Inhibition of Comt with tolcapone slows progression of polycystic kidney disease in the more severely affected PKD/Mhm (cy/+) substrain of the Hannover Sprague-Dawley rat

PubMed Central

Boehn, Susanne N.E.; Spahn, Sonja; Neudecker, Sabine; Keppler, Andrea; Bihoreau, Marie-Thérèse; Kränzlin, Bettina; Pandey, Priyanka; Hoffmann, Sigrid C.; Li, Li; Torres, Vicente E.; Gröne, Hermann-Josef; Gretz, Norbert

2013-01-01

Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human inherited diseases. Modifier genes seem to modulate the disease progression and might therefore be promising drug targets. Although a number of modifier loci have been already identified, no modifier gene has been proven to be a real modifier yet. Methods Gene expression profiling of two substrains of the Han:SPRD rat, namely PKD/Mhm and PKD/US, both harboring the same mutation, was conducted in 36-day-old animals. Catechol-O-methyltransferase (Comt) was identified as a potential modifier gene. A 3-month treatment with tolcapone, a selective inhibitor of Comt, was carried out in PKD/Mhm and PKD/US (cy/+) animals. Results Comt is localized within a known modifier locus of PKD (MOP2). The enzyme encoding gene was found upregulated in the more severely affected PKD/Mhm substrain and was hence presumed to be a putative modifier gene of PKD. The treatment with tolcapone markedly attenuated the loss of renal function, inhibited renal enlargement, shifted the size distribution of renal cysts and retarded cell proliferation, apoptosis, inflammation and fibrosis development in affected (cy/+) male and female PKD/Mhm and PKD/US rats. Conclusions Comt has been confirmed to be the first reported modifier gene for PKD and tolcapone offers a promising drug for treating PKD. PMID:23543593

Social ties may play a critical role in mitigating sleep difficulties in disaster-affected communities: a cross-sectional study in the Ishinomaki area, Japan.

PubMed

Matsumoto, Shoko; Yamaoka, Kazue; Inoue, Machiko; Muto, Shinsuke

2014-01-01

We examined the association between social factors and sleep difficulties among the victims remaining at home in the Ishinomaki area after the Great East Japan Earthquake and Tsunami and identified potentially modifiable factors that may mitigate vulnerability to sleep difficulties during future traumatic events or disasters. A cross-sectional household survey was conducted from October 2011 to March 2012 (6-12 mo after the disaster) in the Ishinomaki area, Japan. Univariate and multivariate logistic regression models were used to examine associations between social factors and sleep difficulties. We obtained data on 4,176 household members who remained in their homes after the earthquake and tsunami. N/A. Sleep difficulties were prevalent in 15.0% of the respondents (9.2% male, 20.2% female). Two potentially modifiable factors (lack of pleasure in life and lack of interaction with/visiting neighbors) and three nonmodifiable or hardly modifiable factors (sex, source of income, and number of household members) were associated with sleep difficulties. Nonmodifiable or hardly modifiable consequences caused directly by the disaster (severity of house damage, change in family structure, and change in working status) were not significantly associated with sleep difficulties. Our data suggest that the lack of pleasure in life and relatively strong networks in the neighborhood, which are potentially modifiable, might have stronger associations with sleep difficulties than do nonmodifiable or hardly modifiable consequences of the disaster (e.g., house damage, change in family structure, and change in work status).

Using spiritually modified cognitive-behavioral therapy in substance dependence treatment: therapists' and clients' perceptions of the presumed benefits and limitations.

PubMed

Hodge, David R; Lietz, Cynthia A

2014-11-01

Cognitive-behavioral therapy (CBT) that has been modified to incorporate clients' spiritual beliefs and practices has been used to treat a variety of problems. This study examines the utility of this modality with the treatment of alcohol dependence and other forms of substance abuse. Toward this end, six focus groups (three therapist groups and three client groups) were conducted to identify the presumed benefits and limitations of using spiritually modified CBT in substance dependence treatment. In terms of benefits, spiritually modified CBT was perceived to enhance outcomes through operationalizing horizontal and vertical sources of social support, divine coping resources, and spiritual motivation. Potential challenges include the risk of therapists inadvertently imposing their own beliefs during the modification process and the possibility of offending clients when conflicts in belief systems emerge, particularly in group setting. The article concludes by providing suggestions for incorporating spiritually modified CBT into treatment and develops a number of illustrative examples of spiritually modified CBT self-statements.

Thermomechanical response of NiTi shape-memory nanoprecipitates in TiV alloys

NASA Astrophysics Data System (ADS)

Maisel, S. B.; Ko, W.-S.; Zhang, J.-L.; Grabowski, B.; Neugebauer, J.

2017-08-01

We study the properties of NiTi shape-memory nanoparticles coherently embedded in TiV matrices using three-dimensional atomistic simulations based on the modified embedded-atom method. To this end, we develop and present a suitable NiTiV potential for our simulations. Employing this potential, we identify the conditions under which the martensitic phase transformation of such a nanoparticle is triggered—specifically, how these conditions can be tuned by modifying the size of the particle, the composition of the surrounding matrix, or the temperature and strain state of the system. Using these insights, we establish how the transformation temperature of such particles can be influenced and discuss the practical implications in the context of shape-memory strengthened alloys.

Modifiable factors associated with caregiver burden among family caregivers of terminally ill Korean cancer patients.

PubMed

Yoon, Seok-Joon; Kim, Jong-Sung; Jung, Jin-Gyu; Kim, Sung-Soo; Kim, Samyong

2014-05-01

Higher caregiver burden is associated with poor quality of life among family caregivers. However, in Korea, very few studies have examined factors associated with caregiver burden. The present study investigated factors associated with caregiver burden among family caregivers of terminally ill Korean cancer patients, particularly modifiable factors as a potential target of intervention strategies. A cross-sectional study using self-administered questionnaires was performed. Sixty-four family caregivers of terminally ill cancer patients who were admitted to the hospice-palliative care unit of a university hospital in South Korea were included. To identify caregiver burden, the Caregiver Reaction Assessment scale (CRA) was used in this study. Time spent in providing care per day, number of visits per week from other family members, family functioning, and a positive subscale, self-esteem, of the CRA were deemed as modifiable factors. Other sociodemographic, caregiving characteristics of the subjects were non-modifiable factors. Longer time spent providing care per day, fewer weekly visits from other family members, poor family functioning, and low self-esteem were considered as modifiable factors associated with caregiver burden. Low monthly income and the spouse being the family caregiver were non-modifiable factors. Our study has practical significance in that it identifies modifiable factors that can be used to devise intervention strategies. Developing and applying such intervention strategies for alleviating the factors associated with high caregiver burden could be important for improving the quality of life of both patients and their families.

A DELPHI STUDY OF RISK FACTORS FOR ACHILLES TENDINOPATHY- OPINIONS OF WORLD TENDON EXPERTS

PubMed Central

Watson, Paul J.; Barry, Simon

2016-01-01

Background and Purpose Achilles tendinopathy can be a debilitating chronic condition for both active and inactive individuals. The identification of risk facors is important both in preventing but also treating tendinopathy, many factors have been proposed but there is a lack of primary epidemiological data. The purpose of this study was to develop a statement of expert consensus on risk factors for Achilles tendinopathy in active and sedentary patient populations to inform a primary epidemiological study. Study design Delphi study Methods and Measures An online Delphi study was completed inviting participation from world tendon experts. The consensus was developed using three rounds of the Delphi technique. The first round developed a complete list of potential risk factors, the second round refined this list but also separated the factors into two population groups – active/athletic and inactive/sedentary. The third round ranked this list in order of perceived importance. Results Forty-four experts were invited to participate, 16 participated in the first round (response rate 40%) and two dropped out in the second round (resulting in a response rate of 35%). A total of 27 intrinsic and eight extrinsic risk factors were identified during round one. During round two only 12 intrinsic and five extrinsic risk factors were identified as important in active/athletic tendinopathy while 14 intrinsic and three extrinsic factors were identified as important for inactive/sedentary tendinopathy. Conclusions Risk factors for Achilles tendinopathy were identified based on expert consensus, and these factors provide a basis for primary epidemiological studies. Plantarflexor strength was identified as the primary modifiable factor in the active/athletic group while systemic factors were identified as important in the inactive/sedentary group, many of the potential factors suggested for either group were non-modifiable. Non-modifiable factors include: previous tendinopathy, previous injury, advancing age, sex, steroid exposure, and antibiotic treatment. Level of evidence Level V PMID:27757281

Cognitive enhancers (Nootropics). Part 3: drugs interacting with targets other than receptors or enzymes. Disease-modifying drugs. Update 2014.

PubMed

Froestl, Wolfgang; Pfeifer, Andrea; Muhs, Andreas

2014-01-01

Scientists working in the field of Alzheimer's disease and, in particular, cognitive enhancers, are very productive. The review "Drugs interacting with Targets other than Receptors or Enzymes. Disease-modifying Drugs" was accepted in October 2012. In the last 20 months, new targets for the potential treatment of Alzheimer's disease were identified. Enormous progress was realized in the pharmacological characterization of natural products with cognitive enhancing properties. This review covers the evolution of research in this field through May 2014.

Factors influencing variation in physician adenoma detection rates: a theory-based approach for performance improvement.

PubMed

Atkins, Louise; Hunkeler, Enid M; Jensen, Christopher D; Michie, Susan; Lee, Jeffrey K; Doubeni, Chyke A; Zauber, Ann G; Levin, Theodore R; Quinn, Virginia P; Corley, Douglas A

2016-03-01

Interventions to improve physician adenoma detection rates for colonoscopy have generally not been successful, and there are little data on the factors contributing to variation that may be appropriate targets for intervention. We sought to identify factors that may influence variation in detection rates by using theory-based tools for understanding behavior. We separately studied gastroenterologists and endoscopy nurses at 3 Kaiser Permanente Northern California medical centers to identify potentially modifiable factors relevant to physician adenoma detection rate variability by using structured group interviews (focus groups) and theory-based tools for understanding behavior and eliciting behavior change: the Capability, Opportunity, and Motivation behavior model; the Theoretical Domains Framework; and the Behavior Change Wheel. Nine factors potentially associated with adenoma detection rate variability were identified, including 6 related to capability (uncertainty about which types of polyps to remove, style of endoscopy team leadership, compromised ability to focus during an examination due to distractions, examination technique during withdrawal, difficulty detecting certain types of adenomas, and examiner fatigue and pain), 2 related to opportunity (perceived pressure due to the number of examinations expected per shift and social pressure to finish examinations before scheduled breaks or the end of a shift), and 1 related to motivation (valuing a meticulous examination as the top priority). Examples of potential intervention strategies are provided. By using theory-based tools, this study identified several novel and potentially modifiable factors relating to capability, opportunity, and motivation that may contribute to adenoma detection rate variability and be appropriate targets for future intervention trials. Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Frequency and distribution of incidental findings deemed appropriate for S modifier designation on low-dose CT in a lung cancer screening program.

PubMed

Reiter, Michael J; Nemesure, Allison; Madu, Ezemonye; Reagan, Lisa; Plank, April

2018-06-01

To describe the frequency, distribution and reporting patterns of incidental findings receiving the Lung-RADS S modifier on low-dose chest computed tomography (CT) among lung cancer screening participants. This retrospective investigation included 581 individuals who received baseline low-dose chest CT for lung cancer screening between October 2013 and June 2017 at a single center. Incidental findings resulting in assignment of Lung-RADS S modifier were recorded as were incidental abnormalities detailed within the body of the radiology report only. A subset of 60 randomly selected CTs was reviewed by a second (blinded) radiologist to evaluate inter-rater variability of Lung-RADS reporting. A total of 261 (45%) participants received the Lung-RADS S modifier on baseline CT with 369 incidental findings indicated as potentially clinically significant. Coronary artery calcification was most commonly reported, accounting for 182 of the 369 (49%) findings. An additional 141 incidentalomas of the same types as these 369 findings were described in reports but were not labelled with the S modifier. Therefore, as high as 69% (402 of 581) of participants could have received the S modifier if reporting was uniform. Inter-radiologist concordance of S modifier reporting in a subset of 60 participants was poor (42% agreement, kappa = 0.2). Incidental findings are commonly identified on chest CT for lung cancer screening, yet reporting of the S modifier within Lung-RADS is inconsistent. Specific guidelines are necessary to better define potentially clinically significant abnormalities and to improve reporting uniformity. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification of local myocardial repolarization time by bipolar electrode potential.

PubMed

Namba, Tsunetoyo; Todo, Takahiro; Yao, Takenori; Ashihara, Takashi; Haraguchi, Ryo; Nakazawa, Kazuo; Ikeda, Takanori; Ohe, Tohru

2007-01-01

The aim of this study was to investigate whether bipolar electrode potentials (BEPs) reflect local myocardial repolarization dynamics, using computer simulation. Simulated action potential and BEP mapping of myocardial tissue during fibrillation was performed. The BEP was modified to make all the fluctuations have the same polarity. Then, the modified BEP (mBEP) was transformed to "dynamic relative amplitude" (DRA) designed to make all the fluctuations have the similar amplitude. The repolarization end point corresponded to the end of the repolarization-related small fluctuation that clearly appeared in the DRA of mBEP. Using the DRA of mBEP, we could reproduce the repolarization dynamics in the myocardial tissue during fibrillation. The BEP may facilitate identifying the repolarization time. Furthermore, BEP mapping has the possibility that it would be available for evaluating repolarization behavior in myocardial tissue even during fibrillation. The accuracy of activation-recovery interval was also reconfirmed.

Evaluating Potential Response-Modifying Factors for Associations between Ozone and Health Outcomes: A Weight-of-Evidence Approach

EPA Science Inventory

Epidemiologic and experimental studies have demonstrated a variety of health effects in response to ozone (O3) exposure. Studies have demonstrated that some populations may be at increased risk of O3-related health effects. Objectives: To identify populations and lifestages pote...

Identification of transformer fault based on dissolved gas analysis using hybrid support vector machine-modified evolutionary particle swarm optimisation

PubMed Central

2018-01-01

Early detection of power transformer fault is important because it can reduce the maintenance cost of the transformer and it can ensure continuous electricity supply in power systems. Dissolved Gas Analysis (DGA) technique is commonly used to identify oil-filled power transformer fault type but utilisation of artificial intelligence method with optimisation methods has shown convincing results. In this work, a hybrid support vector machine (SVM) with modified evolutionary particle swarm optimisation (EPSO) algorithm was proposed to determine the transformer fault type. The superiority of the modified PSO technique with SVM was evaluated by comparing the results with the actual fault diagnosis, unoptimised SVM and previous reported works. Data reduction was also applied using stepwise regression prior to the training process of SVM to reduce the training time. It was found that the proposed hybrid SVM-Modified EPSO (MEPSO)-Time Varying Acceleration Coefficient (TVAC) technique results in the highest correct identification percentage of faults in a power transformer compared to other PSO algorithms. Thus, the proposed technique can be one of the potential solutions to identify the transformer fault type based on DGA data on site. PMID:29370230

Identification of transformer fault based on dissolved gas analysis using hybrid support vector machine-modified evolutionary particle swarm optimisation.

PubMed

Illias, Hazlee Azil; Zhao Liang, Wee

2018-01-01

Early detection of power transformer fault is important because it can reduce the maintenance cost of the transformer and it can ensure continuous electricity supply in power systems. Dissolved Gas Analysis (DGA) technique is commonly used to identify oil-filled power transformer fault type but utilisation of artificial intelligence method with optimisation methods has shown convincing results. In this work, a hybrid support vector machine (SVM) with modified evolutionary particle swarm optimisation (EPSO) algorithm was proposed to determine the transformer fault type. The superiority of the modified PSO technique with SVM was evaluated by comparing the results with the actual fault diagnosis, unoptimised SVM and previous reported works. Data reduction was also applied using stepwise regression prior to the training process of SVM to reduce the training time. It was found that the proposed hybrid SVM-Modified EPSO (MEPSO)-Time Varying Acceleration Coefficient (TVAC) technique results in the highest correct identification percentage of faults in a power transformer compared to other PSO algorithms. Thus, the proposed technique can be one of the potential solutions to identify the transformer fault type based on DGA data on site.

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease

PubMed Central

Karagiannis, Tom C.; Ververis, Katherine

2012-01-01

Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes. PMID:22953035

Potential of chromatin modifying compounds for the treatment of Alzheimer's disease.

PubMed

Karagiannis, Tom C; Ververis, Katherine

2012-01-01

Alzheimer's disease is a very common progressive neurodegenerative disorder affecting the learning and memory centers in the brain. The hallmarks of disease are the accumulation of β-amyloid neuritic plaques and neurofibrillary tangles formed by abnormally phosphorylated tau protein. Alzheimer's disease is currently incurable and there is an intense interest in the development of new potential therapies. Chromatin modifying compounds such as sirtuin modulators and histone deacetylase inhibitors have been evaluated in models of Alzheimer's disease with some promising results. For example, the natural antioxidant and sirtuin 1 activator resveratrol has been shown to have beneficial effects in animal models of disease. Similarly, numerous histone deacetylase inhibitors including Trichostatin A, suberoylanilide hydroxamic acid, valproic acid and phenylbutyrate reduction have shown promising results in models of Alzheimer's disease. These beneficial effects include a reduction of β-amyloid production and stabilization of tau protein. In this review we provide an overview of the histone deacetylase enzymes, with a focus on enzymes that have been identified to have an important role in the pathobiology of Alzheimer's disease. Further, we discuss the potential for pharmacological intervention with chromatin modifying compounds that modulate histone deacetylase enzymes.

Bone regeneration by implantation of adipose-derived stromal cells expressing BMP-2

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

Li Huiwu; Health and Science Center, SIBS CAS and SSMU, 225 South Chongqing Road, Shanghai 200025; Dai Kerong

2007-05-18

In this study, we reported that the adipose-derived stromal cells (ADSCs) genetically modified by bone morphogenetic protein 2 (BMP-2) healed critical-sized canine ulnar bone defects. First, the osteogenic and adipogenic differentiation potential of the ADSCs derived from canine adipose tissue were demonstrated. And then the cells were modified by the BMP-2 gene and the expression and bone-induction ability of BMP-2 were identified. Finally, the cells modified by BMP-2 gene were applied to a {beta}-tricalcium phosphate (TCP) carrier and implanted into ulnar bone defects in the canine model. After 16 weeks, radiographic, histological, and histomorphometry analysis showed that ADSCs modified bymore » BMP-2 gene produced a significant increase of newly formed bone area and healed or partly healed all of the bone defects. We conclude that ADSCs modified by the BMP-2 gene can enhance the repair of critical-sized bone defects in large animals.« less

A Snapshot of the Plant Glycated Proteome

PubMed Central

Bilova, Tatiana; Lukasheva, Elena; Brauch, Dominic; Greifenhagen, Uta; Paudel, Gagan; Tarakhovskaya, Elena; Frolova, Nadezhda; Mittasch, Juliane; Balcke, Gerd Ulrich; Tissier, Alain; Osmolovskaya, Natalia; Vogt, Thomas; Wessjohann, Ludger A.; Birkemeyer, Claudia; Milkowski, Carsten; Frolov, Andrej

2016-01-01

Glycation is the reaction of carbonyl compounds (reducing sugars and α-dicarbonyls) with amino acids, lipids, and proteins, yielding early and advanced glycation end products (AGEs). The AGEs can be formed via degradation of early glycation intermediates (glycoxidation) and by interaction with the products of monosaccharide autoxidation (autoxidative glycosylation). Although formation of these potentially deleterious compounds is well characterized in animal systems and thermally treated foods, only a little information about advanced glycation in plants is available. Thus, the knowledge of the plant AGE patterns and the underlying pathways of their formation are completely missing. To fill this gap, we describe the AGE-modified proteome of Brassica napus and characterize individual sites of advanced glycation by the methods of liquid chromatography-based bottom-up proteomics. The modification patterns were complex but reproducible: 789 AGE-modified peptides in 772 proteins were detected in two independent experiments. In contrast, only 168 polypeptides contained early glycated lysines, which did not resemble the sites of advanced glycation. Similar observations were made with Arabidopsis thaliana. The absence of the early glycated precursors of the AGE-modified protein residues indicated autoxidative glycosylation, but not glycoxidation, as the major pathway of AGE formation. To prove this assumption and to identify the potential modifying agents, we estimated the reactivity and glycative potential of plant-derived sugars using a model peptide approach and liquid chromatography-mass spectrometry-based techniques. Evaluation of these data sets together with the assessed tissue carbohydrate contents revealed dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, ribulose, erythrose, and sucrose as potential precursors of plant AGEs. PMID:26786108

Study plan to identify long term national telecommunications need and priorities applying Delphi techniques (handbook). [technological forecasting - United States of America

NASA Technical Reports Server (NTRS)

1974-01-01

A handbook that explains the basic Delphi methodology and discusses modified Delphi techniques is presented. The selection of communications experts to participate in a study, the construction of questionnaires on potential communications developments, and requisite technology is treated. No two modified Delphi studies were the same, which reflects the flexibility and adaptability of the technique. Each study must be specifically tailored to a particular case, and consists of seeking a consensus of opinion among experts about a particular subject and attendant conditions that may prevail in the future.

Carbonylated plasma proteins as potential biomarkers of obesity induced type 2 diabetes mellitus.

PubMed

Bollineni, Ravi Chand; Fedorova, Maria; Blüher, Matthias; Hoffmann, Ralf

2014-11-07

Protein carbonylation is a common nonenzymatic oxidative post-translational modification, which is often considered as biomarker of oxidative stress. Recent evidence links protein carbonylation also to obesity and type 2 diabetes mellitus (T2DM), though the protein targets of carbonylation in human plasma have not been identified. In this study, we profiled carbonylated proteins in plasma samples obtained from lean individuals and obese patients with or without T2DM. The plasma samples were digested with trypsin, carbonyl groups were derivatized with O-(biotinylcarbazoylmethyl)hydroxylamine, enriched by avidin affinity chromatography, and analyzed by RPC-MS/MS. Signals of potentially modified peptides were targeted in a second LC-MS/MS analysis to retrieve the peptide sequence and the modified residues. A total of 158 unique carbonylated proteins were identified, of which 52 were detected in plasma samples of all three groups. Interestingly, 36 carbonylated proteins were detected only in obese patients with T2DM, whereas 18 were detected in both nondiabetic groups. The carbonylated proteins originated mostly from liver, plasma, platelet, and endothelium. Functionally, they were mainly involved in cell adhesion, signaling, angiogenesis, and cytoskeletal remodeling. Among the identified carbonylated proteins were several candidates, such as VEGFR-2, MMP-1, argin, MKK4, and compliment C5, already connected before to diabetes, obesity and metabolic diseases.

Recognising and referring children exposed to domestic abuse: a multi-professional, proactive systems-based evaluation using a modified Failure Mode and Effects Analysis (FMEA).

PubMed

Ashley, Laura; Armitage, Gerry; Taylor, Julie

2017-03-01

Failure Modes and Effects Analysis (FMEA) is a prospective quality assurance methodology increasingly used in healthcare, which identifies potential vulnerabilities in complex, high-risk processes and generates remedial actions. We aimed, for the first time, to apply FMEA in a social care context to evaluate the process for recognising and referring children exposed to domestic abuse within one Midlands city safeguarding area in England. A multidisciplinary, multi-agency team of 10 front-line professionals undertook the FMEA, using a modified methodology, over seven group meetings. The FMEA included mapping out the process under evaluation to identify its component steps, identifying failure modes (potential errors) and possible causes for each step and generating corrective actions. In this article, we report the output from the FMEA, including illustrative examples of the failure modes and corrective actions generated. We also present an analysis of feedback from the FMEA team and provide future recommendations for the use of FMEA in appraising social care processes and practice. Although challenging, the FMEA was unequivocally valuable for team members and generated a significant number of corrective actions locally for the safeguarding board to consider in its response to children exposed to domestic abuse. © 2016 John Wiley & Sons Ltd.

Universal time-dependent dispersion properties for diffusion in a one-dimensional critically tilted potential

NASA Astrophysics Data System (ADS)

Guérin, T.; Dean, D. S.

2017-01-01

We consider the time-dependent dispersion properties of overdamped tracer particles diffusing in a one-dimensional periodic potential under the influence of an additional constant tilting force F . The system is studied in the region where the force is close to the critical value Fc at which the barriers separating neighboring potential wells disappear. We show that, when F crosses the critical value, the shape of the mean-square displacement (MSD) curves is strongly modified. We identify a diffusive regime at intermediate-time scales with an effective diffusion coefficient which is much larger than the late-time diffusion coefficient for F >Fc , whereas for F

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons

PubMed Central

2012-01-01

Background A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Results Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Conclusions Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. PMID:22413862

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

PubMed

Lejeune, François-Xavier; Mesrob, Lilia; Parmentier, Frédéric; Bicep, Cedric; Vazquez-Manrique, Rafael P; Parker, J Alex; Vert, Jean-Philippe; Tourette, Cendrine; Neri, Christian

2012-03-13

A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD. © 2012 Lejeune et al; licensee BioMed Central Ltd.

Interpreting the results of a modified gravity model: examining access to primary health care physicians in five Canadian provinces and territories.

PubMed

Crooks, Valorie A; Schuurman, Nadine

2012-08-01

Primary health care (PHC) encompasses an array of health and social services that focus on preventative, diagnostic, and basic care measures to maintain wellbeing and address illnesses. In Canada, PHC involves the provision of first-contact health care services by providers such as family physicians and general practitioners - collectively referred as PHC physicians here. Ensuring access is a key requirement of effective PHC delivery. This is because having access to PHC has been shown to positively impact a number of health outcomes. We build on recent innovations in measuring potential spatial access to PHC physicians using geographic information systems (GIS) by running and then interpreting the findings of a modified gravity model. Elsewhere we have introduced the protocol for this model. In this article we run it for five selected Canadian provinces and territories. Our objectives are to present the results of the modified gravity model in order to: (1) understand how potential spatial access to PHC physicians can be interpreted in these Canadian jurisdictions, and (2) provide guidance regarding how findings of the modified gravity model should be interpreted in other analyses. Regarding the first objective, two distinct spatial patterns emerge regarding potential spatial access to PHC physicians in the five selected Canadian provinces: (1) a clear north-south pattern, where southern areas have greater potential spatial access than northern areas; and (2) while gradients of potential spatial access exist in and around urban areas, access outside of densely-to-moderately populated areas is fairly binary. Regarding the second objective, we identify three principles that others can use to interpret the findings of the modified gravity model when used in other research contexts. Future applications of the modified gravity model are needed in order to refine the recommendations we provide on interpreting its results. It is important that studies are undertaken that can help administrators, policy-makers, researchers, and others with characterizing the state of access to PHC, including potential spatial access. We encourage further research to be done using GIS in order to offer new, spatial perspectives on issues of access to health services given the increased recognition that the place-based nature of health services can benefit from the use of the capabilities of GIS to enhance the role that visualization plays in decision-making.

Interpreting the results of a modified gravity model: examining access to primary health care physicians in five Canadian provinces and territories

PubMed Central

2012-01-01

Background Primary health care (PHC) encompasses an array of health and social services that focus on preventative, diagnostic, and basic care measures to maintain wellbeing and address illnesses. In Canada, PHC involves the provision of first-contact health care services by providers such as family physicians and general practitioners – collectively referred as PHC physicians here. Ensuring access is a key requirement of effective PHC delivery. This is because having access to PHC has been shown to positively impact a number of health outcomes. Methods We build on recent innovations in measuring potential spatial access to PHC physicians using geographic information systems (GIS) by running and then interpreting the findings of a modified gravity model. Elsewhere we have introduced the protocol for this model. In this article we run it for five selected Canadian provinces and territories. Our objectives are to present the results of the modified gravity model in order to: (1) understand how potential spatial access to PHC physicians can be interpreted in these Canadian jurisdictions, and (2) provide guidance regarding how findings of the modified gravity model should be interpreted in other analyses. Results Regarding the first objective, two distinct spatial patterns emerge regarding potential spatial access to PHC physicians in the five selected Canadian provinces: (1) a clear north–south pattern, where southern areas have greater potential spatial access than northern areas; and (2) while gradients of potential spatial access exist in and around urban areas, access outside of densely-to-moderately populated areas is fairly binary. Regarding the second objective, we identify three principles that others can use to interpret the findings of the modified gravity model when used in other research contexts. Conclusions Future applications of the modified gravity model are needed in order to refine the recommendations we provide on interpreting its results. It is important that studies are undertaken that can help administrators, policy-makers, researchers, and others with characterizing the state of access to PHC, including potential spatial access. We encourage further research to be done using GIS in order to offer new, spatial perspectives on issues of access to health services given the increased recognition that the place-based nature of health services can benefit from the use of the capabilities of GIS to enhance the role that visualization plays in decision-making. PMID:22852816

Modified TAROT for cross-selling personal financial products

NASA Astrophysics Data System (ADS)

Tee, Ya-Mei; LEE, Lai-Soon; LEE, Chew-Ging; SEOW, Hsin-Vonn

2014-09-01

The Top Application characteristics Remainder Offer characteristics Tree (TAROT) was first introduced in 2007. This is a modified Classification and Regression Trees (CART) used to help decide which question(s) to ask potential applicants to customise an offer of a personal financial product so that it would have a high probability of take up. In this piece of work the authors are presenting, they have further modified the TAROT to cross TAROT, using its properties and modeling steps to deal with the issue of cross-selling. Since the bank already has ready customers, it would be ideal to cross-sell the financial products seeing that one can ask one (or more) further question(s) based on the initial offer to identify and customise another financial product to offer.

Metaphylogenomic and potential functionality of the limpet Patella pellucida's gastrointestinal tract microbiome.

PubMed

Dudek, Magda; Adams, Jessica; Swain, Martin; Hegarty, Matthew; Huws, Sharon; Gallagher, Joe

2014-10-20

This study investigated the microbial diversity associated with the digestive tract of the seaweed grazing marine limpet Patella pellucida. Using a modified indirect DNA extraction protocol and performing metagenomic profiling based on specific prokaryotic marker genes, the abundance of bacterial groups was identified from the analyzed metagenome. The members of three significantly abundant phyla of Proteobacteria, Firmicutes and Bacteroidetes were characterized through the literature and their predicted functions towards the host, as well as potential applications in the industrial environment assessed.

Exploration of Novel Materials for Development of Next Generation OPV Devices: Cooperative Research and Development Final Report, CRADA Number CRD-10-398

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

Olson, D.

2012-09-01

Organic-based solar cells offer the potential for low cost, scalable conversion of solar energy. This project will try to utilize the extensive organic synthetic capabilities of ConocoPhillips to produce novel acceptor and donor materials as well potentially as interface modifiers to produce improved OPV devices with greater efficiency and stability. The synthetic effort will be based on the knowledge base and modeling being done at NREL to identify new candidate materials.

The Modified Hartmann Potential Effects on γ-rigid Bohr Hamiltonian

NASA Astrophysics Data System (ADS)

Suparmi, A.; Cari, C.; Nur Pratiwi, Beta

2018-04-01

In this paper, we present the solution of Bohr Hamiltonian in the case of γ-rigid for the modified Hartmann potential. The modified Hartmann potential was formed from the original Hartmann potential, consists of β function and θ function. By using the separation method, the three-dimensional Bohr Hamiltonian equation was reduced into three one-dimensional Schrodinger-like equation which was solved analytically. The results for the wavefunction were shown in mathematically, while for the binding energy was solved numerically. The numerical binding energy for the presence of the modified Hartmann potential is lower than the binding energy value in the absence of modified Hartmann potential effect.

Characterization of NDM-1- and OXA-23-producing Acinetobacter baumannii isolates from inanimate surfaces in a hospital environment in Algeria.

PubMed

Zenati, K; Touati, A; Bakour, S; Sahli, F; Rolain, J M

2016-01-01

Investigation of several outbreaks of multidrug-resistant Acinetobacter baumannii infection has demonstrated that contamination of the inanimate hospital environment could be implicated in the spread of these multidrug-resistant strains. To investigate the occurrence of carbapenem-resistant A. baumannii on inanimate surfaces and possible dissemination in the hospital environment in Algeria as a potential source of infection in humans. A. baumannii strains were isolated from the hospital environment and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Antimicrobial susceptibility was determined using disc diffusion and E-test methods. Carbapenemase activity was detected using microbiological tests, including modified Hodge test, modified Carba NP test, and EDTA test. Carbapenem resistance determinants were studied by polymerase chain reaction (PCR) and sequencing. Clonal relatedness was determined using multi-locus sequence typing (MLST). A total of 67 A. baumannii isolates were obtained from 868 environmental samples and identified by MALDI-TOF MS. Among them, 61 isolates were resistant to imipenem with minimum inhibitory concentration >32 μg/mL and positive by the modified Hodge test and modified Carba NP test. In addition, the activity of carbapenemase was inhibited by EDTA in 32 strains. PCR and sequencing showed the presence of blaOXA-23 gene in 29 strains, and the blaNDM-1 gene in 32 isolates. MLST demonstrated the presence of five types of ST (ST19, ST2, ST85, ST98, and ST115). Our study demonstrated the dissemination of carbapenemase-producing A. baumannii strains recovered from inanimate surfaces in a hospital environment, surrounding patients, healthcare workers and visitors, in Algeria as a potential source for nosocomial infection. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

The Content, Predictive Power, and Potential Bias in Five Widely Used Teacher Observation Instruments. REL 2017-191

ERIC Educational Resources Information Center

Gill, Brian; Shoji, Megan; Coen, Thomas; Place, Kate

2016-01-01

School districts and states across the Regional Educational Laboratory Mid-Atlantic Region and the country as a whole have been modifying their teacher evaluation systems to identify more effective and less effective teachers and provide better feedback to improve instructional practice. The new systems typically include components related to…

Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis

PubMed Central

Lehert, Philippe; Villaseca, Paulina; Hogervorst, Eef; Maki, Pauline M.; Henderson, Victor W.

2016-01-01

A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually-modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For 10 of these, we used PubMed databases for a systematic review of long-duration (at least six months), randomized controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11 to 0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging. PMID:26361790

Individually modifiable risk factors to ameliorate cognitive aging: a systematic review and meta-analysis.

PubMed

Lehert, P; Villaseca, P; Hogervorst, E; Maki, P M; Henderson, V W

2015-10-01

A number of health and lifestyle factors are thought to contribute to cognitive decline associated with age but cannot be easily modified by the individual patient. We identified 12 individually modifiable interventions that can be implemented during midlife or later with the potential to ameliorate cognitive aging. For ten of these, we used PubMed databases for a systematic review of long-duration (at least 6 months), randomized, controlled trials in midlife and older adults without dementia or mild cognitive impairment with objective measures of neuropsychological performance. Using network meta-analysis, we performed a quantitative synthesis for global cognition (primary outcome) and episodic memory (secondary outcome). Of 1038 publications identified by our search strategy, 24 eligible trials were included in the network meta-analysis. Results suggested that the Mediterranean diet supplemented by olive oil and tai chi exercise may improve global cognition, and the Mediterranean diet plus olive oil and soy isoflavone supplements may improve memory. Effect sizes were no more than small (standardized mean differences 0.11-0.22). Cognitive training may have cognitive benefit as well. Most individually modifiable risk factors have not yet been adequately studied. We conclude that some interventions that can be self-initiated by healthy midlife and older adults may ameliorate cognitive aging.

Modifiable and non-modifiable factors associated with employment outcomes following spinal cord injury: A systematic review

PubMed Central

Trenaman, Logan; Miller, William C; Querée, Matthew; Escorpizo, Reuben

2015-01-01

Context Employment rates in individuals with spinal cord injury (SCI) are approximately 35%, which is considerably lower than that of the general population. In order to improve employment outcomes a clear understanding of what factors influence employment outcomes is needed. Objective To systematically review factors that are consistently and independently associated with employment outcomes in individuals with SCI, and to understand the magnitude of their influence. Methods Through an electronic search of MEDLINE/PubMed, EMBASE, CINAHL, PsycINFO, Social Science Abstracts and Social Work databases, we identified studies published between 1952–2014 that investigated factors associated with employment outcomes following SCI. Exclusion criteria included: (1) reviews (2) studies not published in English (3) studies not controlling for potential confounders through a regression analysis, or (4) studies not providing an effect measure in the form of OR, RR, or HR. Data were categorized based on the International Classification of Functioning, Disability and Health framework, with each domain sub-categorized by modifiability. First author, year of publication, sample size, explanatory and outcome variables, and effect measures were extracted. Results Thirty-nine studies met the inclusion criteria. Twenty modifiable and twelve non-modifiable factors have been investigated in the context of employment following SCI. Education, vocational rehabilitation, functional independence, social support, and financial disincentives were modifiable factors that have been consistently and independently associated with employment outcomes. Conclusion A number of key modifiable factors have been identified and can inform interventions aimed at improving employment outcomes for individuals with SCI. Future research should focus on determining which factors have the greatest effect on employment outcomes, in addition to developing and evaluating interventions targeted at these factors. PMID:25989899

Development of key indicators of hospital resilience: a modified Delphi study.

PubMed

Zhong, Shuang; Clark, Michele; Hou, Xiang-Yu; Zang, Yuli; FitzGerald, Gerard

2015-04-01

Hospital resilience is an emerging concept, which can be defined as 'a hospital's ability to resist, absorb, and respond to the shock of disasters while maintaining its critical health care functions, and then recover to its original state or adapt to a new one'. Our aim was to develop a comprehensive framework of key indicators of hospital resilience. A panel of 33 Chinese experts was invited to participate in a three-round, modified Delphi study to develop a set of potential measures previously derived from a literature review. In the first round, these potential measures were modified to cover the comprehensive domains of hospital resilience. The importance of proposed measures was scored by experts on a five-point Likert scale. Subsequently, the experts reconsidered their voting in light of the previous aggregated results. Agreement on measures was defined as at least 70% of the responders agreeing or strongly agreeing to the inclusion of a measure. A large proportion of preliminary measures (89.5%) were identified as having good potential for assessing hospital resilience. These measures were categorized into eight domains, 17 subdomains, and 43 indicators. The highest rated indicators (mean score) were: equipment for on-site rescue (4.7), plan initiation (4.6), equipment for referral of patients with complex care needs (4.5), the plan execution (4.4), medication management strategies (4.4), emergency medical treatment conditions (4.4), disaster committee (4.4), stock types and quantities for essential medications (4.4), surge capacity of emergency beds (4.4), and mass-casualty triage protocols (4.4). This framework identifies a comprehensive set of indicators of hospital resilience. It can be used for hospital assessment, as well as informing priority practices to address future disasters better. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Modified screening and ranking algorithm for copy number variation detection.

PubMed

Xiao, Feifei; Min, Xiaoyi; Zhang, Heping

2015-05-01

Copy number variation (CNV) is a type of structural variation, usually defined as genomic segments that are 1 kb or larger, which present variable copy numbers when compared with a reference genome. The screening and ranking algorithm (SaRa) was recently proposed as an efficient approach for multiple change-points detection, which can be applied to CNV detection. However, some practical issues arise from application of SaRa to single nucleotide polymorphism data. In this study, we propose a modified SaRa on CNV detection to address these issues. First, we use the quantile normalization on the original intensities to guarantee that the normal mean model-based SaRa is a robust method. Second, a novel normal mixture model coupled with a modified Bayesian information criterion is proposed for candidate change-point selection and further clustering the potential CNV segments to copy number states. Simulations revealed that the modified SaRa became a robust method for identifying change-points and achieved better performance than the circular binary segmentation (CBS) method. By applying the modified SaRa to real data from the HapMap project, we illustrated its performance on detecting CNV segments. In conclusion, our modified SaRa method improves SaRa theoretically and numerically, for identifying CNVs with high-throughput genotyping data. The modSaRa package is implemented in R program and freely available at http://c2s2.yale.edu/software/modSaRa. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Free vibration analysis of embedded magneto-electro-thermo-elastic cylindrical nanoshell based on the modified couple stress theory

NASA Astrophysics Data System (ADS)

Ghadiri, Majid; Safarpour, Hamed

2016-09-01

In this paper, size-dependent effect of an embedded magneto-electro-elastic (MEE) nanoshell subjected to thermo-electro-magnetic loadings on free vibration behavior is investigated. Also, the surrounding elastic medium has been considered as the model of Winkler characterized by the spring. The size-dependent MEE nanoshell is investigated on the basis of the modified couple stress theory. Taking attention to the first-order shear deformation theory (FSDT), the modeled nanoshell and its equations of motion are derived using principle of minimum potential energy. The accuracy of the presented model is validated with some cases in the literature. Finally, using the Navier-type method, an analytical solution of governing equations for vibration behavior of simply supported MEE cylindrical nanoshell under combined loadings is presented and the effects of material length scale parameter, temperature changes, external electric potential, external magnetic potential, circumferential wave numbers, constant of spring, shear correction factor and length-to-radius ratio of the nanoshell on natural frequency are identified. Since there has been no research about size-dependent analysis MEE cylindrical nanoshell under combined loadings based on FSDT, numerical results are presented to be served as benchmarks for future analysis of MEE nanoshells using the modified couple stress theory.

A Modified In vitro Invasion Assay to Determine the Potential Role of Hormones, Cytokines and/or Growth Factors in Mediating Cancer Cell Invasion.

PubMed

Bagati, Archis; Koch, Zethan; Bofinger, Diane; Goli, Haneesha; Weiss, Laura S; Dau, Rosie; Thomas, Megha; Zucker, Shoshanna N

2015-04-24

Blood serum serves as a chemoattractant towards which cancer cells migrate and invade, facilitating their intravasation into microvessels. However, the actual molecules towards which the cells migrate remain elusive. This modified invasion assay has been developed to identify targets which drive cell migration and invasion. This technique compares the invasion index under three conditions to determine whether a specific hormone, growth factor, or cytokine plays a role in mediating the invasive potential of a cancer cell. These conditions include i) normal fetal bovine serum (FBS), ii) charcoal-stripped FBS (CS-FBS), which removes hormones, growth factors, and cytokines and iii) CS-FBS + molecule (denoted "X"). A significant change in cell invasion with CS-FBS as compared to FBS, indicates the involvement of hormones, cytokines or growth factors in mediating the change. Individual molecules can then be added back to CS-FBS to assay their ability to reverse or rescue the invasion phenotype. Furthermore, two or more factors can be combined to evaluate the additive or synergistic effects of multiple molecules in driving or inhibiting invasion. Overall, this method enables the investigator to determine whether hormones, cytokines, and/or growth factors play a role in cell invasion by serving as chemoattractants or inhibitors of invasion for a particular type of cancer cell or a specific mutant. By identifying specific chemoattractants and inhibitors, this modified invasion assay may help to elucidate signaling pathways that direct cancer cell invasion.

Universal time-dependent dispersion properties for diffusion in a one-dimensional critically tilted potential.

PubMed

Guérin, T; Dean, D S

2017-01-01

We consider the time-dependent dispersion properties of overdamped tracer particles diffusing in a one-dimensional periodic potential under the influence of an additional constant tilting force F. The system is studied in the region where the force is close to the critical value F_{c} at which the barriers separating neighboring potential wells disappear. We show that, when F crosses the critical value, the shape of the mean-square displacement (MSD) curves is strongly modified. We identify a diffusive regime at intermediate-time scales with an effective diffusion coefficient which is much larger than the late-time diffusion coefficient for F>F_{c}, whereas for F

New PARP targets for cancer therapy

PubMed Central

Vyas, Sejal; Chang, Paul

2015-01-01

Poly(ADP-ribose) polymerases (PARPs) modify target proteins post-translationally with poly(ADP-ribose) (PAR) or mono(ADP-ribose) (MAR) using NAD+ as substrate. The best-studied PARPs generate PAR modifications and include PARP1 and the tankyrase PARP5a, both of which are targets for cancer therapy with inhibitors in either clinical trials or preclinical development. There are 15 additional PARPs, the majority of which modify proteins with MAR, and their biology is less well understood. Recent data identify potentially cancer relevant functions for these PARPs, indicating that we need to understand more about these PARPs in order to target them effectively. PMID:24898058

RNA-modifying proteins as anticancer drug targets.

PubMed

Boriack-Sjodin, P Ann; Ribich, Scott; Copeland, Robert A

2018-06-01

All major biological macromolecules (DNA, RNA, proteins and lipids) undergo enzyme-catalysed covalent modifications that impact their structure, function and stability. A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA stability and translation to proteins; these mechanisms of translational control have been termed epitranscriptomics. Emerging data suggest that some epitranscriptomic mechanisms are altered in human cancers as well as other human diseases. In this Review, we examine the current understanding of RNA modifications with a focus on mRNA methylation, highlight their possible roles in specific cancer indications and discuss the emerging potential of RNA-modifying proteins as therapeutic targets.

Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans.

PubMed

Winter, Jean M; Curry, Natasha L; Gildea, Derek M; Williams, Kendra A; Lee, Minnkyong; Hu, Ying; Crawford, Nigel P S

2018-06-11

It is well known that development of prostate cancer (PC) can be attributed to somatic mutations of the genome, acquired within proto-oncogenes or tumor-suppressor genes. What is less well understood is how germline variation contributes to disease aggressiveness in PC patients. To map germline modifiers of aggressive neuroendocrine PC, we generated a genetically diverse F2 intercross population using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of germline modifiers of aggressive PC identified in these mice was extensively correlated in human PC datasets and functionally validated in cell lines. Aggressive PC traits were quantified in a population of 30 week old (TRAMP x WSB) F2 mice (n = 307). Correlation of germline genotype with aggressive disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq were analyzed using cis-eQTL and trait correlation analyses to identify candidate genes within each of these loci. Analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harbored both a significant cis-eQTL and mRNA expression correlations with an aggressive PC trait. We further delineated these candidate genes based on their clinical relevance, by interrogating human PC GWAS and PC tumor gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumor tissue. Functional validation studies of these four genes using the human LNCaP prostate adenocarcinoma cell line revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumor growth in vivo. Furthermore, CCDC115 human prostate tumor expression was associated with better survival outcomes. We have demonstrated how modifier locus mapping in mouse models of PC, coupled with in silico analyses of human PC datasets, can reveal novel germline modifier genes of aggressive PC. We have also characterized CCDC115 as being associated with less aggressive PC in humans, placing it as a potential prognostic marker of aggressive PC.

Social Ties May Play a Critical Role in Mitigating Sleep Difficulties in Disaster-Affected Communities: A Cross-Sectional Study in the Ishinomaki Area, Japan

PubMed Central

Matsumoto, Shoko; Yamaoka, Kazue; Inoue, Machiko; Muto, Shinsuke

2014-01-01

Study Objectives: We examined the association between social factors and sleep difficulties among the victims remaining at home in the Ishinomaki area after the Great East Japan Earthquake and Tsunami and identified potentially modifiable factors that may mitigate vulnerability to sleep difficulties during future traumatic events or disasters. Design: A cross-sectional household survey was conducted from October 2011 to March 2012 (6-12 mo after the disaster) in the Ishinomaki area, Japan. Univariate and multivariate logistic regression models were used to examine associations between social factors and sleep difficulties. Participants: We obtained data on 4,176 household members who remained in their homes after the earthquake and tsunami. Interventions: N/A. Results: Sleep difficulties were prevalent in 15.0% of the respondents (9.2% male, 20.2% female). Two potentially modifiable factors (lack of pleasure in life and lack of interaction with/visiting neighbors) and three nonmodifiable or hardly modifiable factors (sex, source of income, and number of household members) were associated with sleep difficulties. Nonmodifiable or hardly modifiable consequences caused directly by the disaster (severity of house damage, change in family structure, and change in working status) were not significantly associated with sleep difficulties. Conclusions: Our data suggest that the lack of pleasure in life and relatively strong networks in the neighborhood, which are potentially modifiable, might have stronger associations with sleep difficulties than do nonmodifiable or hardly modifiable consequences of the disaster (e.g., house damage, change in family structure, and change in work status). Citation: Matsumoto S; Yamaoka K; Inoue M; Muto S. Social ties may play a critical role in mitigating sleep difficulties in disaster-affected communities: a cross-sectional study in the Ishinomaki area, Japan. SLEEP 2014;37(1):137-145. PMID:24470703

Natural and surfactant modified zeolites: A review of their applications for water remediation with a focus on surfactant desorption and toxicity towards microorganisms.

PubMed

Reeve, Peter J; Fallowfield, Howard J

2018-01-01

The objective of this review is to highlight the need for further investigation of microbial toxicity caused by desorption of surfactant from Surfactant Modified Zeolite (SMZ). SMZ is a low cost, versatile permeable reactive media which has the potential to treat multiple classes of contaminants. With this combination of characteristics, SMZ has significant potential to enhance water and wastewater treatment processes. Surfactant desorption has been identified as a potential issue for the ongoing usability of SMZ. Few studies have investigated the toxicity of surfactants used in zeolite modification towards microorganisms and fewer have drawn linkages between surfactant desorption and surfactant toxicity. This review provides an overview of natural zeolite chemistry, characteristics and practical applications. The chemistry of commonly used surfactants is outlined, along with the kinetics that drive their adsorption to the zeolite surface. Methodologies to characterise this surfactant loading are also described. Applications of SMZ in water remediation are highlighted, giving focus to applications which deal with biological pollutants and where microorganisms play a role in the remediation process. Studies that have identified surfactant desorption from SMZ are outlined. Finally, the toxicity of a commonly used cationic surfactant towards microorganisms is discussed. This review highlights the potential for surfactant to desorb from the zeolite surface and the need for further research into the toxicity of this desorbed surfactant towards microorganisms, including pathogens and environmental microbes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Ebola Virus Disease in Children, Sierra Leone, 2014–2015

PubMed Central

Naveed, Asad; Wing, Kevin; Gbessay, Musa; Ross, J.C.G.; Checchi, Francesco; Youkee, Daniel; Jalloh, Mohammed Boie; Baion, David; Mustapha, Ayeshatu; Jah, Hawanatu; Lako, Sandra; Oza, Shefali; Boufkhed, Sabah; Feury, Reynold; Bielicki, Julia A.; Gibb, Diana M.; Klein, Nigel; Sahr, Foday; Yeung, Shunmay

2016-01-01

Little is known about potentially modifiable factors in Ebola virus disease in children. We undertook a retrospective cohort study of children <13 years old admitted to 11 Ebola holding units in the Western Area, Sierra Leone, during 2014–2015 to identify factors affecting outcome. Primary outcome was death or discharge after transfer to Ebola treatment centers. All 309 Ebola virus–positive children 2 days–12 years old were included; outcomes were available for 282 (91%). Case-fatality was 57%, and 55% of deaths occurred in Ebola holding units. Blood test results showed hypoglycemia and hepatic/renal dysfunction. Death occurred swiftly (median 3 days after admission) and was associated with younger age and diarrhea. Despite triangulation of information from multiple sources, data availability was limited, and we identified no modifiable factors substantially affecting death. In future Ebola virus disease epidemics, robust, rapid data collection is vital to determine effectiveness of interventions for children. PMID:27649367

Modifiable risk factors for impaired fertility in women: what nurse practitioners need to know.

PubMed

Kelly-Weeder, Susan; O'Connor, Alane

2006-06-01

To provide an overview of impaired fertility in childbearing-aged women, to review the current research on modifiable lifestyle risk factors implicated in its development, and to suggest strategies for nurse practitioners (NPs) to assist women in behavioral changes that will allow them to protect their fertility. Original research articles and comprehensive review articles identified through Medline, CINAHL, and OVID databases. Research has shown that advancing age, a history of a sexually transmitted infection and/or pelvic inflammatory disease, extremes of body weight, and tobacco and caffeine use are potentially modifiable risk factors in the development of impaired fertility. NPs must be aware of the link between these behaviors and the development of impaired fertility in order to assist women in preserving their fertility. Individual counseling, education, and community-wide education strategies are discussed.

Do Elderly Patients Experience Increased Perioperative or Postoperative Morbidity or Mortality When Given Neoadjuvant Chemoradiation Before Esophagectomy?

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

Fogh, Shannon E., E-mail: foghse@radonc.ucsf.edu; Yu, Anthony; Kubicek, Gregory J.

2011-08-01

Background: The use of induction chemoradiotherapy followed by surgery has been widely used for the treatment of esophageal cancer. The presumed risk of increased postoperative morbidity and mortality with this regimen has led to reluctance to offer this therapy to elderly patients. We compared the perioperative morbidity and mortality of patients 70 years old and older with those of patients younger than 70 who received CRT followed by esophagectomy and sought to identify preoperative risk factors that may predict higher risk of postoperative death or complications. Methods and Materials: We identified 260 patients who underwent preoperative chemoradiotherapy followed by esophagectomy.more » The association of age with postoperative death and complications was evaluated. The Charlson index, prior cardiac history, and diabetes were identified as preoperative risk factors and were evaluated as potential confounders or effect modifiers. Results: Cardiac disease and the Charlson index were potential modifiers of the effect of age on length of hospital stay (p = 0.08 and p = 0.07, respectively) and postoperative complications (p = 0.1 and p = 0.2) but were not statistically significant. There was a slight nonsignificant decrease in the risk of death in elderly patients after adjustment for the Charlson index (p = 0.2). Conclusion: No significant differences were detected with respect to morbidity and mortality in elderly patients. The presence of cardiac disease, higher scores on the Charlson index, or diabetes did not significantly influence length of stay, postoperative complications, or postoperative death. Given the potential to improve outcomes, this regimen should not be discounted in elderly patients.« less

The application of genome-wide 5-hydroxymethylcytosine studies in cancer research.

PubMed

Thomson, John P; Meehan, Richard R

2017-01-01

Early detection and characterization of molecular events associated with tumorgenesis remain high priorities. Genome-wide epigenetic assays are promising diagnostic tools, as aberrant epigenetic events are frequent and often cancer specific. The deposition and analysis of multiple patient-derived cancer epigenomic profiles contributes to our appreciation of the underlying biology; aiding the detection of novel identifiers for cancer subtypes. Modifying enzymes and co-factors regulating these epigenetic marks are frequently mutated in cancers, and as epigenetic modifications themselves are reversible, this makes their study very attractive with respect to pharmaceutical intervention. Here we focus on the novel modified base, 5-hydoxymethylcytosine, and discuss how genome-wide 5-hydoxymethylcytosine profiling expedites our molecular understanding of cancer, serves as a lineage tracer, classifies the mode of action of potentially carcinogenic agents and clarifies the roles of potential novel cancer drug targets; thus assisting the development of new diagnostic/prognostic tools.

Tumor Lysing Genetically Engineered T Cells Loaded with Multi-Modal Imaging Agents

NASA Astrophysics Data System (ADS)

Bhatnagar, Parijat; Alauddin, Mian; Bankson, James A.; Kirui, Dickson; Seifi, Payam; Huls, Helen; Lee, Dean A.; Babakhani, Aydin; Ferrari, Mauro; Li, King C.; Cooper, Laurence J. N.

2014-03-01

Genetically-modified T cells expressing chimeric antigen receptors (CAR) exert anti-tumor effect by identifying tumor-associated antigen (TAA), independent of major histocompatibility complex. For maximal efficacy and safety of adoptively transferred cells, imaging their biodistribution is critical. This will determine if cells home to the tumor and assist in moderating cell dose. Here, T cells are modified to express CAR. An efficient, non-toxic process with potential for cGMP compliance is developed for loading high cell number with multi-modal (PET-MRI) contrast agents (Super Paramagnetic Iron Oxide Nanoparticles - Copper-64; SPION-64Cu). This can now be potentially used for 64Cu-based whole-body PET to detect T cell accumulation region with high-sensitivity, followed by SPION-based MRI of these regions for high-resolution anatomically correlated images of T cells. CD19-specific-CAR+SPIONpos T cells effectively target in vitro CD19+ lymphoma.

Correctional officers' perceptions of a solution-focused training program: potential implications for working with offenders.

PubMed

Pan, Peter Jen Der; Deng, Liang-Yu F; Chang, Shona Shih Hua; Jiang, Karen Jye-Ru

2011-09-01

The purpose of this exploratory study was to explore correctional officers' perceptions and experiences during a solution-focused training program and to initiate development of a modified pattern for correctional officers to use in jails. The study uses grounded theory procedures combined with a follow-up survey. The findings identified six emergent themes: obstacles to doing counseling work in prisons, offenders' amenability to change, correctional officers' self-image, advantages of a solution-focused approach (SFA), potential advantages of applying SFA to offenders, and the need for the consolidation of learning and transformation. Participants perceived the use of solution-focused techniques as appropriate, important, functional, and of only moderate difficulty in interacting with offenders. Finally, a modified pattern was developed for officers to use when working with offenders in jails. Suggestions and recommendations are made for correctional interventions and future studies.

PHOS-Select Iron Affinity beads enrich peptides for detection of organophosphorus adducts on albumin

PubMed Central

Jiang, Wei; Dubrovskii, Yaroslav A; Podolskaya, Ekaterina P; Murashko, Ekaterina A; Babakov, Vladimir; Nachon, Florian; Masson, Patrick; Schopfer, Lawrence M; Lockridge, Oksana

2013-01-01

Albumin is covalently modified by organophosphorus toxicants (OP) on tyrosine 411, but less than 1% of albumin is modified in humans by lethal OP doses that inhibit 95% of plasma butyrylcholinesterase. A method that enriches OP-modified albumin peptides could aid analysis of low dose exposures. Soman or chlorpyrifos oxon treated human plasma was digested with pepsin. Albumin peptides were enriched by binding to Fe3+ beads at pH 11 and eluted with pH 2.6 buffer. Similarly, mouse and guinea pig albumin modified by chlorpyrifos oxon were digested with pepsin and enriched by binding to Fe3+ beads. Peptides were identified by MALDI-TOF/TOF mass spectrometry. PHOS-select Iron Affinity beads specifically enriched albumin peptides VRY411TKKVPQVST and LVRY411TKKVPQVST in a pepsin digest of human plasma. The unmodified as well as OP-modified peptides bound to the beads. The binding capacity of 500 μl beads was the pepsin digest of 2.1 μL human plasma. The limit of detection was 0.2% of OP-modified albumin peptide in 0.43 μL plasma. Enrichment of OP-modified albumin peptides by binding to Fe3+ beads is a method with potential application to diagnosis of OP pesticide and nerve agent exposure in humans, mice, and guinea pigs. PMID:24187955

Kidney disease models: tools to identify mechanisms and potential therapeutic targets

PubMed Central

Bao, Yin-Wu; Yuan, Yuan; Chen, Jiang-Hua; Lin, Wei-Qiang

2018-01-01

Acute kidney injury (AKI) and chronic kidney disease (CKD) are worldwide public health problems affecting millions of people and have rapidly increased in prevalence in recent years. Due to the multiple causes of renal failure, many animal models have been developed to advance our understanding of human nephropathy. Among these experimental models, rodents have been extensively used to enable mechanistic understanding of kidney disease induction and progression, as well as to identify potential targets for therapy. In this review, we discuss AKI models induced by surgical operation and drugs or toxins, as well as a variety of CKD models (mainly genetically modified mouse models). Results from recent and ongoing clinical trials and conceptual advances derived from animal models are also explored. PMID:29515089

Metaphylogenomic and Potential Functionality of the Limpet Patella pellucida’s Gastrointestinal Tract Microbiome

PubMed Central

Dudek, Magda; Adams, Jessica; Swain, Martin; Hegarty, Matthew; Huws, Sharon; Gallagher, Joe

2014-01-01

This study investigated the microbial diversity associated with the digestive tract of the seaweed grazing marine limpet Patella pellucida. Using a modified indirect DNA extraction protocol and performing metagenomic profiling based on specific prokaryotic marker genes, the abundance of bacterial groups was identified from the analyzed metagenome. The members of three significantly abundant phyla of Proteobacteria, Firmicutes and Bacteroidetes were characterized through the literature and their predicted functions towards the host, as well as potential applications in the industrial environment assessed. PMID:25334059

Network analyses reveal novel aspects of ALS pathogenesis.

PubMed

Sanhueza, Mario; Chai, Andrea; Smith, Colin; McCray, Brett A; Simpson, T Ian; Taylor, J Paul; Pennetta, Giuseppa

2015-03-01

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB-induced neurotoxicity. Modifiers cluster in a diverse array of biological functions including processes and genes that have been previously linked to hVAPB function, such as proteolysis and vesicular trafficking. In addition to established mechanisms, the screen identified endocytic trafficking and genes controlling proliferation and apoptosis as potent modifiers of ALS8-mediated defects. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. Computational analysis reveals that most modifiers can be linked into a complex network of interacting genes, and that the human genes homologous to the Drosophila modifiers can be assembled into an interacting network largely overlapping with that in flies. Identity markers of the endocytic process were also found to abnormally accumulate in ALS patients, further supporting the relevance of the fly data for human biology. Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

PubMed Central

Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

2015-01-01

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy. PMID:26324103

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

PubMed

Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

2015-11-01

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Mutational screening in genes related with porto-pulmonary hypertension: An analysis of 6 cases.

PubMed

Pousada, Guillermo; Baloira, Adolfo; Valverde, Diana

2017-04-07

Portopulmonary hypertension (PPH) is a rare disease with a low incidence and without a clearly-identified genetic component. The aim of this work was to check genes and genetic modifiers related to pulmonary arterial hypertension in patients with PPH in order to clarify the molecular basis of the pathology. We selected a total of 6 patients with PPH and amplified the exonic regions and intronic flanking regions of the relevant genes and regions of interest of the genetic modifiers. Six patients diagnosed with PPH were analyzed and compared to 55 healthy individuals. Potentially-pathogenic mutations were identified in the analyzed genes of 5 patients. None of these mutations, which are highly conserved throughout evolution, were detected in the control patients nor different databases analyzed (1000 Genomes, ExAC and DECIPHER). After analyzing for genetic modifiers, we found different variations that could favor the onset of the disease. The genetic analysis carried out in this small cohort of patients with PPH revealed a large number of mutations, with the ENG gene showing the greatest mutational frequency. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

A scoping review of anorexia of aging correlates and their relevance to population health interventions.

PubMed

Roy, Mathieu; Gaudreau, Pierrette; Payette, Hélène

2016-10-01

Anorexia of aging (AA, i.e., loss of appetite and/or reduction of food intake with aging) is an important public health issue. It leads to unintentional weight loss, which is an independent risk factor for morbidity and mortality among seniors. AA has mainly been studied from a biological perspective and regarded as a normal physiological consequence of aging, rather than a negative health outcome with underlying determinants. Some potentially modifiable correlates have however been found to be associated with this geriatric condition. Here, we conducted a scoping review of the literature to: 1) identify AA correlates, and 2) discuss their relevance to population health interventions. Our results indicate two main categories of AA correlates, namely, physiopathological and non-physiopathological. The first category relates to physiological dysfunctions, pathologies involving (or culminating in) biomarker dysregulation, and polypharmacy. These correlates are difficult to modify, especially through population health interventions. The second category, which contains fewer correlates, includes potentially modifiable public health targets, such as food-related properties, psychological, sociocultural, and environmental issues. We conclude that there are several AA correlates. Some of them are modifiable and could be targeted for development and implementation as appropriate population health interventions to prevent appetite loss and promote maintenance of adequate food intake in aging. Copyright © 2016 Elsevier Ltd. All rights reserved.

The 22-Modifier in Reimbursement for Orthopedic Procedures: Hip Arthroplasty and Obesity Are Worth the Effort.

PubMed

Smith, Eric L; Tybor, David J; Daniell, Hayley D; Naccarato, Laura A; Pevear, Mary E; Cassidy, Charles

2018-02-21

Orthopedic surgeons utilize the 22-modifier when billing for complex procedures under the American Medical Association's Current Procedural Terminology (CPT) for reasons such as excessive blood loss, anatomic abnormality, and morbid obesity, cases that would ideally be reimbursed at a higher rate to compensate for additional physician work and time. We investigated how the 22-modifier affects physician reimbursement in knee and hip arthroplasty. We queried hospital billing data from 2009 to 2016, identifying all cases performed at our urban tertiary care orthopedic center for knee arthroplasty (CPT codes 27438, 27447, 27487, and 27488) and hip arthroplasty (CPT codes 27130, 27132, 27134, 27236). We extracted patient insurance status and reimbursement data to compare the average reimbursement between cases with and without the 22-modifier. We analyzed data from 2605 procedures performed by 10 providers. There were 136 cases with 22-modifiers. For knee arthroplasty (n = 1323), the 22-modifier did not significantly increase reimbursement after adjusting for insurer, provider, and fiscal year (4.2% dollars higher on average, P = .159). For hip arthroplasty (n = 1282), cases with a 22-modifier had significantly higher reimbursement than those without the 22-modifier (6.2% dollars more, P = .049). For hip arthroplasty cases with a 22-modifier, those noting morbid obesity were reimbursed 29% higher than those cases with other etiology. The effect of the 22-modifier on reimbursement amount is differential between knee and hip arthroplasty. Hip arthroplasty procedures coded as 22-modifier are reimbursed more than those without the 22-modifier. Providers should consider these potential returns when considering submitting a 22-modifier. Copyright © 2018 Elsevier Inc. All rights reserved.

Evaluation of the Effectiveness of Simulation for M4 Marksmanship Training

DTIC Science & Technology

2014-02-01

DEMOGRAPHIC QUESTIONNAIRE ................................................. 34 APPENDIX C: ANALYSIS OF MARKSMANSHIP PERFORMANCE DATA TO IDENTIFY POTENTIAL...machine guns and anti- armour weapons. In these simulators, firers aim a modified weapon at a target image on a screen. When the firer pulls the trigger...investigate predictors of live-fire LF6 qualification. Specifically, we examined the utility of LF6 simulator scores and trainee demographic data as

Light intensity physical activity and sedentary behavior in relation to body mass index and grip strength in older adults: cross-sectional findings from the Lifestyle Interventions and Independence for Elders (LIFE) study

USDA-ARS?s Scientific Manuscript database

Background: Identifying modifiable determinants of fat mass and muscle strength in older adults is important given their impact on physical functioning and health. Light intensity physical activity and sedentary behavior are potential determinants, but their relations to these outcomes are poorly un...

Intra-abdominal drain fracture following pancreatic necrosectomy.

PubMed

Campbell, W; Wallace, W; Gibson, E; McCallion, K

2011-06-01

We describe a rare case of iatrogenic fracture of an intra-abdominal tube drain (Portex Robinson drain, Smiths Medical, Kent, UK) in a 74-year-old man. The fracture occurred at the level of an additionally placed fenestration and was identified on CT scanning prior to retrieval at planned re-laparotomy. This case highlights the potential dangers of modifying pre-formed drains and recommends against this practice.

Expression, Localization of SUMO-1, and Analyses of Potential SUMOylated Proteins in Bubalus bubalis Spermatozoa

PubMed Central

Brohi, Rahim Dad; Wang, Li; Hassine, Najla Ben; Cao, Jing; Talpur, Hira Sajjad; Wu, Di; Huang, Chun-Jie; Rehman, Zia-Ur; Bhattarai, Dinesh; Huo, Li-Jun

2017-01-01

Mature spermatozoa have highly condensed DNA that is essentially silent both transcriptionally and translationally. Therefore, post translational modifications are very important for regulating sperm motility, morphology, and for male fertility in general. Protein sumoylation was recently demonstrated in human and rodent spermatozoa, with potential consequences for sperm motility and DNA integrity. We examined the expression and localization of small ubiquitin-related modifier-1 (SUMO-1) in the sperm of water buffalo (Bubalus bubalis) using immunofluorescence analysis. We confirmed the expression of SUMO-1 in the acrosome. We further found that SUMO-1 was lost if the acrosome reaction was induced by calcium ionophore A23187. Proteins modified or conjugated by SUMO-1 in water buffalo sperm were pulled down and analyzed by mass spectrometry. Sixty proteins were identified, including proteins important for sperm morphology and motility, such as relaxin receptors and cytoskeletal proteins, including tubulin chains, actins, and dyneins. Forty-six proteins were predicted as potential sumoylation targets. The expression of SUMO-1 in the acrosome region of water buffalo sperm and the identification of potentially SUMOylated proteins important for sperm function implicates sumoylation as a crucial PTM related to sperm function. PMID:28659810

Dye-doped silica-based nanoparticles for bioapplications

NASA Astrophysics Data System (ADS)

Nhung Tran, Hong; Nghiem, Thi Ha Lien; Thuy Duong Vu, Thi; Tan Pham, Minh; Van Nguyen, Thi; Trang Tran, Thu; Chu, Viet Ha; Thuan Tong, Kim; Thuy Tran, Thanh; Le, Thi Thanh Xuan; Brochon, Jean-Claude; Quy Nguyen, Thi; Nhung Hoang, My; Nguyen Duong, Cao; Thuy Nguyen, Thi; Hoang, Anh Tuan; Hoa Nguyen, Phuong

2013-12-01

This paper presents our recent research results on synthesis and bioapplications of dye-doped silica-based nanoparticles. The dye-doped water soluble organically modified silicate (ORMOSIL) nanoparticles (NPs) with the size of 15-100 nm were synthesized by modified Stöber method from methyltriethoxysilane CH3Si(OCH3)3 precursor (MTEOS). Because thousands of fluorescent dye molecules are encapsulated in the silica-based matrix, the dye-doped nanoparticles are extremely bright and photostable. Their surfaces were modified with bovine serum albumin (BSA) and biocompatible chemical reagents. The highly intensive luminescent nanoparticles were combined with specific bacterial and breast cancer antigen antibodies. The antibody-conjugated nanoparticles can identify a variety of bacterium, such as Escherichia coli O157:H7, through antibody-antigen interaction and recognition. A highly sensitive breast cancer cell detection has been achieved with the anti-HER2 monoclonal antibody-nanoparticles complex. These results demonstrate the potential to apply these fluorescent nanoparticles in various biodetection systems.

Association between floods and infectious diarrhea and their effect modifiers in Hunan province, China: A two-stage model.

PubMed

Liu, Zhidong; Zhang, Feifei; Zhang, Ying; Li, Jing; Liu, Xuena; Ding, Guoyong; Zhang, Caixia; Liu, Qiyong; Jiang, Baofa

2018-06-01

Understanding the potential links between floods and infectious diarrhea is important under the context of climate change. However, little is known about the risk of infectious diarrhea after floods and what factors could modify these effects in China. This study aims to quantitatively examine the relationship between floods and infectious diarrhea and their effect modifiers. Weekly number of infectious diarrhea cases from 2004 to 2011 during flood season in Hunan province were supplied by the National Notifiable Disease Surveillance System. Flood and meteorological data over the same period were obtained. A two-stage model was used to estimate a provincial average association and their effect modifiers between floods and infectious diarrhea, accounting for other confounders. A total of 134,571 cases of infectious diarrhea were notified from 2004 to 2011. After controlling for seasonality, long-term trends, and meteorological factors, floods were significantly associated with infectious diarrhea in the provincial level with a cumulative RR of 1.22 (95% CI: 1.05, 1.43) with a lagged effect of 0-1 week. Geographic locations and economic levels were identified as effect modifiers, with a higher impact of floods on infectious diarrhea in the western and regions with a low economic level of Hunan. Our study provides strong evidence of a positive association between floods and infectious diarrhea in the study area. Local control strategies for public health should be taken in time to prevent and reduce the risk of infectious diarrhea after floods, especially for the vulnerable regions identified. Copyright © 2018 Elsevier B.V. All rights reserved.

Screening for Natural Chemoprevention Agents that Modify Human Keap1

PubMed Central

Hu, Chenqi; Nikolic, Dejan; Eggler, Aimee L.; Mesecar, Andrew D.; van Breemen, Richard B.

2012-01-01

Upregulation of cytoprotective enzymes by therapeutic agents to prevent damage by reactive oxygen species and xenobiotic electrophiles is a strategy for cancer chemoprevention. The Kelch-like ECH-associated protein 1 (Keap1) and its binding partner, transcription factor NF-E2-related factor-2 (Nrf2), are chemoprevention targets because of their role in regulating the antioxidant response element (ARE) in response to oxidative stress and exposure to electrophiles. Modification of the sensor protein Keap1 by electrophiles such as the isothiocyanate sulforaphane can direct Nrf2 accumulation in the nucleus and subsequent ARE activation. Since our previous matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS)-based screening method to discover natural products that modify Keap1 does not detect covalent modification of Keap1 by some highly reversible agents such as sulforaphane, a more sensitive screening assay was developed. In this new assay, electrophiles that have reversibly modified Keap1 can be released, trapped and detected as β-mercaptoethanol adducts by mass spectrometry. Isoliquiritigenin and sulforaphane, known ARE activators that target Keap1, were used to validate the assay. To determine the ability of the assay to identify electrophiles in complex matrixes that modify Keap1, sulforaphane was spiked into a cocoa extract, and LC-MS/MS using high resolution mass spectrometry with accurate mass measurement was used to identify β-mercaptoethanol adducts of sulforaphane that had been released from Keap1. This screening assay permits identification of potential chemoprevention agents in complex natural product mixtures that reversibly modify Keap1 but cannot be detected using MALDI-TOF MS. PMID:22074792

Towards optimal intraoperative conditions in esophageal surgery: A review of literature for the prevention of esophageal anastomotic leakage.

PubMed

Bootsma, Boukje Titia; Huisman, Daitlin Esmee; Plat, Victor Dirk; Schoonmade, Linda Jeanne; Stens, Jurre; Hubens, Guy; van der Peet, Donald Leonard; Daams, Freek

2018-04-30

Esophageal anastomotic leakage (EAL) is a severe complication following gastric and esophageal surgery for cancer. Several non-modifiable, patient or surgery related risk factors for EAL have been identified, however, the contribution of modifiable intraoperative parameters remains undetermined. This review provides an overview of current literature on potentially modifiable intraoperative risk factors for EAL. The PubMed, EMBASE and Cochrane databases were searched by two researchers independently. Clinical studies published in English between 1970 and January 2017 that evaluated the effect of intraoperative parameters on the development of EAL were included. Levels of evidence as defined by the Centre of Evidence Based Medicine (CEBM) were assigned to the studies. A total of 25 articles were included in the final analysis. These articles show evidence that anemia, increased amount of blood loss, low pH and high pCO2 values, prolonged duration of procedure and lack of surgical experience independently increase the risk of EAL. Supplemental oxygen therapy, epidural analgesia and selective digestive decontamination seem to have a beneficial effect. Potential risk factors include blood pressure, requirement of blood products, vasopressor use and glucocorticoid administration, however the results are ambiguous. Apart from fixed surgical and patient related factors, several intraoperative factors that can be modified in clinical practice can influence the risk of developing EAL. More prospective, observational studies are necessary focusing on modifiable intraoperative parameters to assess more evidence and to elucidate optimal values of these factors. Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

Development and validation of an oxygen dissociation assay, a screening platform for discovering, and characterizing hemoglobin-oxygen affinity modifiers.

PubMed

Patel, Mira P; Siu, Vincent; Silva-Garcia, Abel; Xu, Qing; Li, Zhe; Oksenberg, Donna

2018-01-01

Hemoglobin (Hb) is a critical molecule necessary for all vertebrates to maintain aerobic metabolism. Hb-oxygen (O 2 ) affinity modifiers have been studied to address various diseases including sickle cell disease, hypoxemia, tumor hypoxia, and wound healing. However, drug development of exogenous Hb modifiers has been hindered by the lack of a technique to rapidly screen compounds for their ability to alter Hb-O 2 affinity. We have developed a novel screening assay based upon the spectral changes observed during Hb deoxygenation and termed it the oxygen dissociation assay (ODA). ODA allows for the quantitation of oxygenated Hb at given time points during Hb deoxygenation on a 96-well plate. This assay was validated by comparing the ability of 500 Hb modifiers to alter the Hb-O 2 affinity in the ODA vs the oxygen equilibrium curves obtained using the industry standard Hemox Analyzer instrument. A correlation ( R 2 ) of 0.7 indicated that the ODA has the potential to screen and identify potent exogenous Hb modifiers. In addition, it allows for concurrent comparison of compounds, concentrations, buffers, or pHs on the level of Hb oxygenation. With a cost-effective, simple, rapid, and highly adaptable assay, the ODA will allow researchers to rapidly characterize Hb-O 2 affinity modifiers.

Eigensolutions, Shannon entropy and information energy for modified Tietz-Hua potential

NASA Astrophysics Data System (ADS)

Onate, C. A.; Onyeaju, M. C.; Ituen, E. E.; Ikot, A. N.; Ebomwonyi, O.; Okoro, J. O.; Dopamu, K. O.

2018-04-01

The Tietz-Hua potential is modified by the inclusion of De ( {{Ch - 1}/{1 - C_{h e^{{ - bh ( {r - re } )}} }}} )be^{{ - bh ( {r - re } )}} term to the Tietz-Hua potential model since a potential of such type is very good in the description and vibrational energy levels for diatomic molecules. The energy eigenvalues and the corresponding eigenfunctions are explicitly obtained using the methodology of parametric Nikiforov-Uvarov. By putting the potential parameter b = 0, in the modified Tietz-Hua potential quickly reduces to the Tietz-Hua potential. To show more applications of our work, we have computed the Shannon entropy and Information energy under the modified Tietz-Hua potential. However, the computation of the Shannon entropy and Information energy is an extension of the work of Falaye et al., who computed only the Fisher information under Tietz-Hua potential.

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases

PubMed Central

Kaifer, Kevin A.; Osman, Erkan Y.; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L.

2017-01-01

The term “motor neuron disease” encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease. PMID:28362802

Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

PubMed

Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

2017-03-01

The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers, and demonstrated SNCA is a modifier of pathology in motor neuron disease.

Quantitative Protein Sulfenic Acid Analysis Identifies Platelet Releasate-Induced Activation of Integrin β2 on Monocytes via NADPH Oxidase.

PubMed

Li, Ru; Klockenbusch, Cordula; Lin, Liwen; Jiang, Honghui; Lin, Shujun; Kast, Juergen

2016-12-02

Physiological stimuli such as thrombin, or pathological stimuli such as lysophosphatidic acid (LPA), activate platelets. The activated platelets bind to monocytes through P-selectin-PSGL-1 interactions but also release the contents of their granules, commonly called "platelet releasate". It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS is considered to be a potential regulator of protein function. In a previous study, we used THP-1 monocytic cells exposed to LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that are influenced by reversible cysteine oxidation. To gain a better understanding of the redox regulation of monocytes in atherosclerosis, we have now altered the modified biotin switch to selectively quantify protein sulfenic acid, a subpopulation of reversible cysteine oxidation. Using arsenite as reducing agent in the modified biotin switch assay, we were able to quantify 1161 proteins, in which more than 100 sulfenic acid sites were identified. Bioinformatics analysis of the quantified sulfenic acid sites highlighted the relevant, previously missed biological process of monocyte transendothelial migration, which included integrin β 2 . Flow cytometry validated the activation of LFA-1 (α L β 2 ) and Mac-1 (α M β 2 ), two subfamilies of integrin β 2 complexes, on human primary monocytes following platelet releasate treatment. The activation of LFA-1 was mediated by ROS from NADPH oxidase (NOX) activation. Production of ROS and activation of LFA-1 in human primary monocytes were independent of P-selectin-PSGL-1 interaction. Our results proved the modified biotin switch assay to be a powerful tool with the ability to reveal new regulatory mechanisms and identify new therapeutic targets.

Mapping of ribosomal 23S ribosomal RNA modifications in Clostridium sporogenes.

PubMed

Kirpekar, Finn; Hansen, Lykke H; Mundus, Julie; Tryggedsson, Stine; Teixeira Dos Santos, Patrícia; Ntokou, Eleni; Vester, Birte

2018-06-27

All organisms contain RNA modifications in their ribosomal RNA (rRNA), but the importance, positions and exact function of these are still not fully elucidated. Various functions such as stabilising structures, controlling ribosome assembly and facilitating interactions have been suggested and in some cases substantiated. Bacterial rRNA contains much fewer modifications than eukaryotic rRNA. The rRNA modification patterns in bacteria differ from each other, but too few organisms have been mapped to draw general conclusions. This study maps 23S ribosomal RNA modifications in Clostridium sporogenes that can be characterised as a non-toxin producing Clostridium botulinum. Clostridia are able to sporulate and thereby survive harsh conditions, and are in general considered to be resilient to antibiotics. Selected regions of the 23S rRNA were investigated by mass spectrometry and by primer extension analysis to pinpoint modified sites and the nature of the modifications. Apparently, C. sporogenes 23S rRNA contains few modifications compared to other investigated bacteria. No modifications were identified in domain II and III of 23S rRNA. Three modifications were identified in domain IV, all of which have also been found in other organisms. Two unusual modifications were identified in domain V, methylated dihydrouridine at position U2449 and dihydrouridine at position U2500 (Escherichia coli numbering), in addition to four previously known modified positions. The enzymes responsible for the modifications were searched for in the C. sporogenes genome using BLAST with characterised enzymes as query. The search identified genes potentially coding for RNA modifying enzymes responsible for most of the found modifications.

Modifiable risk factors for Alzheimer disease and subjective memory impairment across age groups.

PubMed

Chen, Stephen T; Siddarth, Prabha; Ercoli, Linda M; Merrill, David A; Torres-Gil, Fernando; Small, Gary W

2014-01-01

Previous research has identified modifiable risk factors for Alzheimer's disease (AD) in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI), which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups. Trained interviewers conducted daily telephone surveys (Gallup-Healthways) of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years), 6,365 middle-aged (40 to 59 years), and 7,824 older (60 to 99 years) adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups. Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor. These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other dementias later in life remains to be determined.

Families in the Army: Looking Ahead

DTIC Science & Technology

1989-06-01

WRi 0ata FEA14-64) This study considers how aggregate demand for Army family services will change in the future and identifies long-range issues posed...although Army actions and policies could potentially modify that future. Four long-range issues deserve closer study and continued monitoring: (1...important issues those changes pose, and explores their implications for force manage- ment and service delivery policies. It is meant to provide RAND and

Genetic advances in sarcomeric cardiomyopathies: state of the art

PubMed Central

Ho, Carolyn Y.; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y.; Pinto, Yigal

2015-01-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. PMID:25634555

Postoperative Swallowing Assessment After Lung Transplantation.

PubMed

Baumann, Brooke; Byers, Sara; Wasserman-Wincko, Tamara; Smith, Libby; Hathaway, Bridget; Bhama, Jay; Shigemura, Norihisa; Hayanga, J W Awori; D'Cunha, Jonathan; Johnson, Jonas T

2017-07-01

Dysphagia, aspiration, and potential pneumonia represent a major source of morbidity in patients undergoing lung transplantation. Conditions that potentiate dysphagia and aspiration include frailty and prolonged intubation. Our group of speech-language pathologists has been actively involved in performance of a bedside evaluation of swallowing, and instrumental evaluation of swallowing with modified barium swallow, and postoperative management in patients undergoing lung transplantation. All lung transplant patients from April 2009 to September 2012 were evaluated retrospectively. A clinical bedside examination was performed by the speech-language pathology team, followed by a modified barium swallow or fiberoptic endoscopic evaluation of swallowing. A total of 321 patients were referred for evaluation. Twenty-four patients were unable to complete the evaluation. Clinical signs of aspiration were apparent in 160 patients (54%). Deep laryngeal penetration or aspiration were identified in 198 (67%) patients during instrumental testing. A group of 81 patients (27%) had an entirely normal clinical examination, but were found to have either deep penetration or aspiration. The majority of patients aspirate after lung transplantation. Clinical bedside examination is not sensitive enough and will fail to identify patients with silent aspiration. A standard of practice following lung transplantation has been established that helps avoid postoperative aspiration associated with complications. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Electrochemical Characterization of Carbon Nanotubes for Fuel Cell MEA's

NASA Technical Reports Server (NTRS)

Panagaris, Jael; Loyselle, Patricia

2004-01-01

Single-walled and multi-walled carbon nanotubes from different sources have been evaluated before and after sonication to identify structural differences and evaluate electrochemical performance. Raman spectral analysis and cyclic voltammetry in situ with QCM were the principle means of evaluating the tubes. The raman data indicates that sonication in toluene modifies the structural properties of the nanotubes. Sonication also affects the electrochemical performance of single-walled nanotubes and the multi-walled tubes differently. The characterization of different types of carbon nanotubes leads up to identifying a potential candidate for incorporating carbon nanotubes for fuel cell MEA structures.

The Role of eHealth in Optimizing Preventive Care in the Primary Care Setting.

PubMed

Carey, Mariko; Noble, Natasha; Mansfield, Elise; Waller, Amy; Henskens, Frans; Sanson-Fisher, Rob

2015-05-22

Modifiable health risk behaviors such as smoking, overweight and obesity, risky alcohol consumption, physical inactivity, and poor nutrition contribute to a substantial proportion of the world's morbidity and mortality burden. General practitioners (GPs) play a key role in identifying and managing modifiable health risk behaviors. However, these are often underdetected and undermanaged in the primary care setting. We describe the potential of eHealth to help patients and GPs to overcome some of the barriers to managing health risk behaviors. In particular, we discuss (1) the role of eHealth in facilitating routine collection of patient-reported data on lifestyle risk factors, and (2) the role of eHealth in improving clinical management of identified risk factors through provision of tailored feedback, point-of-care reminders, tailored educational materials, and referral to online self-management programs. Strategies to harness the capacity of the eHealth medium, including the use of dynamic features and tailoring to help end users engage with, understand, and apply information need to be considered and maximized. Finally, the potential challenges in implementing eHealth solutions in the primary care setting are discussed. In conclusion, there is significant potential for innovative eHealth solutions to make a contribution to improving preventive care in the primary care setting. However, attention to issues such as data security and designing eHealth interfaces that maximize engagement from end users will be important to moving this field forward.

Antibodies against the mono-methylated arginine-glycine repeat (MMA-RG) of the Epstein-Barr virus nuclear antigen 2 (EBNA2) identify potential cellular proteins targeted in viral transformation.

PubMed

Ayoubian, Hiresh; Fröhlich, Thomas; Pogodski, Dagmar; Flatley, Andrew; Kremmer, Elisabeth; Schepers, Aloys; Feederle, Regina; Arnold, Georg J; Grässer, Friedrich A

2017-08-01

The Epstein-Barr virus is a human herpes virus with oncogenic potential. The virus-encoded nuclear antigen 2 (EBNA2) is a key mediator of viral tumorigenesis. EBNA2 features an arginine-glycine (RG) repeat at amino acids (aa)339-354 that is essential for the transformation of lymphocytes and contains symmetrically (SDMA) and asymmetrically (ADMA) di-methylated arginine residues. The SDMA-modified EBNA2 binds the survival motor neuron protein (SMN), thus mimicking SMD3, a cellular SDMA-containing protein that interacts with SMN. Accordingly, a monoclonal antibody (mAb) specific for the SDMA-modified RG repeat of EBNA2 also binds to SMD3. With the novel mAb 19D4 we now show that EBNA2 contains mono-methylated arginine (MMA) residues within the RG repeat. Using 19D4, we immune-precipitated and analysed by mass spectrometry cellular proteins in EBV-transformed B-cells that feature MMA motifs that are similar to the one in EBNA2. Among the cellular proteins identified, we confirmed by immunoprecipitation and/or Western blot analyses Aly/REF, Coilin, DDX5, FXR1, HNRNPK, LSM4, MRE11, NRIP, nucleolin, PRPF8, RBM26, SMD1 (SNRDP1) and THRAP3 proteins that are either known to contain MMA residues or feature RG repeat sequences that probably serve as methylation substrates. The identified proteins are involved in splicing, tumorigenesis, transcriptional activation, DNA stability and RNA processing or export. Furthermore, we found that several proteins involved in energy metabolism are associated with MMA-modified proteins. Interestingly, the viral EBNA1 protein that features methylated RG repeat motifs also reacted with the antibodies. Our results indicate that the region between aa 34-52 of EBNA1 contains ADMA or SDMA residues, while the region between aa 328-377 mainly contains MMA residues.

The impact of catchment source group classification on the accuracy of sediment fingerprinting outputs.

PubMed

Pulley, Simon; Foster, Ian; Collins, Adrian L

2017-06-01

The objective classification of sediment source groups is at present an under-investigated aspect of source tracing studies, which has the potential to statistically improve discrimination between sediment sources and reduce uncertainty. This paper investigates this potential using three different source group classification schemes. The first classification scheme was simple surface and subsurface groupings (Scheme 1). The tracer signatures were then used in a two-step cluster analysis to identify the sediment source groupings naturally defined by the tracer signatures (Scheme 2). The cluster source groups were then modified by splitting each one into a surface and subsurface component to suit catchment management goals (Scheme 3). The schemes were tested using artificial mixtures of sediment source samples. Controlled corruptions were made to some of the mixtures to mimic the potential causes of tracer non-conservatism present when using tracers in natural fluvial environments. It was determined how accurately the known proportions of sediment sources in the mixtures were identified after unmixing modelling using the three classification schemes. The cluster analysis derived source groups (2) significantly increased tracer variability ratios (inter-/intra-source group variability) (up to 2122%, median 194%) compared to the surface and subsurface groupings (1). As a result, the composition of the artificial mixtures was identified an average of 9.8% more accurately on the 0-100% contribution scale. It was found that the cluster groups could be reclassified into a surface and subsurface component (3) with no significant increase in composite uncertainty (a 0.1% increase over Scheme 2). The far smaller effects of simulated tracer non-conservatism for the cluster analysis based schemes (2 and 3) was primarily attributed to the increased inter-group variability producing a far larger sediment source signal that the non-conservatism noise (1). Modified cluster analysis based classification methods have the potential to reduce composite uncertainty significantly in future source tracing studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prioritizing stream types according to their potential risk to receive crop plant material--A GIS-based procedure to assist in the risk assessment of genetically modified crops and systemic insecticide residues.

PubMed

Bundschuh, Rebecca; Kuhn, Ulrike; Bundschuh, Mirco; Naegele, Caroline; Elsaesser, David; Schlechtriemen, Ulrich; Oehen, Bernadette; Hilbeck, Angelika; Otto, Mathias; Schulz, Ralf; Hofmann, Frieder

2016-03-15

Crop plant residues may enter aquatic ecosystems via wind deposition or surface runoff. In the case of genetically modified crops or crops treated with systemic pesticides, these materials may contain insecticidal Bt toxins or pesticides that potentially affect aquatic life. However, the particular exposure pattern of aquatic ecosystems (i.e., via plant material) is not properly reflected in current risk assessment schemes, which primarily focus on waterborne toxicity and not on plant material as the route of uptake. To assist in risk assessment, the present study proposes a prioritization procedure of stream types based on the freshwater network and crop-specific cultivation data using maize in Germany as a model system. To identify stream types with a high probability of receiving crop materials, we developed a formalized, criteria-based and thus transparent procedure that considers the exposure-related parameters, ecological status--an estimate of the diversity and potential vulnerability of local communities towards anthropogenic stress--and availability of uncontaminated reference sections. By applying the procedure to maize, ten stream types out of 38 are expected to be the most relevant if the ecological effects from plant-incorporated pesticides need to be evaluated. This information is an important first step to identifying habitats within these stream types with a high probability of receiving crop plant material at a more local scale, including accumulation areas. Moreover, the prioritization procedure developed in the present study may support the selection of aquatic species for ecotoxicological testing based on their probability of occurrence in stream types having a higher chance of exposure. Finally, this procedure can be adapted to any geographical region or crop of interest and is, therefore, a valuable tool for a site-specific risk assessment of crop plants carrying systemic pesticides or novel proteins, such as insecticidal Bt toxins, expressed in genetically modified crops. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of neutral gas releases on electron beam injection from electrically tethered spacecraft

NASA Technical Reports Server (NTRS)

Winglee, R. M.

1990-01-01

The presence of high neutral densities at low altitudes and/or during thruster firings is known to modify the spacecraft potential during active electron beam injection. Two-dimensional (three velocity) particle simulations are used to investigate the ionization processes including the neutral density required, the modification of the spacecraft potential, beam profile and spatial distribution of the return current into the spacecraft. Three processes are identified: (1) beam-induced ionization, (2) vehicle-induced ionization, and (3) beam plasma discharge. Only in the first two cases does the beam propagate away with little distortion.

Diverse and divergent protein post-translational modifications in two growth stages of a natural microbial community

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

Li, Zhou; Wang, Yingfeng; Yao, Qiuming

2014-01-01

Detailed characterization of posttranslational modifications (PTMs) of proteins in microbial communities remains a significant challenge. Here we directly identify and quantify a broad range of PTMs (hydroxylation, methylation, citrullination, acetylation, phosphorylation, methylthiolation, S-nitrosylation and nitration) in a natural microbial community from an acid mine drainage site. Approximately 29% of the identified proteins of the dominant Leptospirillum group II bacteria are modified, and 43% of modified proteins carry multiple PTM types. Most PTM events, except S-nitrosylations, have low fractional occupancy. Notably, PTM events are detected on Cas proteins involved in antiviral defense, an aspect of Cas biochemistry not considered previously. Further,more » Cas PTM profiles from Leptospirillum group II differ in early versus mature biofilms. PTM patterns are divergent on orthologues of two closely related, but ecologically differentiated, Leptospirillum group II bacteria. Our results highlight the prevalence and dynamics of PTMs of proteins, with potential significance for ecological adaptation and microbial evolution.« less

Attitudes, perceptions, and trust. Insights from a consumer survey regarding genetically modified banana in Uganda.

PubMed

Kikulwe, Enoch M; Wesseler, Justus; Falck-Zepeda, Jose

2011-10-01

Genetically modified (GM) crops and food are still controversial. This paper analyzes consumers' perceptions and institutional awareness and trust toward GM banana regulation in Uganda. Results are based on a study conducted among 421 banana-consuming households between July and August 2007. Results show a high willingness to purchase GM banana among consumers. An explanatory factor analysis is conducted to identify the perceptions toward genetic modification. The identified factors are used in a cluster analysis that grouped consumers into segments of GM skepticism, government trust, health safety concern, and food and environmental safety concern. Socioeconomic characteristics differed significantly across segments. Consumer characteristics and perception factors influence consumers' willingness to purchase GM banana. The institutional awareness and trust varied significantly across segments as well. The findings would be essential to policy makers when designing risk-communication strategies targeting different consumer segments to ensure proper discussion and addressing potential concerns about GM technology. Copyright © 2011 Elsevier Ltd. All rights reserved.

Influence of Parameters of a Reactive Interatomic Potential on the Properties of Saturated Hydrocarbons

DTIC Science & Technology

2017-01-01

Methodology 3 2.1 Modified Embedded-Atom Method Theory 3 2.1.1 Embedding Energy Function 3 2.1.2 Screening Factor 8 2.1.3 Modified Embedded-Atom...Simulation Methodology 2.1 Modified Embedded-Atom Method Theory In the EAM and MEAM formalisms1,2,5 the total energy of a system of atoms (Etot) is...An interatomic potential for saturated hydrocarbons using the modified embedded-atom method (MEAM), a semiempirical many-body potential based on

Clinic Appointment Attendance in Adults with Serious Mental Illness and Diabetes.

PubMed

Gunzler, Douglas D; Morris, Nathan; Dalton, Jarrod E; McCormick, Richard; Dawson, Neal V; Thomas, Charles; Kanuch, Stephanie; Cassidy, Kristin A; Athey, Melanie; Fuentes-Casiano, Edna; Lawless, Mary Ellen; Martin, Siobhan; Einstadter, Douglas; Sajatovic, Martha

2017-11-01

We assessed characteristics that may predict outpatient appointment attendance in outpatient medical clinics among patients comorbid for serious mental illness (SMI) and type 2 diabetes (DM). Baseline covariate data from 200 individuals with SMI-DM enrolled in a randomized controlled trial (RCT) were used to examine characteristics associated with electronic health record-identified clinic appointment attendance using a generalized estimating equations approach. The analyses evaluated the relationship between clinic attendance and potentially modifiable factors including disease knowledge, self-efficacy, social support, physical health, and mental health, as well as demographic information. Demographic and mental health characteristics were most associated with clinic attendance in adults with SMI-DM. Physical health was not associated with clinic attendance. Information on clinical and demographic characteristics and factors potentially modifiable by psychological interventions may be useful in improving adherence to treatment among SMI-DM patients. It is our hope that clinicians and researchers will use these results to help tailor adherence-facilitating interventions among people at particular risk for poor engagement in care.

Activation of the Ubiquitin Proteasome Pathway by Silk Fibroin Modified Chitosan Nanoparticles in Hepatic Cancer Cells

PubMed Central

Yang, Ming-Hui; Chung, Tze-Wen; Lu, Yi-Shan; Chen, Yi-Ling; Tsai, Wan-Chi; Jong, Shiang-Bin; Yuan, Shyng-Shiou; Liao, Pao-Chi; Lin, Po-Chiao; Tyan, Yu-Chang

2015-01-01

Silk fibroin (SF) is a protein with bulky hydrophobic domains and can be easily purified as sericin-free silk-based biomaterial. Silk fibroin modified chitosan nanoparticle (SF-CSNP), a biocompatible material, has been widely used as a potential drug delivery system. Our current investigation studied the bio-effects of the SF-CSNP uptake by liver cells. In this experiment, the characterizations of SF-CSNPs were measured by particle size analysis and protein assay. The average size of the SF-CSNP was 311.9 ± 10.7 nm, and the average zeta potential was +13.33 ± 0.3 mV. The SF coating on the SF-CSNP was 6.27 ± 0.17 μg/mL. Moreover, using proteomic approaches, several proteins involved in the ubiquitin proteasome pathway were identified by analysis of differential protein expressions of HepG2 cell uptake the SF-CSNP. Our experimental results have demonstrated that the SF-CSNP may be involved in liver cancer cell survival and proliferation. PMID:25588218

Risk factors for first time incidence sciatica: a systematic review.

PubMed

Cook, Chad E; Taylor, Jeffrey; Wright, Alexis; Milosavljevic, Steven; Goode, Adam; Whitford, Maureen

2014-06-01

Characteristically, sciatica involves radiating leg pain that follows a dermatomal pattern along the distribution of the sciatic nerve. To our knowledge, there are no studies that have investigated risk factors associated with first time incidence sciatica. The purpose of the systematic review was to identify the longitudinal risk factors associated with first time incidence sciatica and to report incidence rates for the condition. For the purposes of this review, first time incidence sciatica was defined as either of the following: 1) no prior history of sciatica or 2) transition from a pain-free state to sciatica. Studies included subjects of any age from longitudinal, observational, cohort designs. The study was a systematic review. Eight of the 239 articles identified by electronic search strategies met the inclusion criteria. Risk factors and their respective effect estimates were reported using descriptive analysis and the preferred reporting items for systematic reviews and meta-analyses guidelines. Modifiable risk factors included smoking, obesity, occupational factors and health status. Non-modifiable factors included age, gender and social class. Incidence rates varied among the included studies, in part reflecting the variability in the operationalized definition of sciatica but ranged from <1% to 37%. A majority of the identified risk factors associated with first time sciatica are modifiable, suggesting the potential benefits of primary prevention. In addition, those risk factors are also associated with unhealthy lifestyles, which may function concomitantly toward the development of sciatica. Sciatica as a diagnosis is inconsistently defined among studies. © 2013 John Wiley & Sons, Ltd.

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

PubMed Central

Vigorito, Elena; Kuchenbaecker, Karoline B.; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A.; Andrulis, Irene L.; Arun, Banu K.; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Chan, Salina B.; Claes, Kathleen B. M.; Cohn, David E.; Cook, Jackie; Daly, Mary B.; Damiola, Francesca; Davidson, Rosemarie; de Pauw, Antoine; Delnatte, Capucine; Diez, Orland; Domchek, Susan M.; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F.; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D. Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D.; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A.; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K.; Goldgar, David E.; Hake, Christopher R.; Hansen, Thomas V. O.; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B. L.; Houdayer, Claude; Hulick, Peter J.; Imyanitov, Evgeny N.; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M.; Vijai, Joseph; Karlan, Beth Y.; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L.; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R.; Montagna, Marco; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I.; Ong, Kai-ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M.; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C.; Rookus, Matti A.; Ross, Eric A.; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F.; Slavin, Thomas P.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J.; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N.; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J.; Greene, Mark H.; Couch, Fergus J.; Offit, Kenneth; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Antoniou, Antonis C.

2016-01-01

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10−16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10−6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population. PMID:27463617

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

PubMed

Vigorito, Elena; Kuchenbaecker, Karoline B; Beesley, Jonathan; Adlard, Julian; Agnarsson, Bjarni A; Andrulis, Irene L; Arun, Banu K; Barjhoux, Laure; Belotti, Muriel; Benitez, Javier; Berger, Andreas; Bojesen, Anders; Bonanni, Bernardo; Brewer, Carole; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Chan, Salina B; Claes, Kathleen B M; Cohn, David E; Cook, Jackie; Daly, Mary B; Damiola, Francesca; Davidson, Rosemarie; Pauw, Antoine de; Delnatte, Capucine; Diez, Orland; Domchek, Susan M; Dumont, Martine; Durda, Katarzyna; Dworniczak, Bernd; Easton, Douglas F; Eccles, Diana; Edwinsdotter Ardnor, Christina; Eeles, Ros; Ejlertsen, Bent; Ellis, Steve; Evans, D Gareth; Feliubadalo, Lidia; Fostira, Florentia; Foulkes, William D; Friedman, Eitan; Frost, Debra; Gaddam, Pragna; Ganz, Patricia A; Garber, Judy; Garcia-Barberan, Vanesa; Gauthier-Villars, Marion; Gehrig, Andrea; Gerdes, Anne-Marie; Giraud, Sophie; Godwin, Andrew K; Goldgar, David E; Hake, Christopher R; Hansen, Thomas V O; Healey, Sue; Hodgson, Shirley; Hogervorst, Frans B L; Houdayer, Claude; Hulick, Peter J; Imyanitov, Evgeny N; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jacobs, Lauren; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Vijai, Joseph; Karlan, Beth Y; Kast, Karin; Investigators, KConFab; Khan, Sofia; Kwong, Ava; Laitman, Yael; Lester, Jenny; Lesueur, Fabienne; Liljegren, Annelie; Lubinski, Jan; Mai, Phuong L; Manoukian, Siranoush; Mazoyer, Sylvie; Meindl, Alfons; Mensenkamp, Arjen R; Montagna, Marco; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Olah, Edith; Olopade, Olufunmilayo I; Ong, Kai-Ren; Osorio, Ana; Park, Sue Kyung; Paulsson-Karlsson, Ylva; Pedersen, Inge Sokilde; Peissel, Bernard; Peterlongo, Paolo; Pfeiler, Georg; Phelan, Catherine M; Piedmonte, Marion; Poppe, Bruce; Pujana, Miquel Angel; Radice, Paolo; Rennert, Gad; Rodriguez, Gustavo C; Rookus, Matti A; Ross, Eric A; Schmutzler, Rita Katharina; Simard, Jacques; Singer, Christian F; Slavin, Thomas P; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Sutter, Christian; Szabo, Csilla I; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary Beth; Thomassen, Mads; Tibiletti, Maria Grazia; Tihomirova, Laima; Tognazzo, Silvia; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vratimos, Athanassios; Weitzel, Jeffrey N; McGuffog, Lesley; Kirk, Judy; Toland, Amanda Ewart; Hamann, Ute; Lindor, Noralane; Ramus, Susan J; Greene, Mark H; Couch, Fergus J; Offit, Kenneth; Pharoah, Paul D P; Chenevix-Trench, Georgia; Antoniou, Antonis C

2016-01-01

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Quality indicators for blogs and podcasts used in medical education: modified Delphi consensus recommendations by an international cohort of health professions educators.

PubMed

Lin, Michelle; Thoma, Brent; Trueger, N Seth; Ankel, Felix; Sherbino, Jonathan; Chan, Teresa

2015-10-01

Quality assurance concerns about social media platforms used for education have arisen within the medical education community. As more trainees and clinicians use resources such as blogs and podcasts for learning, we aimed to identify quality indicators for these resources. A previous study identified 151 potentially relevant quality indicators for these social media resources. To identify quality markers for blogs and podcasts using an international cohort of health professions educators. A self-selected group of 44 health professions educators at the 2014 International Conference on Residency Education participated in a Social Media Summit during which a modified Delphi consensus study was conducted to determine which of the 151 quality indicators met the a priori ≥90% inclusion threshold. Thirteen quality indicators classified into the domains of credibility (n=8), content (n=4) and design (n=1) met the inclusion threshold. The quality indicators that were identified may serve as a foundation for further research on quality indicators of social media-based medical education resources and prompt discussion of their legitimacy as a form of educational scholarship. 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.

Legislation affecting governmental assistance for children of parents with substance use: a policy analysis of social justice.

PubMed

Raynor, Phyllis; Williams, Pamela Holtzclaw

2012-11-01

There is legislation that withdraws governmental assistance where parents are using drugs. Social justice is an important consideration in any policy that modifies governmental assistance that benefits vulnerable children. The purpose of this policy analysis is to analyze identified legislation that effect governmental assistance for children in response to parents' substance misuse. A selective review of data-driven studies examined findings describing actual or potential effects on children of legislation targeting parental substance misuse. Challenges in design, processes, and implementation contribute to poor child outcomes. Identifiable constructs of social justice were missing in the reviewed legislation. Social injustice is a potential outcome for children when legislative intent focuses solely on addressing parental drug behaviors. Legislative alternatives to withdrawing support can address substance abuse while maintaining health promotion for these vulnerable children.

A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of α1-antitrypsin deficiency.

PubMed

O'Reilly, Linda P; Long, Olivia S; Cobanoglu, Murat C; Benson, Joshua A; Luke, Cliff J; Miedel, Mark T; Hale, Pamela; Perlmutter, David H; Bahar, Ivet; Silverman, Gary A; Pak, Stephen C

2014-10-01

α1-Antitrypsin deficiency (ATD) is a common genetic disorder that can lead to end-stage liver and lung disease. Although liver transplantation remains the only therapy currently available, manipulation of the proteostasis network (PN) by small molecule therapeutics offers great promise. To accelerate the drug-discovery process for this disease, we first developed a semi-automated high-throughput/content-genome-wide RNAi screen to identify PN modifiers affecting the accumulation of the α1-antitrypsin Z mutant (ATZ) in a Caenorhabditis elegans model of ATD. We identified 104 PN modifiers, and these genes were used in a computational strategy to identify human ortholog-ligand pairs. Based on rigorous selection criteria, we identified four FDA-approved drugs directed against four different PN targets that decreased the accumulation of ATZ in C. elegans. We also tested one of the compounds in a mammalian cell line with similar results. This methodology also proved useful in confirming drug targets in vivo, and predicting the success of combination therapy. We propose that small animal models of genetic disorders combined with genome-wide RNAi screening and computational methods can be used to rapidly, economically and strategically prime the preclinical discovery pipeline for rare and neglected diseases with limited therapeutic options. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

A consensus-based gold standard for the evaluation of mass casualty triage systems.

PubMed

Lerner, E Brooke; McKee, Courtney H; Cady, Charles E; Cone, David C; Colella, M Riccardo; Cooper, Arthur; Coule, Phillip L; Lairet, Julio R; Liu, J Marc; Pirrallo, Ronald G; Sasser, Scott M; Schwartz, Richard; Shepherd, Greene; Swienton, Raymond E

2015-01-01

Accuracy and effectiveness analyses of mass casualty triage systems are limited because there are no gold standard definitions for each of the triage categories. Until there is agreement on which patients should be identified by each triage category, it will be impossible to calculate sensitivity and specificity or to compare accuracy between triage systems. To develop a consensus-based, functional gold standard definition for each mass casualty triage category. National experts were recruited through the lead investigators' contacts and their suggested contacts. Key informant interviews were conducted to develop a list of potential criteria for defining each triage category. Panelists were interviewed in order of their availability until redundancy of themes was achieved. Panelists were blinded to each other's responses during the interviews. A modified Delphi survey was developed with the potential criteria identified during the interview and delivered to all recruited experts. In the early rounds, panelists could add, remove, or modify criteria. In the final rounds edits were made to the criteria until at least 80% agreement was achieved. Thirteen national and local experts were recruited to participate in the project. Six interviews were conducted. Three rounds of voting were performed, with 12 panelists participating in the first round, 12 in the second round, and 13 in the third round. After the first two rounds, the criteria were modified according to respondent suggestions. In the final round, over 90% agreement was achieved for all but one criterion. A single e-mail vote was conducted on edits to the final criterion and consensus was achieved. A consensus-based, functional gold standard definition for each mass casualty triage category was developed. These gold standard definitions can be used to evaluate the accuracy of mass casualty triage systems after an actual incident, during training, or for research.

Tumor Genomic Profiling in Breast Cancer Patients Using Targeted Massively Parallel Sequencing

DTIC Science & Technology

2014-01-01

binding domain mutations in ESR1 ) were identified. Analysis is currently underway to further elucidate causes of resistance in those cases where the... ESR1 , the gene that encodes the estrogen receptor (Wagle, Garraway, and Arteaga, unpublished results). Given the potential importance of ESR...translocations in ER+ breast cancer, we have further modified our bait design to include genomic coordinates across select introns in ESR1 . In addition, two

Bioinformatics analysis to assess potential risks of allergenicity and toxicity of HRAP and PFLP proteins in genetically modified bananas resistant to Xanthomonas wilt disease.

PubMed

Jin, Yuan; Goodman, Richard E; Tetteh, Afua O; Lu, Mei; Tripathi, Leena

2017-11-01

Banana Xanthomonas wilt (BXW) disease threatens banana production and food security throughout East Africa. Natural resistance is lacking among common cultivars. Genetically modified (GM) bananas resistant to BXW disease were developed by inserting the hypersensitive response-assisting protein (Hrap) or/and the plant ferredoxin-like protein (Pflp) gene(s) from sweet pepper (Capsicum annuum). Several of these GM banana events showed 100% resistance to BXW disease under field conditions in Uganda. The current study evaluated the potential allergenicity and toxicity of the expressed proteins HRAP and PFLP based on evaluation of published information on the history of safe use of the natural source of the proteins as well as established bioinformatics sequence comparison methods to known allergens (www.AllergenOnline.org and NCBI Protein) and toxins (NCBI Protein). The results did not identify potential risks of allergy and toxicity to either HRAP or PFLP proteins expressed in the GM bananas that might suggest potential health risks to humans. We recognize that additional tests including stability of these proteins in pepsin assay, nutrient analysis and possibly an acute rodent toxicity assay may be required by national regulatory authorities. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects

PubMed Central

Chang, Howard C.; Sen, Anindya; Kalloo, Geetika; Harris, Jevede; Barsby, Tom; Walsh, Melissa B.; Satterlee, John S.; Li, Chris; Van Vactor, David; Artavanis-Tsakonas, Spyros; Hart, Anne C.

2010-01-01

Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species. PMID:21124729

Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3

PubMed Central

Costa, Maria do Carmo; Ashraf, Naila S.; Fischer, Svetlana; Yang, Yemen; Schapka, Emily; Joshi, Gnanada; McQuade, Thomas J.; Dharia, Rahil M.; Dulchavsky, Mark; Ouyang, Michelle; Cook, David; Sun, Duxin; Larsen, Martha J.; Gestwicki, Jason E.; Todi, Sokol V.; Ivanova, Magdalena I.; Paulson, Henry L.

2016-01-01

No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies. PMID:27645800

Reliability of reporting nosocomial infections in the discharge abstract and implications for receipt of revenues under prospective reimbursement.

PubMed Central

Massanari, R M; Wilkerson, K; Streed, S A; Hierholzer, W J

1987-01-01

Proper reporting of discharge diagnoses, including complications of medical care, is essential for maximum recovery of revenues under the prospective reimbursement system. To evaluate the effectiveness of abstracting techniques in identifying nosocomial infections at discharge, discharge abstracts of patients with nosocomial infections were reviewed during September through November of 1984. Patients with nosocomial infections were identified using modified Centers for Disease Control (CDC) definitions and trained surveillance technicians. Records which did not include the diagnosis of nosocomial infections in the discharge abstract were identified, and potential lost revenues were estimated. We identified 631 infections in 498 patients. On average, only 57 per cent of the infections were properly recorded and coded in the discharge abstract. Of the additional monies which might be anticipated by the health care institution to assist in the cost of care of adverse events, approximately one-third would have been lost due to errors in coding in the discharge abstract. Although these lost revenues are substantial, they constitute but a small proportion of the potential costs to the institution when patients acquire nosocomial infections. PMID:3105338

Synthesis of molecular imprinted polymer modified TiO{sub 2} nanotube array electrode and their photoelectrocatalytic activity

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

Lu Na; Chen Shuo; Wang Hongtao

2008-10-15

A tetracycline hydrochloride (TC) molecularly imprinted polymer (MIP) modified TiO{sub 2} nanotube array electrode was prepared via surface molecular imprinting. Its surface was structured with surface voids and the nanotubes were open at top end with an average diameter of approximately 50 nm. The MIP-modified TiO{sub 2} nanotube array with anatase phase was identified by XRD and a distinguishable red shift in the absorption spectrum was observed. The MIP-modified electrode also exhibited a high adsorption capacity for TC due to its high surface area providing imprinted sites. Photocurrent was generated on the MIP-modified photoanode using the simulated solar spectrum andmore » increased with the increase of positive bias potential. Under simulated solar light irradiation, the MIP-modified TiO{sub 2} nanotube array electrode exhibited enhanced photoelectrocatalytic (PEC) activity with the apparent first-order rate constant being 1.2-fold of that with TiO{sub 2} nanotube array electrode. The effect of the thickness of the MIP layer on the PEC activity was also evaluated. - Graphical abstract: A tetracycline hydrochloride molecularly imprinted polymer modified TiO{sub 2} nanotube array electrode was prepared via surface molecular imprinting. It showed improved response to simulated solar light and higher adsorption capability for tetracycline hydrochloride, thereby exhibiting increased PEC activity under simulated solar light irradiation. The apparent first-order rate constant was 1.2-fold of that on TiO{sub 2} nanotube array electrode.« less

Prevalence and molecular characterization of bovine Cryptosporidium from dairy cows in Northern Thailand.

PubMed

Inpankaew, Tawin; Jiyipong, Tawisa; Sunanta, Chainirun; Kengradomkij, Chanya; Pinyopanuwat, Nongnuch; Jittapalapong, Sathaporn

2017-12-20

Cryptosporidiosis is a common protozoan infection in humans and domestic animals. It is the culprit for significant neonatal morbidity in cattle as well as weight loss and delayed growth, which leads to large economic losses in the farming industry. Furthermore, bovine Cryptosporidium is also a principal source of human Cryptosporidium infections. The purpose of this study is to determine prevalence and genotype of Cryptosporidium spp. from feces of dairy cows from the northern parts of Thailand (Chiang Rai, Chiang Mai, and Lumpang provinces). A total of 500 fecal samples were collected directly from the rectum and they were examined for potential presence of Cryptosporidium infection by using tests such as DMSO-modified acid fast stain, immunofluorescence antibody test (IFAT) and polymerase chain reaction (PCR). The prevalence of Cryptosporidium spp. was 5% by DMSO-modified acid fast stain, 7% by IFAT and 7.6% by PCR respectively. The main genotypes of Cryptosporidium spp. identified were Cryptosporidium parvum and Cryptosporidium bovis. Therefore, as a result of this study, it can be said that, due to the potential cross-species transmission of Cryptosporidium parvum, infected dairy cows may pose a potential zoonotic risk to humans.

Invasive aquarium fish transform ecosystem nutrient dynamics

PubMed Central

Capps, Krista A.; Flecker, Alexander S.

2013-01-01

Trade of ornamental aquatic species is a multi-billion dollar industry responsible for the introduction of myriad fishes into novel ecosystems. Although aquarium invaders have the potential to alter ecosystem function, regulation of the trade is minimal and little is known about the ecosystem-level consequences of invasion for all but a small number of aquarium species. Here, we demonstrate how ecological stoichiometry can be used as a framework to identify aquarium invaders with the potential to modify ecosystem processes. We show that explosive growth of an introduced population of stoichiometrically unique, phosphorus (P)-rich catfish in a river in southern Mexico significantly transformed stream nutrient dynamics by altering nutrient storage and remineralization rates. Notably, changes varied between elements; the P-rich fish acted as net sinks of P and net remineralizers of nitrogen. Results from this study suggest species-specific stoichiometry may be insightful for understanding how invasive species modify nutrient dynamics when their population densities and elemental composition differ substantially from native organisms. Risk analysis for potential aquarium imports should consider species traits such as body stoichiometry, which may increase the likelihood that an invasion will alter the structure and function of ecosystems. PMID:23966642

ANTI-11[E]-PYROGLUTAMATE-MODIFIED AMYLOID β ANTIBODIES CROSS-REACT WITH OTHER PATHOLOGICAL Aβ SPECIES: RELEVANCE FOR IMMUNOTHERAPY

PubMed Central

Perez-Garmendia, Roxanna; Ibarra-Bracamontes, Vanessa; Vasilevko, Vitaly; Luna-Muñoz, Jose; Mena, Raul; Govezensky, Tzipe; Acero, Gonzalo; Manoutcharian, Karen; Cribbs, David H.; Gevorkian, Goar

2010-01-01

N-truncated/modified forms of amyloid beta (Aß) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as animal models of AD, and represent highly desirable therapeutic targets. In the present study we have focused on Ntruncated/modified Aβ peptide bearing amino-terminal pyroglutamate at position 11 (AβN11(pE)). We identified two B-cell epitopes recognized by rabbit anti-AβN11(pE) polyclonal antibodies. Interestingly, rabbit anti-AβN11(pE) polyclonal antibodies bound also to full-length Aβ1-42 and N-truncated/modified AβN3(pE), suggesting that the three peptides may share a common B-cell epitope. Importantly, rabbit anti-AβN11(pE) antibodies bound to naturally occurring Aβ aggregates present in brain samples from AD patients. These results are potentially important for developing novel immunogens for targeting N-truncated/modified Aβ aggregates as well, since the most commonly used immunogens in the majority of vaccine studies have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Aβ, which is absent in N-amino truncated peptides. PMID:20864186

Exploratory Network Meta Regression Analysis of Stroke Prevention in Atrial Fibrillation Fails to Identify Any Interactions with Treatment Effect.

PubMed

Batson, Sarah; Sutton, Alex; Abrams, Keith

2016-01-01

Patients with atrial fibrillation are at a greater risk of stroke and therefore the main goal for treatment of patients with atrial fibrillation is to prevent stroke from occurring. There are a number of different stroke prevention treatments available to include warfarin and novel oral anticoagulants. Previous network meta-analyses of novel oral anticoagulants for stroke prevention in atrial fibrillation acknowledge the limitation of heterogeneity across the included trials but have not explored the impact of potentially important treatment modifying covariates. To explore potentially important treatment modifying covariates using network meta-regression analyses for stroke prevention in atrial fibrillation. We performed a network meta-analysis for the outcome of ischaemic stroke and conducted an exploratory regression analysis considering potentially important treatment modifying covariates. These covariates included the proportion of patients with a previous stroke, proportion of males, mean age, the duration of study follow-up and the patients underlying risk of ischaemic stroke. None of the covariates explored impacted relative treatment effects relative to placebo. Notably, the exploration of 'study follow-up' as a covariate supported the assumption that difference in trial durations is unimportant in this indication despite the variation across trials in the network. This study is limited by the quantity of data available. Further investigation is warranted, and, as justifying further trials may be difficult, it would be desirable to obtain individual patient level data (IPD) to facilitate an effort to relate treatment effects to IPD covariates in order to investigate heterogeneity. Observational data could also be examined to establish if there are potential trends elsewhere. The approach and methods presented have potentially wide applications within any indication as to highlight the potential benefit of extending decision problems to include additional comparators outside of those of primary interest to allow for the exploration of heterogeneity.

Identifying individuals for primary cardiovascular disease prevention in UK general practice: priorities and resource implications

PubMed Central

Holt, Tim A; Thorogood, Margaret; Griffiths, Frances; Munday, Stephen; Stables, David

2008-01-01

Targeted cardiovascular disease prevention relies on risk-factor information held in primary care records. A risk algorithm, the ‘e-Nudge’, was applied to data from a population of ≥50-year-olds in 19 West Midlands practices, to identify those individuals at risk of cardiovascular disease. Altogether, 5.9% were identified aged 50–74 years at ≥20% 10-year risk based on existing data, and a further 26.4% were potentially at risk but had missing risk-factor information; 9.2% of patients aged over 50 years with established cardiovascular disease had at least one modifiable risk factor outside the audit target of the Quality and Outcomes Framework. Implications for resource allocation are discussed. PMID:18611316

Phage display and selection of lanthipeptides on the carboxy-terminus of the gene-3 minor coat protein.

PubMed

Urban, Johannes H; Moosmeier, Markus A; Aumüller, Tobias; Thein, Marcus; Bosma, Tjibbe; Rink, Rick; Groth, Katharina; Zulley, Moritz; Siegers, Katja; Tissot, Kathrin; Moll, Gert N; Prassler, Josef

2017-11-15

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are an emerging class of natural products with drug-like properties. To fully exploit the potential of RiPPs as peptide drug candidates, tools for their systematic engineering are required. Here we report the engineering of lanthipeptides, a subclass of RiPPs characterized by multiple thioether cycles that are enzymatically introduced in a regio- and stereospecific manner, by phage display. This was achieved by heterologous co-expression of linear lanthipeptide precursors fused to the widely neglected C-terminus of the bacteriophage M13 minor coat protein pIII, rather than the conventionally used N-terminus, along with the modifying enzymes from distantly related bacteria. We observe that C-terminal precursor peptide fusions to pIII are enzymatically modified in the cytoplasm of the producing cell and subsequently displayed as mature cyclic peptides on the phage surface. Biopanning of large C-terminal display libraries readily identifies artificial lanthipeptide ligands specific to urokinase plasminogen activator (uPA) and streptavidin.

A modified carrier-to-code leveling method for retrieving ionospheric observables and detecting short-term temporal variability of receiver differential code biases

NASA Astrophysics Data System (ADS)

Zhang, Baocheng; Teunissen, Peter J. G.; Yuan, Yunbin; Zhang, Xiao; Li, Min

2018-03-01

Sensing the ionosphere with the global positioning system involves two sequential tasks, namely the ionospheric observable retrieval and the ionospheric parameter estimation. A prominent source of error has long been identified as short-term variability in receiver differential code bias (rDCB). We modify the carrier-to-code leveling (CCL), a method commonly used to accomplish the first task, through assuming rDCB to be unlinked in time. Aside from the ionospheric observables, which are affected by, among others, the rDCB at one reference epoch, the Modified CCL (MCCL) can also provide the rDCB offsets with respect to the reference epoch as by-products. Two consequences arise. First, MCCL is capable of excluding the effects of time-varying rDCB from the ionospheric observables, which, in turn, improves the quality of ionospheric parameters of interest. Second, MCCL has significant potential as a means to detect between-epoch fluctuations experienced by rDCB of a single receiver.

Green dyeing process of modified cotton fibres using natural dyes extracted from Tamarix aphylla (L.) Karst. leaves.

PubMed

Baaka, Noureddine; Mahfoudhi, Adel; Haddar, Wafa; Mhenni, Mohamed Farouk; Mighri, Zine

2017-01-01

This research work involves an eco-friendly dyeing process of modified cotton with the aqueous extract of Tamarix aphylla leaves. During this process, the dyeing step was carried out on modified cotton by several cationising agents in order to improve its dyeability. The influence of the main dyeing conditions (dye bath pH, dyeing time, dyeing temperature, salt addition) on the performances of this dyeing process were studied. The dyeing performances of this process were appreciated by measuring the colour yield (K/S) and the fastness properties of the dyed samples. The effect of mordant type with different mordanting methods on dyeing quality was also studied. The results showed that mordanting gave deeper shades and enhanced fastness properties. In addition, environmental indicators (BOD 5 , COD and COD/BOD 5 ) were used to describe potential improvements in the biodegradability of the dyebath wastewater. Further, HPLC was used to identify the major phenolic compounds in the extracted dye.

Photouncaged Sequence-specific Interstrand DNA Cross-Linking with Photolabile 4-oxo-enal-modified Oligonucleotides

PubMed Central

Sun, Jingjing; Tang, Xinjing

2015-01-01

DNA cross-linking technology is an attractive tool for the detection, regulation, and manipulation of genes. In this study, a series of photolabile 4-oxo-enal-modified oligonucleotides functionalized with photosensitive ο-nitrobenzyl derivatives were rationally designed as a new kind of photocaged cross-linking agents. A comprehensive evaluation of cross-linking reactions for different nucleobases in complementary strands under different conditions suggested that the modified DNA oligonucleotides tended to form interstrand cross-linking to nucleobases with the potential of thymidine > guanosine » cytidine ~ adenosine. Different from previous literature reports that cytidine and adenosine were preferential cross-linked nucleobases with 4-oxo-enal moieties, our study represents the first example of DNA cross-linking for T and G selectivity using 4-oxo-enal moiety. The cross-linked adducts were identified and their cross-linking mechanism was also illustrated. This greatly expands the applications of 4-oxo-enal derivatives in the studies of DNA damage and RNA structure PMID:26020694

Photouncaged Sequence-specific Interstrand DNA Cross-Linking with Photolabile 4-oxo-enal-modified Oligonucleotides.

PubMed

Sun, Jingjing; Tang, Xinjing

2015-05-28

DNA cross-linking technology is an attractive tool for the detection, regulation, and manipulation of genes. In this study, a series of photolabile 4-oxo-enal-modified oligonucleotides functionalized with photosensitive ο-nitrobenzyl derivatives were rationally designed as a new kind of photocaged cross-linking agents. A comprehensive evaluation of cross-linking reactions for different nucleobases in complementary strands under different conditions suggested that the modified DNA oligonucleotides tended to form interstrand cross-linking to nucleobases with the potential of thymidine > guanosine » cytidine ~ adenosine. Different from previous literature reports that cytidine and adenosine were preferential cross-linked nucleobases with 4-oxo-enal moieties, our study represents the first example of DNA cross-linking for T and G selectivity using 4-oxo-enal moiety. The cross-linked adducts were identified and their cross-linking mechanism was also illustrated. This greatly expands the applications of 4-oxo-enal derivatives in the studies of DNA damage and RNA structure.

Discovery of a Novel Class of Survival Motor Neuron 2 Splicing Modifiers for the Treatment of Spinal Muscular Atrophy.

PubMed

Pinard, Emmanuel; Green, Luke; Reutlinger, Michael; Weetall, Marla; Naryshkin, Nikolai A; Baird, John; Chen, Karen S; Paushkin, Sergey V; Metzger, Friedrich; Ratni, Hasane

2017-05-25

Spinal muscular atrophy (SMA) is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene, resulting in low levels of functional SMN protein. We have reported recently the identification of small molecules (coumarins, iso-coumarins and pyrido-pyrimidinones) that modify the alternative splicing of SMN2, a paralogous gene to SMN1, restoring the survival motor neuron (SMN) protein level in mouse models of SMA. Herein, we report our efforts to identify a novel chemotype as one strategy to potentially circumvent safety concerns from earlier derivatives such as in vitro phototoxicity and in vitro mutagenicity associated with compounds 1 and 2 or the in vivo retinal findings observed in a long-term chronic tox study with 3 at high exposures only. Optimized representative compounds modify the alternative splicing of SMN2, increase the production of full length SMN2 mRNA, and therefore levels of full length SMN protein upon oral administration in two mouse models of SMA.

Determining the Number of Ischemic Strokes Potentially Eligible for Endovascular Thrombectomy: A Population-Based Study.

PubMed

Chia, Nicholas H; Leyden, James M; Newbury, Jonathan; Jannes, Jim; Kleinig, Timothy J

2016-05-01

Endovascular thrombectomy (ET) is standard-of-care for ischemic stroke patients with large vessel occlusion, but estimates of potentially eligible patients from population-based studies have not been published. Such data are urgently needed to rationally plan hyperacute services. Retrospective analysis determined the incidence of ET-eligible ischemic strokes in a comprehensive population-based stroke study (Adelaide, Australia 2009-2010). Stroke patients were stratified via a prespecified eligibility algorithm derived from recent ET trials comprising stroke subtype, pathogenesis, severity, premorbid modified Rankin Score, presentation delay, large vessel occlusion, and target mismatch penumbra. Recognizing centers may interpret recent ET trials either loosely or rigidly; 2 eligibility algorithms were applied: restrictive (key criteria modified Rankin Scale score 0-1, presentation delay <3.5 hours, and target mismatch penumbra) and permissive (modified Rankin Scale score 0-3 and presentation delay <5 hours). In a population of 148 027 people, 318 strokes occurred in the 1-year study period (crude attack rate 215 [192-240] per 100 000 person-years). The number of ischemic strokes eligible by restrictive criteria was 17/258 (7%; 95% confidence intervals 4%-10%) and by permissive criteria, an additional 16 were identified, total 33/258 (13%; 95% confidence intervals 9%-18%). Two of 17 patients (and 6/33 permissive patients) had thrombolysis contraindications. Using the restrictive algorithm, there were 11 (95% confidence intervals 4-18) potential ET cases per 100 000 person-years or 22 (95% confidence intervals 13-31) using the permissive algorithm. In this cohort, ≈7% of ischemic strokes were potentially eligible for ET (13% with permissive criteria). In similar populations, the permissive criteria predict that ≤22 strokes per 100 000 person-years may be eligible for ET. © 2016 American Heart Association, Inc.

A Mixed Methods Approach to Identify Cognitive Warning Signs for Suicide Attempts.

PubMed

Adler, Abby; Bush, Ashley; Barg, Frances K; Weissinger, Guy; Beck, Aaron T; Brown, Gregory K

2016-01-01

This study used a mixed methods approach to examine pathways to suicidal behavior by identifying cognitive warning signs that occurred within 1 day of a suicide attempt. Transcripts of cognitive therapy sessions from 35 patients who attempted suicide were analyzed using a modified grounded theory approach. Cognitive themes emerging from these transcripts included: state hopelessness, focus on escape, suicide as a solution, fixation on suicide, and aloneness. Differences in demographic and baseline diagnostic and symptom data were explored in relation to each cognitive theme. We propose a potential conceptual model of cognitive warning signs for suicide attempts that requires further testing.

Terahertz spectral unmixing based method for identifying gastric cancer

NASA Astrophysics Data System (ADS)

Cao, Yuqi; Huang, Pingjie; Li, Xian; Ge, Weiting; Hou, Dibo; Zhang, Guangxin

2018-02-01

At present, many researchers are exploring biological tissue inspection using terahertz time-domain spectroscopy (THz-TDS) techniques. In this study, based on a modified hard modeling factor analysis method, terahertz spectral unmixing was applied to investigate the relationships between the absorption spectra in THz-TDS and certain biomarkers of gastric cancer in order to systematically identify gastric cancer. A probability distribution and box plot were used to extract the distinctive peaks that indicate carcinogenesis, and the corresponding weight distributions were used to discriminate the tissue types. The results of this work indicate that terahertz techniques have the potential to detect different levels of cancer, including benign tumors and polyps.

Air cushion landing gear applications study

NASA Technical Reports Server (NTRS)

Earl, T. D.

1979-01-01

A series of air cushion landing gear (ACLG) applications was studied and potential benefits analyzed in order to identify the most attractive of these. The selected applications are new integrated designs (not retrofits) and employ a modified design approach with improved characteristics and performance. To aid the study, a survey of potential users was made. Applications were evaluated in the light of comments received. A technology scenario is developed, with discussion of problem areas, current technology level and future needs. Feasible development timetables are suggested. It is concluded that near-term development of small-size ACLG trunks, exploration of flight effects and braking are key items. The most attractive applications are amphibious with very large cargo aircraft and small general aviation having the greatest potential.

Platelet function is modified by common sequence variation in megakaryocyte super enhancers

PubMed Central

Petersen, Romina; Lambourne, John J.; Javierre, Biola M.; Grassi, Luigi; Kreuzhuber, Roman; Ruklisa, Dace; Rosa, Isabel M.; Tomé, Ana R.; Elding, Heather; van Geffen, Johanna P.; Jiang, Tao; Farrow, Samantha; Cairns, Jonathan; Al-Subaie, Abeer M.; Ashford, Sofie; Attwood, Antony; Batista, Joana; Bouman, Heleen; Burden, Frances; Choudry, Fizzah A.; Clarke, Laura; Flicek, Paul; Garner, Stephen F.; Haimel, Matthias; Kempster, Carly; Ladopoulos, Vasileios; Lenaerts, An-Sofie; Materek, Paulina M.; McKinney, Harriet; Meacham, Stuart; Mead, Daniel; Nagy, Magdolna; Penkett, Christopher J.; Rendon, Augusto; Seyres, Denis; Sun, Benjamin; Tuna, Salih; van der Weide, Marie-Elise; Wingett, Steven W.; Martens, Joost H.; Stegle, Oliver; Richardson, Sylvia; Vallier, Ludovic; Roberts, David J.; Freson, Kathleen; Wernisch, Lorenz; Stunnenberg, Hendrik G.; Danesh, John; Fraser, Peter; Soranzo, Nicole; Butterworth, Adam S.; Heemskerk, Johan W.; Turro, Ernest; Spivakov, Mikhail; Ouwehand, Willem H.; Astle, William J.; Downes, Kate; Kostadima, Myrto; Frontini, Mattia

2017-01-01

Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions. PMID:28703137

[The hospital as space and as territory].

PubMed

Stiefel, Friedrich; Marion-Veyron, Régis; Englebert, Jérôme

2018-02-07

Space is lived individually and collectively and can become a source of existential affectation, especially when the lived experience is modified by disease. The fact that the hospital is also a place of territorialisation can potentiate this affectation, with at times surprising consequences. We aim - based on a reflection about the relationship patients and clinicians establish with the territory of the hospital- to identify some psychological and existential issues at stake with regard to space as a social construction.

Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-14-1-0503 TITLE: “Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes PRINCIPAL INVESTIGATOR: Bettina F...and Obesity on Disparities in Prostate Cancer Outcomes 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0503 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...death by identifying potential modifiable factors. 15. SUBJECT TERMS Prostate cancer, disparities, VHA and VACCR data, obesity , mortality, survival

Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-14-1-0503 TITLE: Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes PRINCIPAL INVESTIGATOR: Bettina F...Effect of Diabetes and Obesity on Disparities in Prostate Cancer Outcomes 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0503 5c. PROGRAM ELEMENT...prostate cancer related death by identifying potential modifiable factors. 15. SUBJECT TERMS Prostate cancer, disparities, VHA and VACCR data, obesity

Genetic advances in sarcomeric cardiomyopathies: state of the art.

PubMed

Ho, Carolyn Y; Charron, Philippe; Richard, Pascale; Girolami, Francesca; Van Spaendonck-Zwarts, Karin Y; Pinto, Yigal

2015-04-01

Genetic studies in the 1980s and 1990s led to landmark discoveries that sarcomere mutations cause both hypertrophic and dilated cardiomyopathies. Sarcomere mutations also likely play a role in more complex phenotypes and overlap cardiomyopathies with features of hypertrophy, dilation, diastolic abnormalities, and non-compaction. Identification of the genetic cause of these important conditions provides unique opportunities to interrogate and characterize disease pathogenesis and pathophysiology, starting from the molecular level and expanding from there. With such insights, there is potential for clinical translation that may transform management of patients and families with inherited cardiomyopathies. If key pathways for disease development can be identified, they could potentially serve as targets for novel disease-modifying or disease-preventing therapies. By utilizing gene-based diagnostic testing, we can identify at-risk individuals prior to the onset of clinical disease, allowing for disease-modifying therapy to be initiated early in life, at a time that such treatment may be most successful. In this section, we review the current application of genetics in clinical management, focusing on hypertrophic cardiomyopathy as a paradigm; discuss state-of-the-art genetic testing technology; review emerging knowledge of gene expression in sarcomeric cardiomyopathies; and discuss both the prospects, as well as the challenges, of bringing genetics to medicine. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

In vitro mesenchymal stem cell response to a CO2 laser modified polymeric material.

PubMed

Waugh, D G; Hussain, I; Lawrence, J; Smith, G C; Cosgrove, D; Toccaceli, C

2016-10-01

With an ageing world population it is becoming significantly apparent that there is a need to produce implants and platforms to manipulate stem cell growth on a pharmaceutical scale. This is needed to meet the socio-economic demands of many countries worldwide. This paper details one of the first ever studies in to the manipulation of stem cell growth on CO2 laser surface treated nylon 6,6 highlighting its potential as an inexpensive platform to manipulate stem cell growth on a pharmaceutical scale. Through CO2 laser surface treatment discrete changes to the surfaces were made. That is, the surface roughness of the nylon 6,6 was increased by up to 4.3μm, the contact angle was modulated by up to 5° and the surface oxygen content increased by up to 1atom %. Following mesenchymal stem cell growth on the laser treated samples, it was identified that CO2 laser surface treatment gave rise to an enhanced response with an increase in viable cell count of up to 60,000cells/ml when compared to the as-received sample. The effect of surface parameters modified by the CO2 laser surface treatment on the mesenchymal stem cell response is also discussed along with potential trends that could be identified to govern the mesenchymal stem cell response. Copyright © 2016. Published by Elsevier B.V.

The use of CD47-modified biomaterials to mitigate the immune response

PubMed Central

Tengood, Jillian E; Levy, Robert J

2016-01-01

Addressing the aberrant interactions between immune cells and biomaterials represents an unmet need in biomaterial research. Although progress has been made in the development of bioinert coatings, identifying and targeting relevant cellular and molecular pathways can provide additional therapeutic strategies to address this major healthcare concern. To that end, we describe the immune inhibitory motif, receptor–ligand pairing of signal regulatory protein alpha and its cognate ligand CD47 as a potential signaling pathway to enhance biocompatibility. The goals of this article are to detail the known roles of CD47–signal regulatory protein alpha signal transduction pathway and to describe how immobilized CD47 can be used to mitigate the immune response to biomaterials. Current applications of CD47-modified biomaterials will also be discussed herein. PMID:27190273

Detecting Chemically Modified DNA Bases Using Surface Enhanced Raman Spectroscopy

PubMed Central

Barhoumi, Aoune; Halas, Naomi J.

2013-01-01

Post-translational modifications of DNA- changes in the chemical structure of individual bases that occur without changes in the DNA sequence- are known to alter gene expression. They are believed to result in frequently deleterious phenotypic changes, such as cancer. Methylation of adenine, methylation and hydroxymethylation of cytosine, and guanine oxidation are the primary DNA base modifications identified to date. Here we show it is possible to use surface enhanced Raman spectroscopy (SERS) to detect these primary DNA base modifications. SERS detection of modified DNA bases is label-free and requires minimal additional sample preparation, reducing the possibility of additional chemical modifications induced prior to measurement. This approach shows the feasibility of DNA base modification assessment as a potentially routine analysis that may be further developed for clinical diagnostics. PMID:24427449

Detecting Chemically Modified DNA Bases Using Surface Enhanced Raman Spectroscopy.

PubMed

Barhoumi, Aoune; Halas, Naomi J

2011-12-15

Post-translational modifications of DNA- changes in the chemical structure of individual bases that occur without changes in the DNA sequence- are known to alter gene expression. They are believed to result in frequently deleterious phenotypic changes, such as cancer. Methylation of adenine, methylation and hydroxymethylation of cytosine, and guanine oxidation are the primary DNA base modifications identified to date. Here we show it is possible to use surface enhanced Raman spectroscopy (SERS) to detect these primary DNA base modifications. SERS detection of modified DNA bases is label-free and requires minimal additional sample preparation, reducing the possibility of additional chemical modifications induced prior to measurement. This approach shows the feasibility of DNA base modification assessment as a potentially routine analysis that may be further developed for clinical diagnostics.

CLC-2 single nucleotide polymorphisms (SNPs) as potential modifiers of cystic fibrosis disease severity

PubMed Central

Blaisdell, Carol J; Howard, Timothy D; Stern, Augustus; Bamford, Penelope; Bleecker, Eugene R; Stine, O Colin

2004-01-01

Background Cystic fibrosis (CF) lung disease manifest by impaired chloride secretion leads to eventual respiratory failure. Candidate genes that may modify CF lung disease severity include alternative chloride channels. The objectives of this study are to identify single nucleotide polymorphisms (SNPs) in the airway epithelial chloride channel, CLC-2, and correlate these polymorphisms with CF lung disease. Methods The CLC-2 promoter, intron 1 and exon 20 were examined for SNPs in adult CF dF508/dF508 homozygotes with mild and severe lung disease (forced expiratory volume at one second (FEV1) > 70% and < 40%). Results PCR amplification of genomic CLC-2 and sequence analysis revealed 1 polymorphism in the hClC -2 promoter, 4 in intron 1, and none in exon 20. Fisher's analysis within this data set, did not demonstrate a significant relationship between the severity of lung disease and SNPs in the CLC-2 gene. Conclusions CLC-2 is not a key modifier gene of CF lung phenotype. Further studies evaluating other phenotypes associated with CF may be useful in the future to assess the ability of CLC-2 to modify CF disease severity. PMID:15507145

Electrochemical sensor for multiplex screening of genetically modified DNA: identification of biotech crops by logic-based biomolecular analysis.

PubMed

Liao, Wei-Ching; Chuang, Min-Chieh; Ho, Ja-An Annie

2013-12-15

Genetically modified (GM) technique, one of the modern biomolecular engineering technologies, has been deemed as profitable strategy to fight against global starvation. Yet rapid and reliable analytical method is deficient to evaluate the quality and potential risk of such resulting GM products. We herein present a biomolecular analytical system constructed with distinct biochemical activities to expedite the computational detection of genetically modified organisms (GMOs). The computational mechanism provides an alternative to the complex procedures commonly involved in the screening of GMOs. Given that the bioanalytical system is capable of processing promoter, coding and species genes, affirmative interpretations succeed to identify specified GM event in terms of both electrochemical and optical fashions. The biomolecular computational assay exhibits detection capability of genetically modified DNA below sub-nanomolar level and is found interference-free by abundant coexistence of non-GM DNA. This bioanalytical system, furthermore, sophisticates in array fashion operating multiplex screening against variable GM events. Such a biomolecular computational assay and biosensor holds great promise for rapid, cost-effective, and high-fidelity screening of GMO. Copyright © 2013 Elsevier B.V. All rights reserved.

An IR-Based Approach Utilizing Query Expansion for Plagiarism Detection in MEDLINE.

PubMed

Nawab, Rao Muhammad Adeel; Stevenson, Mark; Clough, Paul

2017-01-01

The identification of duplicated and plagiarized passages of text has become an increasingly active area of research. In this paper, we investigate methods for plagiarism detection that aim to identify potential sources of plagiarism from MEDLINE, particularly when the original text has been modified through the replacement of words or phrases. A scalable approach based on Information Retrieval is used to perform candidate document selection-the identification of a subset of potential source documents given a suspicious text-from MEDLINE. Query expansion is performed using the ULMS Metathesaurus to deal with situations in which original documents are obfuscated. Various approaches to Word Sense Disambiguation are investigated to deal with cases where there are multiple Concept Unique Identifiers (CUIs) for a given term. Results using the proposed IR-based approach outperform a state-of-the-art baseline based on Kullback-Leibler Distance.

Extracellular Vesicles: How the External and Internal Environment Can Shape Cell-To-Cell Communication.

PubMed

Neven, Kristof Y; Nawrot, Tim S; Bollati, Valentina

2017-03-01

To summarize the scientific evidence regarding the effects of environmental exposures on extracellular vesicle (EV) release and their contents. As environmental exposures might influence the aging phenotype in a very strict way, we will also report the role of EVs in the biological aging process. EV research is a new and quickly developing field. With many investigations conducted so far, only a limited number of studies have explored the potential role EVs play in the response and adaptation to environmental stimuli. The investigations available to date have identified several exposures or lifestyle factors able to modify EV trafficking including air pollutants, cigarette smoke, alcohol, obesity, nutrition, physical exercise, and oxidative stress. EVs are a very promising tool, as biological fluids are easily obtainable biological media that, if successful in identifying early alterations induced by the environment and predictive of disease, would be amenable to use for potential future preventive and diagnostic applications.

Detection of Genetically Modified Sugarcane by Using Terahertz Spectroscopy and Chemometrics

NASA Astrophysics Data System (ADS)

Liu, J.; Xie, H.; Zha, B.; Ding, W.; Luo, J.; Hu, C.

2018-03-01

A methodology is proposed to identify genetically modified sugarcane from non-genetically modified sugarcane by using terahertz spectroscopy and chemometrics techniques, including linear discriminant analysis (LDA), support vector machine-discriminant analysis (SVM-DA), and partial least squares-discriminant analysis (PLS-DA). The classification rate of the above mentioned methods is compared, and different types of preprocessing are considered. According to the experimental results, the best option is PLS-DA, with an identification rate of 98%. The results indicated that THz spectroscopy and chemometrics techniques are a powerful tool to identify genetically modified and non-genetically modified sugarcane.

External validation of the Probability of repeated admission (Pra) risk prediction tool in older community-dwelling people attending general practice: a prospective cohort study.

PubMed

Wallace, Emma; McDowell, Ronald; Bennett, Kathleen; Fahey, Tom; Smith, Susan M

2016-11-14

Emergency admission is associated with the potential for adverse events in older people and risk prediction models are available to identify those at highest risk of admission. The aim of this study was to externally validate and compare the performance of the Probability of repeated admission (Pra) risk model and a modified version (incorporating a multimorbidity measure) in predicting emergency admission in older community-dwelling people. 15 general practices (GPs) in the Republic of Ireland. n=862, ≥70 years, community-dwelling people prospectively followed up for 2 years (2010-2012). Pra risk model (original and modified) calculated for baseline year where ≥0.5 denoted high risk (patient questionnaire, GP medical record review) of future emergency admission. Emergency admission over 1 year (GP medical record review). descriptive statistics, model discrimination (c-statistic) and calibration (Hosmer-Lemeshow statistic). Of 862 patients, a total of 154 (18%) had ≥1 emergency admission(s) in the follow-up year. 63 patients (7%) were classified as high risk by the original Pra and of these 26 (41%) were admitted. The modified Pra classified 391 (45%) patients as high risk and 103 (26%) were subsequently admitted. Both models demonstrated only poor discrimination (original Pra: c-statistic 0.65 (95% CI 0.61 to 0.70); modified Pra: c-statistic 0.67 (95% CI 0.62 to 0.72)). When categorised according to risk-category model, specificity was highest for the original Pra at cut-point of ≥0.5 denoting high risk (95%), and for the modified Pra at cut-point of ≥0.7 (95%). Both models overestimated the number of admissions across all risk strata. While the original Pra model demonstrated poor discrimination, model specificity was high and a small number of patients identified as high risk. Future validation studies should examine higher cut-points denoting high risk for the modified Pra, which has practical advantages in terms of application in GP. The original Pra tool may have a role in identifying higher-risk community-dwelling older people for inclusion in future trials aiming to reduce emergency admissions. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

A risk-based classification scheme for genetically modified foods. III: Evaluation using a panel of reference foods.

PubMed

Chao, Eunice; Krewski, Daniel

2008-12-01

This paper presents an exploratory evaluation of four functional components of a proposed risk-based classification scheme (RBCS) for crop-derived genetically modified (GM) foods in a concordance study. Two independent raters assigned concern levels to 20 reference GM foods using a rating form based on the proposed RBCS. The four components of evaluation were: (1) degree of concordance, (2) distribution across concern levels, (3) discriminating ability of the scheme, and (4) ease of use. At least one of the 20 reference foods was assigned to each of the possible concern levels, demonstrating the ability of the scheme to identify GM foods of different concern with respect to potential health risk. There was reasonably good concordance between the two raters for the three separate parts of the RBCS. The raters agreed that the criteria in the scheme were sufficiently clear in discriminating reference foods into different concern levels, and that with some experience, the scheme was reasonably easy to use. Specific issues and suggestions for improvements identified in the concordance study are discussed.

Classification of 'healthier' and 'less healthy' supermarket foods by two Australasian nutrient profiling models.

PubMed

Eyles, Helen; Gorton, Delvina; Ni Mhurchu, Cliona

2010-09-10

To determine whether a modified version of the Heart Foundation Tick (MHFT) nutrient profiling model appropriately classifies supermarket foods to endorse its use for identifying 'healthier' products eligible for promotion in a supermarket intervention trial. Top-selling products (n=550) were selected from an existing supermarket nutrient composition database. Percentage of products classified as 'healthier' by the MHFT and a modified comparator model (Food Standards Australia New Zealand; MFSANZ) were calculated. Percentage agreement, consistency (kappa statistic), and average nutrient values were assessed overall, and across seven food groups. The MHFT model categorised 16% fewer products as 'healthier' than the MFSANZ model. Agreement and consistency between models were 72% and kappa=0.46 (P=0.00), respectively. For both models, 'healthier' products were on average lower in energy, protein, saturated fat, sugar, and sodium than their 'less healthy' counterparts. The MHFT nutrient profiling model categorised regularly purchased supermarket foods similarly to the MFSANZ model, and both appear to distinguish appropriately between 'healthier' and 'less healthy' options. Therefore, both models have the potential to appropriately identify 'healthier' foods for promotion and positively influence food choices.

Scavenger Receptors: Emerging Roles in Cancer Biology and Immunology

PubMed Central

Yu, Xiaofei; Guo, Chunqing; Fisher, Paul B.; Subjeck, John R.; Wang, Xiang-Yang

2015-01-01

Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted. PMID:26216637

Differentiating Positional Isomers of Nucleoside Modifications by Higher-Energy Collisional Dissociation Mass Spectrometry (HCD MS)

NASA Astrophysics Data System (ADS)

Jora, Manasses; Burns, Andrew P.; Ross, Robert L.; Lobue, Peter A.; Zhao, Ruoxia; Palumbo, Cody M.; Beal, Peter A.; Addepalli, Balasubrahmanyam; Limbach, Patrick A.

2018-06-01

The analytical identification of positional isomers (e.g., 3-, N 4-, 5-methylcytidine) within the > 160 different post-transcriptional modifications found in RNA can be challenging. Conventional liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) approaches rely on chromatographic separation for accurate identification because the collision-induced dissociation (CID) mass spectra of these isomers nearly exclusively yield identical nucleobase ions (BH2 +) from the same molecular ion (MH+). Here, we have explored higher-energy collisional dissociation (HCD) as an alternative fragmentation technique to generate more informative product ions that can be used to differentiate positional isomers. LC-MS/MS of modified nucleosides characterized using HCD led to the creation of structure- and HCD energy-specific fragmentation patterns that generated unique fingerprints, which can be used to identify individual positional isomers even when they cannot be separated chromatographically. While particularly useful for identifying positional isomers, the fingerprinting capabilities enabled by HCD also offer the potential to generate HPLC-independent spectral libraries for the rapid analysis of modified ribonucleosides. [Figure not available: see fulltext.

Methanol electro-oxidation on platinum modified tungsten carbides in direct methanol fuel cells: a DFT study.

PubMed

Sheng, Tian; Lin, Xiao; Chen, Zhao-Yang; Hu, P; Sun, Shi-Gang; Chu, You-Qun; Ma, Chun-An; Lin, Wen-Feng

2015-10-14

In exploration of low-cost electrocatalysts for direct methanol fuel cells (DMFCs), Pt modified tungsten carbide (WC) materials are found to be great potential candidates for decreasing Pt usage whilst exhibiting satisfactory reactivity. In this work, the mechanisms, onset potentials and activity for electrooxidation of methanol were studied on a series of Pt-modified WC catalysts where the bare W-terminated WC(0001) substrate was employed. In the surface energy calculations of a series of Pt-modified WC models, we found that the feasible structures are mono- and bi-layer Pt-modified WCs. The tri-layer Pt-modified WC model is not thermodynamically stable where the top layer Pt atoms tend to accumulate and form particles or clusters rather than being dispersed as a layer. We further calculated the mechanisms of methanol oxidation on the feasible models via methanol dehydrogenation to CO involving C-H and O-H bonds dissociating subsequently, and further CO oxidation with the C-O bond association. The onset potentials for the oxidation reactions over the Pt-modified WC catalysts were determined thermodynamically by water dissociation to surface OH* species. The activities of these Pt-modified WC catalysts were estimated from the calculated kinetic data. It has been found that the bi-layer Pt-modified WC catalysts may provide a good reactivity and an onset oxidation potential comparable to pure Pt and serve as promising electrocatalysts for DMFCs with a significant decrease in Pt usage.

Accuracy and Acceptability of a Screening Tool for Identifying Intimate Partner Violence Perpetration among Women Veterans: A Pre-Implementation Evaluation.

PubMed

Portnoy, Galina A; Haskell, Sally G; King, Matthew W; Maskin, Rachel; Gerber, Megan R; Iverson, Katherine M

2018-06-06

Veterans are at heightened risk for perpetrating intimate partner violence (IPV), yet there is limited evidence to inform practice and policy for the detection of IPV perpetration. The present study evaluated the accuracy and acceptability of a potential IPV perpetration screening tool for use with women veterans. A national sample of women veterans completed a 2016 web-based survey that included a modified 5-item Extended-Hurt/Insult/Threaten/Scream (Modified E-HITS) and the Revised Conflict Tactics Scales (CTS-2). Items also assessed women's perceptions of the acceptability and appropriateness of the modified E-HITS questions for use in healthcare settings. Accuracy statistics, including sensitivity and specificity, were calculated using the CTS-2 as the reference standard. Primary measures included the Modified E-HITS (index test), CTS-2 (reference standard), and items assessing acceptability. This study included 187 women, of whom 31 women veterans (16.6%) reported past-6-month IPV perpetration on the CTS-2. The Modified E-HITS demonstrated good overall accuracy (area under the curve, 0.86; 95% confidence interval, 0.78-0.94). In addition, the majority of women perceived the questions to be acceptable and appropriate. Findings demonstrate that the Modified E-HITS is promising as a low-burden tool for detecting of IPV perpetration among women veterans. This tool may help the Veterans Health Administration and other health care providers detect IPV perpetration and offer appropriate referrals for comprehensive assessment and services. Published by Elsevier Inc.

Equity-focused health impact assessment: A tool to assist policy makers in addressing health inequalities

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

Simpson, Sarah; Mahoney, Mary; Harris, Elizabeth

2005-10-15

In Australasia (Australia and New Zealand) the use of health impact assessment (HIA) as a tool for improved policy development is comparatively new. The public health workforce do not routinely assess the potential health and equity impacts of proposed policies or programs. The Australasian Collaboration for Health Equity Impact Assessment was funded to develop a strategic framework for equity-focused HIA (EFHIA) with the intent of strengthening the ways in which equity is addressed in each step of HIA. The collaboration developed a draft framework for EFHIA that mirrored, but modified the commonly accepted steps of HIA; tested the draft frameworkmore » in six different health service delivery settings; analysed the feedback about application of the draft EFHIA framework and modified it accordingly. The strategic framework shows promise in providing a systematic process for identifying potential differential health impacts and assessing the extent to which these are avoidable and unfair. This paper presents the EFHIA framework and discusses some of the issues that arose in the case study sites undertaking equity-focused HIA.« less

Electrocatalytic oxidation of 2-mercaptoethanol using modified glassy carbon electrode by MWCNT in combination with unsymmetrical manganese (II) Schiff base complexes

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

Mohebbi, Sajjad, E-mail: smohebbi@uok.ac.ir; Eslami, Saadat

2015-06-15

Highlights: • High electocatalytic efficiency and stability of modified hybrid electrode GC/MWCNTs/MnSaloph. • Direct reflection of catalytic activity of manganese complexes on electrocatalytic oxidation of 2-ME. • Decreasing overpotential and increasing catalytic peak current toward oxidation of 2-ME. • Deposition of range of novel substituted N{sub 2}O{sub 2} Saloph complexes of manganese(II) on GCE/MWCNT. • Enhancement of electrocatalytic oxidation activity upon electron donating substitutions on the Saloph. - Abstract: The performance of modified hybrid glassy carbon electrode with composite of carbon nanotubes and manganese complexes for the electrocatalytic oxidation of 2-mercaptoethanol is developed. GC electrode was modified using MWCNT andmore » new N{sub 2}O{sub 2} unsymmetrical tetradentate Schiff base complexes of manganese namely Manganese Saloph complexes 1-5, with general formula Mn[(5-x-4-y-Sal)(5-x′-4-y′-Sal) Ph], where x, x′ = H, Br, NO{sub 2} and y, y′ = H, MeO. Direct immobilization of CNT on the surface of GCE is performed by abrasive immobilization, and then modified by manganese(II) complexes via direct deposition method. These novel modified electrodes clearly demonstrate the necessity of modifying bare carbon electrodes to endow them with the desired behavior and were identified by HRTEM. Also complexes were characterized by elemental analyses, MS, UV–vis and IR spectroscopy. Modified hybrid GC/MWCNT/MnSaloph electrode exhibits strong and stable electrocatalytic activity towards the electrooxidation of 2-mercaptoethanol molecules in comparison with bare glassy carbon electrode with advantages of very low over potential and high catalytic current. Such ability promotes the thiol’s electron transfer reaction. Also, electron withdrawing substituent on the Saloph was enhanced electrocatalytic oxidation activity.« less

Assessing Landslide Mobility Using GIS: Application to Kosrae, Micronesia

NASA Astrophysics Data System (ADS)

Reid, M. E.; Brien, D. L.; Godt, J.; Schmitt, R. G.; Harp, E. L.

2015-12-01

Deadly landslides are often mobile landslides, as exemplified by the disastrous landslide that occurred near Oso, Washington in 2014 killing 43. Despite this association, many landslide susceptibility maps do not identify runout areas. We developed a simple, GIS-based method for identifying areas potentially overrun by mobile slides and debris flows. Our method links three processes within a DEM landscape: landslide initiation, transport, and debris-flow inundation (from very mobile slides). Given spatially distributed shear strengths, we first identify initiation areas using an infinite-slope stability analysis. We then delineate transport zones, or regions of potential entrainment and/or deposition, using a height/length runout envelope. Finally, where these transport zones intersect the channel network, we start debris-flow inundation zones. The extent of inundation is computed using the USGS model Laharz, modified to include many debris-flow locations throughout a DEM. Potential debris-flow volumes are computed from upslope initiation areas and typical slide thicknesses. We applied this approach to the main island of Kosrae State, Federated States of Micronesia (FSM). In 2002, typhoon Chata'an triggered numerous landslides on the neighboring islands of Chuuk State, FSM, resulting in 43 fatalities. Using an infinite-slope stability model calibrated to the Chuuk event, we identified potential landslide initiation areas on Kosrae. We then delineated potential transport zones using a 20º runout envelope, based on runout observations from Chuuk. Potential debris-flow inundation zones were then determined using Laharz. Field inspections on Kosrae revealed that our resulting susceptibility map correctly classified areas covered by previous debris-flow deposits and did not include areas covered by fluvial deposits. Our map has the advantage of providing a visual tool to portray initiation, transport, and runout zones from mobile landslides.

The toxicity of cationic surfactant HDTMA-Br, desorbed from surfactant modified zeolite, towards faecal indicator and environmental microorganisms.

PubMed

Reeve, Peter J; Fallowfield, Howard J

2017-10-05

Surfactant Modified Zeolite (SMZ) represents a versatile, cost-effective permeable reactive material, capable of treating multiple classes of contaminants. The potential for HDTMA-Br, a cationic surfactant commonly used to modify zeolite, to desorb from the zeolite surface has been identified as a potential issue for the ongoing use of SMZ in water remediation contexts. This paper investigates the toxicity of HDTMA-Br towards enteric virus surrogates, F-RNA bacteriophage MS2 and E. coli, Bacillus subtilis, and soil microflora. The concentration of surfactant desorbing from SMZ was quantified through a bioassay using E. coli. Results showed HDTMA-Br concentrations of ≥10 -5 M were toxic to MS2, ≥10 -4 M were toxic to E. coli and ≥10 -6 M were toxic to B. subtilis. No toxic relationship was established between HDTMA-Br and soil microflora. Desorption of ≥10 -4 M of HDTMA-Br was shown for the two SMZ samples under the mixing conditions used. Effects of this surfactant on total soil microflora were ambiguous since no toxic relationship could be established, however, HDTMA-Br, at concentrations desorbing from SMZ, were shown to impact the soil bacterium B. subtilis. Further research is required to determine the effect of this surfactant on microbial populations and species diversity in soils. Copyright © 2017 Elsevier B.V. All rights reserved.

Improvement on the Repair Effect of Electrochemical Chloride Extraction Using a Modified Electrode Configuration

PubMed Central

Feng, Wei; Xu, Jinxia; Jiang, Linhua; Song, Yingbin; Cao, Yalong; Tan, Qiping

2018-01-01

To improve the repair effect of electrochemical chloride extraction, a modified electrode configuration is applied in this investigation. In this configuration, two auxiliary electrodes placed in the anodic and cathodic electrolytes were used as the anode and cathode, respectively. Besides this, the steel in the mortar was grounded to protect it from corrosion. By a comparative experiment, the potential evolution, various ions concentrations (Cl−, OH−, Na+, and K+) in different mortar depths, the corrosion potential, and the current density of the steel were measured. The results indicate that compared to electrochemical chloride extraction with the traditional electrode configuration, this electrochemical chloride extraction method with a modified electrode configuration has a similar chloride removal ratio. Besides this, potential of steel is just about 800 mV for a saturated calomel electrode (SCE) during the treatment, which did not reach the hydrogen evolution potential. The phenomenon of the accumulation of OH−, Na+, and K+ did not occur when the modified electrode configuration is applied. Additionally, higher corrosion potentials and lower corrosion current rates were measured after performing electrochemical chloride extraction with the modified electrode configuration. Additionally, it is a short period of time for the steel to go from activation to passivation. On this basis, the modified electrode configuration may overcome the drawbacks of electrochemical chloride extraction. PMID:29389855

Identifying Older Adults at Risk of Delirium Following Elective Surgery: A Systematic Review and Meta-Analysis.

PubMed

Watt, Jennifer; Tricco, Andrea C; Talbot-Hamon, Catherine; Pham, Ba'; Rios, Patricia; Grudniewicz, Agnes; Wong, Camilla; Sinclair, Douglas; Straus, Sharon E

2018-04-01

Postoperative delirium is a common preventable complication experienced by older adults undergoing elective surgery. In this systematic review and meta-analysis, we identified prognostic factors associated with the risk of postoperative delirium among older adults undergoing elective surgery. Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, and AgeLine were searched for articles published between inception and April 21, 2016. A total of 5692 titles and abstracts were screened in duplicate for possible inclusion. Studies using any method for diagnosing delirium were eligible. Two reviewers independently completed all data extraction and quality assessments using the Cochrane Risk-of-Bias Tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale (NOS) for cohort studies. Random effects meta-analysis models were used to derive pooled effect estimates. Forty-one studies (9384 patients) reported delirium-related prognostic factors. Among our included studies, the pooled incidence of postoperative delirium was 18.4% (95% confidence interval [CI] 14.3-23.3%, number needed to follow [NNF] = 6). Geriatric syndromes were important predictors of delirium, namely history of delirium (odds ratio [OR] 6.4, 95% CI 2.2-17.9), frailty (OR 4.1, 95% CI 1.4-11.7), cognitive impairment (OR 2.7, 95% CI 1.9-3.8), impairment in activities of daily living (ADLs; OR 2.1, 95% CI 1.6-2.6), and impairment in instrumental activities of daily living (IADLs; OR 1.9, 95% CI 1.3-2.8). Potentially modifiable prognostic factors such as psychotropic medication use (OR 2.3, 95% CI 1.4-3.6) and smoking status (OR 1.8 95% CI 1.3-2.4) were also identified. Caregiver support was associated with lower odds of postoperative delirium (OR 0.69, 95% CI 0.52-0.91). Though caution must be used in interpreting meta-analyses of non-randomized studies due to the potential influence of unmeasured confounding, we identified potentially modifiable prognostic factors including frailty and psychotropic medication use that should be targeted to optimize care.

Comparison of transport pathways and potential sources of PM10 in two cities around a large Chinese lake using the modified trajectory analysis

NASA Astrophysics Data System (ADS)

Kong, Xiangzhen; He, Wei; Qin, Ning; He, Qishuang; Yang, Bin; Ouyang, Huiling; Wang, Qingmei; Xu, Fuliu

2013-03-01

Trajectory cluster analysis, including the two-stage cluster method based on Euclidean metrics and the one-stage clustering method based on Mahalanobis metrics and self-organizing maps (SOM), was applied and compared to identify the transport pathways of PM10 for the cities of Chaohu and Hefei, both located near Lake Chaohu in China. The two-stage cluster method was modified to further investigate the long trajectories in the second stage in order to eliminate the observed disaggregation among them. Twelve trajectory clusters were identified for both cities. The one-stage clustering method based on Mahalanobis metrics gives the best performance regarding the variances within clusters. The results showed that local PM10 emission was one of the most important sources in both cities and that the local emission in Hefei was higher than in Chaohu. In addition, Chaohu suffered greater effects from the eastern region (Yangtze River Delta, YRD) than Hefei. On the other hand, the long-range transportation from the northwestern pathway had a higher influence on the PM10 level in Hefei. Receptor models, including potential source contribution function (PSCF) and residence time weighted concentrations (RTWC), were utilized to identify the potential source locations of PM10 for both cities. However, the combined PSCF and RTWC results for the two cities provided PM10 source locations that were more consistent with the results of transport pathways and the total anthropogenic PM10 emission inventory. This indicates that the combined method's ability to identify the source regions is superior to that of the individual PSCF or RTWC methods. Henan and Shanxi Provinces and the YRD were important PM10 source regions for the two cities, but the Henan and Shanxi area was more important for Hefei than for Chaohu, while the YRD region was less important. In addition, the PSCF, RTWC and the combined results all had higher correlation coefficients with PM10 emission from traffic than from industry, electricity generation or residential sources, suggesting the relatively higher contribution of traffic emissions to the PM10 pollution in Lake Chaohu.

Application of the STROBE statement to the hypospadias literature: Report of the international pediatric urology task force on hypospadias.

PubMed

Braga, Luis H; Lorenzo, Armando J; Bagli, Darius J; Pippi Salle, Joao L; Caldamone, Anthony

2016-12-01

Observational studies, particularly case series, represent the majority of the current hypospadias research. As a result, this literature lacks standardization of surgical techniques, uniform definitions of hypospadias complications, and consistency of outcome reporting, which may make it difficult to compare results across studies. A modified version of the STROBE statement, containing 20 items, was presented at the International Pediatric Urology Task Force on Hypospadias meeting to assist with clear and transparent reporting of hypospadias studies. The adoption and implementation of this modified tool will allow investigators and health care providers to critically evaluate quality and identify bias within the literature. In addition this instrument will ensure consistency of reporting, improving objective comparisons between studies, unification of results, and development of evidence-based clinical guidelines. In this article, we have applied the modified STROBE statement to the hypospadias literature, aiming to create a guide on study reporting for pediatric urologists, and ultimately improve the quality of research in our field. We present itemized recommendations for adequate reporting of hypospadias studies and case series, ranging from drafting the abstract to addressing biases and potential sources of confounding. Included with each item is a brief explanation of its importance and potential effect on the study, as well as pertinent examples of hypospadias articles. A modified STROBE summary table containing 20 items is presented in (Supplementary Table 1). If properly conducted and reported, hypospadias studies have the potential to provide useful information to clinicians and surgeons. However, authors should recognize the inherent limitations of these observational studies, especially in the form of bias, which may introduce invalid data or limit generalizability. Thus, we expect that the use of this guiding tool will not only improve transparency of hypospadias reporting, but also improve its methodological quality, allowing proper comparison and interpretation of data across different institutions. Copyright © 2016 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Potentially modifiable factors contributing to sepsis-associated encephalopathy.

PubMed

Sonneville, Romain; de Montmollin, Etienne; Poujade, Julien; Garrouste-Orgeas, Maïté; Souweine, Bertrand; Darmon, Michael; Mariotte, Eric; Argaud, Laurent; Barbier, François; Goldgran-Toledano, Dany; Marcotte, Guillaume; Dumenil, Anne-Sylvie; Jamali, Samir; Lacave, Guillaume; Ruckly, Stéphane; Mourvillier, Bruno; Timsit, Jean-François

2017-08-01

Identifying modifiable factors for sepsis-associated encephalopathy may help improve patient care and outcomes. We conducted a retrospective analysis of a prospective multicenter database. Sepsis-associated encephalopathy (SAE) was defined by a score on the Glasgow coma scale (GCS) <15 or when features of delirium were noted. Potentially modifiable risk factors for SAE at ICU admission and its impact on mortality were investigated using multivariate logistic regression analysis and Cox proportional hazard modeling, respectively. We included 2513 patients with sepsis at ICU admission, of whom 1341 (53%) had sepsis-associated encephalopathy. After adjusting for baseline characteristics, site of infection, and type of admission, the following factors remained independently associated with sepsis-associated encephalopathy: acute renal failure [adjusted odds ratio (aOR) = 1.41, 95% confidence interval (CI) 1.19-1.67], hypoglycemia <3 mmol/l (aOR = 2.66, 95% CI 1.27-5.59), hyperglycemia >10 mmol/l (aOR = 1.37, 95% CI 1.09-1.72), hypercapnia >45 mmHg (aOR = 1.91, 95% CI 1.53-2.38), hypernatremia >145 mmol/l (aOR = 2.30, 95% CI 1.48-3.57), and S. aureus (aOR = 1.54, 95% CI 1.05-2.25). Sepsis-associated encephalopathy was associated with higher mortality, higher use of ICU resources, and longer hospital stay. After adjusting for age, comorbidities, year of admission, and non-neurological SOFA score, even mild alteration of mental status (i.e., a score on the GCS of 13-14) remained independently associated with mortality (adjusted hazard ratio = 1.38, 95% CI 1.09-1.76). Acute renal failure and common metabolic disturbances represent potentially modifiable factors contributing to sepsis-associated encephalopathy. However, a true causal relationship has yet to be demonstrated. Our study confirms the prognostic significance of mild alteration of mental status in patients with sepsis.

Early Detection Of Breast Cancer using Post-Translationally Modified Biomarkers

DTIC Science & Technology

2012-03-01

methods are widely used to screen many potential diseases based on changes in blood proteins. Changes in proteins identified by proteomic studies are...suggest that circulating PTM levels can be used as a biomarker for endothelial cell dysfunction, which is of concern in several human diseases . We have...plasmid expressing the wild type PTENP1 3’UTR (pGLU/ψ3’UTR) or the 3’UTR in which the seed matches of the 5 PTEN-targeting microRNAs have been

Commentary on: Subjective cognitive decline is longitudinally associated with lower health-related quality of life.

PubMed

Cooper, Claudia

2017-12-01

Public campaigns to encourage early detection of dementia in the developed world have led to identification of more people with mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Early dementia diagnosis enables earlier information and support, including symptomatic treatments where appropriate. In clinical trials, detection of those with "prodromal dementia," identified from cognitive symptoms and stratified by biomarkers (Schneider, 2010), enables potential disease modifying treatments to be targeted early in the disease process, where success is more likely.

Modified electrical survey for effective leakage detection at concrete hydraulic facilities

NASA Astrophysics Data System (ADS)

Lee, Bomi; Oh, Seokhoon

2018-02-01

Three original electrode arrays for the effective leakage detection of concrete hydraulic facilities through electrical resistivity surveys are proposed: 'cross-potential', 'direct-potential' and modified tomography-like arrays. The main differences with respect to the commonly used arrays are that the current line-sources are separated from potential pole lines and floated upon the water. The potential pole lines are located directly next to the facility in order to obtain intuitive data and useful interpretations of the internal conditions of the hydraulic facility. This modified configuration of the array clearly displays the horizontal variation of the electrical field around the damaged zones of the concrete hydraulic facility, and any anomalous regions that might be found between potential poles placed across the facilities. In order to facilitate the interpretation of these modified electrical surveys, a new and creative way of presenting the measurements is also proposed and an inversion approach is provided for the modified tomography-like array. A numerical modeling and two field tests were performed to verify these new arrays and interpretation methods. The cross and direct potential array implied an ability to detect small variations of the potential field near the measurement poles. The proposed array showed the overall potential distribution across the hydraulic facility which may be used to assist in the search of trouble zones within the structure, in combination with the traditional electrical resistivity array.

An improved ChIP-seq peak detection system for simultaneously identifying post-translational modified transcription factors by combinatorial fusion, using SUMOylation as an example.

PubMed

Cheng, Chia-Yang; Chu, Chia-Han; Hsu, Hung-Wei; Hsu, Fang-Rong; Tang, Chung Yi; Wang, Wen-Ching; Kung, Hsing-Jien; Chang, Pei-Ching

2014-01-01

Post-translational modification (PTM) of transcriptional factors and chromatin remodelling proteins is recognized as a major mechanism by which transcriptional regulation occurs. Chromatin immunoprecipitation (ChIP) in combination with high-throughput sequencing (ChIP-seq) is being applied as a gold standard when studying the genome-wide binding sites of transcription factor (TFs). This has greatly improved our understanding of protein-DNA interactions on a genomic-wide scale. However, current ChIP-seq peak calling tools are not sufficiently sensitive and are unable to simultaneously identify post-translational modified TFs based on ChIP-seq analysis; this is largely due to the wide-spread presence of multiple modified TFs. Using SUMO-1 modification as an example; we describe here an improved approach that allows the simultaneous identification of the particular genomic binding regions of all TFs with SUMO-1 modification. Traditional peak calling methods are inadequate when identifying multiple TF binding sites that involve long genomic regions and therefore we designed a ChIP-seq processing pipeline for the detection of peaks via a combinatorial fusion method. Then, we annotate the peaks with known transcription factor binding sites (TFBS) using the Transfac Matrix Database (v7.0), which predicts potential SUMOylated TFs. Next, the peak calling result was further analyzed based on the promoter proximity, TFBS annotation, a literature review, and was validated by ChIP-real-time quantitative PCR (qPCR) and ChIP-reChIP real-time qPCR. The results show clearly that SUMOylated TFs are able to be pinpointed using our pipeline. A methodology is presented that analyzes SUMO-1 ChIP-seq patterns and predicts related TFs. Our analysis uses three peak calling tools. The fusion of these different tools increases the precision of the peak calling results. TFBS annotation method is able to predict potential SUMOylated TFs. Here, we offer a new approach that enhances ChIP-seq data analysis and allows the identification of multiple SUMOylated TF binding sites simultaneously, which can then be utilized for other functional PTM binding site prediction in future.

Search Algorithms as a Framework for the Optimization of Drug Combinations

PubMed Central

Coquin, Laurence; Schofield, Jennifer; Feala, Jacob D.; Reed, John C.; McCulloch, Andrew D.; Paternostro, Giovanni

2008-01-01

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms—originally developed for digital communication—modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs using only one-third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6–9 interventions in 80–90% of tests, compared with 15–30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution. PMID:19112483

Ozone Exposure, Cardiopulmonary Health, and Obesity: A Substantive Review.

PubMed

Koman, Patricia D; Mancuso, Peter

2017-07-17

From 1999-2014, obesity prevalence increased among adults and youth. Obese individuals may be uniquely susceptible to the proinflammatory effects of ozone because obese humans and animals have been shown to experience a greater decline in lung function than normal-weight subjects. Obesity is independently associated with limitations in lung mechanics with increased ozone dose. However, few epidemiologic studies have examined the interaction between excess weight and ozone exposure among adults. Using PubMed keyword searches and reference lists, we reviewed epidemiologic evidence to identify potential response-modifying factors and determine if obese or overweight adults are at increased risk of ozone-related health effects. We initially identified 170 studies, of which seven studies met the criteria of examining the interaction of excess weight and ozone exposure on cardiopulmonary outcomes in adults, including four short-term ozone exposure studies in controlled laboratory settings and three community epidemiologic studies. In the studies identified, obesity was associated with decreased lung function and increased inflammatory mediators. Results were inconclusive about the effect modification when data were stratified by sex. Obese and overweight populations should be considered as candidate at-risk groups for epidemiologic studies of cardiopulmonary health related to air pollution exposures. Air pollution is a modifiable risk factor that may decrease lung function among obese individuals with implications for environmental and occupational health policy.

Discovery of 2-methylpyridine-based biaryl amides as γ-secretase modulators for the treatment of Alzheimer's disease.

PubMed

Chen, Jian Jeffrey; Qian, Wenyuan; Biswas, Kaustav; Yuan, Chester; Amegadzie, Albert; Liu, Qingyian; Nixey, Thomas; Zhu, Joe; Ncube, Mqhele; Rzasa, Robert M; Chavez, Frank; Chen, Ning; DeMorin, Frenel; Rumfelt, Shannon; Tegley, Christopher M; Allen, Jennifer R; Hitchcock, Stephen; Hungate, Randy; Bartberger, Michael D; Zalameda, Leeanne; Liu, Yichin; McCarter, John D; Zhang, Jianhua; Zhu, Li; Babu-Khan, Safura; Luo, Yi; Bradley, Jodi; Wen, Paul H; Reid, Darren L; Koegler, Frank; Dean, Charles; Hickman, Dean; Correll, Tiffany L; Williamson, Toni; Wood, Stephen

2013-12-01

γ-Secretase modulators (GSMs) are potentially disease-modifying treatments for Alzheimer's disease. They selectively lower pathogenic Aβ42 levels by shifting the enzyme cleavage sites without inhibiting γ-secretase activity, possibly avoiding known adverse effects observed with complete inhibition of the enzyme complex. A cell-based HTS effort identified the sulfonamide 1 as a GSM lead. Lead optimization studies identified compound 25 with improved cell potency, PKDM properties, and it lowered Aβ42 levels in the cerebrospinal fluid (CSF) of Sprague-Dawley rats following oral administration. Further optimization of 25 to improve cellular potency is described. Copyright © 2013 Elsevier Ltd. All rights reserved.

Updates in venous thromboembolism management: evidence published in 2017.

PubMed

Bartlett, Matthew A; Bierle, Dennis M; Saadiq, Rayya A; Mauck, Karen F; Daniels, Paul R

2018-06-20

Venous thromboembolism (VTE) management is rapidly evolving and staying up-to-date is challenging. We identified the most practice-informing articles published in 2017 relevant to the nonspecialist provider managing VTE. We performed a systematic search of the literature (Appendix A), limiting the search to a publication date of 2017. Two reviewers screened the 2735 resulting abstracts to identify high-quality, clinically relevant publications related to VTE management. One-hundred and six full-text articles were considered for inclusion. The five authors used a modified Delphi method to reach consensus on inclusion of seven articles for in-depth appraisal, following predetermined criteria of clinical relevance to nonspecialist providers, potential for practice change, and strength of the evidence.

A Modified Delphi to Identify the Significant Works Pertaining to the Understanding of Reading Comprehension and Content Analysis of the Identified Works

ERIC Educational Resources Information Center

Zunker, Norma D.; Pearce, Daniel L.

2012-01-01

The first part of this study explored the significant works pertaining to the understanding of reading comprehension using a Modified Delphi Method. A panel of reading comprehension experts identified 19 works they considered to be significant to the understanding of reading comprehension. The panel of experts identified the reasons they…

Functional Analysis of Problem Behavior: A Systematic Approach for Identifying Idiosyncratic Variables

PubMed Central

Roscoe, Eileen M.; Schlichenmeyer, Kevin J.; Dube, William V.

2015-01-01

When inconclusive functional analysis (FA) outcomes occur, a number of modifications have been made to enhance the putative establishing operation or consequence associated with behavioral maintenance. However, a systematic method for identifying relevant events to test during modified FAs has not been evaluated. The purpose of this study was to develop and evaluate a technology for systematically identifying events to test in a modified FA after an initial FA led to inconclusive outcomes. Six individuals whose initial FA showed little or no responding or high levels only in the control condition participated. An indirect assessment (IA) questionnaire developed for identifying idiosyncratic variables was administered, and a descriptive analysis (DA) was conducted. Results from the IA only or a combination of the IA and DA were used to inform modified FA test and control conditions. Conclusive FA outcomes were obtained with five of the six participants during the modified FA phase. PMID:25930176

A chemical proteomics approach reveals Hsp27 as a target for proapoptotic clerodane diterpenes.

PubMed

Faiella, Laura; Piaz, Fabrizio Dal; Bisio, Angela; Tosco, Alessandra; De Tommasi, Nunziatina

2012-10-01

Clerodane diterpenoids are a class of naturally occurring molecules widely distributed in the Lamiaceae family. Neo-clerodane diterpenoids from Salvia ssp were recently described as compounds inhibiting the proliferation of human cancer cell lines. To gain new insights into molecular mechanism(s) underlying the antitumor potential of this class of compounds, we used a chemical proteomics approach to analyse the cellular interactome of hardwickiic acid (HAA) selected as a representative molecule. HAA was linked to an opportune 1,1'-carbonyldiimidazole modified by 1,12-dodecanediamine and then immobilized on a matrix support. The modified beads were then used as bait for fishing the potential partners of HAA in a U937 cell lysate. We identified heat shock protein 27 (Hsp27), an ATP-independent antiapoptotic chaperone characterized for its tumorigenic and metastatic properties and now referenced as a major therapeutic target in many types of cancer, as a major HAA partner. Here, we also report the study of HAA-Hsp27 interaction by means of a panel of chemical and biological approaches, including surface plasmon resonance measurements limited proteolysis, and biochemical assays. Our data suggest that HAA could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.

Systematic Analysis of the Genetic Variability That Impacts SUMO Conjugation and Their Involvement in Human Diseases

NASA Astrophysics Data System (ADS)

Xu, Hao-Dong; Shi, Shao-Ping; Chen, Xiang; Qiu, Jian-Ding

2015-07-01

Protein function has been observed to rely on select essential sites instead of requiring all sites to be indispensable. Small ubiquitin-related modifier (SUMO) conjugation or sumoylation, which is a highly dynamic reversible process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified, has shown to be especially valuable in cellular biology. Motivated by the significance of SUMO conjugation in biological processes, we report here on the first exploratory assessment whether sumoylation related genetic variability impacts protein functions as well as the occurrence of diseases related to SUMO. Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs. We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system. More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases. It can be anticipated that our method can provide more instructive guidance to identify the mechanisms of genetic diseases.

The use of CD47-modified biomaterials to mitigate the immune response.

PubMed

Tengood, Jillian E; Levy, Robert J; Stachelek, Stanley J

2016-05-01

Addressing the aberrant interactions between immune cells and biomaterials represents an unmet need in biomaterial research. Although progress has been made in the development of bioinert coatings, identifying and targeting relevant cellular and molecular pathways can provide additional therapeutic strategies to address this major healthcare concern. To that end, we describe the immune inhibitory motif, receptor-ligand pairing of signal regulatory protein alpha and its cognate ligand CD47 as a potential signaling pathway to enhance biocompatibility. The goals of this article are to detail the known roles of CD47-signal regulatory protein alpha signal transduction pathway and to describe how immobilized CD47 can be used to mitigate the immune response to biomaterials. Current applications of CD47-modified biomaterials will also be discussed herein. © 2016 by the Society for Experimental Biology and Medicine.

Role of contextual factors in the rehabilitation of adolescent survivors of traumatic brain injury: emerging concepts identified through modified narrative review.

PubMed

Ciccia, Angela Hein; Threats, Travis

2015-07-01

Recently research in traumatic brain injury (TBI) intervention has identified the benefits of contextualized, embedded, functionally based approaches to maximize treatment outcomes. An essential component of contextualized intervention is the direct and purposeful consideration of the broader context, in which the person with TBI functions. However, systematic consideration of contextual factors remains limited both in research and clinical practice. The purposes of this modified narrative review were (1) to provide a succinct review of the available literature regarding the contextual factors that are specific to adolescent survivors of TBI, one of highest incidence groups for brain injury; (2) to connect these contextual factors to the direct long-term management of TBI and to identify their potential impact on outcome; and (3) to highlight areas that are open to research and clinical advances that could enhance positive outcomes for adolescent survivors of TBI. The framework of the World Health Organization's (WHO) International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY; 2007) was used as a foundation for this review. A systematic literature search was conducted using databases and hand searches. A total of 102 articles were originally identified. Twenty-five original research articles, eight review papers and four expert opinion papers met inclusion and exclusion criteria and were included in the final review. The body of research specifically focused on contextual factors is an emerging area. Early findings indicate that a focus on the direct modification of contextual factors is promising for the facilitation of positive outcomes long into the chronic phase of management for adolescences who have survived a TBI. The contextual factors included in this review were the overall ability of the school to support a student post-TBI, family psychosocial risk (sibling/sibling relationships/stress/burden/support), coping style (TBI survivor and their caregivers), and socioeconomic status of the family. Given the promise of these findings, research and clinical application efforts should be focused on identifying well-prescribed rehabilitation paradigms that capitalize on the modification of contextual factors throughout the recovery process. The results of this modified narrative review provide an initial summary of the available evidence for addressing contextual factors in the rehabilitation process for adolescents with TBI. This is an area that is wide open for both systematic research and clinical application and holds potential to improve long-term outcome for survivors of adolescent TBI. © 2015 Royal College of Speech and Language Therapists.

Recent developments in emerging therapeutic targets of osteoarthritis.

PubMed

Sun, Margaret Man-Ger; Beier, Frank; Pest, Michael A

2017-01-01

Despite the tremendous individual suffering and socioeconomic burden caused by osteoarthritis, there are currently no effective disease-modifying treatment options. This is in part because of our incomplete understanding of osteoarthritis disease mechanism. This review summarizes recent developments in therapeutic targets identified from surgical animal models of osteoarthritis that provide novel insight into osteoarthritis pathology and possess potential for progression into preclinical studies. Several candidate pathways and processes that have been identified include chondrocyte autophagy, growth factor signaling, inflammation, and nociceptive signaling. Major strategies that possess therapeutic potential at the cellular level include inhibiting autophagy suppression and decreasing reactive oxygen species (ROS) production. Cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation, such as TGF-β, TGF-α, and FGF; however, the results are context-dependent and require further investigation. Pain assessment studies in rodent surgical models have demonstrated potential in employing anti-NGF strategies for minimizing osteoarthritis-associated pain. Studies of potential therapeutic targets in osteoarthritis using animal surgical models are helping to elucidate osteoarthritis pathology and propel therapeutics development. Further studies should continue to elucidate pathological mechanisms and therapeutic targets in various joint tissues to improve overall joint health.

AllergenOnline: A peer-reviewed, curated allergen database to assess novel food proteins for potential cross-reactivity.

PubMed

Goodman, Richard E; Ebisawa, Motohiro; Ferreira, Fatima; Sampson, Hugh A; van Ree, Ronald; Vieths, Stefan; Baumert, Joseph L; Bohle, Barbara; Lalithambika, Sreedevi; Wise, John; Taylor, Steve L

2016-05-01

Increasingly regulators are demanding evaluation of potential allergenicity of foods prior to marketing. Primary risks are the transfer of allergens or potentially cross-reactive proteins into new foods. AllergenOnline was developed in 2005 as a peer-reviewed bioinformatics platform to evaluate risks of new dietary proteins in genetically modified organisms (GMO) and novel foods. The process used to identify suspected allergens and evaluate the evidence of allergenicity was refined between 2010 and 2015. Candidate proteins are identified from the NCBI database using keyword searches, the WHO/IUIS nomenclature database and peer reviewed publications. Criteria to classify proteins as allergens are described. Characteristics of the protein, the source and human subjects, test methods and results are evaluated by our expert panel and archived. Food, inhalant, salivary, venom, and contact allergens are included. Users access allergen sequences through links to the NCBI database and relevant references are listed online. Version 16 includes 1956 sequences from 778 taxonomic-protein groups that are accepted with evidence of allergic serum IgE-binding and/or biological activity. AllergenOnline provides a useful peer-reviewed tool for identifying the primary potential risks of allergy for GMOs and novel foods based on criteria described by the Codex Alimentarius Commission (2003). © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Applicability of digital PCR to the investigation of pediatric-onset genetic disorders.

PubMed

Butchbach, Matthew E R

2016-12-01

Early-onset rare diseases have a strong impact on child healthcare even though the incidence of each of these diseases is relatively low. In order to better manage the care of these children, it is imperative to quickly diagnose the molecular bases for these disorders as well as to develop technologies with prognostic potential. Digital PCR (dPCR) is well suited for this role by providing an absolute quantification of the target DNA within a sample. This review illustrates how dPCR can be used to identify genes associated with pediatric-onset disorders, to identify copy number status of important disease-causing genes and variants and to quantify modifier genes. It is also a powerful technology to track changes in genomic biomarkers with disease progression. Based on its capability to accurately and reliably detect genomic alterations with high sensitivity and a large dynamic detection range, dPCR has the potential to become the tool of choice for the verification of pediatric disease-associated mutations identified by next generation sequencing, copy number determination and noninvasive prenatal screening.

Epigenetics and human obesity.

PubMed

van Dijk, S J; Molloy, P L; Varinli, H; Morrison, J L; Muhlhausler, B S

2015-01-01

Recent technological advances in epigenome profiling have led to an increasing number of studies investigating the role of the epigenome in obesity. There is also evidence that environmental exposures during early life can induce persistent alterations in the epigenome, which may lead to an increased risk of obesity later in life. This paper provides a systematic review of studies investigating the association between obesity and either global, site-specific or genome-wide methylation of DNA. Studies on the impact of pre- and postnatal interventions on methylation and obesity are also reviewed. We discuss outstanding questions, and introduce EpiSCOPE, a multidisciplinary research program aimed at increasing the understanding of epigenetic changes in emergence of obesity. An electronic search for relevant articles, published between September 2008 and September 2013 was performed. From the 319 articles identified, 46 studies were included and reviewed. The studies provided no consistent evidence for a relationship between global methylation and obesity. The studies did identify multiple obesity-associated differentially methylated sites, mainly in blood cells. Extensive, but small, alterations in methylation at specific sites were observed in weight loss intervention studies, and several associations between methylation marks at birth and later life obesity were found. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Eventually this may help in predicting an individual's obesity risk at a young age and opens possibilities for introducing targeted prevention strategies. It has also become clear that several epigenetic marks are modifiable, by changing the exposure in utero, but also by lifestyle changes in adult life, which implies that there is the potential for interventions to be introduced in postnatal life to modify unfavourable epigenomic profiles.

Simulations of Cyclic Voltammetry for Electric Double Layers in Asymmetric Electrolytes: A Generalized Modified Poisson-Nernst-Planck Model

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

Wang, Hainan; Thiele, Alexander; Pilon, Laurent

2013-11-15

This paper presents a generalized modified Poisson–Nernst–Planck (MPNP) model derived from first principles based on excess chemical potential and Langmuir activity coefficient to simulate electric double-layer dynamics in asymmetric electrolytes. The model accounts simultaneously for (1) asymmetric electrolytes with (2) multiple ion species, (3) finite ion sizes, and (4) Stern and diffuse layers along with Ohmic potential drop in the electrode. It was used to simulate cyclic voltammetry (CV) measurements for binary asymmetric electrolytes. The results demonstrated that the current density increased significantly with decreasing ion diameter and/or increasing valency |z i| of either ion species. By contrast, the ionmore » diffusion coefficients affected the CV curves and capacitance only at large scan rates. Dimensional analysis was also performed, and 11 dimensionless numbers were identified to govern the CV measurements of the electric double layer in binary asymmetric electrolytes between two identical planar electrodes of finite thickness. A self-similar behavior was identified for the electric double-layer integral capacitance estimated from CV measurement simulations. Two regimes were identified by comparing the half cycle period τ CV and the “RC time scale” τ RC corresponding to the characteristic time of ions’ electrodiffusion. For τ RC ← τ CV, quasi-equilibrium conditions prevailed and the capacitance was diffusion-independent while for τ RC → τ CV, the capacitance was diffusion-limited. The effect of the electrode was captured by the dimensionless electrode electrical conductivity representing the ratio of characteristic times associated with charge transport in the electrolyte and that in the electrode. The model developed here will be useful for simulating and designing various practical electrochemical, colloidal, and biological systems for a wide range of applications.« less

Population attributable risk of factors associated with the repetition of self-harm behaviour in young people presenting to clinical services: a systematic review and meta-analysis.

PubMed

Witt, Katrina; Milner, Allison; Spittal, Matthew J; Hetrick, Sarah; Robinson, Jo; Pirkis, Jane; Carter, Gregory

2018-02-03

The repetition of hospital-treated self-harm by young people is common. However, little work has summarised the modifiable factors associated with this. A thorough understanding of those factors most strongly associated with repetition could guide the development of relevant clinical interventions. We systematically reviewed four databases (EMBASE, Medline, PubMed and PsycINFO) until 15 April 2016 to identify all observational studies of factors for the repetition of self-harm or suicide reattempts (together referred to as 'self-harm behaviour') in young people. We quantified the magnitude of association with odds ratios (OR) and 95% confidence intervals (CIs) and calculated the population attributable risk (PAR) and population preventable fraction (PPF) for modifiable factors to provide an indication of the potential impact in reducing subsequent self-harm behaviour in this population. Seventeen studies were included comprising 10,726 participants. Borderline personality disorder (OR 3.47, 95% CI 1.84-6.53; PAR 42.4%), any personality disorder (OR 2.54, 95% CI 1.71-3.78; PAR 16.3%), and any mood disorder (OR 2.16, 95% CI 1.09-4.29; PAR 42.2%) are important modifiable risk factors. Severity of hopelessness (OR 2.95, 95% CI 1.74-5.01), suicidal ideation (OR 2.01, 95% CI 1.43-2.81), and previous sexual abuse (OR 1.52, 95% CI 1.02-2.28; PAR 12.8%) are also associated with repetition of self-harm. We recommend that clinical services should focus on identifying key modifiable risk factors at the individual patient level, whilst the reduction of exposure to child and adolescent sexual abuse would also be a useful goal for public health interventions.

Matching Adherence Interventions to Patient Determinants Using the Theoretical Domains Framework.

PubMed

Allemann, Samuel S; Nieuwlaat, Robby; van den Bemt, Bart J F; Hersberger, Kurt E; Arnet, Isabelle

2016-01-01

Introduction: Despite much research, interventions to improve medication adherence report disappointing and inconsistent results. Tailored approaches that match interventions and patient determinants of non-adherence were seldom used in clinical trials. The presence of a multitude of theoretical frameworks and models to categorize interventions and patient determinants complicated the development of common categories shared by interventions and determinants. We retrieved potential interventions and patient determinants from published literature on medication adherence, matched them like locks and keys, and categorized them according to the Theoretical Domains Framework (TDF). Methods: We identified the most relevant literature reviews on interventions and determinants in a pragmatic literature search, extracted all interventions and determinants, grouped similar concepts to umbrella terms and assigned them to TDF categories. All steps were finalized in consensus discussion between the authors. Results: Sixteen articles (5 with determinants, 11 with interventions) were included for analysis. We extracted 103 interventions and 42 determinants that we divided in 26 modifiable and 16 unmodifiable determinants. All interventions and modifiable determinants were matched within 11 categories (Knowledge; Skills; Social/professional role and identity; Beliefs about capabilities; Beliefs about consequences; Intentions; Memory, Attention and decision processes; Environmental context and resources; Social influences; Emotion; and Behavioral regulation). Conclusion: In published trials on medication adherence, the congruence between interventions and determinants can be assessed with matching interventions to determinants. To be successful, interventions in medication adherence should target current modifiable determinants and be tailored to the unmodifiable determinants. Modifiable and unmodifiable determinants need to be assessed at inclusion of intervention studies to identify the patients most in need of an adherence intervention. Our matched categories may be useful to develop interventions in trials that investigate the effectiveness of adherence interventions.

A voltammetric method for Fe(iii) in blood serum using a screen-printed electrode modified with a Schiff base ionophore.

PubMed

Mittal, Susheel K; Rana, Sonia; Kaur, Navneet; Banks, Craig E

2018-05-23

Herein, a potent electrochemical ionophore (SMS-2) based on a Schiff base has been used for the modification of a screen-printed electrode (SPE). The modified disposable electrode can selectively detect ferric ions in an aqueous medium. Redox behavior of the proposed strip was characterized using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Incorporation of the ligand in the ink of the SPE enhanced the analytical performance of the electrode, and its surface modification was confirmed by SEM and EDX analysis. Shifting/quenching of the cathodic peak potential of the ionophore after binding with Fe(iii) ions was used to detect and measure the ferric ion concentration. This sensor can identify Fe(iii) in the detection range from 0.625 μM to 7.5 μM. The modified SPE can selectively detect ferric ions in the presence of many other interfering ions and has been successfully used to determine the Fe(iii) content in blood serum samples. The metal-ionophore complex structure was optimized using DFT calculations to study the energetics of the metal-ionophore interactions.

[The modified method registration of kinesthetic evoked potentials and its application for research of proprioceptive sensitivity disorders at spondylogenic cervical myelopathy].

PubMed

Gordeev, S A; Voronin, S G

2016-01-01

To analyze the efficacy of modified (passive radiocarpal articulation flexion/extension) and «standard» (passive radiocarpal articulation flexion) methods of kinesthetic evoked potentials for proprioceptive sensitivity assessment in healthy subjects and patients with spondylotic cervical myelopathy. The study included 14 healthy subjects (4 women and 10 men, mean age 54.1±10.5 years) and 8 patients (2 women and 6 men, mean age 55.8±10.9 years) with spondylotic cervical myelopathy. Muscle-joint sensation was examined during the clinical study. A modified method of kinesthetic evoked potentials was developed. This method differed from the "standard" one by the organization of a cycle including several passive movements,where each new movement differed from the preceding one by the direction. The modified method of kinesthetic evoked potentials ensures more reliable kinesthetic sensitivity assessment due to movement variability. Asignificant increaseof the latent periods of the early components of the response was found in patients compared to healthy subjects. The modified method of kinesthetic evoked potentials can be used for objective diagnosis of proprioceptive sensitivity disorders in patients with spondylotic cervical myelopathy.

The reporting quality of randomized controlled trials in orthodontics.

PubMed

Lempesi, Evangelia; Koletsi, Despina; Fleming, Padhraig S; Pandis, Nikolaos

2014-06-01

Accurate trial reporting facilitates evaluation and better use of study results. The objective of this article is to investigate the quality of reporting of randomized controlled trials (RCTs) in leading orthodontic journals, and to explore potential predictors of improved reporting. The 50 most recent issues of 4 leading orthodontic journals until November 2013 were electronically searched. Reporting quality assessment was conducted using the modified CONSORT statement checklist. The relationship between potential predictors and the modified CONSORT score was assessed using linear regression modeling. 128 RCTs were identified with a mean modified CONSORT score of 68.97% (SD = 11.09). The Journal of Orthodontics (JO) ranked first in terms of completeness of reporting (modified CONSORT score 76.21%, SD = 10.1), followed by American Journal of Orthodontics and Dentofacial Orthopedics (AJODO) (73.05%, SD = 10.1). Journal of publication (AJODO: β = 10.08, 95% CI: 5.78, 14.38; JO: β = 16.82, 95% CI: 11.70, 21.94; EJO: β = 7.21, 95% CI: 2.69, 11.72 compared to Angle), year of publication (β = 0.98, 95% CI: 0.28, 1.67 for each additional year), region of authorship (Europe: β = 5.19, 95% CI: 1.30, 9.09 compared to Asia/other), statistical significance (significant: β = 3.10, 95% CI: 0.11, 6.10 compared to non-significant) and methodologist involvement (involvement: β = 5.60, 95% CI: 1.66, 9.54 compared to non-involvement) were all significant predictors of improved modified CONSORT scores in the multivariable model. Additionally, median overall Jadad score was 2 (IQR = 2) across journals, with JO (median = 3, IQR = 1) and AJODO (median = 3, IQR = 2) presenting the highest score values. The reporting quality of RCTs published in leading orthodontic journals is considered suboptimal in various CONSORT areas. This may have a bearing in trial result interpretation and use in clinical decision making and evidence- based orthodontic treatment interventions. Copyright © 2014 Elsevier Inc. All rights reserved.

Persistence to disease-modifying therapies for multiple sclerosis in a Canadian cohort

PubMed Central

Melesse, Dessalegn Y; Marrie, Ruth Ann; Blanchard, James F; Yu, Bo Nancy; Evans, Charity

2017-01-01

Purpose To examine the long-term persistence to the first-line injectable disease-modifying therapies (DMTs) for multiple sclerosis (MS) and to identify the factors associated with nonpersistence. Patients and methods We used population-based administrative data from Manitoba, Canada. All adult subjects who were diagnosed with MS and dispensed a first-line injectable DMT (beta-interferon-1b, beta-interferon-1a, and glatiramer acetate) between 1996 and 2011 and had a minimum of 1 year of follow-up were included. The primary outcome was the median time to discontinuation of any DMT. The associations between potential predictors and persistence were estimated using multivariable Cox-proportional hazard models. Results Overall, 721 subjects were followed for a median of 7.8 years (interquartile range 6.1). The median time to discontinuation of all first-line DMTs was 4.2 years (25th and 75th percentile: 1.7, 10.6 years). Of the 451 (62.6%) subjects who discontinued their DMT during the study period, 259 (57.4%) eventually resumed or restarted a DMT. Subjects who were younger when starting a DMT, had prior MS-related hospitalizations, were more recently diagnosed with MS, or had a greater lag time between their MS diagnosis and DMT initiation were more likely to discontinue therapy. Conclusion Over half of the individuals receiving a DMT for MS in Manitoba remained on therapy for at least 4 years. DMT discontinuation occurred in 60% of the cohort, but most restarted a DMT within 1 year. While not all of the factors identified with discontinuing DMT are modifiable, they may help practitioners enhance MS care by identifying individuals who may be at particular risk for DMT discontinuation. PMID:28721023

Classification of drugs with different risk profiles.

PubMed

Saedder, Eva Aggerholm; Brock, Birgitte; Nielsen, Lars Peter; Bonnerup, Dorthe Krogsgaard; Lisby, Marianne

2015-08-01

A risk stratification approach is needed to identify patients at high risk of medication errors and a resulting high need of medication review. The aim of this study was to perform risk stratification (distinguishing between low-risk, medium-risk and high-risk drugs) for drugs found to cause serious adverse reactions due to medication errors. The study employed a modified Delphi technique. Drugs from a systematic literature search were included into two rounds of a Delphi process. A panel of experts was asked to evaluate each identified drug's potential for harm and for clinically relevant drug-drug interactions on a scale from 1 (low risk) to 9 (high risk). A total of 36 experts were appointed to serve on the panel. Consensus was reached for 29/57 (51%) drugs or drug classes that cause harm, and for 32/57 (56%) of the drugs or drug classes that cause interactions. For the remaining drugs, a decision was made based on the median score. Two lists, one stating the drugs' potential for causing harm and the other stating clinically relevant drug-drug interactions, were stratified into low-risk, medium-risk and high-risk drugs. Based on a modified Delphi technique, we created two lists of drugs stratified into a low-risk, a medium-risk and a high-risk group of clinically relevant interactions or risk of harm to patients. The lists could be incorporated into a risk-scoring tool that stratifies the performance of medication reviews according to patients' risk of experiencing adverse reactions. none. not relevant.

Reef Fish Survey Techniques: Assessing the Potential for Standardizing Methodologies.

PubMed

Caldwell, Zachary R; Zgliczynski, Brian J; Williams, Gareth J; Sandin, Stuart A

2016-01-01

Dramatic changes in populations of fishes living on coral reefs have been documented globally and, in response, the research community has initiated efforts to assess and monitor reef fish assemblages. A variety of visual census techniques are employed, however results are often incomparable due to differential methodological performance. Although comparability of data may promote improved assessment of fish populations, and thus management of often critically important nearshore fisheries, to date no standardized and agreed-upon survey method has emerged. This study describes the use of methods across the research community and identifies potential drivers of method selection. An online survey was distributed to researchers from academic, governmental, and non-governmental organizations internationally. Although many methods were identified, 89% of survey-based projects employed one of three methods-belt transect, stationary point count, and some variation of the timed swim method. The selection of survey method was independent of the research design (i.e., assessment goal) and region of study, but was related to the researcher's home institution. While some researchers expressed willingness to modify their current survey protocols to more standardized protocols (76%), their willingness decreased when methodologies were tied to long-term datasets spanning five or more years. Willingness to modify current methodologies was also less common among academic researchers than resource managers. By understanding both the current application of methods and the reported motivations for method selection, we hope to focus discussions towards increasing the comparability of quantitative reef fish survey data.

A case-crossover study on transient risk factors of work-related eye injuries.

PubMed

Chen, S-Y; Fong, P-C; Lin, S-F; Chang, C-H; Chan, C-C

2009-08-01

To investigate modifiable risk and preventive factors of work-related eye injuries. A case-crossover study conducted to explore the associations between transient risk factors and work-related eye injuries. Patients seen at seven medical centres in Taiwan with work-related eye injuries over a 4-year period were enrolled in the study. Clinical information was collected from medical charts and detailed information on exposure to eight potentially modifiable factors during the 60 minutes prior to the occurrence of each injury, as well as during the same time interval on the last work day prior to the injury, were obtained using questionnaire surveys. Matched-pair interval analysis was adopted to assess the odds ratios (ORs) for work-related eye injuries given exposure to the eight modifiable factors. A total of 283 subjects were interviewed. Most of these injured workers were young, male, and self-employed or small enterprise workers. The most common injury type was photokeratitis (33.2%), mainly caused by welding (30.4%). The OR for a work-related eye injury was increased with the performance of an unfamiliar task (57.0), operation of a faulty tool or piece of equipment (48.5), distractions (24.0), being rushed (13.0), or fatigued (10.0), and a poor work environment (4.3). Wearing eye protection devices was found to have a significant protective effect on workers who might otherwise have been exposed to eye injuries (OR = 0.4; 95% CI 0.2 to 0.7). Potential modifiable risk and preventive factors for work-related eye injuries were identified using a case-crossover study. This information should be helpful in the development of preventive strategies.

Horse species symposium: a novel approach to monitoring pathogen progression during uterine and placental infection in the mare using bioluminescence imaging technology and lux-modified bacteria.

PubMed

Ryan, P L; Christiansen, D L; Hopper, R M; Walters, F K; Moulton, K; Curbelo, J; Greene, J M; Willard, S T

2011-05-01

Uterine and placental infections are the leading cause of abortion, stillbirth, and preterm delivery in the mare. Whereas uterine and placental infections in women have been studied extensively, a comprehensive examination of the pathogenic processes leading to this unsatisfactory pregnancy outcome in the mare has yet to be completed. Most information in the literature relating to late-term pregnancy loss in mares is based on retrospective studies of clinical cases submitted for necropsy. Here we report the development and application of a novel approach, whereby transgenically modified bacteria transformed with lux genes of Xenorhabdus luminescens or Photorhabdus luminescens origin and biophotonic imaging are utilized to better understand pathogen-induced preterm birth in late-term pregnant mares. This technology uses highly sensitive bioluminescence imaging camera systems to localize and monitor pathogen progression during tissue invasion by measuring the bioluminescent signatures emitted by the lux-modified pathogens. This method has an important advantage in that it allows for the potential tracking of pathogens in vivo in real time and over time, which was hitherto impossible. Although the application of this technology in domestic animals is in its infancy, investigators were successful in identifying the fetal lungs, sinuses, nares, urinary, and gastrointestinal systems as primary tissues for pathogen invasion after experimental infection of pregnant mares with lux-modified Escherichia coli. It is important that pathogens were not detected in other vital organs, such as the liver, brain, and cardiac system. Such precision in localizing sites of pathogen invasion provides potential application for this novel approach in the development of more targeted therapeutic interventions for pathogen-related diseases in the equine and other domestic species.

Ovalbumin Modified with Pyrraline, a Maillard Reaction Product, shows Enhanced T-cell Immunogenicity*

PubMed Central

Heilmann, Monika; Wellner, Anne; Gadermaier, Gabriele; Ilchmann, Anne; Briza, Peter; Krause, Maren; Nagai, Ryoji; Burgdorf, Sven; Scheurer, Stephan; Vieths, Stefan; Henle, Thomas; Toda, Masako

2014-01-01

The Maillard reaction (also referred to as “glycation”) takes place between reducing sugars and compounds with free amino groups during thermal processing of foods. In the final stage of the complex reaction cascade, the so-called advanced glycation end products (AGEs) are formed, including proteins with various glycation structures. It has been suggested that some AGEs could have immunostimulatory effects. Here, we aimed to identify specific glycation structure(s) that could influence the T-cell immunogenicity and potential allergenicity of food allergens, using ovalbumin (OVA, an egg white allergen) as a model allergen. OVA was specifically modified with representative glycation structures: Nϵ-carboxymethyl lysine (CM-OVA), Nϵ-carboxyethyl lysine (CE-OVA), pyrraline (Pyr-OVA), or methylglyoxal-derived arginine derivatives (MGO-OVA). As well as AGE-OVA, a crude glycation product in thermal incubation of OVA with glucose, only Pyr-OVA, and not other modified OVAs, was efficiently taken up by bone marrow-derived murine dendritic cells (BMDCs). The uptake of Pyr-OVA was reduced in scavenger receptor class A (SR-A)-deficient BMDCs, but not in cells treated with inhibitors of scavenger receptor class B, galectin-3, or blocking antibodies against CD36, suggesting that pyrraline binds to SR-A. Compared with other modified OVAs, Pyr-OVA induced higher activation of OVA-specific CD4+ T-cells in co-culture with BMDCs. Furthermore, compared with native OVA, AGE-OVA and Pyr-OVA induced higher IgE production in mice. Pyrraline could induce better allergen uptake by DCs via association with SR-A and subsequently enhance CD4+ T-cell activation and IgE production. Our findings help us to understand how Maillard reaction enhances the potential allergenicity of food allergens. PMID:24505139

The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers.

PubMed

Estruch, Sara B; Graham, Sarah A; Deriziotis, Pelagia; Fisher, Simon E

2016-02-12

Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo.

The language-related transcription factor FOXP2 is post-translationally modified with small ubiquitin-like modifiers

PubMed Central

Estruch, Sara B.; Graham, Sarah A.; Deriziotis, Pelagia; Fisher, Simon E.

2016-01-01

Mutations affecting the transcription factor FOXP2 cause a rare form of severe speech and language disorder. Although it is clear that sufficient FOXP2 expression is crucial for normal brain development, little is known about how this transcription factor is regulated. To investigate post-translational mechanisms for FOXP2 regulation, we searched for protein interaction partners of FOXP2, and identified members of the PIAS family as novel FOXP2 interactors. PIAS proteins mediate post-translational modification of a range of target proteins with small ubiquitin-like modifiers (SUMOs). We found that FOXP2 can be modified with all three human SUMO proteins and that PIAS1 promotes this process. An aetiological FOXP2 mutation found in a family with speech and language disorder markedly reduced FOXP2 SUMOylation. We demonstrate that FOXP2 is SUMOylated at a single major site, which is conserved in all FOXP2 vertebrate orthologues and in the paralogues FOXP1 and FOXP4. Abolishing this site did not lead to detectable changes in FOXP2 subcellular localization, stability, dimerization or transcriptional repression in cellular assays, but the conservation of this site suggests a potential role for SUMOylation in regulating FOXP2 activity in vivo. PMID:26867680

Enhanced anticancer efficacy and tumor targeting through folate-PEG modified nanoliposome loaded with 5-fluorouracil

NASA Astrophysics Data System (ADS)

Le, Van Minh; Tran Nho, Trung Duc; Trieu Ly, Hai; Vo, Thanh Sang; Dung Nguyen, Hoang; Thu Huong Phung, Thi; Zou, Aihua; Liu, Jianwen

2017-03-01

Cancer targeted therapies have attracted considerable attention over the past year. Recently, 5-fluouracil (5-FU), which has high toxicity to normal cells and short half-life associated with rapid metabolism, is one of the most commonly used therapies in the treatment of cancer. In this study the folic acid-conjugated pegylated nanoliposomes were synthesized and then loaded into them with 5-FU to improve the anti-tumor efficacy. The average size of liposomes (LPs) was about 52.7 nm which was identified by TEM. In the liposome uptake studies, the level uptake of folate-conjugated liposomes has increased compared to non-conjugated LPs according to LPs concentration, incubation time and presence of concentration of free folic acid (FA). The MTT assay and apoptotic test were carried out in HCT116 and MCF-7 cells for 24 or 48 h. The results revealed that the folate-PEG modified 5-Fu loaded nanoliposomes had strong cytotoxicity to cancer cell compared to pure 5-FU or PEG modified 5-FU loaded liposomes in a concentration- and time-dependent manner, and mainly enhanced the cancer cell death through folate-mediated endocytosis. Hence, the folate-PEG modified nanoliposome is a potential targeted drug-delivery system for the treatment of FR-positive cancers.

Accountability in public health units: using a modified nominal group technique to develop a balanced scorecard for performance measurement.

PubMed

Robinson, Victoria A; Hunter, Duncan; Shortt, Samuel E D

2003-01-01

Little attention has been paid to the need for accountability instruments applicable across all health units in the public health system. One tool, the balanced scorecard was created for industry and has been successfully adapted for use in Ontario hospitals. It consists of 4 quadrants: financial performance, outcomes, customer satisfaction and organizational development. The aim of the present study was to determine if a modified nominal group technique could be used to reach consensus among public health unit staff and public health specialists in Ontario about the components of a balanced scorecard for public health units. A modified nominal group technique consensus method was used with the public health unit staff in 6 Eastern Ontario health units (n=65) and public health specialists (n=18). 73.8% of the public health unit personnel from all six health units in the eastern Ontario region participated in the survey of potential indicators. A total of 74 indicators were identified in each of the 4 quadrants: program performance (n=44); financial performance (n=11); public perceptions (n=11); and organizational performance (n=8). The modified nominal group technique was a successful method of incorporating the views of public health personnel and specialists in the development of a balanced scorecard for public health.

The HTLV-1 oncoprotein Tax is modified by the ubiquitin related modifier 1 (Urm1).

PubMed

Hleihel, Rita; Khoshnood, Behzad; Dacklin, Ingrid; Omran, Hayssam; Mouawad, Carine; Dassouki, Zeina; El-Sabban, Marwan; Shirinian, Margret; Grabbe, Caroline; Bazarbachi, Ali

2018-04-17

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy secondary to chronic human T-cell lymphotropic virus 1 infection, triggered by the virally encoded oncoprotein Tax. The transforming activity and subcellular localization of Tax is strongly influenced by posttranslational modifications, among which ubiquitylation and SUMOylation have been identified as key regulators of the nuclear/cytoplasmic shuttling of Tax, as well as its ability to activate NF-κB signaling. Adding to the complex posttranslational modification landscape of Tax, we here demonstrate that Tax also interacts with the ubiquitin-related modifier 1 (Urm1). Conjugation of Urm1 to Tax results in a redistribution of Tax to the cytoplasm and major increase in the transcription of the NF-ĸB targets Rantes and interleukin-6. Utilizing a tax-transgenic Drosophila model, we show that the Urm1-dependent subcellular targeting of Tax is evolutionary conserved, and that the presence of Urm1 is strongly correlated with the transcriptional output of Diptericin, an antimicrobial peptide and established downstream target of NF-κB in flies. These data put forward Urm1 as a novel Tax modifier that modulates its oncogenic activity and hence represents a potential novel target for developing new strategies for treating ATL.

Identifying Objective Physiological Markers and Modifiable Behaviors for Self-Reported Stress and Mental Health Status Using Wearable Sensors and Mobile Phones: Observational Study.

PubMed

Sano, Akane; Taylor, Sara; McHill, Andrew W; Phillips, Andrew Jk; Barger, Laura K; Klerman, Elizabeth; Picard, Rosalind

2018-06-08

Wearable and mobile devices that capture multimodal data have the potential to identify risk factors for high stress and poor mental health and to provide information to improve health and well-being. We developed new tools that provide objective physiological and behavioral measures using wearable sensors and mobile phones, together with methods that improve their data integrity. The aim of this study was to examine, using machine learning, how accurately these measures could identify conditions of self-reported high stress and poor mental health and which of the underlying modalities and measures were most accurate in identifying those conditions. We designed and conducted the 1-month SNAPSHOT study that investigated how daily behaviors and social networks influence self-reported stress, mood, and other health or well-being-related factors. We collected over 145,000 hours of data from 201 college students (age: 18-25 years, male:female=1.8:1) at one university, all recruited within self-identified social groups. Each student filled out standardized pre- and postquestionnaires on stress and mental health; during the month, each student completed twice-daily electronic diaries (e-diaries), wore two wrist-based sensors that recorded continuous physical activity and autonomic physiology, and installed an app on their mobile phone that recorded phone usage and geolocation patterns. We developed tools to make data collection more efficient, including data-check systems for sensor and mobile phone data and an e-diary administrative module for study investigators to locate possible errors in the e-diaries and communicate with participants to correct their entries promptly, which reduced the time taken to clean e-diary data by 69%. We constructed features and applied machine learning to the multimodal data to identify factors associated with self-reported poststudy stress and mental health, including behaviors that can be possibly modified by the individual to improve these measures. We identified the physiological sensor, phone, mobility, and modifiable behavior features that were best predictors for stress and mental health classification. In general, wearable sensor features showed better classification performance than mobile phone or modifiable behavior features. Wearable sensor features, including skin conductance and temperature, reached 78.3% (148/189) accuracy for classifying students into high or low stress groups and 87% (41/47) accuracy for classifying high or low mental health groups. Modifiable behavior features, including number of naps, studying duration, calls, mobility patterns, and phone-screen-on time, reached 73.5% (139/189) accuracy for stress classification and 79% (37/47) accuracy for mental health classification. New semiautomated tools improved the efficiency of long-term ambulatory data collection from wearable and mobile devices. Applying machine learning to the resulting data revealed a set of both objective features and modifiable behavioral features that could classify self-reported high or low stress and mental health groups in a college student population better than previous studies and showed new insights into digital phenotyping. ©Akane Sano, Sara Taylor, Andrew W McHill, Andrew JK Phillips, Laura K Barger, Elizabeth Klerman, Rosalind Picard. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 08.06.2018.

Haemochromatosis HFE gene polymorphisms as potential modifiers of hereditary nonpolyposis colorectal cancer risk and onset age.

PubMed

Shi, Zumin; Johnstone, Daniel; Talseth-Palmer, Bente A; Evans, Tiffany-Jane; Spigelman, Allan D; Groombridge, Claire; Milward, Elizabeth A; Olynyk, John K; Suchy, Janina; Kurzawski, Grzegorz; Lubinski, Jan; Scott, Rodney J

2009-07-01

Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by germline mutations in DNA mismatch repair genes; however, variation in disease expression suggests that there are potential modifying factors. Polymorphisms of the HFE gene, which cause the iron overload disorder hereditary haemochromatosis, have been proposed as potential risk factors for the development of colorectal cancer (CRC). To understand the relationship between HNPCC disease phenotype and polymorphisms of the HFE gene, a total of 362 individuals from Australia and Poland with confirmed causative MMR gene mutations were genotyped for the HFE C282Y and H63D polymorphisms. A significantly increased risk of developing CRC was observed for H63D homozygotes when compared with combined wild-type homozygotes and heterozygotes (hazard ratio = 2.93, p = 0.007). Evidence for earlier CRC onset was also observed in H63D homozygotes with a median age of onset 6 years earlier than wild type or heterozygous participants (44 vs. 50 years of age). This effect was significant by all tests used (log-rank test p = 0.026, Wilcoxon p = 0.044, Tarone-Ware p = 0.035). No association was identified for heterozygosity of either polymorphism and limitations on power-prevented investigation of C282Y homozygosity or compound C282Y/H63D heterozygosity. In the Australian sample only, women had a significantly reduced risk of developing CRC when compared with men (hazard ratio = 0.58, p = 0.012) independent of HFE genotype for either single nucleotide polymorphisms. In conclusion, homozygosity for the HFE H63D polymorphism seems to be a genetic modifier of disease expression in HNPCC. Understanding the mechanisms by which HFE interrelates with colorectal malignancies could lead to reduction of disease risk in HNPCC.

An Innovative Approach to Improve Completeness of Treatment and Other Key Data Elements in a Population-Based Cancer Registry: A15-Month Data Submission.

PubMed

Hsieh, Mei-Chin; Mumphrey, Brent; Pareti, Lisa; Yi, Yong; Wu, Xiao-Cheng

2017-01-01

BACKGROUND: In order to comply with the Louisiana legislative obligation and meet funding agencies’ requirement of case completeness for 12-month data submission, hospital cancer registries are mandated to submit cancer incidence data to the Louisiana Tumor Registry (LTR) within 6 months of diagnosis. However, enforcing compliance with timely reporting may result in incomplete data on adjuvant treatment received by the LTR. Although additional treatment information can be obtained via retransmission of the North American Association of Central Cancer Registries (NAACCR)–modified abstracts, consolidating multiple NAACCR-modified abstracts for the same case is extremely time consuming. To avoid a huge amount of work while obtaining timely and complete data, the LTR has requested hospital cancer registries resubmit their data 15 months after the close of the diagnosis year. The purpose of this report is to assess the improvement in the completeness of data items related to treatment, staging and site specific factors. METHODS: The LTR requested that hospital cancer registries resubmit 15-month data between April 1, 2016 and April 15, 2016 for cases diagnosed in 2014. Microsoft Visual Studio Visual Basic script was used to link and compare resubmitted data with existing data in the LTR database. Data elements used for matching same patient/tumor were name, Social Security number, date of birth, primary site, laterality, and hospital identifier number. Treatment data items were compared as known vs none/ unknown and known vs known with different code. Matched records with updated information were imported into the LTR database and flagged as modified abstract records for manual consolidation. Nonmatched records were also loaded in the LTR database as potential new cases for further investigation. RESULTS: A total of 25,207 resubmitted NAACCR abstracts were received from 38 hospitals and freestanding radiation centers. About 11.1% had at least 1 update related to treatment and/or other data item; an average of 3.3 updates per updated abstract. The majority of the updates (45.7%) for treatment were changes from none/unknown to known value and 42.6% of the updates were related to radiation treatment fields. In addition, 172 potential new cases were identified. Approximately 10.5% (18 cases) of these new cases were confirmed to be truly missed cases after investigation. CONCLUSION: The 15-month data resubmission is a cost-effective approach to obtaining complete information on treatment and other key data items from reporting facilities and can also be used to identify potential missed cases.

40 CFR 721.5908 - Modified phenolic resin (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified phenolic resin (generic). 721... Substances § 721.5908 Modified phenolic resin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as modified phenolic resin (PMN P...

40 CFR 721.5905 - Modified phenolic resin (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified phenolic resin (generic). 721... Substances § 721.5905 Modified phenolic resin (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a modified phenolic resin (PMN...

Modifiable risk factors for schizophrenia and autism--shared risk factors impacting on brain development.

PubMed

Hamlyn, Jess; Duhig, Michael; McGrath, John; Scott, James

2013-05-01

Schizophrenia and autism are two poorly understood clinical syndromes that differ in age of onset and clinical profile. However, recent genetic and epidemiological research suggests that these two neurodevelopmental disorders share certain risk factors. The aims of this review are to describe modifiable risk factors that have been identified in both disorders, and, where available, collate salient systematic reviews and meta-analyses that have examined shared risk factors. Based on searches of Medline, Embase and PsycINFO, inspection of review articles and expert opinion, we first compiled a set of candidate modifiable risk factors associated with autism. Where available, we next collated systematic-reviews (with or without meta-analyses) related to modifiable risk factors associated with both autism and schizophrenia. We identified three modifiable risk factors that have been examined in systematic reviews for both autism and schizophrenia. Advanced paternal age was reported as a risk factor for schizophrenia in a single meta-analysis and as a risk factor in two meta-analyses for autism. With respect to pregnancy and birth complications, for autism one meta-analysis identified maternal diabetes and bleeding during pregnancy as risks factors for autism whilst a meta-analysis of eight studies identified obstetric complications as a risk factor for schizophrenia. Migrant status was identified as a risk factor for both autism and schizophrenia. Two separate meta-analyses were identified for each disorder. Despite distinct clinical phenotypes, the evidence suggests that at least some non-genetic risk factors are shared between these two syndromes. In particular, exposure to drugs, nutritional excesses or deficiencies and infectious agents lend themselves to public health interventions. Studies are now needed to quantify any increase in risk of either autism or schizophrenia that is associated with these modifiable environmental factors. Copyright © 2012 Elsevier Inc. All rights reserved.

Identification of prostate cancer modifier pathways using parental strain expression mapping

PubMed Central

Xu, Qing; Majumder, Pradip K.; Ross, Kenneth; Shim, Yeonju; Golub, Todd R.; Loda, Massimo; Sellers, William R.

2007-01-01

Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease. PMID:17978178

Finite element analysis of low speed viscous and inviscid aerodynamic flows

NASA Technical Reports Server (NTRS)

Baker, A. J.; Manhardt, P. D.

1977-01-01

A weak interaction solution algorithm was established for aerodynamic flow about an isolated airfoil. Finite element numerical methodology was applied to solution of each of differential equations governing potential flow, and viscous and turbulent boundary layer and wake flow downstream of the sharp trailing edge. The algorithm accounts for computed viscous displacement effects on the potential flow. Closure for turbulence was accomplished using both first and second order models. The COMOC finite element fluid mechanics computer program was modified to solve the identified equation systems for two dimensional flows. A numerical program was completed to determine factors affecting solution accuracy, convergence and stability for the combined potential, boundary layer, and parabolic Navier-Stokes equation systems. Good accuracy and convergence are demonstrated. Each solution is obtained within the identical finite element framework of COMOC.

Postconditioning signalling in the heart: mechanisms and translatability

PubMed Central

Bice, Justin S; Baxter, Gary F

2015-01-01

The protective effect of ischaemic postconditioning (short cycles of reperfusion and reocclusion of a previously occluded vessel) was identified over a decade ago commanding intense interest as an approach for modifying reperfusion injury which contributes to infarct size in acute myocardial infarction. Elucidation of the major mechanisms of postconditioning has identified potential pharmacological targets for limitation of reperfusion injury. These include ligands for membrane-associated receptors, activators of phosphokinase survival signalling pathways and inhibitors of the mitochondrial permeability transition pore. In experimental models, numerous agents that target these mechanisms have shown promise as postconditioning mimetics. Nevertheless, clinical studies of ischaemic postconditioning and pharmacological postconditioning mimetics are equivocal. The majority of experimental research is conducted in animal models which do not fully portray the complexity of risk factors and comorbidities with which patients present and which we now know modify the signalling pathways recruited in postconditioning. Cohort size and power, patient selection, and deficiencies in clinical infarct size estimation may all represent major obstacles to assessing the therapeutic efficacy of postconditioning. Furthermore, chronic treatment of these patients with drugs like ACE inhibitors, statins and nitrates may modify signalling, inhibiting the protective effect of postconditioning mimetics, or conversely induce a maximally protected state wherein no further benefit can be demonstrated. Arguably, successful translation of postconditioning cannot occur until all of these issues are addressed, that is, experimental investigation requires more complex models that better reflect the clinical setting, while clinical investigation requires bigger trials with appropriate patient selection and standardization of clinical infarct size measurements. PMID:25303373

21 CFR 178.3520 - Industrial starch-modified.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Industrial starch-modified. 178.3520 Section 178... SANITIZERS Certain Adjuvants and Production Aids § 178.3520 Industrial starch-modified. Industrial starch... provisions of this section. (a) Industrial starch-modified is identified as follows: (1) A food starch...

21 CFR 178.3520 - Industrial starch-modified.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Industrial starch-modified. 178.3520 Section 178... SANITIZERS Certain Adjuvants and Production Aids § 178.3520 Industrial starch-modified. Industrial starch... provisions of this section. (a) Industrial starch-modified is identified as follows: (1) A food starch...

40 CFR 721.10145 - Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Modified reaction products of alkyl... Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino compound... identified generically as modified reaction products of alkyl alcohol, halogenated alkane, substituted...

40 CFR 721.10145 - Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified reaction products of alkyl... Modified reaction products of alkyl alcohol, halogenated alkane, substituted epoxide, and amino compound... identified generically as modified reaction products of alkyl alcohol, halogenated alkane, substituted...

40 CFR 721.4380 - Modified hydrocarbon resin.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Modified hydrocarbon resin. 721.4380... Substances § 721.4380 Modified hydrocarbon resin. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as a modified hydrocarbon resin (P-91-1418) is...

Improving organ donation rates by modifying the family approach process.

PubMed

Ebadat, Aileen; Brown, Carlos V R; Ali, Sadia; Guitierrez, Tim; Elliot, Eric; Dworaczyk, Sarah; Kadric, Carie; Coopwood, Ben

2014-06-01

The purpose of this study was to identify steps during family approach for organ donation that may be modified to improve consent rates of potential organ donors. Retrospective study of our local organ procurement organization (OPO) database of potential organ donors. Modifiable variables involved in the family approach of potential organ donors were collected and included race and sex of OPO representative, individual initiating approach discussion with family (RN or MD vs. OPO), length of donation discussion, use of a translator, and time of day of approach. Of 1137 potential organ donors, 661 (58%) consented and 476 (42%) declined. Consent rates were higher with matched race of donor and OPO representative (66% vs. 52%, p < 0.001), family approach by female OPO representative (67% vs. 56%, p = 0.002), if approach was initiated by OPO representative (69% vs. 49%, p < 0.001), and if consent rate was dependent on time of day the approach occurred: 6:00 am to noon (56%), noon to 6:00 pm (67%), 6:00 pm to midnight (68%), and midnight to 6:00 am (45%), p = 0.04. Family approach that led to consent lasted longer than those declining (67 vs. 43 minutes, p < 0.001). Independent predictors of consent to donation included female OPO representative (odds ratio [OR], 1.7; p = 0.006), approach discussion initiated by OPO representative (OR, 1.9; p = 0.001), and longer approach discussions (OR, 1.02; p < 0.001). The independent predictor of declined donation was the use of a translator (OR, 0.39; p = 0.01). Variables such as race and sex of OPO representative and time of day should be considered before approaching a family for organ donation. Avoiding translators during the approach process may improve donation rates. Education for health care providers should reinforce the importance of allowing OPO representatives to initiate the family approach for organ donation. Epidemiologic study, level IV. Therapeutic study, level IV.

The development of the modified blaylock tool for occupational therapy referral (MBTOTR): a preliminary evaluation of its utility in acute care.

PubMed

Tan, Emma Su Zan; Mackenzie, Lynette; Travasssaros, Katrina; Yeo, Megan

2016-08-01

Acute hospitals are facing more complex admissions with older people at increased risk of functional decline. This study aimed to create and trial the feasibility of a new screening tool designed to identify patients at risk of functional decline who need an occupational therapy referral within acute care. Ten screening tools were reviewed and the Modified Blaylock Tool for Occupational Therapy Referral (MBTOTR) was developed. The MBTOTR was applied in a retrospective chart review of 50 patients over the age of 65 years who were admitted to five acute wards. Data on patients identified at risk of functional decline were compared to patients who were referred to occupational therapy. Occupational therapy referrals were made by ward staff for 14 out of the 50 patients reviewed (32.5%). Only 14% (n = 7) of patients did not require a referral. The MBTOTR identified no irrelevant occupational therapy referrals. However, 66.5% of patients identified as needing an occupational therapy referral did not get one. The MBTOTR identified high risk acute patients requiring an occupational therapy referral who were not referred to occupational therapy. Use of the MBTOTR would facilitate early occupational therapy referrals for complex patients, and potentially better discharge outcomes. Implications for rehabilitation The MBTOTR can be used in acute care settings to facilitate relevant occupational therapy referrals. Without a screening tool, many older people who should have an occupational therapy assessment may not receive a referral for occupational therapy. Nursing and medical staff need to use this tool to identify older people in their care who may benefit from occupational therapy assessment and intervention. If occupational therapy referrals can be made early, this may contribute to reducing delays to discharge plans for complex patients.

A knowledge-based approach to estimating the magnitude and spatial patterns of potential threats to soil biodiversity.

PubMed

Orgiazzi, Alberto; Panagos, Panos; Yigini, Yusuf; Dunbar, Martha B; Gardi, Ciro; Montanarella, Luca; Ballabio, Cristiano

2016-03-01

Because of the increasing pressures exerted on soil, below-ground life is under threat. Knowledge-based rankings of potential threats to different components of soil biodiversity were developed in order to assess the spatial distribution of threats on a European scale. A list of 13 potential threats to soil biodiversity was proposed to experts with different backgrounds in order to assess the potential for three major components of soil biodiversity: soil microorganisms, fauna, and biological functions. This approach allowed us to obtain knowledge-based rankings of threats. These classifications formed the basis for the development of indices through an additive aggregation model that, along with ad-hoc proxies for each pressure, allowed us to preliminarily assess the spatial patterns of potential threats. Intensive exploitation was identified as the highest pressure. In contrast, the use of genetically modified organisms in agriculture was considered as the threat with least potential. The potential impact of climate change showed the highest uncertainty. Fourteen out of the 27 considered countries have more than 40% of their soils with moderate-high to high potential risk for all three components of soil biodiversity. Arable soils are the most exposed to pressures. Soils within the boreal biogeographic region showed the lowest risk potential. The majority of soils at risk are outside the boundaries of protected areas. First maps of risks to three components of soil biodiversity based on the current scientific knowledge were developed. Despite the intrinsic limits of knowledge-based assessments, a remarkable potential risk to soil biodiversity was observed. Guidelines to preliminarily identify and circumscribe soils potentially at risk are provided. This approach may be used in future research to assess threat at both local and global scale and identify areas of possible risk and, subsequently, design appropriate strategies for monitoring and protection of soil biota. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Characterization and safety evaluation of HPPD W336, a modified 4-hydroxyphenylpyruvate dioxygenase protein, and the impact of its expression on plant metabolism in herbicide-tolerant MST-FGØ72-2 soybean.

PubMed

Dreesen, Rozemarijn; Capt, Annabelle; Oberdoerfer, Regina; Coats, Isabelle; Pallett, Kenneth Edward

2018-06-09

By transgenic expression technology, a modified 4-hydroxyphenylpyruvate dioxygenase enzyme (HPPD W336) originating from Pseudomonas fluorescens is expressed in MST-FGØ72-2 soybean to confer tolerance to 4-benzoyl isoxazole and triketone type of herbicides1F. Characterization and safety assessment of HPPD W336 were performed. No relevant sequence homologies were found with known allergens or toxins. Although sequence identity to known toxins showed identity to HPPD proteins annotated as hemolysins, the absence of hemolytic activity of HPPD W336 was demonstrated in vitro. HPPD W336 degrades rapidly in simulated gastric fluid. The absence of toxicity and hemolytic potential of HPPD W336 was confirmed by in vivo studies. The substrate spectrum of HPPD W336 was compared with wild type HPPD proteins, demonstrating that its expression is unlikely to induce any metabolic shifts in soybean. The potential effect of expression of HPPD W336 on metabolic pathways related to tyrosine was investigated by comparing seed composition of MST-FGØ72-2 soybean with non-genetically modified varieties, demonstrating that expression of HPPD W336 does not change aromatic amino acid, homogentisate and tocochromanol levels. In conclusion, HPPD W336 was demonstrated to be as safe as other food proteins. No adverse metabolic effects were identified related to HPPD W336 expression in MST-FGØ72-2 soybean. Copyright © 2018. Published by Elsevier Inc.

Study of properties of modified silicones at solid-liquid interface: fabric-silicone interactions.

PubMed

Purohit, P; Somasundaran, P; Kulkarni, R

2006-06-15

Silicones are special reagents that impart desired surface properties such as softness, bounciness and antiwrinkle properties to fabrics and related materials. Although these finishing processes have been practiced routinely, very little is known about the mechanisms involved in modification so that they could be improved. The current study was undertaken to develop basic understanding of the mechanisms responsible for surface modification of fibers using silicones. PDMS based amino silicone emulsions, quaternized to various degrees using dimethyl sulphate, were used in the present study. The electrokinetic properties of the modified silicones were studied as a function of pH. It was expected that the silicone emulsions would show a steady positive zeta potential throughout the pH range due to the quaternization by dimethyl sulphate. Surprisingly, a sudden drop in the zeta potential was observed around pH 8 with the samples turning hazy in the pH range of 8-10. Turbidimetric studies also showed a sudden increase in the turbidity in the pH range 8-10 where commercial processes also encounter problems. It was concluded that the emulsions were destabilized at pH 8-10 thus rendering them ineffective for surface treatment. In order to identify reason for the improvement in fabric properties, fiber structure was monitored using atomic force microscopy. It was observed that the treated fibers were far smoother, relaxed and uniform as compared to the untreated fibers. Thus the morphology of the fabric is modified in a specific way by treatment with specialty silicones.

The development of a modified human IFN-alpha2b linked to the Fc portion of human IgG1 as a novel potential therapeutic for the treatment of hepatitis C virus infection.

PubMed

Jones, Tim D; Hanlon, Marian; Smith, Beverley J; Heise, Charles T; Nayee, Prakash D; Sanders, Deborah A; Hamilton, Anita; Sweet, Clive; Unitt, Esther; Alexander, Graeme; Lo, Kin-Ming; Gillies, Stephen D; Carr, Frank J; Baker, Matthew P

2004-09-01

Interferon-alpha (IFN-alpha), in conjunction with ribavirin, is the current standard for the treatment of chronic hepatitis C virus (HCV) infection. This treatment requires frequent dosing, with a significant risk of the development of anti-IFN-alpha neutralizing antibodies that correlates with lack of efficacy or relapse. We have developed an IFN-alpha linked to the Fc region of human IgG1 for improved half-life and less frequent dosing. We have also identified, using a human T cell proliferation assay, three regions of IFN-alpha2b that are potentially immunogenic, and a variant containing a total of six mutations within these regions was made. This variant was made as a fusion to Fc either with or without a flexible linker between the fusion partners. Both configurations of the variant were less active than native IFN-alpha alone, although the variant containing the flexible linker had in vitro antiviral activity within the range of other modified IFN-alphas currently in clinical use. Peptides spanning the modified regions were tested in T cell proliferation assays and found to be less immunogenic than native controls when using peripheral blood mononuclear cells (PBMCs) from both healthy individuals and HCV-infected patients who had been treated previously with IFN-alpha2b. Copyright Mary Ann Liebert, Inc.

Potentially Modifiable Factors Associated With Physical Activity in Individuals With Multiple Sclerosis.

PubMed

Reider, Nadia; Salter, Amber R; Cutter, Gary R; Tyry, Tuula; Marrie, Ruth Ann

2017-04-01

Physical activity levels among persons with multiple sclerosis (MS) are worryingly low. We aimed to identify the factors associated with physical activity for people with MS, with an emphasis on factors that have not been studied previously (bladder and hand dysfunction) and are potentially modifiable. This study was a secondary analysis of data collected in the spring of 2012 during the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry. NARCOMS participants were surveyed regarding smoking using questions from the Behavioral Risk Factor Surveillance Survey; disability using the Patient Determined Disease Steps; fatigue, cognition, spasticity, sensory, bladder, vision and hand function using self-reported Performance Scales; health literacy using the Medical Term Recognition Test; and physical activity using questions from the Health Information National Trends Survey. We used a forward binary logistic regression to develop a predictive model in which physical activity was the outcome variable. Of 8,755 respondents, 1,707 (19.5%) were classified as active and 7,068 (80.5%) as inactive. In logistic regression, being a current smoker, moderate or severe level of disability, depression, fatigue, hand, or bladder dysfunction and minimal to mild spasticity were associated with lower odds of meeting physical activity guidelines. MS type was not linked to activity level. Several modifiable clinical and lifestyle factors influenced physical activity in MS. Prospective studies are needed to evaluate whether modification of these factors can increase physical activity participation in persons with MS. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Creatine kinase: Essential arginine residues at the nucleotide binding site identified by chemical modification and high-resolution tandem mass spectrometry

PubMed Central

Wood, Troy D.; Guan, Ziqiang; Borders, Charles L.; Chen, Lorenzo H.; Kenyon, George L.; McLafferty, Fred W.

1998-01-01

Phenylglyoxal is an arginine-specific reagent that inactivates creatine kinase (CK). Previous results suggest that modification of the dimeric enzyme at a single arginine residue per subunit causes complete inactivation accompanied by the loss of nucleotide binding; the actual site of modification was not identified. Here, high-resolution tandem mass spectrometry (MS/MS) was used to identify three phenylglyoxal-modified Arg residues in monomeric rabbit muscle CK. Electrospray ionizaton Fourier-transform MS of the phenylglyoxal-modified CK that had lost ≈80% activity identified three species: unmodified, once-modified (+116 Da), and twice-modified (+232 Da) enzyme in a ratio of approximately 1:4:1. MS/MS restricts the derivatized sites to P122-P212 and P283-V332, whereas MS of Lys-C digestions revealed two modified peptides, A266-K297 and G116-K137. The only Arg in A266-K297 is Arg-291 (invariant), whereas MS/MS of modified G116-K137 shows that two of the three sites Arg-129, Arg-131, or Arg-134 (all invariant) can contain the modification. The recently reported x-ray crystal structure for the octameric chicken mitochondrial CK indicates that its nucleotide triphosphate-binding site indeed contains the equivalent of R291, R129, and R131 reported here to be at the active site of rabbit muscle CK. PMID:9520370

A next generation multiscale view of inborn errors of metabolism

PubMed Central

Argmann, Carmen A.; Houten, Sander M.; Zhu, Jun; Schadt, Eric E.

2015-01-01

Inborn errors of metabolism (IEM) are not unlike common diseases. They often present as a spectrum of disease phenotypes that correlates poorly with the severity of the disease-causing mutations. This greatly impacts patient care and reveals fundamental gaps in our knowledge of disease modifying biology. Systems biology approaches that integrate multi-omics data into molecular networks have significantly improved our understanding of complex diseases. Similar approaches to study IEM are rare despite their complex nature. We highlight that existing common disease-derived datasets and networks can be repurposed to generate novel mechanistic insight in IEM and potentially identify candidate modifiers. While understanding disease pathophysiology will advance the IEM field, the ultimate goal should be to understand per individual how their phenotype emerges given their primary mutation on the background of their whole genome, not unlike personalized medicine. We foresee that panomics and network strategies combined with recent experimental innovations will facilitate this. PMID:26712461

Phenotype-Based Screening of Small Molecules to Modify Plant Cell Walls Using BY-2 Cells.

PubMed

Okubo-Kurihara, Emiko; Matsui, Minami

2018-01-01

The plant cell wall is an important and abundant biomass with great potential for use as a modern recyclable resource. For effective utilization of this cellulosic biomass, its ability to degrade efficiently is key point. With the aim of modifying the cell wall to allow easy decomposition, we used chemical biological technology to alter its structure. As a first step toward evaluating the chemicals in the cell wall we employed a phenotype-based approach using high-throughput screening. As the plant cell wall is essential in determining cell morphology, phenotype-based screening is particularly effective in identifying compounds that bring about alterations in the cell wall. For rapid and reproducible screening, tobacco BY-2 cell is an excellent system in which to observe cell morphology. In this chapter, we provide a detailed chemical biological methodology for studying cell morphology using tobacco BY-2 cells.

DTREEv2, a computer-based support system for the risk assessment of genetically modified plants.

PubMed

Pertry, Ine; Nothegger, Clemens; Sweet, Jeremy; Kuiper, Harry; Davies, Howard; Iserentant, Dirk; Hull, Roger; Mezzetti, Bruno; Messens, Kathy; De Loose, Marc; de Oliveira, Dulce; Burssens, Sylvia; Gheysen, Godelieve; Tzotzos, George

2014-03-25

Risk assessment of genetically modified organisms (GMOs) remains a contentious area and a major factor influencing the adoption of agricultural biotech. Methodologically, in many countries, risk assessment is conducted by expert committees with little or no recourse to databases and expert systems that can facilitate the risk assessment process. In this paper we describe DTREEv2, a computer-based decision support system for the identification of hazards related to the introduction of GM-crops into the environment. DTREEv2 structures hazard identification and evaluation by means of an Event-Tree type of analysis. The system produces an output flagging identified hazards and potential risks. It is intended to be used for the preparation and evaluation of biosafety dossiers and, as such, its usefulness extends to researchers, risk assessors and regulators in government and industry. Copyright © 2013 Elsevier B.V. All rights reserved.

Quasi-experimental study designs series-paper 9: collecting data from quasi-experimental studies.

PubMed

Aloe, Ariel M; Becker, Betsy Jane; Duvendack, Maren; Valentine, Jeffrey C; Shemilt, Ian; Waddington, Hugh

2017-09-01

To identify variables that must be coded when synthesizing primary studies that use quasi-experimental designs. All quasi-experimental (QE) designs. When designing a systematic review of QE studies, potential sources of heterogeneity-both theory-based and methodological-must be identified. We outline key components of inclusion criteria for syntheses of quasi-experimental studies. We provide recommendations for coding content-relevant and methodological variables and outlined the distinction between bivariate effect sizes and partial (i.e., adjusted) effect sizes. Designs used and controls used are viewed as of greatest importance. Potential sources of bias and confounding are also addressed. Careful consideration must be given to inclusion criteria and the coding of theoretical and methodological variables during the design phase of a synthesis of quasi-experimental studies. The success of the meta-regression analysis relies on the data available to the meta-analyst. Omission of critical moderator variables (i.e., effect modifiers) will undermine the conclusions of a meta-analysis. Copyright © 2017 Elsevier Inc. All rights reserved.

Noninvasive multi–photon fluorescence microscopy resolves retinol and retinal–condensation products in mouse eyes

PubMed Central

Palczewska, Grazyna; Maeda, Tadao; Imanishi, Yoshikazu; Sun, Wenyu; Chen, Yu; Williams, David R.; Piston, David; Maeda, Akiko; Palczewski, Krzysztof

2010-01-01

Multi–photon excitation fluorescence microscopy (MPM) can image certain molecular processes in vivo. In the eye, fluorescent retinyl esters in sub–cellular structures called retinosomes mediate regeneration of the visual chromophore, 11–cis–retinal, by the visual cycle. But harmful fluorescent condensation products were also identified previously. We report that in wild type mice, excitation with λ ~730 nm identified retinosomes in the retinal pigment epithelium, whereas excitation with λ ~910 nm revealed at least one additional retinal fluorophore. The latter fluorescence was absent in eyes of genetically modified mice lacking a functional visual cycle, but accentuated in eyes of older WT mice and mice with defective clearance of all–trans–retinal, an intermediate in the visual cycle. MPM, a noninvasive imaging modality that facilitates concurrent monitoring of retinosomes along with potentially harmful products in aging eyes, has the potential to detect early molecular changes due to age–related macular degeneration and other defects in retinoid metabolism. PMID:21076393

Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models.

PubMed

Hannan, Shabab B; Dräger, Nina M; Rasse, Tobias M; Voigt, Aaron; Jahn, Thomas R

2016-04-01

Abnormal tau accumulations were observed and documented in post-mortem brains of patients affected by Alzheimer's disease (AD) long before the identification of mutations in the Microtubule-associated protein tau (MAPT) gene, encoding the tau protein, in a different neurodegenerative disease called Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17). The discovery of mutations in the MAPT gene associated with FTDP-17 highlighted that dysfunctions in tau alone are sufficient to cause neurodegeneration. Invertebrate models have been diligently utilized in investigating tauopathies, contributing to the understanding of cellular and molecular pathways involved in disease etiology. An important discovery came with the demonstration that over-expression of human tau in Drosophila leads to premature mortality and neuronal dysfunction including neurodegeneration, recapitulating some key neuropathological features of the human disease. The simplicity of handling invertebrate models combined with the availability of a diverse range of experimental resources make these models, in particular Drosophila a powerful invertebrate screening tool. Consequently, several large-scale screens have been performed using Drosophila, to identify modifiers of tau toxicity. The screens have revealed not only common cellular and molecular pathways, but in some instances the same modifier has been independently identified in two or more screens suggesting a possible role for these modifiers in regulating tau toxicity. The purpose of this review is to discuss the genetic modifier screens on tauopathies performed in Drosophila and C. elegans models, and to highlight the common cellular and molecular pathways that have emerged from these studies. Here, we summarize results of tau toxicity screens providing mechanistic insights into pathological alterations in tauopathies. Key pathways or modifiers that have been identified are associated with a broad range of processes including, but not limited to, phosphorylation, cytoskeleton organization, axonal transport, regulation of cellular proteostasis, transcription, RNA metabolism, cell cycle regulation, and apoptosis. We discuss the utility and application of invertebrate models in elucidating the cellular and molecular functions of novel and uncharacterized disease modifiers identified in large-scale screens as well as for investigating the function of genes identified as risk factors in genome-wide association studies from human patients in the post-genomic era. In this review, we combined and summarized several large-scale modifier screens performed in invertebrate models to identify modifiers of tau toxicity. A summary of the screens show that diverse cellular processes are implicated in the modification of tau toxicity. Kinases and phosphatases are the most predominant class of modifiers followed by components required for cellular proteostasis and axonal transport and cytoskeleton elements. © 2016 International Society for Neurochemistry.

Workshop overview: approaches to the assessment of the allergenic potential of food from genetically modified crops.

PubMed

Ladics, Gregory S; Holsapple, Michael P; Astwood, James D; Kimber, Ian; Knippels, Leon M J; Helm, Ricki M; Dong, Wumin

2003-05-01

There is a need to assess the safety of foods deriving from genetically modified (GM) crops, including the allergenic potential of novel gene products. Presently, there is no single in vitro or in vivo model that has been validated for the identification or characterization of potential food allergens. Instead, the evaluation focuses on risk factors such as source of the gene (i.e., allergenic vs. nonallergenic sources), physicochemical and genetic comparisons to known allergens, and exposure assessments. The purpose of this workshop was to gather together researchers working on various strategies for assessing protein allergenicity: (1) to describe the current state of knowledge and progress that has been made in the development and evaluation of appropriate testing strategies and (2) to identify critical issues that must now be addressed. This overview begins with a consideration of the current issues involved in assessing the allergenicity of GM foods. The second section presents information on in vitro models of digestibility, bioinformatics, and risk assessment in the context of clinical prevention and management of food allergy. Data on rodent models are presented in the next two sections. Finally, nonrodent models for assessing protein allergenicity are discussed. Collectively, these studies indicate that significant progress has been made in developing testing strategies. However, further efforts are needed to evaluate and validate the sensitivity, specificity, and reproducibility of many of these assays for determining the allergenicity potential of GM foods.

The applicability of animal health surveillance systems for post-market monitoring of potential adverse effects of genetically modified (GM) feed.

PubMed

Vince, L; Kleter, G A; Kostov, K; Pfeiffer, D U; Guitian, J

2018-04-20

A facultative post market monitoring of potential health impacts of genetically modified (GM) feedstuffs on livestock consuming these feeds after pre-market risk assessment is under ongoing consideration. Within the IPAFEED database, scientific studies on health effects beyond performance in livestock and the results of a systematic search for evidence of outcome effects due to GM feed are consolidated. These outcomes were reviewed and checked for consistency in order to identify plausible syndromes suitable for conducting surveillance. The 24 selected studies showed no consistent changes in any health parameter. There were no repeated studies in any species by GM crop type and animal species. As such, there is insufficient evidence to inform the design of surveillance systems for detecting known adverse effects. Animal health surveillance systems have been proposed for the post market monitoring of potential adverse effects in animals. Such systems were evaluated for their applicability to the detection of hypothetical adverse effects and their strengths and weaknesses to detect syndromes of concern are presented. For known adverse effects, applied controlled post-market studies may yield conclusive and high-quality evidence. For detecting unknown adverse effects, the use of existing surveillance systems may still be of interest. A simulation tool developed within the project can be adapted and applied to existing surveillance systems to explore their applicability to the detection of potential adverse effects of GM feed. Copyright © 2018. Published by Elsevier Ltd.

Post-Operative Cognitive Dysfunction: An exploration of the inflammatory hypothesis and novel therapies.

PubMed

Skvarc, David R; Berk, Michael; Byrne, Linda K; Dean, Olivia M; Dodd, Seetal; Lewis, Matthew; Marriott, Andrew; Moore, Eileen M; Morris, Gerwyn; Page, Richard S; Gray, Laura

2018-01-01

Post-Operative Cognitive Dysfunction (POCD) is a highly prevalent condition with significant clinical, social and financial impacts for patients and their communities. The underlying pathophysiology is becoming increasingly understood, with the role of neuroinflammation and oxidative stress secondary to surgery and anaesthesia strongly implicated. This review aims to describe the putative mechanisms by which surgery-induced inflammation produces cognitive sequelae, with a focus on identifying potential novel therapies based upon their ability to modify these pathways. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Communication strategies to improve HIV treatment adherence.

PubMed

Rochon, Donna; Ross, Michael W; Looney, Carol; Nepal, Vishnu P; Price, Andrea J; Giordano, Thomas P

2011-01-01

Although antiretroviral therapy has increased the survival of HIV-positive patients, traditional approaches to improving medication adherence have failed consistently. Acknowledging the role of communication in health behavior, we conducted a qualitative study to learn about patients' HIV treatment adherence experiences and to identify which communication strategies might influence adherence. Findings indicate that five constructs--cultural beliefs/language, stigma, cues to action, self-efficacy, and mood state--are potentially modifiable by improved communication. Results will be used to create a direct marketing campaign targeted to HIV-infected patients. Copyright © Taylor & Francis Group, LLC

Factors associated with stress among adolescents in the city of Nawabshah, Pakistan.

PubMed

Parpio, Yasmin; Farooq, Salima; Gulzar, Saleema; Tharani, Ambreen; Javed, Fawad; Ali, Tazeen Saeed

2012-11-01

To identify the risk factors of stress among school-going adolescents in rural Nawabshah, Pakistan. The cross-sectional study was conducted in 2005, comprising 800 school-going children of 10-16 years of age in Nawabshah, through simple random sampling. Data was collected using a structured questionnaire to assess the potential risk factors of stress. A modified version of Perceived stress scale was utilized to measure stress level. SPSS 12 was used for statistical analysis, while multiple linear regression analysis was run to identify the factors associated with stress in the study population. Of the total, 529 (66%) children belonged to state-run schools while 271 (34%) were studying at private facilities. The mean age was 13.7+/-1.3 years. The level of stress was positively associated with the number of siblings, parental conflicts, the age of the mother and the number of rooms in the household. There was decreased level of stress among female adolescents (n=474; 59.3%) who had prior information about pubertal body changes than the boys (n=326; 40.8%). The study showed that stress among adolescents can be reduced by modifying socio-economic and demographic factors.

Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

PubMed Central

Okeke, Malachy I.; Okoli, Arinze S.; Offor, Collins; Oludotun, Taiwo G.; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

2017-01-01

Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines. PMID:29109380

Hazard Characterization of Modified Vaccinia Virus Ankara Vector: What Are the Knowledge Gaps?

PubMed

Okeke, Malachy I; Okoli, Arinze S; Diaz, Diana; Offor, Collins; Oludotun, Taiwo G; Tryland, Morten; Bøhn, Thomas; Moens, Ugo

2017-10-29

Modified vaccinia virus Ankara (MVA) is the vector of choice for human and veterinary applications due to its strong safety profile and immunogenicity in vivo. The use of MVA and MVA-vectored vaccines against human and animal diseases must comply with regulatory requirements as they pertain to environmental risk assessment, particularly the characterization of potential adverse effects to humans, animals and the environment. MVA and recombinant MVA are widely believed to pose low or negligible risk to ecosystem health. However, key aspects of MVA biology require further research in order to provide data needed to evaluate the potential risks that may occur due to the use of MVA and MVA-vectored vaccines. The purpose of this paper is to identify knowledge gaps in the biology of MVA and recombinant MVA that are of relevance to its hazard characterization and discuss ongoing and future experiments aimed at providing data necessary to fill in the knowledge gaps. In addition, we presented arguments for the inclusion of uncertainty analysis and experimental investigation of verifiable worst-case scenarios in the environmental risk assessment of MVA and recombinant MVA. These will contribute to improved risk assessment of MVA and recombinant MVA vaccines.

Para-nitrobenzyl esterases with enhanced activity in aqueous and nonaqueous media

DOEpatents

Arnold, Frances H.; Moore, Jeffrey C.

1998-01-01

A method for isolating and identifying modified para-nitrobenzyl esterases which exhibit improved stability and/or esterase hydrolysis activity toward selected substrates and under selected reaction conditions relative to the unmodified para-nitrobenzyl esterase. The method involves preparing a library of modified para-nitrobenzyl esterase nucleic acid segments (genes) which have nucleotide sequences that differ from the nucleic acid segment which encodes for unmodified para-nitrobenzyl esterase. The library of modified para-nitrobenzyl nucleic acid segments is expressed to provide a plurality of modified enzymes. The clones expressing modified enzymes are then screened to identify which enzymes have improved esterase activity by measuring the ability of the enzymes to hydrolyze the selected substrate under the selected reaction conditions. Specific modified para-nitrobenzyl esterases are disclosed which have improved stability and/or ester hydrolysis activity in aqueous or aqueous-organic media relative to the stability and/or ester hydrolysis activity of unmodified naturally occurring para-nitrobenzyl esterase.

Para-nitrobenzyl esterases with enhanced activity in aqueous and nonaqueous media

DOEpatents

Arnold, Frances H.; Moore, Jeffrey C.

1999-01-01

A method for isolating and identifying modified para-nitrobenzyl esterases which exhibit improved stability and/or esterase hydrolysis activity toward selected substrates and under selected reaction conditions relative to the unmodified para-nitrobenzyl esterase. The method involves preparing a library of modified para-nitrobenzyl esterase nucleic acid segments (genes) which have nucleotide sequences that differ from the nucleic acid segment which encodes for unmodified para-nitrobenzyl esterase. The library of modified para-nitrobenzyl nucleic acid segments is expressed to provide a plurality of modified enzymes. The clones expressing modified enzymes are then screened to identify which enzymes have improved esterase activity by measuring the ability of the enzymes to hydrolyze the selected substrate under the selected reaction conditions. Specific modified para-nitrobenzyl esterases are disclosed which have improved stability and/or ester hydrolysis activity in aqueous or aqueous-organic media relative to the stability and/or ester hydrolysis activity of unmodified naturally occurring para-nitrobenzyl esterase.

Top-down and bottom-up characterization of nitrated birch pollen allergen Bet v 1a with CZE hyphenated to an Orbitrap mass spectrometer.

PubMed

Gusenkov, Sergey; Stutz, Hanno

2018-02-01

Tyrosine (Tyr) residues of the major pollen allergen of birch Betula verrucosa, Bet v 1a, were nitrated by peroxynitrite. This modification enhances the allergenicity. Modified tyrosines were identified by analyzing intact allergen variants in combination with top-down and bottom-up approaches. Therefore, a laboratory-built sheath-liquid assisted ESI interface was applied for hyphenation of CE to an Orbitrap mass spectrometer to localize individual nitration sites. The major focus was on identification of primary nitration sites. The top-down approach unambiguously identified Tyr 5 as the most prominent modification site. Fragments from the allergen core and the C-terminal part carried up to three potential nitration sites, respectively. Thus, a bottom-up approach with tryptic digest was used as a complementary strategy which allowed for the unambiguous localization of nitration sites within the respective peptides. Nitration propensity for individual Tyr residues was addressed by comparison of MS signals of nitrated peptides relative to all cognates of homolog primary sequence. Combined data identified surface exposed Tyr 5 and Tyr 66 as major nitration sites followed by less accessible Tyr 158 whereas Tyr 81, 83 and 150 possess a lower nitration tendency and are apparently modified in variants with higher nitration levels. © 2018 The Authors. Electrophoresis published by Wiley-VCH Verlag GmbH & Co. KGaA.

Genetically modified plants and food hypersensitivity diseases: usage and implications of experimental models for risk assessment.

PubMed

Prescott, Vanessa E; Hogan, Simon P

2006-08-01

The recent advances in biotechnology in the plant industry have led to increasing crop production and yield that in turn has increased the usage of genetically modified (GM) food in the human food chain. The usage of GM foods for human consumption has raised a number of fundamental questions including the ability of GM foods to elicit potentially harmful immunological responses, including allergic hypersensitivity. To assess the safety of foods derived from GM plants including allergenic potential, the US FDA, Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO), and the EU have developed approaches for evaluation assessment. One assessment approach that has been a very active area of research and debate is the development and usage of animal models to assess the potential allergenicity of GM foods. A number of specific animal models employing rodents, pigs, and dogs have been developed for allergenicity assessment. However, validation of these models is needed and consideration of the criteria for an appropriate animal model for the assessment of allergenicity in GM plants is required. We have recently employed a BALB/c mouse model to assess the potential allergenicity of GM plants. We have been able to demonstrate that this model is able to detect differences in antigenicity and identify aspects of protein post-translational modifications that can alter antigenicity. Furthermore, this model has also enabled us to examine the usage of GM plants as a therapeutic approach for the treatment of allergic diseases. This review discusses the current approaches to assess the allergenic potential of GM food and particularly focusing on the usage of animal models to determine the potential allergenicity of GM foods and gives an overview of our recent findings and implications of these studies.

Physical characteristics, antimicrobial and odontogenesis potentials of calcium silicate cement containing hinokitiol.

PubMed

Huang, Ming-Hsien; Shen, Yu-Fang; Hsu, Tuan-Ti; Huang, Tsui-Hsien; Shie, Ming-You

2016-08-01

Hinokitiol is a natural material and it has antibacterial and anti-inflammatory effects. The purpose of this study was to evaluate the material characterization, cell viability, antibacterial and anti-inflammatory abilities of the hinokitiol-modified calcium silicate (CS) cement as a root end filling material. The setting times, diametral tensile strength (DTS) values and XRD patterns of CS cements with 0-10mM hinokitiol were examined. Then, the antibacterial effect and the expression levels of cyclooxygenase 2 (COX-2) and interleukin-1 (IL-1) of the hinokitiol-modified CS cements were evaluated. Furthermore, the cytocompatibility, the expression levels of the markers of odontoblastic differentiation, mineralized nodule formation and calcium deposition of human dental pulp cells (hDPCs) cultured on hinokitiol-modified CS cements were determined. The hinokitiol-modified CS cements had better antibacterial and anti-inflammatory abilities and cytocompatibility than non-modified CS cements. Otherwise, the hinokitiol-modified CS cements had suitable setting times and better odontoblastic potential of hDPCs. Previous report pointed out that the root-end filling materials may induce inflammatory cytokines reaction. In our study, hinokitiol-modified CS cements not only inhibited the expression level of inflammatory cytokines, but also had better cytocompatibility, antimicrobial properties and active ability of odontoblastic differentiation of hDPCs. Therefore, the hinokitiol-modified CS cement may be a potential root end filling material for clinic. Copyright © 2016 Elsevier B.V. All rights reserved.

40 CFR 721.10044 - Metal oxide, modified with alkyl and vinyl terminated polysiloxanes (generic).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Metal oxide, modified with alkyl and... SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10044 Metal oxide, modified with alkyl... to reporting. (1) The chemical substance identified generically as metal oxide, modified with alkyl...

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Modified polymer of vinyl acetate and... Significant New Uses for Specific Chemical Substances § 721.8658 Modified polymer of vinyl acetate and.... (1) The chemical substance identified generically as modified polymer of vinyl acetate and quaternary...

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Modified polymer of vinyl acetate and... Significant New Uses for Specific Chemical Substances § 721.8658 Modified polymer of vinyl acetate and.... (1) The chemical substance identified generically as modified polymer of vinyl acetate and quaternary...

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Modified polymer of vinyl acetate and... Significant New Uses for Specific Chemical Substances § 721.8658 Modified polymer of vinyl acetate and.... (1) The chemical substance identified generically as modified polymer of vinyl acetate and quaternary...

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Modified polymer of vinyl acetate and... Significant New Uses for Specific Chemical Substances § 721.8658 Modified polymer of vinyl acetate and.... (1) The chemical substance identified generically as modified polymer of vinyl acetate and quaternary...

40 CFR 721.8658 - Modified polymer of vinyl acetate and quaternary ammonium compound (generic).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Modified polymer of vinyl acetate and... Significant New Uses for Specific Chemical Substances § 721.8658 Modified polymer of vinyl acetate and.... (1) The chemical substance identified generically as modified polymer of vinyl acetate and quaternary...

77 FR 20822 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Initial Review

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-06

... announced below concerns Identifying Modifiable Protective Factors for Intimate Partner Violence or Sexual Violence Perpetration, Funding Opportunity Announcement (FOA) CE12-003, Initial Review In accordance with... in response to ``Identifying Modifiable Protective Factors for Intimate Partner Violence or Sexual...

A Case Study on Improving Intensive Care Unit (ICU) Services Reliability: By Using Process Failure Mode and Effects Analysis (PFMEA)

PubMed Central

Yousefinezhadi, Taraneh; Jannesar Nobari, Farnaz Attar; Goodari, Faranak Behzadi; Arab, Mohammad

2016-01-01

Introduction: In any complex human system, human error is inevitable and shows that can’t be eliminated by blaming wrong doers. So with the aim of improving Intensive Care Units (ICU) reliability in hospitals, this research tries to identify and analyze ICU’s process failure modes at the point of systematic approach to errors. Methods: In this descriptive research, data was gathered qualitatively by observations, document reviews, and Focus Group Discussions (FGDs) with the process owners in two selected ICUs in Tehran in 2014. But, data analysis was quantitative, based on failures’ Risk Priority Number (RPN) at the base of Failure Modes and Effects Analysis (FMEA) method used. Besides, some causes of failures were analyzed by qualitative Eindhoven Classification Model (ECM). Results: Through FMEA methodology, 378 potential failure modes from 180 ICU activities in hospital A and 184 potential failures from 99 ICU activities in hospital B were identified and evaluated. Then with 90% reliability (RPN≥100), totally 18 failures in hospital A and 42 ones in hospital B were identified as non-acceptable risks and then their causes were analyzed by ECM. Conclusions: Applying of modified PFMEA for improving two selected ICUs’ processes reliability in two different kinds of hospitals shows that this method empowers staff to identify, evaluate, prioritize and analyze all potential failure modes and also make them eager to identify their causes, recommend corrective actions and even participate in improving process without feeling blamed by top management. Moreover, by combining FMEA and ECM, team members can easily identify failure causes at the point of health care perspectives. PMID:27157162

Identifying Risk for Acute Kidney Injury in Infants and Children Following Cardiac Arrest.

PubMed

Neumayr, Tara M; Gill, Jeff; Fitzgerald, Julie C; Gazit, Avihu Z; Pineda, Jose A; Berg, Robert A; Dean, J Michael; Moler, Frank W; Doctor, Allan

2017-10-01

Our goal was to identify risk factors for acute kidney injury in children surviving cardiac arrest. Retrospective analysis of a public access dataset. Fifteen children's hospitals associated with the Pediatric Emergency Care Applied Research Network. Two hundred ninety-six subjects between 1 day and 18 years old who experienced in-hospital or out-of-hospital cardiac arrest between July 1, 2003, and December 31, 2004. None. Our primary outcome was development of acute kidney injury as defined by the Acute Kidney Injury Network criteria. An ordinal probit model was developed. We found six critical explanatory variables, including total number of epinephrine doses, postcardiac arrest blood pressure, arrest location, presence of a chronic lung condition, pH, and presence of an abnormal baseline creatinine. Total number of epinephrine doses received as well as rate of epinephrine dosing impacted acute kidney injury risk and severity of acute kidney injury. This study is the first to identify risk factors for acute kidney injury in children after cardiac arrest. Our findings regarding the impact of epinephrine dosing are of particular interest and suggest potential for epinephrine toxicity with regard to acute kidney injury. The ability to identify and potentially modify risk factors for acute kidney injury after cardiac arrest may lead to improved morbidity and mortality in this population.

Promoting and Protecting Against Stigma in Assisted Living and Nursing Homes

PubMed Central

Zimmerman, Sheryl; Dobbs, Debra; Roth, Erin G.; Goldman, Susan; Peeples, Amanda D.; Wallace, Brandy

2016-01-01

Purpose of the Study: To determine the extent to which structures and processes of care in multilevel settings (independent living, assisted living, and nursing homes) result in stigma in assisted living and nursing homes. Design and Methods: Ethnographic in-depth interviews were conducted in 5 multilevel settings with 256 residents, families, and staff members. Qualitative analyses identified the themes that resulted when examining text describing either structures of care or processes of care in relation to 7 codes associated with stigma. Results: Four themes related to structures of care and stigma were identified, including the physical environment, case mix, staff training, and multilevel settings; five themes related to processes of care and stigma, including dining, independence, respect, privacy, and care provision. For each theme, examples were identified illustrating how structures and processes of care can potentially promote or protect against stigma. Implications: In no instance were examples or themes identified that suggested the staff intentionally promoted stigma; on the other hand, there was indication that some structures and processes were intentionally in place to protect against stigma. Perhaps the most important theme is the stigma related to multilevel settings, as it has the potential to reduce individuals’ likelihood to seek and accept necessary care. Results suggest specific recommendations to modify care and reduce stigma. PMID:24928555

Risk factors for Dandy-Walker malformation: a population-based assessment.

PubMed

Reeder, Matthew R; Botto, Lorenzo D; Keppler-Noreuil, Kim M; Carey, John C; Byrne, Janice L B; Feldkamp, Marcia L

2015-09-01

Dandy-Walker malformation (DWM) is the most common congenital malformation of the cerebellum, but its causes are largely unknown. An increasing number of genes associated with congenital cerebellar malformations have been identified; however, few studies have examined the potential role of non-genetic, potentially modifiable risk factors. From the National Birth Defects Prevention Study, we examined maternal, paternal, and infant characteristics and maternal conditions and periconceptional exposures (from 1 month before to 3 months after conception) among infants with DWM (n = 160) and unaffected controls (n = 10,200), delivered between 1997 and 2009. Odds ratios, crude (cOR) and adjusted (aOR) were computed using logistic regression. Maternal factors associated with DWM included non-Hispanic black race/ethnicity (aOR = 2.0, 95%CI: 1.3-3.2). Among maternal conditions, a history of infertility increased the risk for DWM (all: aOR = 2.4, 95%CI: 1.3-4.6; multiple: aOR = 3.9, 95%CI: 1.7-8.9). The lack of association with many maternal exposures supports the hypothesis of a major contribution of genetic factors to the risk for DWM; however, the observed associations with maternal non-Hispanic black race/ethnicity and maternal history of infertility indicate that further research into factors underlying these characteristics may uncover potentially modifiable risk factors, acting alone or as a component of gene-environment interactions. © 2015 Wiley Periodicals, Inc.

Case studies on genetically modified organisms (GMOs): Potential risk scenarios and associated health indicators.

PubMed

de Santis, Barbara; Stockhofe, Norbert; Wal, Jean-Michel; Weesendorp, Eefke; Lallès, Jean-Paul; van Dijk, Jeroen; Kok, Esther; De Giacomo, Marzia; Einspanier, Ralf; Onori, Roberta; Brera, Carlo; Bikker, Paul; van der Meulen, Jan; Kleter, G

2018-07-01

Within the frame of the EU-funded MARLON project, background data were reviewed to explore the possibility of measuring health indicators during post-market monitoring for potential effects of feeds, particularly genetically modified (GM) feeds, on livestock animal health, if applicable. Four case studies (CSs) of potential health effects on livestock were framed and the current knowledge of a possible effect of GM feed was reviewed. Concerning allergenicity (CS-1), there are no case-reports of allergic reactions or immunotoxic effects resulting from GM feed consumption as compared with non-GM feed. The likelihood of horizontal gene transfer (HGT; CS-2) of GMO-related DNA to different species is not different from that for other DNA and is unlikely to raise health concerns. Concerning mycotoxins (CS-3), insect-resistant GM maize may reduce fumonisins contamination as a health benefit, yet other Fusarium toxins and aflatoxins show inconclusive results. For nutritionally altered crops (CS-4), the genetic modifications applied lead to compositional changes which require special considerations of their nutritional impacts. No health indicators were thus identified except for possible beneficial impacts of reduced mycotoxins and nutritional enhancement. More generally, veterinary health data should ideally be linked with animal exposure information so as to be able to establish cause-effect relationships. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interobserver and intraobserver variability in the identification of the Lenke classification lumbar modifier in adolescent idiopathic scoliosis.

PubMed

Duong, Luc; Cheriet, Farida; Labelle, Hubert; Cheung, Kenneth M C; Abel, Mark F; Newton, Peter O; McCall, Richard E; Lenke, Lawrence G; Stokes, Ian A F

2009-08-01

Interobserver and intraobserver reliability study for the identification of the Lenke classification lumbar modifier by a panel of experts compared with a computer algorithm. To measure the variability of the Lenke classification lumbar modifier and determine if computer assistance using 3-dimensional spine models can improve the reliability of classification. The lumbar modifier has been proposed to subclassify Lenke scoliotic curve types into A, B, and C on the basis of the relationship between the central sacral vertical line (CSVL) and the apical lumbar vertebra. Landmarks for identification of the CSVL have not been clearly defined, and the reliability of the actual CSVL position and lumbar modifier selection have never been tested independently. Therefore, the value of the lumbar modifier for curve classification remains unknown. The preoperative radiographs of 68 patients with adolescent idiopathic scoliosis presenting a Lenke type 1 curve were measured manually twice by 6 members of the Scoliosis Research Society 3-dimensional classification committee at 6 months interval. Intraobserver and interobserver reliability was quantified using the percentage of agreement and kappa statistics. In addition, the lumbar curve of all subjects was reconstructed in 3-dimension using a stereoradiographic technique and was submitted to a computer algorithm to infer the lumbar modifier according to measurements from the pedicles. Interobserver rates for the first trial showed a mean kappa value of 0.56. Second trial rates were higher with a mean kappa value of 0.64. Intraobserver rates were evaluated at a mean kappa value of 0.69. The computer algorithm was successful in identifying the lumbar curve type and was in agreement with the observers by a proportion up to 93%. Agreement between and within observers for the Lenke lumbar modifier is only moderate to substantial with manual methods. Computer assistance with 3-dimensional models of the spine has the potential to decrease this variability.

Controversies in Alzheimer's disease drug development.

PubMed

Cummings, Jeffrey L

2008-08-01

Understanding of the pathophysiological basis of Alzheimer's disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer's disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described.

An explanatory model for state Medicaid per capita prescription drug expenditures.

PubMed

Roy, Sanjoy; Madhavan, S Suresh

2012-01-01

Rising prescription drug expenditure is a growing concern for publicly funded drug benefit programs like Medicaid. To be able to contain drug expenditures in Medicaid, it is important that cause(s) for such increases are identified. This study attempts to establish an explanatory model for Medicaid prescription drugs expenditure based on the impacts of key influencers/predictors identified using a comprehensive framework of drug utilization. A modified Andersen's behavior model of health services utilization is employed to identify potential determinants of pharmaceutical expenditures in state Medicaid programs. Level of federal matching funds, access to primary care, severity of diseases, unemployment, and education levels were found to be key influencers of Medicaid prescription drug expenditure. Increases in all, except education levels, were found to result in increases in drug expenditures. Findings from this study could better inform intervention policies and cost-containment strategies for state Medicaid drug benefit programs.

Determinants of Sunburn and Sun Protection of Agricultural Workers During Occupational and Recreational Activities.

PubMed

Backes, Claudine; Milon, Antoine; Koechlin, Alice; Vernez, David; Bulliard, Jean-Luc

2017-11-01

The aim of this study was to identify determinants of occupational sunburn in agricultural workers and assess their occupational and recreational sun protection habits. Specific surveys of agricultural workers in Switzerland and France were conducted (N = 1538). Multivariate logistic regressions identified occupational sunburn determinants. Occupational and recreational sun protection habits were estimated and correlated. One-year occupational and recreational sunburn prevalences were 19.8% and 11.5%, respectively. Occupational sunburn increased with having a recent recreational sunburn, highly sensitive skin, young age, high perceived skin cancer risk, using sunscreen, and not wearing a hat. Correlation between protection habits during work and leisure was substantial (rs 0.5 to 0.7). Skin health knowledge was high and pro-tanning attitude moderate. Potentially modifiable sunburn determinants and suboptimal recreational and occupational sun protection practices were identified in agricultural workers. Refining and tailoring sun protection messages targeting the agricultural sector are needed.

Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.

PubMed

Jóri, Balazs; Kamps, Rick; Xanthoulea, Sofia; Delvoux, Bert; Blok, Marinus J; Van de Vijver, Koen K; de Koning, Bart; Oei, Felicia Trups; Tops, Carli M; Speel, Ernst Jm; Kruitwagen, Roy F; Gomez-Garcia, Encarna B; Romano, Andrea

2015-12-01

The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer. A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis. A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype. A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.

Unpacking personalized feedback: an exploratory study of the impact of its components and the reactions it elicits among problem drinking men who have sex with men.

PubMed

Kuerbis, Alexis Noel; Schaumberg, Katherine; Davis, Christine M; Hail, Lisa; Morgenstern, Jon

2014-03-01

Personalized feedback (PF) has demonstrated effectiveness in reducing drinking. Few studies have examined its effectiveness with adult problem drinkers or its potential mediators or moderators, including developing discrepancy. This study aimed to identify potential mediators and moderators of PF provided to adult problem drinking men who have sex with men (PDMSM). An exploratory analysis of PF provided to PDMSM in the context of modified behavioral self-control therapy (N = 90). The association of individual items of PF, severity of PF, and independently rated, in-session participant reactions to PF with drinking outcomes (mean drinks per drinking day, MDDD) were examined using correlations and logistic and linear regression. Significant pre-post differences in MDDD emerged. Other drug risk, family risk, and having an abnormal liver enzyme test result were significantly associated with proxies for developed discrepancy in expected directions; however, no PF item or reaction to PF predicted drinking outcomes. Severity of PF was not associated with participant reactions or drinking outcome. PF may be an effective intervention for PDMSM. Further research is needed to identify potential mediators and moderators of PF among adults.

Wet deposition of mercury at a New York state rural site: Concentrations, fluxes, and source areas

NASA Astrophysics Data System (ADS)

Lai, Soon-onn; Holsen, Thomas M.; Hopke, Philip K.; Liu, Peng

Event-based mercury (Hg) precipitation samples were collected with a modified MIC-B sampler between September 2003 and April 2005 at Potsdam, NY to investigate Hg in wet deposition and identify potential source areas using the potential source contribution function (PCSF) and residence time weighted concentration (RTWC) models. The volume-weighted mean (VWM) concentration and wet deposition flux were 5.5ngL-1 and 7.6μgm-2 during the study period, and 5.5ngL-1 and 5.9μgm-2 in 2004, respectively, and show seasonal trends with larger values in the spring and summer. The PSCF model results matched known source areas based on an emission inventory better than did the RTWC results based on the spatial correlation index. Both modeling results identified large Hg source areas that contain a number of coal-fired power plants located in the Upper Ohio River Valley and in southeastern Michigan, as well as in Quebec and Ontario where there are metal production facilities, waste incinerators and paper mills. Emissions from the Atlantic Ocean were also determined to be a potential source.

21 CFR 177.1635 - Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene).

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Poly(p-methylstyrene) and rubber-modified poly(p... Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene). Poly(p-methylstyrene) and rubber-modified poly(p-methylstyrene) identified in this section may be safely used as components of articles...

21 CFR 177.1635 - Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene).

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Poly(p-methylstyrene) and rubber-modified poly(p... Components of Single and Repeated Use Food Contact Surfaces § 177.1635 Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene). Poly(p-methylstyrene) and rubber-modified poly(p-methylstyrene) identified...

21 CFR 177.1635 - Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene).

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Poly(p-methylstyrene) and rubber-modified poly(p... Poly(p-methylstyrene) and rubber-modified poly(p-methyl-styrene). Poly(p-methylstyrene) and rubber-modified poly(p-methylstyrene) identified in this section may be safely used as components of articles...

The use of genetically modified mice in cancer risk assessment: challenges and limitations.

PubMed

Eastmond, David A; Vulimiri, Suryanarayana V; French, John E; Sonawane, Babasaheb

2013-09-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53⁺/⁻, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

The use of genetically modified mice in cancer risk assessment: Challenges and limitations*

PubMed Central

Eastmond, David A.; Vulimiri, Suryanarayana V.; French, John E.; Sonawane, Babasaheb

2015-01-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. PMID:23985072

The effect of chemically modified electrospun silica nanofiber on the mRNA and miRNA expression profile of neural stem cell differentiation.

PubMed

Mercado, Augustus T; Yeh, Jui-Ming; Chin, Ting Yu; Chen, Wen Shuo; Chen-Yang, Yui Whei; Chen, Chung-Yung

2016-11-01

A detailed genomic and epigenomic analyses of neural stem cells (NSCs) differentiation in synthetic microenvironments is essential for the advancement of regenerative medicine and therapeutic treatment of diseases. This study identified the changes in mRNA and miRNA expression profile during NSC differentiation on an artificial matrix. NSCs were grown on a surface-modified, electrospun tetraethyl-orthosilicate nanofiber (designated as SNF-AP) by providing a 3D-environment for cell growth and differentiation. Differentially expressed mRNAs and miRNAs of NSC differentiated in this microenvironment were identified through microarray analysis. The genes and miRNA targets responsible for the differentiation fate of NSCs and neuron development process were determined using Ingenuity Pathway Analysis (IPA). SNF-AP enhanced the expression of genes that activates the proliferation, development, and outgrowth of neurons, differentiation and generation of cells, neuritogenesis, outgrowth of neurites, microtubule dynamics, formation of cellular protrusions, and long-term potentiation during NSC differentiation. On the other hand, PDL inhibited neuritogenesis, microtubule dynamics, and proliferation and differentiation of cells and activated the apoptosis function. Moreover, the nanomaterial promoted the expression of more let-7 miRNAs, which have vital roles in NSC differentiation. Overall, SNF-AP is biocompatible and applicable scaffold for NSC differentiation in the development of neural tissue engineering. These findings are useful in enhancing in vitro NSC differentiation potential for preclinical studies and future clinical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2730-2743, 2016. © 2016 Wiley Periodicals, Inc.

Validation and Development of a Modified Breast Graded Prognostic Assessment As a Tool for Survival in Patients With Breast Cancer and Brain Metastases.

PubMed

Subbiah, Ishwaria M; Lei, Xiudong; Weinberg, Jeffrey S; Sulman, Erik P; Chavez-MacGregor, Mariana; Tripathy, Debu; Gupta, Rohan; Varma, Ankur; Chouhan, Jay; Guevarra, Richard P; Valero, Vicente; Gilbert, Mark R; Gonzalez-Angulo, Ana M

2015-07-10

Several indices have been developed to predict overall survival (OS) in patients with breast cancer with brain metastases, including the breast graded prognostic assessment (breast-GPA), comprising age, tumor subtype, and Karnofsky performance score. However, number of brain metastases-a highly relevant clinical variable-is less often incorporated into the final model. We sought to validate the existing breast-GPA in an independent larger cohort and refine it integrating number of brain metastases. Data were retrospectively gathered from a prospectively maintained institutional database. Patients with newly diagnosed brain metastases from 1996 to 2013 were identified. After validating the breast-GPA, multivariable Cox regression and recursive partitioning analysis led to the development of the modified breast-GPA. The performances of the breast-GPA and modified breast-GPA were compared using the concordance index. In our cohort of 1,552 patients, the breast-GPA was validated as a prognostic tool for OS (P < .001). In multivariable analysis of the breast-GPA and number of brain metastases (> three v ≤ three), both were independent predictors of OS. We therefore developed the modified breast-GPA integrating a fourth clinical parameter. Recursive partitioning analysis reinforced the prognostic significance of these four factors. Concordance indices were 0.78 (95% CI, 0.77 to 0.80) and 0.84 (95% CI, 0.83 to 0.85) for the breast-GPA and modified breast-GPA, respectively (P < .001). The modified breast-GPA incorporates four simple clinical parameters of high prognostic significance. This index has an immediate role in the clinic as a formative part of the clinician's discussion of prognosis and direction of care and as a potential patient selection tool for clinical trials. © 2015 by American Society of Clinical Oncology.

[Nematodes with zoonotic potential in parks of the city of Tunja, Colombia].

PubMed

Díaz-Anaya, Adriana María; Pulido-Medellín, Martín Orlando; Giraldo-Forero, Julio César

2015-01-01

To identify the presence of parasites with zoonotic potential in major parks in the city of Tunja, Boyacá. Twenty eight parks in the city were selected, where 124 samples of feces of dogs and soil were collected with the help of a spatula, gathering approximately 150 g per sample. They were processed by the method of concentration of Ritchie modified making the identification of parasitic forms in an optical microscope. A 60.7% of the parks were positive to nematodes in samples of canine fecal material and 100% on soil. Found nematodes were eggs and larvae of Toxocara spp., Ancylostoma spp., Trichuris vulpis and Strongiloides spp. This study demonstrated the potential risk of transmission of zoonoses caused by nematodes in canines and for the need to strengthen public health measures to reduce the risk shows the population exposed to such zoonoses.

Chiba Tendril-Less locus determines tendril organ identity in melon (Cucumis melo L.) and potentially encodes a tendril-specific TCP homolog.

PubMed

Mizuno, Shinji; Sonoda, Masatoshi; Tamura, Yayoi; Nishino, Eisho; Suzuki, Hideyuki; Sato, Takahide; Oizumi, Toshikatsu

2015-11-01

Tendrils are filamentous plant organs that coil on contact with an object, thereby providing mechanical support for climbing to reach more sunlight. Plant tendrils are considered to be modified structure of leaves, stems, or inflorescence, but the origin of cucurbit tendrils is still argued because of the complexity in the axillary organ patterning. We carried out morphological and genetic analyses of the Chiba Tendril-Less (ctl) melon (Cucumis melo) mutant, and found strong evidence that the melon tendril is a modified organ derived from a stem-leaf complex of a lateral shoot. Heterozygous (CTL/ctl) plants showed traits intermediate between tendril and shoot, and ontogenies of wild-type tendrils and mutant modified shoots coincided. We identified the CTL locus in a 200-kb region in melon linkage group IX. A single base deletion in a melon TCP transcription factor gene (CmTCP1) was detected in the mutant ctl sequence, and the expression of CmTCP1 was specifically high in wild-type tendrils. Phylogenetic analysis demonstrated the novelty of the CmTCP1 protein and the unique molecular evolution of its orthologs in the Cucurbitaceae. Our results move us closer to answering the long-standing question of which organ was modified to become the cucurbit tendril, and suggest a novel function of the TCP transcription factor in plant development.

Liquid Phase adsorption kinetics and equilibrium of toluene by novel modified-diatomite.

PubMed

Sheshdeh, Reza Khalighi; Abbasizadeh, Saeed; Nikou, Mohammad Reza Khosravi; Badii, Khashayar; Sharafi, Mohammad Sadegh

2014-01-01

The adsorption equilibria of toluene from aqueous solutions on natural and modified diatomite were examined at different operation parameters such as pH, contact time, initial toluene concentration was evaluated and optimum experimental conditions were identified. The surface area and morphology of the nanoparticles were characterized by SEM, BET, XRD, FTIR and EDX analysis. It was found that in order to obtain the highest possible removal of toluene, the experiments can be carried out at pH 6, temperature 25°C, an agitation speed of 200 rpm, an initial toluene concentration of 150 mg/L, a centrifugal rate of 4000 rpm, adsorbent dosage = 0.1 g and a process time of 90 min. The results of this work show that the maximum percentage removal of toluene from aqueous solution in the optimum conditions for NONMD was 96.91% (145.36 mg/g). Furthermore, under same conditions, the maximum adsorption of natural diatomite was 71.45% (107.18 mg/g). Both adsorption kinetic and isotherm experiments were carried out. The experimental data showed that the adsorption follows the Langmuir model and Freundlich model on natural and modified diatomite respectively. The kinetics results were found to conform well to pseudo-second order kinetics model with good correlation. Thus, this study demonstrated that the modified diatomite could be used as potential adsorbent for removal of toluene from aqueous solution.

Evaluation of cephamycins as supplements to selective agar for detecting Campylobacter spp. in chicken carcass rinses.

PubMed

Chon, Jung-Whan; Kim, Young-Ji; Kim, Hong-Seok; Kim, Dong-Hyeon; Kim, Hyunsook; Song, Kwang-Young; Sung, Kidon; Seo, Kun-Ho

2016-04-16

Although cefoperazone is the most commonly used antibiotic in Campylobacter-selective media, the distribution of cefoperazone-resistant bacteria such as extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is increasing. Here we evaluated the potential of cephamycins for use as supplements to improve modified charcoal-cefoperazone-deoxycholate agar (mCCDA) by replacing cefoperazone with the same concentrations (32 mg/L) of cefotetan (modified charcoal-cefotetan-deoxycholate agar, mCCtDA) and cefoxitin (modified charcoal-cefoxitin-deoxycholate agar, mCCxDA). In chicken carcass rinse samples, the number of mCCDA plates detecting for Campylobacter (18/70, 26%) was significantly lower than that of mCCtDA (42/70, 60%) or mCCxDA plates (40/70, 57%). The number of mCCDA plates (70/70, 100%) that were contaminated with non-Campylobacter species was significantly higher than that of mCCtDA (20/70, 29%) or mCCxDA plates (21/70, 30%). The most common competing species identified using mCCDA was ESBL-producing E. coli, while Pseudomonas species frequently appeared on mCCtDA and mCCxDA. Copyright © 2016. Published by Elsevier B.V.

Mapping Risks of Indonesian Tuna Supply Chain

NASA Astrophysics Data System (ADS)

Karningsih, P. D.; Anggrahini, D.; Kurniati, N.; Suef, M.; Fachrur, A. R.; Syahroni, N.

2018-04-01

Due to its high economic value and is produced by many countries, Tuna is considered as one of the world’s popular fish. Demand for Tuna species are very high and it usually sells in three form: fresh, frozen or canned. Competition in Tuna trading is challengin with the potential risk of price and supply fluctuations. With recent focus of Indonesia government that see the future of Indonesia civilization depend on the oceans and as the three biggest Tuna producing country, Ministry of Marine Affairs and Fisheries should ensure sustainability and competitiveness of Indonesian tuna. Therefore, there is a great need to develop a proper and effective strategy to manage potential risks in Indonesian Tuna supply chain. This paper is aimed at identifying and mapping potential Tuna supply chain risks and its interrelationships that would assist government in determining proper strategies to manage Indonesian Tuna. A framework for identifying Tuna supply chain risks is proposed. Generic risk structure of Supply Chain Risk Identification System is adopted and modified to match with particular object, which is Indonesian Tuna. The proposed model consists of hierarchical and causal structure that encompass potential risks of Tuna supply chain operations from fishing, trading, processing and distribution. The causal structure consist of risk events and its risk agents which is the cause of risk events. To ensure the root cause of risk events are identified properly, five why’s analysis is utilized to obtain risk agents. This proposed model also captures risk interrelationship between internal and external environment of Tuna supply chain. Preliminary result of this study identifies 15 risk events and 13 risk factors on fishing and trading operations and maps their interrelationships.

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

PubMed Central

Faraji, Farhoud; Hu, Ying; Wu, Gang; Goldberger, Natalie E.; Walker, Renard C.; Zhang, Jinghui; Hunter, Kent W.

2014-01-01

Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. Small RNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis. PMID:24322557

40 CFR 721.6498 - Modified polyisocyanates (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.6498 Modified polyisocyanates (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as modified polyisocyanates (PMN P...

40 CFR 721.6498 - Modified polyisocyanates (generic).

Code of Federal Regulations, 2012 CFR

2012-07-01

... SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.6498 Modified polyisocyanates (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as modified polyisocyanates (PMN P...

40 CFR 721.6498 - Modified polyisocyanates (generic).

Code of Federal Regulations, 2011 CFR

2011-07-01

... SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.6498 Modified polyisocyanates (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as modified polyisocyanates (PMN P...

ASSESSMENT OF ALLERGENIC POTENTIAL OF GENETICALLY MODIFIED FOODS: AN AGENDA FOR FUTURE RESEARCH

EPA Science Inventory

Abstract
Speakers and participants in the Workshop Assessment of the Allergenic Potential of Genetically Modified Foods met in breakout groups to discuss a number of issues including needs for future research. There was agreement that research should move forward quickly in t...

BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

EPA Science Inventory

Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
Cancer Responses
.
There has been a concerted effort in the field of radiation biology to better understand cellular
responses that could have an impact on the estin1ation of cancer...

Modified coulomb law in a strongly magnetized vacuum.

PubMed

Shabad, Anatoly E; Usov, Vladimir V

2007-05-04

We study the electric potential of a charge placed in a strong magnetic field B>B(0) approximately 4.4x10(13) G, as modified by the vacuum polarization. In such a field the electron Larmour radius is much less than its Compton length. At the Larmour distances a scaling law occurs, with the potential determined by a magnetic-field-independent function. The scaling regime implies short-range interaction, expressed by the Yukawa law. The electromagnetic interaction regains its long-range character at distances larger than the Compton length, the potential decreasing across B faster than along. Correction to the nonrelativistic ground-state energy of a hydrogenlike atom is found. In the limit B = infinity, the modified potential becomes the Dirac delta function plus a regular background. With this potential the ground-state energy is finite--the best pronounced effect of the vacuum polarization.

Searching for modified growth patterns with tomographic surveys

NASA Astrophysics Data System (ADS)

Zhao, Gong-Bo; Pogosian, Levon; Silvestri, Alessandra; Zylberberg, Joel

2009-04-01

In alternative theories of gravity, designed to produce cosmic acceleration at the current epoch, the growth of large scale structure can be modified. We study the potential of upcoming and future tomographic surveys such as Dark Energy Survey (DES) and Large Synoptic Survey Telescope (LSST), with the aid of cosmic microwave background (CMB) and supernovae data, to detect departures from the growth of cosmic structure expected within general relativity. We employ parametric forms to quantify the potential time- and scale-dependent variation of the effective gravitational constant and the differences between the two Newtonian potentials. We then apply the Fisher matrix technique to forecast the errors on the modified growth parameters from galaxy clustering, weak lensing, CMB, and their cross correlations across multiple photometric redshift bins. We find that even with conservative assumptions about the data, DES will produce nontrivial constraints on modified growth and that LSST will do significantly better.

Obesity and Sex Interact in the Regulation of Alzheimer’s Disease

PubMed Central

Moser, V. Alexandra; Pike, Christian J.

2015-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, for which a number of genetic, environmental, and lifestyle risk factors have been identified. A significant modifiable risk factor is obesity in mid-life. Interestingly, both obesity and AD exhibit sex differences and are regulated by sex steroid hormones. Accumulating evidence suggests interactions between obesity and sex in regulation of AD risk, although the pathways underlying this relationship are unclear. Inflammation and the E4 allele of apolipoprotein E have been identified as independent risk factors for AD and both interact with obesity and sex steroid hormones. We review the individual and cooperative effects of obesity and sex on development of AD and examine the potential contributions of apolipoprotein E, inflammation, and their interactions to this relationship. PMID:26708713

Guidelines on the diagnosis of noise-induced hearing loss for medicolegal purposes.

PubMed

Coles, R R; Lutman, M E; Buffin, J T

2000-08-01

These guidelines aim to assist in the diagnosis of noise-induced hearing loss (NIHL) in medicolegal settings. The task is to distinguish between possibility and probability, the legal criterion being 'more probable than not'. It is argued that the amount of NIHL needed to qualify for that diagnosis is that which is reliably measurable and identifiable on the audiogram. The three main requirements for the diagnosis of NIHL are defined: R1, high-frequency hearing impairment; R2, potentially hazardous amount of noise exposure; R3, identifiable high-frequency audiometric notch or bulge. Four modifying factors also need consideration: MF1, the clinical picture; MF2, compatibility with age and noise exposure; MF3, Robinson's criteria for other causation; MF4, complications such as asymmetry, mixed disorder and conductive hearing impairment.

RNAi Screening with Self-Delivering, Synthetic siRNAs for Identification of Genes That Regulate Primary Human T Cell Migration.

PubMed

Freeley, Michael; Derrick, Emily; Dempsey, Eugene; Hoff, Antje; Davies, Anthony; Leake, Devin; Vermeulen, Annaleen; Kelleher, Dermot; Long, Aideen

2015-09-01

Screening of RNA interference (RNAi) libraries in primary T cells is labor-intensive and technically challenging because these cells are hard to transfect. Chemically modified, self-delivering small interfering RNAs (siRNAs) offer a solution to this problem, because they enter hard-to-transfect cell types without needing a delivery reagent and are available in library format for RNAi screening. In this study, we have screened a library of chemically modified, self-delivering siRNAs targeting the expression of 72 distinct genes in conjunction with an image-based high-content-analysis platform as a proof-of-principle strategy to identify genes involved in lymphocyte function-associated antigen-1 (LFA-1)-mediated migration in primary human T cells. Our library-screening strategy identified the small GTPase RhoA as being crucial for T cell polarization and migration in response to LFA-1 stimulation and other migratory ligands. We also demonstrate that multiple downstream assays can be performed within an individual RNAi screen and have used the remainder of the cells for additional assays, including cell viability and adhesion to ICAM-1 (the physiological ligand for LFA-1) in the absence or presence of the chemokine SDF-1α. This study therefore demonstrates the ease and benefits of conducting siRNA library screens in primary human T cells using self-delivering, chemically modified siRNAs, and it emphasizes the feasibility and potential of this approach for elucidating the signaling pathways that regulate T cell function. © 2015 Society for Laboratory Automation and Screening.

Computational study of β-N-acetylhexosaminidase from Talaromyces flavus, a glycosidase with high substrate flexibility.

PubMed

Kulik, Natallia; Slámová, Kristýna; Ettrich, Rüdiger; Křen, Vladimír

2015-01-28

β-N-Acetylhexosaminidase (GH20) from the filamentous fungus Talaromyces flavus, previously identified as a prominent enzyme in the biosynthesis of modified glycosides, lacks a high resolution three-dimensional structure so far. Despite of high sequence identity to previously reported Aspergillus oryzae and Penicilluim oxalicum β-N-acetylhexosaminidases, this enzyme tolerates significantly better substrate modification. Understanding of key structural features, prediction of effective mutants and potential substrate characteristics prior to their synthesis are of general interest. Computational methods including homology modeling and molecular dynamics simulations were applied to shad light on the structure-activity relationship in the enzyme. Primary sequence analysis revealed some variable regions able to influence difference in substrate affinity of hexosaminidases. Moreover, docking in combination with consequent molecular dynamics simulations of C-6 modified glycosides enabled us to identify the structural features required for accommodation and processing of these bulky substrates in the active site of hexosaminidase from T. flavus. To access the reliability of predictions on basis of the reported model, all results were confronted with available experimental data that demonstrated the principal correctness of the predictions as well as the model. The main variable regions in β-N-acetylhexosaminidases determining difference in modified substrate affinity are located close to the active site entrance and engage two loops. Differences in primary sequence and the spatial arrangement of these loops and their interplay with active site amino acids, reflected by interaction energies and dynamics, account for the different catalytic activity and substrate specificity of the various fungal and bacterial β-N-acetylhexosaminidases.

Relevant patient characteristics for guiding tailored integrated diabetes primary care: a systematic review.

PubMed

Hertroijs, Dorijn F L; Elissen, Arianne M J; Brouwers, Martijn C G J; Schaper, Nicolaas C; Ruwaard, Dirk

2018-02-06

Aim To identify which patient-related effect modifiers influence the outcomes of integrated care programs for type 2 diabetes in primary care. Integrated care is a widespread management strategy for the treatment of type 2 diabetes. However, most integrated care programs are not tailored to patients' needs, preferences and abilities. There is increasing consensus that such a patient-centered approach could improve the management of type 2 diabetes. Thus far, it remains unclear which patient-related effect modifiers should guide such an approach. PubMed, CINAHL and EMBASE were searched for empirical studies published after 1998. A systematic literature review was conducted according to the PRISMA guidelines. Findings In total, 23 out of 1015 studies were included. A total of 21 studies measured the effects of integrated diabetes care programs on hemoglobin A1c (HbA1c) and three on low-density lipoprotein cholesterol, systolic blood pressure and health-care utilization. In total, 49 patient characteristics were assessed as potential effect modifiers with HbA1c as an outcome, of which 46 were person or health-related and only three were context-related. Younger age, insulin therapy and longer disease duration were associated with higher HbA1c levels in cross-sectional and longitudinal studies. Higher baseline HbA1c was associated with higher HbA1c at follow-up in longitudinal studies. Information on context- and person-related characteristics was limited, but is necessary to help identify the care needs of individual patients and implement an effective integrated type 2 diabetes tailored care program.

Para-nitrobenzyl esterases with enhanced activity in aqueous and nonaqueous media

DOEpatents

Arnold, F.H.; Moore, J.C.

1999-05-25

A method is disclosed for isolating and identifying modified para-nitrobenzyl esterases which exhibit improved stability and/or esterase hydrolysis activity toward selected substrates and under selected reaction conditions relative to the unmodified para-nitrobenzyl esterase. The method involves preparing a library of modified para-nitrobenzyl esterase nucleic acid segments (genes) which have nucleotide sequences that differ from the nucleic acid segment which encodes for unmodified para-nitrobenzyl esterase. The library of modified para-nitrobenzyl nucleic acid segments is expressed to provide a plurality of modified enzymes. The clones expressing modified enzymes are then screened to identify which enzymes have improved esterase activity by measuring the ability of the enzymes to hydrolyze the selected substrate under the selected reaction conditions. Specific modified para-nitrobenzyl esterases are disclosed which have improved stability and/or ester hydrolysis activity in aqueous or aqueous-organic media relative to the stability and/or ester hydrolysis activity of unmodified naturally occurring para-nitrobenzyl esterase. 43 figs.

Para-nitrobenzyl esterases with enhanced activity in aqueous and nonaqueous media

DOEpatents

Arnold, F.H.; Moore, J.C.

1998-04-21

A method is disclosed for isolating and identifying modified para-nitrobenzyl esterases. These enzymes exhibit improved stability and/or esterase hydrolysis activity toward selected substrates and under selected reaction conditions relative to the unmodified para-nitrobenzyl esterase. The method involves preparing a library of modified para-nitrobenzyl esterase nucleic acid segments (genes) which have nucleotide sequences that differ from the nucleic acid segment which encodes for unmodified para-nitrobenzyl esterase. The library of modified para-nitrobenzyl nucleic acid segments is expressed to provide a plurality of modified enzymes. The clones expressing modified enzymes are then screened to identify which enzymes have improved esterase activity by measuring the ability of the enzymes to hydrolyze the selected substrate under the selected reaction conditions. Specific modified para-nitrobenzyl esterases are disclosed which have improved stability and/or ester hydrolysis activity in aqueous or aqueous-organic media relative to the stability and/or ester hydrolysis activity of unmodified naturally occurring para-nitrobenzyl esterase. 43 figs.

Rapid preparation of nuclei-depleted detergent-resistant membrane fractions suitable for proteomics analysis.

PubMed

Adam, Rosalyn M; Yang, Wei; Di Vizio, Dolores; Mukhopadhyay, Nishit K; Steen, Hanno

2008-06-05

Cholesterol-rich membrane microdomains known as lipid rafts have been implicated in diverse physiologic processes including lipid transport and signal transduction. Lipid rafts were originally defined as detergent-resistant membranes (DRMs) due to their relative insolubility in cold non-ionic detergents. Recent findings suggest that, although DRMs are not equivalent to lipid rafts, the presence of a given protein within DRMs strongly suggests its potential for raft association in vivo. Therefore, isolation of DRMs represents a useful starting point for biochemical analysis of lipid rafts. The physicochemical properties of DRMs present unique challenges to analysis of their protein composition. Existing methods of isolating DRM-enriched fractions involve flotation of cell extracts in a sucrose density gradient, which, although successful, can be labor intensive, time consuming and results in dilute sucrose-containing fractions with limited utility for direct proteomic analysis. In addition, several studies describing the proteomic characterization of DRMs using this and other approaches have reported the presence of nuclear proteins in such fractions. It is unclear whether these results reflect trafficking of nuclear proteins to DRMs or whether they arise from nuclear contamination during isolation. To address these issues, we have modified a published differential detergent extraction method to enable rapid DRM isolation that minimizes nuclear contamination and yields fractions compatible with mass spectrometry. DRM-enriched fractions isolated using the conventional or modified extraction methods displayed comparable profiles of known DRM-associated proteins, including flotillins, GPI-anchored proteins and heterotrimeric G-protein subunits. Thus, the modified procedure yielded fractions consistent with those isolated by existing methods. However, we observed a marked reduction in the percentage of nuclear proteins identified in DRM fractions isolated with the modified method (15%) compared to DRMs isolated by conventional means (36%). Furthermore, of the 21 nuclear proteins identified exclusively in modified DRM fractions, 16 have been reported to exist in other subcellular sites, with evidence to suggest shuttling of these species between the nucleus and other organelles. We describe a modified DRM isolation procedure that generates DRMs that are largely free of nuclear contamination and that is compatible with downstream proteomic analyses with minimal additional processing. Our findings also imply that identification of nuclear proteins in DRMs is likely to reflect legitimate movement of proteins between compartments, and is not a result of contamination during extraction.

Importance of investigating epigenetic alterations for industry and regulators: An appraisal of current efforts by the Health and Environmental Sciences Institute.

PubMed

Miousse, Isabelle R; Currie, Richard; Datta, Kaushik; Ellinger-Ziegelbauer, Heidrun; French, John E; Harrill, Alison H; Koturbash, Igor; Lawton, Michael; Mann, Derek; Meehan, Richard R; Moggs, Jonathan G; O'Lone, Raegan; Rasoulpour, Reza J; Pera, Renee A Reijo; Thompson, Karol

2015-09-01

Recent technological advances have led to rapid progress in the characterization of epigenetic modifications that control gene expression in a generally heritable way, and are likely involved in defining cellular phenotypes, developmental stages and disease status from one generation to the next. On November 18, 2013, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) held a symposium entitled "Advances in Assessing Adverse Epigenetic Effects of Drugs and Chemicals" in Washington, D.C. The goal of the symposium was to identify gaps in knowledge and highlight promising areas of progress that represent opportunities to utilize epigenomic profiling for risk assessment of drugs and chemicals. Epigenomic profiling has the potential to provide mechanistic information in toxicological safety assessments; this is especially relevant for the evaluation of carcinogenic or teratogenic potential and also for drugs that directly target epigenetic modifiers, like DNA methyltransferases or histone modifying enzymes. Furthermore, it can serve as an endpoint or marker for hazard characterization in chemical safety assessment. The assessment of epigenetic effects may also be approached with new model systems that could directly assess transgenerational effects or potentially sensitive stem cell populations. These would enhance the range of safety assessment tools for evaluating xenobiotics that perturb the epigenome. Here we provide a brief synopsis of the symposium, update findings since that time and then highlight potential directions for future collaborative efforts to incorporate epigenetic profiling into risk assessment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Potential Use of γ-Secretase Modulators in the Treatment of Alzheimer Disease

PubMed Central

Wagner, Steven L.; Tanzi, Rudolph E.; Mobley, William C.; Galasko, Douglas

2013-01-01

Although significant progress has occurred in the past 20 years regarding our understanding of Alzheimer disease pathogenesis, we have yet to identify disease-modifying therapeutics capable of substantially altering the clinical course of this prevalent neurodegenerative disease. In this short review, we discuss 2 approaches that are currently being tested clinically (γ-secretase inhibition and γ-secretase modulation) and emphasize the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in developing a useful therapeutic agent. PMID:22801784

TIA Management

PubMed Central

Mijalski, Christina

2015-01-01

Transient ischemic attack (TIA) has gained increasing attention over the last 2 decades with the realization that the condition is common, portends potentially serious consequences, and, when identified early, can be evaluated and treated to modify future risk. In this review, we examine the issues of whether all TIA patients need admission and whether such patients should receive short-term dual antiplatelet therapy. Not all patients require admission if evaluation and treatment are done promptly. There may be a role for dual antiplatelet therapy, but the results of further clinical trials will help provide better clarity on which patients are the best candidates for this treatment. PMID:26288673

Epigenetics of kidney disease.

PubMed

Wanner, Nicola; Bechtel-Walz, Wibke

2017-07-01

DNA methylation and histone modifications determine renal programming and the development and progression of renal disease. The identification of the way in which the renal cell epigenome is altered by environmental modifiers driving the onset and progression of renal diseases has extended our understanding of the pathophysiology of kidney disease progression. In this review, we focus on current knowledge concerning the implications of epigenetic modifications during renal disease from early development to chronic kidney disease progression including renal fibrosis, diabetic nephropathy and the translational potential of identifying new biomarkers and treatments for the prevention and therapy of chronic kidney disease and end-stage kidney disease.

British Pharmacological Society Cambridge Symposia. 5-7 January 2000, Cambridge, UK.

PubMed

Lawson, K

2000-04-01

This meeting covered a broad range of pharmacological topics, although the main themes were covered in four mini-symposia. This report concentrates on the cannabinoid, pain and cardiac ischemia symposia. The cannabinoid system was identified as a major area of potential therapeutic interest, offering a number of clinical targets that may be modified through the actions of selective ligands. Novel approaches to the treatment of neurogenic pain, where conventional analgesics have limited value, are being explored with significant success. The role of delayed preconditioning in cardiac ischemia was also addressed as a mechanism of cardioprotection.

Genetic modification technology for nutrition and improving diets: an ethical perspective.

PubMed

Glass, Sara; Fanzo, Jessica

2017-04-01

Genetically modified (GM) techniques to improve the nutrition and health content of foods is a highly debated area riddled with ethical dilemmas. Assessing GM technology with a public health ethical framework, this paper identifies public health goals, the potential burdens of the technology, and areas to consider for minimizing burdens and ensuring beneficence, autonomy, and little infringements on justice. Both policymakers and food producers should acknowledge local food environments and the agricultural context of each community in order to effectively prepare communication strategies and equitably distribute any proposed GM food intervention. Copyright © 2016 Elsevier Ltd. All rights reserved.

Screening for Behavioral Health Issues in Children Enrolled in Massachusetts Medicaid

PubMed Central

Penfold, Robert; Arsenault, Lisa; Zhang, Fang; Murphy, Michael; Wissow, Larry

2014-01-01

OBJECTIVES: To understand mandated behavioral health (BH) screening in Massachusetts Medicaid including characteristics of screened children, predictors of positive screens, and whether screening identifies children without a previous BH history. METHODS: Massachusetts mandated BH screening in particularly among underidentified groups. 2008. Providers used a billing code and modifier to indicate a completed screen and whether a BH need was identified. Using MassHealth claims data, children with ≥300 days of eligibility in fiscal year (FY) 2009 were identified and categorized into groups based on first use of the modifier, screening code, or claim. Bivariate analyses were conducted to determine differences among groups. BH history was examined by limiting the sample to those continuously enrolled in FY 2008 and 2009. Multivariate logistic regression was used to determine predictors of positive screens. RESULTS: Of 355 490 eligible children, 46% had evidence of screening. Of those with modifiers, 12% were positive. Among continuously enrolled children (FY 2008 and FY 2009) with evidence of screening, 43% with positive modifiers had no BH history. This “newly identified” group were more likely to be female, younger, minority, and from rural residences (P < .0001). Among children with modifiers; gender (male), age (5–7), being in foster care, recent BH history, and Hispanic ethnicity predicted having a positive modifier. CONCLUSIONS: The high rate of newly identified Medicaid children with a BH need suggests that screening is performing well, particularly among underidentified groups. To better assess screening value, future work on cost-effectiveness and the impact on subsequent mental health treatment is needed. PMID:24298005

KEY ISSUES FOR THE ASSESSMENT OF THE ALLERGENIC POTENTIAL OF GENETICALLY MODIFIED FOODS: BREAKOUT GROUP REPORTS

EPA Science Inventory

Abstract
On the final afternoon of the Workshop, Assessment of the Allergenic Potential of Genetically Modified Foods, speakers and participants met in breakout groups to discuss specific questions in the areas of 1) Use of Human Clinical Data; 2) Animal Models to Assess Food ...

Controversies in Alzheimer’s disease drug development

PubMed Central

Cummings, Jeffrey L.

2010-01-01

Understanding of the pathophysiological basis of Alzheimer’s disease (AD) is increasing rapidly and a variety of potential treatment modalities have emerged based on these improved mechanistic insights. The optimal way of proceeding with disease-modifying drug development remains to be clarified and controversies have emerged regarding the definition of Alzheimer’s disease, the participation of mild cognitive impairment patients in clinical trials, the definition of disease modification, the potential impediments to satisfaction from patients receiving disease-modifying therapy, the importance of add-on therapy with symptomatic agents, the optimal clinical trial design to demonstrate disease modification, the best means of minimizing time spent in Phase II of drug development, the potential role of adaptive designs in clinical trials, the use of enrichment designs in clinical trials, the role of biomarkers in clinical trials, the treatment of advanced patients with disease-modifying agents, and distinctions between disease modification and disease prevention. The questions surrounding these issues must be resolved as disease-modifying therapies for AD are advanced. These controversies are framed and potential directions towards resolution described. PMID:18925488

CHROMIUM ELECTROANALYSIS AT SCREEN PRINTED ELECTRODE MODIFIED BY THIN FILMS OF NICKEL

EPA Science Inventory

A rapid and potentially cost-effective electrochemical method is reported for analysis of chromium (VI) and Chromium(III) using a nickel modified screen printed carbon ink electrode. Electrochemical characteristics of nickel modified electrode as well voltammetric behavior f...

Identifying and Prioritizing Gaps in Neuroendocrine Tumor Research: A Modified Delphi Process With Patients and Health Care Providers to Set the Research Action Plan for the Newly Formed Commonwealth Neuroendocrine Tumor Collaboration

PubMed Central

Chan, David; Lawrence, Ben; Pavlakis, Nick; Kennecke, Hagen F.; Jackson, Christopher; Law, Calvin; Singh, Simron

2017-01-01

Purpose Neuroendocrine tumors (NETs) are a diverse group of malignancies that pose challenges common to all rare tumors. The Commonwealth Neuroendocrine Tumor Collaboration (CommNETS) was established in 2015 to enhance outcomes for patients with NETs in Canada, Australia, and New Zealand. A modified Delphi process was undertaken involving patients, clinicians, and researchers to identify gaps in NETs research to produce a comprehensive and defensible research action plan. Methods A three-round modified Delphi process was undertaken with larger representation than usual for medical consensus processes. Patient/advocate and health care provider/researcher expert panels undertook Round 1, which canvassed 17 research priorities and 42 potential topics; in Round 2, these priorities were ranked. Round 3 comprised a face-to-face meeting to generate final consensus rankings and formulate the research action plan. Results The Delphi groups consisted of 203 participants in Round 1 (64% health care providers/researchers, 36% patient/advocates; 52% Canadian, 32% Australian, and 17% New Zealander), of whom 132 participated in Round 2. The top eight priorities were biomarker development; peptide receptor radionuclide therapy optimization; trials of new agents in advanced NETs; functional imaging; sequencing therapies for metastatic NETs, including development of validated surrogate end points for studies; pathologic classification; early diagnosis; interventional therapeutics; and curative surgery. Two major areas were ranked significantly higher by patients/advocates: early diagnosis and curative surgery. Six CommNETS working parties were established. Conclusion This modified Delphi process resulted in a well-founded set of research priorities for the newly formed CommNETS collaboration by involving a large, diverse group of stakeholders. This approach to setting a research agenda for a new collaborative group should be adopted to ensure that research plans reflect unmet needs and priorities in the field. PMID:28831446

Genetic modifiers of nutritional status in cystic fibrosis1234

PubMed Central

Bradley, Gia M; Blackman, Scott M; Watson, Christopher P; Doshi, Vishal K; Cutting, Garry R

2012-01-01

Background: Improved nutrition early in life is associated with better pulmonary function for patients with cystic fibrosis (CF). However, nutritional status is poorly correlated with the CFTR genotype. Objective: We investigated the extent to which modifier genes influence nutrition in children with CF. Design: BMI data were longitudinally collected from the CF Twin-Sibling Study and Cystic Fibrosis Foundation Patient Registry for twins and siblings from 2000 to 2010. A nutritional phenotype was derived for 1124 subjects by calculating the average BMI z score from 5–10 y of age (BMI-z5to10). The genetic contribution to the variation in BMI-z5to10 (ie, heritability) was estimated by comparing the similarity of the phenotype in monozygous twins to that in dizygous twins and siblings. Linkage analysis identified potential modifier-gene loci. Results: The median BMI-z5to10 was −0.07 (range: −3.89 to 2.30), which corresponded to the 47th CDC percentile. BMI-z5to10 was negatively correlated with pancreatic insufficiency, history of meconium ileus, and female sex but positively correlated with later birth cohorts and lung function. Monozygous twins showed greater concordance for BMI-z5to10 than did dizygous twins and siblings; heritability estimates from same-sex twin-only analyses ranged from 0.54 to 0.82. For 1010 subjects with pancreatic insufficiency, genome-wide significant linkage was identified on chromosomes 1p36.1 [log of odds (LOD): 5.3] and 5q14 (LOD: 5.1). These loci explained ≥16% and ≥15%, respectively, of the BMI variance. Conclusions: The analysis of twins and siblings with CF indicates a prominent role for genes other than CFTR to BMI variation. Specifically, regions on chromosomes 1 and 5 appear to harbor genetic modifiers of substantial effect. PMID:23134884

Identifying and Prioritizing Gaps in Neuroendocrine Tumor Research: A Modified Delphi Process With Patients and Health Care Providers to Set the Research Action Plan for the Newly Formed Commonwealth Neuroendocrine Tumor Collaboration.

PubMed

Segelov, Eva; Chan, David; Lawrence, Ben; Pavlakis, Nick; Kennecke, Hagen F; Jackson, Christopher; Law, Calvin; Singh, Simron

2017-08-01

Neuroendocrine tumors (NETs) are a diverse group of malignancies that pose challenges common to all rare tumors. The Commonwealth Neuroendocrine Tumor Collaboration (CommNETS) was established in 2015 to enhance outcomes for patients with NETs in Canada, Australia, and New Zealand. A modified Delphi process was undertaken involving patients, clinicians, and researchers to identify gaps in NETs research to produce a comprehensive and defensible research action plan. A three-round modified Delphi process was undertaken with larger representation than usual for medical consensus processes. Patient/advocate and health care provider/researcher expert panels undertook Round 1, which canvassed 17 research priorities and 42 potential topics; in Round 2, these priorities were ranked. Round 3 comprised a face-to-face meeting to generate final consensus rankings and formulate the research action plan. The Delphi groups consisted of 203 participants in Round 1 (64% health care providers/researchers, 36% patient/advocates; 52% Canadian, 32% Australian, and 17% New Zealander), of whom 132 participated in Round 2. The top eight priorities were biomarker development; peptide receptor radionuclide therapy optimization; trials of new agents in advanced NETs; functional imaging; sequencing therapies for metastatic NETs, including development of validated surrogate end points for studies; pathologic classification; early diagnosis; interventional therapeutics; and curative surgery. Two major areas were ranked significantly higher by patients/advocates: early diagnosis and curative surgery. Six CommNETS working parties were established. This modified Delphi process resulted in a well-founded set of research priorities for the newly formed CommNETS collaboration by involving a large, diverse group of stakeholders. This approach to setting a research agenda for a new collaborative group should be adopted to ensure that research plans reflect unmet needs and priorities in the field.

A molecular tool for detection and tracking of a potential indigenous Beauveria bassiana strain for managing emerald ash borer populations in Canada.

PubMed

Johny, Shajahan; Kyei-Poku, George

2014-10-01

Emerald ash borer is an invasive species from Asia. Beauveria bassiana strain L49-1AA is being tested for the control of emerald ash borer in Canada, using an autocontamination trapping system. We have developed a simplified allele discrimination polymerase chain reaction (PCR) assay to screen B. bassiana strain, L49-1AA from other Beauveria species by targeting the inter-strain genetic differences in 5' end of EF1-α gene of the genus Beauveria. A single nucleotide polymorphism (SNP) site, T→C was identified only in L49-1AA and was used to develop a simplified allele discrimination polymerase chain reaction (PCR) assay based on a modified allelic inhibition of displacement activity (AIDA) approach for distinguishing B. bassiana L49-1AA from all background Beauveria isolates. The SNP site was employed to design inner primers but with a deliberate mismatch introduced at the 3' antepenultimate from the mutation site in order to maximize specificity and detection efficiency. Amplification was specific to L49-1AA without cross-reaction with DNA from other Beauveria strains. In addition, the designed primers were also tested against environmental samples in L49-1AA released plots and observed to be highly efficient in detecting and discriminating the target strain, L49-1AA from both pure and crude DNA samples. This new method can potentially allow for more discriminatory tracking and monitoring of released L49-1AA in our autocontamination and dissemination projects for managing EAB populations. Additionally, the modified-AIDA format has potential as a tool for simultaneously identifying and differentiating closely related Beauveria species, strains/isolates as well as general classification of other pathogens or organisms. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Childhood trauma, attachment style, and a couple's experience of terminal cancer: case study.

PubMed

McLean, Linda M; Hales, Sarah

2010-06-01

The primary objective of this article is to elucidate the significance of psychosocial distress and risk in a sub-population of end-stage cancer patients and their spouse caregivers who present with an especially challenging attachment style and histories of childhood trauma. The case study presented highlights the need to both identify and offer an empirically validated couple-based intervention, along with a multi-disciplinary team approach over the trajectory of the illness and at end of life. A validated marital protocol (emotionally focused couple therapy [EFT]) is modified for this population and conducted by an EFT-trained psychologist as part of a pilot investigation as to the feasibility and effectiveness of EFT for the terminal cancer population. Measures of marital distress, depression, hopelessness, and attachment security are completed at baseline and subsequent intervals, as reported in another publication. Attachment insecurity and the exquisitely intimate relationship with caregiving and care receiving are underscored, given the couple's traumatic childhood history. The couple described herein, followed from diagnosis of metastatic disease to end of life illuminates the potential effectiveness of a modified EFT protocol, and underscores the need to both identify and intervene with a population potentially at significantly high risk for marital distress, suicidality, depression, and hopelessness. The benefits of a multidisciplinary team is evident as the patient's symptoms of physical distress increased toward end of life and she returned to earlier behaviors, namely suicidal ideation and an attempt to alleviate her experience of suffering. The strength of the marital bond, possibly as a result of the intervention, and the efforts of the multidisciplinary team approach, demonstrate potential to mitigate a catastrophic end of life and a complicated spousal bereavement. This case study adds to the current empirical literature in an area that is currently under-studied and under-reported.

Systems for the Intermodal Routing of Spent Nuclear Fuel

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

Peterson, Steven K; Liu, Cheng

The safe and secure movement of spent nuclear fuel from shutdown and active reactor facilities to intermediate or long term storage sites may, in some instances, require the use of several modes of transportation to accomplish the move. To that end, a fully operable multi-modal routing system is being developed within Oak Ridge National Laboratory s (ORNL) WebTRAGIS (Transportation Routing Analysis Geographic Information System). This study aims to provide an overview of multi-modal routing, the existing state of the TRAGIS networks, the source data needs, and the requirements for developing structural relationships between various modes to create a suitable systemmore » for modeling the transport of spent nuclear fuel via a multimodal network. Modern transportation systems are comprised of interconnected, yet separate, modal networks. Efficient transportation networks rely upon the smooth transfer of cargoes at junction points that serve as connectors between modes. A key logistical impediment to the shipment of spent nuclear fuel is the absence of identified or designated transfer locations between transport modes. Understanding the potential network impacts on intermodal transportation of spent nuclear fuel is vital for planning transportation routes from origin to destination. By identifying key locations where modes intersect, routing decisions can be made to prioritize cost savings, optimize transport times and minimize potential risks to the population and environment. In order to facilitate such a process, ORNL began the development of a base intermodal network and associated routing code. The network was developed using previous intermodal networks and information from publicly available data sources to construct a database of potential intermodal transfer locations with likely capability to handle spent nuclear fuel casks. The coding development focused on modifying the existing WebTRAGIS routing code to accommodate intermodal transfers and the selection of prioritization constraints and modifiers to determine route selection. The limitations of the current model and future directions for development are discussed, including the current state of information on possible intermodal transfer locations for spent fuel.« less

Identifying and prioritising systematic review topics with public health stakeholders: A protocol for a modified Delphi study in Switzerland to inform future research agendas

PubMed Central

Mütsch, Margot; Kien, Christina; Gerhardus, Ansgar; Lhachimi, Stefan K

2017-01-01

Introduction The Cochrane Collaboration aims to produce relevant and top priority evidence that responds to existing evidence gaps. Hence, research priority setting (RPS) is important to identify which potential research gaps are deemed most important. Moreover, RPS supports future health research to conform both health and health evidence needs. However, studies that are prioritising systematic review topics in public health are surprisingly rare. Therefore, to inform the research agenda of Cochrane Public Health Europe (CPHE), we introduce the protocol of a priority setting study on systematic review topics in several European countries, which is conceptualised as pilot. Methods and analysis We will conduct a two-round modified Delphi study in Switzerland, incorporating an anonymous web-based questionnaire, to assess which topics should be prioritised for systematic reviews in public health. In the first Delphi round public health stakeholders will suggest relevant assessment criteria and potential priority topics. In the second Delphi round the participants indicate their (dis)agreement to the aggregated results of the first round and rate the potential review topics with the predetermined criteria on a four-point Likert scale. As we invite a wide variety of stakeholders we will compare the results between the different stakeholder groups. Ethics and dissemination We have received ethical approval from the ethical board of the University of Bremen, Germany (principal investigation is conducted at the University of Bremen) and a certificate of non-objection from the Canton of Zurich, Switzerland (fieldwork will be conducted in Switzerland). The results of this study will be further disseminated through peer reviewed publication and will support systematic review author groups (i.a. CPHE) to improve the relevance of the groups´ future review work. Finally, the proposed priority setting study can be used as a framework by other systematic review groups when conducting a priority setting study in a different context. PMID:28780546

A modified Stillinger-Weber potential for TlBr and its polymorphic extension

DOE PAGES

Zhou, Xiaowang; Foster, Michael E.; Jones, Reese E.; ...

2015-04-30

TlBr is promising for g- and x- radiation detection, but suffers from rapid performance degradation under the operating external electric fields. To enable molecular dynamics (MD) studies of this degradation, we have developed a Stillinger-Weber type of TlBr interatomic potential. During this process, we have also addressed two problems of wider interests. First, the conventional Stillinger-Weber potential format is only applicable for tetrahedral structures (e.g., diamond-cubic, zinc-blende, or wurtzite). Here we have modified the analytical functions of the Stillinger-Weber potential so that it can now be used for other crystal structures. Second, past modifications of interatomic potentials cannot always bemore » applied by a broad community because any new analytical functions of the potential would require corresponding changes in the molecular dynamics codes. Here we have developed a polymorphic potential model that simultaneously incorporates Stillinger-Weber, Tersoff, embedded-atom method, and any variations (i.e., modified functions) of these potentials. As a result, we have implemented this polymorphic model in MD code LAMMPS, and demonstrated that our TlBr potential enables stable MD simulations under external electric fields.« less

Intervening in disease through genetically-modified bacteria.

PubMed

Ferreira, Adilson K; Mambelli, Lisley I; Pillai, Saravanan Y

2017-12-01

The comprehension of the molecular basis of different diseases is rapidly being dissected as a consequence of advancing technology. Consequently, proteins with potential therapeutic usefulness, including cytokines and signaling molecules have been identified in the last decades. However, their clinical use is hampered by disadvantageous functional and economic considerations. One of the most important of these considerations is targeted topical delivery and also the synthesis of such proteins, which for intravenous use requires rigorous purification whereas proteins often do not withstand digestive degradation and thus cannot be applied per os. Recently, the idea of using genetically modified bacteria has emerged as an attempt to evade these important barriers. Using such bacteria can deliver therapeutic proteins or other molecules at place of disease, especially when disease is at a mucosal surface. Further, whereas intravenously applied therapeutic proteins require expensive methodology in order to become endotoxin-free, this is not necessary for local application of therapeutic proteins in the intestine. In addition, once created further propagation of genetically modified bacteria is both cheap and requires relatively little in conditioning with respect to transport of the medication, making such organisms also suitable for combating disease in developing countries with poor infrastructure. Although first human trials with such bacteria were already performed more as a decade ago, the recent revolution in our understanding of the role of human gut microbiome in health and diseases has unleashed a revolution in this field resulting in a plethora of potential novel prophylactic and therapeutic intervention against disease onset and development employing such organisms. Today, the engineering of human microbiome for health benefits and related applications now chances many aspects of biology, nanotechnology and chemistry. Here, we review genetically modified bacteria methodology as possible carriers of drug delivering and provided the origin and inspirations for new drug delivery systems. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transcriptome Analysis of Yellow Horn (Xanthoceras sorbifolia Bunge): A Potential Oil-Rich Seed Tree for Biodiesel in China

PubMed Central

Liu, Yulin; Huang, Zhedong; Ao, Yan; Li, Wei; Zhang, Zhixiang

2013-01-01

Background Yellow horn (Xanthoceras sorbifolia Bunge) is an oil-rich seed shrub that grows well in cold, barren environments and has great potential for biodiesel production in China. However, the limited genetic data means that little information about the key genes involved in oil biosynthesis is available, which limits further improvement of this species. In this study, we describe sequencing and de novo transcriptome assembly to produce the first comprehensive and integrated genomic resource for yellow horn and identify the pathways and key genes related to oil accumulation. In addition, potential molecular markers were identified and compiled. Methodology/Principal Findings Total RNA was isolated from 30 plants from two regions, including buds, leaves, flowers and seeds. Equal quantities of RNA from these tissues were pooled to construct a cDNA library for 454 pyrosequencing. A total of 1,147,624 high-quality reads with total and average lengths of 530.6 Mb and 462 bp, respectively, were generated. These reads were assembled into 51,867 unigenes, corresponding to a total of 36.1 Mb with a mean length, N50 and median of 696, 928 and 570 bp, respectively. Of the unigenes, 17,541 (33.82%) were unmatched in any public protein databases. We identified 281 unigenes that may be involved in de novo fatty acid (FA) and triacylglycerol (TAG) biosynthesis and metabolism. Furthermore, 6,707 SSRs, 16,925 SNPs and 6,201 InDels with high-confidence were also identified in this study. Conclusions This transcriptome represents a new functional genomics resource and a foundation for further studies on the metabolic engineering of yellow horn to increase oil content and modify oil composition. The potential molecular markers identified in this study provide a basis for polymorphism analysis of Xanthoceras, and even Sapindaceae; they will also accelerate the process of breeding new varieties with better agronomic characteristics. PMID:24040247

Genetically modified crops and aquatic ecosystems: considerations for environmental risk assessment and non-target organism testing.

PubMed

Carstens, Keri; Anderson, Jennifer; Bachman, Pamela; De Schrijver, Adinda; Dively, Galen; Federici, Brian; Hamer, Mick; Gielkens, Marco; Jensen, Peter; Lamp, William; Rauschen, Stefan; Ridley, Geoff; Romeis, Jörg; Waggoner, Annabel

2012-08-01

Environmental risk assessments (ERA) support regulatory decisions for the commercial cultivation of genetically modified (GM) crops. The ERA for terrestrial agroecosystems is well-developed, whereas guidance for ERA of GM crops in aquatic ecosystems is not as well-defined. The purpose of this document is to demonstrate how comprehensive problem formulation can be used to develop a conceptual model and to identify potential exposure pathways, using Bacillus thuringiensis (Bt) maize as a case study. Within problem formulation, the insecticidal trait, the crop, the receiving environment, and protection goals were characterized, and a conceptual model was developed to identify routes through which aquatic organisms may be exposed to insecticidal proteins in maize tissue. Following a tiered approach for exposure assessment, worst-case exposures were estimated using standardized models, and factors mitigating exposure were described. Based on exposure estimates, shredders were identified as the functional group most likely to be exposed to insecticidal proteins. However, even using worst-case assumptions, the exposure of shredders to Bt maize was low and studies supporting the current risk assessments were deemed adequate. Determining if early tier toxicity studies are necessary to inform the risk assessment for a specific GM crop should be done on a case by case basis, and should be guided by thorough problem formulation and exposure assessment. The processes used to develop the Bt maize case study are intended to serve as a model for performing risk assessments on future traits and crops.

Flagellar glycosylation in Clostridium botulinum.

PubMed

Twine, Susan M; Paul, Catherine J; Vinogradov, Evgeny; McNally, David J; Brisson, Jean-Robert; Mullen, James A; McMullin, David R; Jarrell, Harold C; Austin, John W; Kelly, John F; Logan, Susan M

2008-09-01

Flagellins from Clostridium botulinum were shown to be post-translationally modified with novel glycan moieties by top-down MS analysis of purified flagellin protein from strains of various toxin serotypes. Detailed analyses of flagellin from two strains of C. botulinum demonstrated that the protein is modified by a novel glycan moiety of mass 417 Da in O-linkage. Bioinformatic analysis of available C. botulinum genomes identified a flagellar glycosylation island containing homologs of genes recently identified in Campylobacter coli that have been shown to be responsible for the biosynthesis of legionaminic acid derivatives. Structural characterization of the carbohydrate moiety was completed utilizing both MS and NMR spectroscopy, and it was shown to be a novel legionaminic acid derivative, 7-acetamido-5-(N-methyl-glutam-4-yl)-amino-3,5,7,9-tetradeoxy-D-glycero-alpha-D-galacto-nonulosonic acid, (alphaLeg5GluNMe7Ac). Electron transfer dissociation MS with and without collision-activated dissociation was utilized to map seven sites of O-linked glycosylation, eliminating the need for chemical derivatization of tryptic peptides prior to analysis. Marker ions for novel glycans, as well as a unique C-terminal flagellin peptide marker ion, were identified in a top-down analysis of the intact protein. These ions have the potential for use in for rapid detection and discrimination of C. botulinum cells, indicating botulinum neurotoxin contamination. This is the first report of glycosylation of Gram-positive flagellar proteins by the 'sialic acid-like' nonulosonate sugar, legionaminic acid.

S-Nitrosylation Proteome Profile of Peripheral Blood Mononuclear Cells in Human Heart Failure

PubMed Central

Spratt, Heidi M.; Gupta, Shivali; Petersen, John R.; Kuyumcu-Martinez, Muge N.

2016-01-01

Nitric oxide (NO) protects the heart against ischemic injury; however, NO- and superoxide-dependent S-nitrosylation (S-NO) of cysteines can affect function of target proteins and play a role in disease outcome. We employed 2D-GE with thiol-labeling FL-maleimide dye and MALDI-TOF MS/MS to capture the quantitative changes in abundance and S-NO proteome of HF patients (versus healthy controls, n = 30/group). We identified 93 differentially abundant (59-increased/34-decreased) and 111 S-NO-modified (63-increased/48-decreased) protein spots, respectively, in HF subjects (versus controls, fold-change | ≥1.5|, p ≤ 0.05). Ingenuity pathway analysis of proteome datasets suggested that the pathways involved in phagocytes' migration, free radical production, and cell death were activated and fatty acid metabolism was decreased in HF subjects. Multivariate adaptive regression splines modeling of datasets identified a panel of proteins that will provide >90% prediction success in classifying HF subjects. Proteomic profiling identified ATP-synthase, thrombospondin-1 (THBS1), and vinculin (VCL) as top differentially abundant and S-NO-modified proteins, and these proteins were verified by Western blotting and ELISA in different set of HF subjects. We conclude that differential abundance and S-NO modification of proteins serve as a mechanism in regulating cell viability and free radical production, and THBS1 and VCL evaluation will potentially be useful in the prediction of heart failure. PMID:27635260

Curated Collection for Educators: Five Key Papers about the Flipped Classroom Methodology.

PubMed

King, Andrew; Boysen-Osborn, Megan; Cooney, Robert; Mitzman, Jennifer; Misra, Asit; Williams, Jennifer; Dulani, Tina; Gottlieb, Michael

2017-10-25

The flipped classroom (FC) pedagogy is becoming increasingly popular in medical education due to its appeal to the millennial learner and potential benefits in knowledge acquisition. Despite its popularity and effectiveness, the FC educational method is not without challenges. In this article, we identify and summarize several key papers relevant to medical educators interested in exploring the FC teaching methodology. The authors identified an extensive list of papers relevant to FC pedagogy via online discussions within the Academic Life in Emergency Medicine (ALiEM) Faculty Incubator. This list was augmented by an open call on Twitter (utilizing the #meded, #FOAMed, and #flippedclassroom hashtags) yielding a list of 33 papers. We then conducted a three-round modified Delphi process within the authorship group, which included both junior and senior clinician educators, to identify the most impactful papers for educators interested in FC pedagogy. The three-round modified Delphi process ranked all of the selected papers and selected the five most highly-rated papers for inclusion. The authorship group reviewed and summarized these papers with specific consideration given to their value to junior faculty educators and faculty developers interested in the flipped classroom approach. The list of papers featured in this article serves as a key reading list for junior clinician educators and faculty developers interested in the flipped classroom technique. The associated commentaries contextualize the importance of these papers for medical educators aiming to optimize their understanding and implementation of the flipped classroom methodology in their teaching and through faculty development.

A proteomic study to identify soya allergens--the human response to transgenic versus non-transgenic soya samples.

PubMed

Batista, Rita; Martins, Isabel; Jeno, Paul; Ricardo, Cândido Pinto; Oliveira, Maria Margarida

2007-01-01

In spite of being among the main foods responsible for allergic reactions worldwide, soybean (Glycine max)-derived products continue to be increasingly widespread in a variety of food products due to their well-documented health benefits. Soybean also continues to be one of the elected target crops for genetic modification. The aim of this study was to characterize the soya proteome and, specifically, IgE-reactive proteins as well as to compare the IgE response in soya-allergic individuals to genetically modified Roundup Ready soya versus its non-transgenic control. We performed two-dimensional gel electrophoresis of protein extracts from a 5% genetically modified Roundup Ready flour sample and its non-transgenic control followed by Western blotting with plasma from 5 soya-sensitive individuals. We used peptide tandem mass spectrometry to identify soya proteins (55 protein matches), specifically IgE-binding ones, and to evaluate differences between transgenic and non-transgenic samples. We identified 2 new potential soybean allergens--one is maturation associated and seems to be part of the late embryogenesis abundant proteins group and the other is a cysteine proteinase inhibitor. None of the individuals tested reacted differentially to the transgenic versus non-transgenic samples under study. Soybean endogenous allergen expression does not seem to be altered after genetic modification. Proteomics should be considered a powerful tool for functional characterization of plants and for food safety assessment. Copyright (c) 2007 S. Karger AG, Basel.

Timing and teamwork--an observational pilot study of patients referred to a Rapid Response Team with the aim of identifying factors amenable to re-design of a Rapid Response System.

PubMed

Peebles, Emma; Subbe, Christian P; Hughes, Paul; Gemmell, Les

2012-06-01

Rapid Response Teams aim to accelerate recognition and treatment of acutely unwell patients. Delays in delivery might undermine efficiency of the intervention. Our understanding of the causes of these delays is, as yet, incomplete. To identify modifiable causes of delays in the treatment of critically ill patients outside intensive care with a focus on factors amenable to system design. Review of care records and direct observation with process mapping of care delivered to 17 acutely unwell patients attended by a Rapid Response Team in a District General Hospital in the United Kingdom. Delays were defined as processes with no added value for patient care. Essential diagnostic and therapeutic procedures accounted for only 31% of time of care processes. Causes for delays could be classified into themes as (1) delays in call-out of the Rapid Response Team, (2) problems with team cohesion including poor communication and team efficiency and (3) lack of resources including lack of first line antibiotics, essential equipment, experienced staff and critical care beds. We identified a number of potentially modifiable causes for delays in care of acutely ill patients. Improved process design could include automated call-outs, a dedicated kit for emergency treatment in relevant clinical areas, increased usage of standard operating procedures and staff training using crew resource management techniques. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Procedure to select test organisms for environmental risk assessment of genetically modified crops in aquatic systems.

PubMed

Hilbeck, Angelika; Bundschuh, Rebecca; Bundschuh, Mirco; Hofmann, Frieder; Oehen, Bernadette; Otto, Mathias; Schulz, Ralf; Trtikova, Miluse

2017-11-01

For a long time, the environmental risk assessment (ERA) of genetically modified (GM) crops focused mainly on terrestrial ecosystems. This changed when it was scientifically established that aquatic ecosystems are exposed to GM crop residues that may negatively affect aquatic species. To assist the risk assessment process, we present a tool to identify ecologically relevant species usable in tiered testing prior to authorization or for biological monitoring in the field. The tool is derived from a selection procedure for terrestrial ecosystems with substantial but necessary changes to adequately consider the differences in the type of ecosystems. By using available information from the Water Framework Directive (2000/60/EC), the procedure can draw upon existing biological data on aquatic systems. The proposed procedure for aquatic ecosystems was tested for the first time during an expert workshop in 2013, using the cultivation of Bacillus thuringiensis (Bt) maize as the GM crop and 1 stream type as the receiving environment in the model system. During this workshop, species executing important ecological functions in aquatic environments were identified in a stepwise procedure according to predefined ecological criteria. By doing so, we demonstrated that the procedure is practicable with regard to its goal: From the initial long list of 141 potentially exposed aquatic species, 7 species and 1 genus were identified as the most suitable candidates for nontarget testing programs. Integr Environ Assess Manag 2017;13:974-979. © 2017 SETAC. © 2017 SETAC.

40 CFR 721.10149 - Carbon black, (3-methylphenyl)-modified, substituted (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Carbon black, (3-methylphenyl... Significant New Uses for Specific Chemical Substances § 721.10149 Carbon black, (3-methylphenyl)-modified... substance identified generically as carbon black, (3-methylphenyl)-modified, substituted (PMN P-07-522) is...

40 CFR 721.10150 - Carbon black, (4-methylphenyl)-modified, substituted (generic).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Carbon black, (4-methylphenyl... Significant New Uses for Specific Chemical Substances § 721.10150 Carbon black, (4-methylphenyl)-modified... substance identified generically as carbon black, (4-methylphenyl)-modified, substituted (PMN P-07-523) is...

Effect modification of perinatal exposure to air pollution and childhood asthma incidence

PubMed Central

Lavigne, Éric; Bélair, Marc-André; Rodriguez Duque, Daniel; Do, Minh T.; Stieb, David M.; Hystad, Perry; van Donkelaar, Aaron; Martin, Randall V.; Crouse, Daniel L.; Crighton, Eric; Chen, Hong; Burnett, Richard T.; Weichenthal, Scott; Villeneuve, Paul J.; To, Teresa; Brook, Jeffrey R.; Johnson, Markey; Cakmak, Sabit; Yasseen, Abdool S.; Walker, Mark

2018-01-01

Perinatal exposure to ambient air pollution has been associated with childhood asthma incidence; however, less is known regarding the potential effect modifiers in this association. We examined whether maternal and infant characteristics modified the association between perinatal exposure to air pollution and development of childhood asthma. 761 172 births occurring between 2006 and 2012 were identified in the province of Ontario, Canada. Associations between exposure to ambient air pollutants and childhood asthma incidence (up to age 6 years) were estimated using Cox regression models. 110 981 children with asthma were identified. In models adjusted for postnatal exposures, second-trimester exposures to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (hazard ratio (HR) per interquartile range (IQR) increase 1.07, 95% CI 1.06–1.09) and nitrogen dioxide (HR per IQR increase 1.06, 95% CI 1.03–1.08) were associated with childhood asthma development. Enhanced impacts were found among children born to mothers with asthma, who smoked during pregnancy or lived in urban areas during pregnancy, males and children born preterm or of low birthweight. Prenatal exposure to air pollution may have a differential impact on the risk of asthma development, according to maternal and infant characteristics. PMID:29419440

Proteomic profiling of liver from Atlantic salmon (Salmo salar) fed genetically modified soy compared to the near-isogenic non-GM line.

PubMed

Sissener, Nini H; Martin, Samuel A M; Cash, Phillip; Hevrøy, Ernst M; Sanden, Monica; Hemre, Gro-Ingunn

2010-06-01

The aim of this study was to investigate potential differences in liver protein expression of Atlantic salmon fed genetically modified (GM) Roundup Ready soy at a high inclusion level (25% inclusion, constituting 21% of crude protein in the diet) for 7 months or a compositionally similar non-GM diet. The liver was selected as the target organ due to its importance in the general metabolism, and 2D gel electrophoresis used as a screening tool. Samples from 12 individual fish from each diet group were evaluated. Of a total of 781 analysed protein spots, only 36 were significantly different by ANOVA (p < 0.05) in abundance between the diet groups. All these spots had low fold differences (1.2-1.6) and high false discovery rate (q = 0.44), indicating minor differences in liver protein synthesis between fish fed GM and non-GM soy. Additionally, low fold differences were observed. Four protein spots were analyzed by liquid chromatography tandem mass spectrometry and identified using a combination of online searches in NCBI and searches in an inhouse database containing salmonid expressed sequence tags and contigs. Follow-up on these proteins by real-time polymerase chain reaction did not identify differences at the transcriptional level.

The DASS-14: Improving the Construct Validity and Reliability of the Depression, Anxiety, and Stress Scale in a Cohort of Health Professionals.

PubMed

Wise, Frances M; Harris, Darren W; Olver, John H

2017-01-01

Considerable research has been undertaken in evaluating the DASS-21 in a variety of clinical populations, but studies of the instrument's psychometric adequacy in healthcare professionals is lacking. This study aimed to establish and improve the construct validity and reliability of the DASS-21 in a cohort of Australian health professionals. 343 rehabilitation health professionals completed the DASS-21, along with a demographic questionnaire. Principal components analysis was performed to identify potential factors in the DASS-21. Factors were interpreted against theoretical constructs underlying the instrument. Items loading on separate factors were then subjected to reliability analysis to determine internal consistency of subscales. Items that demonstrated poor fit, or loaded onto more than one factor, were deleted to maximise the reliability of each subscale. Principal components analysis identified three dimensions (depression, anxiety, stress) in a modified version of the DASS-21 (renamed DASS-14), with appropriate construct validity and good reliability (a=0.73 to 0.88). The three dimensions accounted for over 62% of variance between items. The modified DASS-14 scale is a more parsimonious measure of depression, anxiety, and stress, with acceptable reliability and construct validity, in rehabilitation health professionals and is appropriate for use in studies of similar populations.

Selection of RNA Aptamers Against Botulinum Neurotoxin Type A Light Chain Through a Non-Radioactive Approach.

PubMed

Chang, Tzuu-Wang; Janardhanan, Pavithra; Mello, Charlene M; Singh, Bal Ram; Cai, Shuowei

2016-09-01

Botulinum neurotoxin (BoNT), a category A agent, is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study, a non-radioactive-based systematic evolution of ligands by exponential enrichment (SELEX) process is developed by utilizing surface plasmon resonance to monitor the binding enrichment. Two RNA aptamers have been identified as strong binders against light chain of botulinum neurotoxin type A. These two aptamers showed strong inhibition activity on LCA, with IC50 in nanomolar range. Inhibition kinetic studies reveal mid nanomolar KI and non-competitive nature of their inhibition, suggesting that they have strong potential as antidotes that can reverse the symptom caused by BoNT/A. More importantly, we observed that the 2'-fluorine-pyrimidine-modified RNA aptamers identified here do not change their binding and biological activities. This observation could lead to a cost-effective way for SELEX, by using regular nucleotide during SELEX, and 2'-fluorine-pyrimidine-modified nucleotide for final application to enhance their RNase-resistance.

Selection of RNA aptamers against botulinum neurotoxin type A light chain through a non-radioactive approach

PubMed Central

Chang, Tzuu-Wang; Janardhanan, Pavithra; Mello, Charlene; Singh, Bal Ram; Cai, Shuowei

2016-01-01

Botulinum neurotoxin (BoNT), a category A agent, is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study, a non-radioactive based SELEX process is developed by utilizing surface plasmon resonance to monitor the binding enrichment. Two RNA aptamers have been identified as strong binders against light chain of botulinum neurotoxin type A. These two aptamers showed strong inhibition activity on LCA, with IC50 in nM range. Inhibition kinetic studies reveal mid nanomolar KI and non-competitive nature of their inhibition, suggesting they have strong potential as antidotes that can reverse the symptom caused by BoNT/A. More importantly, we observed that 2′-fluorine-pyrimidines modified RNA aptamers identified here do not change their binding and biological activities. This observation could lead to a cost-effective way for Systematic Evolution of Ligands by EXponential enrichment (SELEX), by using regular nucleotide during SELEX, and 2′-fluorine-pyrimidines modified nucleotide for final application to enhance their RNase-resistance. PMID:27085355

Risk factors for relinquishment of cats to an animal shelter.

PubMed

Patronek, G J; Glickman, L T; Beck, A M; McCabe, G P; Ecker, C

1996-08-01

To identify feline and household characteristics associated with relinquishment of a pet cat to an animal shelter. Case-control study. Households that relinquished cats for adoption (case households) and a random sample of current cat-owning households in the same community (control households). Potentially modifiable risk factors with the highest population attributable risk for relinquishment were owners having specific expectations about the cat's role in the household, allowing the cat outdoors, owning a sexually intact cat, never having read a book about cat behavior, cats having daily or weekly inappropriate elimination, and inappropriate care expectations. Frequency of inappropriate elimination and aggression toward people were not associated with declaw status, but these behaviors were more common among sexually intact cats, compared with sterilized cats. Owners of cats in case households were more likely than owners in control households to cite cost of sterilization as a reason a cat was sexually intact. Cats found as strays and cats acquired with minimal planning were at decreased risk of relinquishment. The identified risk factors can be modified by cat owners and veterinarians to decrease the estimated 4 million cats euthanatized annually in animal shelters. Owner education programs are needed as well as increased awareness on the part of cat owners and veterinarians of the importance of resolving feline inappropriate elimination problems.

Landmarks in the history of cancer epidemiology.

PubMed

Greenwald, Peter; Dunn, Barbara K

2009-03-15

The application of epidemiology to cancer prevention is relatively new, although observations of the potential causes of cancer have been reported for more than 2,000 years. Cancer was generally considered incurable until the late 19th century. Only with a refined understanding of the nature of cancer and strategies for cancer treatment could a systematic approach to cancer prevention emerge. The 20th century saw the elucidation of clues to cancer causation from observed associations with population exposures to tobacco, diet, environmental chemicals, and other exogenous factors. With repeated confirmation of such associations, researchers entertained for the first time the possibility that cancer, like many of the infectious diseases of the time, might be prevented. By the mid-20th century, with antibiotics successfully addressing the majority of infectious diseases and high blood pressure treatment beginning to affect the prevalence of heart disease in a favorable direction, the focus of much of epidemiology shifted to cancer. The early emphasis was on exploring, in greater depth, the environmental, dietary, hormonal, and other exogenous exposures for their potential associations with increased cancer risk. The first major breakthrough in identifying a modifiable cancer risk factor was the documentation of an association between tobacco smoking and lung cancer. During the past four decades, epidemiologic studies have generated population data identifying risk factors for cancers at almost every body site, with many cancers having multiple risk factors. The development of technologies to identify biological molecules has facilitated the incorporation of these molecular manifestations of biological variation into epidemiologic studies, as markers of exposure as well as putative surrogate markers of cancer outcome. This technological trend has, during the past two decades, culminated in emphasis on the identification of genetic variants and their products as correlates of cancer risk, in turn, creating opportunities to incorporate the discipline of molecular/genetic epidemiology into the study of cancer prevention. Epidemiology will undoubtedly continue contributing to cancer prevention by using traditional epidemiologic study designs to address broad candidate areas of interest, with molecular/genetic epidemiology investigations honing in on promising areas to identify specific factors that can be modified with the goal of reducing risk.

Impact of Contextual Factors on the Effect of Interventions to Improve Health Worker Performance in Sub-Saharan Africa: Review of Randomised Clinical Trials.

PubMed

Blacklock, Claire; Gonçalves Bradley, Daniela C; Mickan, Sharon; Willcox, Merlin; Roberts, Nia; Bergström, Anna; Mant, David

2016-01-01

Africa bears 24% of the global burden of disease but has only 3% of the world's health workers. Substantial variation in health worker performance adds to the negative impact of this significant shortfall. We therefore sought to identify interventions implemented in sub-Saharan African aiming to improve health worker performance and the contextual factors likely to influence local effectiveness. A systematic search for randomised controlled trials of interventions to improve health worker performance undertaken in sub-Saharan Africa identified 41 eligible trials. Data were extracted to define the interventions' components, calculate the absolute improvement in performance achieved, and document the likelihood of bias. Within-study variability in effect was extracted where reported. Statements about contextual factors likely to have modified effect were subjected to thematic analysis. Interventions to improve health worker performance can be very effective. Two of the three trials assessing mortality impact showed significant reductions in death rates (age<5 case fatality 5% versus 10%, p<0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p<0.05). Eight of twelve trials focusing on prescribing had a statistically significant positive effect, achieving an absolute improvement varying from 9% to 48%. However, reported range of improvement between centres within trials varied substantially, in many cases exceeding the mean effect. Nine contextual themes were identified as modifiers of intervention effect across studies; most frequently cited were supply-line failures, inadequate supervision or management, and failure to follow-up training interventions with ongoing support, in addition to staff turnover. Interventions to improve performance of existing staff and service quality have the potential to improve patient care in underserved settings. But in order to implement interventions effectively, policy makers need to understand and address the contextual factors which can contribute to differences in local effect. Researchers therefore must recognise the importance of reporting how context may modify effect size.

OGT (O-GlcNAc Transferase) Selectively Modifies Multiple Residues Unique to Lamin A.

PubMed

Simon, Dan N; Wriston, Amanda; Fan, Qiong; Shabanowitz, Jeffrey; Florwick, Alyssa; Dharmaraj, Tejas; Peterson, Sherket B; Gruenbaum, Yosef; Carlson, Cathrine R; Grønning-Wang, Line M; Hunt, Donald F; Wilson, Katherine L

2018-05-17

The LMNA gene encodes lamins A and C with key roles in nuclear structure, signaling, gene regulation, and genome integrity. Mutations in LMNA cause over 12 diseases ('laminopathies'). Lamins A and C are identical for their first 566 residues. However, they form separate filaments in vivo, with apparently distinct roles. We report that lamin A is β- O -linked N -acetylglucosamine- (O -GlcNAc)-modified in human hepatoma (Huh7) cells and in mouse liver. In vitro assays with purified O -GlcNAc transferase (OGT) enzyme showed robust O -GlcNAcylation of recombinant mature lamin A tails (residues 385⁻646), with no detectable modification of lamin B1, lamin C, or 'progerin' (Δ50) tails. Using mass spectrometry, we identified 11 O -GlcNAc sites in a 'sweet spot' unique to lamin A, with up to seven sugars per peptide. Most sites were unpredicted by current algorithms. Double-mutant (S612A/T643A) lamin A tails were still robustly O -GlcNAc-modified at seven sites. By contrast, O -GlcNAcylation was undetectable on tails bearing deletion Δ50, which causes Hutchinson⁻Gilford progeria syndrome, and greatly reduced by deletion Δ35. We conclude that residues deleted in progeria are required for substrate recognition and/or modification by OGT in vitro. Interestingly, deletion Δ35, which does not remove the majority of identified O -GlcNAc sites, does remove potential OGT-association motifs (lamin A residues 622⁻625 and 639⁻645) homologous to that in mouse Tet1. These biochemical results are significant because they identify a novel molecular pathway that may profoundly influence lamin A function. The hypothesis that lamin A is selectively regulated by OGT warrants future testing in vivo, along with two predictions: genetic variants may contribute to disease by perturbing OGT-dependent regulation, and nutrient or other stresses might cause OGT to misregulate wildtype lamin A.

Impact of Contextual Factors on the Effect of Interventions to Improve Health Worker Performance in Sub-Saharan Africa: Review of Randomised Clinical Trials

PubMed Central

Mickan, Sharon; Willcox, Merlin; Roberts, Nia; Bergström, Anna; Mant, David

2016-01-01

Background Africa bears 24% of the global burden of disease but has only 3% of the world’s health workers. Substantial variation in health worker performance adds to the negative impact of this significant shortfall. We therefore sought to identify interventions implemented in sub-Saharan African aiming to improve health worker performance and the contextual factors likely to influence local effectiveness. Methods and Findings A systematic search for randomised controlled trials of interventions to improve health worker performance undertaken in sub-Saharan Africa identified 41 eligible trials. Data were extracted to define the interventions’ components, calculate the absolute improvement in performance achieved, and document the likelihood of bias. Within-study variability in effect was extracted where reported. Statements about contextual factors likely to have modified effect were subjected to thematic analysis. Interventions to improve health worker performance can be very effective. Two of the three trials assessing mortality impact showed significant reductions in death rates (age<5 case fatality 5% versus 10%, p<0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p<0.05). Eight of twelve trials focusing on prescribing had a statistically significant positive effect, achieving an absolute improvement varying from 9% to 48%. However, reported range of improvement between centres within trials varied substantially, in many cases exceeding the mean effect. Nine contextual themes were identified as modifiers of intervention effect across studies; most frequently cited were supply-line failures, inadequate supervision or management, and failure to follow-up training interventions with ongoing support, in addition to staff turnover. Conclusions Interventions to improve performance of existing staff and service quality have the potential to improve patient care in underserved settings. But in order to implement interventions effectively, policy makers need to understand and address the contextual factors which can contribute to differences in local effect. Researchers therefore must recognise the importance of reporting how context may modify effect size. PMID:26731097

Hounsfield units are a useful predictor of pleural effusion cytological type in dogs but not in cats.

PubMed

Woods, Sarah J; Spriet, Mathieu; Safra, Noa; Cissell, Derek D; Borjesson, Dori L

2018-04-23

All categories of pleural effusion subjectively display as soft tissue opacity on computed tomography (CT). Quantitative measurement using Hounsfield units (HU) has the potential to bring additional information regarding the nature of the fluid in a noninvasive way. The purposes of this retrospective cross-sectional analytical study were to compare Hounsfield units of different pleural effusion categories in dogs and cats, assess association between specific cytologic parameters and Hounsfield units, and evaluate the effect of dependent vs. nondependent aspect of the effusion pool on Hounsfield unit. A total of 111 patients (74 dogs and 37 cats) with pleural effusion, that underwent thoracic CT and diagnostic thoracocentesis, were included in the study. Effusions were cytologically categorized as exudate, transudate, modified transudate, hemorrhage, or chyle. Significant differences existed in Hounsfield units between categories in dogs (P < 0.0001) but not in cats (P = 0.334). Canine chylous effusion (6.1 ± 4.7 HU (mean ± standard deviation)) and transudate (5.6 ± 2.0) were significantly lower than exudate (20.3 ± 9.5) and hemorrhage (21.4 ± 9.2). No significant differences were found between modified transudate (13.6 ± 10.3) and other categories. Significant, weak linear correlation was identified in dogs between Hounsfield units and total protein (P = 0.018, R   = 0.089), red blood cells (P = 0.021, R   = 0.077), and total nucleated cells (P = 0.013, R   = 0.089). The Hounsfield units of dependent effusion was not significantly higher than the nondependent effusion, except for canine chylous effusion (P = 0.008). Fourteen Hounsfield units was identified as the most clinically useful threshold: <14 HU identified transudate or chylous effusion with a sensitivity of 100% and a specificity of 69%. A threshold >14 HU had a specificity of 100% and a sensitivity of 69% for identifying exudate, modified transudate, or hemorrhage. © 2018 American College of Veterinary Radiology.

Personalized Medicine and Customized Drug Delivery Systems: The New Trend of Drug Delivery and Disease Management.

PubMed

Soni, Abhishek; Gowthamarajan, Kuppusamy; Radhakrishnan, Arun

2018-01-01

Over the past few decades, the concept of personalized medicine has proved to play an important role in the healthcare sector. Personalized medicine modifies the current dosage forms according to the needs of the patient. Based on this improved concept, we are now able to bring out best treatment options for a particular individual leading to better therapeutic outcomes and decreased adverse effects. It also has the potential to identify the disease at an earlier stage. It links the diseased condition of a person to the basic genetic and molecular profile causing better understanding of the condition of the patient and to pick out better treatment options. This review is to enlighten the past, present, and future perspective of personalized medicine and how the personalized-medicine approach is used as customized drug delivery, as well as the regulatory aspects towards it. Personalized medicine has the potential to modify the way we recognize and manage our health problems and has already proven to have a huge impact on patient care and on clinical research. The impact of personalized medicine is expected to increase with an increased knowledge about the term and related technologies. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Global profiling of proteolytically modified proteins in human metastatic hepatocellular carcinoma cell lines reveals CAPN2 centered network.

PubMed

Shen, Chengpin; Yu, Yanyan; Li, Hong; Yan, Guoquan; Liu, Mingqi; Shen, Huali; Yang, Pengyuan

2012-06-01

Proteolysis affects every protein at some point in its life cycle. Many biomarkers of disease or cancer are stable proteolytic fragments in biological fluids. There is great interest and a challenge in proteolytically modified protein study to identify physiologic protease-substrate relationships and find potential biomarkers. In this study, two human hepatocellular carcinoma (HCC) cell lines with different metastasis potential, MHCC97L, and HCCLM6, were researched with a high-throughput and sensitive PROTOMAP platform. In total 391 proteins were found to be proteolytically processed and many of them were cleaved into persistent fragments instead of completely degraded. Fragments related to 161 proteins had different expressions in these two cell lines. Through analyzing these significantly changed fragments with bio-informatic tools, several bio-functions such as tumor cell migration and anti-apoptosis were enriched. A proteolysis network was also built up, of which the CAPN2 centered subnetwork, including SPTBN1, ATP5B, and VIM, was more active in highly metastatic HCC cell line. Interestingly, proteolytic modifications of CD44 and FN1 were found to affect their secretion. This work suggests that proteolysis plays an important role in human HCC metastasis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Explosives detection in the marine environment using UUV-modified immunosensor

NASA Astrophysics Data System (ADS)

Charles, Paul T.; Adams, André A.; Deschamps, Jeffrey R.; Veitch, Scott P.; Hanson, Alfred; Kusterbeck, Anne W.

2011-05-01

Port and harbor security has rapidly become a point of interest and concern with the emergence of new improvised explosive devices (IEDs). The ability to provide physical surveillance and identification of IEDs and unexploded ordnances (UXO) at these entry points has led to an increased effort in the development of unmanned underwater vehicles (UUVs) equipped with sensing devices. Traditional sensors used to identify and locate potential threats are side scan sonar/acoustic methods and magnetometers. At the Naval Research Laboratory (NRL), we have developed an immunosensor capable of detecting trace levels of explosives that has been integrated into a REMUS payload for use in the marine environment. Laboratory tests using a modified PMMA microfluidic device with immobilized monoclonal antibodies specific for TNT and RDX have been conducted yielding detection levels in the low parts-per-billion (ppb) range. New designs and engineered improvements in microfluidic devices, fluorescence signal probes, and UUV internal fluidic and optical components have been investigated and integrated into the unmanned underwater prototype. Results from laboratory and recent field demonstrations using the prototype UUV immunosensor will be discussed. The immunosensor in combination with acoustic and other sensors could serve as a complementary characterization tool for the detection of IEDs, UXOs and other potential chemical or biological threats.

"Urban geosites" as an alternative geotourism destination - evidence from Belgrade

NASA Astrophysics Data System (ADS)

Petrović, Marko D.; Lukić, Dobrila M.; Radovanović, Milan; Vujko, Aleksandra; Gajić, Tamara; Vuković, Darko

2017-10-01

The research aimed at testing the combination of GAM/M-GAM models (Geosite Assessment Model/Modified Geosite Assessment Model) on selected geoheritage sites (geosites) of great scientific significance and geotourism potential. Testing was done on eight sites in the City of Belgrade (Serbian capital), an area which has significant potential for geotourism development in typical urban conditions. For this purpose, an assessment scale was used to highlight differences and similarities between main and additional values of the observed geosites. The modification of the original GAM model is based on the inclusion of visitors' opinions regarding the importance of indicators in the assessment process. The assessment was done by using both GAM/M-GAM and its results were analyzed and compared afterwards. The analysis has successfully identified locations and features of geosites that require action for maintaining or increasing their overall value and function. Moreover, the principal aim of the paper was to analyze the relevance of each sub-indicator for the assessment process by introducing the importance factor in the modified model. The authors were able to point out those values of principal importance for geosite visitors, as well as to attach a different relevance to sub-indicators, which can influence the position of the geosites in the GAM/M-GAM matrices.

Amide and Ester-Functionalized Humic Acid for Fuel Combustion Enhancement

NASA Astrophysics Data System (ADS)

Riggs, Mark

Humic acid is a class of naturally occurring molecules composed of large sheet-like regions of cyclic aromatic hydrocarbon networks with surface and edge functional groups including phenols, carboxylic acids, and epoxides. These naturally occurring molecules are found in brown coal deposits near lignite formations. Humic acid has gained attention from the scientific community as a precursor for graphene. Graphene is a 2-dimensional honeycomb structure of fully unsaturated carbon atoms that has exceptional material properties and inherent aromaticity. Graphene's incredible properties are matched by the difficulty associated with reproducibly manufacturing it on a large scale. This issue has limited the use of graphene for commercial applications. The polar functional groups of humic acid contribute to the hydrophilic nature of the molecule, limiting its miscibility in any alkyl-based solvent. Surfactants containing long alkyl chains can affect the miscibility of the molecule in an organic solvent. Surfactants are often difficult to remove from the system. It is theorized that alkylation of the functional sites of humic acid can affect the hydrophilic nature of the molecule, and effectively enable its dispersion into organic solvents without simultaneous incorporation of surfactants. This dissertation investigated the amidation and esterification of humic acid molecules extracted from leonardite. The resulting change in the modified humic acid dispersibility in organic solvents and its potential usage as a fuel additive were evaluated. Butyl, hexyl, octyl, and decyl amide-modified and ester-modified humic acids were synthesized. These products were characterized to confirm successful chemical reaction through thermogravimetric analysis, Fourier-transform infrared spectroscopy, and scanning electron microscopy. The decyl-modified humic acids remained suspended in kerosene mixtures for longer than 1 week. Other organo-humic acids showed varying degrees of flocculation. The modified humic acid samples were diluted with kerosene to identify the influence on combustion properties. Butyl-modified humic acid samples decreased the molar enthalpy of combustion. Hexyl, octyl, and decyl-modified humic acids improved the combustion values. Decyl amide-modified humic acid showed the largest improvement of these mixtures with a 0.9% increase from the expected molar enthalpy of combustion with a loading percentage of 0.36% in kerosene. Octyl amide-modified and octyl ester-modified humic acid mixtures were prepared in 0.05, 0.1, and 1% loading percentage dilutions to study the effect of modified humic acid loading percent on combustion properties. The 0.1% dilution showed the largest increase of the expected molar enthalpy of combustion by 1.14% and 0.4% for amide-modified HA and ester-modified HA, respectively.

Identifying Links Between Sexual Violence and Youth Violence Perpetration: New Opportunities for Sexual Violence Prevention

PubMed Central

DeGue, Sarah; Massetti, Greta M.; Holt, Melissa K.; Tharp, Andra Teten; Valle, Linda Anne; Matjasko, Jennifer L.; Lippy, Caroline

2018-01-01

Objective One promising opportunity for advancing sexual violence (SV) research and identifying new avenues for prevention involves examining other forms of violence that may share risk factors with SV. Youth violence (YV) is ideal for consideration given evidence of overlap in SV and YV risk factors, a large set of established YV risk factors across the social ecology, and the number of evidence-based YV prevention strategies available. The current paper identifies shared and unique risk factors for SV and YV and highlights evidence-based YV prevention strategies that impact these shared risk factors. Conclusions Researchers and program developers should consider adapting and evaluating evidence-based YV prevention strategies to prevent SV. Modifying these programs to address SV’s unique risk factors may maximize their potential effectiveness. In addition, expanding SV research at the outer levels of the social ecology is critical to developing community-level prevention strategies. The YV literature suggests several potential risk factors at these levels in need of research for SV, including school connectedness, social disorganization, and availability of alcohol and drugs. Using the YV literature as a starting point for expanding SV research leverages prior investments in YV research, may help identify new SV prevention strategies at a limited cost, and moves the field more quickly toward implementation of cost-effective, multidomain violence prevention strategies in communities. PMID:29644117

Promoting and Protecting Against Stigma in Assisted Living and Nursing Homes.

PubMed

Zimmerman, Sheryl; Dobbs, Debra; Roth, Erin G; Goldman, Susan; Peeples, Amanda D; Wallace, Brandy

2016-06-01

To determine the extent to which structures and processes of care in multilevel settings (independent living, assisted living, and nursing homes) result in stigma in assisted living and nursing homes. Ethnographic in-depth interviews were conducted in 5 multilevel settings with 256 residents, families, and staff members. Qualitative analyses identified the themes that resulted when examining text describing either structures of care or processes of care in relation to 7 codes associated with stigma. Four themes related to structures of care and stigma were identified, including the physical environment, case mix, staff training, and multilevel settings; five themes related to processes of care and stigma, including dining, independence, respect, privacy, and care provision. For each theme, examples were identified illustrating how structures and processes of care can potentially promote or protect against stigma. In no instance were examples or themes identified that suggested the staff intentionally promoted stigma; on the other hand, there was indication that some structures and processes were intentionally in place to protect against stigma. Perhaps the most important theme is the stigma related to multilevel settings, as it has the potential to reduce individuals' likelihood to seek and accept necessary care. Results suggest specific recommendations to modify care and reduce stigma. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Challenges and barriers for implementation of the World Health Organization Global Disability Action Plan in low- and middle- income countries.

PubMed

Khan, Fary; Owolabi, Mayowa Ojo; Amatya, Bhasker; Hamzat, Talhatu Kolapo; Ogunniyi, Adesola; Oshinowo, Helen; Elmalik, Alaeldin; Galea, Mary P

2018-04-18

To identify potential barriers and facilitators for implementation of the World Health Organization Global Disability Action Plan (GDAP) in Nigeria and compare these with other low- and middle-income countries. A rehabilitation team from the Royal Melbourne Hospital, Parkville, Australia, conducted intensive workshops at medical/academic institutions in Nigeria for healthcare professionals from various local Physical Medicine and Rehabilitation facilities. A modified Delphi method identified challenges for person with disability, using 3 GDAP objectives. Findings were compared with similar exercises in Madagascar, Pakistan and Mongolia. Despite differences in the healthcare system and practice, the challenges reported in Nigeria were similar to those in other 3 low- and middle-income countries, at both macro (governmental/policymakers) and micro levels (community/social/individual). Common challenges identified were: limited knowledge of disability services, limited Physical Medicine and Rehabilitation workforce, guidelines and accreditation standards; coordination amongst healthcare sectors; social issues; data and research; legislation and political commitment. Common potential facilitators included: need for strong leadership; advocacy of disability-inclusive development; investment in infrastructure/human resources; coordination/partnerships in healthcare sector; and research. Disability care is an emerging priority in low- and middle-income countries to address the needs of people with disability. The challenges identified in Nigeria are common to most low- and middle-income countries. The GDAP framework can facilitate access and strengthen Physical Medicine and Rehabilitation services.

Factors influencing parents' decision-making when sending children with respiratory tract infections to nursery.

PubMed

Carroll, Fran E; Rooshenas, Leila; Owen-Smith, Amanda; Al-Janabi, Hareth; Hollinghurst, Sandra; Hay, Alastair D

2016-06-01

Many families rely on formal day care provision, which can be problematic when children are unwell. Attendance in these circumstances may impact on the transmission of infections in both day care and the wider community. Thirty-one semi-structured interviews were conducted to investigate how parents make decisions about nursery care when children are unwell. Topics for discussion included: illness attitudes, current practice during childhood illness and potential nursery policy changes that could affect decision-making. A combination of illness perceptions and external factors affected decision-making. Parents: (i) considered the severity of respiratory and non-respiratory symptoms differently, and stated that while most other contagious illnesses required nursery exclusion, coughs/colds did not; (ii) said decisions were not solely based on nursery policy, but on practical challenges such as work absences, financial penalties and alternative care availability; (iii) identified modifiable nursery policy factors that could potentially help parents keep unwell children at home, potentially reducing transmission of infectious illness. Decision-making is a complex interaction between the child's illness, personal circumstance and nursery policy. Improving our understanding of the modifiable aspects of nursery policies and the extent to which these factors affect decision-making could inform the design and implementation of interventions to reduce the transmission of infectious illness and the associated burden on NHS services. © The Author 2015. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genetic polymorphisms associated with breast cancer in malaysian cohort.

PubMed

Chahil, Jagdish Kaur; Munretnam, Khamsigan; Samsudin, Nurulhafizah; Lye, Say Hean; Hashim, Nikman Adli Nor; Ramzi, Nurul Hanis; Velapasamy, Sharmila; Wee, Ler Lian; Alex, Livy

2015-04-01

Genome-wide association studies have discovered multiple single nucleotide polymorphisms (SNPs) associated with the risk of common diseases. The objective of this study was to demonstrate the replication of previously published SNPs that showed statistical significance for breast cancer in the Malaysian population. In this case-control study, 80 subjects for each group were recruited from various hospitals in Malaysia. A total of 768 SNPs were genotyped and analyzed to distinguish risk and protective alleles. A total of three SNPs were found to be associated with increased risk of breast cancer while six SNPs showed protective effect. All nine were statistically significant SNPs (p ≤ 0.01), five SNPs from previous studies were successfully replicated in our study. Significant modifiable (diet) and non-modifiable (family history of breast cancer in first degree relative) risk factors were also observed. We identified nine SNPs from this study to be either conferring susceptibility or protection to breast cancer which may serve as potential markers in risk prediction.

Modifying murine von Willebrand factor A1 domain for in vivo assessment of human platelet therapies.

PubMed

Chen, Jianchun; Tan, Kui; Zhou, Hairu; Lo, Hsuan-Fu; Tronik-Le Roux, Diana; Liddington, Robert C; Diacovo, Thomas G

2008-01-01

The A1 domain of von Willebrand factor (VWF-A1) plays a crucial role in hemostasis and thrombosis by initiating platelet adhesion at sites of arterial injury through interactions with the platelet receptor glycoprotein Ib alpha (GPIbalpha). Here we report that murine VWF-A1 supports limited binding of human platelets. However, atomic models of GPIbalpha-VWF-A1 complexes identified an electrostatic 'hot-spot' that, when mutated in murine VWF-A1, switches its binding specificity from mouse to human GPIbalpha. Furthermore, mice expressing this mutant VWF-A1 display a bleeding phenotype that can be corrected by infusion of human platelets. Mechanistically, human platelets correct the phenotype by forming occlusive thrombi, an event that can be abrogated by blockade of GPIbalpha or by the preadministration of inhibitors of platelet activation or adhesion (clopidogrel (Plavix) and abciximab (ReoPro), respectively). Thus, by modifying a protein interface, we have generated a potential biological platform for preclinical screening of antithrombotics that specifically target human platelets.

A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods

NASA Astrophysics Data System (ADS)

Novinec, Marko; Korenč, Matevž; Caflisch, Amedeo; Ranganathan, Rama; Lenarčič, Brigita; Baici, Antonio

2014-02-01

Allosteric modifiers have the potential to fine-tune enzyme activity. Therefore, targeting allosteric sites is gaining increasing recognition as a strategy in drug design. Here we report the use of computational methods for the discovery of the first small-molecule allosteric inhibitor of the collagenolytic cysteine peptidase cathepsin K, a major target for the treatment of osteoporosis. The molecule NSC13345 is identified by high-throughput docking of compound libraries to surface sites on the peptidase that are connected to the active site by an evolutionarily conserved network of residues (protein sector). The crystal structure of the complex shows that NSC13345 binds to a novel allosteric site on cathepsin K. The compound acts as a hyperbolic mixed modifier in the presence of a synthetic substrate, it completely inhibits collagen degradation and has good selectivity for cathepsin K over related enzymes. Altogether, these properties qualify our methodology and NSC13345 as promising candidates for allosteric drug design.

Potential bioavailability assessment, source apportionment and ecological risk of heavy metals in the sediment of Brisbane River estuary, Australia.

PubMed

Duodu, Godfred Odame; Goonetilleke, Ashantha; Ayoko, Godwin A

2017-04-15

A weak acid extraction was used to mobilize the loosely bound metals in estuary sediment samples. More than 30% of Ag, As, Ca, Cd, Co, Cu, Hg, Mn Ni, Pb and Zn were leached from the sediment showing that these metals are significantly present in the bioavailable form. PCA/APCS identified three sources of the metals, namely: lithogenic accounting for 72%, shipping related contributing 15% and traffic related representing 13% of the total load. Application of pollution index (PI) and modified pollution index (MPI) revealed that the sediment range from unpolluted to heavily polluted while ecological risk index (RI) classifies the sediment as posing low ecological risk modified ecological risk index (MRI) suggests considerable to very high ecological risk. To provide holistic insights into the ecological risks posed by metals, enrichment factor, MPI and MRI are recommended for the assessment of sediment in complex environments such as estuaries. Copyright © 2017 Elsevier Ltd. All rights reserved.

Structurally distinct ubiquitin- and sumo-modified PCNA: implications for their distinct roles in the DNA damage response.

PubMed

Tsutakawa, Susan E; Yan, Chunli; Xu, Xiaojun; Weinacht, Christopher P; Freudenthal, Bret D; Yang, Kun; Zhuang, Zhihao; Washington, M Todd; Tainer, John A; Ivanov, Ivaylo

2015-04-07

Proliferating cell nuclear antigen (PCNA) is a pivotal replication protein, which also controls cellular responses to DNA damage. Posttranslational modification of PCNA by SUMO and ubiquitin modulate these responses. How the modifiers alter PCNA-dependent DNA repair and damage tolerance pathways is largely unknown. We used hybrid methods to identify atomic models of PCNAK107-Ub and PCNAK164-SUMO consistent with small-angle X-ray scattering data of these complexes in solution. We show that SUMO and ubiquitin have distinct modes of association to PCNA. Ubiquitin adopts discrete docked binding positions. By contrast, SUMO associates by simple tethering and adopts extended flexible conformations. These structural differences are the result of the opposite electrostatic potentials of SUMO and Ub. The unexpected contrast in conformational behavior of Ub-PCNA and SUMO-PCNA has implications for interactions with partner proteins, interacting surfaces accessibility, and access points for pathway regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Protective Role of Recent and Past Long-Term Physical Activity on Age-Related Cognitive Decline: The Moderating Effect of Sex.

PubMed

Lopez-Fontana, Iréné; Castanier, Carole; Le Scanff, Christine; Perrot, Alexandra

2018-06-13

This study aimed to investigate if the impact of both recent and long-term physical activity on age-related cognitive decline would be modified by sex. One-hundred thirty-five men (N = 67) and women (N = 68) aged 18 to 80 years completed the Modifiable Activity Questionnaire and the Historical Leisure Activity Questionnaire. A composite score of cognitive functions was computed from five experimental tasks. Hierarchical regression analyses performed to test the moderating effect of recent physical activity on age-cognition relationship had not revealed significant result regardless of sex. Conversely, past long-term physical activity was found to slow down the age-related cognitive decline among women (β = 0.22, p = .03), but not men. The findings support a lifecourse approach in identifying determinants of cognitive aging and the importance of taking into account the moderating role of sex. This article presented potential explanations for these moderators and future avenues to explore.

Skull removal in MR images using a modified artificial bee colony optimization algorithm.

PubMed

Taherdangkoo, Mohammad

2014-01-01

Removal of the skull from brain Magnetic Resonance (MR) images is an important preprocessing step required for other image analysis techniques such as brain tissue segmentation. In this paper, we propose a new algorithm based on the Artificial Bee Colony (ABC) optimization algorithm to remove the skull region from brain MR images. We modify the ABC algorithm using a different strategy for initializing the coordinates of scout bees and their direction of search. Moreover, we impose an additional constraint to the ABC algorithm to avoid the creation of discontinuous regions. We found that our algorithm successfully removed all bony skull from a sample of de-identified MR brain images acquired from different model scanners. The obtained results of the proposed algorithm compared with those of previously introduced well known optimization algorithms such as Particle Swarm Optimization (PSO) and Ant Colony Optimization (ACO) demonstrate the superior results and computational performance of our algorithm, suggesting its potential for clinical applications.

Modifiable Risk Factors for West Nile Virus Infection during an Outbreak—Arizona, 2010

PubMed Central

Gibney, Katherine B.; Colborn, James; Baty, Steven; Bunko Patterson, Andrean M.; Sylvester, Tammy; Briggs, Graham; Stewart, Tasha; Levy, Craig; Komatsu, Ken; MacMillan, Katherine; Delorey, Mark J.; Mutebi, John-Paul; Fischer, Marc; Staples, J. Erin

2012-01-01

West Nile virus (WNV) is the leading cause of mosquito-borne disease in the United States; however, risk factors for infection are poorly defined. We performed a case-control study to identify modifiable risk factors for WNV infection. Case-patients (N = 49) had laboratory evidence of recent WNV infection, whereas control-subjects (N = 74) had negative WNV serology. We interviewed participants, surveyed households, and assessed environmental data. WNV infection was associated with living in or near Water District X within Gilbert Township (adjusted odds ratio [aOR] 5.2; 95% confidence interval [95% CI] = 1.5–18.1), having water-holding containers in their yard (aOR 5.0; 95% CI = 1.5–17.3), and not working or attending school outside the home (aOR 2.4; 95% CI = 1.1–5.5). During this outbreak, WNV infection was likely primarily acquired peri-domestically with increased risk associated with potential mosquito larval habitats around the home and neighborhood. PMID:22556093

Oral sensations and secretions.

PubMed

Running, Cordelia A

2018-04-10

Sensations experienced in the mouth influence food choices, both immediately and in the long term. Such sensations are themselves influenced by experience with flavors, the chemical environment of the mouth, genetics of receptors for flavors, and individual behavior in the chewing of food. Gustation, the sense of taste, yields information about nutrients, influences palatability, and feeds into the human body's preparation to receive those nutrients. Olfaction, the sense of smell, contributes enormously to defining and identifying food flavors (and is experienced even after placing food inside the mouth). Another vital component of food flavor is texture, which contributes to palatability, especially if a food's texture violates a person's expectations. Next, chemesthesis is the sense of chemically induced irritancy and temperature, for example spiciness and stinging. All of these sensations are potentially modified by saliva, the chemical and physical media of the mouth. As a person experiences the culmination of these oral sensations, modified through an individual's own unique saliva, the flavors in turn influence both what and how a person eats. Copyright © 2018 Elsevier Inc. All rights reserved.

Bacterial resistance modifying tetrasaccharide agents from Ipomoea murucoides.

PubMed

Chérigo, Lilia; Pereda-Miranda, Rogelio; Gibbons, Simon

2009-01-01

As part of an ongoing project to identify oligosaccharides which modulate bacterial multidrug resistance, the CHCl(3)-soluble extract from flowers of a Mexican arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded five lipophilic tetrasaccharide inhibitors of Staphylococcusaureus multidrug efflux pumps, murucoidins XII-XVI (1-5). The macrocyclic lactone-type structures for these linear hetero-tetraglycoside derivatives of jalapinolic acid were established by spectroscopic methods. These compounds were tested for in vitro antibacterial and resistance modifying activity against strains of Staphylococcus aureus possessing multidrug resistance efflux mechanisms. Only murucoidin XIV (3) displayed antimicrobial activity against SA-1199B (MIC 32microg/ml), a norfloxacin-resistant strain that over-expresses the NorA MDR efflux pump. The four microbiologically inactive (MIC>512microg/ml) tetrasaccharides increased norfloxacin susceptibility of this strain by 4-fold (8microg/ml from 32microg/ml) at concentrations of 25microg/ml, while murucoidin XIV (3) exerted the same potentiation effect at a concentration of 5microg/ml.

Arthropods dataset from different genetically modified maize events and associated controls

NASA Astrophysics Data System (ADS)

Pálinkás, Zoltán; Zalai, Mihály; Szénási, Ágnes; Dorner, Zita; Kiss, József; North, Samuel; Woodward, Guy; Balog, Adalbert

2018-02-01

Arthropods from four genetically modified (GM) maize hybrids (coleopteran resistant, coleopteran and lepidopteran resistant, lepidopteran resistant+herbicide tolerant and coleopteran resistant and herbicide tolerant) and non-GM varieties were sampled during a two-year field assessment. A total number of 363 555 arthropod individuals were collected. This represents the most comprehensive arthropod dataset from GM maize, and together with weed data, is reasonable to determine functional groups of arthropods and interactions between species. Trophic groups identified from both phytophagous and predatory arthropods were previously considered non-target organisms on which possible detrimental effects of Bacillus thuringiensis (Bt) toxins may have been directly (phytophagous species) or indirectly (predators) detected. The high number of individuals and species and their dynamics through the maize growing season can predict that interactions are highly correlational, and can thus be considered a useful tool to assess potential deleterious effects of Bt toxins on non-target organisms, serving to develop biosafety risk hypotheses for invertebrates exposed to GM maize plants.

Structurally Distinct Ubiquitin- and Sumo-Modified PCNA: Implications for Their Distinct Roles in the DNA Damage Response

DOE PAGES

Tsutakawa, Susan E.; Yan, Chunli; Xu, Xiaojun; ...

2015-03-12

Proliferating cell nuclear antigen (PCNA) is a pivotal replication protein, which also controls cellular responses to DNA damage. Posttranslational modification of PCNA by SUMO and ubiquitin modulate these responses. How the modifiers alter PCNA-dependent DNA repair and damage tolerance pathways is largely unknown. Here, we used hybrid methods to identify atomic models of PCNA K107-Ub and PCNA K164-SUMO consistent with small-angle X-ray scattering data of these complexes in solution. We show that SUMO and ubiquitin have distinct modes of association to PCNA. Ubiquitin adopts discrete docked binding positions. By contrast, SUMO associates by simple tethering and adopts extended flexible conformations.more » These structural differences are the result of the opposite electrostatic potentials of SUMO and Ub. In conclusion, the unexpected contrast in conformational behavior of Ub-PCNA and SUMO-PCNA has implications for interactions with partner proteins, interacting surfaces accessibility, and access points for pathway regulation.« less

Targeted delivery of non-viral vectors to cartilage in vivo using a chondrocyte-homing peptide identified by phage display.

PubMed

Pi, Yanbin; Zhang, Xin; Shi, Junjun; Zhu, Jinxian; Chen, Wenqing; Zhang, Chenguang; Gao, Weiwei; Zhou, Chunyan; Ao, Yingfang

2011-09-01

Gene therapy is a promising method for osteoarthritis and cartilage injury. However, specifically delivering target genes into chondrocytes is a great challenge because of their non-vascularity and the dense extracellular matrix of cartilage. In our study, we identified a chondrocyte-affinity peptide (CAP, DWRVIIPPRPSA) by phage display technology. Subsequent analysis suggests that the peptide can efficiently interact specifically with chondrocytes without any species specificity. Polyethylenimine (PEI) was covalently modified with CAP to construct a non-viral vector for cartilage-targeted therapy. To investigate the cartilage-targeting property of the CAP-modified vector, FITC-labeled CAP conjugated PEI/DNA particles were injected into rabbit knee joints, and visualized under confocal microscope. Higher concentrations of CAP-modified vector were detected in the cartilage and specifically taken up by chondrocytes compared with a randomly scrambled peptide (SP)-modified vector. To evaluate cartilage-targeting transfection efficiency, the GFP and luciferase genes were delivered into knee joints using CAP- and SP-modified PEI. Cartilage transfections mediated by CAP-modified PEI were much more efficient and specific than those by SP-modified PEI. This result suggests that CAP-modified PEI could be used as a specific cartilage-targeting vector for cartilage disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Gene doping: an overview and current implications for athletes.

PubMed

van der Gronde, Toon; de Hon, Olivier; Haisma, Hidde J; Pieters, Toine

2013-07-01

The possibility of gene doping, defined as the transfer of nucleic acid sequences and/or the use of normal or genetically modified cells to enhance sport performance, is a real concern in sports medicine. The abuse of knowledge and techniques gained in the area of gene therapy is a form of doping, and is prohibited for competitive athletes. As yet there is no conclusive evidence that that gene doping has been practiced in sport. However, given that gene therapy techniques improve continuously, the likelihood of abuse will increase. A literature search was conducted to identify the most relevant proteins based on their current gene doping potential using articles from Pubmed, Scopus and Embase published between 2006 and 2011. The final list of selected proteins were erythropoietin, insulin-like growth factor, growth hormone, myostatin, vascular endothelial growth factor, fibroblast growth factor, endorphin and enkephalin, α actinin 3, peroxisome proliferator-activated receptor-delta (PPARδ) and cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C). We discuss these proteins with respect to their potential benefits, existing gene therapy experience in humans, potential risks, and chances of detection in current and future anti-doping controls. We have identified PPARδ and PEPCK-C as having high potential for abuse. But we expect that for efficiency reasons, there will be a preference for inserting gene target combinations rather than single gene doping products. This will also further complicate detection.

Program interruptions and short-stay transfers represent potential targets for inpatient rehabilitation care-improvement efforts

PubMed Central

Middleton, Addie; Graham, James E.; Krishnan, Shilpa; Ottenbacher, Kenneth J.

2016-01-01

Objective To present comprehensive descriptive summaries of program interruptions and short-stay transfers among Medicare fee-for-service beneficiaries receiving inpatient rehabilitation following stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI). Design Retrospective cohort study of Medicare beneficiaries with any of the three conditions of interest who were admitted to inpatient rehabilitation directly from an acute hospital between July 1, 2012 and November 15, 2013. Results In the final sample (stroke: n=71 769; TBI: n=7109; SCI: n=659), program interruption rates were 0.9% (stroke), 0.8% (TBI), and 1.4% (SCI). Short-stay transfer rates were 22.3% (stroke), 21.8% (TBI), and 31.6% (SCI). 14.7% of short-stay transfers and 12.3% of interruptions resulting in a return to acute care were identified as potentially preventable among those with stroke, 10.2% of transfers and 11.7% of interruptions among those with TBI, and 3.8% of transfers and 11.1% of interruptions among those with SCI. Conclusions Broad healthcare policies aimed at improving quality and reducing costs are currently being implemented. Reducing program interruptions and short-stay transfers during inpatient rehabilitative care represents a potential target for care-improvement efforts. Future research focused on identifying modifiable risk factors for potentially undesirable outcomes will allow for targeted preventative interventions. PMID:27631389

Program Interruptions and Short-Stay Transfers Represent Potential Targets for Inpatient Rehabilitation Care-Improvement Efforts.

PubMed

Middleton, Addie; Graham, James E; Krishnan, Shilpa; Ottenbacher, Kenneth J

2016-11-01

The objective of this work was to present comprehensive descriptive summaries of program interruptions and short-stay transfers among Medicare fee-for-service beneficiaries receiving inpatient rehabilitation after stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI). Retrospective cohort study of Medicare beneficiaries with any of the 3 conditions of interest who were admitted to inpatient rehabilitation directly from an acute hospital between July 1, 2012, and November 15, 2013. In the final sample (stroke, n = 71 769; TBI, n = 7109; SCI, n = 659), program interruption rates were 0.9% (stroke), 0.8% (TBI), and 1.4% (SCI). Short-stay transfer rates were 22.3% (stroke), 21.8% (TBI), and 31.6% (SCI); 14.7% of short-stay transfers and 12.3% of interruptions resulting in a return to acute care were identified as potentially preventable among those with stroke; 10.2% of transfers and 11.7% of interruptions among those with TBI, and 3.8% of transfers and 11.1% of interruptions among those with SCI. Broad health care policies aimed at improving quality and reducing costs are currently being implemented. Reducing program interruptions and short-stay transfers during inpatient rehabilitative care represents a potential target for care-improvement efforts. Future research focused on identifying modifiable risk factors for potentially undesirable outcomes will allow for targeted preventative interventions.

Childhood sexual abuse and HIV-related risks among men who have sex with men in Washington, DC.

PubMed

Phillips, Gregory; Magnus, Manya; Kuo, Irene; Rawls, Anthony; Peterson, James; Montanez, Luz; West-Ojo, Tiffany; Jia, Yujiang; Opoku, Jenevieve; Greenberg, Alan E

2014-05-01

Childhood sexual abuse (CSA) has been reported to be disproportionately higher among men who have sex with men (MSM) than among heterosexual men; it has also been found to be significantly positively associated with HIV status and HIV risk factors, including unprotected anal intercourse. The purpose of this study was to assess the correlates of CSA in a sample of community-recruited MSM, investigate race as a potential effect modifier, and describe the independent association between CSA and HIV infection in Washington, DC. A total of 500 MSM were recruited by venue-based sampling in 2008 as part of the National HIV Behavioral Surveillance. More than one-half of MSM identified as White, while one-third identified as Black. CSA was reported by 17.5 % of the 451 MSM, with the first instance of abuse occurring at a median age of 8.3 (interquartile range = 5.0, 11.0). In multivariable analysis, HIV-positive men were significantly more likely to report a history of CSA compared to HIV-negative men after adjusting for intimate partner violence in the last 12 months, having been arrested in the last 12 months, and depressive symptoms. HIV-positive MSM had more than four times the odds of reporting CSA after controlling for other correlates (aOR = 4.19; 95 % CI 2.26, 7.75). Despite hypothesizing that race modified the effect of CSA on HIV infection we found this was not the case in this sample. More research is needed to investigate the potential pathway between a history of CSA and HIV infection, and how this contributes to driving the HIV epidemic among MSM in Washington, DC.

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection.

PubMed

LoRicco, Josephine G; Xu, Changmingzi Sherry; Neidleman, Jason; Bergkvist, Magnus; Greene, Warner C; Roan, Nadia R; Makhatadze, George I

2016-07-01

Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248-286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86-107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Saving lives, maintaining safety, and science-based policy: qualitative interview findings from the Blood Donation Rules Opinion Study (Blood DROPS).

PubMed

Hughes, Shana; Sheon, Nicolas; Siedle-Khan, Bob; Custer, Brian

2015-12-01

Indefinite deferral from donation for any man who discloses having had sex with another man even once since 1977 (MSM77) is the US FDA's standing policy. This qualitative component of the Blood Donation Rules and Opinion Study was designed to provide insight into the perceptions and practices of current or previous donors with MSM history. Forty human immunodeficiency virus (HIV)-negative MSM completed an online survey, indicating that they had donated blood and were willing to be interviewed. Semistructured, individual interviews with these key informants covered donation experience and motivations, perceptions of MSM77, policy change preferences, and possible impact of a change to a time-limited deferral. Transcripts were coded deductively and inductively, following a modified Grounded Theory approach. Analysis identified recurrent and divergent themes. Ninety-five percent of participants endorsed modifying MSM77. Preferred deferral length ranged from none to 5 years; a common opinion was that a science-based deferral period would be less than 1 year. Other policy change recommendations included incorporating questions about specific HIV risk behaviors to the donor questionnaire for all potential donors. Interviewees recognized HIV infection rates are higher in MSM than the general US population, but participants considered themselves low-risk for HIV, donated blood "to save lives," and justified their recommendations as being more effective ways to identify donors at risk for HIV. Results suggest that MSM donors are concerned with blood safety; they can be appealed to as such. Communications about a new deferral policy should include scientific explanations and acknowledge altruistic motivations of potential donors. © 2015 AABB.

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection*

PubMed Central

LoRicco, Josephine G.; Xu, Changmingzi Sherry; Neidleman, Jason; Bergkvist, Magnus; Greene, Warner C.; Roan, Nadia R.; Makhatadze, George I.

2016-01-01

Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248–286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86–107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection. PMID:27226574

Genetically Modified Plants: Public and Scientific Perceptions

PubMed Central

2013-01-01

The potential of genetically modified plants to meet the requirements of growing population is not being recognized at present. This is a consequence of concerns raised by the public and the critics about their applications and release into the environment. These include effect on human health and environment, biosafety, world trade monopolies, trustworthiness of public institutions, integrity of regulatory agencies, loss of individual choice, and ethics as well as skepticism about the real potential of the genetically modified plants, and so on. Such concerns are enormous and prevalent even today. However, it should be acknowledged that most of them are not specific for genetically modified plants, and the public should not forget that the conventionally bred plants consumed by them are also associated with similar risks where no information about the gene(s) transfer is available. Moreover, most of the concerns are hypothetical and lack scientific background. Though a few concerns are still to be disproved, it is viewed that, with proper management, these genetically modified plants have immense potential for the betterment of mankind. In the present paper, an overview of the raised concerns and wherever possible reasons assigned to explain their intensity or unsuitability are reviewed. PMID:25937981

HYBRIDIZATION STUDY BETWEEN GENETICALLY MODIFIED BRASSICA NAPUS AND NON-GENETICALLY MODIFIED B. NAPUS AND B. RAPA

EPA Science Inventory

Gene exchange between cultivated crops and wild species has gained significance in recent years because of concerns regarding the potential for gene flow between genetically modified (GM) crops and their domesticated and wild relatives. As part of our ecological effects of gene ...

MATERNAL EFFECTS IN ADVANCED HYBRIDS OF GENETICALLY MODIFIED AND NON-GENETICALLY MODIFIED BRASSICA SPECIES

EPA Science Inventory

Identification of fitness traits potentially impacted by gene flow from genetically modified (GM) crops to compatible relatives is of interest in risk assessments for GM crops. Reciprocal crosses were made between GM canola, Brassica napus cv. RaideRR that expresses CP4 EPSPS fo...

Improving Behavioral Support for Smoking Cessation in Pregnancy: What Are the Barriers to Stopping and Which Behavior Change Techniques Can Influence Them? Application of Theoretical Domains Framework

PubMed Central

Coleman-Haynes, Tom; Lorencatto, Fabiana; Ussher, Michael; Dyas, Jane; Coleman, Tim

2018-01-01

Behavioral support interventions are used to help pregnant smokers stop; however, of those tested, few are proven effective. Systematic research developing effective pregnancy-specific behavior change techniques (BCTs) is ongoing. This paper reports contributory work identifying potentially-effective BCTs relative to known important barriers and facilitators (B&Fs) to smoking cessation in pregnancy; to detect priority areas for BCTs development. A Nominal Group Technique with cessation experts (n = 12) elicited an expert consensus on B&Fs most influencing women’s smoking cessation and those most modifiable through behavioral support. Effective cessation interventions in randomized trials from a recent Cochrane review were coded into component BCTs using existing taxonomies. B&Fs were categorized using Theoretical Domains Framework (TDF) domains. Matrices, mapping BCT taxonomies against TDF domains, were consulted to investigate the extent to which BCTs in existing interventions target key B&Fs. Experts ranked ‘smoking a social norm’ and ‘quitting not a priority’ as most important barriers and ‘desire to protect baby’ an important facilitator to quitting. From 14 trials, 23 potentially-effective BCTs were identified (e.g., ‘information about consequences). Most B&Fs fell into ‘Social Influences’, ‘Knowledge’, ‘Emotions’ and ‘Intentions’ TDF domains; few potentially-effective BCTs mapped onto every TDF domain. B&Fs identified by experts as important to cessation, are not sufficiently targeted by BCT’s currently within interventions for smoking cessation in pregnancy. PMID:29462994

Improving Behavioral Support for Smoking Cessation in Pregnancy: What Are the Barriers to Stopping and Which Behavior Change Techniques Can Influence These? Application of Theoretical Domains Framework.

PubMed

Campbell, Katarzyna A; Fergie, Libby; Coleman-Haynes, Tom; Cooper, Sue; Lorencatto, Fabiana; Ussher, Michael; Dyas, Jane; Coleman, Tim

2018-02-17

Behavioral support interventions are used to help pregnant smokers stop; however, of those tested, few are proven effective. Systematic research developing effective pregnancy-specific behavior change techniques (BCTs) is ongoing. This paper reports contributory work identifying potentially-effective BCTs relative to known important barriers and facilitators (B&Fs) to smoking cessation in pregnancy; to detect priority areas for BCTs development. A Nominal Group Technique with cessation experts ( n = 12) elicited an expert consensus on B&Fs most influencing women's smoking cessation and those most modifiable through behavioral support. Effective cessation interventions in randomized trials from a recent Cochrane review were coded into component BCTs using existing taxonomies. B&Fs were categorized using Theoretical Domains Framework (TDF) domains. Matrices, mapping BCT taxonomies against TDF domains, were consulted to investigate the extent to which BCTs in existing interventions target key B&Fs. Experts ranked "smoking a social norm" and "quitting not a priority" as most important barriers and "desire to protect baby" an important facilitator to quitting. From 14 trials, 23 potentially-effective BCTs were identified (e.g., information about consequences). Most B&Fs fell into "Social Influences", "Knowledge", "Emotions" and "Intentions" TDF domains; few potentially-effective BCTs mapped onto every TDF domain. B&Fs identified by experts as important to cessation, are not sufficiently targeted by BCT's currently within interventions for smoking cessation in pregnancy.

Selecting antagonistic antibodies that control differentiation through inducible expression in embryonic stem cells

PubMed Central

Melidoni, Anna N.; Dyson, Michael R.; Wormald, Sam; McCafferty, John

2013-01-01

Antibodies that modulate receptor function have great untapped potential in the control of stem cell differentiation. In contrast to many natural ligands, antibodies are stable, exquisitely specific, and are unaffected by the regulatory mechanisms that act on natural ligands. Here we describe an innovative system for identifying such antibodies by introducing and expressing antibody gene populations in ES cells. Following induced antibody expression and secretion, changes in differentiation outcomes of individual antibody-expressing ES clones are monitored using lineage-specific gene expression to identify clones that encode and express signal-modifying antibodies. This in-cell expression and reporting system was exemplified by generating blocking antibodies to FGF4 and its receptor FGFR1β, identified through delayed onset of ES cell differentiation. Functionality of the selected antibodies was confirmed by addition of exogenous antibodies to three different ES reporter cell lines, where retained expression of pluripotency markers Oct4, Nanog, and Rex1 was observed. This work demonstrates the potential for discovery and utility of functional antibodies in stem cell differentiation. This work is also unique in constituting an example of ES cells carrying an inducible antibody that causes a functional protein “knock-down” and allows temporal control of stable signaling components at the protein level. PMID:24082130

Association of Day Length and Weather Conditions with Physical Activity Levels in Older Community Dwelling People

PubMed Central

Witham, Miles D.; Donnan, Peter T.; Vadiveloo, Thenmalar; Sniehotta, Falko F.; Crombie, Iain K.; Feng, Zhiqiang; McMurdo, Marion E. T.

2014-01-01

Background Weather is a potentially important determinant of physical activity. Little work has been done examining the relationship between weather and physical activity, and potential modifiers of any relationship in older people. We therefore examined the relationship between weather and physical activity in a cohort of older community-dwelling people. Methods We analysed prospectively collected cross-sectional activity data from community-dwelling people aged 65 and over in the Physical Activity Cohort Scotland. We correlated seven day triaxial accelerometry data with daily weather data (temperature, day length, sunshine, snow, rain), and a series of potential effect modifiers were tested in mixed models: environmental variables (urban vs rural dwelling, percentage of green space), psychological variables (anxiety, depression, perceived behavioural control), social variables (number of close contacts) and health status measured using the SF-36 questionnaire. Results 547 participants, mean age 78.5 years, were included in this analysis. Higher minimum daily temperature and longer day length were associated with higher activity levels; these associations remained robust to adjustment for other significant associates of activity: age, perceived behavioural control, number of social contacts and physical function. Of the potential effect modifier variables, only urban vs rural dwelling and the SF-36 measure of social functioning enhanced the association between day length and activity; no variable modified the association between minimum temperature and activity. Conclusions In older community dwelling people, minimum temperature and day length were associated with objectively measured activity. There was little evidence for moderation of these associations through potentially modifiable health, environmental, social or psychological variables. PMID:24497925

Association of day length and weather conditions with physical activity levels in older community dwelling people.

PubMed

Witham, Miles D; Donnan, Peter T; Vadiveloo, Thenmalar; Sniehotta, Falko F; Crombie, Iain K; Feng, Zhiqiang; McMurdo, Marion E T

2014-01-01

Weather is a potentially important determinant of physical activity. Little work has been done examining the relationship between weather and physical activity, and potential modifiers of any relationship in older people. We therefore examined the relationship between weather and physical activity in a cohort of older community-dwelling people. We analysed prospectively collected cross-sectional activity data from community-dwelling people aged 65 and over in the Physical Activity Cohort Scotland. We correlated seven day triaxial accelerometry data with daily weather data (temperature, day length, sunshine, snow, rain), and a series of potential effect modifiers were tested in mixed models: environmental variables (urban vs rural dwelling, percentage of green space), psychological variables (anxiety, depression, perceived behavioural control), social variables (number of close contacts) and health status measured using the SF-36 questionnaire. 547 participants, mean age 78.5 years, were included in this analysis. Higher minimum daily temperature and longer day length were associated with higher activity levels; these associations remained robust to adjustment for other significant associates of activity: age, perceived behavioural control, number of social contacts and physical function. Of the potential effect modifier variables, only urban vs rural dwelling and the SF-36 measure of social functioning enhanced the association between day length and activity; no variable modified the association between minimum temperature and activity. In older community dwelling people, minimum temperature and day length were associated with objectively measured activity. There was little evidence for moderation of these associations through potentially modifiable health, environmental, social or psychological variables.

A Dual Role for NOTCH Signaling in Joint Cartilage Maintenance and Osteoarthritis

PubMed Central

Liu, Zhaoyang; Chen, Jianquan; Mirando, Anthony; Wang, Cuicui; Zuscik, Michael J.; O’Keefe, Regis J.; Hilton, Matthew J.

2015-01-01

Loss of NOTCH signaling in postnatal murine joints results in osteoarthritis (OA), indicating a requirement for NOTCH during joint cartilage maintenance. Unexpectedly, NOTCH components are significantly up-regulated in human and murine post-traumatic OA, suggesting either a reparative or pathological role for NOTCH activation in OA. Here we investigated the potential dual role for NOTCH in joint maintenance and OA by generating two mouse models overexpressing the NOTCH1 intracellular domain within postnatal joint cartilage; one with sustained NOTCH activation that likely resembles pathological NOTCH signaling and one with transient NOTCH activation that more closely reflects physiological NOTCH signaling. Sustained NOTCH signaling in joint cartilage leads to an early and progressive OA pathology, while on the contrary, transient NOTCH activation enhances cartilage matrix synthesis and promotes joint maintenance under normal physiological conditions. Using RNA-seq, immunohistochemical, and biochemical approaches we identified several novel targets potentially responsible for NOTCH-mediated cartilage degradation, fibrosis, and OA progression, including components of the IL6/STAT3 and ERK/p38 MAPK pathways; factors that may also contribute to post-traumatic OA development. Collectively, these data demonstrate a dual role for the NOTCH pathway in joint cartilage and identify important downstream NOTCH effectors as potential targets for disease modifying osteoarthritis drugs (DMOADs). PMID:26198357

Residential Exposure to Urban Traffic Is Associated with Increased Carotid Intima-Media Thickness in Children

PubMed Central

Armijos, Rodrigo X.; Weigel, M. Margaret; Myers, Orrin B.; Li, Wen-Whai; Racines, Marcia; Berwick, Marianne

2015-01-01

Chronic exposure to urban traffic pollution is documented to promote atherosclerosis in adults but little is known about its potential effects in children. Our study examined the association of long-term exposure to traffic with carotid intima-media thickness (cIMT) in 287 healthy children. Residential proximity and distance-weighted traffic density (DWTD) were used as proximity markers for traffic-related air pollution exposure. The multivariable analyses revealed that children residing <100 meters from the nearest heavily trafficked road had cIMT mean and maximum measurements that were increased by 15% and 11% compared to those living ≥ 200 meters away (P = 0.0001). Similar increases in cIMT were identified for children in the highest versus lowest DWTD tertile. Children who resided 100–199 meters from traffic or in the middle DWTD tertile also exhibited increased cIMT but these differences were not statistically significant. No statistically significant differences were identified between residential distance to traffic or DWTD and systemic inflammation indicators (CRP, IL-6). The study results suggest that exposure to urban traffic promotes arterial remodeling in children. This finding is important since even small increases in cIMT over time can potentially lead to earlier progression to atherosclerosis. It is also important because traffic-related pollution is potentially modifiable. PMID:25685160

Residential exposure to urban traffic is associated with increased carotid intima-media thickness in children.

PubMed

Armijos, Rodrigo X; Weigel, M Margaret; Myers, Orrin B; Li, Wen-Whai; Racines, Marcia; Berwick, Marianne

2015-01-01

Chronic exposure to urban traffic pollution is documented to promote atherosclerosis in adults but little is known about its potential effects in children. Our study examined the association of long-term exposure to traffic with carotid intima-media thickness (cIMT) in 287 healthy children. Residential proximity and distance-weighted traffic density (DWTD) were used as proximity markers for traffic-related air pollution exposure. The multivariable analyses revealed that children residing <100 meters from the nearest heavily trafficked road had cIMT mean and maximum measurements that were increased by 15% and 11% compared to those living ≥ 200 meters away (P = 0.0001). Similar increases in cIMT were identified for children in the highest versus lowest DWTD tertile. Children who resided 100-199 meters from traffic or in the middle DWTD tertile also exhibited increased cIMT but these differences were not statistically significant. No statistically significant differences were identified between residential distance to traffic or DWTD and systemic inflammation indicators (CRP, IL-6). The study results suggest that exposure to urban traffic promotes arterial remodeling in children. This finding is important since even small increases in cIMT over time can potentially lead to earlier progression to atherosclerosis. It is also important because traffic-related pollution is potentially modifiable.

The environmental and medical geochemistry of potentially hazardous materials produced by disasters

USGS Publications Warehouse

Plumlee, Geoffrey S.; Morman, Suzette A.; Meeker, G.P.; Hoefen, Todd M.; Hageman, Philip L.; Wolf, Ruth E.

2014-01-01

Many natural or human-caused disasters release potentially hazardous materials (HM) that may pose threats to the environment and health of exposed humans, wildlife, and livestock. This chapter summarizes the environmentally and toxicologically significant physical, mineralogical, and geochemical characteristics of materials produced by a wide variety of recent disasters, such as volcanic eruptions, hurricanes and extreme storms, spills of mining/mineral-processing wastes or coal extraction by-products, and the 2001 attacks on and collapse of the World Trade Center towers. In describing these characteristics, this chapter also illustrates the important roles that geochemists and other earth scientists can play in environmental disaster response and preparedness. In addition to characterizing in detail the physical, chemical, and microbial makeup of HM generated by the disasters, these roles also include (1) identifying and discriminating potential multiple sources of the materials; (2) monitoring, mapping, and modeling dispersal and evolution of the materials in the environment; (3) understanding how the materials are modified by environmental processes; (4) identifying key characteristics and processes that influence the materials' toxicity to exposed humans and ecosystems; (5) estimating shifts away from predisaster environmental baseline conditions; and (6) using geochemical insights learned from past disasters to help estimate, prepare for, and increase societal resilience to the environmental and related health impacts of future disasters.

Serum-deprived human multipotent mesenchymal stromal cells (MSCs) are highly angiogenic

PubMed Central

Oskowitz, Adam; McFerrin, Harris; Gutschow, Miriam; Carter, Mary Leita; Pochampally, Radhika

2016-01-01

Recent reports have indicated that mesenchymal stromal cells (MSCs) from bone marrow have a potential in vascular remodeling and angiogenesis. Here, we report a unique phenomenon that under serum-deprived conditions MSCs survive and replicate. Secretome analysis of MSCs grown under serum-deprived conditions (SD-MSCs) identified a significant upregulation of prosurvival and angiogenic factors including VEGF-A, ANGPTs, IGF-1, and HGF. An ex vivo rat aortic assay demonstrated longer neovascular sprouts generated from rat aortic rings cultured in SD-MSC-conditioned media compared to neovascular sprouts from aortas grown in MSC-conditioned media. With prolonged serum deprivation, a subpopulation of SD-MSCs began to exhibit an endothelial phenotype. This population expressed endothelial-specific proteins including VEGFR2, Tie2/TEK, PECAM/CD31, and eNOS and also demonstrated the ability to uptake acetylated LDL. SD-MSCs also exhibited enhanced microtubule formation in an in vitro angiogenesis assay. Modified chick chorioallantoic membrane (CAM) angiogenesis assays showed significantly higher angiogenic potential for SD-MSCs compared to MSCs. Analysis of CAMs grown with SD-MSCs identified human-specific CD31-positive cells in vascular structures. We conclude that under the stress of serum deprivation MSCs are highly angiogenic and a population of these cells has the potential to differentiate into endothelial-like cells. PMID:21421339

A scoping review of epidemiologic risk factors for pediatric obesity: Implications for future childhood obesity and dental caries prevention research.

PubMed

Chi, Donald L; Luu, Monique; Chu, Frances

2017-06-01

What are the non-modifiable (socioeconomic, genetic) and modifiable factors (physical activity, dietary behaviors) related to childhood (under age 12) obesity? How can this knowledge be applied to oral health professionals' efforts to prevent or manage dental caries in children? Studies have identified risk factors for childhood obesity. The purpose of this scoping review was to develop a conceptual model to identify non-modifiable and modifiable risk factors for childhood obesity and to illustrate how these findings are relevant in developing interventions aimed at preventing obesity and dental caries in children. The authors searched PubMed and Embase and limited the study to English-language publications. A total of 2,572 studies were identified. After de-duplication, 2,479 studies remained and were downloaded into a citation-management tool. Two authors screened the titles and abstracts for relevance. Two hundred and sixty studies remained and were retrieved for a full-text review, and 80 studies were excluded, resulting in 180 studies included in the scoping review. An inductive content analytic methods was used to organize all statistically significant obesity risk factors into seven domains, which were classified as non-modifiable or modifiable; then a conceptual model of common risk factors associated with childhood obesity and dental caries was developed. Non-modifiable obesity risk factors include biological and developmental (e.g., genes, developmental conditions, puberty), sociodemographic and household (e.g., race/ethnicity, socioeconomic status, parent education, unemployment), cultural (e.g., degree of acculturation), and community (e.g., neighborhood composition). Modifiable risk factors included behavioral (e.g., diet, physical activity, weight), psychosocial (e.g., maternal stress, family functioning, parenting practices, child temperament), and medical (e.g., parent smoking, maternal health, child health). Identifying common risk factors has important implications for future oral health research aimed at preventing childhood obesity and dental caries. Epidemiologic knowledge gleaned from the literature can be used to develop rigorous interventions and programs aimed at preventing these highly prevalent diseases and improving health outcomes for children. © 2017 American Association of Public Health Dentistry.

Association mapping of seed quality traits using the Canadian flax (Linum usitatissimum L.) core collection.

PubMed

Soto-Cerda, Braulio J; Duguid, Scott; Booker, Helen; Rowland, Gordon; Diederichsen, Axel; Cloutier, Sylvie

2014-04-01

The identification of stable QTL for seed quality traits by association mapping of a diverse panel of linseed accessions establishes the foundation for assisted breeding and future fine mapping in linseed. Linseed oil is valued for its food and non-food applications. Modifying its oil content and fatty acid (FA) profiles to meet market needs in a timely manner requires clear understanding of their quantitative trait loci (QTL) architectures, which have received little attention to date. Association mapping is an efficient approach to identify QTL in germplasm collections. In this study, we explored the quantitative nature of seed quality traits including oil content (OIL), palmitic acid, stearic acid, oleic acid, linoleic acid (LIO) linolenic acid (LIN) and iodine value in a flax core collection of 390 accessions assayed with 460 microsatellite markers. The core collection was grown in a modified augmented design at two locations over 3 years and phenotypic data for all seven traits were obtained from all six environments. Significant phenotypic diversity and moderate to high heritability for each trait (0.73-0.99) were observed. Most of the candidate QTL were stable as revealed by multivariate analyses. Nine candidate QTL were identified, varying from one for OIL to three for LIO and LIN. Candidate QTL for LIO and LIN co-localized with QTL previously identified in bi-parental populations and some mapped nearby genes known to be involved in the FA biosynthesis pathway. Fifty-eight percent of the QTL alleles were absent (private) in the Canadian cultivars suggesting that the core collection possesses QTL alleles potentially useful to improve seed quality traits. The candidate QTL identified herein will establish the foundation for future marker-assisted breeding in linseed.

Lentiviral vectors in cancer immunotherapy.

PubMed

Oldham, Robyn Aa; Berinstein, Elliot M; Medin, Jeffrey A

2015-01-01

Basic science advances in cancer immunotherapy have resulted in various treatments that have recently shown success in the clinic. Many of these therapies require the insertion of genes into cells to directly kill them or to redirect the host's cells to induce potent immune responses. Other analogous therapies work by modifying effector cells for improved targeting and enhanced killing of tumor cells. Initial studies done using γ-retroviruses were promising, but safety concerns centered on the potential for insertional mutagenesis have highlighted the desire to develop other options for gene delivery. Lentiviral vectors (LVs) have been identified as potentially more effective and safer alternative delivery vehicles. LVs are now in use in clinical trials for many different types of inherited and acquired disorders, including cancer. This review will discuss current knowledge of LVs and the applications of this viral vector-based delivery vehicle to cancer immunotherapy.

The Role of Epigenomics in Aquatic Toxicology.

PubMed

Brander, Susanne M; Biales, Adam D; Connon, Richard E

2017-10-01

Over the past decade, the field of molecular biology has rapidly incorporated epigenetic studies to evaluate organism-environment interactions that can result in chronic effects. Such responses arise from early life stage stress, the utilization of genetic information over an individual's life time, and transgenerational inheritance. Knowledge of epigenetic mechanisms provides the potential for a comprehensive evaluation of multigenerational and heritable effects from environmental stressors, such as contaminants. Focused studies have provided a greater understanding of how many responses to environmental stressors are driven by epigenetic modifiers. We discuss the promise of epigenetics and suggest future research directions within the field of aquatic toxicology, with a particular focus on the potential for identifying key heritable marks with consequential impacts at the organism and population levels. Environ Toxicol Chem 2017;36:2565-2573. © 2017 SETAC. © 2017 SETAC.

Luminescent solar concentrators utilizing stimulated emission.

PubMed

Kaysir, Md Rejvi; Fleming, Simon; MacQueen, Rowan W; Schmidt, Timothy W; Argyros, Alexander

2016-03-21

Luminescent solar concentrators (LSCs) are an emerging technology that aims primarily to reduce the cost of solar energy, with great potential for building integrated photovoltaic (PV) structures. However, realizing LSCs with commercially viable efficiency is currently hindered by reabsorption losses. Here, we introduce an approach to reducing reabsorption as well as improving directional emission in LSCs by using stimulated emission. Light from a seed laser (potentially an inexpensive laser diode) passes through the entire area of the LSC panel, modifying the emission spectrum of excited dye molecules such that it is spectrally narrower, at wavelengths that minimize reabsorption to allow net gain in the system, and directed towards a small PV cell. A mathematical model, taking into account thermodynamic considerations, of such a system is presented which identifies key parameters and allows evaluation in terms of net effective output power.

12P-conjugated PEG-modified gold nanorods combined with near-infrared laser for tumor targeting and photothermal therapy.

PubMed

Zhan, Tao; Li, Pengfei; Bi, Shan; Dong, Biao; Song, Hongwei; Ren, Hui; Wang, Liping

2012-09-01

Gold nanorods have been reported as potential tumor photothermal therapy in vivo and in vitro. However, development of the safe and efficient tumor-targeting gold nanorods for in vivo localized tumor therapy is still a challenge. In our present study, we synthesized the PEG modified gold nanorods and demonstrated its negligible cytotoxicity in vitro. These nanorods also have been demonstrated to efficiently ablate the different kinds of tumor cells in vitro after exposure to the near-infrared laser. When the PEG modified gold nanorods conjugated with the 12P (sequence: TACHQHVRMVRP), this conjugate showed great tumor-targeting and hyperthermia effects on the human liver cancer cell line HepG2 in vitro when coupled with the near-infrared laser treatment. To determine the potential hyperthermia effect of PEG modified gold nanorods or 12P conjugate on tumor cells in vivo, the mice hepatic cancer cells were used to induce the subcutaneous tumor-bearing model in ICR mice. The significant inhibition effects of near-infrared laser mediated PEG modified gold nanorods or 12P conjugate on the tumor growth were observed. These composite results suggest that the 12P-conjugated PEG modified gold nanorods exhibit great biocompatible, particular tumor-targeting and effective photothermal ablation of tumor cells, which warrant the potential therapeutic value of this conjugate for further application in in vivo localized tumor therapy.

One-Step Synthesis of Silver Nanoparticles on Polydopamine-Coated Sericin/Polyvinyl Alcohol Composite Films for Potential Antimicrobial Applications.

PubMed

Cai, Rui; Tao, Gang; He, Huawei; Song, Kai; Zuo, Hua; Jiang, Wenchao; Wang, Yejing

2017-04-30

Silk sericin has great potential as a biomaterial for biomedical applications due to its good hydrophilicity, reactivity, and biodegradability. To develop multifunctional sericin materials for potential antibacterial application, a one-step synthesis method for preparing silver nanoparticles (AgNPs) modified on polydopamine-coated sericin/polyvinyl alcohol (PVA) composite films was developed. Polydopamine (PDA) acted as both metal ion chelating and reducing agent to synthesize AgNPs in situ on the sericin/PVA composite film. Scanning electron microscopy and energy dispersive spectroscopy analysis revealed that polydopamine could effectively facilitate the high-density growth of AgNPs as a 3-D matrix. X-ray diffractometry studies suggested the synthesized AgNPs formed good face-centered cubic crystalline structures. Contact angle measurement and mechanical test indicated AgNPs modified PDA-sericin/PVA composite film had good hydrophilicity and mechanical property. The bacterial growth curve and inhibition zone assays showed the AgNPs modified PDA-sericin/PVA composite film had long-term antibacterial activities. This work develops a new method for the preparation of AgNPs modified PDA-sericin/PVA film with good hydrophilicity, mechanical performance and antibacterial activities for the potential antimicrobial application in biomedicine.

Modified method for estimating petroleum source-rock potential using wireline logs, with application to the Kingak Shale, Alaska North Slope

USGS Publications Warehouse

Rouse, William A.; Houseknecht, David W.

2016-02-11

In 2012, the U.S. Geological Survey completed an assessment of undiscovered, technically recoverable oil and gas resources in three source rocks of the Alaska North Slope, including the lower part of the Jurassic to Lower Cretaceous Kingak Shale. In order to identify organic shale potential in the absence of a robust geochemical dataset from the lower Kingak Shale, we introduce two quantitative parameters, $\\Delta DT_\\bar{x}$ and $\\Delta DT_z$, estimated from wireline logs from exploration wells and based in part on the commonly used delta-log resistivity ($\\Delta \\text{ }log\\text{ }R$) technique. Calculation of $\\Delta DT_\\bar{x}$ and $\\Delta DT_z$ is intended to produce objective parameters that may be proportional to the quality and volume, respectively, of potential source rocks penetrated by a well and can be used as mapping parameters to convey the spatial distribution of source-rock potential. Both the $\\Delta DT_\\bar{x}$ and $\\Delta DT_z$ mapping parameters show increased source-rock potential from north to south across the North Slope, with the largest values at the toe of clinoforms in the lower Kingak Shale. Because thermal maturity is not considered in the calculation of $\\Delta DT_\\bar{x}$ or $\\Delta DT_z$, total organic carbon values for individual wells cannot be calculated on the basis of $\\Delta DT_\\bar{x}$ or $\\Delta DT_z$ alone. Therefore, the $\\Delta DT_\\bar{x}$ and $\\Delta DT_z$ mapping parameters should be viewed as first-step reconnaissance tools for identifying source-rock potential.

Energy determinants GAPDH and NDPK act as genetic modifiers for hepatocyte inclusion formation

PubMed Central

Weerasinghe, Sujith V.W.; Singla, Amika; Leonard, Jessica M.; Hanada, Shinichiro; Andrews, Philip C.; Lok, Anna S.; Omary, M. Bishr

2011-01-01

Genetic factors impact liver injury susceptibility and disease progression. Prominent histological features of some chronic human liver diseases are hepatocyte ballooning and Mallory-Denk bodies. In mice, these features are induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) in a strain-dependent manner, with the C57BL and C3H strains showing high and low susceptibility, respectively. To identify modifiers of DDC-induced liver injury, we compared C57BL and C3H mice using proteomic, biochemical, and cell biological tools. DDC elevated reactive oxygen species (ROS) and oxidative stress enzymes preferentially in C57BL livers and isolated hepatocytes. C57BL livers and hepatocytes also manifested significant down-regulation, aggregation, and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDH knockdown depleted bioenergetic and antioxidant enzymes and elevated hepatocyte ROS, whereas GAPDH overexpression decreased hepatocyte ROS. On the other hand, C3H livers had higher expression and activity of the energy-generating nucleoside-diphosphate kinase (NDPK), and knockdown of hepatocyte NDPK augmented DDC-induced ROS formation. Consistent with these findings, cirrhotic, but not normal, human livers contained GAPDH aggregates and NDPK complexes. We propose that GAPDH and NDPK are genetic modifiers of murine DDC-induced liver injury and potentially human liver disease. PMID:22006949

Economic analysis of opportunities to accelerate Alzheimer’s disease research and development

PubMed Central

Scott, Troy J; O'Connor, Alan C; Link, Albert N; Beaulieu, Travis J

2014-01-01

The development of disease-modifying treatments for Alzheimer's disease (AD) faces a number of barriers. Among these are the lack of surrogate biomarkers, the exceptional size and duration of clinical trials, difficulties in identifying appropriate populations for clinical trials, and the limitations of monotherapies in addressing such a complex multifactorial disease. This study sets out to first estimate the consequent impact on the expected cost of developing disease-modifying treatments for AD and then to estimate the potential benefits of bringing together industry, academic, and government stakeholders to co-invest in, for example, developing better biomarkers and cognitive assessment tools, building out advanced registries and clinical trial-readiness cohorts, and establishing clinical trial platforms to investigate combinations of candidate drugs and biomarkers from the portfolios of multiple companies. Estimates based on interviews with experts on AD research and development suggest that the cost of one new drug is now $5.7 billion (95% confidence interval (CI) $3.7–9.5 billion) and could be reduced to $2.0 billion (95% CI $1.5–2.9 billion). The associated acceleration in the arrival of disease-modifying treatments could reduce the number of case years of dementia by 7.0 million (95% CI 4.4–9.4 million) in the United States from 2025 through 2040. PMID:24673372

Enzyme-driven metabolomic screening: a proof-of-principle method for discovery of plant defence compounds targeted by pathogens.

PubMed

Carere, Jason; Colgrave, Michelle L; Stiller, Jiri; Liu, Chunji; Manners, John M; Kazan, Kemal; Gardiner, Donald M

2016-11-01

Plants produce a variety of secondary metabolites to defend themselves from pathogen attack, while pathogens have evolved to overcome plant defences by producing enzymes that degrade or modify these defence compounds. However, many compounds targeted by pathogen enzymes currently remain enigmatic. Identifying host compounds targeted by pathogen enzymes would enable us to understand the potential importance of such compounds in plant defence and modify them to make them insensitive to pathogen enzymes. Here, a proof of concept metabolomics-based method was developed to discover plant defence compounds modified by pathogens using two pathogen enzymes with known targets in wheat and tomato. Plant extracts treated with purified pathogen enzymes were subjected to LC-MS, and the relative abundance of metabolites before and after treatment were comparatively analysed. Using two enzymes from different pathogens the in planta targets could be found by combining relatively simple enzymology with the power of untargeted metabolomics. Key to the method is dataset simplification based on natural isotope occurrence and statistical filtering, which can be scripted. The method presented here will aid in our understanding of plant-pathogen interactions and may lead to the development of new plant protection strategies. © 2016 CSIRO. New Phytologist © 2016 New Phytologist Trust.

Comparison of Helicopter Emergency Medical Services Transport Types and Delays on Patient Outcomes at Two Level I Trauma Centers.

PubMed

Nolan, Brodie; Tien, Homer; Sawadsky, Bruce; Rizoli, Sandro; McFarlan, Amanda; Phillips, Andrea; Ackery, Alun

2017-01-01

Helicopter emergency medical services (HEMS) have become an engrained component of trauma systems. In Ontario, transportation for trauma patients is through one of three ways: scene call, modified scene call, or interfacility transfer. We hypothesize that differences exist between these types of transports in both patient demographics and patient outcomes. This study compares the characteristics of patients transported by each of these methods to two level 1 trauma centers and assesses for any impact on morbidity or mortality. As a secondary outcome reasons for delay were identified. A local trauma registry was used to identify and abstract data for all patients transported to two trauma centers by HEMS over a 36-month period. Further chart abstraction using the HEMS patient care reports was done to identify causes of delay during HEMS transport. During the study period HEMS transferred a total of 911 patients of which 139 were scene calls, 333 were modified scene calls and 439 were interfacility transfers. Scene calls had more patients with an ISS of less than 15 and had more patients discharged home from the ED. Modified scene calls had more patients with an ISS greater than 25. The most common delays that were considered modifiable included the sending physician doing a procedure, waiting to meet a land EMS crew, delays for diagnostic imaging and confirming disposition or destination. Differences exist between the types of transports done by HEMS for trauma patients. Many identified reasons for delay to HEMS transport are modifiable and have practical solutions. Future research should focus on solutions to identified delays to HEMS transport. Key words: helicopter emergency medical services; trauma; prehospital care; delays.

Learning potential and cognitive abilities in preschool boys with fragile X and Down syndrome.

PubMed

Valencia-Naranjo, Nieves; Robles-Bello, Mª Auxiliadora

2017-01-01

Enhancing cognitive abilities is relevant when devising treatment plans. This study examined the performance of preschool boys with Down syndrome and fragile X syndrome in cognitive tasks (e.g., nonverbal reasoning and short-term memory), as well as in improving cognitive functions by means of a learning potential methodology. The basic scales corresponding to the Skills and Learning Potential Preschool Scale were administered to children with Down syndrome and others with fragile X syndrome, matched for chronological age and nonverbal cognitive development level. The fragile X syndrome group showed stronger performance on short-term memory tasks than the Down syndrome group prior to intervention, with no differences recorded in nonverbal reasoning tasks. In addition, both groups' cognitive performance improved significantly between pre- and post-intervention. However, learning potential relative to auditory memory was limited in both groups, and for rule-based categorization in Down syndrome children. The scale offered the opportunity to assess young children's abilities and identify the degree of cognitive modifiability. Furthermore, factors that may potentially affect the children's performance before and during learning potential assessment are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Quantitative targeted proteomic analysis of potential markers of tyrosine kinase inhibitor (TKI) sensitivity in EGFR mutated lung adenocarcinoma.

PubMed

Awasthi, Shivangi; Maity, Tapan; Oyler, Benjamin L; Qi, Yue; Zhang, Xu; Goodlett, David R; Guha, Udayan

2018-04-13

Lung cancer causes the highest mortality among all cancers. Patients harboring kinase domain mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine kinase inhibitors (TKIs), however, acquired resistance always develops. Moreover, 30-40% of patients with EGFR mutations exhibit primary resistance. Hence, there is an unmet need for additional biomarkers of TKI sensitivity that complement EGFR mutation testing and predict treatment response. We previously identified phosphopeptides whose phosphorylation is inhibited upon treatment with EGFR TKIs, erlotinib and afatinib in TKI sensitive cells, but not in resistant cells. These phosphosites are potential biomarkers of TKI sensitivity. Here, we sought to develop modified immuno-multiple reaction monitoring (immuno-MRM)-based quantitation assays for select phosphosites including EGFR-pY1197, pY1172, pY998, AHNAK-pY160, pY715, DAPP1-pY139, CAV1-pY14, INPPL1-pY1135, NEDD9-pY164, NF1-pY2579, and STAT5A-pY694. These sites were significantly hypophosphorylated by erlotinib and a 3rd generation EGFR TKI, osimertinib, in TKI-sensitive H3255 cells, which harbor the TKI-sensitizing EGFR L858R mutation. However, in H1975 cells, which harbor the TKI-resistant EGFR L858R/T790M mutant, osimertinib, but not erlotinib, could significantly inhibit phosphorylation of EGFR-pY-1197, STAT5A-pY694 and CAV1-pY14, suggesting these sites also predict response in TKI-resistant cells. We could further validate EGFR-pY-1197 as a biomarker of TKI sensitivity by developing a calibration curve-based modified immuno-MRM assay. In this report, we have shown the development and optimization of MRM assays coupled with global phosphotyrosine enrichment (modified immuno-MRM) for a list of 11 phosphotyrosine peptides. Our optimized assays identified the targets reproducibly in biological samples with good selectivity. We also developed and characterized quantitation methods to determine endogenous abundance of these targets and correlated the results of the relative quantification with amounts estimated from the calibration curves. This approach represents a way to validate and verify biomarker candidates discovered from large-scale global phospho-proteomics analysis. The application of these modified immuno-MRM assays in lung adenocarcinoma cells provides proof-of concept for the feasibility of clinical applications. These assays may be used in prospective clinical studies of EGFR TKI treatment of EGFR mutant lung cancer to correlate treatment response and other clinical endpoints. Copyright © 2018. Published by Elsevier B.V.

Modified in vivo comet assay detects the genotoxic potential of 14-hydroxycodeinone, an α,β-unsaturated ketone in oxycodone.

PubMed

Pant, Kamala; Roden, Nicholas; Zhang, Charles; Bruce, Shannon; Wood, Craig; Pendino, Kimberly

2015-12-01

14-Hydroxycodeinone (14-HC) is an α,β-unsaturated ketone impurity found in oxycodone drug substance and has a structural alert for genotoxicity. 14-HC was tested in a combined Modified and Standard Comet Assay to determine if the slight decrease in % Tail DNA noted in a previously conducted Standard Comet Assay with 14-HC could be magnified to clarify if the response was due to cross-linking activity. One limitation of the Standard Comet Assay is that DNA cross-links cannot be reliably detected. However, under certain modified testing conditions, DNA cross-links and chemical moieties that elicit such cross-links can be elucidated. One such modification involves the induction of additional breakages of DNA strands by gamma or X-ray irradiation. To determine if 14-HC is a DNA crosslinker in vivo, a Modified Comet Assay was conducted using X-ray irradiation as the modification to visualize crosslinking activity. In this assay, 14-HC was administered orally to mice up to 320 mg/kg/day. Results showed a statistically significant reduction in percent tail DNA in duodenal cells at 320 mg/kg/day, with a nonstatistically significant but dose-related reduction in percent tail DNA also observed at the mid dose of 160 mg/kg/day. Similar decreases were not observed in cells from the liver or stomach, and no increases in percent tail DNA were noted for any tissue in the concomitantly conducted Standard Comet Assay. Taken together, 14-HC was identified as a cross-linking agent in the duodenum in the Modified Comet Assay. © 2015 Wiley Periodicals, Inc.

A Study of Biomolecules as Growth Modifiers of Calcium Oxalate Crystals

NASA Astrophysics Data System (ADS)

Kwak, Junha John

Crystallization processes are ubiquitous in nature, science, and technology. Controlling crystal growth is pivotal in many industries as material properties and functions can be tailored by tuning crystal habits (e.g. size, shape, phase). In biomineralization, organisms exert excellent control over bottom-up synthesis and assembly of inorganic-organic structures (e.g. bones, teeth, exoskeletons). This is made possible by growth modifiers that range from small molecules to macromolecules, such as proteins. Molecular recognition of the mineral phase allows proteins to function as nucleation templates, matrices, and growth inhibitors or promoters. We are interested in taking a biomimetic approach to control crystallization via biomolecular growth modifiers. We investigated calcium oxalate monohydrate (COM), found in plants and kidney stones, as a model system of crystallization. We studied the effects of four common proteins on COM crystallization: bovine serum albumin (BSA), transferrin, lactoferrin, and lysozyme. Through kinetic studies of COM crystallization, we classified BSA and lysozyme as COM growth inhibitor and promoter respectively. Their inhibition and promotion effects were also evident in the macroscopic crystal habit. Through adsorption and microscopy experiments, we showed that BSA exhibits binding specificity for the apical surfaces of macroscopic COM crystals. Lysozyme, on the other, functions via a non-binding mechanism at the surface to accelerate the growth of the apical surfaces. We also synthesized and studied peptides derived from the protein primary sequences to identify putative domains responsible for these inhibition and promotion effects. Collectively, our study of physiologically relevant biomolecules suggests potential roles of COM modifiers in pathological crystallization and helps to develop guidelines for rational design of biomolecular growth modifiers for applications in crystal engineering.

Radiographic-directed local coordinate systems critical in kinematic analysis of walking in diabetes-related medial column foot deformity.

PubMed

Hastings, Mary K; Woodburn, James; Mueller, Michael J; Strube, Michael J; Johnson, Jeffrey E; Beckert, Krista S; Stein, Michelle L; Sinacore, David R

2014-01-01

Diabetic foot deformity onset and progression maybe associated with abnormal foot and ankle motion. The modified Oxford multi-segmental foot model allows kinematic assessment of inter-segmental foot motion. However, there are insufficient anatomical landmarks to accurately representation the alignment of the hindfoot and forefoot segments during model construction. This is most notable for the sagittal plane which is referenced parallel to the floor, allowing comparison of inter-segmental excursion but not capturing important sagittal hind-to-forefoot deformity associated with diabetic foot disease and can potentially underestimate true kinematic differences. The purpose of the study was to compare walking kinematics using local coordinate systems derived from the modified Oxford model and the radiographic directed model which incorporated individual calcaneal and 1st metatarsal declination pitch angles for the hindfoot and forefoot. We studied twelve participants in each of the following groups: (1) diabetes mellitus, peripheral neuropathy and medial column foot deformity (DMPN+), (2) DMPN without medial column deformity (DMPN-) and (3) age- and weight-match controls. The modified Oxford model coordinate system did not identify differences between groups in the initial, peak, final, or excursion hindfoot relative to shank or forefoot relative to hindfoot dorsiflexion/plantarflexion during walking. The radiographic coordinate system identified the DMPN+ group to have an initial, peak and final position of the forefoot relative to hindfoot that was more dorsiflexed (lower arch phenotype) than the DMPN- group (p<.05). Use of radiographic alignment in kinematic modeling of those with foot deformity reveals segmental motion occurring upon alignment indicative of a lower arch. Copyright © 2014 Elsevier B.V. All rights reserved.

The rate of decline of joint space width in patients with osteoarthritis of the knee: a systematic review and meta-analysis of randomized placebo-controlled trials of chondroitin sulfate .

PubMed

Hochberg, Marc C; Zhan, Min; Langenberg, Patricia

2008-11-01

Chondroitin sulfate has been shown to relieve pain and improve functional limitation in patients with osteoarthritis (OA) of the knee in numerous clinical trials and meta-analyses. Its role as a potential structure-modifying drug for knee OA, however, remains controversial. To perform a meta-analysis of randomized double-blind placebo-controlled clinical trials to assess the efficacy of chondroitin sulfate as a structure-modifying drug for knee OA. A Medline search was conducted from 1996 through 2007 and five articles that reported results from three trials were identified; one additional trial was identified through review of presentations at annual rheumatology meetings. There was no evidence of heterogeneity across the trials and results were pooled using a fixed effects meta-analysis. Pooled results demonstrated a small significant effect of chondroitin sulfate on the reduction in rate of decline in minimum joint space width of 0.07 mm/year (95% CI 0.03, 0.10) that corresponded to an effect size of 0.26 (95% CI 0.14, 0.38) (p < 0.0001). This result was robust in sensitivity analyses. The individual studies included in the meta-analysis varied in the number of patients enrolled and the techniques used to acquire knee radiographs and to measure joint space width. These results demonstrate that chondroitin sulfate is effective for reducing the rate of decline in minimum joint space width in patients with OA of the knee. Chondroitin sulfate may have a role as a structure-modifying agent in the management of patients with knee OA.

Code-based Diagnostic Algorithms for Idiopathic Pulmonary Fibrosis. Case Validation and Improvement.

PubMed

Ley, Brett; Urbania, Thomas; Husson, Gail; Vittinghoff, Eric; Brush, David R; Eisner, Mark D; Iribarren, Carlos; Collard, Harold R

2017-06-01

Population-based studies of idiopathic pulmonary fibrosis (IPF) in the United States have been limited by reliance on diagnostic code-based algorithms that lack clinical validation. To validate a well-accepted International Classification of Diseases, Ninth Revision, code-based algorithm for IPF using patient-level information and to develop a modified algorithm for IPF with enhanced predictive value. The traditional IPF algorithm was used to identify potential cases of IPF in the Kaiser Permanente Northern California adult population from 2000 to 2014. Incidence and prevalence were determined overall and by age, sex, and race/ethnicity. A validation subset of cases (n = 150) underwent expert medical record and chest computed tomography review. A modified IPF algorithm was then derived and validated to optimize positive predictive value. From 2000 to 2014, the traditional IPF algorithm identified 2,608 cases among 5,389,627 at-risk adults in the Kaiser Permanente Northern California population. Annual incidence was 6.8/100,000 person-years (95% confidence interval [CI], 6.1-7.7) and was higher in patients with older age, male sex, and white race. The positive predictive value of the IPF algorithm was only 42.2% (95% CI, 30.6 to 54.6%); sensitivity was 55.6% (95% CI, 21.2 to 86.3%). The corrected incidence was estimated at 5.6/100,000 person-years (95% CI, 2.6-10.3). A modified IPF algorithm had improved positive predictive value but reduced sensitivity compared with the traditional algorithm. A well-accepted International Classification of Diseases, Ninth Revision, code-based IPF algorithm performs poorly, falsely classifying many non-IPF cases as IPF and missing a substantial proportion of IPF cases. A modification of the IPF algorithm may be useful for future population-based studies of IPF.

Modification and properties characterization of heterogeneous anion-exchange membranes by electrodeposition of graphene oxide (GO)

NASA Astrophysics Data System (ADS)

Li, Yujiao; Shi, Shaoyuan; Cao, Hongbin; Zhao, Zhijuan; Wen, Hao

2018-06-01

The heterogeneous anion exchange membranes (AEMs) were modified by electrodeposition of graphene oxide (GO) under different conditions. The physicochemical properties of GO-modified membranes were characterized systemically to obtain the optimized conditions for the electrodeposition of GO on the surface of AEMs. The results indicated that the contact angle and zeta potential of the modified AEMs decreased when increasing the concentration of GO from 0.05 g/L to 0.1 g/L. The higher concentration of NaCl, as the supporting electrolyte, could hinder the electrodeposition of GO on the AEMs for the competitive migration between the GO and Cl- ions. The increase of current density had a positive effect on properties of GO-modified membranes in the range of 1-5 mA/cm2. Compared with the pristine AEM, all the GO-modified AEMs exhibited smoother surface, higher hydrophilicity and negative zeta potential. It was also found that the GO modifying layer did not increase electrical resistance and had only a negligible effect on the desalination performance of AEMs. In the fouling experiments with sodium dodecyl benzene sulfonate (SDBS) as the model foulant, the GO-modified AEMs exhibited improved fouling resistance to SDBS.

Multiplex giant magnetoresistive biosensor microarrays identify interferon-associated autoantibodies in systemic lupus erythematosus

NASA Astrophysics Data System (ADS)

Lee, Jung-Rok; Haddon, D. James; Wand, Hannah E.; Price, Jordan V.; Diep, Vivian K.; Hall, Drew A.; Petri, Michelle; Baechler, Emily C.; Balboni, Imelda M.; Utz, Paul J.; Wang, Shan X.

2016-06-01

High titer, class-switched autoantibodies are a hallmark of systemic lupus erythematosus (SLE). Dysregulation of the interferon (IFN) pathway is observed in individuals with active SLE, although the association of specific autoantibodies with chemokine score, a combined measurement of three IFN-regulated chemokines, is not known. To identify autoantibodies associated with chemokine score, we developed giant magnetoresistive (GMR) biosensor microarrays, which allow the parallel measurement of multiple serum antibodies to autoantigens and peptides. We used the microarrays to analyze serum samples from SLE patients and found individuals with high chemokine scores had significantly greater reactivity to 13 autoantigens than individuals with low chemokine scores. Our findings demonstrate that multiple autoantibodies, including antibodies to U1-70K and modified histone H2B tails, are associated with IFN dysregulation in SLE. Further, they show the microarrays are capable of identifying autoantibodies associated with relevant clinical manifestations of SLE, with potential for use as biomarkers in clinical practice.

Sex determination in plants.

PubMed

Monéger, Françoise

2007-05-01

Most dioecious plant species are believed to derive from hermaphrodite ancestors. The regulatory pathways that have been modified during evolution of the hermaphrodite ancestors and led to the emergence of dioecious species (with separate sexes) still remain unknown. Silene latifolia is a dioecious plant species harbouring XY sex chromosomes. To identify the molecular mechanisms involved in female organ suppression in male flowers of S. latifolia, we looked for genes potentially involved in the establishment of floral organ and whorl boundaries. We identified Arabidopsis thaliana homologs of SHOOTMERISTEMLESS (STM) and CUP SHAPED COTYLEDON 1 (CUC1) and CUC2 genes in S. latifolia. Our phylogenetic analyses suggest that we identified true orthologs for both types of genes. Detailed expression analyses showed a conserved expression pattern for these genes between S. latifolia and A. thaliana, suggesting a conserved function of the corresponding proteins. Both orthologs showed clear differences in their expression pattern between males and females or hermaphrodites suggesting their possible involvement in the sex determination pathway in S. latifolia.

Anti-inflammatory and antioxidant properties of Piper species: a perspective from screening to molecular mechanisms.

PubMed

Kumar, Sarvesh; Malhotra, Shashwat; Prasad, Ashok K; Van der Eycken, Erik V; Bracke, Marc E; Stetler-Stevenson, William G; Parmar, Virinder S; Ghosh, Balaram

2015-01-01

Identifying novel therapeutic agents from natural sources and their possible intervention studies has been one of the major areas in biomedical research in recent years. Piper species are highly important - commercially, economically and medicinally. Our groups have been working for more than two decades on the identification and characterization of novel therapeutic lead molecules from Piper species. We have extensively studied the biological activities of various extracts of Piper longum and Piper galeatum, and identified and characterized novel molecules from these species. Using synthetic chemistry, various functional groups of the lead molecules were modified and structure activity relationship (SAR) studies identified synthetic molecules with better efficacy and lower IC50 values. Moreover, the mechanisms of actions of some of these molecules were studied at the molecular level. The objective of this review is to summarize experimental data published from our laboratories and others on antioxidant and anti-inflammatory potentials of Piper species and their chemical constituents.

Risk factors for acute nerve injury after total knee arthroplasty.

PubMed

Shetty, Teena; Nguyen, Joseph T; Sasaki, Mayu; Wu, Anita; Bogner, Eric; Burge, Alissa; Cogsil, Taylor; Dalal, Aashka; Halvorsen, Kristin; Cummings, Kelianne; Su, Edwin P; Lyman, Stephen

2018-06-01

In this we study identified potential risk factors for post-total knee arthroplasty (TKA) nerve injury, a catastrophic complication with a reported incidence of 0.3%-1.3%. Patients who developed post-TKA nerve injury from 1998 to 2013 were identified, and each was matched with 2 controls. A multivariable logistic regression model was built to calculate odds ratios (ORs). Sixty-five nerve injury cases were identified in 39,990 TKAs (0.16%). Females (OR 3.28, P = 0.003) and patients with history of lumbar pathology (OR 6.12, P = 0.026) were associated with increased risk of nerve injury. Tourniquet pressure < 300 mm Hg and longer duration of anesthesia may also be risk factors. Surgical planning for females and patients with lumbar pathology should be modified to mitigate their higher risk of neurologic complications after TKA. Our finding that lower tourniquet pressure was associated with higher risk of nerve injury was unexpected and requires further investigation. Muscle Nerve 57: 946-950, 2018. © 2017 Wiley Periodicals, Inc.

Exome sequencing of extreme phenotypes identifies DCTN4 as a modifier of chronic Pseudomonas aeruginosa infection in cystic fibrosis.

PubMed

Emond, Mary J; Louie, Tin; Emerson, Julia; Zhao, Wei; Mathias, Rasika A; Knowles, Michael R; Wright, Fred A; Rieder, Mark J; Tabor, Holly K; Nickerson, Deborah A; Barnes, Kathleen C; Gibson, Ronald L; Bamshad, Michael J

2012-07-08

Exome sequencing has become a powerful and effective strategy for the discovery of genes underlying Mendelian disorders. However, use of exome sequencing to identify variants associated with complex traits has been more challenging, partly because the sample sizes needed for adequate power may be very large. One strategy to increase efficiency is to sequence individuals who are at both ends of a phenotype distribution (those with extreme phenotypes). Because the frequency of alleles that contribute to the trait are enriched in one or both phenotype extremes, a modest sample size can potentially be used to identify novel candidate genes and/or alleles. As part of the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP), we used an extreme phenotype study design to discover that variants in DCTN4, encoding a dynactin protein, are associated with time to first P. aeruginosa airway infection, chronic P. aeruginosa infection and mucoid P. aeruginosa in individuals with cystic fibrosis.

An innovative and integrated approach based on DNA walking to identify unauthorised GMOs.

PubMed

Fraiture, Marie-Alice; Herman, Philippe; Taverniers, Isabel; De Loose, Marc; Deforce, Dieter; Roosens, Nancy H

2014-03-15

In the coming years, the frequency of unauthorised genetically modified organisms (GMOs) being present in the European food and feed chain will increase significantly. Therefore, we have developed a strategy to identify unauthorised GMOs containing a pCAMBIA family vector, frequently present in transgenic plants. This integrated approach is performed in two successive steps on Bt rice grains. First, the potential presence of unauthorised GMOs is assessed by the qPCR SYBR®Green technology targeting the terminator 35S pCAMBIA element. Second, its presence is confirmed via the characterisation of the junction between the transgenic cassette and the rice genome. To this end, a DNA walking strategy is applied using a first reverse primer followed by two semi-nested PCR rounds using primers that are each time nested to the previous reverse primer. This approach allows to rapidly identify the transgene flanking region and can easily be implemented by the enforcement laboratories. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

A screen for E3 ubiquitination ligases that genetically interact with the adaptor protein Cindr during Drosophila eye patterning

PubMed Central

Ketosugbo, Kwami F.; Bushnell, Henry L.

2017-01-01

Ubiquitination is a crucial post-translational modification that can target proteins for degradation. The E3 ubiquitin ligases are responsible for recognizing substrate proteins for ubiquitination, hence providing specificity to the process of protein degradation. Here, we describe a genetic modifier screen that identified E3 ligases that modified the rough-eye phenotype generated by expression of cindrRNAi transgenes during Drosophila eye development. In total, we identified 36 E3 ligases, as well as 4 Cullins, that modified the mild cindrRNA mis-patterning phenotype. This indicates possible roles for these E3s/Cullins in processes that require Cindr function, including cytoskeletal regulation, cell adhesion, cell signaling and cell survival. Three E3 ligases identified in our screen had previously been linked to regulating JNK signaling. PMID:29117266

Effect of Plant Antimicrobial Agents Containing Marinades on Storage Stability and Microbiological Quality of Broiler Chicken Cuts Packed with Modified Atmosphere Packaging.

PubMed

Alakomi, H-L; Maukonen, J; Honkapää, K; Storgårds, E; Quirin, K-W; Yang, B; Saarela, M

2017-10-01

The food industry, including the meat industry, is currently looking for natural preservatives to prevent the growth of harmful microbes in foods. The potential of plant-derived antimicrobial extracts to increase the shelf life and to delay the microbiological spoilage of marinated broiler chicken cuts in modified atmosphere packages during cold storage was investigated in this study. We evaluated the impact of aqueous ethanolic extracts of Finnish sea buckthorn berries and lingonberries and supercritical CO 2 -extracted herbal extracts from an antimicrobial blend and oregano leaves on the shelf life of broiler meat. The commercial antimicrobial blend extract and the oregano extract inhibited the growth of lactic acid bacteria (LAB) and Brochothrix thermosphacta in the marinated samples. The antimicrobial blend extract also reduced the growth of psychrotrophic aerobic bacteria, whereas the sea buckthorn and lingonberry extracts did not. Only minor antimicrobial activity against Enterobacteriaceae by all the extracts was observed. Plate count analysis, denaturing gradient gel electrophoresis, and quantitative real-time PCR indicated that LAB, which are the major spoilage group in marinated modified atmosphere-packaged poultry products, were not significantly affected by the berry extracts studied. During this shelf-life study, LAB isolates of Lactobacillus and Leuconostoc were identified in the marinated samples. Antimicrobial blends and oregano leaf extracts can act as antimicrobial agents in marinade blends, although tailoring of the dose is needed because of their strong taste. Further studies for exploiting synergistic effects of plant extracts could contribute to the development of potential and more effective antimicrobial blends. Studies are needed in meat matrices and in product applications to demonstrate the efficacy of these compounds.

Evaluating the potential for site-specific modification of LiDAR DEM derivatives to improve environmental planning-scale wetland identification using Random Forest classification

NASA Astrophysics Data System (ADS)

O'Neil, Gina L.; Goodall, Jonathan L.; Watson, Layne T.

2018-04-01

Wetlands are important ecosystems that provide many ecological benefits, and their quality and presence are protected by federal regulations. These regulations require wetland delineations, which can be costly and time-consuming to perform. Computer models can assist in this process, but lack the accuracy necessary for environmental planning-scale wetland identification. In this study, the potential for improvement of wetland identification models through modification of digital elevation model (DEM) derivatives, derived from high-resolution and increasingly available light detection and ranging (LiDAR) data, at a scale necessary for small-scale wetland delineations is evaluated. A novel approach of flow convergence modelling is presented where Topographic Wetness Index (TWI), curvature, and Cartographic Depth-to-Water index (DTW), are modified to better distinguish wetland from upland areas, combined with ancillary soil data, and used in a Random Forest classification. This approach is applied to four study sites in Virginia, implemented as an ArcGIS model. The model resulted in significant improvement in average wetland accuracy compared to the commonly used National Wetland Inventory (84.9% vs. 32.1%), at the expense of a moderately lower average non-wetland accuracy (85.6% vs. 98.0%) and average overall accuracy (85.6% vs. 92.0%). From this, we concluded that modifying TWI, curvature, and DTW provides more robust wetland and non-wetland signatures to the models by improving accuracy rates compared to classifications using the original indices. The resulting ArcGIS model is a general tool able to modify these local LiDAR DEM derivatives based on site characteristics to identify wetlands at a high resolution.

A chemometrics approach applied to Fourier transform infrared spectroscopy (FTIR) for monitoring the spoilage of fresh salmon (Salmo salar) stored under modified atmospheres.

PubMed

Saraiva, C; Vasconcelos, H; de Almeida, José M M M

2017-01-16

The aim of this work was to investigate the potential of Fourier transform infrared spectroscopy (FTIR) to detect and predict the bacterial load of salmon fillets (Salmo salar) stored at 3, 8 and 30°C under three packaging conditions: air packaging (AP) and two modified atmospheres constituted by a mixture of 50%N 2 /40%CO 2 /10%O 2 with lemon juice (MAPL) and without lemon juice (MAP). Fresh salmon samples were periodically examined for total viable counts (TVC), specific spoilage organisms (SSO) counts, pH, FTIR and sensory assessment of freshness. Principal components analysis (PCA) allowed identification of the wavenumbers potentially correlated with the spoilage process. Linear discriminant analysis (LDA) of infrared spectral data was performed to support sensory data and to accurately identify samples freshness. The effect of the packaging atmospheres was assessed by microbial enumeration and LDA was used to determine sample packaging from the measured infrared spectra. It was verified that modified atmospheres can decrease significantly the bacterial load of fresh salmon. Lemon juice combined with MAP showed a more pronounced delay in the growth of Brochothrix thermosphacta, Photobacterium phosphoreum, psychrotrophs and H 2 S producers. Partial least squares regression (PLS-R) allowed estimates of TVC and psychrotrophs, lactic acid bacteria, molds and yeasts, Brochothrix thermosphacta, Enterobacteriaceae, Pseudomonas spp. and H 2 S producer counts from the infrared spectral data. For TVC, the root mean square error of prediction (RMSEP) value was 0.78logcfug -1 for an external set of samples. According to the results, FTIR can be used as a reliable, accurate and fast method for real time freshness evaluation of salmon fillets stored under different temperatures and packaging atmospheres. Copyright © 2016 Elsevier B.V. All rights reserved.

A simple method to prepare magnetic modified beer yeast and its application for cationic dye adsorption.

PubMed

Yu, Jun-Xia; Wang, Li-Yan; Chi, Ru-An; Zhang, Yue-Fei; Xu, Zhi-Gao; Guo, Jia

2013-01-01

The purpose of this research is to use a simple method to prepare magnetic modified biomass with good adsorption performances for cationic ions. The magnetic modified biomass was prepared by two steps: (1) preparation of pyromellitic dianhydride (PMDA) modified biomass in N, N-dimethylacetamide solution and (2) preparation of magnetic PMDA modified biomass by a situ co-precipitation method under the assistance of ultrasound irradiation in ammonia water. The adsorption potential of the as-prepared magnetic modified biomass was analyzed by using cationic dyes: methylene blue and basic magenta as model dyes. Optical micrograph and x-ray diffraction analyses showed that Fe(3)O(4) particles were precipitated on the modified biomass surface. The as-prepared biosorbent could be recycled easily by using an applied magnetic field. Titration analysis showed that the total concentration of the functional groups on the magnetic PMDA modified biomass was calculated to be 0.75 mmol g(-1) by using the first derivative method. The adsorption capacities (q(m)) of the magnetic PMDA modified biomass for methylene blue and basic magenta were 609.0 and 520.9 mg g(-1), respectively, according to the Langmuir equation. Kinetics experiment showed that adsorption could be completed within 150 min for both dyes. The desorption experiment showed that the magnetic sorbent could be used repeatedly after regeneration. The as-prepared magnetic modified sorbent had a potential in the dyeing industry wastewater treatment.

Tannic acid-modified silver nanoparticles for wound healing: the importance of size

PubMed Central

Orlowski, Piotr; Zmigrodzka, Magdalena; Tomaszewska, Emilia; Ranoszek-Soliwoda, Katarzyna; Czupryn, Monika; Antos-Bielska, Malgorzata; Szemraj, Janusz; Celichowski, Grzegorz; Grobelny, Jaroslaw

2018-01-01

Introduction Silver nanoparticles (AgNPs) have been shown to promote wound healing and to exhibit antimicrobial properties against a broad range of bacteria. In our previous study, we prepared tannic acid (TA)-modified AgNPs showing a good toxicological profile and immunomodulatory properties useful for potential dermal applications. Methods In this study, in vitro scratch assay, antimicrobial tests, modified lymph node assay as well as a mouse splint wound model were used to access the wound healing potential of TA-modified and unmodified AgNPs. Results TA-modified but not unmodified AgNPs exhibited effective antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli and stimulated migration of keratinocytes in vitro. The tests using the mouse splint wound model showed that TA-modified 33 and 46 nm AgNPs promoted better wound closure, epithelialization, angiogenesis and formation of the granulation tissue. Additionally, AgNPs elicited expression of VEGF-α, PDGF-β and TGF-β1 cytokines involved in wound healing more efficiently in comparison to control and TA-treated wounds. However, both the lymph node assay and the wound model showed that TA-modified AgNPs sized 13 nm can elicit strong inflammatory response not only during wound healing but also when applied to the damaged skin. Conclusion TA-modified AgNPs sized >26 nm promote wound healing better than TA-modified or unmodified AgNPs. These findings suggest that TA-modified AgNPs sized >26 nm may have a promising application in wound management. PMID:29497293

A BSL-4 high-throughput screen identifies sulfonamide inhibitors of Nipah virus.

PubMed

Tigabu, Bersabeh; Rasmussen, Lynn; White, E Lucile; Tower, Nichole; Saeed, Mohammad; Bukreyev, Alexander; Rockx, Barry; LeDuc, James W; Noah, James W

2014-04-01

Nipah virus is a biosafety level 4 (BSL-4) pathogen that causes severe respiratory illness and encephalitis in humans. To identify novel small molecules that target Nipah virus replication as potential therapeutics, Southern Research Institute and Galveston National Laboratory jointly developed an automated high-throughput screening platform that is capable of testing 10,000 compounds per day within BSL-4 biocontainment. Using this platform, we screened a 10,080-compound library using a cell-based, high-throughput screen for compounds that inhibited the virus-induced cytopathic effect. From this pilot effort, 23 compounds were identified with EC50 values ranging from 3.9 to 20.0 μM and selectivities >10. Three sulfonamide compounds with EC50 values <12 μM were further characterized for their point of intervention in the viral replication cycle and for broad antiviral efficacy. Development of HTS capability under BSL-4 containment changes the paradigm for drug discovery for highly pathogenic agents because this platform can be readily modified to identify prophylactic and postexposure therapeutic candidates against other BSL-4 pathogens, particularly Ebola, Marburg, and Lassa viruses.

Lysine Ubiquitination and Acetylation of Human Cardiac 20S Proteasomes

PubMed Central

Lau, Edward; Choi, Howard JH; Ng, Dominic CM; Meyer, David; Fang, Caiyun; Li, Haomin; Wang, Ding; Zelaya, Ivette M; Yates, John R; Lam, Maggie PY

2016-01-01

Purpose Altered proteasome functions are associated with multiple cardiomyopathies. While the proteasome targets poly-ubiquitinated proteins for destruction, it itself is modifiable by ubiquitination. We aim to identify the exact ubiquitination sites on cardiac proteasomes and examine whether they are also subject to acetylations. Experimental design Assembled cardiac 20S proteasome complexes were purified from five human hearts with ischemic cardiomyopathy, then analyzed by high-resolution MS to identify ubiquitination and acetylation sites. We developed a library search strategy that may be used to complement database search in identifying PTM in different samples. Results We identified 63 ubiquitinated lysines from intact human cardiac 20S proteasomes. In parallel, 65 acetylated residues were also discovered, 39 of which shared with ubiquitination sites. Conclusion and clinical relevance This is the most comprehensive characterization of cardiac proteasome ubiquitination to-date. There are significant overlaps between the discovered ubiquitination and acetylation sites, permitting potential crosstalk in regulating proteasome functions. The information presented here will aid future therapeutic strategies aimed at regulating the functions of cardiac proteasomes. PMID:24957502

Lysine ubiquitination and acetylation of human cardiac 20S proteasomes.

PubMed

Zong, Nobel; Ping, Peipei; Lau, Edward; Choi, Howard Jh; Ng, Dominic Cm; Meyer, David; Fang, Caiyun; Li, Haomin; Wang, Ding; Zelaya, Ivette M; Yates, John R; Lam, Maggie Py

2014-08-01

Altered proteasome functions are associated with multiple cardiomyopathies. While the proteasome targets polyubiquitinated proteins for destruction, it itself is modifiable by ubiquitination. We aim to identify the exact ubiquitination sites on cardiac proteasomes and examine whether they are also subject to acetylations. Assembled cardiac 20S proteasome complexes were purified from five human hearts with ischemic cardiomyopathy, then analyzed by high-resolution MS to identify ubiquitination and acetylation sites. We developed a library search strategy that may be used to complement database search in identifying PTM in different samples. We identified 63 ubiquitinated lysines from intact human cardiac 20S proteasomes. In parallel, 65 acetylated residues were also discovered, 39 of which shared with ubiquitination sites. This is the most comprehensive characterization of cardiac proteasome ubiquitination to date. There are significant overlaps between the discovered ubiquitination and acetylation sites, permitting potential crosstalk in regulating proteasome functions. The information presented here will aid future therapeutic strategies aimed at regulating the functions of cardiac proteasomes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A BSL-4 High-Throughput Screen Identifies Sulfonamide Inhibitors of Nipah Virus

PubMed Central

Tigabu, Bersabeh; Rasmussen, Lynn; White, E. Lucile; Tower, Nichole; Saeed, Mohammad; Bukreyev, Alexander; Rockx, Barry; LeDuc, James W.

2014-01-01

Abstract Nipah virus is a biosafety level 4 (BSL-4) pathogen that causes severe respiratory illness and encephalitis in humans. To identify novel small molecules that target Nipah virus replication as potential therapeutics, Southern Research Institute and Galveston National Laboratory jointly developed an automated high-throughput screening platform that is capable of testing 10,000 compounds per day within BSL-4 biocontainment. Using this platform, we screened a 10,080-compound library using a cell-based, high-throughput screen for compounds that inhibited the virus-induced cytopathic effect. From this pilot effort, 23 compounds were identified with EC50 values ranging from 3.9 to 20.0 μM and selectivities >10. Three sulfonamide compounds with EC50 values <12 μM were further characterized for their point of intervention in the viral replication cycle and for broad antiviral efficacy. Development of HTS capability under BSL-4 containment changes the paradigm for drug discovery for highly pathogenic agents because this platform can be readily modified to identify prophylactic and postexposure therapeutic candidates against other BSL-4 pathogens, particularly Ebola, Marburg, and Lassa viruses. PMID:24735442

75 FR 26102 - Approval and Promulgation of Implementation Plans, State of California, San Joaquin Valley...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-11

... provide for review of new and modified stationary sources (``new source review'' or NSR) within the... the requirements and exemptions for review of new or modified stationary sources (``new source review... Modified Stationary 12/18/08 03/17/09 Source Review Rule. SJVUAPCD 2530 Federally Enforceable Potential 12...

Unintended Effects in Genetically Modified Food/Feed Safety: A Way Forward.

PubMed

Fernandez, Antonio; Paoletti, Claudia

2018-04-20

Identifying and assessing unintended effects in genetically modified food and feed are considered paramount by the Food and Agricultural Organization (FAO), World Health Organization (WHO), and Codex Alimentarius, despite heated debate. This paper addresses outstanding needs: building consensus on the history-of-safe-use concept, harmonizing criteria to select appropriate conventional counterparts, and improving endpoint selection to identify unintended effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

The stability behavior of sol-emulsion systems

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

Sunkel, J.M.; Berg, J.C.

1996-05-10

Sol-emulsion systems, i.e., colloids consisting of mixed populations of solid particles and emulsion droplets, are encountered in a number of applications, e.g., oil-assisted agglomeration for particle removal (coal fines from water). The stability characteristics of mixed aqueous dispersions of titanium dioxide and mineral oil emulsion droplets are examined as a function of pH and emulsifier type and content. Zeta potentials of both the titanium dioxide and the mineral oil particles are measured under all conditions to identify regions of expected heterocoagulation and to quantify the electrostatic boundary conditions. The latter are used in the numerical solution of the pair interactionmore » potentials based on the recent theory of McCormack et al. The potential functions are used in a modified version of the stability model of Hogg, Healy, and Fuerstenau to calculate early-stage aggregation rates. Photon correlation spectroscopy is used to determine stability ratios for homo- and heterocoagulation, and initial results indicate good agreement between experiments and computations.« less

Hydrotropism: how roots search for water.

PubMed

Dietrich, Daniela

2018-05-19

Fresh water is an increasingly scarce resource for agriculture. Plant roots mediate water uptake from the soil and have developed a number of adaptive traits such as hydrotropism to aid water foraging. Hydrotropism modifies root growth to respond to a water potential gradient in soil and grow towards areas with a higher moisture content. Abscisic acid (ABA) and a small number of genes, including those encoding ABA signal transducers, MIZ2/GNOM, and the hydrotropism-specific MIZ1, are known to be necessary for the response in Arabidopsis thaliana, whereas the role of auxin in hydrotropism appears to vary depending on the plant species. This review will describe recent progress characterizing the hormonal regulation of hydrotropism. Recent advances in identifying the sites of hydrotropic perception and response, together with its interaction with gravitropism, will also be discussed. Finally, I will describe putative mechanisms for perception of the water potential gradient and a potential role for hydrotropism in acclimatizing plants to drought conditions.

EVALLER: a web server for in silico assessment of potential protein allergenicity

PubMed Central

Barrio, Alvaro Martinez; Soeria-Atmadja, Daniel; Nistér, Anders; Gustafsson, Mats G.; Hammerling, Ulf; Bongcam-Rudloff, Erik

2007-01-01

Bioinformatics testing approaches for protein allergenicity, involving amino acid sequence comparisons, have evolved appreciably over the last several years to increased sophistication and performance. EVALLER, the web server presented in this article is based on our recently published ‘Detection based on Filtered Length-adjusted Allergen Peptides’ (DFLAP) algorithm, which affords in silico determination of potential protein allergenicity of high sensitivity and excellent specificity. To strengthen bioinformatics risk assessment in allergology EVALLER provides a comprehensive outline of its judgment on a query protein's potential allergenicity. Each such textual output incorporates a scoring figure, a confidence numeral of the assignment and information on high- or low-scoring matches to identified allergen-related motifs, including their respective location in accordingly derived allergens. The interface, built on a modified Perl Open Source package, enables dynamic and color-coded graphic representation of key parts of the output. Moreover, pertinent details can be examined in great detail through zoomed views. The server can be accessed at http://bioinformatics.bmc.uu.se/evaller.html. PMID:17537818

The potential of the combination of CRISPR/Cas9 and pluripotent stem cells to provide human organs from chimaeric pigs.

PubMed

Feng, Wanyou; Dai, Yifan; Mou, Lisha; Cooper, David K C; Shi, Deshun; Cai, Zhiming

2015-03-23

Clinical organ allotransplantation is limited by the availability of deceased human donors. However, the transplantation of human organs produced in other species would provide an unlimited number of organs. The pig has been identified as the most suitable source of organs for humans as organs of any size would be available. Genome editing by RNA-guided endonucleases, also known as clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), in combination with induced pluripotent stem cells (iPSC), may have the potential to enable the creation of human organs from genetically-modified chimaeric pigs. These could potentially provide an unlimited supply of organs that would not be rejected by the recipient's immune system. However, substantial research is needed to prove that this approach will work. Genetic modification of chimaeric pigs could also provide useful models for developing therapies for various human diseases, especially in relation to drug development.

Sleep duration and overweight/obesity in children: implication for pediatric nursing

PubMed Central

Liu, Jianghong; Zhang, Angelina; Li, Linda

2012-01-01

Purpose The purpose of this study was to review evidence from the last 5 years (2006-2011) regarding a relationship between sleep duration and childhood overweight/obesity. Conclusions Among the 25 studies selected from PubMed and Web of Knowledge databases, all indicated significant associations between short sleep duration and childhood overweight/obesity. Studies explored a range of pediatric populations, methodologies, and potential contributing factors. Practice Implications Childhood sleep duration may be a modifiable risk factor in preventing obesity. In addition to identifying and assessing patients’ sleep habits, nurses play important roles as educators regarding the importance of adequate sleep and promoting it in children. PMID:22734873

A Cognitive Engineering Analysis of the Vertical Navigation (VNAV) Function

NASA Technical Reports Server (NTRS)

Sherry, Lance; Feary, Michael; Polson, Peter; Mumaw, Randall; Palmer, Everett

2001-01-01

A cognitive engineering analysis of the Flight Management System (FMS) Vertical Navigation (VNAV) function has identified overloading of the VNAV button and overloading of the Flight Mode Annunciator (FMA) used by the VNAV function. These two types of overloading, resulting in modal input devices and ambiguous feedback, are well known sources of operator confusion, and explain, in part, the operational issues experienced by airline pilots using VNAV in descent and approach. A proposal to modify the existing VNAV design to eliminate the overloading is discussed. The proposed design improves pilot's situational awareness of the VNAV function, and potentially reduces the cost of software development and improves safety.

Probiotics and Diverticular Disease: Evidence-based?

PubMed

Lahner, Edith; Annibale, Bruno

Diverticular disease (DD) is a common gastrointestinal condition. Clinical spectrum ranges from asymptomatic diverticulosis to symptomatic uncomplicated or complicated DD. Symptoms related to uncomplicated DD are not specific and may be indistinguishable from those of irritable bowel syndrome. Low-grade inflammation, altered intestinal microbiota, visceral hypersensitivity, and abnormal colonic motility have been identified as factors potentially contributing to symptoms. Probiotics may modify the gut microbial balance leading to health benefits. Probiotics, due to their anti-inflammatory effects and ability to maintain an adequate bacterial colonization in the colon, are promising treatment options for DD. This review focuses on the available evidence on the efficacy of prebiotics in uncomplicated DD.

Participation in modified sports programs: a longitudinal study of children's transition to club sport competition.

PubMed

Eime, Rochelle M; Casey, Meghan M; Harvey, Jack T; Charity, Melanie J; Young, Janet A; Payne, Warren R

2015-07-14

Many children are not physically active enough for a health benefit. One avenue of physical activity is modified sport programs, designed as an introduction to sport for young children. This longitudinal study identified trends in participation among children aged 4-12 years. Outcomes included continuation in the modified sports program, withdrawal from the program or transition to club sport competition. De-identified data on participant membership registrations in three popular sports in the Australian state of Victoria were obtained from each sport's state governing body over a 4-year period (2009-2012 for Sport A and 2010-2013 for Sports B and C). From the membership registrations, those who were enrolled in a modified sports program in the first year were tracked over the subsequent three years and classified as one of: transition (member transitioned from a modified sport program to a club competition); continue (member continued participation in a modified sport program; or withdraw (member discontinued a modified program and did not transition to club competition). Many modified sports participants were very young, especially males aged 4-6 years. More children withdrew from their modified sport program rather than transitioning. There were age differences between when boys and girls started, withdrew and transitioned from the modified sports programs. If we can retain children in sport it is likely to be beneficial for their health. This study highlights considerations for the development and implementation of sport policies and programming to ensure lifelong participation is encouraged for both males and females.

Study of polyethyleneimine- and amidoxime-functionalized hybrid biomass of Spirulina (Arthrospira) platensis for adsorption of uranium (VI) ion.

PubMed

Bayramoglu, Gulay; Akbulut, Aydin; Arica, M Yakup

2015-11-01

This study investigates the potential application of the polyethyleneimine- (PEI) and amidoxime-modified Spirulina (Arthrospira) platensis biomasses for the removal of uranium ion in batch mode using the native biomass as a control system. The uranium ion adsorption was also characterized by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectra, zeta potential analysis, and surface area measurement studies. The effects of pH, biomass amount, contact time, initial uranium ion concentration, and ionic strength were evaluated by using native and modified algal biomass preparations. The uranium ion removal was rapid, with more than 70% of total adsorption taking place in 40 min, and equilibrium was established within 60 min. From the experimental data, it was found that the amount of adsorption uranium ion on the algal preparations decreased in the following series: amidoxime-modified algal biomass > PEI-modified algal biomass > native algal biomass. Maximum adsorption capacities of amidoxime- and PEI-modified, and native algal biomasses were found to be 366.8, 279.5, and 194.6 mg/g, respectively, in batchwise studies. The adsorption rate of U(VI) ion by amidoxime-modified algal biomass was higher than those of the native and PEI-modified counterparts. The adsorption processes on all the algal biomass preparations followed by the Dubinin-Radushkevitch (D-R) and Temkin isotherms and pseudo-second-order kinetic models. The thermodynamic parameters were determined at four different temperatures (i.e., 15, 25, 35, and 45 °C) using the thermodynamics constant of the Temkin isotherm model. The ΔH° and ΔG° values of U(VI) ion adsorption on algal preparations show endothermic heat of adsorption; higher temperatures favor the process. The native and modified algal biomass preparations were regenerated using 10 mM HNO3. These results show that amidoxime-modified algal biomass can be a potential candidate for effective removal of U(VI) ion from aqueous solution.

Full-field drift Hamiltonian particle orbits in 3D geometry

NASA Astrophysics Data System (ADS)

Cooper, W. A.; Graves, J. P.; Brunner, S.; Isaev, M. Yu

2011-02-01

A Hamiltonian/Lagrangian theory to describe guiding centre orbit drift motion which is canonical in the Boozer coordinate frame has been extended to include full electromagnetic perturbed fields in anisotropic pressure 3D equilibria with nested magnetic flux surfaces. A redefinition of the guiding centre velocity to eliminate the motion due to finite equilibrium radial magnetic fields and the choice of a gauge condition that sets the radial component of the electromagnetic vector potential to zero are invoked to guarantee that the Boozer angular coordinates retain the canonical structure. The canonical momenta are identified and the guiding centre particle radial drift motion and parallel gyroradius evolution are derived. The particle coordinate position is linearly modified by wave-particle interactions. All the nonlinear wave-wave interactions appear explicitly only in the evolution of the parallel gyroradius. The radial variation of the electrostatic potential is related to the binormal component of the displacement vector for MHD-type perturbations. The electromagnetic vector potential projections can then be determined from the electrostatic potential and the radial component of the MHD displacement vector.

Modified water regimes affect photosynthesis, xylem water potential, cambial growth and resistance of juvenile Pinus taeda L. to Dendroctonus frontalis (Coleoptera: Scolytidae)

Treesearch

James P. Dunn; Peter L. Jr. Lorio

1993-01-01

We modified soil water supply to two groups of juvenile loblolly pines, Pinus taeda L., by sheltering or irrigating root systems in early summer or in later summer and measured oleoresin flow (primary defense), net photosynthesis, xylem water potential, and cambial growth throughout the growing season. When consistent significant differences in...

An individual-tree basal area growth model for loblolly pine stands

Treesearch

Paul A. Murphy; Michael G. Shelton

1996-01-01

Tree basal area growth has been modeled as a combination of a potential growth function and a modifier function, in which the potential function is fitted separately from open-grown tree data or a subset of the data and the modifier function includes stand and site variables. We propose a modification of this by simultaneously fitting both a growth component and a...

Modified Light Duty AM2 Capability Assessment

DTIC Science & Technology

The Modified Light -Duty AM2 matting was designed specifically for lightweight, remote-piloted aircraft (RPA) applications. An in- depth study was... Ratio (CBR) of 6. To understand the full potential of the Modified Light -Duty AM2, a full- scale evaluation was performed with contingency C-17 and...stir welding for use in fabrication of the lightweight RPA matting in conjunction with a full- scale test on the Modified Light -Duty AM2 matting system

Stakeholder Engagement to Identify Priorities for Improving the Quality and Value of Critical Care.

PubMed

Stelfox, Henry T; Niven, Daniel J; Clement, Fiona M; Bagshaw, Sean M; Cook, Deborah J; McKenzie, Emily; Potestio, Melissa L; Doig, Christopher J; O'Neill, Barbara; Zygun, David

2015-01-01

Large amounts of scientific evidence are generated, but not implemented into patient care (the 'knowledge-to-care' gap). We identified and prioritized knowledge-to-care gaps in critical care as opportunities to improve the quality and value of healthcare. We used a multi-method community-based participatory research approach to engage a Network of all adult (n = 14) and pediatric (n = 2) medical-surgical intensive care units (ICUs) in a fully integrated geographically defined healthcare system serving 4 million residents. Participants included Network oversight committee members (n = 38) and frontline providers (n = 1,790). Network committee members used a modified RAND/University of California Appropriateness Methodology, to serially propose, rate (validated 9 point scale) and revise potential knowledge-to-care gaps as priorities for improvement. The priorities were sent to frontline providers for evaluation. Results were relayed back to all frontline providers for feedback. Initially, 68 knowledge-to-care gaps were proposed, rated and revised by the committee (n = 32 participants) over 3 rounds of review and resulted in 13 proposed priorities for improvement. Then, 1,103 providers (62% response rate) evaluated the priorities, and rated 9 as 'necessary' (median score 7-9). Several factors were associated with rating priorities as necessary in multivariable logistic regression, related to the provider (experience, teaching status of ICU) and topic (strength of supporting evidence, potential to benefit the patient, potential to improve patient/family experience, potential to decrease costs). A community-based participatory research approach engaged a diverse group of stakeholders to identify 9 priorities for improving the quality and value of critical care. The approach was time and cost efficient and could serve as a model to prioritize areas for research quality improvement across other settings.

Improving foaming properties of yolk-contaminated egg albumen by basic soy protein.

PubMed

Wang, Guang; Wang, Tong

2009-10-01

Yolk contamination of egg white is a common problem in the egg breaking industry. Foaming properties of egg white protein are affected by such contamination, but proteins of basic nature may restore the foaming properties of the yolk-contaminated egg white protein. The purpose of this study was to chemically modify a soy protein, that is, to esterify the acidic groups on the protein and to study the potential of such modified protein in improving foaming. We showed that the modification changed the isoelectric point of soy protein isolate (SPI) from 4.5 to about 10. Sonication was proven to be a very effective means to redisperse the methanol-denatured soy protein during reaction, as shown by the improved solubility profile. Such modified basic protein, that is, the sonicated-modified SPI (SMSPI), when added to the yolk-contaminated (at 0.4% level, as-is basis) egg white, gave significantly improved foaming properties. We have shown that the slight change in pH due to the addition of SMSPI was not the reason for improved foaming performance; instead, the modified protein itself was the main reason for such improvement. Addition of SMSPI increased the foaming performance of both pure egg white and yolk-contaminated egg white. SMSPI consistently performed better than the unmodified SPI for improving foaming. Addition of SMSPI (16%, based on dry egg white, and 1.6% based on liquid egg white) fully restored foam expansion and foam liquid stability of 0.4% yolk-contaminated egg white, and it even out-performed the foaming of pure white protein. Therefore, a feasible solution to restore the foaming properties of yolk-contaminated egg white has been identified. It is expected that such modified SPI can be used as an additive or ingredient in foaming formulation, especially when the egg white protein is suspected of lipid contamination.

Identification of ubiquitin/ubiquitin-like protein modification from tandem mass spectra with various PTMs

PubMed Central

2011-01-01

Background Various solutions have been introduced for the identification of post-translational modification (PTM) from tandem mass spectrometry (MS/MS) in proteomics field but the identification of peptide modifiers, such as Ubiquitin (Ub) and ubiquitin-like proteins (Ubls), is still a challenge. The fragmentation of peptide modifier produce complex shifted ion mass patterns in combination with other PTMs, which makes it difficult to identify and locate the PTMs on a protein sequence. Currently, most PTM identification methods do not consider the complex fragmentation of peptide modifier or deals it separately from the other PTMs. Results We developed an advanced PTM identification method that inspects possible ion patterns of the most known peptide modifiers as well as other known biological and chemical PTMs to make more comprehensive and accurate conclusion. The proposed method searches all detectable mass differences of measured peaks from their theoretical values and the mass differences within mass tolerance range are grouped as mass shift classes. The most possible locations of multiple PTMs including peptide modifiers can be determined by evaluating all possible scenarios generated by the combination of the qualified mass shift classes.The proposed method showed excellent performance in the test with simulated spectra having various PTMs including peptide modifiers and in the comparison with recently developed methods such as QuickMod and SUMmOn. In the analysis of HUPO Brain Proteome Project (BPP) datasets, the proposed method could find the ubiquitin modification sites that were not identified by other conventional methods. Conclusions This work presents a novel method for identifying bothpeptide modifiers that generate complex fragmentation patternsand PTMs that are not fragmented during fragmentation processfrom tandem mass spectra. PMID:22373085

Probing baryogenesis through the Higgs boson self-coupling

NASA Astrophysics Data System (ADS)

Reichert, M.; Eichhorn, A.; Gies, H.; Pawlowski, J. M.; Plehn, T.; Scherer, M. M.

2018-04-01

The link between a modified Higgs self-coupling and the strong first-order phase transition necessary for baryogenesis is well explored for polynomial extensions of the Higgs potential. We broaden this argument beyond leading polynomial expansions of the Higgs potential to higher polynomial terms and to nonpolynomial Higgs potentials. For our quantitative analysis we resort to the functional renormalization group, which allows us to evolve the full Higgs potential to higher scales and finite temperature. In all cases we find that a strong first-order phase transition manifests itself in an enhancement of the Higgs self-coupling by at least 50%, implying that such modified Higgs potentials should be accessible at the LHC.

Sequence tagging reveals unexpected modifications in toxicoproteomics

PubMed Central

Dasari, Surendra; Chambers, Matthew C.; Codreanu, Simona G.; Liebler, Daniel C.; Collins, Ben C.; Pennington, Stephen R.; Gallagher, William M.; Tabb, David L.

2010-01-01

Toxicoproteomic samples are rich in posttranslational modifications (PTMs) of proteins. Identifying these modifications via standard database searching can incur significant performance penalties. Here we describe the latest developments in TagRecon, an algorithm that leverages inferred sequence tags to identify modified peptides in toxicoproteomic data sets. TagRecon identifies known modifications more effectively than the MyriMatch database search engine. TagRecon outperformed state of the art software in recognizing unanticipated modifications from LTQ, Orbitrap, and QTOF data sets. We developed user-friendly software for detecting persistent mass shifts from samples. We follow a three-step strategy for detecting unanticipated PTMs in samples. First, we identify the proteins present in the sample with a standard database search. Next, identified proteins are interrogated for unexpected PTMs with a sequence tag-based search. Finally, additional evidence is gathered for the detected mass shifts with a refinement search. Application of this technology on toxicoproteomic data sets revealed unintended cross-reactions between proteins and sample processing reagents. Twenty five proteins in rat liver showed signs of oxidative stress when exposed to potentially toxic drugs. These results demonstrate the value of mining toxicoproteomic data sets for modifications. PMID:21214251

Cellobiose Dehydrogenase Aryl Diazonium Modified Single Walled Carbon Nanotubes: Enhanced Direct Electron Transfer through a Positively Charged Surface

PubMed Central

2011-01-01

One of the challenges in the field of biosensors and biofuel cells is to establish a highly efficient electron transfer rate between the active site of redox enzymes and electrodes to fully access the catalytic potential of the biocatalyst and achieve high current densities. We report on very efficient direct electron transfer (DET) between cellobiose dehydrogenase (CDH) from Phanerochaete sordida (PsCDH) and surface modified single walled carbon nanotubes (SWCNT). Sonicated SWCNTs were adsorbed on the top of glassy carbon electrodes and modified with aryl diazonium salts generated in situ from p-aminobenzoic acid and p-phenylenediamine, thus featuring at acidic pH (3.5 and 4.5) negative or positive surface charges. After adsorption of PsCDH, both electrode types showed excellent long-term stability and very efficient DET. The modified electrode presenting p-aminophenyl groups produced a DET current density of 500 μA cm−2 at 200 mV vs normal hydrogen reference electrode (NHE) in a 5 mM lactose solution buffered at pH 3.5. This is the highest reported DET value so far using a CDH modified electrode and comes close to electrodes using mediated electron transfer. Moreover, the onset of the electrocatalytic current for lactose oxidation started at 70 mV vs NHE, a potential which is 50 mV lower compared to when unmodified SWCNTs were used. This effect potentially reduces the interference by oxidizable matrix components in biosensors and increases the open circuit potential in biofuel cells. The stability of the electrode was greatly increased compared with unmodified but cross-linked SWCNTs electrodes and lost only 15% of the initial current after 50 h of constant potential scanning. PMID:21417322

Cellobiose dehydrogenase aryl diazonium modified single walled carbon nanotubes: enhanced direct electron transfer through a positively charged surface.

PubMed

Tasca, Federico; Harreither, Wolfgang; Ludwig, Roland; Gooding, John Justin; Gorton, Lo

2011-04-15

One of the challenges in the field of biosensors and biofuel cells is to establish a highly efficient electron transfer rate between the active site of redox enzymes and electrodes to fully access the catalytic potential of the biocatalyst and achieve high current densities. We report on very efficient direct electron transfer (DET) between cellobiose dehydrogenase (CDH) from Phanerochaete sordida (PsCDH) and surface modified single walled carbon nanotubes (SWCNT). Sonicated SWCNTs were adsorbed on the top of glassy carbon electrodes and modified with aryl diazonium salts generated in situ from p-aminobenzoic acid and p-phenylenediamine, thus featuring at acidic pH (3.5 and 4.5) negative or positive surface charges. After adsorption of PsCDH, both electrode types showed excellent long-term stability and very efficient DET. The modified electrode presenting p-aminophenyl groups produced a DET current density of 500 μA cm(-2) at 200 mV vs normal hydrogen reference electrode (NHE) in a 5 mM lactose solution buffered at pH 3.5. This is the highest reported DET value so far using a CDH modified electrode and comes close to electrodes using mediated electron transfer. Moreover, the onset of the electrocatalytic current for lactose oxidation started at 70 mV vs NHE, a potential which is 50 mV lower compared to when unmodified SWCNTs were used. This effect potentially reduces the interference by oxidizable matrix components in biosensors and increases the open circuit potential in biofuel cells. The stability of the electrode was greatly increased compared with unmodified but cross-linked SWCNTs electrodes and lost only 15% of the initial current after 50 h of constant potential scanning. © 2011 American Chemical Society

Discovery and characterization of inhibitors of human palmitoyl acyltransferases.

PubMed

Ducker, Charles E; Griffel, Lindsay K; Smith, Ryan A; Keller, Staci N; Zhuang, Yan; Xia, Zuping; Diller, John D; Smith, Charles D

2006-07-01

The covalent attachment of palmitate to specific proteins by the action of palmitoyl acyltransferases (PAT) plays critical roles in the biological activities of several oncoproteins. Two PAT activities are expressed by human cells: type 1 PATs that modify the farnesyl-dependent palmitoylation motif found in H- and N-Ras, and type 2 PATs that modify the myristoyl-dependent palmitoylation motif found in the Src family of tyrosine kinases. We have previously shown that the type 1 PAT HIP14 causes cellular transformation. In the current study, we show that mRNA encoding HIP14 is up-regulated in a number of types of human tumors. To assess the potential of HIP14 and other PATs as targets for new anticancer drugs, we developed three cell-based assays suitable for high-throughput screening to identify inhibitors of these enzymes. Using these screens, five chemotypes, with activity toward either type 1 or type 2 PAT activity, were identified. The activity of the hits were confirmed using assays that quantify the in vitro inhibition of PAT activity, as well as a cell-based assay that determines the abilities of the compounds to prevent the localization of palmitoylated green fluorescent proteins to the plasma membrane. Representative compounds from each chemotype showed broad antiproliferative activity toward a panel of human tumor cell lines and inhibited the growth of tumors in vivo. Together, these data show that PATs, and HIP14 in particular, are interesting new targets for anticancer compounds, and that small molecules with such activity can be identified by high-throughput screening.

Discovery and characterization of inhibitors of human palmitoyl acyltransferases

PubMed Central

Ducker, Charles E.; Griffel, Lindsay K.; Smith, Ryan A.; Keller, Staci N.; Zhuang, Yan; Xia, Zuping; Diller, John D.; Smith, Charles D.

2010-01-01

The covalent attachment of palmitate to specific proteins by the action of palmitoyl acyltransferases (PAT) plays critical roles in the biological activities of several oncoproteins. Two PAT activities are expressed by human cells: type 1 PATs that modify the farnesyl-dependent palmitoylation motif found in H- and N-Ras, and type 2 PATs that modify the myristoyl-dependent palmitoylation motif found in the Src family of tyrosine kinases. We have previously shown that the type 1 PAT HIP14 causes cellular transformation. In the current study, we show that mRNA encoding HIP14 is up-regulated in a number of types of human tumors. To assess the potential of HIP14 and other PATs as targets for new anticancer drugs, we developed three cell-based assays suitable for high-throughput screening to identify inhibitors of these enzymes. Using these screens, five chemotypes, with activity toward either type 1 or type 2 PAT activity, were identified. The activity of the hits were confirmed using assays that quantify the in vitro inhibition of PAT activity, as well as a cell-based assay that determines the abilities of the compounds to prevent the localization of palmitoylated green fluorescent proteins to the plasma membrane. Representative compounds from each chemotype showed broad antiproliferative activity toward a panel of human tumor cell lines and inhibited the growth of tumors in vivo. Together, these data show that PATs, and HIP14 in particular, are interesting new targets for anticancer compounds, and that small molecules with such activity can be identified by high-throughput screening. PMID:16891450

Texture evolution during thermomechanical processing in rare earth free magnesium alloys

NASA Astrophysics Data System (ADS)

Miller, Victoria Mayne

The use of wrought magnesium alloys is highly desirable for a wide range of applications where low component weight is desirable due to the high specific strength and stiffness the alloys can achieve. However, the implementation of wrought magnesium has been hindered by the limited room temperature formability which typically results from deformation processing. This work identifies opportunities for texture modification during thermomechanical processing of conventional (rare earth free) magnesium alloys via a combination of experimental investigation and polycrystal plasticity simulations. During deformation, it is observed that a homogeneous distribution of coarse intermetallic particles efficiently weakens deformation texture at all strain levels, while a highly inhomogeneous particle distribution is only effective at high strains. The particle deformation effects are complemented by the addition of alkaline earth solute, which modifies the relative deformation mode activity. During recrystallization, grains with basal orientations recrystallize more readily than off-basal grains, despite similar levels of internal misorientation. Dislocation substructure investigations revealed that this is a result of enhanced nucleation in the basal grains due to the dominance of prismatic slip. This dissertation identifies avenues to enhance the potential formability of magnesium alloys during thermomechanical processing by minimizing the evolved texture strength. The following are the identified key aspects of microstructural control: -Maintaining a fine grain size, likely via Zener pinning, to favorably modify deformation mode activity and homogenize deformation. -Developing a coarse, homogeneously distributed population of coarse intermetallic particles to promote a diffuse deformation texture. -Minimizing the activity of prismatic slip to retard the recrystallization of grains with basal orientations, allowing the development of a more diffuse recrystallization texture.

Deriving ICD-10 Codes for Patient Safety Indicators for Large-scale Surveillance Using Administrative Hospital Data.

PubMed

Southern, Danielle A; Burnand, Bernard; Droesler, Saskia E; Flemons, Ward; Forster, Alan J; Gurevich, Yana; Harrison, James; Quan, Hude; Pincus, Harold A; Romano, Patrick S; Sundararajan, Vijaya; Kostanjsek, Nenad; Ghali, William A

2017-03-01

Existing administrative data patient safety indicators (PSIs) have been limited by uncertainty around the timing of onset of included diagnoses. We undertook de novo PSI development through a data-driven approach that drew upon "diagnosis timing" information available in some countries' administrative hospital data. Administrative database analysis and modified Delphi rating process. All hospitalized adults in Canada in 2009. We queried all hospitalizations for ICD-10-CA diagnosis codes arising during hospital stay. We then undertook a modified Delphi panel process to rate the extent to which each of the identified diagnoses has a potential link to suboptimal quality of care. We grouped the identified quality/safety-related diagnoses into relevant clinical categories. Lastly, we queried Alberta hospital discharge data to assess the frequency of the newly defined PSI events. Among 2,416,413 national hospitalizations, we found 2590 unique ICD-10-CA codes flagged as having arisen after admission. Seven panelists evaluated these in a 2-round review process, and identified a listing of 640 ICD-10-CA diagnosis codes judged to be linked to suboptimal quality of care and thus appropriate for inclusion in PSIs. These were then grouped by patient safety experts into 18 clinically relevant PSI categories. We then analyzed data on 2,381,652 Alberta hospital discharges from 2005 through 2012, and found that 134,299 (5.2%) hospitalizations had at least 1 PSI diagnosis. The resulting work creates a foundation for a new set of PSIs for routine large-scale surveillance of hospital and health system performance.

Curated Collection for Educators: Five Key Papers about the Flipped Classroom Methodology

PubMed Central

Boysen-Osborn, Megan; Cooney, Robert; Mitzman, Jennifer; Misra, Asit; Williams, Jennifer; Dulani, Tina; Gottlieb, Michael

2017-01-01

The flipped classroom (FC) pedagogy is becoming increasingly popular in medical education due to its appeal to the millennial learner and potential benefits in knowledge acquisition. Despite its popularity and effectiveness, the FC educational method is not without challenges. In this article, we identify and summarize several key papers relevant to medical educators interested in exploring the FC teaching methodology. The authors identified an extensive list of papers relevant to FC pedagogy via online discussions within the Academic Life in Emergency Medicine (ALiEM) Faculty Incubator. This list was augmented by an open call on Twitter (utilizing the #meded, #FOAMed, and #flippedclassroom hashtags) yielding a list of 33 papers. We then conducted a three-round modified Delphi process within the authorship group, which included both junior and senior clinician educators, to identify the most impactful papers for educators interested in FC pedagogy. The three-round modified Delphi process ranked all of the selected papers and selected the five most highly-rated papers for inclusion. The authorship group reviewed and summarized these papers with specific consideration given to their value to junior faculty educators and faculty developers interested in the flipped classroom approach. The list of papers featured in this article serves as a key reading list for junior clinician educators and faculty developers interested in the flipped classroom technique. The associated commentaries contextualize the importance of these papers for medical educators aiming to optimize their understanding and implementation of the flipped classroom methodology in their teaching and through faculty development. PMID:29282445

What causes breast cancer? A systematic review of causal attributions among breast cancer survivors and how these compare to expert-endorsed risk factors.

PubMed

Dumalaon-Canaria, Jo Anne; Hutchinson, Amanda D; Prichard, Ivanka; Wilson, Carlene

2014-07-01

The aim of this paper was to review published research that analyzed causal attributions for breast cancer among women previously diagnosed with breast cancer. These attributions were compared with risk factors identified by published scientific evidence in order to determine the level of agreement between cancer survivors' attributions and expert opinion. A comprehensive search for articles, published between 1982 and 2012, reporting studies on causal attributions for breast cancer among patients and survivors was undertaken. Of 5,135 potentially relevant articles, 22 studies met the inclusion criteria. Two additional articles were sourced from reference lists of included studies. Results indicated a consistent belief among survivors that their own breast cancer could be attributed to family history, environmental factors, stress, fate, or chance. Lifestyle factors were less frequently identified, despite expert health information highlighting the importance of these factors in controlling and modifying cancer risk. This review demonstrated that misperceptions about the contribution of modifiable lifestyle factors to the risk of breast cancer have remained largely unchanged over the past 30 years. The findings of this review indicate that beliefs about the causes of breast cancer among affected women are not always consistent with the judgement of experts. Breast cancer survivors did not regularly identify causal factors supported by expert consensus such as age, physical inactivity, breast density, alcohol consumption, and reproductive history. Further research examining psychological predictors of attributions and the impact of cancer prevention messages on adjustment and well-being of cancer survivors is warranted.

From miracle fruit to transgenic tomato: mass production of the taste-modifying protein miraculin in transgenic plants.

PubMed

Hiwasa-Tanase, Kyoko; Hirai, Tadayoshi; Kato, Kazuhisa; Duhita, Narendra; Ezura, Hiroshi

2012-03-01

The utility of plants as biofactories has progressed in recent years. Some recombinant plant-derived pharmaceutical products have already reached the marketplace. However, with the exception of drugs and vaccines, a strong effort has not yet been made to bring recombinant products to market, as cost-effectiveness is critically important for commercialization. Sweet-tasting proteins and taste-modifying proteins have a great deal of potential in industry as substitutes for sugars and as artificial sweeteners. The taste-modifying protein, miraculin, functions to change the perception of a sour taste to a sweet one. This taste-modifying function can potentially be used not only as a low-calorie sweetener but also as a new seasoning that could be the basis of a new dietary lifestyle. However, miraculin is far from inexpensive, and its potential as a marketable product has not yet been fully developed. For the last several years, biotechnological production of this taste-modifying protein has progressed extensively. In this review, the characteristics of miraculin and recent advances in its production using transgenic plants are summarized, focusing on such topics as the suitability of plant species as expression hosts, the cultivation method for transgenic plants, the method of purifying miraculin and future advances required to achieve industrial use.

Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium.

PubMed

Janićijević, Jelena; Krajišnik, Danina; Čalija, Bojan; Vasiljević, Bojana Nedić; Dobričić, Vladimir; Daković, Aleksandra; Antonijević, Milan D; Milić, Jela

2015-12-30

Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (∼373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drug's XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier. Copyright © 2015 Elsevier B.V. All rights reserved.

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy.

PubMed

Bedoya, Felipe; Frigault, Matthew J; Maus, Marcela V

2017-02-01

Autologous T cells modified to recognize novel antigen targets are a novel form of therapy for cancer. We review the various potential forms of observed and hypothetical toxicities associated with genetically modified T cells. Despite the focus on toxicities in this review, re-directed T cells represent a powerful and highly effective form of anti-cancer therapy; we remain optimistic that the common toxicities will become routinely manageable and that some theoretical toxicity will be exceedingly rare, if ever observed. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Pseudospin symmetry for modified Rosen-Morse potential including a Pekeris-type approximation to the pseudo-centrifugal term

NASA Astrophysics Data System (ADS)

Wei, Gao-Feng; Dong, Shi-Hai

2010-11-01

By applying a Pekeris-type approximation to the pseudo-centrifugal term, we study the pseudospin symmetry of a Dirac nucleon subjected to scalar and vector modified Rosen-Morse (MRM) potentials. A complicated quartic energy equation and spinor wave functions with arbitrary spin-orbit coupling quantum number k are presented. The pseudospin degeneracy is checked numerically. Pseudospin symmetry is discussed theoretically and numerically in the limit case α rightarrow 0 . It is found that the relativistic MRM potential cannot trap a Dirac nucleon in this limit.

Gout: a review of non-modifiable and modifiable risk factors

PubMed Central

MacFarlane, Lindsey A.; Kim, Seoyoung C.

2014-01-01

Gout is a common inflammatory arthritis triggered by the crystallization of uric acid within the joints. Gout affects millions worldwide and has an increasing prevalence. Recent research has been carried out to better qualify and quantify the risk factors predisposing individuals to gout. These can largely be broken into non-modifiable risk factors such as sex, age, race, and genetics, and modifiable risk factors such as diet and lifestyle. Increasing knowledge of factors predisposing certain individuals to gout could potentially lead to improved preventive practices. This review summarizes the non-modifiable and modifiable risk factors associated with development of gout. PMID:25437279

Aspects of the Fracture Toughness of Carbon Nanotube Modified Epoxy Polymer Composites

NASA Astrophysics Data System (ADS)

Mirjalili, Vahid

Epoxy resins used in fibre reinforced composites exhibit a brittle fracture behaviour, because they show no sign of damage prior to a catastrophic failure. Rubbery materials and micro-particles have been added to epoxy resins to improve their fracture toughness, which reduces strength and elastic properties. In this research, carbon nanotubes (CNTs) are investigated as a potential toughening agent for epoxy resins and carbon fibre reinforced composites, which can also enhance strength and elastic properties. More specifically, the toughening mechanisms of CNTs are investigated theoretically and experimentally. The effect of aligned and randomly oriented carbon nanotubes (CNTs) on the fracture toughness of polymers was modelled using Elastic Plastic Fracture Mechanics. Toughening from CNT pull-out and rupture were considered, depending on the CNTs critical length. The model was used to identify the effect of CNTs geometrical and mechanical properties on the fracture toughness of CNT-modified epoxies. The modelling results showed that a uniform dispersion and alignment of a high volume fraction of CNTs normal to the crack growth plane would lead to the maximum fracture toughness enhancement. To achieve a uniform dispersion, the effect of processing on the dispersion of single walled and multi walled CNTs in epoxy resins was investigated. An instrumented optical microscope with a hot stage was used to quantify the evolution of the CNT dispersion during cure. The results showed that the reduction of the resin viscosity at temperatures greater than 100 °C caused an irreversible re-agglomeration of the CNTs in the matrix. The dispersion quality was then directly correlated to the fracture toughness of the modified resin. It was shown that the fine tuning of the ratio of epoxy resin, curing agent and CNT content was paramount to the improvement of the base resin fracture toughness. For the epoxy resin (MY0510 from Hexcel), an improvement of 38% was achieved with 0.3 wt.% of Single Walled CNT (SWNT). Finally, the CNT-modified epoxy resin was used to manufacture carbon fibre laminates by resin film infusion and prepreg technologies. The Mode I and Mode II delamination properties of the CNT-modified composite increased by 140% and 127%, respectively. In contrast, this improvement was not observed for the base CNT-modified polymers, used to manufacture the composite laminates. A qualitative analysis of the fractured surface using a Scanning Electron Microscope revealed a good dispersion in the composites samples, confirming the importance of processing to harness the full potential of carbon nanotubes for toughening polymer composites.

Fitness trade-offs modify community composition under contrasting disturbance regimes in Pseudomonas fluorescens microcosms.

PubMed

Engelmoer, Daniel J P; Rozen, Daniel E

2009-11-01

Disturbance is thought to be a major factor influencing patterns of biodiversity. In addition, disturbance can modify community composition if there are species specific trade-offs between fitness and disturbance tolerance. Here, we examine the role of disturbance on the evolution of coexisting biofilm-forming morphotypes of Pseudomonas fluorescens maintained in spatially structured laboratory microcosms. We identified four heritably stable ecotypes that varied significantly in their competitiveness under different disturbance treatments. Furthermore, we identified significant trade-offs in competitiveness across disturbance treatments for three of four of these ecotypes. These trade-offs modified dominance relationships between strains and thus altered community composition, with a peak of ecotype diversity occurring at intermediate disturbance frequencies.

Detection of polymer modifiers in asphalt binder.

DOT National Transportation Integrated Search

2006-01-01

This study addressed the evaluation of alternative test methods to identify the presence of polymer modifiers in performance-graded binders for the purpose of quality assurance. A method of identification is presented in AASHTO T302, Polymer Content ...

Cloning of a long HIV-1 readthrough transcript and detection of an increased level of early growth response protein-1 (Egr-1) mRNA in chronically infected U937 cells.

PubMed

Dron, M; Hameau, L; Benboudjema, L; Guymarho, J; Cajean-Feroldi, C; Rizza, P; Godard, C; Jasmin, C; Tovey, M G; Lang, M C

1999-01-01

To identify the pathways involved in HIV-1 modification of cellular gene expression, chronically infected U937 cells were screened by mRNA differential display. A chimeric transcript consisting of the 3' end of the LTR of a HIV-1 provirus, followed by 3.7 kb of cellular RNA was identified suggesting that long readthrough transcription might be one of the mechanisms by which gene expression could be modified in individual infected cells. Such a phenomenon may also be the first step towards the potential transduction of cellular sequences. Furthermore, the mRNA encoding for the transcription factor Egr-1 was detected as an over-represented transcript in infected cells. Northern blot analysis confirmed the increase of Egr-1 mRNA content in both HIV-1 infected promonocytic U937 cells and T cell lines such as Jurkat and CEM. Interestingly a similar increase of Egr-1 mRNA has previously been reported to occur in HTLV-1 and HTLV-2 infected T cell lines. Despite the consistent increase in the level of Egr-1 mRNA, the amount of the encoded protein did not appear to be modified in HIV-1 infected cells, suggesting an increased turn over of the protein in chronically infected cells.

The human embryonic stem cell proteome revealed by multidimensional fractionation followed by tandem mass spectrometry

PubMed Central

Zhao, Peng; Schulz, Thomas C.; Sherrer, Eric S.; Weatherly, D. Brent; Robins, Allan J.; Wells, Lance

2015-01-01

Human embryonic stem cells (hESCs) have received considerable attention due to their therapeutic potential and usefulness in understanding early development and cell fate commitment. In order to appreciate the unique properties of these pluripotent, self-renewing cells, we have performed an in-depth multidimensional fractionation followed by LC-MS/MS analysis of the hESCs harvested from defined media to elucidate expressed, phosphorylated, O-linked β-N-acetylglucosamine (O-GlcNAc) modified, and secreted proteins. From the triplicate analysis, we were able to assign more than 3000 proteins with less than 1% false-discovery rate. This analysis also allowed us to identify nearly 500 phosphorylation sites and 68 sites of O-GlcNAc modification with the same high confidence. Investigation of the phosphorylation sites allowed us to deduce the set of kinases that are likely active in these cells. We also identified more than 100 secreted proteins of hESCs that likely play a role in extracellular matrix formation and remodeling, as well as autocrine signaling for self-renewal and maintenance of the undifferentiated state. Finally, by performing in-depth analysis in triplicate, spectral counts were obtained for these proteins and posttranslationally modified peptides, which will allow us to perform relative quantitative analysis between these cells and any derived cell type in the future. PMID:25367160

Evaluation of modified crystal violet chromoendoscopy procedure using new mucosal pit pattern classification for detection of Barrett's dysplastic lesions.

PubMed

Yuki, T; Amano, Y; Kushiyama, Y; Takahashi, Y; Ose, T; Moriyama, I; Fukuhara, H; Ishimura, N; Koshino, K; Furuta, K; Ishihara, S; Adachi, K; Kinoshita, Y

2006-05-01

Pit pattern diagnosis is important for endoscopic detection of dysplastic Barrett's lesions, though using magnification endoscopy can be difficult and laborious. We investigated the usefulness of a modified crystal violet chromoendoscopy procedure and utilised a new pit pattern classification for diagnosis of dysplastic Barrett's lesions. A total of 1,030 patients suspected of having a columnar lined oesophagus were examined, of whom 816 demonstrated a crystal violet-stained columnar lined oesophagus. The early group of patients underwent 0.05% crystal violet chromoendoscopy, while the later group was examined using 0.03% crystal violet with 3.0% acetate. A targeted biopsy of the columnar lined oesophagus was performed using crystal violet staining after making a diagnosis of closed or open type pit pattern with a newly proposed system of classification. The relationship between type of pit pattern and histologically identified dysplastic Barrett's lesions was evaluated. Dysplastic Barrett's lesions were identified in biopsy samples with an open type pit pattern with a sensitivity of 96.0%. Further, Barrett's mucosa with the intestinal predominant mucin phenotype was closely associated with the open type pit pattern (sensitivity 81.9%, specificity 95.6%). The new pit pattern classification for diagnosis of Barrett's mucosa was found to be useful for identification of cases with dysplastic lesions and possible malignant potential using a crystal violet chromoendoscopic procedure.

Growth potential of blue mussels (M. edulis) exposed to different salinities evaluated by a Dynamic Energy Budget model

NASA Astrophysics Data System (ADS)

Maar, Marie; Saurel, Camille; Landes, Anja; Dolmer, Per; Petersen, Jens Kjerulf

2015-08-01

For blue mussels, Mytilus edulis, one major constrain in the Baltic Sea is the low salinities that reduce the efficiency of mussel production. However, the effects of living in low and variable salinity regimes are rarely considered in models describing mussel growth. The aim of the present study was to incorporate the effects of low salinity into an eco-physiological model of blue mussels and to identify areas suitable for mussel production. A Dynamic Energy Budget (DEB) model was modified with respect to i) the morphological parameters (DW/WW-ratio, shape factor), ii) change in ingestion rate and iii) metabolic costs due to osmoregulation in different salinity environments. The modified DEB model was validated with experimental data from different locations in the Western Baltic Sea (including the Limfjorden) with salinities varying from 8.5 to 29.9 psu. The identified areas suitable for mussel production in the Baltic Sea are located in the Little Belt area, the Great Belt, the southern Kattegat and the Limfjorden according to the prevailing salinity regimes. The new model can be used for supporting site selection of new mussel nutrient extraction cultures in the Baltic Sea that suffers from high eutrophication symptoms or as part of integrated multi-trophic aquaculture production. The model can also be used to predict the effects of salinity changes on mussel populations e.g. in climate change studies.

DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders.

PubMed

Ryan, Niamh M; Lihm, Jayon; Kramer, Melissa; McCarthy, Shane; Morris, Stewart W; Arnau-Soler, Aleix; Davies, Gail; Duff, Barbara; Ghiban, Elena; Hayward, Caroline; Deary, Ian J; Blackwood, Douglas H R; Lawrie, Stephen M; McIntosh, Andrew M; Evans, Kathryn L; Porteous, David J; McCombie, W Richard; Thomson, Pippa A

2018-06-07

Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.

Integrating Health Promotion Into Physical Therapy Practice to Improve Brain Health and Prevent Alzheimer Disease.

PubMed

McGough, Ellen; Kirk-Sanchez, Neva; Liu-Ambrose, Teresa

2017-07-01

Alzheimer disease is the most common cause of dementia, and brain pathology appears years before symptoms are evident. Primary prevention through health promotion can incorporate lifestyle improvement across the lifespan. Risk factor assessment and identifying markers of disease might also trigger preventive measures needed for high-risk individuals and groups. Many potential risk factors are modifiable through exercise, and may be responsive to early intervention strategies to reduce the downward slope toward disability. Through the use of common clinical tests to identify cognitive and noncognitive functional markers of disease, detection and intervention can occur at earlier stages, including preclinical stages of disease. Physical activity and exercise interventions to address modifiable risk factors and impairments can play a pivotal role in the prevention and delay of functional decline, ultimately reducing the incidence of dementia. This article discusses prevention, prediction, plasticity, and participation in the context of preserving brain health and preventing Alzheimer disease and related dementias in aging adults. Rehabilitation professionals have opportunities to slow disease progression through research, practice, and education initiatives. From a clinical perspective, interventions that target brain health through lifestyle changes and exercise interventions show promise for preventing stroke and associated neurovascular diseases in addition to dementia. Physical therapists are well positioned to integrate primary health promotion into practice for the prevention of dementia and other neurological conditions in older adults.

Epigenetic regulation of miR-200 as the potential strategy for the therapy against triple-negative breast cancer.

PubMed

Mekala, Janaki Ramaiah; Naushad, Shaik Mohammad; Ponnusamy, Lavanya; Arivazhagan, Gayatri; Sakthiprasad, Vaishnave; Pal-Bhadra, Manika

2018-01-30

MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are involved in the regulation of gene expression at the post-transcriptional level. MicroRNAs play an important role in cancer cell proliferation, survival and apoptosis. Epigenetic modifiers regulate the microRNA expression. Among the epigenetic players, histone deacetylases (HDACs) function as the key regulators of microRNA expression. Epigenetic machineries such as DNA and histone modifying enzymes and various microRNAs have been identified as the important contributors in cancer initiation and progression. Recent studies have shown that developing innovative microRNA-targeting therapies might improve the human health, specifically against the disease areas of high unmet medical need. Thus microRNA based therapeutics are gaining importance for anti-cancer therapy. Studies on Triple negative breast cancer (TNBC) have revealed the early relapse and poor overall survival of patients which needs immediate therapeutic attention. In this report, we focus the effect of HDAC inhibitors on TNBC cell proliferation, regulation of microRNA gene expression by a series of HDAC genes, chromatin epigenetics, epigenetic remodelling at miR-200 promoter and its modulation by various HDACs. We also discuss the need for identifying novel HDAC inhibitors for modulation of miR-200 in triple negative breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

A modified receptor model for source apportionment of heavy metal pollution in soil.

PubMed

Huang, Ying; Deng, Meihua; Wu, Shaofu; Japenga, Jan; Li, Tingqiang; Yang, Xiaoe; He, Zhenli

2018-07-15

Source apportionment is a crucial step toward reduction of heavy metal pollution in soil. Existing methods are generally based on receptor models. However, overestimation or underestimation occurs when they are applied to heavy metal source apportionment in soil. Therefore, a modified model (PCA-MLRD) was developed, which is based on principal component analysis (PCA) and multiple linear regression with distance (MLRD). This model was applied to a case study conducted in a peri-urban area in southeast China where soils were contaminated by arsenic (As), cadmium (Cd), mercury (Hg) and lead (Pb). Compared with existing models, PCA-MLRD is able to identify specific sources and quantify the extent of influence for each emission. The zinc (Zn)-Pb mine was identified as the most important anthropogenic emission, which affected approximately half area for Pb and As accumulation, and approximately one third for Cd. Overall, the influence extent of the anthropogenic emissions decreased in the order of mine (3 km) > dyeing mill (2 km) ≈ industrial hub (2 km) > fluorescent factory (1.5 km) > road (0.5 km). Although algorithm still needs to improved, the PCA-MLRD model has the potential to become a useful tool for heavy metal source apportionment in soil. Copyright © 2018 Elsevier B.V. All rights reserved.

A distributed national network for label-free rapid identification of emerging pathogens

NASA Astrophysics Data System (ADS)

Robinson, J. Paul; Rajwa, Bartek P.; Dundar, M. Murat; Bae, Euiwon; Patsekin, Valery; Hirleman, E. Daniel; Roumani, Ali; Bhunia, Arun K.; Dietz, J. Eric; Davisson, V. Jo; Thomas, John G.

2011-05-01

Typical bioterrorism prevention scenarios assume well-known and well-characterized pathogens like anthrax or tularemia, which are serious public concerns if released into food and/or water supplies or distributed using other vectors. Common governmental contingencies include rapid response to these biological threats with predefined treatments and management operations. However, bioterrorist attacks may follow a far more sophisticated route. With the widely known and immense progress in genetics and the availability of molecular biology tools worldwide, the potential for malicious modification of pathogenic genomes is very high. Common non-pathogenic microorganisms could be transformed into dangerous, debilitating pathogens. Known pathogens could also be modified to avoid detection, because organisms are traditionally identified on the basis of their known physiological or genetic properties. In the absence of defined primers a laboratory using genetic biodetection methods such as PCR might be unable to quickly identify a modified microorganism. Our concept includes developing a nationwide database of signatures based on biophysical (such as elastic light scattering (ELS) properties and/or Raman spectra) rather than genetic properties of bacteria. When paired with a machine-learning system for emerging pathogen detection these data become an effective detection system. The approach emphasizes ease of implementation using a standardized collection of phenotypic information and extraction of biophysical features of pathogens. Owing to the label-free nature of the detection modalities ELS is significantly less costly than any genotypic or mass spectrometry approach.

Uncovering potential anti-neuroinflammatory components of Modified Wuziyanzong Prescription through a target-directed molecular docking fingerprint strategy.

PubMed

Chen, Jinfeng; Wang, Jinlong; Lu, Yingyuan; Zhao, Shaoyang; Yu, Qian; Wang, Xuemei; Tu, Pengfei; Zeng, Kewu; Jiang, Yong

2018-05-01

Neuroinflammation is a main factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease. Our previous studies indicated that the modified Wuziyanzong Prescription (MWP) can suppress neuroinflammatory responses via nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. However, the anti-neuroinflammatory components of MWP remain unclear. Herein, a target-directed molecular docking fingerprint (TMDF) strategy, via integrating the chemical profiling and molecular docking approaches, was developed to identify the potential anti-neuroinflammatory components of MWP. First, as many as 120 possible structures, including 49 flavonoids, 28 phenylpropionic acids, 18 amides, 10 carotenoids, eight phenylethanoid glycosides, four lignans, two iridoids, and one triterpenoid were deduced by the source attribution and structural classification-assisted strategy. Then, their geometries were docked against five major targets of the NF-κB and MAPKs signaling cascades, including p38-α, IKKβ, ERK1, ERK2, and TRAF6. The docking results revealed diverse contributions of different components towards the protein targets. Collectively, prenylated flavonoids showed intensive or moderate anti-neuroinflammatory activities, while phenylpropanoids, amides, phenylethanoid glycosides, lignans, and triterpenoids exhibited moderate or weak anti-neuroinflammatory effects. The anti-neuroinflammatory activities of four retrieved prenylated flavonoids were tested by Western blotting assay, and the results mostly agreed with those predicted by the docking method. These gained information demonstrates that the established TMDF strategy could be a rapid and feasible methodology to investigate the potential active components in herbal compound prescriptions. Copyright © 2018 Elsevier B.V. All rights reserved.

Prognostic factors for chronic headache

PubMed Central

Bowers, Hannah; Caldwell, Fiona; Mistry, Dipesh; Underwood, Martin; Matharu, Manjit; Pincus, Tamar

2017-01-01

Objective: To identify predictors of prognosis and trial outcomes in prospective studies of people with chronic headache. Methods: This was a systematic review of published literature in peer-reviewed journals. We included (1) randomized controlled trials (RCTs) of interventions for chronic headache that reported subgroup analyses and (2) prospective cohort studies, published in English, since 1980. Participants included adults with chronic headache (including chronic headache, chronic migraine, and chronic tension-type headache with or without medication overuse headache). We searched key databases using free text and MeSH terms. Two reviewers independently extracted data and assessed the methodologic quality of studies and overall quality of evidence identified using appropriate published checklists. Results: We identified 16,556 titles, removed 663 duplicates, and reviewed 199 articles, of which 27 were included in the review—17 prospective cohorts and 10 RCTs with subgroup analyses reported. There was moderate-quality evidence indicating that depression, anxiety, poor sleep and stress, medication overuse, and poor self-efficacy for managing headaches are potential prognostic factors for poor prognosis and unfavorable outcomes from preventive treatment in chronic headache. There was inconclusive evidence about treatment expectations, age, age at onset, body mass index, employment, and several headache features. Conclusions: This review identified several potential predictors of poor prognosis and worse outcome postinterventions in people with chronic headache. The majority of these are modifiable. The findings also highlight the need for more longitudinal high-quality research of prognostic factors in chronic headache. PMID:28615422

Use of modeling to identify vulnerabilities to human error in laparoscopy.

PubMed

Funk, Kenneth H; Bauer, James D; Doolen, Toni L; Telasha, David; Nicolalde, R Javier; Reeber, Miriam; Yodpijit, Nantakrit; Long, Myra

2010-01-01

This article describes an exercise to investigate the utility of modeling and human factors analysis in understanding surgical processes and their vulnerabilities to medical error. A formal method to identify error vulnerabilities was developed and applied to a test case of Veress needle insertion during closed laparoscopy. A team of 2 surgeons, a medical assistant, and 3 engineers used hierarchical task analysis and Integrated DEFinition language 0 (IDEF0) modeling to create rich models of the processes used in initial port creation. Using terminology from a standardized human performance database, detailed task descriptions were written for 4 tasks executed in the process of inserting the Veress needle. Key terms from the descriptions were used to extract from the database generic errors that could occur. Task descriptions with potential errors were translated back into surgical terminology. Referring to the process models and task descriptions, the team used a modified failure modes and effects analysis (FMEA) to consider each potential error for its probability of occurrence, its consequences if it should occur and be undetected, and its probability of detection. The resulting likely and consequential errors were prioritized for intervention. A literature-based validation study confirmed the significance of the top error vulnerabilities identified using the method. Ongoing work includes design and evaluation of procedures to correct the identified vulnerabilities and improvements to the modeling and vulnerability identification methods. Copyright 2010 AAGL. Published by Elsevier Inc. All rights reserved.

Molecular diagnostics in the management of rhabdomyosarcoma.

PubMed

Arnold, Michael A; Barr, Fredric G

2017-02-01

A classification of rhabdomyosarcoma (RMS) with prognostic relevance has primarily relied on clinical features and histologic classification as either embryonal or alveolar RMS. The PAX3-FOXO1 and PAX7-FOXO1 gene fusions occur in 80% of cases with the alveolar subtype and are more predictive of outcome than histologic classification. Identifying additional molecular hallmarks that further subclassify RMS is an active area of research. Areas Covered: The authors review the current state of the PAX3-FOXO1 and PAX7-FOXO1 fusions as prognostic biomarkers. Emerging biomarkers, including mRNA expression profiling, MYOD1 mutations, RAS pathway mutations and gene fusions involving NCOA2 or VGLL2 are also reviewed. Expert commentary: Strategies for modifying RMS risk stratification based on molecular biomarkers are emerging with the potential to transform the clinical management of RMS, ultimately improving patient outcomes by tailoring therapy to predicted patient risk and identifying targets for novel therapies.

An Extensive Study on Data Anonymization Algorithms Based on K-Anonymity

NASA Astrophysics Data System (ADS)

Simi, Ms. M. S.; Sankara Nayaki, Mrs. K.; Sudheep Elayidom, M., Dr.

2017-08-01

For business and research oriented works engaging Data Analysis and Cloud services needing qualitative data, many organizations release huge microdata. It excludes an individual’s explicit identity marks like name, address and comprises of specific information like DOB, Pin-code, sex, marital status, which can be combined with other public data to recognize a person. This implication attack can be manipulated to acquire any sensitive information from social network platform, thereby putting the privacy of a person in grave danger. To prevent such attacks by modifying microdata, K-anonymization is used. With potentially increasing data, the effective method to anonymize it stands challenging. After series of trails and systematic comparison, in this paper, we propose three best algorithms along with its efficiency and effectiveness. Studies help researchers to identify the relationship between the values of k, degree of anonymization, choosing a quasi-identifier and focus on execution time.

Academic Achievement in Children With Oral Clefts Versus Unaffected Siblings

PubMed Central

Wehby, George L.; Barron, Sheila; Romitti, Paul A.; Ansley, Timothy N.; Speltz, Matthew L.

2014-01-01

Objective To compare academic achievement in children with oral-facial clefts (OFC) with their unaffected siblings. Methods 256 children with OFC were identified from the Iowa Registry for Congenital and Inherited Disorders, and 387 unaffected siblings were identified from birth certificates. These data were linked to Iowa Testing Programs achievement data. We compared academic achievement in children with OFC with their unaffected siblings using linear regression models, adjusted for potential confounders. In post hoc analyses, we explored modifiers of siblings’ academic performance. Results Achievement scores were similar between children with OFC and their siblings. Children with cleft palate only were significantly more likely to use special education than their unaffected siblings. Siblings’ academic achievement was inversely related to distance in birth order and age from the affected child. Conclusion Children with OFC and their siblings received similar achievement scores. Younger siblings, in particular, may share a vulnerability to poor academic outcomes. PMID:24993102

Profiling the Serum Protein Corona of Fibrillar Human Islet Amyloid Polypeptide.

PubMed

Pilkington, Emily H; Gustafsson, Ove J R; Xing, Yanting; Hernandez-Fernaud, Juan; Zampronio, Cleidi; Kakinen, Aleksandr; Faridi, Ava; Ding, Feng; Wilson, Paul; Ke, Pu Chun; Davis, Thomas P

2018-05-16

Amyloids may be regarded as native nanomaterials that form in the presence of complex protein mixtures. By drawing an analogy with the physicochemical properties of nanoparticles in biological fluids, we hypothesized that amyloids should form a protein corona in vivo that would imbue the underlying amyloid with a modified biological identity. To explore this hypothesis, we characterized the protein corona of human islet amyloid polypeptide (IAPP) fibrils in fetal bovine serum using two complementary methodologies developed herein: quartz crystal microbalance and "centrifugal capture", coupled with nanoliquid chromatography tandem mass spectroscopy. Clear evidence for a significant protein corona was obtained. No trends were identified for amyloid corona proteins based on their physicochemical properties, whereas strong binding with IAPP fibrils occurred for linear proteins or multidomain proteins with structural plasticity. Proteomic analysis identified amyloid-enriched proteins that are known to play significant roles in mediating cellular machinery and processing, potentially leading to pathological outcomes and therapeutic targets.

Detection and molecular identification of Cryptosporidium species in laboratory rats (Rattus norvegicus) in Ibadan, Nigeria

PubMed

Ayinmode, Adekunle Bamidele; Ogbonna, Nkeiruka Fortunate; Widmer, Giovanni

To study the occurrence of Cryptosporidium infection in laboratory rats (Rattus norvegicus) raised for experimental usage, 134 faecal samples were obtained from two rearing houses in Ibadan and examined for the presence of Cryptosporidium oocyst using the modified acid fast staining technique. Cryptosporidium species in 2 samples positive for microscopy were further characterized by a nested polymerase chain reaction (PCR) amplifying the 18S rRNA gene. Two of 134 samples were positive for the Cryptosporidium oocysts. Sequencing of the small-subunit rRNA amplicons identified the species in the two PCR positive samples as Cryptosporidium andersoni and Cryptosporidium rat genotype. These findings showed that laboratory rat is a potential reservoir for diverse Cryptosporidium species and suggests that laboratory rats should be screened for Cryptosporidium infection prior to experiments, especially where pathogen free animals are not available. This the first report to identify Cryptosporidium species infecting laboratory rats in Nigeria.

RNA editing in Drosophila melanogaster: new targets and functionalconsequences

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

Stapleton, Mark; Carlson, Joseph W.; Celniker, Susan E.

2006-09-05

Adenosine deaminases that act on RNA (ADARs) catalyze the site-specific conversion of adenosine to inosine in primary mRNA transcripts. These re-coding events affect coding potential, splice-sites, and stability of mature mRNAs. ADAR is an essential gene and studies in mouse, C. elegans, and Drosophila suggest its primary function is to modify adult behavior by altering signaling components in the nervous system. By comparing the sequence of isogenic cDNAs to genomic DNA, we have identified and experimentally verified 27 new targets of Drosophila ADAR. Our analyses lead us to identify new classes of genes whose transcripts are targets of ADAR includingmore » components of the actin cytoskeleton, and genes involved in ion homeostasis and signal transduction. Our results indicate that editing in Drosophila increases the diversity of the proteome, and does so in a manner that has direct functional consequences on protein function.« less

Safety Challenges and Improvement Strategies of Ethnic Minority Construction Workers: A Case Study in Hong Kong.

PubMed

Wu, Chunlin; Luo, Xiaowei; Wang, Tao; Wang, Yue; Sapkota, Bibek

2018-04-18

Due to cultural differences, ethnic minority construction workers are more difficult to manage and more vulnerable to accidents. This study aims to identify the major barriers faced by ethnic minority workers from their own perspectives and determine potential strategies to enhance safety climate of construction projects, thus ultimately improve their safety performance. A survey with modified Nordic safety climate questionnaire was conducted in a certain sub-contractor in Hong Kong. In-depth interviews, status quo description, major challenge investigation and safety knowledge tests were carried as well. The top three most important safety challenges identified are improper stereotypes from the whole industry, lack of opportunities for job assignment, and language barriers. To improve the safety performance, employers should allocate sufficient personal protective equipment and governments should organize unannounced site visits more frequently. Besides, the higher-level management should avoid giving contradictory instructions to foremen against to the standards of supervisors.

Wildlife disease prevalence in human-modified landscapes.

PubMed

Brearley, Grant; Rhodes, Jonathan; Bradley, Adrian; Baxter, Greg; Seabrook, Leonie; Lunney, Daniel; Liu, Yan; McAlpine, Clive

2013-05-01

Human-induced landscape change associated with habitat loss and fragmentation places wildlife populations at risk. One issue in these landscapes is a change in the prevalence of disease which may result in increased mortality and reduced fecundity. Our understanding of the influence of habitat loss and fragmentation on the prevalence of wildlife diseases is still in its infancy. What is evident is that changes in disease prevalence as a result of human-induced landscape modification are highly variable. The importance of infectious diseases for the conservation of wildlife will increase as the amount and quality of suitable habitat decreases due to human land-use pressures. We review the experimental and observational literature of the influence of human-induced landscape change on wildlife disease prevalence, and discuss disease transmission types and host responses as mechanisms that are likely to determine the extent of change in disease prevalence. It is likely that transmission dynamics will be the key process in determining a pathogen's impact on a host population, while the host response may ultimately determine the extent of disease prevalence. Finally, we conceptualize mechanisms and identify future research directions to increase our understanding of the relationship between human-modified landscapes and wildlife disease prevalence. This review highlights that there are rarely consistent relationships between wildlife diseases and human-modified landscapes. In addition, variation is evident between transmission types and landscape types, with the greatest positive influence on disease prevalence being in urban landscapes and directly transmitted disease systems. While we have a limited understanding of the potential influence of habitat loss and fragmentation on wildlife disease, there are a number of important areas to address in future research, particularly to account for the variability in increased and decreased disease prevalence. Previous studies have been based on a one-dimensional comparison between unmodified and modified sites. What is lacking are spatially and temporally explicit quantitative approaches which are required to enable an understanding of the range of key causal mechanisms and the reasons for variability. This is particularly important for replicated studies across different host-pathogen systems. Furthermore, there are few studies that have attempted to separate the independent effects of habitat loss and fragmentation on wildlife disease, which are the major determinants of wildlife population dynamics in human-modified landscapes. There is an urgent need to understand better the potential causal links between the processes of human-induced landscape change and the associated influences of habitat fragmentation, matrix hostility and loss of connectivity on an animal's physiological stress, immune response and disease susceptibility. This review identified no study that had assessed the influence of human-induced landscape change on the prevalence of a wildlife sexually transmitted disease. A better understanding of the various mechanisms linking human-induced landscape change and the prevalence of wildlife disease will lead to more successful conservation management outcomes. © 2012 The Authors. Biological Reviews © 2012 Cambridge Philosophical Society.

Synthesis and application of a triazene-ferrocene modifier for immobilization and characterization of oligonucleotides at electrodes.

PubMed

Hansen, Majken N; Farjami, Elaheh; Kristiansen, Martin; Clima, Lilia; Pedersen, Steen Uttrup; Daasbjerg, Kim; Ferapontova, Elena E; Gothelf, Kurt V

2010-04-16

A new DNA modifier containing triazene, ferrocene, and activated ester functionalities was synthesized and applied for electrochemical grafting and characterization of DNA at glassy carbon (GC) and gold electrodes. The modifier was synthesized from ferrocenecarboxylic acid by attaching a phenyltriazene derivative to one of the ferrocene Cp rings, while the other Cp ring containing the carboxylic acid was converted to an activated ester. The modifier was conjugated to an amine-modified DNA sequence. For immobilization of the conjugate at Au or GC electrodes, the triazene was activated by dimethyl sulfate for release of the diazonium salt. The salt was reductively converted to the aryl radical which was readily immobilized at the surface. DNA grafted onto electrodes exhibited remarkable hybridization properties, as detected through a reversible shift in the redox potential of the Fc redox label upon repeated hybridization/denaturation procedures with a complementary target DNA sequence. By using a methylene blue (MB) labeled target DNA sequence the hybridization could also be followed through the MB redox potential. Electrochemical studies demonstrated that grafting through the triazene modifier can successfully compete with existing protocols for DNA immobilization through the commonly used alkanethiol linkers and diazonium salts. Furthermore, the triazene modifier provides a practical one-step immobilization procedure.

Mimosa: Mixture Model of Co-expression to Detect Modulators of Regulatory Interaction

NASA Astrophysics Data System (ADS)

Hansen, Matthew; Everett, Logan; Singh, Larry; Hannenhalli, Sridhar

Functionally related genes tend to be correlated in their expression patterns across multiple conditions and/or tissue-types. Thus co-expression networks are often used to investigate functional groups of genes. In particular, when one of the genes is a transcription factor (TF), the co-expression-based interaction is interpreted, with caution, as a direct regulatory interaction. However, any particular TF, and more importantly, any particular regulatory interaction, is likely to be active only in a subset of experimental conditions. Moreover, the subset of expression samples where the regulatory interaction holds may be marked by presence or absence of a modifier gene, such as an enzyme that post-translationally modifies the TF. Such subtlety of regulatory interactions is overlooked when one computes an overall expression correlation. Here we present a novel mixture modeling approach where a TF-Gene pair is presumed to be significantly correlated (with unknown coefficient) in a (unknown) subset of expression samples. The parameters of the model are estimated using a Maximum Likelihood approach. The estimated mixture of expression samples is then mined to identify genes potentially modulating the TF-Gene interaction. We have validated our approach using synthetic data and on three biological cases in cow and in yeast. While limited in some ways, as discussed, the work represents a novel approach to mine expression data and detect potential modulators of regulatory interactions.

Rat medium-term multi-organ carcinogenesis bioassay of Agaricus blazei Murrill fruit-body extract.

PubMed

Doi, Yuko; Furukawa, Fumio; Suguro, Mayuko; Ito, Hikaru; Imai, Norio; Nabae, Kyoko; Toda, Yosuke; Inatomi, Satoshi; Kinugasa, Satomi; Kobayashi, Hitoshi

2010-01-01

The modifying potential of Agaricus blazei Murrill fruit-body extract (ABFE) on tumor development was investigated in a medium-term multi-organ carcinogenesis bioassay. Male 6-week-old F344 rats were treated with N-nitrosodiethylamine (DEN), N-methyl-N-nitrosourea (MNU), 1,2-dimethylhydrazine dihydrochloride (DMH), N-butyl-N-(hydroxybutyl)-nitrosamine (BBN), and diisopropanolnitrosamine (DHPN) for initiation (DMBDD treatment). After a 1-week withdrawal period, the animals received distilled water (vehicle control) or ABFE A, gamma-amino butyric acid (GABA) at 0.8 mg/kg, ABFE B (GABA level of 3.0mg/kg) or ABFE C (GABA level of 12.0mg/kg) by gavage for 24 weeks. There were no effects of ABFE on survival rate, general condition, body weight, food and water consumption, and organ weights. The multiplicity of large intestinal nodules, smaller than 2mm was significantly increased in the ABFE C group with DMBDD treatment. However, there were no significantly inter-group differences in incidences of hyperplastic or neoplastic lesions in colon or other organs, or in immunohistochemically identified preneoplastic lesions in the liver. In conclusion, A. blazei Murrill fruit-body extract, even at a GABA level up to 12 mg/kg, did not exert modifying potential in the present medium-term multi-organ carcinogenesis bioassay in male F344 rats (DMBDD method). Copyright 2009 Elsevier Ltd. All rights reserved.

In situ characterization of N-carboxy anhydride polymerization in nanoporous anodic alumina.

PubMed

Lau, K H Aaron; Duran, Hatice; Knoll, Wolfgang

2009-03-12

Poly(gamma-benzyl-L-glutamate) (PBLG) has been a popular model polypeptide for a range of physicochemical studies, and its modifiable ester side chains make it an attractive platform for various potential applications. Thin films of Poly(gamma-benzyl-L-glutamate) PBLG were surface grafted within nanoporous anodic alumina (AAO) by surface-initiated polymerization of the N-carboxy anhydride of benzyl-L-glutamate (BLG-NCA). The grafting process was characterized by optical waveguide spectroscopy (OWS), infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). OWS was able to track the PBLG layer thickness increase in situ, and ex situ FT-IR gave complementary information on the PBLG chain's secondary structure. Transitions in the PBLG growth rate could be correlated with transitions in the polypeptide secondary structure. The emergence of a three-dimensional, anisotropic PBLG morphology within the cylindrical pores of the AAO membrane was also identified as the grafted PBLG average layer thickness increased. Comparison of the PBLG/AAO results with those on a planar silicon dioxide surface indicated that both the conformational transitions and the PBLG nanostructure development could be attributed to the confining geometry within the pores of the nanoporous AAO matrix. The use of a nanoporous AAO matrix, combined with the surface grafting of a thin film of PBLG chains with multiple modifiable side chains, could potentially offer a nanoporous platform with a very high density of functional sites.

The combined impact of social support and perceived stress on quality of life in adults with autism spectrum disorder and without intellectual disability.

PubMed

Bishop-Fitzpatrick, Lauren; Mazefsky, Carla A; Eack, Shaun M

2017-06-01

Identifying modifiable correlates of good quality of life in adults with autism spectrum disorder is of paramount importance for intervention development as the population of adults with autism spectrum disorder increases. This study sought to examine social support and perceived stress as potential modifiable correlates of quality of life in adults with autism spectrum disorder. We hypothesized that adults with autism spectrum disorder without co-occurring intellectual disabilities ( N = 40; aged 18-44 years) would report lower levels of social support and quality of life than typical community volunteers who were matched for age, sex, and race ( N = 25). We additionally hypothesized that social support would buffer the effect of perceived stress on quality of life in adults with autism spectrum disorder. Results indicated that adults with autism spectrum disorder reported significantly lower levels of social support and quality of life than matched typical community volunteers. In addition, findings showed significant direct effects of social support and perceived stress on quality of life in adults with autism spectrum disorder. Social support did not buffer the effect of perceived stress on quality of life. Interventions that teach adults with autism spectrum disorder skills to help them better manage stress and cultivate supportive social relationships have the potential to improve quality of life.

Fabrication of phosphonic acid films on nitinol nanoparticles by dynamic covalent assembly

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

Quinones, Rosalynn; Garretson, Samantha; Behnke, Grayce

Nitinol (NiTi) nanoparticles are a valuable metal alloy due to many unique properties that allow for medical applications. NiTi nanoparticles have the potential to form nanofluids, which can advance the thermal conductivity of fluids by controlling the surface functionalization through chemical attachment of organic acids to the surface to form self-assembled alkylphosphonate films. In this study, phosphonic functional head groups such as 16-phosphonohexadecanoic acid, octadecylphosphonic acid, and 12-aminododecylphosphonic acid were used to form an ordered and strongly chemically bounded film on the NiTi nanopowder. The surface of the NiTi nanoparticles was modified in order to tailor the chemical and physicalmore » properties to the desired application. The modified NiTi nanoparticles were characterized using infrared spectroscopy, powder X-ray diffraction, X-ray photoelectron spectroscopy, and 31P solid-state nuclear magnetic resonance. The interfacial bonding was identified by spectroscopic data suggesting the phosphonic head group adsorbs in a mixed bidentate/monodentate binding motif on the NiTi nanoparticles. Dynamic light scattering and scanning electron microscopy-energy dispersive X-ray spectroscopy revealed the particle sizes. Differential scanning calorimetry was used to examine the phase transitions. Zeta potential determination as a function of pH was examined to investigate the surface properties of charged nanoparticles. In conclusion, the influence of environmental stability of the surface modifications was also assessed.« less

Assessing environmental impacts of genetically modified plants on non-target organisms: The relevance of in planta studies.

PubMed

Arpaia, Salvatore; Birch, A Nicholas E; Kiss, Jozsef; van Loon, Joop J A; Messéan, Antoine; Nuti, Marco; Perry, Joe N; Sweet, Jeremy B; Tebbe, Christoph C

2017-04-01

In legal frameworks worldwide, genetically modified plants (GMPs) are subjected to pre-market environmental risk assessment (ERA) with the aim of identifying potential effects on the environment. In the European Union, the EFSA Guidance Document introduces the rationale that GMPs, as well as their newly produced metabolites, represent the potential stressor to be evaluated during ERA. As a consequence, during several phases of ERA for cultivation purposes, it is considered necessary to use whole plants or plant parts in experimental protocols. The importance of in planta studies as a strategy to address impacts of GMPs on non-target organisms is demonstrated, to evaluate both effects due to the intended modification in plant phenotype (e.g. expression of Cry proteins) and effects due to unintended modifications in plant phenotype resulting from the transformation process (e.g. due to somaclonal variations or pleiotropic effects). In planta tests are also necessary for GMPs in which newly expressed metabolites cannot easily be studied in vitro. This paper reviews the scientific literature supporting the choice of in planta studies as a fundamental tool in ERA of GMPs in cultivation dossiers; the evidence indicates they can realistically mimic the ecological relationships occurring in their receiving environments and provide important insights into the biology and sustainable management of GMPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Fabrication of phosphonic acid films on nitinol nanoparticles by dynamic covalent assembly

DOE PAGES

Quinones, Rosalynn; Garretson, Samantha; Behnke, Grayce; ...

2017-09-25

Nitinol (NiTi) nanoparticles are a valuable metal alloy due to many unique properties that allow for medical applications. NiTi nanoparticles have the potential to form nanofluids, which can advance the thermal conductivity of fluids by controlling the surface functionalization through chemical attachment of organic acids to the surface to form self-assembled alkylphosphonate films. In this study, phosphonic functional head groups such as 16-phosphonohexadecanoic acid, octadecylphosphonic acid, and 12-aminododecylphosphonic acid were used to form an ordered and strongly chemically bounded film on the NiTi nanopowder. The surface of the NiTi nanoparticles was modified in order to tailor the chemical and physicalmore » properties to the desired application. The modified NiTi nanoparticles were characterized using infrared spectroscopy, powder X-ray diffraction, X-ray photoelectron spectroscopy, and 31P solid-state nuclear magnetic resonance. The interfacial bonding was identified by spectroscopic data suggesting the phosphonic head group adsorbs in a mixed bidentate/monodentate binding motif on the NiTi nanoparticles. Dynamic light scattering and scanning electron microscopy-energy dispersive X-ray spectroscopy revealed the particle sizes. Differential scanning calorimetry was used to examine the phase transitions. Zeta potential determination as a function of pH was examined to investigate the surface properties of charged nanoparticles. In conclusion, the influence of environmental stability of the surface modifications was also assessed.« less

Applications of nutrient profiling: potential role in diet-related chronic disease prevention and the feasibility of a core nutrient-profiling system.

PubMed

Sacks, G; Rayner, M; Stockley, L; Scarborough, P; Snowdon, W; Swinburn, B

2011-03-01

A number of different nutrient-profiling models have been proposed and several applications of nutrient profiling have been identified. This paper outlines the potential role of nutrient-profiling applications in the prevention of diet-related chronic disease (DRCD), and considers the feasibility of a core nutrient-profiling system, which could be modified for purpose, to underpin the multiple potential applications in a particular country. The 'Four 'P's of Marketing' (Product, Promotion, Place and Price) are used as a framework for identifying and for classifying potential applications of nutrient profiling. A logic pathway is then presented that can be used to gauge the potential impact of nutrient-profiling interventions on changes in behaviour, changes in diet and, ultimately, changes in DRCD outcomes. The feasibility of a core nutrient-profiling system is assessed by examining the implications of different model design decisions and their suitability to different purposes. There is substantial scope to use nutrient profiling as part of the policies for the prevention of DRCD. A core nutrient-profiling system underpinning the various applications is likely to reduce discrepancies and minimise the confusion for regulators, manufacturers and consumers. It seems feasible that common elements, such as a standard scoring method, a core set of nutrients and food components, and defined food categories, could be incorporated as part of a core system, with additional application-specific criteria applying. However, in developing and in implementing such a system, several country-specific contextual and technical factors would need to be balanced.

Selective in situ potential-assisted SAM formation on multi electrode arrays

NASA Astrophysics Data System (ADS)

Haag, Ann-Lauriene; Toader, Violeta; Lennox, R. Bruce; Grutter, Peter

2016-11-01

The selective modification of individual components in a biosensor array is challenging. To address this challenge, we present a generalizable approach to selectively modify and characterize individual gold surfaces in an array, in an in situ manner. This is achieved by taking advantage of the potential dependent adsorption/desorption of surface-modified organic molecules. Control of the applied potential of the individual sensors in an array where each acts as a working electrode provides differential derivatization of the sensor surfaces. To demonstrate this concept, two different self-assembled monolayer (SAM)-forming electrochemically addressable ω-ferrocenyl alkanethiols (C11) are chemisorbed onto independent but spatially adjacent gold electrodes. The ferrocene alkanethiol does not chemisorb onto the surface when the applied potential is cathodic relative to the adsorption potential and the electrode remains underivatized. However, applying potentials that are modestly positive relative to the adsorption potential leads to extensive coverage within 10 min. The resulting SAM remains in a stable state while held at potentials <200 mV above the adsorption potential. In this state, the chemisorbed SAM does not significantly desorb nor do new ferrocenylalkythiols adsorb. Using three set applied potentials provides for controlled submonolayer alkylthiol marker coverage of each independent gold electrode. These three applied potentials are dependent upon the specifics of the respective adsorbate. Characterization of the ferrocene-modified electrodes via cyclic voltammetry demonstrates that each specific ferrocene marker is exclusively adsorbed to the desired target electrode.

Applying a weed risk assessment approach to GM crops.

PubMed

Keese, Paul K; Robold, Andrea V; Myers, Ruth C; Weisman, Sarah; Smith, Joe

2014-12-01

Current approaches to environmental risk assessment of genetically modified (GM) plants are modelled on chemical risk assessment methods, which have a strong focus on toxicity. There are additional types of harms posed by plants that have been extensively studied by weed scientists and incorporated into weed risk assessment methods. Weed risk assessment uses robust, validated methods that are widely applied to regulatory decision-making about potentially problematic plants. They are designed to encompass a broad variety of plant forms and traits in different environments, and can provide reliable conclusions even with limited data. The knowledge and experience that underpin weed risk assessment can be harnessed for environmental risk assessment of GM plants. A case study illustrates the application of the Australian post-border weed risk assessment approach to a representative GM plant. This approach is a valuable tool to identify potential risks from GM plants.

A program of data synthesis from the ALSEP/CPLEE ALSEP/SIDE, and Explorer 35 magnetometer to investigate lunar terminator and nightside particle fluxes and surface interactions

NASA Technical Reports Server (NTRS)

Reasoner, D. L.

1976-01-01

Lunar nightside electron fluxes were studied with the aid of the ALSEP/CPLEE and other instruments. The flux events were shown to be due to (a) electrons propagating upstream from the earth's bow shock, (b) electrons thermalized and scattered to the lunar surface by disturbances along the boundary of the lunar solarwind cavity, and (c) solar wind electrons scattered to the lunar surface by lunar limb shocks and/or compressional disturbances. These electrons were identified as a cause of the high night surface negative potentials observed in tha ALSEP/SIDE ion data. A study was also made of the shadowing of magnetotail plasma sheet electrons by interactions between the lunar body and the ambient magnetic field and by interactions between charged particles and lunar remnant magnetic fields. These shadowing effects were shown to modify lunar surface and near-lunar potential distributions.

Mediation and moderation of the association between cynical hostility and systolic blood pressure in low-income women.

PubMed

Versey, H Shellae; Kaplan, George A

2012-04-01

Hostility may be related to risk factors for cardiovascular disease (CVD), such as blood pressure. However, the process by which hostility affects blood pressure is not fully understood. The current study sought to evaluate abdominal obesity (waist-to-hip ratio [WHR]) as a potential mediator and modifier of the relationship between cynical hostility and systolic blood pressure (SBP) in a group of disadvantaged women. Path analysis and multiple regression models were used to identify mediating and moderating pathways in the relationship between cynical hostility and SBP. Results indicate a significant interaction between WHR and cynical hostility. WHR was a partial mediator and significant moderator of the association between hostility and blood pressure. These findings highlight the potential importance of examining abdominal obesity and psychosocial factors as conjunctive determinants of CVD and risk factors for related metabolic conditions.

Current progress in orchid flowering/flower development research

PubMed Central

Wang, Hsin-Mei; Tong, Chii-Gong

2017-01-01

ABSTRACT Genetic pathways relevant to flowering of Arabidopsis are under the control of environmental cues such as day length and temperatures, and endogenous signals including phytohormones and developmental aging. However, genes and even regulatory pathways for flowering identified in crops show divergence from those of Arabidopsis and often do not have functional equivalents to Arabidopsis and/or existing species- or genus-specific regulators and show modified or novel pathways. Orchids are the largest, most highly evolved flowering plants, and form an extremely peculiar group of plants. Here, we briefly summarize the flowering pathways of Arabidopsis, rice and wheat and present them alongside recent discoveries/progress in orchid flowering and flower developmental processes including our transgenic Phalaenopsis orchids for LEAFY overexpression. Potential biotechnological applications in flowering/flower development of orchids with potential target genes are also discussed from an interactional and/or comparative viewpoint. PMID:28448202

Known knowns, known unknowns and unknown unknowns in prokaryotic transposition.

PubMed

Siguier, Patricia; Gourbeyre, Edith; Chandler, Michael

2017-08-01

Although the phenomenon of transposition has been known for over 60 years, its overarching importance in modifying and streamlining genomes took some time to recognize. In spite of a robust understanding of transposition of some TE, there remain a number of important TE groups with potential high genome impact and unknown transposition mechanisms and yet others, only recently identified by bioinformatics, yet to be formally confirmed as mobile. Here, we point to some areas of limited understanding concerning well established important TE groups with DDE Tpases, to address central gaps in our knowledge of characterised Tn with other types of Tpases and finally, to highlight new potentially mobile DNA species. It is not exhaustive. Examples have been chosen to provide encouragement in the continued exploration of the considerable prokaryotic mobilome especially in light of the current threat to public health posed by the spread of multiple Ab R . Copyright © 2017 Elsevier Ltd. All rights reserved.

Optimizing Cognitive Function in Persons With Chronic Pain.

PubMed

Baker, Katharine S; Georgiou-Karistianis, Nellie; Gibson, Stephen J; Giummarra, Melita J

2017-05-01

Cognitive functioning is commonly disrupted in people living with chronic pain, yet it is an aspect of pain that is often not routinely assessed in pain management settings, and there is a paucity of research on treatments or strategies to alleviate the problem. The purpose of this review is to outline recent research on cognitive deficits seen in chronic pain, to give an overview of the mechanisms involved, advocate cognitive functioning as an important target for treatment in pain populations, and discuss ways in which it may be assessed and potentially remediated. A narrative review. There are several options for remediation, including compensatory, restorative, and neuromodulatory approaches to directly modify cognitive functioning, as well as physical, psychological, and medication optimization methods to target secondary factors (mood, sleep, and medications) that may interfere with cognition. We highlight the potential to enhance cognitive functions and identify the major gaps in the research literature.

Understanding the Role of O-GlcNAc Modifications in Plant Development

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

Olszewski, Neil, E.

2011-06-16

This project has contributed towards understanding the role of O-GlcNAc (O-linked N-acetylglucosamine) transferases (OGTs) in plants. Through analyses of single and double mutants, we have investigated the unique and overlapping functions of SECRET AGENT (SEC) and SPINDLY (SPY), the arabidopsis OGTs. This work showed that SEC functions as negative regulators of the long-day flowering pathway. SEC also has a positive role in regulation of rosette. An E. coli co-expression system that allows potential substrates to be co-expressed with and O-GlcNAc modified by SEC was developed. We showed that SEC is a bona fide OGT that modifies itself with single O-linkedmore » GlcNAc(s). Using this system, we tested a number of proteins that were hypothesized to be substrates of SEC and identified a number of substrates include GIGANTEA (GI), a component of the long day flowering pathway. The hypothesis that O-GlcNAc modification controls GI activity was tested by first mapping where E. coli-expressed SEC modifies GI and then assessing the activity of a non-modifiable mutant form of GI. The activity of the mutant form of GI was indistinguishable from that of wild type suggesting that either O-GlcNAc does not regulate GI activity or that additional modification sites exist on GI. In collaboration with Dr. Juan Antonio Garcia at Universidad Autónoma de Madrid the role of O-GlcNAc modification of the plum pox virus coat protein (PPV-CP) was investigated. SEC was shown to O-GlcNAc modify PPV-CP and the modification was shown to facilitate the infection process. E. coli-expressed SEC was shown to modify the same PPV-CP sites that are modified in plants. SEC has a large protein interaction domain called the TPR domain that has been hypothesized to have a role in determining the substrate specificity of the enzyme and/or to regulate its activity. A mutational analysis of the TPR domain did not find evidence for a role in substrate specificity but did obtain evidence that the domain regulates enzyme activity.« less

Handgrip strength and associated factors in hospitalized patients.

PubMed

Guerra, Rita S; Fonseca, Isabel; Pichel, Fernando; Restivo, Maria T; Amaral, Teresa F

2015-03-01

Handgrip strength (HGS) is a marker of nutrition status. Many factors are associated with HGS. Age, height, body mass index, number of diagnoses, and number and type of drugs have been shown to modify the association between undernutrition and HGS. Nevertheless, other patient characteristics that could modify this association and its joint modifier effect have not been studied yet. To evaluate the association of inpatients' HGS and undernutrition considering the potential modifier effect of cognitive status, functional activity, disease severity, anthropometrics, and other patient characteristics on HGS. A cross-sectional study was conducted in a university hospital. Sex, age, abbreviated mental test score, functional activity score, Charlson index, number of drugs, Patient-Generated Subjective Global Assessment (PG-SGA) score, body weight, mid-arm muscle circumference, adductor pollicis muscle thickness, body height, wrist circumference, hand length, and palm width were included in a linear regression model to identify independent factors associated with HGS (dependent variable). The study sample was composed of 688 inpatients (18-91 years old). All variables included in the model were associated with HGS (β, -0.16 to 0.38; P ≤ .049) and explained 68.5% of HGS. Age, functional activity decline, Charlson index, number of drugs, PG-SGA score, body weight, and wrist circumference had a negative association with HGS. All other studied variables were positively associated with HGS. Nutrition status evaluated by PG-SGA was still associated with HGS after considering the joint effect of other patient characteristics, which reinforces the value of HGS as an indicator of undernutrition. © 2013 American Society for Parenteral and Enteral Nutrition.

Understanding the Early Signs of Chronic Disease by Investigating the Overlap of Mental Health Needs and Adolescent Obesity.

PubMed

Smith, Tyler C; Smith, Besa

2015-01-01

Childhood obesity has reached epidemic proportions with two to three-fold increases in prevalence in the past three decades. Sedentary lifestyles and nutrition have been linked to these increases though little is known about mental health illnesses in children and teens which may be precursors to negative modifiable health risk factors. The objective of this study was to investigate for a potentially more clinically practical indicator of depression over a multi-item screen in respect to reporting of overweight and obesity in adolescents. This study further investigated modifiers to this association and stability of association. This cross-sectional study aggregated 2007/2009 California Health Interview Survey data (n = 6,917 adolescents). Univariate analyses of population characteristics and modifiable behaviors with obesity/overweight and depression are presented. Multivariable weighted logistic regression was used to compare the adjusted odds of overweight and obesity for those children with reported depression. After controlling for gender, race/ethnicity, age, and modifiable behaviors, there was a statistically significant relationship between reported depression and overweight/obesity (OR = 1.24; 95% CI = 1.04, 1.49). This effect size was consistent in hierarchical models overall and stratified by gender. Overweight and obesity in adolescents should be understood clinically in the context of depression and other mental health illness. This study highlights a routine primary care or parental screening assessment that could indicate tendencies in adolescent boys and girls which may be precursors to overweight or obesity. Further research should be conducted to identify ways for integrating adolescent mental health screens into primary care.

Comparison of a modified mid-coronal sectioning technique and Wilson's technique when conducting eye and brain examinations in rabbit teratology studies.

PubMed

Ziejewski, Mary K; Solomon, Howard M; Rendemonti, Joyce; Stanislaus, Dinesh

2015-02-01

There are two methods used when examining fetal rabbit eyes and brain in teratology studies. One method employs prior fixation before serial sectioning (Wilson's technique) and the other uses fresh tissue (mid-coronal sectioning). We modified the mid-coronal sectioning technique to include removal of eyes and brain for closer examination and to increase the number of structures that can be evaluated and compared it to the Wilson's technique. We found that external examination of the head, in conjunction with either sectioning method, is equally sensitive in identifying developmental defects. We evaluated 40,401 New Zealand White (NZW) and Dutch-Belted (DB) rabbit fetuses for external head alterations, of which 28,538 fetuses were further examined for eye and brain alterations using the modified mid-coronal sectioning method (16,675 fetuses) or Wilson's technique (11,863 fetuses). The fetuses were from vehicle control or drug-treated pregnant rabbits in embryo-fetal development studies conducted to meet international regulatory requirements for the development of new drugs. Both methods detected the more common alterations (microphthalmia and dilated lateral cerebral ventricles) and other less common findings (changes in size and/or shape of eye and brain structures). While both methods are equally sensitive at detecting common and rare developmental defects, the modified mid-coronal sectioning technique eliminates the use of chemicals and concomitant fixation artifacts that occur with the Wilson's technique and allows for examination of 100% intact fetuses thereby increasing potential for detecting eye and brain alterations as these findings occur infrequently in rabbits. © 2015 Wiley Periodicals, Inc.

Proteomic Analysis Reveals Aberrant O-GlcNAcylation of Extracellular Proteins from Breast Cancer Cell Secretion.

PubMed

Netsirisawan, Pukkavadee; Chokchaichamnankit, Daranee; Srisomsap, Chantragan; Svasti, Jisnuson; Champattanachai, Voraratt

2015-01-01

O-GlcNAcylation is a unique intracellular protein modification; however, few extracellular O-GlcNAc-modified proteins have been discovered. We have previously demonstrated that many cellular proteins were aberrant in O-GlcNAcylation in breast cancer tissues. In the present study, therefore, we investigated whether O-GlcNAc-modified proteins were abnormally secreted from breast cancer cells. Intracellular and extracellular proteins were prepared from cell lysates of breast cancer cells (MCF-7 and MDA-MB-231) and normal breast cells (HMEC) and from their serum-free media (SFM), respectively. O-GlcNAcylation level was examined by immunoblotting. O-GlcNAc-Modified proteins were identified using two-dimensional gel electrophoresis and Liquid Chromatography-tandem Mass Spectrometry. O-GlcNAcylation level was significantly increased in the extracellular compartment of both types of cancer cells compared to normal cells. Interestingly, O-GlcNAc patterns differed between intracellular and extracellular proteins. Proteomic analysis revealed that many O-GlcNAc spots in MCF-7 secretions were abnormally increased in comparison to those in HMEC secretions. Among these, transitional endoplasmic reticulum ATPase (TER ATPase) and heat-shock 70 kDa (HSP70) were confirmed to be O-GlcNAc-modified. The levels of O-GlcNAc-HSP70 and O-GlcNAc-TER ATPase were higher in SFM from MCF-7 cells than in that from HMEC. O-GlcNAcomic study of the extracellular compartments reveals aberrant O-GlcNAc-secreted proteins, which may be of interest as potential biomarkers in breast cancer. Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation

PubMed Central

Ambegaokar, Surendra S.; Jackson, George R.

2011-01-01

A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, as potent modifiers; here, we report 37 additional genes identified from ∼1900 genes screened, including the kinases shaggy/GSK-3beta, par-1/MARK, CamKI and Mekk1. Tau acts synergistically with Mekk1 and p38 to down-regulate extracellular regulated kinase activity, with a corresponding decrease in AT8 immunoreactivity (pS202/T205), suggesting that tau can participate in signaling pathways to regulate its own kinases. Modifiers showed poor correlation with tau phosphorylation (using the AT8, 12E8 and AT270 epitopes); moreover, tested suppressors of wild-type tau were equally effective in suppressing toxicity of a phosphorylation-resistant S11A tau construct, demonstrating that changes in tau phosphorylation state are not required to suppress or enhance its toxicity. Genes related to autophagy, the cell cycle, RNA-associated proteins and chromatin-binding proteins constitute a large percentage of identified modifiers. Other functional categories identified include mitochondrial proteins, lipid trafficking, Golgi proteins, kinesins and dynein and the Hsp70/Hsp90-organizing protein (Hop). Network analysis uncovered several other genes highly associated with the functional modifiers, including genes related to the PI3K, Notch, BMP/TGF-β and Hedgehog pathways, and nuclear trafficking. Activity of GSK-3β is strongly upregulated due to TDP-43 expression, and reduced GSK-3β dosage is also a common suppressor of Aβ42 and TDP-43 toxicity. These findings suggest therapeutic targets other than mitigation of tau phosphorylation. PMID:21949350

Environmental pollutants, diet, physical activity, body size, and breast cancer: where do we stand in research to identify opportunities for prevention?

PubMed

Brody, Julia Green; Rudel, Ruthann A; Michels, Karin B; Moysich, Kirsten B; Bernstein, Leslie; Attfield, Kathleen R; Gray, Sharon

2007-06-15

Breast cancer is the most common invasive cancer in women worldwide and the leading cause of death in US women in mid-life. Treatment has adverse effects, adding to the importance of finding modifiable risk factors. At the invitation of Susan G. Komen for the Cure, we reviewed studies of breast cancer and environmental pollutants, diet (assessed prospectively), body size, and physical activity, and animal studies that identify chemicals as potential mammary carcinogens. Databases developed in the review include information on 216 chemicals that increased mammary gland tumors in animal studies and 450 epidemiologic studies (accessible at www.silentspring.org/sciencereview and www.komen.org/environment). Exposure to potential mammary carcinogens is widespread from chemicals found in consumer products, air and drinking water pollution, food, and women's workplaces. Epidemiologic studies have included only a small number of chemicals identified as mammary carcinogens or as hormone disruptors, which may have implications for breast cancer; however, evidence is emerging for associations between breast cancer and polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and organic solvents. Prospective diet studies have not revealed consistent associations with breast cancer. Improved exposure assessment methods will help advance future human studies of both diet and environmental pollutants. Studies of physical activity show that it is protective. In the same vein as evidence-based medicine, messages for patients, policymakers, and the public should support decision-making based on the strength of current evidence; such messages might address exposure reduction for some pollutants. Investments in research on environmental factors in breast cancer have potentially large public health benefits.

Mutagenicity in a Molecule: Identification of Core Structural Features of Mutagenicity Using a Scaffold Analysis

PubMed Central

Hsu, Kuo-Hsiang; Su, Bo-Han; Tu, Yi-Shu; Lin, Olivia A.; Tseng, Yufeng J.

2016-01-01

With advances in the development and application of Ames mutagenicity in silico prediction tools, the International Conference on Harmonisation (ICH) has amended its M7 guideline to reflect the use of such prediction models for the detection of mutagenic activity in early drug safety evaluation processes. Since current Ames mutagenicity prediction tools only focus on functional group alerts or side chain modifications of an analog series, these tools are unable to identify mutagenicity derived from core structures or specific scaffolds of a compound. In this study, a large collection of 6512 compounds are used to perform scaffold tree analysis. By relating different scaffolds on constructed scaffold trees with Ames mutagenicity, four major and one minor novel mutagenic groups of scaffold are identified. The recognized mutagenic groups of scaffold can serve as a guide for medicinal chemists to prevent the development of potentially mutagenic therapeutic agents in early drug design or development phases, by modifying the core structures of mutagenic compounds to form non-mutagenic compounds. In addition, five series of substructures are provided as recommendations, for direct modification of potentially mutagenic scaffolds to decrease associated mutagenic activities. PMID:26863515

A geospatial suitability model for drought-tolerant switchgrass

NASA Astrophysics Data System (ADS)

Lewis, S. M.; Kelly, M.

2011-12-01

A perennial grass native to the North America, switchgrass (Panicum virgatum) has been targeted by the USDA as a model mass bioenergy crop to replace petroleum energy products and meet policy demands. Although highly water use efficient, as a warm-season crop, switchgrass requires a significant amount of water during the growing season (April -September). However, locations that have highly reliable water availability are also ideal for profitable food crops (e.g. corn and soy growing regions) and food competition is a significant concern in regards to biofuel crops being grown on productive agricultural lands. Drier, marginal lands (lands on which normal agricultural crops are difficult to cultivate) are therefore potentially ideal locations to grow biofuel crops to ensure that food competition is not an issue. Genetics scientists at UC Davis are in the process of developing a modified variety of switchgrass that can withstand extended periods of drought while not substantially affecting overall yield. As this product is being developed, it is important to identify the potential geographical niche for this new drought-tolerant variety of switchgrass. This project introduces a geospatial approach that utilizes both physical and economic variables to identify ideal geographic locations for this innovative crop.

Diet and pancreatic cancer: many questions with few certainties.

PubMed

Cappellani, A; Cavallaro, A; Di Vita, M; Zanghi, A; Piccolo, G; Lo Menzo, E; Cavallaro, V; Malaguarnera, M; Giaquinta, A; Veroux, M; Cimino, L; Berretta, M

2012-02-01

BACKGROUND, OBJECTIVES: Pancreatic cancer ranks fourth for cancer mortality for men and women in the United States. This is a particularly devastating cancer since the case-fatality proportion approaches 90% within 12 months following diagnosis. Therefore, understanding the etiology and identifying the risk factors are essential for the primary prevention of this deadly disease. Of the few potentially modifiable risk factors that have been identified, cigarette smoking, history of diabetes mellitus, and obesity seem to be among the most consistent, but the effect of dietary factors is still unclear. The aim of our study is to review of the literature examining the potential role of carbohydrates, fatty acids, meat, fruit and vegetables, alcohol. Although large prospective cohort studies with questionnaire based analyses will continue to have much to offer in defining predisposing factors for difficult diseases, such as pancreatic cancer, unfortunately dietary questionnaires do not reflect the bioavailability of the nutrients from various foods, the level of absorption from the digestive tract, or individual differences in metabolism. Greater use of participant-derived biological samples, banked plasma, germline DNA, and tumour tissue samples may help to the understanding of pancreatic cancer pathogenesis.

Genetic analysis of indefinite division in human cells: Evidence for a cell senescence-related gene(s) on human chromosome 4

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

Yi Ning; Ledbetter, D.H.; Smith, J.R.

1991-07-01

Earlier studies had demonstrated that fusion of normal with immortal human cells yielded hybrids having limited division potential. This indicated that the phenotype of limited proliferation (cellular senescence) is dominant and that immortal cells result from recessive changes in normal growth-regulatory genes. In additional studies, the authors exploited the fact that the immortal phenotype is recessive and, by fusing various immortal human cell lines with each other, identified four complementation groups for indefinite division. Assignment of cell lines to specific groups allowed us to take a focused approach to identify the chromosomes and genes involved in growth regulation that havemore » been modified in immortal cells. They report here that introduction of a normal human chromosome 4 into three immortal cell lines (HeLa, J82, T98G) assigned to complementation group B resulted in loss of proliferation and reversal of the immortal phenotype. No effect on the proliferation potential of cell lines representative of the other complementation groups was observed. This result suggests that a gene(s) involved in cellular senescence and normal growth regulation resides on chromosome 4.« less

Semiautomated TaqMan PCR screening of GMO labelled samples for (unauthorised) GMOs.

PubMed

Scholtens, Ingrid M J; Molenaar, Bonnie; van Hoof, Richard A; Zaaijer, Stephanie; Prins, Theo W; Kok, Esther J

2017-06-01

In most countries, systems are in place to analyse food products for the potential presence of genetically modified organisms (GMOs), to enforce labelling requirements and to screen for the potential presence of unauthorised GMOs. With the growing number of GMOs on the world market, a larger diversity of methods is required for informative analyses. In this paper, the specificity of an extended screening set consisting of 32 screening methods to identify different crop species (endogenous genes) and GMO elements was verified against 59 different GMO reference materials. In addition, a cost- and time-efficient strategy for DNA isolation, screening and identification is presented. A module for semiautomated analysis of the screening results and planning of subsequent event-specific tests for identification has been developed. The Excel-based module contains information on the experimentally verified specificity of the element methods and of the EU authorisation status of the GMO events. If a detected GMO element cannot be explained by any of the events as identified in the same sample, this may indicate the presence of an unknown unauthorised GMO that may not yet have been assessed for its safety for humans, animals or the environment.

Measuring AT Usability with the Modified System Usability Scale (SUS).

PubMed

Friesen, Emma L

2017-01-01

The modified System Usability Scale (SUS) is a widely used generic measure of product usability. This study concerns the usability of mobile shower commodes using correlations between the SUS and AT device-specific measures. Results suggest the modified SUS, and corresponding adjective-anchored rating scale, are appropriate for measuring MSC usability, and have potential for use with other AT devices.

Topographical and functional anatomy of trapezius muscle innervation by spinal accessory nerve and C2 to C4 nerves of cervical plexus.

PubMed

Gavid, M; Mayaud, A; Timochenko, A; Asanau, A; Prades, J M

2016-10-01

The aim of this study was to determine the existence and the frequency of communicating branches between the spinal accessory nerve (SAN) and the C2, C3 and C4 roots of the cervical plexus. The present study also aimed to elucidate whether these branches contain motor fibers or not. Dissection of the cervical region was performed on twelve adult cadavers. A powered operating microscope was necessary to dissect the SAN and its branches and also to dissect C2, C3 and C4 nerve branches. In a second step, data from 13 patients who underwent 25 modified neck dissections under trapezius muscle's monitoring were collected. At the end of surgery, intraoperative stimulation on the SAN, C2, C3 and C4 nerve branches was performed. Registered potentials in the three parts of the trapezius muscle, using the NIM Medtronic system, were analyzed. During cadaver dissection, 18 (78 %) communicating branches were identified between the SAN and C2, 11 (48 %) between the SAN and C3, 12 (52 %) between the SAN and C4. Intraoperative stimulation of the SAN and its branch for the trapezius muscle provided a significant electroneurographic response in the three parts of the trapezius muscle in all subjects. Intraoperative stimulation of C3 led to recordable contractions of the trapezius muscle in 5 (20 %) modified neck surgeries, stimulation of C4 led to recordable contractions during 5 (20 %) modified neck dissections. One case of contraction was recorded after intraoperative stimulation of C2 (7 %). Although we were able to identify at least one communicating branch between the SAN and the roots of the cervical plexus in each cadaver dissection, the cervical plexus is not always involved in trapezius motor innervation. Intraoperative electroneurography demonstrated that a motor input from the cervical plexus to the trapezius muscle was provided in only 32 % of cases. Therefore, SAN trunk and C3-C4 roots should be carefully preserved during modified neck dissection to protect trapezius and shoulder functions.

High health satisfaction among emerging adults with diabetes: Factors predicting resilience.

PubMed

Corathers, Sarah D; Kichler, Jessica C; Fino, Nora F; Lang, Wei; Lawrence, Jean M; Raymond, Jennifer K; Yi-Frazier, Joyce P; Dabelea, Dana; Liese, Angela D; Saydah, Sharon H; Seid, Michael; Dolan, Lawrence M

2017-03-01

This study was conducted to identify factors contributing to health satisfaction outcomes among emerging adults (ages 18-25) with diabetes. SEARCH for Diabetes in Youth study participants whose diabetes was prevalent in 2001 and were ≥18 years of age when they completed a 2008-2009 follow-up survey (n = 340) were included. We developed a health resilience model (HRM) to identify potentially modifiable factors (anticipatory guidance, social support, physical activity, quality of life) associated with health outcomes (satisfaction with health care, overall personal health, self-report of hemoglobin A1c [HbA1c]). Proportional odds logistic regression models were used to examine relationships between modifiable factors and health outcomes while adjusting for predetermined characteristics; linear regression models were used for reported HbA1c. Comparison of participants who reported HbA1c versus nonreporters was conducted. A majority (70%) of participants rated satisfaction with health care ≥7 out of 10, and most (71%) rated overall health as good, very good, or excellent. Satisfaction with health care was independent of change in provider between the ages of 17 and 24. After controlling for predetermined characteristics, we found that the odds of increased satisfaction with health care and overall personal health were 1.3 and 1.2 greater, respectively, when participants discussed additional diabetes-related anticipatory guidance topics with a provider and 1.3 and 2.1, respectively, for each 10-unit change in quality of life score. Relationship between HbA1c level and modifiable factors was not significant; however, participants reporting HbA1c had higher ratings of health care and overall health versus nonreporters. HRM describes relationships between modifiable factors and patient-reported outcomes of satisfaction with health care and overall personal health among a cohort of ethnically and racially diverse emerging adults with longstanding diabetes, over half of whom experienced a change in provider. HRM may discern candidate areas for intervention, such as effective anticipatory guidance that can impact satisfaction with health care and overall health, to promote positive health outcomes. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Tomography of a Probe Potential Using Atomic Sensors on Graphene.

PubMed

Wyrick, Jonathan; Natterer, Fabian D; Zhao, Yue; Watanabe, Kenji; Taniguchi, Takashi; Cullen, William G; Zhitenev, Nikolai B; Stroscio, Joseph A

2016-12-27

Our ability to access and explore the quantum world has been greatly advanced by the power of atomic manipulation and local spectroscopy with scanning tunneling and atomic force microscopes, where the key technique is the use of atomically sharp probe tips to interact with an underlying substrate. Here we employ atomic manipulation to modify and quantify the interaction between the probe and the system under study that can strongly affect any measurement in low charge density systems, such as graphene. We transfer Co atoms from a graphene surface onto a probe tip to change and control the probe's physical structure, enabling us to modify the induced potential at a graphene surface. We utilize single Co atoms on a graphene field-effect device as atomic scale sensors to quantitatively map the modified potential exerted by the scanning probe over the whole relevant spatial and energy range.

Modified screening interaction potential on dust lattice waves in dusty plasma ring

NASA Astrophysics Data System (ADS)

He, Kerong; Chen, Hui; Liu, Sanqiu

2017-05-01

In the present paper, the modified screening interaction potential was adopted to investigate the dust lattice waves in dusty ring. Firstly, the influence of parameter ε on the modified screening interaction potential was analyzed; and it was found that the parameter ε has a long-range effect on the pairwise interaction between the particles. Secondly, the dispersion relations of longitudinal and transverse waves are obtained, and the effect of long-range action parameter ε, dimensionless lattice parameter α and dimensionless shielding parameter \\tilde{κ } on the dust lattice waves propagation in dusty ring are studied. Some interesting phenomena, such as the coupling of longitudinal and transverse waves, and instabilities of transverse waves are found, which are in good agreement with some previous works. Finally, the transverse wave instabilities and the relevant critical lattice parameter αc are presented and discussed.

Radiative corrections in the (varying power)-law modified gravity

NASA Astrophysics Data System (ADS)

Hammad, Fayçal

2015-06-01

Although the (varying power)-law modified gravity toy model has the attractive feature of unifying the early- and late-time expansions of the Universe, thanks to the peculiar dependence of the scalar field's potential on the scalar curvature, the model still suffers from the fine-tuning problem when used to explain the actually observed Hubble parameter. Indeed, a more correct estimate of the mass of the scalar field needed to comply with actual observations gives an unnaturally small value. On the other hand, for a massless scalar field the potential would have no minimum and hence the field would always remain massless. What solves these issues are the radiative corrections that modify the field's effective potential. These corrections raise the field's effective mass, rendering the model free from fine-tuning, immune against positive fifth-force tests, and better suited to tackle the dark matter sector.

[Safety assessment of foods derived from genetically modified plants].

PubMed

Pöting, A; Schauzu, M

2010-06-01

The placing of genetically modified plants and derived food on the market falls under Regulation (EC) No. 1829/2003. According to this regulation, applicants need to perform a safety assessment according to the Guidance Document of the Scientific Panel on Genetically Modified Organisms of the European Food Safety Authority (EFSA), which is based on internationally agreed recommendations. This article gives an overview of the underlying legislation as well as the strategy and scientific criteria for the safety assessment, which should generally be based on the concept of substantial equivalence and carried out in relation to an unmodified conventional counterpart. Besides the intended genetic modification, potential unintended changes also have to be assessed with regard to potential adverse effects for the consumer. All genetically modified plants and derived food products, which have been evaluated by EFSA so far, were considered to be as safe as products derived from the respective conventional plants.

Interaction between dimethyldioctadecylammonium bromide-modified PLGA microspheres and hyaluronic acid

NASA Astrophysics Data System (ADS)

Mulia, Kamarza; Devi, Krisanti, Elsa

2017-02-01

In application of intravitreal injection, an extended drug delivery system is desired so that the frequency of injection to treat diabetic retinopathy may be reduced. Poly(lactic-co-glycolic acid) polymer (PLGA) was used to encapsulate a model drug in the form of microspheres. The zeta potential of dimethyldioctadecylammonium bromide (DDAB)-modified PLGA microspheres in water was proportional to the DDAB concentration used in the preparation step, up to +57.8 mV. The scanning electron microscope pictures and the zeta potential data (SEM) confirmed that the surface of the PLGA has been modified by the cationic surfactant and that electrostatic interaction between the positively charged microspheres and the negatively charged vitreous were present.

Somatic mutations in histiocytic sarcoma identified by next generation sequencing.

PubMed

Liu, Qingqing; Tomaszewicz, Keith; Hutchinson, Lloyd; Hornick, Jason L; Woda, Bruce; Yu, Hongbo

2016-08-01

Histiocytic sarcoma is a rare malignant neoplasm of presumed hematopoietic origin showing morphologic and immunophenotypic evidence of histiocytic differentiation. Somatic mutation importance in the pathogenesis or disease progression of histiocytic sarcoma was largely unknown. To identify somatic mutations in histiocytic sarcoma, we studied 5 histiocytic sarcomas [3 female and 2 male patients; mean age 54.8 (20-72), anatomic sites include lymph node, uterus, and pleura] and matched normal tissues from each patient as germ line controls. Somatic mutations in 50 "Hotspot" oncogenes and tumor suppressor genes were examined using next generation sequencing. Three (out of five) histiocytic sarcoma cases carried somatic mutations in BRAF. Among them, G464V [variant frequency (VF) of 43.6 %] and G466R (VF of 29.6 %) located at the P loop potentially interfere with the hydrophobic interaction between P and activating loops and ultimately activation of BRAF. Also detected was BRAF somatic mutation N581S (VF of 7.4 %), which was located at the catalytic loop of BRAF kinase domain: its role in modifying kinase activity was unclear. A similar mutational analysis was also performed on nine acute monocytic/monoblastic leukemia cases, which did not identify any BRAF somatic mutations. Our study detected several BRAF mutations in histiocytic sarcomas, which may be important in understanding the tumorigenesis of this rare neoplasm and providing mechanisms for potential therapeutical opportunities.

Field evaluation of Wisconsin modified binder selection guidelines - phase II.

DOT National Transportation Integrated Search

2013-12-01

The purpose of this project was to continue phase I of the study with the objective of identifying promising procedures and applicable modified binder specification criteria for use in Wisconsin, based on comparison of test results to field performan...