultured phylotype (unFirm_1) accounting for approximately 5% of the 16S rRNA gene inventory and sharing 88% 16S rRNA gene identity with its closest characterized relative. Reconstructed genome and quantitative metaproteomic analyses imply unFirm_1's metabolic dominance and SAO capabilities, whereby the key enzymes required for acetate oxidation are among the most highly detected in the reactor microbiome. While culturable SAOB were identified in genomic analyses of the reactor, their limited proteomic representation suggests that unFirm_1 plays an important role in channeling acetate toward methane. Notably, unFirm_1-like populations were found in other high-ammonia biogas installations, conjecturing a broader importance for this novel clade of SAOB in anaerobic fermentations. IMPORTANCE The microbial production of methane or "biogas" is an attractive renewable energy technology that can recycle organic waste into biofuel. Biogas reactors operating with protein-rich substrates such as household municipal or agricultural wastes have significant industrial and societal value; however, they are highly unstable and frequently collapse due to the accumulation of ammonia. We report the discovery of a novel uncultured phylotype (unFirm_1) that is highly detectable in metaproteomic data generated from an ammonia-tolerant commercial reactor. Importantly, unFirm_1 is proposed to perform a key metabolic step in biogas microbiomes, whereby it syntrophically oxidizes acetate to hydrogen and carbon dioxide, which methanogens then covert to methane. Only very few culturable syntrophic acetate-oxidizing bacteria have been described, and all were detected at low in situ levels compared to unFirm_1. Broader comparisons produced the hypothesis that unFirm_1 is a key mediator toward the successful long-term stable operation of biogas production using protein-rich substrates.

Demonstrating Enzyme Activation: Calcium/Calmodulin Activation of Phosphodiesterase

ERIC Educational Resources Information Center

Porta, Angela R.

2004-01-01

Demonstrating the steps of a signal transduction cascade usually involves radioactive materials and thus precludes its use in undergraduate teaching labs. Developing labs that allow the visual demonstration of these steps without the use of radioactivity is important for allowing students hands-on methods of illustrating each step of a signal…

Steps in the open space planning process

Treesearch

Stephanie B. Kelly; Melissa M. Ryan

1995-01-01

This paper presents the steps involved in developing an open space plan. The steps are generic in that the methods may be applied various size communities. The intent is to provide a framework to develop an open space plan that meets Massachusetts requirements for funding of open space acquisition.

New MKLP-2 inhibitors in the paprotrain series: Design, synthesis and biological evaluations.

PubMed

Labrière, Christophe; Talapatra, Sandeep K; Thoret, Sylviane; Bougeret, Cécile; Kozielski, Frank; Guillou, Catherine

2016-02-15

Members of the kinesin superfamily are involved in key functions during intracellular transport and cell division. Their involvement in cell division makes certain kinesins potential targets for drug development in cancer chemotherapy. The two most advanced kinesin targets are Eg5 and CENP-E with inhibitors in clinical trials. Other mitotic kinesins are also being investigated for their potential as prospective drug targets. One recently identified novel potential cancer therapeutic target is the Mitotic kinesin-like protein 2 (MKLP-2), a member of the kinesin-6 family, which plays an essential role during cytokinesis. Previous studies have shown that inhibition of MKLP-2 leads to binucleated cells due to failure of cytokinesis. We have previously identified compound 1 (paprotrain) as the first selective inhibitor of MKLP-2. Herein we describe the synthesis and biological evaluation of new analogs of 1. Our structure-activity relationship (SAR) study reveals the key chemical elements in the paprotrain family necessary for MKLP-2 inhibition. We have successfully identified one MKLP-2 inhibitor 9a that is more potent than paprotrain. In addition, in vitro analysis of a panel of kinesins revealed that this compound is selective for MKLP-2 compared to other kinesins tested and also does not have an effect on microtubule dynamics. Upon testing in different cancer cell lines, we find that the more potent paprotrain analog is also more active than paprotrain in 10 different cancer cell lines. Increased selectivity and higher potency is therefore a step forward toward establishing MKLP-2 as a potential cancer drug target. Copyright © 2015 Elsevier Ltd. All rights reserved.

Using causal loop diagrams for the initialization of stakeholder engagement in soil salinity management in agricultural watersheds in developing countries: a case study in the Rechna Doab watershed, Pakistan.

PubMed

Inam, Azhar; Adamowski, Jan; Halbe, Johannes; Prasher, Shiv

2015-04-01

Over the course of the last twenty years, participatory modeling has increasingly been advocated as an integral component of integrated, adaptive, and collaborative water resources management. However, issues of high cost, time, and expertise are significant hurdles to the widespread adoption of participatory modeling in many developing countries. In this study, a step-wise method to initialize the involvement of key stakeholders in the development of qualitative system dynamics models (i.e. causal loop diagrams) is presented. The proposed approach is designed to overcome the challenges of low expertise, time and financial resources that have hampered previous participatory modeling efforts in developing countries. The methodological framework was applied in a case study of soil salinity management in the Rechna Doab region of Pakistan, with a focus on the application of qualitative modeling through stakeholder-built causal loop diagrams to address soil salinity problems in the basin. Individual causal loop diagrams were developed by key stakeholder groups, following which an overall group causal loop diagram of the entire system was built based on the individual causal loop diagrams to form a holistic qualitative model of the whole system. The case study demonstrates the usefulness of the proposed approach, based on using causal loop diagrams in initiating stakeholder involvement in the participatory model building process. In addition, the results point to social-economic aspects of soil salinity that have not been considered by other modeling studies to date. Copyright © 2015 Elsevier Ltd. All rights reserved.

Integrated analysis of transcriptomic and metabolomic data reveals critical metabolic pathways involved in rotenoid biosynthesis in the medicinal plant Mirabilis himalaica.

PubMed

Gu, Li; Zhang, Zhong-Yi; Quan, Hong; Li, Ming-Jie; Zhao, Fang-Yu; Xu, Yuan-Jiang; Liu, Jiang; Sai, Man; Zheng, Wei-Lie; Lan, Xiao-Zhong

2018-06-01

Mirabilis himalaica (Edgew.) Heimerl is among the most important genuine medicinal plants in Tibet. However, the biosynthesis mechanisms of the active compounds in this species are unclear, severely limiting its application. To clarify the molecular biosynthesis mechanism of the key representative active compounds, specifically rotenoid, which is of special medicinal value for M. himalaica, RNA sequencing and TOF-MS technologies were used to construct transcriptomic and metabolomic libraries from the roots, stems, and leaves of M. himalaica plants collected from their natural habitat. As a result, each of the transcriptomic libraries from the different tissues was sequenced, generating more than 10 Gb of clean data ultimately assembled into 147,142 unigenes. In the three tissues, metabolomic analysis identified 522 candidate compounds, of which 170 metabolites involved in 114 metabolic pathways were mapped to the KEGG. Of these genes, 61 encoding enzymes were identified to function at key steps of the pathways related to rotenoid biosynthesis, where 14 intermediate metabolites were also located. An integrated analysis of metabolic and transcriptomic data revealed that most of the intermediate metabolites and enzymes related to rotenoid biosynthesis were synthesized in the roots, stems and leaves of M. himalaica, which suggested that the use of non-medicinal tissues to extract compounds was feasible. In addition, the CHS and CHI genes were found to play important roles in rotenoid biosynthesis, especially, since CHS might be an important rate-limiting enzyme. This study provides a hypothetical basis for the screening of new active metabolites and the metabolic engineering of rotenoid in M. himalaica.

A qualitative case study of the legislative process of the hygienist-therapist bill in a large Midwestern state.

PubMed

Dollins, Haley E; Bray, Kimberly Krust; Gadbury-Amyot, Cynthia C

2013-10-01

Inequitable access to dental care contributes to oral health disparities. Midlevel dental provider models are utilized across the globe as a way to bridge the gap between preventive and restorative dental professionals and increase access to dental care. The purpose of this study was threefold: to examine lessons learned from the state legislative process related to creation of the hygienist-therapist in a Midwestern state, to improve understanding of the relationship between alternative oral health delivery models and public policy and to inform the development and passage of future policies aimed at addressing the unmet dental needs of the public. This research investigation utilized a qualitative research methodology to examine the process of legislation relating to an alternative oral health delivery model (hygienist-therapist) through the eyes of key stakeholders. Interview data was analyzed and then triangulated with 3 data sources: interviews with key stakeholders, documents and researcher participant field notes. Data analysis resulted in consensus on 3 emergent themes with accompanying categories. The themes that emerged included social justice, partnerships and coalitions, and the legislative process. This qualitative case study suggests that the creation of a new oral health workforce model was a long and arduous process involving multiple stakeholders and negotiation between the parties involved. The creation of this new workforce model was recognized as a necessary step to increasing access to dental care at the state and national level. The research in this case study may serve to inform advocates of access to oral health care as other states pursue their own workforce models.

Engineering Escherichia coli Nicotinic Acid Mononucleotide Adenylyltransferase for Fully Active Amidated NAD Biosynthesis.

PubMed

Wang, Xueying; Zhou, Yongjin J; Wang, Lei; Liu, Wujun; Liu, Yuxue; Peng, Chang; Zhao, Zongbao K

2017-07-01

NAD and its reduced form NADH function as essential redox cofactors and have major roles in determining cellular metabolic features. NAD can be synthesized through the deamidated and amidated pathways, for which the key reaction involves adenylylation of nicotinic acid mononucleotide (NaMN) and nicotinamide mononucleotide (NMN), respectively. In Escherichia coli , NAD de novo biosynthesis depends on the protein NadD-catalyzed adenylylation of NaMN to nicotinic acid adenine dinucleotide (NaAD), followed by NAD synthase-catalyzed amidation. In this study, we engineered NadD to favor NMN for improved amidated pathway activity. We designed NadD mutant libraries, screened by a malic enzyme-coupled colorimetric assay, and identified two variants, 11B4 (Y84V/Y118D) and 16D8 (A86W/Y118N), with a high preference for NMN. Whereas in the presence of NMN both variants were capable of enabling the viability of cells of E. coli BW25113-derived NAD-auxotrophic strain YJE003, for which the last step of the deamidated pathway is blocked, the 16D8 expression strain could grow without exogenous NMN and accumulated a higher cellular NAD(H) level than BW25113 in the stationary phase. These mutants established fully active amidated NAD biosynthesis and offered a new opportunity to manipulate NAD metabolism for biocatalysis and metabolic engineering. IMPORTANCE Adenylylation of nicotinic acid mononucleotide (NaMN) and adenylylation of nicotinamide mononucleotide (NMN), respectively, are the key steps in the deamidated and amidated pathways for NAD biosynthesis. In most organisms, canonical NAD biosynthesis follows the deamidated pathway. Here we engineered Escherichia coli NaMN adenylyltransferase to favor NMN and expressed the mutant enzyme in an NAD-auxotrophic E. coli strain that has the last step of the deamidated pathway blocked. The engineered strain survived in M9 medium, which indicated the implementation of a functional amidated pathway for NAD biosynthesis. These results enrich our understanding of NAD biosynthesis and are valuable for manipulation of NAD homeostasis for metabolic engineering. Copyright © 2017 American Society for Microbiology.

Biotin and Lipoic Acid: Synthesis, Attachment and Regulation

PubMed Central

Cronan, John E.

2014-01-01

Summary Two vitamins, biotin and lipoic acid, are essential in all three domains of life. Both coenzymes function only when covalently attached to key metabolic enzymes. There they act as “swinging arms” that shuttle intermediates between two active sites (= covalent substrate channeling) of key metabolic enzymes. Although biotin was discovered over 100 years ago and lipoic acid 60 years ago, it was not known how either coenzyme is made until recently. In Escherichia coli the synthetic pathways for both coenzymes have now been worked out for the first time. The late steps of biotin synthesis, those involved in assembling the fused rings, were well-described biochemically years ago, although recent progress has been made on the BioB reaction, the last step of the pathway in which the biotin sulfur moiety is inserted. In contrast, the early steps of biotin synthesis, assembly of the fatty acid-like “arm” of biotin were unknown. It has now been demonstrated that the arm is made by using disguised substrates to gain entry into the fatty acid synthesis pathway followed by removal of the disguise when the proper chain length is attained. The BioC methyltransferase is responsible for introducing the disguise and the BioH esterase for its removal. In contrast to biotin, which is attached to its cognate proteins as a finished molecule, lipoic acid is assembled on its cognate proteins. An octanoyl moiety is transferred from the octanoyl-ACP of fatty acid synthesis to a specific lysine residue of a cognate protein by the LipB octanoyl transferase followed by sulfur insertion at carbons C6 and C8 by the LipA lipoyl synthetase. Assembly on the cognate proteins regulates the amount of lipoic acid synthesized and thus there is no transcriptional control of the synthetic genes. In contrast transcriptional control of the biotin synthetic genes is wielded by a remarkably sophisticated, yet simple, system, exerted through BirA a dual function protein that both represses biotin operon transcription and ligates biotin to its cognate protein. PMID:26442940

Synthesis of fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-β-neohesperidoside based on site-selective deacetylation and deoxygenation.

PubMed

Tsunekawa, Ryuji; Hanaya, Kengo; Higashibayashi, Shuhei; Sugai, Takeshi

2018-04-26

Fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-β-neohesperidoside were synthesized from commercially available quercetin and naringin in five steps. The key steps are site-selective deacetylation and subsequent deoxygenation. The target molecules were obtained in 37% and 23% yields from the starting materials, respectively.

How to Develop Children as Researchers: A Step-by-Step Guide to Teaching the Research Process

ERIC Educational Resources Information Center

Kellett, Mary

2005-01-01

The importance of research in professional and personal development is increasingly being acknowledged. So why should children not benefit in a similar way? Traditionally, children have been excluded from this learning process because research methodology is considered too difficult for them. Principal obstacles focus around three key barriers:…

Reinventing Your Board: A Step-by-Step Guide to Implementing Policy Governance. The Jossey-Bass Nonprofit and Public Management Series.

ERIC Educational Resources Information Center

Carver, John; Carver, Miriam Mayhew

This guide provides practical advice regarding implementation of the Policy Governance model for school boards. Chapter 1, "Setting the Stage," explores questions commonly raised by boards prior to implementation of the Policy Governance model. Chapter 2, "The Theoretical Foundation," reviews the key theoretical principles of…

Healthy Connections. A Training Program for Volunteers Working with At-Risk Pregnant Women. Leader's Manual.

ERIC Educational Resources Information Center

Harris, Carolyn DeMeyer; McKinney, David D., Ed.

This leader's manual, keyed to an accompanying videotape, contains step-by-step instructions for conducting a training session for volunteers who are preparing to work with young unmarried pregnant women. The manual, which includes transparency masters of handouts, is laid out with the outside column of each page containing instructions to the…

Linking Costs and Postsecondary Degrees: Key Issues for Policymakers. Working Paper 2011-03

ERIC Educational Resources Information Center

Johnson, Nate

2011-01-01

In this paper the author offers practical advice for decision-makers who are struggling to rein in college costs while improving productivity. He provides a step-by-step guide to different approaches for calculating costs, highlights the tremendous variability in cost across programs within institutions, and documents some of the "hidden costs" of…

Taking a Step Back: Learning without the Facilitator on Solo Activities

ERIC Educational Resources Information Center

Williams, Andy

2012-01-01

The purpose of this study is to report on the nature of student learning resulting from an open facilitation approach to solo activities. Three key moments of facilitator intervention were identified at which the facilitator was encouraged to take a step back from directing the experience. They are the pre-activity brief, the mid-activity visit…

Positioning the Learning Asset Portfolio as a Key Component in an Organization's Enterprise Risk Management Strategy

ERIC Educational Resources Information Center

McAliney, Peter J.

2009-01-01

This article presents a process for valuing a portfolio of learning assets used by line executives across industries to value traditional business assets. Embedded within the context of enterprise risk management, this strategic asset allocation process is presented step by step, providing readers the operational considerations to implement this…

Domain Definition and Search Techniques in Meta-Analyses of L2 Research (or Why 18 Meta-Analyses of Feedback Have Different Results)

ERIC Educational Resources Information Center

Plonsky, Luke; Brown, Dan

2015-01-01

Applied linguists have turned increasingly in recent years to meta-analysis as the preferred means of synthesizing quantitative research. The first step in the meta-analytic process involves defining a domain of interest. Despite its apparent simplicity, this step involves a great deal of subjectivity on the part of the meta-analyst. This article…

Hypertonicity-induced transmitter release at Drosophila neuromuscular junctions is partly mediated by integrins and cAMP/protein kinase A

NASA Technical Reports Server (NTRS)

Suzuki, Kazuhiro; Grinnell, Alan D.; Kidokoro, Yoshiaki

2002-01-01

The frequency of quantal transmitter release increases upon application of hypertonic solutions. This effect bypasses the Ca(2+) triggering step, but requires the presence of key molecules involved in vesicle fusion, and hence could be a useful tool for dissecting the molecular process of vesicle fusion. We have examined the hypertonicity response at neuromuscular junctions of Drosophila embryos in Ca(2+)-free saline. Relative to wild-type, the response induced by puff application of hypertonic solution was enhanced in a mutant, dunce, in which the cAMP level is elevated, or in wild-type embryos treated with forskolin, an activator of adenylyl cyclase, while protein kinase A (PKA) inhibitors decreased it. The response was also smaller in a mutant, DC0, which lacks the major subunit of PKA. Thus the cAMP/PKA cascade is involved in the hypertonicity response. Peptides containing the sequence Arg-Gly-Asp (RGD), which inhibit binding of integrins to natural ligands, reduced the response, whereas a peptide containing the non-binding sequence Arg-Gly-Glu (RGE) did not. A reduced response persisted in a mutant, myospheroid, which expresses no integrins, and the response in DC0 was unaffected by RGD peptides. These data indicate that there are at lease two components in the hypertonicity response: one that is integrin mediated and involves the cAMP/PKA cascade, and another that is not integrin mediated and does not involve the cAMP/PKA cascade.

IMAT graphics manual

NASA Technical Reports Server (NTRS)

Stockwell, Alan E.; Cooper, Paul A.

1991-01-01

The Integrated Multidisciplinary Analysis Tool (IMAT) consists of a menu driven executive system coupled with a relational database which links commercial structures, structural dynamics and control codes. The IMAT graphics system, a key element of the software, provides a common interface for storing, retrieving, and displaying graphical information. The IMAT Graphics Manual shows users of commercial analysis codes (MATRIXx, MSC/NASTRAN and I-DEAS) how to use the IMAT graphics system to obtain high quality graphical output using familiar plotting procedures. The manual explains the key features of the IMAT graphics system, illustrates their use with simple step-by-step examples, and provides a reference for users who wish to take advantage of the flexibility of the software to customize their own applications.

Comparison of 12-step Groups to Mutual Help Alternatives for AUD in a Large, National Study: Differences in Membership Characteristics and Group Participation, Cohesion, and Satisfaction

PubMed Central

Zemore, Sarah E.; Kaskutas, Lee Ann; Mericle, Amy; Hemberg, Jordana

2016-01-01

Background Many studies suggest that participation in 12-step groups contributes to better recovery outcomes, but people often object to such groups and most do not sustain regular involvement. Yet, research on alternatives to 12-step groups is very sparse. The present study aimed to extend the knowledge base on mutual help group alternatives for those with an alcohol use disorder (AUD), sampling from large, active, abstinence-focused groups including Women for Sobriety (WFS), LifeRing, and SMART Recovery (SMART). This paper presents a cross-sectional analysis of this longitudinal study, using baseline data to describe the profile and participation characteristics of attendees of these groups in comparison to 12-step members. Methods Data from participants 18 and over with a lifetime AUD (N=651) were collected using web-based surveys. Members of alternative 12-step groups were recruited in collaboration with group directors, who helped publicize the study by emailing meeting conveners and attendees and posting announcements on social media. A comparison group of current (past-30-day) 12-step attendees was recruited from an online meeting hub for recovering persons. Interested parties were directed to a webpage where they were screened, and eligible participants completed an online survey assessing demographic and clinical variables; in-person and online mutual help involvement; and group satisfaction and cohesion. Analyses involved comparing those identifying WFS, SMART, and LifeRing as their primary group to 12-step members on the above characteristics. Results Compared to 12-step members, members of the mutual help alternatives were less religious and generally higher on education and income. WFS and LifeRing members were also older, more likely to be married, and lower on lifetime drug and psychiatric severity; meanwhile, LifeRing and SMART members were less likely to endorse the most stringent abstinence goal. Finally, despite lower levels of in-person meeting attendance, members of all the 12-step alternatives showed equivalent activity involvement and higher levels of satisfaction and cohesion, compared to 12-step members. Conclusions Results suggest differences across 12-step groups and their alternatives that may be relevant when advising clients on a choice of mutual help group. Meanwhile, findings for high levels of participation, satisfaction, and cohesion among members of the mutual help alternatives suggest promise for these groups in addressing addiction problems. PMID:28017180

Comparison of 12-step groups to mutual help alternatives for AUD in a large, national study: Differences in membership characteristics and group participation, cohesion, and satisfaction.

PubMed

Zemore, Sarah E; Kaskutas, Lee Ann; Mericle, Amy; Hemberg, Jordana

2017-02-01

Many studies suggest that participation in 12-step groups contributes to better recovery outcomes, but people often object to such groups and most do not sustain regular involvement. Yet, research on alternatives to 12-step groups is very sparse. The present study aimed to extend the knowledge base on mutual help group alternatives for those with an alcohol use disorder (AUD), sampling from large, active, abstinence-focused groups including Women for Sobriety (WFS), LifeRing, and SMART Recovery (SMART). This paper presents a cross-sectional analysis of this longitudinal study, using baseline data to describe the profile and participation characteristics of attendees of these groups in comparison to 12-step members. Data from participants 18 and over with a lifetime AUD (N=651) were collected using Web-based surveys. Members of alternative 12-step groups were recruited in collaboration with group directors, who helped publicize the study by emailing meeting conveners and attendees and posting announcements on social media. A comparison group of current (past-30-day) 12-step attendees was recruited from an online meeting hub for recovering persons. Interested parties were directed to a Webpage where they were screened, and eligible participants completed an online survey assessing demographic and clinical variables; in-person and online mutual help involvement; and group satisfaction and cohesion. Analyses involved comparing those identifying WFS, SMART, and LifeRing as their primary group to 12-step members on the above characteristics. Compared to 12-step members, members of the mutual help alternatives were less religious and generally higher on education and income. WFS and LifeRing members were also older, more likely to be married, and lower on lifetime drug and psychiatric severity; meanwhile, LifeRing and SMART members were less likely to endorse the most stringent abstinence goal. Finally, despite lower levels of in-person meeting attendance, members of all the 12-step alternatives showed equivalent activity involvement and higher levels of satisfaction and cohesion, compared to 12-step members. Results suggest differences across 12-step groups and their alternatives that may be relevant when advising clients on a choice of mutual help group. Meanwhile, findings for high levels of participation, satisfaction, and cohesion among members of the mutual help alternatives suggest promise for these groups in addressing addiction problems. Copyright © 2016 Elsevier Inc. All rights reserved.

A step-by-step translation of evidence into a psychosocial intervention for everyday activities in dementia: a focus group study.

PubMed

Giebel, Clarissa M; Challis, David; Hooper, Nigel M; Ferris, Sally

2018-03-01

In order to increase the efficacy of psychosocial interventions in dementia, a step-by-step process translating evidence and public engagement should be adhered to. This paper describes such a process by involving a two-stage focus group with people with dementia (PwD), informal carers, and staff. Based on previous evidence, general aspects of effective interventions were drawn out. These were tested in the first stage of focus groups, one with informal carers and PwD and one with staff. Findings from this stage helped shape the intervention further specifying its content. In the second stage, participants were consulted about the detailed components. The extant evidence base and focus groups helped to identify six practical and situation-specific elements worthy of consideration in planning such an intervention, including underlying theory and personal motivations for participation. Carers, PwD, and staff highlighted the importance of rapport between practitioners and PwD prior to commencing the intervention. It was also considered important that the intervention would be personalised to each individual. This paper shows how valuable public involvement can be to intervention development, and outlines a process of public involvement for future intervention development. The next step would be to formally test the intervention.

Characterization of systemic disease in primary Sjögren's syndrome: EULAR-SS Task Force recommendations for articular, cutaneous, pulmonary and renal involvements.

PubMed

Ramos-Casals, Manuel; Brito-Zerón, Pilar; Seror, Raphaèle; Bootsma, Hendrika; Bowman, Simon J; Dörner, Thomas; Gottenberg, Jacques-Eric; Mariette, Xavier; Theander, Elke; Bombardieri, Stefano; De Vita, Salvatore; Mandl, Thomas; Ng, Wan-Fai; Kruize, Aike; Tzioufas, Athanasios; Vitali, Claudio

2015-12-01

To reach a European consensus on the definition and characterization of the main organ-specific extraglandular manifestations in primary SS. The EULAR-SS Task Force Group steering committee agreed to approach SS-related systemic involvement according to the EULAR SS Disease Activity Index (ESSDAI) classification and proposed the preparation of four separate manuscripts: articular, cutaneous, pulmonary and renal ESSDAI involvement; muscular, peripheral nervous system, CNS and haematological ESSDAI involvement; organs not included in the ESSDAI classification; and lymphoproliferative disease. Currently available evidence was obtained by a systematic literature review focused on SS-related systemic features. The following information was summarized for articular, cutaneous, pulmonary and renal involvement: a clear, consensual definition of the clinical feature, a brief epidemiological description including an estimate of the prevalence reported in the main clinical series and a brief list of the key clinical and diagnostic features that could help physicians clearly identify these features. Unfortunately we found that the body of evidence relied predominantly on information retrieved from individual cases, and the scientific information provided was heterogeneous. The analysis of types of involvement was biased due to the unbalanced reporting of severe cases over non-severe cases, although the main sources of bias were the heterogeneous definitions of organ involvement (or even the lack of definition in some studies) and the heterogeneous diagnostic approach used in studies to investigate involvment of each organ. The proposals included in this article are a first step to developing an optimal diagnostic approach to systemic involvement in primary SS and may pave the way for further development of evidence-based diagnostic and therapeutic guidelines. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Developing a conceptual model for the application of patient and public involvement in the healthcare system in Iran.

PubMed

Azmal, Mohammad; Sari, Ali Akbari; Foroushani, Abbas Rahimi; Ahmadi, Batoul

2016-06-01

Patient and public involvement is engaging patients, providers, community representatives, and the public in healthcare planning and decision-making. The purpose of this study was to develop a model for the application of patient and public involvement in decision making in the Iranian healthcare system. A mixed qualitative-quantitative approach was used to develop a conceptual model. Thirty three key informants were purposely recruited in the qualitative stage, and 420 people (patients and their companions) were included in a protocol study that was implemented in five steps: 1) Identifying antecedents, consequences, and variables associated with the patient and the publics' involvement in healthcare decision making through a comprehensive literature review; 2) Determining the main variables in the context of Iran's health system using conceptual framework analysis; 3) Prioritizing and weighting variables by Shannon entropy; 4) designing and validating a tool for patient and public involvement in healthcare decision making; and 5) Providing a conceptual model of patient and the public involvement in planning and developing healthcare using structural equation modeling. We used various software programs, including SPSS (17), Max QDA (10), EXCEL, and LISREL. Content analysis, Shannon entropy, and descriptive and analytic statistics were used to analyze the data. In this study, seven antecedents variable, five dimensions of involvement, and six consequences were identified. These variables were used to design a valid tool. A logical model was derived that explained the logical relationships between antecedent and consequent variables and the dimensions of patient and public involvement as well. Given the specific context of the political, social, and innovative environments in Iran, it was necessary to design a model that would be compatible with these features. It can improve the quality of care and promote the patient and the public satisfaction with healthcare and legitimate the representative of people they served for. This model can provide a practical guide for managers and policy makers to involve people in making the decisions that influence their lives.

Morphological Study on Porous Silicon Carbide Membrane Fabricated by Double-Step Electrochemical Etching

NASA Astrophysics Data System (ADS)

Omiya, Takuma; Tanaka, Akira; Shimomura, Masaru

2012-07-01

The structure of porous silicon carbide membranes that peeled off spontaneously during electrochemical etching was studied. They were fabricated from n-type 6H SiC(0001) wafers by a double-step electrochemical etching process in a hydrofluoric electrolyte. Nanoporous membranes were obtained after double-step etching with current densities of 10-20 and 60-100 mA/cm2 in the first and second steps, respectively. Microporous membranes were also fabricated after double-step etching with current densities of 100 and 200 mA/cm2. It was found that the pore diameter is influenced by the etching current in step 1, and that a higher current is required in step 2 when the current in step 1 is increased. During the etching processes in steps 1 and 2, vertical nanopore and lateral crack formations proceed, respectively. The influx pathway of hydrofluoric solution, expansion of generated gases, and transfer limitation of positive holes to the pore surface are the key factors in the peeling-off mechanism of the membrane.

How to Involve Concessionaires & Vendors in Your Recycling Program

EPA Pesticide Factsheets

This fact sheet is written for operations managers, recycling and event coordinators, and other key decisionmakers involved in planning and managing public venues and events. It explains the key role in recycling played by concessionaires.

Summer Training and Education Program (STEP): Report on the 1987 Experience.

ERIC Educational Resources Information Center

Sipe, Cynthia L.; And Others

The Summer Training and Education Program (STEP) was developed in 1984 as a strategy for reducing the number of young people who leave school without the skills and motivation necessary for productive employment. The STEP intervention involves collaboration between the public schools and the federal Summer Youth Employment and Training Program…

Abundance of ammonia oxidizing bacteria and archaea under long-term maize cropping systems.

USDA-ARS?s Scientific Manuscript database

Nitrification involves the oxidation of ammonium and is an important component of the overall N cycle. Nitrification occurs in two steps; first by oxidizing ammonium to nitrite, and then to nitrate. The first step is often the rate limiting step. Until recently ammonia-oxidizing bacteria were though...

Lights, Camera, Action: Facilitating the Design and Production of Effective Instructional Videos

ERIC Educational Resources Information Center

Di Paolo, Terry; Wakefield, Jenny S.; Mills, Leila A.; Baker, Laura

2017-01-01

This paper outlines a rudimentary process intended to guide faculty in K-12 and higher education through the steps involved to produce video for their classes. The process comprises four steps: planning, development, delivery and reflection. Each step is infused with instructional design information intended to support the collaboration between…

Ethnography, Step by Step (2nd Edition), by David M. Fetterman, Thousand Oaks, Ca: Sage, 1998..

ERIC Educational Resources Information Center

Green, Jennifer C.; Buell, James

2000-01-01

Reviews this edition, which like the first is primarily an organized presentation of fieldwork vignettes and instructive examples from research and evaluation contexts. The presentation is organized by the steps involved in ethnographic fieldwork. This edition is updated with references to electronic technology. (SLD)

Limits of acceptable change and natural resources planning: when is LAC useful, when is it not?

Treesearch

David N. Cole; Stephen F. McCool

1997-01-01

There are ways to improve the LAC process and its implementational procedures. One significant procedural modification is the addition of a new step. This step — which becomes the first step in the process — involves more explicitly defining goals and desired conditions. For other steps in the process, clarifications of concept and terminology are advanced, as are...

High level expression of chorismate pyruvate-lyase (UbiC) and HMG-CoA reductase in hairy root cultures of Lithospermum erythrorhizon.

PubMed

Köhle, Annegret; Sommer, Susanne; Yazaki, Kazufumi; Ferrer, Albert; Boronat, Albert; Li, Shu-Ming; Heide, Lutz

2002-08-01

Shikonin, a red naphthoquinone pigment, is produced by cell cultures of Lithospermum erythrorhizon (Boraginaceae). It is biosynthetically derived from two key precursors, 4-hydroxybenzoate (4HB) and geranyldiphosphate (GPP). The bacterial ubiC gene, encoding chorismate pyruvate-lyase (CPL) which converts chorismate to 4-hydroxybenzoate, was expressed in L. erythrorhizon under the control of the strong (ocs)(3)mas-promoter. This introduced an efficient biosynthetic pathway to 4HB, i.e. a one-step reaction from chorismate, in addition to the endogeneous multi-step phenylpropanoid pathway. Feeding experiments with [1,7-(13)C(2)]shikimic acid showed that in the most active transgenic line, 73% of 4HB was synthesized via the genetically introduced pathway. However, there was no correlation between CPL activity and 4HB glucoside or shikonin accumulation in the transgenic lines. HMG-CoA reductase (HMGR) is involved in the biosynthesis of GPP in L. erythrorhizon. Two forms of HMGR1 of Arabidopsis thaliana were expressed in Lithospermum under control of the (ocs)(3)mas promoter. Only moderate increases in enzyme activity were obtained with the complete enzyme, but high activity was achieved using the soluble cytosolic domain of HMGR1. Shikonin accumulation remained unchanged even upon high expression of soluble HMGR.

ExcelAutomat: a tool for systematic processing of files as applied to quantum chemical calculations

NASA Astrophysics Data System (ADS)

Laloo, Jalal Z. A.; Laloo, Nassirah; Rhyman, Lydia; Ramasami, Ponnadurai

2017-07-01

The processing of the input and output files of quantum chemical calculations often necessitates a spreadsheet as a key component of the workflow. Spreadsheet packages with a built-in programming language editor can automate the steps involved and thus provide a direct link between processing files and the spreadsheet. This helps to reduce user-interventions as well as the need to switch between different programs to carry out each step. The ExcelAutomat tool is the implementation of this method in Microsoft Excel (MS Excel) using the default Visual Basic for Application (VBA) programming language. The code in ExcelAutomat was adapted to work with the platform-independent open-source LibreOffice Calc, which also supports VBA. ExcelAutomat provides an interface through the spreadsheet to automate repetitive tasks such as merging input files, splitting, parsing and compiling data from output files, and generation of unique filenames. Selected extracted parameters can be retrieved as variables which can be included in custom codes for a tailored approach. ExcelAutomat works with Gaussian files and is adapted for use with other computational packages including the non-commercial GAMESS. ExcelAutomat is available as a downloadable MS Excel workbook or as a LibreOffice workbook.

Data multiplexing in radio interferometric calibration

NASA Astrophysics Data System (ADS)

Yatawatta, Sarod; Diblen, Faruk; Spreeuw, Hanno; Koopmans, L. V. E.

2018-03-01

New and upcoming radio interferometers will produce unprecedented amount of data that demand extremely powerful computers for processing. This is a limiting factor due to the large computational power and energy costs involved. Such limitations restrict several key data processing steps in radio interferometry. One such step is calibration where systematic errors in the data are determined and corrected. Accurate calibration is an essential component in reaching many scientific goals in radio astronomy and the use of consensus optimization that exploits the continuity of systematic errors across frequency significantly improves calibration accuracy. In order to reach full consensus, data at all frequencies need to be calibrated simultaneously. In the SKA regime, this can become intractable if the available compute agents do not have the resources to process data from all frequency channels simultaneously. In this paper, we propose a multiplexing scheme that is based on the alternating direction method of multipliers with cyclic updates. With this scheme, it is possible to simultaneously calibrate the full data set using far fewer compute agents than the number of frequencies at which data are available. We give simulation results to show the feasibility of the proposed multiplexing scheme in simultaneously calibrating a full data set when a limited number of compute agents are available.

A Christian faith-based recovery theory: understanding God as sponsor.

PubMed

Timmons, Shirley M

2012-12-01

This article reports the development of a substantive theory to explain an evangelical Christian-based process of recovery from addiction. Faith-based, 12-step, mutual aid programs can improve drug abstinence by offering: (a) an intervention option alone and/or in conjunction with secular programs and (b) an opportunity for religious involvement. Although literature on religion, spirituality, and addiction is voluminous, traditional 12-step programs fail to explain the mechanism that underpins the process of Christian-based recovery (CR). This pilot study used grounded theory to explore and describe the essence of recovery of 10 former crack cocaine-addicted persons voluntarily enrolled in a CR program. Data were collected from in-depth interviews during 4 months of 2008. Audiotapes were transcribed verbatim, and the constant comparative method was used to analyze data resulting in the basic social process theory, understanding God as sponsor. The theory was determined through writing theoretical memos that generated key elements that allow persons to recover: acknowledging God-centered crises, communicating with God, and planning for the future. Findings from this preliminary study identifies important factors that can help persons in recovery to sustain sobriety and program administrators to benefit from theory that guides the development of evidence-based addiction interventions.

Plasmid pVAX1-NH36 purification by membrane and bead perfusion chromatography.

PubMed

Franco-Medrano, Diana Ivonne; Guerrero-Germán, Patricia; Montesinos-Cisneros, Rosa María; Ortega-López, Jaime; Tejeda-Mansir, Armando

2017-03-01

The demand for plasmid DNA (pDNA) has increased in response to the rapid advances in vaccines applications to prevent and treat infectious diseases caused by virus, bacteria or parasites, such as Leishmania species. The immunization protocols require large amounts of supercoiled plasmid DNA (sc-pDNA) challenging the development of efficient and profitable processes for capturing and purified pDNA molecules from large volumes of lysates. A typical bioprocess involves four steps: fermentation, primary recovery, intermediate recovery and final purification. Ion-exchange chromatography is one of the key operations in the purification schemes of pDNA owing the chemical structure of these macromolecules. The goal of this research was to compare the performance of the final purification step of pDNA using ion-exchange chromatography on columns packed with Mustang Q membranes or perfusive beads POROS 50 HQ. The experimental results showed that both matrixes could separate the plasmid pVAX1-NH36 (3936 bp) from impurities in clarified Escherichia coli lysates with an adequate resolution. In addition, a 24- and 21-fold global purification factor was obtained. An 88 and 63% plasmid recuperation was achieved with ion-exchange membranes and perfusion beads, respectively. A better understanding of perfusion-based matrices for the purification of pDNA was developed in this research.