The Achilles tendon: fundamental properties and mechanisms governing healing

PubMed Central

Freedman, Benjamin R.; Gordon, Joshua A.; Soslowsky, Louis J.

2014-01-01

Summary This review highlights recent research on Achilles tendon healing, and comments on the current clinical controversy surrounding the diagnosis and treatment of injury. The processes of Achilles tendon healing, as demonstrated through changes in its structure, composition, and biomechanics, are reviewed. Finally, a review of tendon developmental biology and mechano transductive pathways is completed to recognize recent efforts to augment injured Achilles tendons, and to suggest potential future strategies for therapeutic intervention and functional tissue engineering. Despite an abundance of clinical evidence suggesting that current treatments and rehabilitation strategies for Achilles tendon ruptures are equivocal, significant questions remain to fully elucidate the basic science mechanisms governing Achilles tendon injury, healing, treatment, and rehabilitation. PMID:25332943

Role of Integrin in Mechanical Loading of Osteoblasts

NASA Technical Reports Server (NTRS)

Globus, Ruth; Demsky, Caroline

2000-01-01

Mechanical forces generated by gravity, weightbearing, and muscle contraction play a key role in the genesis and maintenance of skeletal structure. The molecular mechanisms that mediate changes in osteoblast activity in response to altered patterns of skeletal loading are not known, and a better understanding of these processes may be essential for developing effective treatment strategies to prevent disuse osteoporosis. We have elucidated specific integrin/ECM (extracellular matrix) interactions that are required for osteoblast differentiation and survival and have developed a useful loading system to further explore the molecular basis of mechano-sensitivity of osteoblasts. The long term goal of our collaborative research is to understand how the ECM and cell adhesion proteins and integrins interaction to mediate the response of osteoblasts and their progenitors to mechanical loading. We suggest that integrin/ECM interactions are crucial for basic cellular processes, including differentiation and survival, as well as to participate in detecting and mediating cellular responses to mechanical stimuli.

Affective science perspectives on cancer control: Strategically crafting a mutually beneficial research agenda

PubMed Central

Ferrer, Rebecca A.; McDonald, Paige Green; Barrett, Lisa Feldman

2015-01-01

Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality, and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally-laden. As such, affective science research to elucidate questions related to basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this paper is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive, but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. PMID:25987511

Basic dynamics from a pulse-coupled network of autonomous integrate-and-fire chaotic circuits.

PubMed

Nakano, H; Saito, T

2002-01-01

This paper studies basic dynamics from a novel pulse-coupled network (PCN). The unit element of the PCN is an integrate-and-fire circuit (IFC) that exhibits chaos. We an give an iff condition for the chaos generation. Using two IFC, we construct a master-slave PCN. It exhibits interesting chaos synchronous phenomena and their breakdown phenomena. We give basic classification of the phenomena and their existence regions can be elucidated in the parameter space. We then construct a ring-type PCN and elucidate that the PCN exhibits interesting grouping phenomena based on the chaos synchronization patterns. Using a simple test circuit, some of typical phenomena can be verified in the laboratory.

Malassezia species and seborrheic dermatitis.

PubMed

Zisova, Lilia G

2009-01-01

Malassezia spp. are medically important dimorphic, lipophilic yeasts that form part of the normal cutaneous microflora of human. Seborrheic dermatitis is a multifactor disease that needs endogenous and exogenous predisposing factors for its development. Presence of these factors leads to reproduction of the saprophytic opportunistic pathogen Malassezia spp. and development of a disease. The inflammatory reaction against the yeast Malassezia is considered basic in the etiology of the seborrheic dermatitis. The pathogenesis and exact mechanisms via which these yeasts cause inflammation are still not fully elucidated. They are rather complex and subject of controversy in literature. Most probably Malassezia spp. cause seborrheic dermatitis by involving and combining both nonummune and immune mechanisms (nonspecific and specific). Which of these mechanisms will dominate in any single case depends on the number and virulence of the yeasts as well as on the microorganism reactivity. In the recent years a great interest have been aroused by the epidemiological investigations. Depending on the geographical place of the countries different Malassezia species in seborrheic dermatitis dominate in the different countries. In view of the etiology and pathogenesis of the seborrheic dermatitis comprehensive antifungal preparations have been recently introduced and are nowadays the basic therapeutic resource in the treatment of this disease.

Effects of biological sex on the pathophysiology of the heart.

PubMed

Fazal, Loubina; Azibani, Feriel; Vodovar, Nicolas; Cohen Solal, Alain; Delcayre, Claude; Samuel, Jane-Lise

2014-02-01

Cardiovascular diseases are the leading causes of death in men and women in industrialized countries. While the effects of biological sex on cardiovascular pathophysiology have long been known, the sex-specific mechanisms mediating these processes have been further elucidated over recent years. This review aims at analysing the sex-based differences in cardiac structure and function in adult mammals, and the sex-based differences in the main molecular mechanisms involved in the response of the heart to pathological situations. It emerged from this review that the sex-based difference is a variable that should be dealt with, not only in basic science or clinical research, but also with regards to therapeutic approaches. © 2013 The British Pharmacological Society.

The fabulous destiny of the Drosophila heart.

PubMed

Medioni, Caroline; Sénatore, Sébastien; Salmand, Pierre-Adrien; Lalevée, Nathalie; Perrin, Laurent; Sémériva, Michel

2009-10-01

For the last 15 years the fly cardiovascular system has attracted developmental geneticists for its potential as a model system of organogenesis. Heart development in Drosophila indeed provides a remarkable system for elucidating the basic molecular and cellular mechanisms of morphogenesis and, more recently, for understanding the genetic control of cardiac physiology. The success of these studies can in part be attributed to multidisciplinary approaches, the multiplicity of existing genetic tools, and a detailed knowledge of the system. Striking similarities with vertebrate cardiogenesis have long been stressed, in particular concerning the conservation of key molecular regulators of cardiogenesis and the new data presented here confirm Drosophila cardiogenesis as a model not only for organogenesis but also for the study of molecular mechanisms of human cardiac disease.

Discovery and structural elucidation of the illegal azo dye Basic Red 46 in sumac spice.

PubMed

Ruf, J; Walter, P; Kandler, H; Kaufmann, A

2012-01-01

An unknown red dye was discovered in a sumac spice sample during routine analysis for Sudan dyes. LC-DAD and LC-MS/MS did not reveal the identity of the red substance. Nevertheless, using LC-high-resolution MS and isotope ratio comparisons the structure was identified as Basic Red 46. The identity of the dye was further confirmed by comparison with a commercial hair-staining product and two textile dye formulations containing Basic Red 46. Analogous to the Sudan dyes, Basic Red 46 is an azo dye. However, some of the sample clean-up methodology utilised for the analysis of Sudan dyes in food prevents its successful detection. In contrast to the Sudan dyes, Basic Red 46 is a cation. Its cationic properties make it bind strongly to gel permeation columns and silica solid-phase extraction cartridges and prevent elution with standard eluents. This is the first report of Basic Red 46 in food. The structure elucidation of this compound as well as the disadvantages of analytical methods focusing on a narrow group of targeted analytes are discussed.

EVENT PREDICTION AND AFFECTIVE FORECASTING IN DEPRESSIVE COGNITION: USING EMOTION AS INFORMATION ABOUT THE FUTURE

PubMed Central

MARROQUÍN, BRETT; NOLEN-HOEKSEMA, SUSAN

2015-01-01

Depression is characterized by a bleak view of the future, but the mechanisms through which depressed mood is integrated into basic processes of future-oriented cognition are unclear. We hypothesized that dysphoric individuals’ predictions of what will happen in the future (likelihood estimation) and how the future will feel (affective forecasting) are attributable to individual differences in incorporating present emotion as judgment-relevant information. Dysphoric individuals (n = 77) made pessimistic likelihood estimates and blunted positive affective forecasts relative to controls (n = 84). These differences were mediated by dysphoric individuals’ tendencies to rely on negative emotion as information more than controls—and on positive emotion less—independent of anhedonia. These findings suggest that (1) blunted positive affective forecasting is a distinctive component of depressive future-oriented cognition, and (2) future-oriented cognitive processes are linked not just to current emotional state, but also to individual variation in using that emotion as information. This role of individual differences elucidates basic mechanisms in future-oriented cognition, and suggests routes for intervention on interrelated cognitive and affective processes in depression. PMID:26146452

Noradrenaline effects on social behaviour, intergroup relations, and moral decisions.

PubMed

Terbeck, S; Savulescu, J; Chesterman, L P; Cowen, P J

2016-07-01

Recent research has begun to elucidate the neural basis of higher order social concepts, such as the mechanisms involved in intergroup relations, and moral judgments. Most theories have concentrated on higher order emotions, such as guilt, shame, or empathy, as core mechanisms. Accordingly, psychopharmacological and neurobiological studies have investigated the effects of manipulating serotonin or oxytocin activity on moral and social decisions and attitudes. However, recently it has been determined that changes in more basic emotions, such as fear and anger, might also have a significant role in social and moral cognition. This article summarizes psychopharmacological and fMRI research on the role of noradrenaline in higher order social cognition suggesting that indeed noradrenergic mediated affective changes might play key - and probably causal - role in certain social attitudes and moral judgments. Social judgments may also be directly influenced by numerous neurotransmitter manipulations but these effects could be mediated by modulation of basic emotions which appear to play an essential role in the formation of social concepts and moral behaviour. Copyright © 2016. Published by Elsevier Ltd.

EVENT PREDICTION AND AFFECTIVE FORECASTING IN DEPRESSIVE COGNITION: USING EMOTION AS INFORMATION ABOUT THE FUTURE.

PubMed

Marroquín, Brett; Nolen-Hoeksema, Susan

2015-02-01

Depression is characterized by a bleak view of the future, but the mechanisms through which depressed mood is integrated into basic processes of future-oriented cognition are unclear. We hypothesized that dysphoric individuals' predictions of what will happen in the future ( likelihood estimation ) and how the future will feel ( affective forecasting ) are attributable to individual differences in incorporating present emotion as judgment-relevant information. Dysphoric individuals ( n = 77) made pessimistic likelihood estimates and blunted positive affective forecasts relative to controls ( n = 84). These differences were mediated by dysphoric individuals' tendencies to rely on negative emotion as information more than controls-and on positive emotion less-independent of anhedonia. These findings suggest that (1) blunted positive affective forecasting is a distinctive component of depressive future-oriented cognition, and (2) future-oriented cognitive processes are linked not just to current emotional state, but also to individual variation in using that emotion as information. This role of individual differences elucidates basic mechanisms in future-oriented cognition, and suggests routes for intervention on interrelated cognitive and affective processes in depression.

Application of metabolomics to toxicology of drugs of abuse: A mini review of metabolomics approach to acute and chronic toxicity studies.

PubMed

Zaitsu, Kei; Hayashi, Yumi; Kusano, Maiko; Tsuchihashi, Hitoshi; Ishii, Akira

2016-02-01

Metabolomics has been widely applied to toxicological fields, especially to elucidate the mechanism of action of toxicity. In this review, metabolomics application with focus on the studies of chronic and acute toxicities of drugs of abuse like stimulants, opioids and the recently-distributed designer drugs will be presented in addition to an outline of basic analytical techniques used in metabolomics. Limitation of metabolomics studies and future perspectives will be also provided. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Regenerative endodontics and tissue engineering: what the future holds?

PubMed

Goodis, Harold E; Kinaia, Bassam Michael; Kinaia, Atheel M; Chogle, Sami M A

2012-07-01

The work performed by researchers in regenerative endodontics and tissue engineering over the last decades has been superb; however, many questions remain to be answered. The basic biologic mechanisms must be elucidated that will allow the development of dental pulp and dentin in situ. Stress must be placed on the many questions that will lead to the design of effective, safe treatment options and therapies. This article discusses those questions, the answers to which may become the future of regenerative endodontics. The future remains bright, but proper support and patience are required. Copyright © 2012 Elsevier Inc. All rights reserved.

The Nucleosome Remodeling and Deacetylase (NuRD) Complex in Development and Disease

PubMed Central

Basta, Jeannine; Rauchman, Michael

2014-01-01

The Nucleosome Remodeling and Deacetylase (NuRD) complex is one of the major chromatin remodeling complexes found in cells. It plays an important role in regulating gene transcription, genome integrity and cell cycle progression. Through its impact on these basic cellular processes, increasing evidence indicates that alterations in the activity of this macromolecular complex can lead to developmental defects, oncogenesis and accelerated ageing. Recent genetic and biochemical studies have elucidated the mechanisms of NuRD action in modifying the chromatin landscape. These advances have the potential to lead to new therapeutic approaches to birth defects and cancer. PMID:24880148

[Basic research in ophthalmology in Germany and its international context].

PubMed

Schlötzer-Schrehardt, U; Cursiefen, C

2017-09-01

Experimental basic research provides the foundations for the elucidation of pathophysiological mechanisms of diseases and the development of novel diagnostic and therapeutic strategies for ophthalmological diseases. The objective of this contribution is to provide an overview of the international interconnection of basic research in ophthalmology in Germany. The international context of ophthalmological research conducted in Germany is presented by means of personal experiences and data published by the German Ophthalmological Society (DOG), the German Research Foundation (DFG) and the European Union (EU). Due to the lack of organized databases this article lays no claim to completeness. Basic research in ophthalmology in Germany is mainly conducted in university eye departments and is mainly related to the etiology, pathophysiology and therapy development for various ophthalmic diseases. It is primarily funded by the DFG, the Federal Ministry of Education and Research (BMBF) and the EU plays an increasingly important role. Thus, ophthalmological research is integrated into numerous European research networks and beyond that into many international interconnections and relationships. In Germany, both clinical and basic research in ophthalmology is integrated into many international networks and is only functionally viable in an international context; however, given the increasing impact of ophthalmological research in Asian countries, future strategies require a continued focus on career development, research infrastructure, working environment and international cooperation.

Affective science perspectives on cancer control: strategically crafting a mutually beneficial research agenda.

PubMed

Ferrer, Rebecca A; Green, Paige A; Barrett, Lisa Feldman

2015-05-01

Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally laden. As such, affective science research to elucidate questions related to the basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this article is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. © The Author(s) 2015.

Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease

PubMed Central

Duncker, Dirk J.; Koller, Akos; Merkus, Daphne; Canty, John M.

2018-01-01

The major factors determining myocardial perfusion and oxygen delivery have been elucidated over the past several decades, and this knowledge has been incorporated into the management of patients with ischemic heart disease (IHD). The basic understanding of the fluid mechanical behavior of coronary stenoses has also been translated to the cardiac catheterization laboratory where measurements of coronary pressure distal to a stenosis and coronary flow are routinely obtained. However, the role of perturbations in coronary microvascular structure and function, due to myocardial hypertrophy or coronary microvascular dysfunction, in IHD is becoming increasingly recognized. Future studies should therefore be aimed at further improving our understanding of the integrated coronary microvascular mechanisms that control coronary blood flow, and of the underlying causes and mechanisms of coronary microvascular dysfunction. This knowledge will be essential to further improve the treatment of patients with IHD. PMID:25475073

Comparing Core-Image-Based Basic Verb Learning in an EFL Junior High School: Learner-Centered and Teacher-Centered Approaches

ERIC Educational Resources Information Center

Yamagata, Satoshi

2018-01-01

The present study investigated the effects of two types of core-image-based basic verb learning approaches: the learner-centered and the teacher-centered approaches. The learner-centered approach was an activity in which participants found semantic relationships among several definitions of each basic target verb through a picture-elucidated card…

Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

PubMed

Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M

2013-05-10

A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

Naturally occurring alkaline amino acids function as efficient catalysts on Knoevenagel condensation at physiological pH: a mechanistic elucidation.

PubMed

Li, Weina; Fedosov, Sergey; Tan, Tianwei; Xu, Xuebing; Guo, Zheng

2014-05-01

To maintain biological functions, thousands of different reactions take place in human body at physiological pH (7.0) and mild conditions, which is associated with health and disease. Therefore, to examine the catalytic function of the intrinsically occurring molecules, such as amino acids at neutral pH, is of fundamental interests. Natural basic α-amino acid of L-lysine, L-arginine, and L-histidine neutralized to physiological pH as salts were investigated for their ability to catalyze Knoevenagel condensation of benzaldehyde and ethyl cyanoacetate. Compared with their free base forms, although neutralized alkaline amino acid salts reduced the catalytic activity markedly, they were still capable to perform an efficient catalysis at physiological pH as porcine pancreatic lipase (PPL), one of the best enzymes that catalyze Knoevenagel condensation. In agreement with the fact that the three basic amino acids were well neutralized, stronger basic amino acid Arg and Lys showed more obvious variation in NH bend peak from the FTIR spectroscopy study. Study of ethanol/water system and quantitative kinetic analysis suggested that the microenvironment in the vicinity of amino acid salts and protonability/deprotonability of the amine moiety may determine their catalytic activity and mechanism. The kinetic study of best approximation suggested that the random binding might be the most probable catalytic mechanism for the neutralized alkaline amino acid salt-catalyzed Knoevenagel condensation.

Theory of chemical bonds in metalloenzymes XXI. Possible mechanisms of water oxidation in oxygen evolving complex of photosystem II

NASA Astrophysics Data System (ADS)

Yamaguchi, Kizashi; Shoji, Mitsuo; Isobe, Hiroshi; Yamanaka, Shusuke; Kawakami, Takashi; Yamada, Satoru; Katouda, Michio; Nakajima, Takahito

2018-03-01

Possible mechanisms for water cleavage in oxygen evolving complex (OEC) of photosystem II (PSII) have been investigated based on broken-symmetry (BS) hybrid DFT (HDFT)/def2 TZVP calculations in combination with available XRD, XFEL, EXAFS, XES and EPR results. The BS HDFT and the experimental results have provided basic concepts for understanding of chemical bonds of the CaMn4O5 cluster in the catalytic site of OEC of PSII for elucidation of the mechanism of photosynthetic water cleavage. Scope and applicability of the hybrid DFT (HDFT) methods have been examined in relation to relative stabilities of possible nine intermediates such as Mn-hydroxide, Mn-oxo, Mn-peroxo, Mn-superoxo, etc., in order to understand the O-O (O-OH) bond formation in the S3 and/or S4 states of OEC of PSII. The relative stabilities among these intermediates are variable, depending on the weight of the Hartree-Fock exchange term of HDFT. The Mn-hydroxide, Mn-oxo and Mn-superoxo intermediates are found to be preferable in the weak, intermediate and strong electron correlation regimes, respectively. Recent different serial femtosecond X-ray (SFX) results in the S3 state are investigated based on the proposed basic concepts under the assumption of different water-insertion steps for water cleavage in the Kok cycle. The observation of water insertion in the S3 state is compatible with previous large-scale QM/MM results and previous theoretical proposal for the chemical equilibrium mechanism in the S3 state . On the other hand, the no detection of water insertion in the S3 state based on other SFX results is consistent with previous proposal of the O-OH (or O-O) bond formation in the S4 state . Radical coupling and non-adiabatic one-electron transfer (NA-OET) mechanisms for the OO-bond formation are examined using the energy diagrams by QM calculations and by QM(UB3LYP)/MM calculations . Possible reaction pathways for the O-O and O-OH bond formations are also investigated based on two water-inlet pathways for oxygen evolution in OEC of PSII. Future perspectives are discussed in relation to post HDFT calculations of the energy diagrams for elucidation of the mechanism of water oxidation in OEC of PSII.

Urinary tract infections: epidemiology, mechanisms of infection and treatment options

PubMed Central

Flores-Mireles, Ana L.; Walker, Jennifer N.; Caparon, Michael; Hultgren, Scott J.

2015-01-01

Urinary tract infections (UTIs) are a severe public health problem and are caused by a range of pathogens, but most commonly by Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus. High recurrence rates and increasing antimicrobial resistance among uropathogens threaten to greatly increase the economic burden of these infections. In this Review, we discuss how basic science studies are elucidating the molecular details of the crosstalk that occurs at the host–pathogen interface, as well as the consequences of these interactions for the pathophysiology of UTIs. We also describe current efforts to translate this knowledge into new clinical treatments for UTIs. PMID:25853778

Computational Elucidation of a Role That Brønsted Acidification of the Lewis Acid-Bound Water Might Play in the Hydrogenation of Carbonyl Compounds with H2 in Lewis Basic Solvents.

PubMed

Heshmat, Mojgan; Privalov, Timofei

2017-08-25

Brønsted acidification of water by Lewis acid (LA) complexation is one of the fundamental principles in chemistry. Using transition-state calculations (TS), herein we investigate the role that Brønsted acidification of the LA-bound water might play in the mechanism of the hydrogenation of carbonyl compounds in Lewis basic solvents under non-anhydrous conditions. The potential energy scans and TS calculations were carried out with a series of eight borane LAs as well as the commonly known strong LA AlCl 3 in 1,4-dioxane or THF as Lewis basic solvents. Our molecular model consists of the dative LA-water adduct with hydrogen bonds to acetone and a solvent molecule plus one additional solvent molecule that participates is the TS structure describing the cleavage of H 2 at acetone's carbonyl carbon atom. In all the molecular models applied here, acetone (O=CMe 2 ) is the archetypical carbonyl substrate. We demonstrate that Brønsted acidification of the LA-bound water can indeed lower the barrier height of the solvent-involving H 2 -cleavage at the acetone's carbonyl carbon atom. This is significant because at present it is believed that the mechanism of the herein considered reaction is described by the same mechanism regardless of whether the reaction conditions are strictly anhydrous or non-anhydrous. Our results offer an alternative to this belief that warrants consideration and further study. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Social Learning Modulates the Lateralization of Emotional Valence

ERIC Educational Resources Information Center

Shamay-Tsoory, Simone G.; Lavidor, Michal; Aharon-Peretz, Judith

2008-01-01

Although neuropsychological studies of lateralization of emotion have emphasized valence (positive vs. negative) or type (basic vs. complex) dimensions, the interaction between the two dimensions has yet to be elucidated. The purpose of the current study was to test the hypothesis that recognition of basic emotions is processed preferentially by…

Dysfunctions of decision-making and cognitive control as transdiagnostic mechanisms of mental disorders: advances, gaps, and needs in current research.

PubMed

Goschke, Thomas

2014-01-01

Disadvantageous decision-making and impaired volitional control over actions, thoughts, and emotions are characteristics of a wide range of mental disorders such as addiction, eating disorders, depression, and anxiety disorders and may reflect transdiagnostic core mechanisms and possibly vulnerability factors. Elucidating the underlying neurocognitive mechanisms is a precondition for moving from symptom-based to mechanism-based disorder classifications and ultimately mechanism-targeted interventions. However, despite substantial advances in basic research on decision-making and cognitive control, there are still profound gaps in our current understanding of dysfunctions of these processes in mental disorders. Central unresolved questions are: (i) to which degree such dysfunctions reflect transdiagnostic mechanisms or disorder-specific patterns of impairment; (ii) how phenotypical features of mental disorders relate to dysfunctional control parameter settings and aberrant interactions between large-scale brain systems involved in habit and reward-based learning, performance monitoring, emotion regulation, and cognitive control; (iii) whether cognitive control impairments are consequences or antecedent vulnerability factors of mental disorders; (iv) whether they reflect generalized competence impairments or context-specific performance failures; (v) whether not only impaired but also chronic over-control contributes to mental disorders. In the light of these gaps, needs for future research are: (i) an increased focus on basic cognitive-affective mechanisms underlying decision and control dysfunctions across disorders; (ii) longitudinal-prospective studies systematically incorporating theory-driven behavioural tasks and neuroimaging protocols to assess decision-making and control dysfunctions and aberrant interactions between underlying large-scale brain systems; (iii) use of latent-variable models of cognitive control rather than single tasks; (iv) increased focus on the interplay of implicit and explicit cognitive-affective processes; (v) stronger focus on computational models specifying neurocognitive mechanisms underlying phenotypical expressions of mental disorders. Copyright © 2013 John Wiley & Sons, Ltd.

[Construction of automatic elucidation platform for mechanism of traditional Chinese medicine].

PubMed

Zhang, Bai-xia; Luo, Si-jun; Yan, Jing; Gu, Hao; Luo, Ji; Zhang, Yan-ling; Tao, Ou; Wang, Yun

2015-10-01

Aim at the two problems in the field of traditional Chinese medicine (TCM) mechanism elucidation, one is the lack of detailed biological processes information, next is the low efficient in constructing network models, we constructed an auxiliary elucidation system for the TCM mechanism and realize the automatic establishment of biological network model. This study used the Entity Grammar Systems (EGS) as the theoretical framework, integrated the data of formulae, herbs, chemical components, targets of component, biological reactions, signaling pathways and disease related proteins, established the formal models, wrote the reasoning engine, constructed the auxiliary elucidation system for the TCM mechanism elucidation. The platform provides an automatic modeling method for biological network model of TCM mechanism. It would be benefit to perform the in-depth research on TCM theory of natures and combination and provides the scientific references for R&D of TCM.

A Low-Testosterone State Associated with Endometrioma Leads to the Apoptosis of Granulosa Cells

PubMed Central

Ono, Yoshihiro J.; Tanabe, Akiko; Nakamura, Yoko; Yamamoto, Hikaru; Hayashi, Atsushi; Tanaka, Tomohito; Sasaki, Hiroshi; Hayashi, Masami; Terai, Yoshito; Ohmichi, Masahide

2014-01-01

Although endometriosis is suspected to be a cause of premature ovarian insufficiency (POI), the mechanism(s) underlying this process have not been elucidated. Recently, androgens were shown to promote oocyte maturation and to play a role in folliculogenesis. In addition, several reports have documented low testosterone levels in the follicular fluid obtained from endometriosis patients. We therefore examined whether the low levels of serum testosterone are associated with the apoptosis of granulosa cells in follicles obtained from endometriosis patients. Serum samples were collected from 46 patients with endometriosis and from 62 patients without endometriosis who received assisted reproductive therapy. Specimens of the ovaries obtained from 10 patients with endometrioma were collected using laparoscopy. The mean serum testosterone concentration in the patients with endometriosis was significantly lower than that observed in the patients without endometriosis. Furthermore, high expression of a pro-apoptotic Bcl-2 member, BimEL, in the follicles was found to be associated with a low serum testosterone level. We clarified the underlying mechanisms using a basic approach employing human immortalized granulosa cells derived from a primary human granulosa cell tumor, the COV434 cell line. The in vitro examination demonstrated that testosterone inhibited apoptosis induced by sex steroids depletion via the PI3K/Akt-FoxO3a pathway in the COV434 cells. In conclusion, we elucidated the mechanism underlying the anti-apoptotic effects of testosterone on granulosa cells, and found that a low-testosterone status is a potentially important step in the development of premature ovarian insufficiency in patients with endometriosis. PMID:25536335

Modulatory mechanisms of cortisol effects on emotional learning and memory: novel perspectives.

PubMed

van Ast, Vanessa A; Cornelisse, Sandra; Marin, Marie-France; Ackermann, Sandra; Garfinkel, Sarah N; Abercrombie, Heather C

2013-09-01

It has long been known that cortisol affects learning and memory processes. Despite a wealth of research dedicated to cortisol effects on learning and memory, the strength or even directionality of the effects often vary. A number of the factors that alter cortisol's effects on learning and memory are well-known. For instance, effects of cortisol can be modulated by emotional arousal and the memory phase under study. Despite great advances in understanding factors that explain variability in cortisol's effects, additional modulators of cortisol effects on memory exist that are less widely acknowledged in current basic experimental research. The goal of the current review is to disseminate knowledge regarding less well-known modulators of cortisol effects on learning and memory. Since several models for the etiology of anxiety, such as post-traumatic stress disorder (PTSD), incorporate stress and the concomitant release of cortisol as important vulnerability factors, enhanced understanding of mechanisms by which cortisol exerts beneficial as opposed to detrimental effects on memory is very important. Further elucidation of the factors that modulate (or alter) cortisol's effects on memory will allow reconciliation of seemingly inconsistent findings in the basic and clinical literatures. The present review is based on a symposium as part of the 42nd International Society of Psychoneuroendocrinology Conference, New York, USA, that highlighted some of those modulators and their underlying mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes

PubMed Central

Makris, Konstantinos; Spanou, Loukia

2016-01-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI. PMID:28303073

Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes.

PubMed

Makris, Konstantinos; Spanou, Loukia

2016-05-01

Acute kidney injury (AKI) is a clinical syndrome that complicates the course and worsens the outcome in a significant number of hospitalised patients. Recent advances in clinical and basic research will help with a more accurate definition of this syndrome and in the elucidation of its pathogenesis. With this knowledge we will be able to conduct more accurate epidemiologic studies in an effort to gain a better understanding of the impact of this syndrome. AKI is a syndrome that rarely has a sole and distinct pathophysiology. Recent evidence, in both basic science and clinical research, is beginning to change our view for AKI from a single organ failure syndrome to a syndrome where the kidney plays an active role in the progress of multi-organ dysfunction. Accurate and prompt recognition of AKI and better understanding of the pathophysiologic mechanisms underlying the various clinical phenotypes are of great importance to research for effective therapeutic interventions. In this review we provide the most recent updates in the definition, epidemiology and pathophysiology of AKI.

[Role of G-protein alpha sub-units in the morphogenic processes of filamentous Ascomycota fungi].

PubMed

García-Rico, Ramón O; Fierro, Francisco

The phylum Ascomycota comprises about 75% of all the fungal species described, and includes species of medical, phytosanitary, agricultural, and biotechnological importance. The ability to spread, explore, and colonise new substrates is a feature of critical importance for this group of organisms. In this regard, basic processes such as conidial germination, the extension of hyphae and sporulation, make up the backbone of development in most filamentous fungi. These processes require specialised morphogenic machinery, coordinated and regulated by mechanisms that are still being elucidated. In recent years, substantial progress has been made in understanding the role of the signalling pathway mediated by heterotrimericG proteins in basic biological processes of many filamentous fungi. This review focuses on the role of the alpha subunits of heterotrimericG proteins in the morphogenic processes of filamentous Ascomycota. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Muscle Satellite Cells: Exploring the Basic Biology to Rule Them.

PubMed

Almeida, Camila F; Fernandes, Stephanie A; Ribeiro Junior, Antonio F; Keith Okamoto, Oswaldo; Vainzof, Mariz

2016-01-01

Adult skeletal muscle is a postmitotic tissue with an enormous capacity to regenerate upon injury. This is accomplished by resident stem cells, named satellite cells, which were identified more than 50 years ago. Since their discovery, many researchers have been concentrating efforts to answer questions about their origin and role in muscle development, the way they contribute to muscle regeneration, and their potential to cell-based therapies. Satellite cells are maintained in a quiescent state and upon requirement are activated, proliferating, and fusing with other cells to form or repair myofibers. In addition, they are able to self-renew and replenish the stem pool. Every phase of satellite cell activity is highly regulated and orchestrated by many molecules and signaling pathways; the elucidation of players and mechanisms involved in satellite cell biology is of extreme importance, being the first step to expose the crucial points that could be modulated to extract the optimal response from these cells in therapeutic strategies. Here, we review the basic aspects about satellite cells biology and briefly discuss recent findings about therapeutic attempts, trying to raise questions about how basic biology could provide a solid scaffold to more successful use of these cells in clinics.

(Per)chlorate in Biology on Earth and Beyond.

PubMed

Youngblut, Matthew D; Wang, Ouwei; Barnum, Tyler P; Coates, John D

2016-09-08

Respiration of perchlorate and chlorate [collectively, (per)chlorate] was only recognized in the last 20 years, yet substantial advances have been made in our understanding of the underlying metabolisms. Although it was once considered solely anthropogenic, pervasive natural sources, both terrestrial and extraterrestrial, indicate an ancient (per)chlorate presence across our solar system. These discoveries stimulated interest in (per)chlorate microbiology, and the application of advanced approaches highlights exciting new facets. Forward and reverse genetics revealed new information regarding underlying molecular biology and associated regulatory mechanisms. Structural and functional analysis characterized core enzymes and identified novel reaction sequences. Comparative genomics elucidated evolutionary aspects, and stress analysis identified novel response mechanisms to reactive chlorine species. Finally, systems biology identified unique metabolic versatility and novel mechanisms of (per)chlorate respiration, including symbiosis and a hybrid enzymatic-abiotic metabolism. While many published studies focus on (per)chlorate and their basic metabolism, this review highlights seminal advances made over the last decade and identifies new directions and potential novel applications.

Fluidization, resolidification, and reorientation of the endothelial cell in response to slow tidal stretches

PubMed Central

Krishnan, Ramaswamy; Canović, Elizabeth Peruski; Iordan, Andreea L.; Rajendran, Kavitha; Manomohan, Greeshma; Pirentis, Athanassios P.; Smith, Michael L.; Butler, James P.; Fredberg, Jeffrey J.

2012-01-01

Mechanical stretch plays an important role in regulating shape and orientation of the vascular endothelial cell. This morphological response to stretch is basic to angiogenesis, neovascularization, and vascular homeostasis, but mechanism remains unclear. To elucidate mechanisms, we used cell mapping rheometry to measure traction forces in primary human umbilical vein endothelial cells subjected to periodic uniaxial stretches. Onset of periodic stretch of 10% strain amplitude caused a fluidization response typified by attenuation of traction forces almost to zero. As periodic stretch continued, the prompt fluidization response was followed by a slow resolidification response typified by recovery of the traction forces, but now aligned along the axis perpendicular to the imposed stretch. Reorientation of the cell body lagged reorientation of the traction forces, however. Together, these observations demonstrate that cellular reorientation in response to periodic stretch is preceded by traction attenuation by means of cytoskeletal fluidization and subsequent traction recovery transverse to the stretch direction by means of cytoskeletal resolidification. PMID:22700796

Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

PubMed Central

Hagerman, Randi; Hagerman, Paul

2014-01-01

Summary Fragile X syndrome, the leading heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (FMR1) gene consequent to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, “premutation” expansions (55–200 repeats) can give rise to a family of neurodevelopmental (ADHD, autism spectrum disorder, seizure disorder) and neurodegenerative (FXTAS) clinical phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the spectrum of clinical involvement. Whereas advances on both mechanistic and clinical fronts are driving new approaches to targeted treatment, two important issues/needs are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in light of its differing presentations and associated features. PMID:23867198

Mechanical stress mediated by both endosperm softening and embryo growth underlies endosperm elimination in Arabidopsis seeds.

PubMed

Fourquin, Chloé; Beauzamy, Léna; Chamot, Sophy; Creff, Audrey; Goodrich, Justin; Boudaoud, Arezki; Ingram, Gwyneth

2016-09-15

Seed development in angiosperms demands the tightly coordinated development of three genetically distinct structures. The embryo is surrounded by the endosperm, which is in turn enclosed within the maternally derived seed coat. In Arabidopsis, final seed size is determined by early expansion of the coenocytic endosperm, which then cellularises and subsequently undergoes developmental programmed cell death, breaking down as the embryo grows. Endosperm breakdown requires the endosperm-specific basic helix-loop-helix transcription factor ZHOUPI. However, to date, the mechanism underlying the Arabidopsis endosperm breakdown process has not been elucidated. Here, we provide evidence that ZHOUPI does not induce the developmental programmed cell death of the endosperm directly. Instead ZHOUPI indirectly triggers cell death by regulating the expression of cell wall-modifying enzymes, thus altering the physical properties of the endosperm to condition a mechanical environment permitting the compression of the cellularised endosperm by the developing embryo. © 2016. Published by The Company of Biologists Ltd.

Evaluation of the Effects of Platelet-Rich Plasma (PRP) Therapy Involved in the Healing of Sports-Related Soft Tissue Injuries

PubMed Central

Middleton, Kellie K.; Barro, Victor; Muller, Bart; Terada, Satosha; Fu, Freddie H.

2012-01-01

Abstract Musculoskeletal injuries are the most common cause of severe long-term pain and physical disability, and affect hundreds of millions of people around the world. One of the most popular methods used to biologically enhance healing in the fields of orthopaedic surgery and sports medicine includes the use of autologous blood products, namely, platelet rich plasma (PRP). PRP is an autologous concentration of human platelets to supra-physiologic levels. At baseline levels, platelets function as a natural reservoir for growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor-beta 1 (TGF-β1), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and insulin-like growth factor (IGF-I). PRP is commonly used in orthopaedic practice to augment healing in sports-related injuries of skeletal muscle, tendons, and ligaments. Despite its pervasive use, the clinical efficacy of PrP therapy and varying mechanisms of action have yet to be established. Basic science research has revealed that PRP exerts is effects through many downstream events secondary to release of growth factors and other bioactive factors from its alpha granules. These effects may vary depending on the location of injury and the concentration of important growth factors involved in various soft tissue healing responses. This review focuses on the effects of PrP and its associated bioactive factors as elucidated in basic science research. Current findings in PRP basic science research, which have shed light on its proposed mechanisms of action, have opened doors for future areas of PrP research. PMID:23576936

Using spatial capture–recapture to elucidate population processes and space-use in herpetological studies

USGS Publications Warehouse

Muñoz, David J.; Miller, David A.W.; Sutherland, Chris; Grant, Evan H. Campbell

2016-01-01

The cryptic behavior and ecology of herpetofauna make estimating the impacts of environmental change on demography difficult; yet, the ability to measure demographic relationships is essential for elucidating mechanisms leading to the population declines reported for herpetofauna worldwide. Recently developed spatial capture–recapture (SCR) methods are well suited to standard herpetofauna monitoring approaches. Individually identifying animals and their locations allows accurate estimates of population densities and survival. Spatial capture–recapture methods also allow estimation of parameters describing space-use and movement, which generally are expensive or difficult to obtain using other methods. In this paper, we discuss the basic components of SCR models, the available software for conducting analyses, and the experimental designs based on common herpetological survey methods. We then apply SCR models to Red-backed Salamander (Plethodon cinereus), to determine differences in density, survival, dispersal, and space-use between adult male and female salamanders. By highlighting the capabilities of SCR, and its advantages compared to traditional methods, we hope to give herpetologists the resource they need to apply SCR in their own systems.

Study of the interaction of deoxynivalenol with human serum albumin by spectroscopic technique and molecular modelling.

PubMed

Li, Yuqin; Wang, Hao; Jia, Baoxiu; Liu, Caihong; Liu, Ke; Qi, Yongxiu; Hu, Zhide

2013-01-01

The mechanism of interaction between deoxynivalenol (DON) and human serum albumin (HSA) was studied using spectroscopic methods including fluorescence spectra, UV-VIS, Fourier transform infrared (FT-IR) and circular dichroism (CD). The quenching mechanism was investigated in terms of the association constants, number of binding sites and basic thermodynamic parameters. The distance between the HSA donor and the acceptor DON was 2.80 nm as derived from fluorescence resonance energy transfer. The secondary structure compositions of free HSA and its DON complexes were estimated by the FT-IR spectra. Alteration of the secondary protein structure in the presence of DON was confirmed by UV-VIS and CD spectroscopy. Molecular modelling revealed that a DON-protein complex was stabilised by hydrophobic forces and hydrogen bonding. It was potentially useful for elucidating the toxigenicity of DON when combined with biomolecular function effect, transmembrane transport, toxicological testing and the other experiments.

Chemical processes involved in the initiation of hot corrosion of B-1900 and NASA-TRW VIA. [high temperature tests of superalloys

NASA Technical Reports Server (NTRS)

Fryburg, G. C.; Kohl, F. J.; Stearns, C. A.

1979-01-01

Sodium surface-induced hot corrosion of B-1900 and NASA-TRW VIA alloys at 900 C has been studied, with special attention to the chemical reactions during and immediately after the induction period. Thermogravimetric tests were run and data were obtained by chemical analysis of water soluble metal salts and of residual sulfate. Surface analyses of hot corroded samples were obtained by spectroscopic techniques (ESCA). A chemical mechanism for elucidating Na2SO4-induced hot corrosion is proposed indicating that hot corrosion is initiated by basic fluxing of the protective Al2O3 scale. The sequential, catastrophic corrosion results from molybdenum content. The self-sustaining feature is a consequence of the cyclic nature of the acidic fluxing. It is believed that the mechanism is applicable not only to laboratory results, but also to the practical problem of hot corrosion encountered in gas turbine engines.

Castleman's Disease: From Basic Mechanisms to Molecular Therapeutics

PubMed Central

El-Osta, Hazem E.

2011-01-01

Castleman's disease is a rare lymphoproliferative disorder in which there has been recent progress in elucidating underlying mechanisms with potential therapeutic implications. Unicentric Castleman's disease is an indolent condition that is often treated with local approaches. In contrast, patients with multicentric Castleman's disease (MCD) have a less favorable prognosis and require systemic treatment. Cytotoxic chemotherapy, with its attendant risk for toxicity, has been widely used to treat MCD, with variable efficacy. The discovery of putative etiologic factors and targets in MCD, particularly human herpes virus 8, CD20, and interleukin (IL)-6, has been translated into the use of rituximab and anti–IL-6-based therapy, as well as antiviral agents. In this article, we review the current state of the art of our understanding of Castleman's disease and its treatment and we provide insight into future treatment strategies based on disease biology. PMID:21441298

Initiation of the Immune Response by Extracellular Hsp72: Chaperokine Activity of Hsp72

PubMed Central

Asea, Alexzander

2007-01-01

Heat shock proteins exert their beneficial effects via basically two modes of action depending on their relative location within the host. Intracellular heat shock proteins found within cells serve a cytoprotective role by chaperoning naïve, misfolded and/or denatured proteins in response to stressful stimuli by a process known as the stress response. However, stressful stimuli also induce the release of intracellular heat shock proteins into the extracellular milieu and circulation. The extracellular heat shock protein proteins serve a cytostimulatory role by initiating immune responses designed to fend off microbial infection and destroy neoplastic transformed cells. This review will briefly cover recent advances into elucidating the mechanism(s) by which stress induces the release of heat shock proteins into the circulation, how it initiates immune responses and suggest the possible biological significance of circulating Hsp to the host. PMID:17502920

Initiation of the Immune Response by Extracellular Hsp72: Chaperokine Activity of Hsp72.

PubMed

Asea, Alexzander

2006-08-01

Heat shock proteins exert their beneficial effects via basically two modes of action depending on their relative location within the host. Intracellular heat shock proteins found within cells serve a cytoprotective role by chaperoning naïve, misfolded and/or denatured proteins in response to stressful stimuli by a process known as the stress response. However, stressful stimuli also induce the release of intracellular heat shock proteins into the extracellular milieu and circulation. The extracellular heat shock protein proteins serve a cytostimulatory role by initiating immune responses designed to fend off microbial infection and destroy neoplastic transformed cells. This review will briefly cover recent advances into elucidating the mechanism(s) by which stress induces the release of heat shock proteins into the circulation, how it initiates immune responses and suggest the possible biological significance of circulating Hsp to the host.

Development of New Treatments for Prostate Cancer

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

DiPaola, R. S.; Abate-Shen, C.; Hait, W. N.

2005-02-01

The Dean and Betty Gallo Prostate Cancer Center (GPCC) was established with the goal of eradicating prostate cancer and improving the lives of men at risk for the disease through research, treatment, education and prevention. GPCC was founded in the memory of Dean Gallo, a beloved New Jersey Congressman who died tragically of prostate cancer diagnosed at an advanced stage. GPCC unites a team of outstanding researchers and clinicians who are committed to high-quality basic research, translation of innovative research to the clinic, exceptional patient care, and improving public education and awareness of prostate cancer. GPCC is a center ofmore » excellence of The Cancer Institute of New Jersey, which is the only NCI-designated comprehensive cancer center in the state. GPCC efforts are now integrated well as part of our Prostate Program at CINJ, in which Dr. Robert DiPaola and Dr. Cory Abate-Shen are co-leaders. The Prostate Program unites 19 investigators from 10 academic departments who have broad and complementary expertise in prostate cancer research. The overall goal and unifying theme is to elucidate basic mechanisms of prostate growth and oncogenesis, with the ultimate goal of promoting new and effective strategies for the eradication of prostate cancer. Members' wide range of research interests collectively optimize the chances of providing new insights into normal prostate biology and unraveling the molecular pathophysiology of prostate cancer. Cell culture and powerful animal models developed by program members recapitulate the various stages of prostate cancer progression, including prostatic intraepithelial neoplasia, adenocarcinoma, androgen-independence, invasion and metastases. These models promise to further strengthen an already robust program of investigator-initiated therapeutic clinical trials, including studies adopted by national cooperative groups. Efforts to translate laboratory results into clinical studies of early detection and chemoprevention are underway. The specific goals of this program are: (1) To investigate the molecular mechanisms underlying normal prostate growth and differentiation and elucidate the molecular mechanisms underlying prostate oncogenesis. (2) To build on fundamental knowledge to develop effective therapeutic approaches for the treatment of prostate cancer. (3) To improve the control of prostate cancer through early detection, chemoprevention, and outreach and education. This new disease-based program is structured to improve interdisciplinary interactions and translational results. Already, through the dynamic leadership of Drs. Cory Abate-Shen and Robert DiPaola, new investigators were attracted to the field, new collaborations engendered, and numerous investigator-initiated trials implemented. Progress in GPCC and the program overall has been outstanding. The Center has success in uniting investigators with broad and complementary expertise in prostate cancer research. The overall goal and unifying theme is to elucidate basic mechanisms of prostate growth and oncogenesis, with the ultimate goal of promoting new and effective strategies for the eradication of prostate cancer in patients and populations at risk. Members wide range of research interests collectively optimize the chances of providing new insights into normal prostate biology and unraveling the molecular pathophysiology of prostate cancer. Studies in cell culture and powerful animal models developed recapitulate the various stages of prostate cancer progression, including prostatic intraepithelial neoplasia, adenocarcinoma, androgen-independence, invasion and metastases. These models promise to further strengthen an already robust program of investigator-initiated therapeutic clinical trials, including studies adopted by national cooperative groups. Efforts to translate laboratory results into clinical studies of early detection and chemoprevention are underway.« less

Social Physique Anxiety, Mental Health, and Exercise: Analyzing the Role of Basic Psychological Needs and Psychological Inflexibility.

PubMed

Alcaraz-Ibáñez, Manuel; Sicilia, Álvaro; Burgueño, Rafael

2017-02-22

This study aimed to determine the usefulness of integrating basic psychological needs theory (BPNT) and relational frames theory (RFT) in order to explain the effects of social physique anxiety (SPA) - in the context of exercise - on exercisers' mental health. A total of 296 recreational cyclists and triathletes (100% males) aged 18 to 60 years old (M age = 35.65, SD = 9.49) completed a multi-section questionnaire assessing the target variables. Two models of structural equations with multiple mediators were tested using 5000 bootstrap samples. While the BPNT-based model explained 20% of variance in satisfaction with life (SWL) and 25% of variance in mental health (MH), the model that also incorporated RFT explained 43% of variance in both of those variables. Results showed that SPA negatively impacted exercisers' mental health via two different mechanisms: a) through a decrease in perceived satisfaction of basic psychological needs (β = -.05, p = .045 for SWL; β = -.07, p = .002 for MH); b) through an increase in psychological inflexibility, generated directly by SPA (β = -.24, p < .001 for SWL; β = -.20, p < .001 for MH) and also mediated by basic psychological need thwarting (β = -.09, p < .001 for SWL; β = -.08, p = .002 for MH). Results supported integrating the two theories, elucidating the processes by which a controlling social factor like SPA can affect the potential benefits of exercise.

Pernicious plans revealed: Plasmodium falciparum genome wide expression analysis.

PubMed

Llinás, Manuel; DeRisi, Joseph L

2004-08-01

The asexual intraerythrocytic developmental cycle (IDC) of Plasmodium falciparum is responsible for the majority of the clinical manifestations of malaria in humans. Although malaria has been studied for over a century, the elucidation of the full genome sequence of P. falciparum has now allowed for in-depth studies of gene expression throughout the entire intraerythrocytic stage. As the mainstays of anti-malarial chemotherapy become increasingly ineffective, we need a deeper understanding of fundamental plasmodial bioregulatory mechanisms to successfully subvert them. Recent gene expression studies have begun to examine different aspects of the IDC and are providing key insights into the basic mechanisms of Plasmodium gene regulation and are helping to define gene functions. However, to date, no transcription factor has been fully characterized from Plasmodium and the definitive identification of cis-acting regulatory elements along with their corresponding trans-acting partners is still lacking. The characterization of the transcriptome of P. falciparum is the first major step towards the understanding of the genome wide regulation of gene expression in this parasite. IDC expression data for almost every gene in the P. falciparum genome can now be publicly queried at and. The results of these studies suggest promising leads for identifying novel targets for anti-malarial therapeutics and vaccines in addition to providing a solid foundation for the ongoing elucidation of plasmodial gene expression.

Obesity Pathogenesis: An Endocrine Society Scientific Statement.

PubMed

Schwartz, Michael W; Seeley, Randy J; Zeltser, Lori M; Drewnowski, Adam; Ravussin, Eric; Redman, Leanne M; Leibel, Rudolph L

2017-08-01

Obesity is among the most common and costly chronic disorders worldwide. Estimates suggest that in the United States obesity affects one-third of adults, accounts for up to one-third of total mortality, is concentrated among lower income groups, and increasingly affects children as well as adults. A lack of effective options for long-term weight reduction magnifies the enormity of this problem; individuals who successfully complete behavioral and dietary weight-loss programs eventually regain most of the lost weight. We included evidence from basic science, clinical, and epidemiological literature to assess current knowledge regarding mechanisms underlying excess body-fat accumulation, the biological defense of excess fat mass, and the tendency for lost weight to be regained. A major area of emphasis is the science of energy homeostasis, the biological process that maintains weight stability by actively matching energy intake to energy expenditure over time. Growing evidence suggests that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight. We need to elucidate the mechanisms underlying this "upward setting" or "resetting" of the defended level of body-fat mass, whether inherited or acquired. The ongoing study of how genetic, developmental, and environmental forces affect the energy homeostasis system will help us better understand these mechanisms and are therefore a major focus of this statement. The scientific goal is to elucidate obesity pathogenesis so as to better inform treatment, public policy, advocacy, and awareness of obesity in ways that ultimately diminish its public health and economic consequences. Copyright © 2017 Endocrine Society.

VQS (vapor-quasiliquid-solid, vapor-quasisolid-solid) mechanism presents a unified foundation for the syntheses of nanotubes, primarily carbon nanotubes

NASA Astrophysics Data System (ADS)

Mohammad, S. Noor

2017-09-01

Nanotubes are synthesized almost entirely by metal-catalyst-free and metal-catalyst-mediated non-eutectic mechanism(s). An investigation has been carried out to understand the basics of this mechanism. Various possible chemical and physical processes involved in nanotube synthesis have been researched. Various components and attributes of nanotube synthesis have been evaluated. Phase transitions, alloy formation, porosity, carrier transport and the fundamentals underlying them have been examined. Nanoparticle surfaces conducive to nanotube synthesis have been examined. The role of surface treatment, which includes oxidation, oxygenation, acid treatment, plasma treatment, water treatment, sputtering, etc in creating such surfaces, has been investigated. The role of surface treatment and phase transitions as functions of temperature, pressure, ambient, contaminants, surface amorphicity, etc in creating diffusion paths for the diffusion of growth species for supersaturation and nucleation has been explored. Interdiffusion of catalyst and source materials, and hence exchange of materials, on the nanoparticle surface, have been elucidated. This exchange of materials on catalyst surface appears to add a new dimension to the synthesis kinetics. Integrated together, they reveal a general mechanism for probably all metal-catalyst-free and metal-catalyst-mediated non-eutectic nanotube synthesis. Available experiments strongly support the proposed mechanism; they suggest that this mechanism has a broad appeal.

Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive and Metastatic Breast Carcinomas

DTIC Science & Technology

2004-06-01

cells in mitosis. Mutations in any of these genes result in failure to arrest Keywords: BCSG I: BubRl; mitotic checkpoint; yeast the cell cycle at G2...AD Award Number: DAMD17-02-1-0534 TITLE: Elucidation of the Molecular Mechanisms for Aberrant Expression of Breast Cancer Specific Gene 1 in Invasive...SUBTITLE 5. FUNDING NUMBERS Elucidation of the Molecular Mechanisms for Aberrant DAMD17-02-1-0534 Expression of Breast Cancer Specific Gene 1 in Invasive

Empathy as a driver of prosocial behaviour: highly conserved neurobehavioural mechanisms across species

PubMed Central

Decety, Jean; Bartal, Inbal Ben-Ami; Uzefovsky, Florina; Knafo-Noam, Ariel

2016-01-01

Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well-being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions. PMID:26644596

Local immunological mechanisms of sublingual immunotherapy.

PubMed

Allam, Jean-Pierre; Novak, Natalija

2011-12-01

To summarize novel insights into the immunological mechanisms of sublingual immunotherapy (SLIT). Within the recent decades, several alternative noninvasive allergen application strategies have been investigated in allergen-specific immunotherapy (AIT), of which intra-oral allergen application to sublingual mucosa has been proven to be well tolerated and effective. To date, SLIT is widely accepted by most allergists as an alternative option to conventional subcutaneous immunotherapy (SCIT). Although detailed immunological mechanisms remain to be elucidated, much scientific effort has been made to shed some light on local and systemic immunological responses to SLIT in mice as well as humans. Only a few studies focused on the detailed mechanisms following allergen application to the oral mucosa as part of the sophisticated mucosal immunological network. Within this network, the pro-tolerogenic properties of local antigen-presenting cells (APCs) such as dendritic cells - which are able to enforce tolerogenic mechanisms and to induce T-cell immune responses - play a central role. Further on, basic research focused not only on the immune response in nasal and bronchial mucosa but also on the systemic T-cell immune response. Thus, much exiting data have been published providing a better understanding of immunological features of SLIT but far more investigations are necessary to uncover further exciting details on the key mechanisms of SLIT.

High throughput de novo RNA sequencing elucidates novel responses in Penicillium chrysogenum under microgravity.

PubMed

Sathishkumar, Yesupatham; Krishnaraj, Chandran; Rajagopal, Kalyanaraman; Sen, Dwaipayan; Lee, Yang Soo

2016-02-01

In this study, the transcriptional alterations in Penicillium chrysogenum under simulated microgravity conditions were analyzed for the first time using an RNA-Seq method. The increasing plethora of eukaryotic microbial flora inside the spaceship demands the basic understanding of fungal biology in the absence of gravity vector. Penicillium species are second most dominant fungal contaminant in International Space Station. Penicillium chrysogenum an industrially important organism also has the potential to emerge as an opportunistic pathogen for the astronauts during the long-term space missions. But till date, the cellular mechanisms underlying the survival and adaptation of Penicillium chrysogenum to microgravity conditions are not clearly elucidated. A reference genome for Penicillium chrysogenum is not yet available in the NCBI database. Hence, we performed comparative de novo transcriptome analysis of Penicillium chrysogenum grown under microgravity versus normal gravity. In addition, the changes due to microgravity are documented at the molecular level. Increased response to the environmental stimulus, changes in the cell wall component ABC transporter/MFS transporters are noteworthy. Interestingly, sustained increase in the expression of Acyl-coenzyme A: isopenicillin N acyltransferase (Acyltransferase) under microgravity revealed the significance of gravity in the penicillin production which could be exploited industrially.

A Peptidomics Strategy to Elucidate the Proteolytic Pathways that Inactivate Peptide Hormones

PubMed Central

Tinoco, Arthur D.; Kim, Yun-Gon; Tagore, Debarati M.; Wiwczar, Jessica; Lane, William S.; Danial, Nika N.; Saghatelian, Alan

2011-01-01

Proteolysis plays a key role in regulating the levels and activity of peptide hormones. Characterization of the proteolytic pathways that cleave peptide hormones is of basic interest and can, in some cases, spur the development of novel therapeutics. The lack, however, of an efficient approach to identify endogenous fragments of peptide hormones has hindered the elucidation of these proteolytic pathways. Here, we apply a mass spectrometry (MS)-based peptidomics approach to characterize the intestinal fragments of peptide histidine isoleucine (PHI), a hormone that promotes glucose-stimulated insulin secretion (GSIS). Our approach reveals a proteolytic pathway in the intestine that truncates PHI at its C-terminus to produce a PHI fragment that is inactive in a GSIS assay—a result that provides a potential mechanism of PHI regulation in vivo. Differences between these in vivo peptidomics studies and in vitro lysate experiments, which showed N- and C-terminal processing of PHI, underscore the effectiveness of this approach to discover physiologically relevant proteolytic pathways. Moreover, integrating this peptidomics approach with bioassays (i.e. GSIS) provides a general strategy to reveal proteolytic pathways that may regulate the activity of peptide hormones. PMID:21299233

Possible neuronal mechanisms of sleep disturbances in patients with autism spectrum disorders and attention-deficit/hyperactivity disorder.

PubMed

Kohyama, Jun

2016-12-01

The most common form of sleep disturbance among both patients with autism spectrum disorders and patients with attention-deficit/hyperactivity disorder is sleep-onset insomnia, but the neuronal mechanisms underlying it have yet to be elucidated and no specific treatment strategy has been proposed. This means that many caregivers struggle to manage this problem on a daily basis. This paper presents a hypothesis about the neuronal mechanisms underlying insomnia in patients with autism spectrum disorders and attention-deficit/hyperactivity disorder based on recent clinical and basic research. It is proposed that three neuronal mechanisms (increased orexinergic system activity, reduced 5-hydroxytryptamine and melatonergic system activity, rapid eye movement sleep reduction) are involved in insomnia in both autism spectrum disorders and attention-deficit/hyperactivity disorder. This suggests that antagonists against the orexin receptors may have beneficial effects on insomnia in patients with autism spectrum disorders or attention-deficit/hyperactivity disorder. To the best of the author's knowledge there has been no research into the effects of this agent on insomnia in these patient groups. Large, controlled trials should be carried out. Copyright © 2016 Elsevier Ltd. All rights reserved.

Response threshold variance as a basis of collective rationality

PubMed Central

Yamamoto, Tatsuhiro

2017-01-01

Determining the optimal choice among multiple options is necessary in various situations, and the collective rationality of groups has recently become a major topic of interest. Social insects are thought to make such optimal choices by collecting individuals' responses relating to an option's value (=a quality-graded response). However, this behaviour cannot explain the collective rationality of brains because neurons can make only ‘yes/no’ responses on the basis of the response threshold. Here, we elucidate the basic mechanism underlying the collective rationality of such simple units and show that an ant species uses this mechanism. A larger number of units respond ‘yes’ to the best option available to a collective decision-maker using only the yes/no mechanism; thus, the best option is always selected by majority decision. Colonies of the ant Myrmica kotokui preferred the better option in a binary choice experiment. The preference of a colony was demonstrated by the workers, which exhibited variable thresholds between two options' qualities. Our results demonstrate how a collective decision-maker comprising simple yes/no judgement units achieves collective rationality without using quality-graded responses. This mechanism has broad applicability to collective decision-making in brain neurons, swarm robotics and human societies. PMID:28484636

Response threshold variance as a basis of collective rationality.

PubMed

Yamamoto, Tatsuhiro; Hasegawa, Eisuke

2017-04-01

Determining the optimal choice among multiple options is necessary in various situations, and the collective rationality of groups has recently become a major topic of interest. Social insects are thought to make such optimal choices by collecting individuals' responses relating to an option's value (=a quality-graded response). However, this behaviour cannot explain the collective rationality of brains because neurons can make only 'yes/no' responses on the basis of the response threshold. Here, we elucidate the basic mechanism underlying the collective rationality of such simple units and show that an ant species uses this mechanism. A larger number of units respond 'yes' to the best option available to a collective decision-maker using only the yes/no mechanism; thus, the best option is always selected by majority decision. Colonies of the ant Myrmica kotokui preferred the better option in a binary choice experiment. The preference of a colony was demonstrated by the workers, which exhibited variable thresholds between two options' qualities. Our results demonstrate how a collective decision-maker comprising simple yes/no judgement units achieves collective rationality without using quality-graded responses. This mechanism has broad applicability to collective decision-making in brain neurons, swarm robotics and human societies.

Recent progress in structural biology: lessons from our research history.

PubMed

Nitta, Ryo; Imasaki, Tsuyoshi; Nitta, Eriko

2018-05-16

The recent 'resolution revolution' in structural analyses of cryo-electron microscopy (cryo-EM) has drastically changed the research strategy for structural biology. In addition to X-ray crystallography and nuclear magnetic resonance spectroscopy, cryo-EM has achieved the structural analysis of biological molecules at near-atomic resolution, resulting in the Nobel Prize in Chemistry 2017. The effect of this revolution has spread within the biology and medical science fields affecting everything from basic research to pharmaceutical development by visualizing atomic structure. As we have used cryo-EM as well as X-ray crystallography since 2000 to elucidate the molecular mechanisms of the fundamental phenomena in the cell, here we review our research history and summarize our findings. In the first half of the review, we describe the structural mechanisms of microtubule-based motility of molecular motor kinesin by using a joint cryo-EM and X-ray crystallography method. In the latter half, we summarize our structural studies on transcriptional regulation by X-ray crystallography of in vitro reconstitution of a multi-protein complex.

How synthetic membrane systems contribute to the understanding of lipid-driven endocytosis.

PubMed

Schubert, Thomas; Römer, Winfried

2015-11-01

Synthetic membrane systems, such as giant unilamellar vesicles and solid supported lipid bilayers, have widened our understanding of biological processes occurring at or through membranes. Artificial systems are particularly suited to study the inherent properties of membranes with regard to their components and characteristics. This review critically reflects the emerging molecular mechanism of lipid-driven endocytosis and the impact of model membrane systems in elucidating the complex interplay of biomolecules within this process. Lipid receptor clustering induced by binding of several toxins, viruses and bacteria to the plasma membrane leads to local membrane bending and formation of tubular membrane invaginations. Here, lipid shape, and protein structure and valency are the essential parameters in membrane deformation. Combining observations of complex cellular processes and their reconstitution on minimal systems seems to be a promising future approach to resolve basic underlying mechanisms. This article is part of a Special Issue entitled: Mechanobiology. Copyright © 2015 Elsevier B.V. All rights reserved.

An Experimental Model Using Cultured Cardiac Myocytes for a Study of the Generation of Premature Ventricular Contractions Under Ultrasound Exposure

NASA Astrophysics Data System (ADS)

Kudo, Nobuki; Yamamoto, Masaya

2011-09-01

It is known that use of a contrast agents in echocardiography increases the probability of generation of premature ventricular contractions (PVCs). As a basic study to elucidate the mechanisms and to reduce adverse effects, the generation of PVCs was investigated using cultured cardiac myocytes instead of the intact heart in vivo. Cardiac myocytes were isolated from neonatal rats and cultured on a cover slip. The myocyte sample was exposed to pulsed ultrasound with microbubbles adjacent to the myocytes, and generation of PVCs was examined with ultrasound exposure at various delay times after onset of myocyte contraction. The experimental results showed that generation of PVCs had a stable threshold delay time and that PVCs were generated only when myocytes were exposed to ultrasound with delay times longer than the threshold. The results indicate that the model used in this study is useful for revealing the mechanisms by which PVCs are induced by ultrasound exposure.

Theory for plasticity of face-centered cubic metals.

PubMed

Jo, Minho; Koo, Yang Mo; Lee, Byeong-Joo; Johansson, Börje; Vitos, Levente; Kwon, Se Kyun

2014-05-06

The activation of plastic deformation mechanisms determines the mechanical behavior of crystalline materials. However, the complexity of plastic deformation and the lack of a unified theory of plasticity have seriously limited the exploration of the full capacity of metals. Current efforts to design high-strength structural materials in terms of stacking fault energy have not significantly reduced the laborious trial and error works on basic deformation properties. To remedy this situation, here we put forward a comprehensive and transparent theory for plastic deformation of face-centered cubic metals. This is based on a microscopic analysis that, without ambiguity, reveals the various deformation phenomena and elucidates the physical fundaments of the currently used phenomenological correlations. We identify an easily accessible single parameter derived from the intrinsic energy barriers, which fully specifies the potential diversity of metals. Based entirely on this parameter, a simple deformation mode diagram is shown to delineate a series of convenient design criteria, which clarifies a wide area of material functionality by texture control.

Theory for plasticity of face-centered cubic metals

PubMed Central

Jo, Minho; Koo, Yang Mo; Lee, Byeong-Joo; Johansson, Börje; Vitos, Levente; Kwon, Se Kyun

2014-01-01

The activation of plastic deformation mechanisms determines the mechanical behavior of crystalline materials. However, the complexity of plastic deformation and the lack of a unified theory of plasticity have seriously limited the exploration of the full capacity of metals. Current efforts to design high-strength structural materials in terms of stacking fault energy have not significantly reduced the laborious trial and error works on basic deformation properties. To remedy this situation, here we put forward a comprehensive and transparent theory for plastic deformation of face-centered cubic metals. This is based on a microscopic analysis that, without ambiguity, reveals the various deformation phenomena and elucidates the physical fundaments of the currently used phenomenological correlations. We identify an easily accessible single parameter derived from the intrinsic energy barriers, which fully specifies the potential diversity of metals. Based entirely on this parameter, a simple deformation mode diagram is shown to delineate a series of convenient design criteria, which clarifies a wide area of material functionality by texture control. PMID:24753563

Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor.

PubMed

Vilanova, B; Fernández, D; Casasnovas, R; Pomar, A M; Alvarez-Idaboy, J R; Hernández-Haro, N; Grand, A; Adrover, M; Donoso, J; Frau, J; Muñoz, F; Ortega-Castro, J

2017-05-01

DNA nucleobases undergo non-enzymatic glycation to nucleobase adducts which can play important roles in vivo. In this work, we conducted a comprehensive experimental and theoretical kinetic study of the mechanisms of formation of glyoxal-guanine adducts over a wide pH range in order to elucidate the molecular basis for the glycation process. Also, we performed molecular dynamics simulations to investigate how open or cyclic glyoxal-guanine adducts can cause structural changes in an oligonucleotide model. A thermodynamic study of other glycating agents including methylglyoxal, acrolein, crotonaldehyde, 4-hydroxynonenal and 3-deoxyglucosone revealed that, at neutral pH, cyclic adducts were more stable than open adducts; at basic pH, however, the open adducts of 3-deoxyglucosone, methylglyoxal and glyoxal were more stable than their cyclic counterparts. This result can be ascribed to the ability of the adducts to cross-link DNA. The new insights may contribute to improve our understanding of the connection between glycation and DNA cross-linking. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecular mechanism of Mg2+-dependent gating in CorA

NASA Astrophysics Data System (ADS)

Dalmas, Olivier; Sompornpisut, Pornthep; Bezanilla, Francisco; Perozo, Eduardo

2014-04-01

CorA is the major transport system responsible for Mg2+ uptake in bacteria and can functionally substitute for its homologue Mrs2p in the yeast inner mitochondrial membrane. Although several CorA crystal structures are available, the molecular mechanism of Mg2+ uptake remains to be established. Here we use electron paramagnetic resonance spectroscopy, electrophysiology and molecular dynamic simulations to show that CorA is regulated by cytoplasmic Mg2+ acting as a ligand and elucidate the basic conformational rearrangements responsible for Mg2+-dependent gating. Mg2+ unbinding at the divalent cation sensor triggers a conformational change that leads to the inward motion of the stalk helix, which propagates to the pore-forming transmembrane helix TM1. Helical tilting and rotation in TM1 generates an iris-like motion that increases the diameter of the permeation pathway, triggering ion conduction. This work establishes the molecular basis of a Mg2+-driven negative feedback loop in CorA as the key physiological event controlling Mg2+ uptake and homeostasis in prokaryotes.

Oncolytic viruses: a new class of immunotherapy drugs.

PubMed

Kaufman, Howard L; Kohlhapp, Frederick J; Zloza, Andrew

2015-09-01

Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.

Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.

PubMed

Sturm, Amy C; Kline, Crystal F; Glynn, Patric; Johnson, Benjamin L; Curran, Jerry; Kilic, Ahmet; Higgins, Robert S D; Binkley, Philip F; Janssen, Paul M L; Weiss, Raul; Raman, Subha V; Fowler, Steven J; Priori, Silvia G; Hund, Thomas J; Carnes, Cynthia A; Mohler, Peter J

2015-05-26

Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment. We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito. We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

A Guide to Neurotoxic Animal Models of Parkinson’s Disease

PubMed Central

Tieu, Kim

2011-01-01

Parkinson’s disease (PD) is a neurological movement disorder primarily resulting from damage to the nigrostriatal dopaminergic pathway. To elucidate the pathogenesis, mechanisms of cell death, and to evaluate therapeutic strategies for PD, numerous animal models have been developed. Understanding the strengths and limitations of these models can significantly impact the choice of model, experimental design, and data interpretation. The primary objectives of this article are twofold: First, to assist new investigators who are contemplating embarking on PD research to navigate through the available animal models. Emphasis will be placed on common neurotoxic murine models in which toxic molecules are used to lesion the nigrostriatal dopaminergic system. And second, to provide an overview of basic technical requirements for assessing the pathology, structure, and function of the nigrostriatal pathway. PMID:22229125

Single-molecule spectroscopic methods.

PubMed

Haustein, Elke; Schwille, Petra

2004-10-01

Being praised for the mere fact of enabling the detection of individual fluorophores a dozen years ago, single-molecule techniques nowadays represent standard methods for the elucidation of the structural rearrangements of biologically relevant macromolecules. Single-molecule-sensitive techniques, such as fluorescence correlation spectroscopy, allow real-time access to a multitude of molecular parameters (e.g. diffusion coefficients, concentration and molecular interactions). As a result of various recent advances, this technique shows promise even for intracellular applications. Fluorescence imaging can reveal the spatial localization of fluorophores on nanometer length scales, whereas fluorescence resonance energy transfer supports a wide range of different applications, including real-time monitoring of conformational rearrangements (as in protein folding). Still in their infancy, single-molecule spectroscopic methods thus provide unprecedented insights into basic molecular mechanisms. Copyright 2004 Elsevier Ltd.

Defence reactions of plants to fungal pathogens: principles and perspectives, using powdery mildew on cereals as an example

NASA Astrophysics Data System (ADS)

Heitefuss, Rudolf

2001-06-01

Diseases of crop plants may lead to considerable yield losses. To control fungal diseases, fungicides are used extensively in present-day agricultural production. In order to reduce such external inputs, cultivars with natural resistance to important fungal pathogens are recommended in systems of integrated plant protection. Basic research, including genetics and molecular methods, is required to elucidate the mechanisms by which plants react to an attack by fungal pathogens and successfully defend themselves. This review examines our knowledge with respect to the multicomponent systems of resistance in plants, using powdery mildew on barley as an example. In addition, the question is adressed whether systemic acquired resistance and plants with transgenic resistance may be utilized in future plant protection strategies.

Interpretation of Genomic Data Questions and Answers

PubMed Central

Simon, Richard

2008-01-01

Using a question and answer format we describe important aspects of using genomic technologies in cancer research. The main challenges are not managing the mass of data, but rather the design, analysis and accurate reporting of studies that result in increased biological knowledge and medical utility. Many analysis issues address the use of expression microarrays but are also applicable to other whole genome assays. Microarray based clinical investigations have generated both unrealistic hyperbole and excessive skepticism. Genomic technologies are tremendously powerful and will play instrumental roles in elucidating the mechanisms of oncogenesis and in devlopingan era of predictive medicine in which treatments are tailored to individual tumors. Achieving these goals involves challenges in re-thinking many paradigms for the conduct of basic and clinical cancer research and for the organization of interdisciplinary collaboration. PMID:18582627

Tissue morphodynamics shaping the early mouse embryo.

PubMed

Sutherland, Ann E

2016-07-01

Generation of the elongated vertebrate body plan from the initially radially symmetrical embryo requires comprehensive changes to tissue form. These shape changes are generated by specific underlying cell behaviors, coordinated in time and space. Major principles and also specifics are emerging, from studies in many model systems, of the cell and physical biology of how region-specific cell behaviors produce regional tissue morphogenesis, and how these, in turn, are integrated at the level of the embryo. New technical approaches have made it possible more recently, to examine the morphogenesis of the mouse embryo in depth, and to elucidate the underlying cellular mechanisms. This review focuses on recent advances in understanding the cellular basis for the early fundamental events that establish the basic form of the embryo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Fluctuations of conserved charges in relativistic heavy ion collisions: An introduction

NASA Astrophysics Data System (ADS)

Asakawa, Masayuki; Kitazawa, Masakiyo

2016-09-01

Bulk fluctuations of conserved charges measured by event-by-event analysis in relativistic heavy ion collisions are observables which are believed to carry significant amount of information on the hot medium created by the collisions. Active studies have been done recently experimentally, theoretically, and on the lattice. In particular, non-Gaussianity of the fluctuations has acquired much attention recently. In this review, we give a pedagogical introduction to these issues, and survey recent developments in this field of research. Starting from the definition of cumulants, basic concepts in fluctuation physics, such as thermal fluctuations in statistical mechanics and time evolution of fluctuations in diffusive systems, are described. Phenomena which are expected to occur in finite temperature and/or density QCD matter and their measurement by event-by-event analyses are also elucidated.

A Tutorial Review on Fractal Spacetime and Fractional Calculus

NASA Astrophysics Data System (ADS)

He, Ji-Huan

2014-11-01

This tutorial review of fractal-Cantorian spacetime and fractional calculus begins with Leibniz's notation for derivative without limits which can be generalized to discontinuous media like fractal derivative and q-derivative of quantum calculus. Fractal spacetime is used to elucidate some basic properties of fractal which is the foundation of fractional calculus, and El Naschie's mass-energy equation for the dark energy. The variational iteration method is used to introduce the definition of fractional derivatives. Fractal derivative is explained geometrically and q-derivative is motivated by quantum mechanics. Some effective analytical approaches to fractional differential equations, e.g., the variational iteration method, the homotopy perturbation method, the exp-function method, the fractional complex transform, and Yang-Laplace transform, are outlined and the main solution processes are given.

High-Resolution Digital Two-Color PIV for Turbomachinery Flows

NASA Astrophysics Data System (ADS)

Copenhaver, W.; Gogineni, S.; Goss, L.

1996-11-01

Turbomachinery flows are inherently unsteady. However, steady design methods are currently used to develop turbomachinery, with the lack of basic understanding of unsteady effects being compensated by use of extensive empirical correlations. Conventional laser anemometry provides quantitative evidence of unsteady effects in turbomachinery but is limited in fully exploring this phenomenon. The PIV technique holds great promise for elucidating unsteady flow mechanisms in turbomachinery if obstacles to its application in a transonic turbomachine can be overcome. Implementation involves critical issues such as tracer seeding and optical access for transmitter and receiver. Initially, an 18-in.-dia. axial fan is used to explore these issues. One optical configuration considered is the fiber-optic fanning light sheet in conjunction with high-power pulsed lasers. Instantaneous velocity measurements are made between blades at different spanwise locations.

Underlying Mechanisms of Tinnitus: Review and Clinical Implications

PubMed Central

Henry, James A.; Roberts, Larry E.; Caspary, Donald M.; Theodoroff, Sarah M.; Salvi, Richard J.

2016-01-01

Background The study of tinnitus mechanisms has increased tenfold in the last decade. The common denominator for all of these studies is the goal of elucidating the underlying neural mechanisms of tinnitus with the ultimate purpose of finding a cure. While these basic science findings may not be immediately applicable to the clinician who works directly with patients to assist them in managing their reactions to tinnitus, a clear understanding of these findings is needed to develop the most effective procedures for alleviating tinnitus. Purpose The goal of this review is to provide audiologists and other health-care professionals with a basic understanding of the neurophysiological changes in the auditory system likely to be responsible for tinnitus. Results It is increasingly clear that tinnitus is a pathology involving neuroplastic changes in central auditory structures that take place when the brain is deprived of its normal input by pathology in the cochlea. Cochlear pathology is not always expressed in the audiogram but may be detected by more sensitive measures. Neural changes can occur at the level of synapses between inner hair cells and the auditory nerve and within multiple levels of the central auditory pathway. Long-term maintenance of tinnitus is likely a function of a complex network of structures involving central auditory and nonauditory systems. Conclusions Patients often have expectations that a treatment exists to cure their tinnitus. They should be made aware that research is increasing to discover such a cure and that their reactions to tinnitus can be mitigated through the use of evidence-based behavioral interventions. PMID:24622858

Modulation of macrophage functions by sheeppox virus provides clues to understand interaction of the virus with host immune system.

PubMed

Abu-El-Saad, Abdel-Aziz S; Abdel-Moneim, Ahmed S

2005-03-22

Poxviruses encode a range of immunomodulatory genes to subvert or evade the challenges posed by the innate and adaptive immune responses. However, the inactivated poxviruses possessed immunostimulating capacity and were used as a prophylactic or metaphylactic application that efficiently reduced susceptibility to infectious diseases in different species. This fact is intensively studied in different genera of poxviruses. However, little is known about the basic mechanisms adopted by sheeppox virus (SPPV). SPPV causes an acute disease of sheep that recently, has been observed to reinfect its host in spite of vaccination. By injecting inactivated or attenuated sheeppox virus SPPV vaccine in adult male Swiss mice, SPPV was found to reduce macrophages' functions in a local event that occurs at the site of application 12 h after vaccine administration as indicated by increased level of IL-10 and decreased level of SOD from cultured peritoneal macrophages. In contrast increased levels of IL-12, and SOD activity from cultured splenic macrophages, lymphocyte response to PHA-P, and in-vivo response to T-dependant Ag were detected. These effects were observed in both attenuated and inactivated SPPV, but more prominent in attenuated one. The results of this study help to elucidate, the phenomenon of existence natural SPPV infections in sheep instead of vaccination and the basic mechanisms responsible for the immunostimulating capacity of sheeppox virus. Locally, SPPV shows evidence for an immune escape mechanism that alleviates the host's immune response. Later and systemically, the virus protects the host from any fatal consequences of the immune system suppression.

Brain imaging in the context of food perception and eating.

PubMed

Hollmann, Maurice; Pleger, Burkhard; Villringer, Arno; Horstmann, Annette

2013-02-01

Eating behavior depends heavily on brain function. In recent years, brain imaging has proved to be a powerful tool to elucidate brain function and brain structure in the context of eating. In this review, we summarize recent findings in the fast growing body of literature in the field and provide an overview of technical aspects as well as the basic brain mechanisms identified with imaging. Furthermore, we highlight findings linking neural processing of eating-related stimuli with obesity. The consumption of food is based on a complex interplay between homeostatic and hedonic mechanisms. Several hormones influence brain activity to regulate food intake and interact with the brain's reward circuitry, which is partly mediated by dopamine signaling. Additionally, it was shown that food stimuli trigger cognitive control mechanisms that incorporate internal goals into food choice. The brain mechanisms observed in this context are strongly influenced by genetic factors, sex and personality traits. Overall, a complex picture arises from brain-imaging findings, because a multitude of factors influence human food choice. Although several key mechanisms have been identified, there is no comprehensive model that is able to explain the behavioral observations to date. Especially a careful characterization of patients according to genotypes and phenotypes could help to better understand the current and future findings in neuroimaging studies.

Hypoxia and the Edema Syndrome: Elucidation of a Mechanism of Teratogenesis

EPA Science Inventory

The elucidation of mechanisms and pathogenesis of birth defects is exceedingly complex. Consequently, there are few examples where the etiology of birth defects caused by a specific agent has been well described. One such example is the "Edema Syndrome" first described by Casimer...

The Paradox of ApoA5 Modulation of Triglycerides: Evidences from Clinical and Basic Research

PubMed Central

Garelnabi, Mahdi; Lor, Kenton; Jin, Jun; Chai, Fei; Santanam, Nalini

2012-01-01

Apolipoprotein A5 (ApoA5) is a key regulator of plasma triglycerides (TG), although its plasma concentration is very low compared to other known apoproteins. Over the years, researchers have attempted to elucidate the molecular mechanisms by which ApoA5 regulates plasma TG in vivo. Though still under debate, two theories broadly describe how ApoA5 modulates TG levels: (i) ApoA5 enhances the catabolism of TG-rich lipoproteins and (ii) it inhibits the rate of production of very low-density lipoprotein (VLDL), the major carrier of TGs. This review will summarize the basic and clinical studies that have attempted to describe the importance of ApoA5 in TG metabolism. Population studies conducted in various countries have demonstrated an association between single nucleotide polymorphisms (SNPs) in ApoA5 and the increased risk to cardiovascular disease and metabolic syndrome (including diabetes and obesity). ApoA5 is also highly expressed during liver regeneration and is an acute phase protein associated with HDL which was independent of its effects on TG metabolism. Conclusion Despite considerable evidences available from clinical and basic research studies, on the role of ApoA5 in TG metabolism and its indirect link to metabolic diseases, additional investigations are needed to understand the paradoxical role of this important apoprotein shown modulated by diet and from it polymorphism variants. PMID:23000317

The phenoptosis problem: what is causing the death of an organism? Lessons from acute kidney injury.

PubMed

Zorov, D B; Plotnikov, E Y; Jankauskas, S S; Isaev, N K; Silachev, D N; Zorova, L D; Pevzner, I B; Pulkova, N V; Zorov, S D; Morosanova, M A

2012-07-01

Programmed execution of various cells and intracellular structures is hypothesized to be not the only example of elimination of biological systems - the general mechanism can also involve programmed execution of organs and organisms. Modern rating of programmed cell death mechanisms includes 13 mechanistic types. As for some types, the mechanism of actuation and manifestation of cell execution has been basically elucidated, while the causes and intermediate steps of the process of fatal failure of organs and organisms remain unknown. The analysis of deaths resulting from a sudden heart arrest or multiple organ failure and other acute and chronic pathologies leads to the conclusion of a special role of mitochondria and oxidative stress activating the immune system. Possible mechanisms of mitochondria-mediated induction of the signaling cascades involved in organ failure and death of the organism are discussed. These mechanisms include generation of reactive oxygen species and damage-associated molecular patterns in mitochondria. Some examples of renal failure-induced deaths are presented with mechanisms and settings determined by some hypothetical super system rather than by the kidneys themselves. This system plays the key role in the process of physiological senescence and termination of an organism. The facts presented suggest that it is the immune system involved in mitochondrial signaling that can act as the system responsible for the organism's death.

Palatal Seam Disintegration: To Die or Not to Die? That Is No Longer the Question

PubMed Central

Nawshad, Ali

2008-01-01

Formation of the medial epithelial seam (MES) by palatal shelf fusion is a crucial step of palate development. Complete disintegration of the MES is the final essential phase of palatal confluency with surrounding mesenchymal cells. In general, the mechanisms of palatal seam disintegration are not overwhelmingly complex, but given the large number of interacting constituents; their complicated circuitry involving feedforward, feedback, and crosstalk; and the fact that the kinetics of interaction matter, this otherwise simple mechanism can be quite difficult to interpret. As a result of this complexity, apparently simple but highly important questions remain unanswered. One such question pertains to the fate of the palatal seam. Such questions may be answered by detailed and extensive quantitative experimentation of basic biological studies (cellular, structural) and the newest molecular biological determinants (genetic/dye cell lineage, gene activity, kinase/enzyme activity), as well as animal model (knockouts, transgenic) approaches. System biology and cellular kinetics play a crucial role in cellular MES function; omissions of such critical contributors may lead to inaccurate understanding of the fate of MES. Excellent progress has been made relevant to elucidation of the mechanism(s) of palatal seam disintegration. Current understanding of palatal seam disintegration suggests epithelial–mesenchymal transition and/or programmed cell death as two most common mechanisms of MES disintegration. In this review, I discuss those two mechanisms and the differences between them. PMID:18629865

Functions of MicroRNAs in Cardiovascular Biology and Disease

PubMed Central

Hata, Akiko

2015-01-01

In 1993, lin-4 was discovered as a critical modulator of temporal development in Caenorhabditis elegans and, most notably, as the first in the class of small, single-stranded noncoding RNAs now defined as microRNAs (miRNAs). Another eight years elapsed before miRNA expression was detected in mammalian cells. Since then, explosive advancements in the field of miRNA biology have elucidated the basic mechanism of miRNA biogenesis, regulation, and gene-regulatory function. The discovery of this new class of small RNAs has augmented the complexity of gene-regulatory programs as well as the understanding of developmental and pathological processes in the cardiovascular system. Indeed, the contributions of miRNAs in cardiovascular development and function have been widely explored, revealing the extensive role of these small regulatory RNAs in cardiovascular physiology. PMID:23157557

Orienting attention within visual short-term memory: development and mechanisms.

PubMed

Shimi, Andria; Nobre, Anna C; Astle, Duncan; Scerif, Gaia

2014-01-01

How does developing attentional control operate within visual short-term memory (VSTM)? Seven-year-olds, 11-year-olds, and adults (total n = 205) were asked to report whether probe items were part of preceding visual arrays. In Experiment 1, central or peripheral cues oriented attention to the location of to-be-probed items either prior to encoding or during maintenance. Cues improved memory regardless of their position, but younger children benefited less from cues presented during maintenance, and these benefits related to VSTM span over and above basic memory in uncued trials. In Experiment 2, cues of low validity eliminated benefits, suggesting that even the youngest children use cues voluntarily, rather than automatically. These findings elucidate the close coupling between developing visuospatial attentional control and VSTM. © 2013 The Authors. Child Development © 2013 Society for Research in Child Development, Inc.

The challenge of understanding the brain: where we stand in 2015

PubMed Central

Lisman, John

2015-01-01

Starting with the work of Cajal more than 100 years ago, neuroscience has sought to understand how the cells of the brain give rise to cognitive functions. How far has neuroscience progressed in this endeavor? This Perspective assesses progress in elucidating five basic brain processes: visual recognition, long-term memory, short-term memory, action selection, and motor control. Each of these processes entails several levels of analysis: the behavioral properties, the underlying computational algorithm, and the cellular/network mechanisms that implement that algorithm. At this juncture, while many questions remain unanswered, achievements in several areas of research have made it possible to relate specific properties of brain networks to cognitive functions. What has been learned reveals, at least in rough outline, how cognitive processes can be an emergent property of neurons and their connections. PMID:25996132

Extracellular matrix and cell shape: potential control points for inhibition of angiogenesis

NASA Technical Reports Server (NTRS)

Ingber, D.

1991-01-01

Capillary endothelial (CE) cells require two extracellular signals in order to switch from quiescence to growth and back to differentiation during angiogenesis: soluble angiogenic factors and insoluble extracellular matrix (ECM) molecules. Soluble endothelial mitogens, such as basic fibroblast growth factor (FGF), act over large distances to trigger capillary growth, whereas ECM molecules act locally to modulate cell responsiveness to these soluble cues. Recent studies reveal that ECM molecules regulate CE cell growth and differentiation by modulating cell shape and by activating intracellular chemical signaling pathways inside the cell. Recognition of the importance of ECM and cell shape during capillary morphogenesis has led to the identification of a series of new angiogenesis inhibitors. Elucidation of the molecular mechanism of capillary regulation may result in development of even more potent angiogenesis modulators in the future.

A model for production, perception, and acquisition of actions in face-to-face communication.

PubMed

Kröger, Bernd J; Kopp, Stefan; Lowit, Anja

2010-08-01

The concept of action as basic motor control unit for goal-directed movement behavior has been used primarily for private or non-communicative actions like walking, reaching, or grasping. In this paper, literature is reviewed indicating that this concept can also be used in all domains of face-to-face communication like speech, co-verbal facial expression, and co-verbal gesturing. Three domain-specific types of actions, i.e. speech actions, facial actions, and hand-arm actions, are defined in this paper and a model is proposed that elucidates the underlying biological mechanisms of action production, action perception, and action acquisition in all domains of face-to-face communication. This model can be used as theoretical framework for empirical analysis or simulation with embodied conversational agents, and thus for advanced human-computer interaction technologies.

DNA Shape Dominates Sequence Affinity in Nucleosome Formation

NASA Astrophysics Data System (ADS)

Freeman, Gordon S.; Lequieu, Joshua P.; Hinckley, Daniel M.; Whitmer, Jonathan K.; de Pablo, Juan J.

2014-10-01

Nucleosomes provide the basic unit of compaction in eukaryotic genomes, and the mechanisms that dictate their position at specific locations along a DNA sequence are of central importance to genetics. In this Letter, we employ molecular models of DNA and proteins to elucidate various aspects of nucleosome positioning. In particular, we show how DNA's histone affinity is encoded in its sequence-dependent shape, including subtle deviations from the ideal straight B-DNA form and local variations of minor groove width. By relying on high-precision simulations of the free energy of nucleosome complexes, we also demonstrate that, depending on DNA's intrinsic curvature, histone binding can be dominated by bending interactions or electrostatic interactions. More generally, the results presented here explain how sequence, manifested as the shape of the DNA molecule, dominates molecular recognition in the problem of nucleosome positioning.

Research progress on combat trauma treatment in cold regions.

PubMed

Wang, Hui-Shan; Han, Jin-Song

2014-01-01

Cold regions are a special combat environment in which low temperatures have a great impact on human metabolism and other vital functions, including the nervous, motion, cardiovascular, circulatory, respiratory, and urinary systems; consequently, low temperatures often aggravate existing trauma, leading to high mortality rates if rapid and appropriate treatment is not provided. Hypothermia is an independent risk factor of fatality following combat trauma; therefore, proactive preventative measures are needed to reduce the rate of mortality. After summarizing the basic research on battlefield environments and progress in the prevention and treatment of trauma, this article concludes that current treatment and prevention measures for combat trauma in cold regions are inadequate. Future molecular biology studies are needed to elucidate the mechanisms and relevant cell factors underlying bodily injury caused by cold environment, a research goal will also allow further exploration of corresponding treatments.

A review of processable high temperature resistant addition-type laminating resins

NASA Technical Reports Server (NTRS)

Serafini, T. T.; Delvigs, P.

1973-01-01

An important finding that resulted from research that was conducted to develop improved ablative resins was the discovery of a novel approach to synthesize processable high temperature resistant polymers. Low molecular weight polyimide prepolymers end-capped with norbornene groups were polymerized into thermo-oxidatively stable modified polyimides without the evolution of void producing volatile materials. This paper reviews basic studies that were performed using model compounds to elucidate the polymerization mechanism of the so-called addition-type polyimides. The fabrication and properties of polyimide/graphite fiber composites using A-type polyimide prepolymer as the matrix are described. An alternate method for preparing processable A-type polyimides by means of in situ polymerization of monomeric reactants on the fiber reinforcement is also described. Polyimide/graphite fiber composite performance at elevated temperatures is presented for A-type polyimides.

From Genes to Networks: Characterizing Gene-Regulatory Interactions in Plants.

PubMed

Kaufmann, Kerstin; Chen, Dijun

2017-01-01

Plants, like other eukaryotes, have evolved complex mechanisms to coordinate gene expression during development, environmental response, and cellular homeostasis. Transcription factors (TFs), accompanied by basic cofactors and posttranscriptional regulators, are key players in gene-regulatory networks (GRNs). The coordinated control of gene activity is achieved by the interplay of these factors and by physical interactions between TFs and DNA. Here, we will briefly outline recent technological progress made to elucidate GRNs in plants. We will focus on techniques that allow us to characterize physical interactions in GRNs in plants and to analyze their regulatory consequences. Targeted manipulation allows us to test the relevance of specific gene-regulatory interactions. The combination of genome-wide experimental approaches with mathematical modeling allows us to get deeper insights into key-regulatory interactions and combinatorial control of important processes in plants.

Advances in basic and clinical immunology in 2006.

PubMed

Chinen, Javier; Shearer, William T

2007-08-01

This article reviews the progress in the field of basic and clinical immunology in 2006, focusing on the articles published in the Journal. The role of Toll-like receptors in the immune response was explored in detail in several articles. The knowledge gained in these investigations is being used to develop strategies that enhance the immunogenicity of vaccines to prevent infectious diseases and to have an immunomodulatory effect on allergic diseases. Other components of the innate immunity reported on were the recognition of allergens with lipid-derived motifs by CD1d-restricted T cells and the role of dendritic cells in the development of an allergic response. More than 120 primary immunodeficiencies were defined at a molecular level, and biological agents such as TNF-alpha antagonists and IFN-alpha were shown to have therapeutic use. New anti-HIV drugs that block cell entry were proven to be effective, thus offering alternative therapies to respond to the development of multidrug-resistant HIV strains. The modern understanding of immunologic concepts is helping to elucidate the mechanisms of defense against viruses, bacteria, and parasites; as a result, strategies to improve management and prevention continue to emerge.

The Effects of Obesity on Drug Metabolism in Children.

PubMed

Oeser, Steffen G; Rougee, Luc R A; Collier, Abby C

2015-01-01

Obesity in children is a significant clinical concern. There are many anecdotes and case studies regarding specific reactions of obese children to medications including therapeutic failure, adverse drug reactions and/or requirements for higher weight-adjusted dosing. There isis, however, a lack of basic and clinical data dissecting the mechanisms of these effects on pharmaceutical efficacy and safety. At present it is unknown how much of the difference in drug disposition in obese children can be attributed to obesity, to maturation or to an interaction between the two. Since a major determinant of drug disposition is hepatic metabolism, here we review how obesity alters hepatic drug disposition in children. Basic as well as clinical data summarizing the current knowledge of biochemical, physiological and clinical effects of pediatric obesity on drug disposition are considered. We conclude that there is a dire need for increased research into the direct effects of obesity on absorption, distribution, metabolism and excretion, as well as changes to pharmacokinetic parameters such as bioavailability and clearance. Increased effort in this area may elucidate the effects of obesity on clinical drug disposition with sufficient detail to provide better dosing guidelines where needed for children.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research.

PubMed

Ruggiero, Rafael N; Rossignoli, Matheus T; De Ross, Jana B; Hallak, Jaime E C; Leite, Joao P; Bueno-Junior, Lezio S

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB 1 and TRPV 1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV 1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

Enhanced Mechanical Performance of Bio-Inspired Hybrid Structures Utilising Topological Interlocking Geometry.

PubMed

Djumas, Lee; Molotnikov, Andrey; Simon, George P; Estrin, Yuri

2016-05-24

Structural composites inspired by nacre have emerged as prime exemplars for guiding materials design of fracture-resistant, rigid hybrid materials. The intricate microstructure of nacre, which combines a hard majority phase with a small fraction of a soft phase, achieves superior mechanical properties compared to its constituents and has generated much interest. However, replicating the hierarchical microstructure of nacre is very challenging, not to mention improving it. In this article, we propose to alter the geometry of the hard building blocks by introducing the concept of topological interlocking. This design principle has previously been shown to provide an inherently brittle material with a remarkable flexural compliance. We now demonstrate that by combining the basic architecture of nacre with topological interlocking of discrete hard building blocks, hybrid materials of a new type can be produced. By adding a soft phase at the interfaces between topologically interlocked blocks in a single-build additive manufacturing process, further improvement of mechanical properties is achieved. The design of these fabricated hybrid structures has been guided by computational work elucidating the effect of various geometries. To our knowledge, this is the first reported study that combines the advantages of nacre-inspired structures with the benefits of topological interlocking.

Empathy as a driver of prosocial behaviour: highly conserved neurobehavioural mechanisms across species.

PubMed

Decety, Jean; Bartal, Inbal Ben-Ami; Uzefovsky, Florina; Knafo-Noam, Ariel

2016-01-19

Empathy reflects the natural ability to perceive and be sensitive to the emotional states of others, coupled with a motivation to care for their well-being. It has evolved in the context of parental care for offspring, as well as within kinship bonds, to help facilitate group living. In this paper, we integrate the perspectives of evolution, animal behaviour, developmental psychology, and social and clinical neuroscience to elucidate our understanding of the proximate mechanisms underlying empathy. We focus, in particular, on processing of signals of distress and need, and their relation to prosocial behaviour. The ability to empathize, both in animals and humans, mediates prosocial behaviour when sensitivity to others' distress is paired with a drive towards their welfare. Disruption or atypical development of the neural circuits that process distress cues and integrate them with decision value leads to callous disregard for others, as is the case in psychopathy. The realization that basic forms of empathy exist in non-human animals is crucial for gaining new insights into the underlying neurobiological and genetic mechanisms of empathy, enabling translation towards therapeutic and pharmacological interventions. © 2015 The Author(s).

[The significance of Ulex europaeus agglutinin I lectin binding fibers in various muscular diseases].

PubMed

Yatabe, K; Hiraguri, M; Sueishi, M; Takeuchi, M; Nonaka, I; Kawai, M

1998-05-01

In the present study, we have reported that Ulex europaeus agglutinin I (UEA I) lectin labeled muscle fibers in distal myopathy with rimmed vacuole formation (DMRV). UEA I binding to muscle fibers was also observed in a small number of biopsies with inflammatory myopathy, but not in other diseases, including neurogenic muscular atrophies and muscular dystrophies. In order to elucidate the relationship between this UEA I binding, rimmed vacuole formation and active autophagocytosis, we examined the UEA I binding fibers in other myopathies which frequently showed rimmed vacuoles, including adult onset acid maltase deficiency, oculo-pharyngo-distal type myopathy and oculopharyngeal muscular dystrophy. No UEA I lectin labeling fiber was observed in the diseases examined. We then studied UEA I binding behavior on 70 biopsies of inflammatory myopathy to characterize the clinical features of UEA I binding positive patients. UEA I binding fibers were observed in 3 of 28 patients (11%) with other collagen diseases, 11 of 36 (31%) without these disorders, and 2 of 6 (33%) with inclusion body myositis. There were no common clinical histories, complications or laboratory findings among the UEA I binding positive patients. In conclusion, a common process may exist between the muscle fiber degeneration in DMRV and subgroups of inflammatory myopathy patients, but the basic mechanism remains to be elucidated.

Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors.

PubMed

Shao, Yi; Zhong, Dian-Sheng

2018-04-01

Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8-16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.

The meridian system and mechanism of acupuncture: a comparative review. Part 3: Mechanisms of acupuncture therapies.

PubMed

Chang, Shyang

2013-06-01

The human body is a hierarchical organism containing many levels of mutually interacting oscillatory systems. From the viewpoint of traditional Chinese medicine, health is a state of harmony emergent from the interactions of these systems and disease is a state of discord. Hence, human diseases are considered as disturbed functions rather than changed structures. Indeed, the change from normal to abnormal structure may be beneficent rather than maleficent. For example, when one kidney becomes twice the normal size following the destruction of the other kidney, it is good and not bad for us because we might be dead otherwise. Therefore, in Part 3 of this three-part series, emphasis is mainly laid on the acupuncture mechanisms of treating disturbed physiological functions rather than disordered structures. At first, the basic tenets of conventional neuroscience and cardiology are reevaluated so that clear understanding of how nervous and cardiovascular systems work together can be obtained. Then, the general principles of diagnosis and treatment in traditional Chinese medicine from the integrative perspective of complex dynamic systems are proposed. Finally, mechanisms of acupuncture therapies for treating 14 different categories of disorders will be elucidated via the magneto-electric inductive effects of the meridian system. Copyright © 2013. Published by Elsevier B.V.

Proton Mediated Chemistry and Catalysis in a Self-Assembled Supramolecular Host

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

Pluth, Michael; Bergman, Robert; Raymond, Kenneth

2009-04-10

Synthetic supramolecular host assemblies can impart unique reactivity to encapsulated guest molecules. Synthetic host molecules have been developed to carry out complex reactions within their cavities, despite the fact that they lack the type of specifically tailored functional groups normally located in the analogous active sites of enzymes. Over the past decade, the Raymond group has developed a series of self-assembled supramolecules and the Bergman group has developed and studied a number of catalytic transformations. In this Account, we detail recent collaborative work between these two groups, focusing on chemical catalysis stemming from the encapsulation of protonated guests and expandingmore » to acid catalysis in basic solution. We initially investigated the ability of a water-soluble, self-assembled supramolecular host molecule to encapsulate protonated guests in its hydrophobic core. Our study of encapsulated protonated amines revealed rich host-guest chemistry. We established that self-exchange (that is, in-out guest movement) rates of protonated amines were dependent on the steric bulk of the amine rather than its basicity. The host molecule has purely rotational tetrahedral (T) symmetry, so guests with geminal N-methyl groups (and their attendant mirror plane) were effectively desymmetrized; this allowed for the observation and quantification of the barriers for nitrogen inversion followed by bond rotation. Furthermore, small nitrogen heterocycles, such as N-alkylaziridines, N-alkylazetidines, and N-alkylpyrrolidines, were found to be encapsulated as proton-bound homodimers or homotrimers. We further investigated the thermodynamic stabilization of protonated amines, showing that encapsulation makes the amines more basic in the cavity. Encapsulation raises the effective basicity of protonated amines by up to 4.5 pK{sub a} units, a difference almost as large as that between the moderate and strong bases carbonate and hydroxide. The thermodynamic stabilization of protonated guests was translated into chemical catalysis by taking advantage of the potential for accelerating reactions that take place via positively charged transition states, which could be potentially stabilized by encapsulation. Orthoformates, generally stable in neutral or basic solution, were found to be suitable substrates for catalytic hydrolysis by the assembly. Orthoformates small enough to undergo encapsulation were readily hydrolyzed by the assembly in basic solution, with rate acceleration factors up to 3900 compared with those of the corresponding uncatalyzed reactions. Furthering the analogy to enzymes that obey Michaelis-Menten kinetics, we observed competitive inhibition with the inhibitor NPr{sub 4}{sup +}, thereby confirming that the interior cavity of the assembly was the active site for catalysis. Mechanistic studies revealed that the assembly is required for catalysis and that the rate-limiting step of the reaction involves proton transfer from hydronium to the encapsulated substrate. Encapsulation in the assembly changes the orthoformate hydrolysis from an A-1 mechanism (in which decomposition of the protonated substrate is the rate-limiting step) to an A-S{sub E}2 mechanism (in which proton transfer is the rate-limiting step). The study of hydrolysis in the assembly was next extended to acetals, which were also catalytically hydrolyzed by the assembly in basic solution. Acetal hydrolysis changed from the A-1 mechanism in solution to an A-2 mechanism inside the assembly, where attack of water on the protonated substrate is rate limiting. This work provides rare examples of assembly-catalyzed reactions that proceed with substantial rate accelerations despite the absence of functional groups in the cavity and with mechanisms fully elucidated by quantitative kinetic studies.« less

Elucidating compound mechanism of action by network perturbation analysis | Office of Cancer Genomics

Cancer.gov

Genome-wide identification of the mechanism of action (MoA) of small-molecule compounds characterizing their targets, effectors, and activity modulators represents a highly relevant yet elusive goal, with critical implications for assessment of compound efficacy and toxicity. Current approaches are labor intensive and mostly limited to elucidating high-affinity binding target proteins.

Renocardiac syndromes: physiopathology and treatment stratagems.

PubMed

Kingma, J G; Simard, D; Rouleau, J R

2015-01-01

Bidirectional inter-organ interactions are essential for normal functioning of the human body; however, they may also promote adverse conditions in remote organs. This review provides a narrative summary of the epidemiology, physiopathological mechanisms and clinical management of patients with combined renal and cardiac disease (recently classified as type 3 and 4 cardiorenal syndrome). Findings are also discussed within the context of basic research in animal models with similar comorbidities. Pertinent published articles were identified by literature search of PubMed, MEDLINE and Google Scholar. Additional data from studies in the author's laboratory were also consulted. The prevalence of renocardiac syndrome throughout the world is increasing in part due to an aging population and to other risk factors including hypertension, diabetes and dyslipidemia. Pathogenesis of this disorder involves multiple bidirectional interactions between the kidneys and heart; however, participation of other organs cannot be excluded. Our own work supports the hypothesis that the uremic milieu, caused by kidney dysfunction, produces major alterations in vasoregulatory control particularly at the level of the microvasculature that results in impaired oxygen delivery and blood perfusion. Recent clinical literature is replete with articles discussing the necessity to clearly define or characterize what constitutes cardiorenal syndrome in order to improve clinical management of affected patients. Patients are treated after onset of symptoms with limited available information regarding etiology. While understanding of mechanisms involved in pathogenesis of inter-organ crosstalk remains a challenging objective, basic research data remains limited partly because of the lack of animal models. Preservation of microvascular integrity may be the most critical factor to limit progression of multi-organ disorders including renocardiac syndrome. More fundamental studies are needed to help elucidate physiopathological mechanisms and for development of treatments to improve clinical outcomes.

Dissipation of contractile forces: the missing piece in cell mechanics.

PubMed

Kurzawa, Laetitia; Vianay, Benoit; Senger, Fabrice; Vignaud, Timothée; Blanchoin, Laurent; Théry, Manuel

2017-07-07

Mechanical forces are key regulators of cell and tissue physiology. The basic molecular mechanism of fiber contraction by the sliding of actin filament upon myosin leading to conformational change has been known for decades. The regulation of force generation at the level of the cell, however, is still far from elucidated. Indeed, the magnitude of cell traction forces on the underlying extracellular matrix in culture is almost impossible to predict or experimentally control. The considerable variability in measurements of cell-traction forces indicates that they may not be the optimal readout to properly characterize cell contractile state and that a significant part of the contractile energy is not transferred to cell anchorage but instead is involved in actin network dynamics. Here we discuss the experimental, numerical, and biological parameters that may be responsible for the variability in traction force production. We argue that limiting these sources of variability and investigating the dissipation of mechanical work that occurs with structural rearrangements and the disengagement of force transmission is key for further understanding of cell mechanics. © 2017 Kurzawa et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Microscopic mechanics of biomolecules in living cells

NASA Astrophysics Data System (ADS)

Cleri, Fabrizio

The exporting of theoretical concepts and modelling methods from physics and mechanics to the world of biomolecules and cell biology is increasing at a fast pace. The role of mechanical forces and stresses in biology and genetics is just starting to be appreciated, with implications going from cell adhesion, migration, division, to DNA transcription and replication, to the mechanochemical transduction and operation of molecular motors, and more. Substantial advances in experimental techniques over the past 10 years allowed to get unprecedented insight into the elasticity and mechanical response of many different proteins, cytoskeletal filaments, nucleic acids, both in vitro and, more recently, directly inside the cell. In a parallel effort, also theoretical models and computational methods are evolving into a rather specialized toolbox. However, several key issues need to be addressed when applying to life sciences the theories and methods typically originating from the fields of condensed matter and solid mechanics. The presence of a solvent and its dielectric properties, the many subtle effects of entropy, the non-equilibrium thermodynamics conditions, the dominating role of weak forces such as Van der Waals dispersion, hydrophobic interactions, and hydrogen bonding, impose a special caution and a thorough consideration, up to possibly rethinking some basic physics concepts. Discussing and trying to elucidate at least some of the above issues is the main aim of the present, partial and non-exhaustive, contribution.

Microscopic mechanics of biomolecules in living cells

NASA Astrophysics Data System (ADS)

Cleri, Fabrizio

2008-04-01

The exporting of theoretical concepts and modelling methods from physics and mechanics to the world of biomolecules and cell biology is increasing at a fast pace. The role of mechanical forces and stresses in biology and genetics is just starting to be appreciated, with implications going from cell adhesion, migration, division, to DNA transcription and replication, to the mechanochemical transduction and operation of molecular motors, and more. Substantial advances in experimental techniques over the past 10 years allowed to get unprecedented insight into the elasticity and mechanical response of many different proteins, cytoskeletal filaments, nucleic acids, both in vitro and, more recently, directly inside the cell. In a parallel effort, also theoretical models and computational methods are evolving into a rather specialized toolbox. However, several key issues need to be addressed when applying to life sciences the theories and methods typically originating from the fields of condensed matter and solid mechanics. The presence of a solvent and its dielectric properties, the many subtle effects of entropy, the non-equilibrium thermodynamics conditions, the dominating role of weak forces such as Van der Waals dispersion, hydrophobic interactions, and hydrogen bonding, impose a special caution and a thorough consideration, up to possibly rethinking some basic physics concepts. Discussing and trying to elucidate at least some of the above issues is the main aim of the present, partial and non-exhaustive, contribution.

On the generation of tangential ground motion by underground explosions in jointed rocks

NASA Astrophysics Data System (ADS)

Vorobiev, Oleg; Ezzedine, Souheil; Antoun, Tarabay; Glenn, Lewis

2015-03-01

This paper describes computational studies of tangential ground motions generated by spherical explosions in a heavily jointed granite formation. Various factors affecting the shear wave generation are considered, including joint spacing, orientation and frictional properties. Simulations are performed both in 2-D for a single joint set to elucidate the basic response mechanisms, and in 3-D for multiple joint sets to realistically represent in situ conditions in a realistic geological setting. The joints are modelled explicitly using both contact elements and weakness planes in the material. Simulations are performed both deterministically and stochastically to quantify the effects of geological uncertainties on near field ground motions. The mechanical properties of the rock and the joints as well as the joint spacing and orientation are taken from experimental test data and geophysical logs corresponding to the Climax Stock granitic outcrop, which is the geological setting of the source physics experiment (SPE). Agreement between simulation results and near field wave motion data from SPE enables newfound understanding of the origin and extent of non-spherical motions associated with underground explosions in fractured geological media.

Origin and evolution of osmoregulatory mechanisms in blue-green algae (cyanobacteria) as a function of metabolic and structural complexity: Reflections of Precambrian paleobiology

NASA Technical Reports Server (NTRS)

Yopp, John H.; Tindall, Donald R.; Pavlicek, Kenneth

1987-01-01

Major accomplishments underlying the basic understanding of cyanobacterial resistance to salt tolerance and osmotic stress were made. The methodology proposed included: the tracing of the pathways of formation of osmoregulatory solutes by traditional methods involving C-14 labelled substrates; gas chromatography; amino acid analysis; X-ray analysis using scanning transmission electron microscopy; and most importantly, C-13 labelled substrates, followed by Nuclear Magnetic Resonance (NMR) spectroscopy. It was found that the cyanobacteria employ a diversity of organic, osmoregulatory solutes. Osmoregulatory solutes were found to serve four functions: adjustment of water activity, noninhibition of enzymes; lowering of K sub m of enzymes to allow functioning at normal levels when the intracellular salt accumulates, and extending the pH optimum of enzymes as intracellular pH rises due to proton-potassium ion pump action during osmoregulation. Differences in osmoregulatory solutes may, but are not always, be attributed to differences in nutritional capabilities. The mechanism of osmoregulation and concomitant salt tolerance in halophilic cyanobacteria was elucidated. The activities of betaine and S-Adenosylhomocysteine hydrolase are discussed.

Evolutionary developmental genetics of fruit morphological variation within the Solanaceae

PubMed Central

Wang, Li; Li, Jing; Zhao, Jing; He, Chaoying

2015-01-01

Morphological variations of fruits such as shape and size, and color are a result of adaptive evolution. The evolution of morphological novelties is particularly intriguing. An understanding of these evolutionary processes calls for the elucidation of the developmental and genetic mechanisms that result in particular fruit morphological characteristics, which determine seed dispersal. The genetic and developmental basis for fruit morphological variation was established at a microevolutionary time scale. Here, we summarize the progress on the evolutionary developmental genetics of fruit size, shape and color in the Solanaceae. Studies suggest that the recruitment of a pre-existing gene and subsequent modification of its interaction and regulatory networks are frequently involved in the evolution of morphological diversity. The basic mechanisms underlying changes in plant morphology are alterations in gene expression and/or gene function. We also deliberate on the future direction in evolutionary developmental genetics of fruit morphological variation such as fruit type. These studies will provide insights into plant developmental processes and will help to improve the productivity and fruit quality of crops. PMID:25918515

Elucidation of wear mechanisms by ferrographic analysis

NASA Technical Reports Server (NTRS)

Jones, W. R., Jr.

1981-01-01

The use of ferrographic analysis in conjunction with light and scanning electron microscopy is described for the elucidation of wear mechanisms taking place in operating equipment. Example of adhesive wear, abrasive wear, corrosive wear, rolling element fatigue, lubricant breakdown, and other wear modes are illustrated. In addition, the use of magnetic solutions to precipitate nonmagnetic debris from aqueous and nonaqueous fluids is described.

The paradox of ApoA5 modulation of triglycerides: evidence from clinical and basic research.

PubMed

Garelnabi, Mahdi; Lor, Kenton; Jin, Jun; Chai, Fei; Santanam, Nalini

2013-01-01

Apolipoprotein A5 (ApoA5) is a key regulator of plasma triglycerides (TG), even though its plasma concentration is very low compared to other known apoproteins. Over the years, researchers have attempted to elucidate the molecular mechanisms by which ApoA5 regulates plasma TG in vivo. Though still under debate, two theories broadly describe how ApoA5 modulates TG levels: (i) ApoA5 enhances the catabolism of TG-rich lipoproteins and (ii) it inhibits the rate of production of very low-density lipoprotein (VLDL), the major carrier of TGs. This review will summarize the basic and clinical studies that describe the importance of ApoA5 in TG metabolism. Population studies conducted in various countries have demonstrated an association between single nucleotide polymorphisms (SNPs) in ApoA5 and the increased risk to cardiovascular disease and metabolic syndrome (including diabetes and obesity). ApoA5 is also highly expressed during liver regeneration and is an acute phase protein associated with HDL, which is independent of its effects on TG metabolism. Despite considerable evidences available from clinical and basic research studies on the role of ApoA5 in TG metabolism and its indirect link to metabolic diseases, additional investigations are needed to understand the paradoxical role of this important apoprotein is modulated by both diet and its polymorphism variants. Copyright © 2012 The Canadian Society of Clinical Chemists. All rights reserved.

Development of a Rapid Insulin Assay by Homogenous Time-Resolved Fluorescence

PubMed Central

Vallaghe, Julie; Gregor, Nathalie; Donthamsetti, Prashant; Harris, Paul E.; Pierre, Nicolas; Freyberg, Robin; Charrier-Savournin, Fabienne; Javitch, Jonathan A.; Freyberg, Zachary

2016-01-01

Direct measurement of insulin is critical for basic and clinical studies of insulin secretion. However, current methods are expensive and time-consuming. We developed an insulin assay based on homogenous time-resolved fluorescence that is significantly more rapid and cost-effective than current commonly used approaches. This assay was applied effectively to an insulin secreting cell line, INS-1E cells, as well as pancreatic islets, allowing us to validate the assay by elucidating mechanisms by which dopamine regulates insulin release. We found that dopamine functioned as a significant negative modulator of glucose-stimulated insulin secretion. Further, we showed that bromocriptine, a known dopamine D2/D3 receptor agonist and newly approved drug used for treatment of type II diabetes mellitus, also decreased glucose-stimulated insulin secretion in islets to levels comparable to those caused by dopamine treatment. PMID:26849707

Pulsed laser ablation of complex oxides: The role of congruent ablation and preferential scattering for the film stoichiometry

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

Wicklein, S.; Koehl, A.; Dittmann, R.

2012-09-24

By combining structural and chemical thin film analysis with detailed plume diagnostics and modeling of the laser plume dynamics, we are able to elucidate the different physical mechanisms determining the stoichiometry of the complex oxides model material SrTiO{sub 3} during pulsed laser deposition. Deviations between thin film and target stoichiometry are basically a result of two effects, namely, incongruent ablation and preferential scattering of lighter ablated species during their motion towards the substrate in the O{sub 2} background gas. On the one hand, a progressive preferential ablation of the Ti species with increasing laser fluence leads to a regime ofmore » Ti-rich thin film growth at larger fluences. On the other hand, in the low laser fluence regime, a more effective scattering of the lighter Ti plume species results in Sr rich films.« less

Molecular description of the propagation of chirality from molecules to complex systems: different mechanisms controlled by hydrophobic interactions.

PubMed

Marinelli, Fabrizio; Sorrenti, Alessandro; Corvaglia, Valentina; Leone, Vanessa; Mancini, Giovanna

2012-11-12

In this work a combined theoretical and experimental approach was used to elucidate and describe at the molecular level the basic interactions that drive the transfer of the chiral information from chiral surfactant molecules to dye/surfactant assemblies. It was found that both hydrophobic interactions and relative concentrations strongly influence the chiroptical features of the heteroaggregates. In particular it was observed that, depending on the length of the surfactant hydrophobic chain, the chiral information is transferred to the dye by stabilizing an enantiomer either of a chiral conformer or of a chiral topological arrangement. These findings underline the role of hydrophobic interactions in the transfer of chirality and provide an example of the potential of in silico simulations for providing an accurate description of the process of chirality propagation. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cell models of arrhythmogenic cardiomyopathy: advances and opportunities

PubMed Central

Stadiotti, Ilaria; Perrucci, Gianluca L.; Tondo, Claudio; Pompilio, Giulio

2017-01-01

ABSTRACT Arrhythmogenic cardiomyopathy is a rare genetic disease that is mostly inherited as an autosomal dominant trait. It is associated predominantly with mutations in desmosomal genes and is characterized by the replacement of the ventricular myocardium with fibrous fatty deposits, arrhythmias and a high risk of sudden death. In vitro studies have contributed to our understanding of the pathogenic mechanisms underlying this disease, including its genetic determinants, as well as its cellular, signaling and molecular defects. Here, we review what is currently known about the pathogenesis of arrhythmogenic cardiomyopathy and focus on the in vitro models that have advanced our understanding of the disease. Finally, we assess the potential of established and innovative cell platforms for elucidating unknown aspects of this disease, and for screening new potential therapeutic agents. This appraisal of in vitro models of arrhythmogenic cardiomyopathy highlights the discoveries made about this disease and the uses of these models for future basic and therapeutic research. PMID:28679668

Computational Psychiatry

PubMed Central

Wang, Xiao-Jing; Krystal, John H.

2014-01-01

Psychiatric disorders such as autism and schizophrenia arise from abnormalities in brain systems that underlie cognitive, emotional and social functions. The brain is enormously complex and its abundant feedback loops on multiple scales preclude intuitive explication of circuit functions. In close interplay with experiments, theory and computational modeling are essential for understanding how, precisely, neural circuits generate flexible behaviors and their impairments give rise to psychiatric symptoms. This Perspective highlights recent progress in applying computational neuroscience to the study of mental disorders. We outline basic approaches, including identification of core deficits that cut across disease categories, biologically-realistic modeling bridging cellular and synaptic mechanisms with behavior, model-aided diagnosis. The need for new research strategies in psychiatry is urgent. Computational psychiatry potentially provides powerful tools for elucidating pathophysiology that may inform both diagnosis and treatment. To achieve this promise will require investment in cross-disciplinary training and research in this nascent field. PMID:25442941

Giant exchange interaction in mixed lanthanides

PubMed Central

Vieru, Veacheslav; Iwahara, Naoya; Ungur, Liviu; Chibotaru, Liviu F.

2016-01-01

Combining strong magnetic anisotropy with strong exchange interaction is a long standing goal in the design of quantum magnets. The lanthanide complexes, while exhibiting a very strong ionic anisotropy, usually display a weak exchange coupling, amounting to only a few wavenumbers. Recently, an isostructural series of mixed (Ln = Gd, Tb, Dy, Ho, Er) have been reported, in which the exchange splitting is estimated to reach hundreds wavenumbers. The microscopic mechanism governing the unusual exchange interaction in these compounds is revealed here by combining detailed modeling with density-functional theory and ab initio calculations. We find it to be basically kinetic and highly complex, involving non-negligible contributions up to seventh power of total angular momentum of each lanthanide site. The performed analysis also elucidates the origin of magnetization blocking in these compounds. Contrary to general expectations the latter is not always favored by strong exchange interaction. PMID:27087470

An Overview of Biological Macromolecule Crystallization

PubMed Central

Krauss, Irene Russo; Merlino, Antonello; Vergara, Alessandro; Sica, Filomena

2013-01-01

The elucidation of the three dimensional structure of biological macromolecules has provided an important contribution to our current understanding of many basic mechanisms involved in life processes. This enormous impact largely results from the ability of X-ray crystallography to provide accurate structural details at atomic resolution that are a prerequisite for a deeper insight on the way in which bio-macromolecules interact with each other to build up supramolecular nano-machines capable of performing specialized biological functions. With the advent of high-energy synchrotron sources and the development of sophisticated software to solve X-ray and neutron crystal structures of large molecules, the crystallization step has become even more the bottleneck of a successful structure determination. This review introduces the general aspects of protein crystallization, summarizes conventional and innovative crystallization methods and focuses on the new strategies utilized to improve the success rate of experiments and increase crystal diffraction quality. PMID:23727935

Understanding the cellular basis and pathophysiology of Peyronie’s disease to optimize treatment for erectile dysfunction

PubMed Central

Alzubaidi, Raidh

2017-01-01

Erectile dysfunction (ED) is a common condition that significantly impacts a man’s physical and psychological well-being. ED is often associated with Peyronie’s disease (PD), which is an abnormal curvature of the penis. Delayed treatment of or surgical invention for PD often results in ED and therefore unsatisfied patients. The pathophysiology of PD is incompletely understood, but has been studied extensively and based on our current understanding of PD physiology, many medical treatment options have been proposed. In this paper, we will review what is known about the pathophysiology of PD and the medical treatment options that have been trialed as a result. More investigations in regards to the basic science of PD need to be carried out in order to elucidate the exact mechanisms of the fibrosis, and propose new, more successful treatment options which should be implemented prior to the onset of ED. PMID:28217450

The role of the cell wall in fungal pathogenesis

PubMed Central

Arana, David M.; Prieto, Daniel; Román, Elvira; Nombela, César; Alonso‐Monge, Rebeca; Pla, Jesús

2009-01-01

Summary Fungal infections are a serious health problem. In recent years, basic research is focusing on the identification of fungal virulence factors as promising targets for the development of novel antifungals. The wall, as the most external cellular component, plays a crucial role in the interaction with host cells mediating processes such as adhesion or phagocytosis that are essential during infection. Specific components of the cell wall (called PAMPs) interact with specific receptors in the immune cell (called PRRs), triggering responses whose molecular mechanisms are being elucidated. We review here the main structural carbohydrate components of the fungal wall (glucan, mannan and chitin), how their biogenesis takes place in fungi and the specific receptors that they interact with. Different model fungal pathogens are chosen to illustrate the functional consequences of this interaction. Finally, the identification of the key components will have important consequences in the future and will allow better approaches to treat fungal infections. PMID:21261926

Structure and Function of Caltrin (Calcium Transport Inhibitor) Proteins

PubMed Central

Grasso, Ernesto Javier; Coronel, Carlos Enrique

2017-01-01

Caltrin (calcium transport inhibitor) is a family of small and basic proteins of the mammalian seminal plasma which bind to sperm cells during ejaculation and inhibit the extracellular Ca2+ uptake, preventing the premature acrosomal exocytosis and hyperactivation when sperm cells ascend through the female reproductive tract. The binding of caltrin proteins to specific areas of the sperm surface suggests the existence of caltrin receptors, or precise protein-phospholipid arrangements in the sperm membrane, distributed in the regions where Ca2+ influx may take place. However, the molecular mechanisms of recognition and interaction between caltrin and spermatozoa have not been elucidated. Therefore, the aim of this article is to describe in depth the known structural features and functional properties of caltrin proteins, to find out how they may possibly interact with the sperm membranes to control the intracellular signaling that trigger physiological events required for fertilization. PMID:29308010

A brief review of the clinical anatomy of the vestibular-ocular connections-how much do we know?

PubMed

Bronstein, A M; Patel, M; Arshad, Q

2015-02-01

The basic connectivity from the vestibular labyrinth to the eye muscles (vestibular ocular reflex, VOR) has been elucidated in the past decade, and we summarise this in graphic format. We also review the concept of 'velocity storage', a brainstem integrator that prolongs vestibular responses. Finally, we present new discoveries of how complex visual stimuli, such as binocular rivalry, influence VOR processing. In contrast to the basic brainstem circuits, cortical vestibular circuits are far from being understood, but parietal-vestibular nuclei projections are likely to be involved.

Sources and Sinks: Elucidating Mechanisms, Documenting Patterns, and Forecasting Impacts

DTIC Science & Technology

2017-01-18

Molecular Ecology 17: 3628-3639. Fazio III, V. W., Miles, D. B., & White, M. M. 2004. Genetic differentiation in the endangered Black-capped Vireo...exploration of accuracy and power. Molecular Ecology 13: 55–65. Raymond, M., & Rousset, F. 1995. GENEPOP (version 1.2): population genetics software for...SUPPLEMENTAL GENETICS MEMO Sources and Sinks: Elucidating Mechanisms, Documenting Patterns, and Forecasting Impacts SERDP Project RC-2120

Simulations of cellulose translocation in the bacterial cellulose synthase suggest a regulatory mechanism for the dimeric structure of cellulose.

PubMed

Knott, Brandon C; Crowley, Michael F; Himmel, Michael E; Zimmer, Jochen; Beckham, Gregg T

2016-05-01

The processive cycle of the bacterial cellulose synthase (Bcs) includes the addition of a single glucose moiety to the end of a growing cellulose chain followed by the translocation of the nascent chain across the plasma membrane. The mechanism of this translocation and its precise location within the processive cycle are not well understood. In particular, the molecular details of how a polymer (cellulose) whose basic structural unit is a dimer (cellobiose) can be constructed by adding one monomer (glucose) at a time are yet to be elucidated. Here, we have utilized molecular dynamics simulations and free energy calculations to the shed light on these questions. We find that translocation forward by one glucose unit is quite favorable energetically, giving a free energy stabilization of greater than 10 kcal/mol. In addition, there is only a small barrier to translocation, implying that translocation is not rate limiting within the Bcs processive cycle (given experimental rates for cellulose synthesis in vitro ). Perhaps most significantly, our results also indicate that steric constraints at the transmembrane tunnel entrance regulate the dimeric structure of cellulose. Namely, when a glucose molecule is added to the cellulose chain in the same orientation as the acceptor glucose, the terminal glucose freely rotates upon forward motion, thus suggesting a regulatory mechanism for the dimeric structure of cellulose. We characterize both the conserved and non-conserved enzyme-polysaccharide interactions that drive translocation, and find that 20 of the 25 residues that strongly interact with the translocating cellulose chain in the simulations are well conserved, mostly with polar or aromatic side chains. Our results also allow for a dynamical analysis of the role of the so-called `finger helix' in cellulose translocation that has been observed structurally. Taken together, these findings aid in the elucidation of the translocation steps of the Bcs processive cycle and may be widely relevant to polysaccharide synthesizing or degrading enzymes that couple catalysis with chain translocation.

Global Genetic Response in a Cancer Cell: Self-Organized Coherent Expression Dynamics

PubMed Central

Tsuchiya, Masa; Hashimoto, Midori; Takenaka, Yoshiko; Motoike, Ikuko N.; Yoshikawa, Kenichi

2014-01-01

Understanding the basic mechanism of the spatio-temporal self-control of genome-wide gene expression engaged with the complex epigenetic molecular assembly is one of major challenges in current biological science. In this study, the genome-wide dynamical profile of gene expression was analyzed for MCF-7 breast cancer cells induced by two distinct ErbB receptor ligands: epidermal growth factor (EGF) and heregulin (HRG), which drive cell proliferation and differentiation, respectively. We focused our attention to elucidate how global genetic responses emerge and to decipher what is an underlying principle for dynamic self-control of genome-wide gene expression. The whole mRNA expression was classified into about a hundred groups according to the root mean square fluctuation (rmsf). These expression groups showed characteristic time-dependent correlations, indicating the existence of collective behaviors on the ensemble of genes with respect to mRNA expression and also to temporal changes in expression. All-or-none responses were observed for HRG and EGF (biphasic statistics) at around 10–20 min. The emergence of time-dependent collective behaviors of expression occurred through bifurcation of a coherent expression state (CES). In the ensemble of mRNA expression, the self-organized CESs reveals distinct characteristic expression domains for biphasic statistics, which exhibits notably the presence of criticality in the expression profile as a route for genomic transition. In time-dependent changes in the expression domains, the dynamics of CES reveals that the temporal development of the characteristic domains is characterized as autonomous bistable switch, which exhibits dynamic criticality (the temporal development of criticality) in the genome-wide coherent expression dynamics. It is expected that elucidation of the biophysical origin for such critical behavior sheds light on the underlying mechanism of the control of whole genome. PMID:24831017

Analysis of physiological and miRNA responses to Pi deficiency in alfalfa (Medicago sativa L.).

PubMed

Li, Zhenyi; Xu, Hongyu; Li, Yue; Wan, Xiufu; Ma, Zhao; Cao, Jing; Li, Zhensong; He, Feng; Wang, Yufei; Wan, Liqiang; Tong, Zongyong; Li, Xianglin

2018-03-01

The induction of miR399 and miR398 and the inhibition of miR156, miR159, miR160, miR171, miR2111, and miR2643 were observed under Pi deficiency in alfalfa. The miRNA-mediated genes involved in basic metabolic process, root and shoot development, stress response and Pi uptake. Inorganic phosphate (Pi) deficiency is known to be a limiting factor in plant development and growth. However, the underlying miRNAs associated with the Pi deficiency-responsive mechanism in alfalfa are unclear. To elucidate the molecular mechanism at the miRNA level, we constructed four small RNA (sRNA) libraries from the roots and shoots of alfalfa grown under normal or Pi-deficient conditions. In the present study, alfalfa plants showed reductions in biomass, photosynthesis, and Pi content and increases in their root-to-shoot ratio and citric, malic, and succinic acid contents under Pi limitation. Sequencing results identified 47 and 44 differentially expressed miRNAs in the roots and shoots, respectively. Furthermore, 909 potential target genes were predicted, and some targets were validated by RLM-RACE assays. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed prominent enrichment in signal transducer activity, binding and basic metabolic pathways for carbohydrates, fatty acids and amino acids; cellular response to hormone stimulus and response to auxin pathways were also enriched. qPCR results verified that the differentially expressed miRNA profile was consistent with sequencing results, and putative target genes exhibited opposite expression patterns. In this study, the miRNAs associated with the response to Pi limitation in alfalfa were identified. In addition, there was an enrichment of miRNA-targeted genes involved in biological regulatory processes such as basic metabolic pathways, root and shoot development, stress response, Pi transportation and citric acid secretion.

Reliable and versatile immortal muscle cell models from healthy and myotonic dystrophy type 1 primary human myoblasts.

PubMed

Pantic, Boris; Borgia, Doriana; Giunco, Silvia; Malena, Adriana; Kiyono, Tohru; Salvatori, Sergio; De Rossi, Anita; Giardina, Emiliano; Sangiuolo, Federica; Pegoraro, Elena; Vergani, Lodovica; Botta, Annalisa

2016-03-01

Primary human skeletal muscle cells (hSkMCs) are invaluable tools for deciphering the basic molecular mechanisms of muscle-related biological processes and pathological alterations. Nevertheless, their use is quite restricted due to poor availability, short life span and variable purity of the cells during in vitro culture. Here, we evaluate a recently published method of hSkMCs immortalization, relying on ectopic expression of cyclin D1 (CCND1), cyclin-dependent kinase 4 (CDK4) and telomerase (TERT) in myoblasts from healthy donors (n=3) and myotonic dystrophy type 1 (DM1) patients (n=2). The efficacy to maintain the myogenic and non-transformed phenotype, as well as the main pathogenetic hallmarks of DM1, has been assessed. Combined expression of the three genes i) maintained the CD56(NCAM)-positive myoblast population and differentiation potential; ii) preserved the non-transformed phenotype and iii) maintained the CTG repeat length, amount of nuclear foci and aberrant alternative splicing in immortal muscle cells. Moreover, immortal hSkMCs displayed attractive additional features such as structural maturation of sarcomeres, persistence of Pax7-positive cells during differentiation and complete disappearance of nuclear foci following (CAG)7 antisense oligonucleotide (ASO) treatment. Overall, the CCND1, CDK4 and TERT immortalization yields versatile, reliable and extremely useful human muscle cell models to investigate the basic molecular features of human muscle cell biology, to elucidate the molecular pathogenetic mechanisms and to test new therapeutic approaches for DM1 in vitro. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced Mechanical Performance of Bio-Inspired Hybrid Structures Utilising Topological Interlocking Geometry

PubMed Central

Djumas, Lee; Molotnikov, Andrey; Simon, George P.; Estrin, Yuri

2016-01-01

Structural composites inspired by nacre have emerged as prime exemplars for guiding materials design of fracture-resistant, rigid hybrid materials. The intricate microstructure of nacre, which combines a hard majority phase with a small fraction of a soft phase, achieves superior mechanical properties compared to its constituents and has generated much interest. However, replicating the hierarchical microstructure of nacre is very challenging, not to mention improving it. In this article, we propose to alter the geometry of the hard building blocks by introducing the concept of topological interlocking. This design principle has previously been shown to provide an inherently brittle material with a remarkable flexural compliance. We now demonstrate that by combining the basic architecture of nacre with topological interlocking of discrete hard building blocks, hybrid materials of a new type can be produced. By adding a soft phase at the interfaces between topologically interlocked blocks in a single-build additive manufacturing process, further improvement of mechanical properties is achieved. The design of these fabricated hybrid structures has been guided by computational work elucidating the effect of various geometries. To our knowledge, this is the first reported study that combines the advantages of nacre-inspired structures with the benefits of topological interlocking. PMID:27216277

Selectivity Mechanism of the Voltage-gated Proton Channel, HV1

NASA Astrophysics Data System (ADS)

Dudev, Todor; Musset, Boris; Morgan, Deri; Cherny, Vladimir V.; Smith, Susan M. E.; Mazmanian, Karine; Decoursey, Thomas E.; Lim, Carmay

2015-05-01

Voltage-gated proton channels, HV1, trigger bioluminescence in dinoflagellates, enable calcification in coccolithophores, and play multifarious roles in human health. Because the proton concentration is minuscule, exquisite selectivity for protons over other ions is critical to HV1 function. The selectivity of the open HV1 channel requires an aspartate near an arginine in the selectivity filter (SF), a narrow region that dictates proton selectivity, but the mechanism of proton selectivity is unknown. Here we use a reduced quantum model to elucidate how the Asp-Arg SF selects protons but excludes other ions. Attached to a ring scaffold, the Asp and Arg side chains formed bidentate hydrogen bonds that occlude the pore. Introducing H3O+ protonated the SF, breaking the Asp-Arg linkage and opening the conduction pathway, whereas Na+ or Cl- was trapped by the SF residue of opposite charge, leaving the linkage intact, thus preventing permeation. An Asp-Lys SF behaved like the Asp-Arg one and was experimentally verified to be proton-selective, as predicted. Hence, interacting acidic and basic residues form favorable AspH0-H2O0-Arg+ interactions with hydronium but unfavorable Asp--X-/X+-Arg+ interactions with anions/cations. This proposed mechanism may apply to other proton-selective molecules engaged in bioenergetics, homeostasis, and signaling.

Flowering shoots of ornamental crops as a model to study cellular and molecular aspects of plant gravitropism.

PubMed

Philosoph-Hadas, Sonia; Friedman, Haya; Meir, Shimon

2015-01-01

Flowering shoots offer a very convenient and excellent model system for in-depth study of shoot gravitropism in regular stems rather than in special aboveground organs, showing how plants cope with the force of gravity on Earth and change in orientation. Regarding the emerging notion that roots and shoots execute their gravitropic bending by different mechanisms, the use of flowering shoots offers additional confirmation for the suggested shoot-sensing mechanisms initially found in Arabidopsis. As a part of confirming this mechanism, studying this unique model system also enabled elucidation of the sequence of events operating in gravity signalling in shoots. Hence, using the system of flowering shoots provided an additional dimension to our understanding of shoot gravitropism and its hormonal regulation, which has been less advanced than root gravitropism. This is particularly important since the term "shoots" includes various aboveground organs. Hence, unlike other aboveground organs such as pulvini, the asymmetric growth in response to change in shoot orientation is accompanied in cut ornamental spikes by a continuous growth process. This chapter provides an overview of the basic methods, specifically developed or adapted from other graviresponding systems, for determining the main components which play a key role in gravistimulation signalling in flowering shoots.

Studies Relevent to Catalytic Activation Co & other small Molecules

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

Ford, Peter C

2005-02-22

Detailed annual and triannual reports describing the progress accomplished during the tenure of this grant were filed with the Program Manager for Catalysis at the Office of Basic Energy Sciences. To avoid unnecessary duplication, the present report will provide a brief overview of the research areas that were sponsored by this grant and list the resulting publications and theses based on this DOE supported research. The scientific personnel participating in (and trained by) this grant's research are also listed. Research carried out under this DOE grant was largely concerned with the mechanisms of the homogeneous catalytic and photocatalytic activation ofmore » small molecules such as carbon monoxide, dihydrogen and various hydrocarbons. Much of the more recent effort has focused on the dynamics and mechanisms of reactions relevant to substrate carbonylations by homogeneous organometallic catalysts. A wide range of modern investigative techniques were employed, including quantitative fast reaction methodologies such as time-resolved optical (TRO) and time-resolved infrared (TRIR) spectroscopy and stopped flow kinetics. Although somewhat diverse, this research falls within the scope of the long-term objective of applying quantitative techniques to elucidate the dynamics and understand the principles of mechanisms relevant to the selective and efficient catalytic conversions of fundamental feedstocks to higher value materials.« less

Advances toward regenerative medicine in the central nervous system: challenges in making stem cell therapy a viable clinical strategy.

PubMed

Stoll, Elizabeth A

2014-01-01

Over recent years, there has been a great deal of interest in the prospects of stem cell-based therapies for the treatment of nervous system disorders. The eagerness of scientists, clinicians, and spin-out companies to develop new therapies led to premature clinical trials in human patients, and now the initial excitement has largely turned to skepticism. Rather than embracing a defeatist attitude or pressing blindly ahead, I argue it is time to evaluate the challenges encountered by regenerative medicine in the central nervous system and the progress that is being made to solve these problems. In the twenty years since the adult brain was discovered to have an endogenous regenerative capacity, much basic research has been done to elucidate mechanisms controlling proliferation and cellular identity; how stem cells may be directed into neuronal lineages; genetic, pharmacological, and behavioral interventions that modulate neurogenic activity; and the exact nature of limitations to regeneration in the adult, aged, diseased and injured CNS. These findings should prove valuable in designing realistic clinical strategies to improve the prospects of stem cell-based therapies. In this review, I discuss how basic research continues to play a critical role in identifying both barriers and potential routes to regenerative therapy in the CNS.

Basic fibroblast growth factor protects against influenza A virus-induced acute lung injury by recruiting neutrophils.

PubMed

Wang, Keyu; Lai, Chengcai; Li, Tieling; Wang, Cheng; Wang, Wei; Ni, Bing; Bai, Changqing; Zhang, Shaogeng; Han, Lina; Gu, Hongjing; Zhao, Zhongpeng; Duan, Yueqiang; Yang, Xiaolan; Xing, Li; Zhao, Lingna; Zhou, Shanshan; Xia, Min; Jiang, Chengyu; Wang, Xiliang; Yang, Penghui

2017-11-07

Influenza virus (IAV) infection is a major cause of severe respiratory illness that affects almost every country in the world. IAV infections result in respiratory illness and even acute lung injury and death, but the underlying mechanisms responsible for IAV pathogenesis have not yet been fully elucidated. In this study, the basic fibroblast growth factor 2 (FGF2) level was markedly increased in H1N1 virus-infected humans and mice. FGF2, which is predominately derived from epithelial cells, recruits and activates neutrophils via the FGFR2-PI3K-AKT-NFκB signaling pathway. FGF2 depletion or knockout exacerbated influenza-associated disease by impairing neutrophil recruitment and activation. More importantly, administration of the recombinant FGF2 protein significantly alleviated the severity of IAV-induced lung injury and promoted the survival of IAV-infected mice. Based on the results from experiments in which neutrophils were depleted and adoptively transferred, FGF2 protected mice against IAV infection by recruiting neutrophils. Thus, FGF2 plays a critical role in preventing IAV-induced lung injury, and FGF2 is a promising potential therapeutic target during IAV infection. © The Author (2017). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

Vagal-immune interactions involved in cholinergic anti-inflammatory pathway.

PubMed

Zila, I; Mokra, D; Kopincova, J; Kolomaznik, M; Javorka, M; Calkovska, A

2017-09-22

Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

PubMed Central

Ruggiero, Rafael N.; Rossignoli, Matheus T.; De Ross, Jana B.; Hallak, Jaime E. C.; Leite, Joao P.; Bueno-Junior, Lezio S.

2017-01-01

Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools. PMID:28680405

Theory of buckling and post-buckling behavior of elastic structures

NASA Technical Reports Server (NTRS)

Budiansky, B.

1974-01-01

The present paper provides a unified, general presentation of the basic theory of the buckling and post-buckling behavior of elastic structures in a form suitable for application to a wide variety of special problems. The notation of functional analysis is used for this purpose. Before the general analysis, simple conceptual models are used to elucidate the basic concepts of bifurcation buckling, snap buckling, imperfection sensitivity, load-shortening relations, and stability. The energy approach, the virtual-work approach, and mode interaction are discussed. The derivations and results are applicable to continua and finite-dimensional systems. The virtual-work and energy approaches are given separate treatments, but their equivalence is made explicit. The basic concepts of stability occupy a secondary position in the present approach.

Integration of kinetic isotope effect analyses to elucidate ribonuclease mechanism.

PubMed

Harris, Michael E; Piccirilli, Joseph A; York, Darrin M

2015-11-01

The well-studied mechanism of ribonuclease A is believed to involve concerted general acid-base catalysis by two histidine residues, His12 and His119. The basic features of this mechanism are often cited to explain rate enhancement by both protein and RNA enzymes that catalyze RNA 2'-O-transphosphorylation. Recent kinetic isotope effect analyses and computational studies are providing a more chemically detailed description of the mechanism of RNase A and the rate limiting transition state. Overall, the results support an asynchronous mechanism for both solution and ribonuclease catalyzed reactions in which breakdown of a transient dianoinic phosphorane intermediate by 5'OP bond cleavage is rate limiting. Relative to non-enzymatic reactions catalyzed by specific base, a smaller KIE on the 5'O leaving group and a less negative βLG are observed for RNase A catalysis. Quantum mechanical calculations consistent with these data support a model in which electrostatic and H-bonding interactions with the non-bridging oxygens and proton transfer from His119 render departure of the 5'O less advanced and stabilize charge buildup in the transition state. Both experiment and computation indicate advanced 2'OP bond formation in the rate limiting transition state. However, this feature makes it difficult to resolve the chemical steps involved in 2'O activation. Thus, modeling the transition state for RNase A catalysis underscores those elements of its chemical mechanism that are well resolved, as well as highlighting those where ambiguity remains. This article is part of a Special Issue entitled: Enzyme Transition States from Theory and Experiment. Published by Elsevier B.V.

Basic research in PCOS: are we reaching new frontiers?

PubMed

Ben-Shlomo, Izhar; Younis, Johnny S

2014-06-01

Polycystic ovarian syndrome (PCOS) is the leading cause for anovulatory infertility. It is diagnosed by two of the following three clinical criteria: oligomenorrhoea, hyperandrogenism and polycystic appearance of the ovaries. Weight loss and physical activity can lead to ovulation and conception. Lowering of serum insulin normalizes androgen concentrations whereas ovulation induction often causes ovarian hyperstimulation. Theca cells from PCOS ovaries may be more responsive to insulin than cells from non-PCOS ovaries. Herein we review the research efforts at the genomic and cell function levels, as well as animal models, which have been made to elucidate the underlying mechanism that leads to PCOS. It appears that, despite the impressive amount of data that have been generated in these studies, the mechanism of this syndrome is still only partially understood. Polycystic ovarian syndrome (PCOS) is the leading cause for infertility, which is caused by anovulation. It is diagnosed by two of the following three clinical criteria: irregular and prolonged menstrual cycles, overt symptoms of excess androgens, which is revealed by acne and excess hair, and ultrasonographic appearance of the ovaries with multiple small follicles spread mainly near the ovarian surface, which gave it its name. Intentional weight loss and physical activity can lead to resumption of ovulation and not infrequently to conception as well. It was shown that lowering of serum insulin accounts for normalization of serum androgen levels, whereas ovulation induction with FSH often causes ovarian hyperstimulation. It is suggested that theca cells from PCOS ovaries may be more responsive to insulin than cells from non-PCOS ovaries. In this article we review the efforts to define the genes responsible for the syndrome and the studies at the cell function level, as well as animal models, which have been done to elucidate the underlying mechanism that leads to PCOS. Overall, it appears that despite the impressive amount of data that have been generated in these studies, the mechanism of this syndrome is still only partially understood. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Grasping the Concept of Personal Property

ERIC Educational Resources Information Center

Constable, Merryn D.; Kritikos, Ada; Bayliss, Andrew P.

2011-01-01

The concept of property is integral to personal and societal development, yet understanding of the cognitive basis of ownership is limited. Objects are the most basic form of property, so our physical interactions with owned objects may elucidate nuanced aspects of ownership. We gave participants a coffee mug to decorate, use and keep. The…

A Time-Cost Management System for use in Educational Planning.

ERIC Educational Resources Information Center

McIsaac, Donald N., Jr.; and Others

Prepared specifically for the Denver Public Schools, this manual nevertheless provides some of the basic understanding required for the proper execution of educational planning based upon PERT/CPM techniques. The theory of PERT/CPM and the fundamental processes involved therein are elucidated in the first part of the manual while the operating…

Doomed to Read in a Second Language: Implications for Learning

ERIC Educational Resources Information Center

Miller, Paul; Peleg, Ora

2010-01-01

The aim of the study was to elucidate whether and how reliance on a second language impacts the learning of new information under very basic learning conditions. The paradigm used to investigate this issue required individuals to learn a series of associations between numerals and particular letter strings. Participants were two groups of…

Translational Behavior Analysis: From Laboratory Science in Stimulus Control to Intervention with Persons with Neurodevelopmental Disabilities

ERIC Educational Resources Information Center

McIlvane, William J.

2009-01-01

Throughout its history, laboratory research in the experimental analysis of behavior has been successful in elucidating and clarifying basic learning principles and processes in both humans and nonhumans. In parallel, applied behavior analysis has shown how fundamental behavior-analytic principles and procedures can be employed to promote…

Social learning modulates the lateralization of emotional valence.

PubMed

Shamay-Tsoory, Simone G; Lavidor, Michal; Aharon-Peretz, Judith

2008-08-01

Although neuropsychological studies of lateralization of emotion have emphasized valence (positive vs. negative) or type (basic vs. complex) dimensions, the interaction between the two dimensions has yet to be elucidated. The purpose of the current study was to test the hypothesis that recognition of basic emotions is processed preferentially by the right prefrontal cortex (PFC), whereas recognition of complex social emotions is processed preferentially by the left PFC. Experiment 1 assessed the ability of healthy controls and patients with right and left PFC lesions to recognize basic and complex emotions. Experiment 2 modeled the patient's data of Experiment 1 on healthy participants under lateralized displays of the emotional stimuli. Both experiments support the Type as well as the Valence Hypotheses. However, our findings indicate that the Valence Hypothesis holds for basic but less so for complex emotions. It is suggested that, since social learning overrules the basic preference of valence in the hemispheres, the processing of complex emotions in the hemispheres is less affected by valence.

Slow, fast and furious: understanding the physics of plant movements.

PubMed

Forterre, Yoël

2013-11-01

The ability of plants to move is central to many physiological processes from development to tropisms, from nutrition to reproduction. The movement of plants or plant parts occurs over a wide range of sizes and time scales. This review summarizes the main physical mechanisms plants use to achieve motility, highlighting recent work at the frontier of biology and physics on rapid movements. Emphasis is given to presenting in a single framework pioneering biological studies of water transport and growth with more recent physics research on poroelasticity and mechanical instabilities. First, the basic osmotic and hydration/dehydration motors are described that contribute to movement by growth and reversible swelling/shrinking of cells and tissues. The speeds of these water-driven movements are shown to be ultimately limited by the transport of water through the plant body. Some plant structures overcome this hydraulic limit to achieve much faster movement by using a mechanical instability. The principle is to impose an 'energy barrier' to the system, which can originate from geometrical constraint or matter cohesion, allowing elastic potential energy to be stored until the barrier is overcome, then rapidly transformed into kinetic energy. Three of these rapid motion mechanisms have been elucidated recently and are described here: the snapping traps of two carnivorous plants, the Venus flytrap and Utricularia, and the catapult of fern sporangia. Finally, movement mechanisms are reconsidered in the context of the timescale of important physiological processes at the cellular and molecular level.

On the generation of horizontal shear waves by underground explosions in jointed rocks

DOE PAGES

Vorobiev, Oleg; Ezzedine, Souheil; Antoun, Tarabay; ...

2015-02-04

This paper describes computational studies of non-spherical ground motions generated by spherical explosions in a heavily jointed granite formation. Various factors affecting the shear wave generation are considered, including joint spacing, orientation, persistence and properties. Simulations are performed both in 2D for a single joint set to elucidate the basic response mechanisms, and in 3D for multiple joint sets to realistically represent in situ conditions in a realistic geologic setting. The joints are modeled explicitly using both contact elements and weakness planes in the material. Simulations are performed both deterministically and stochastically to quantify the effects of geologic uncertainties onmore » near field ground motions. The mechanical properties of the rock and the joints as well as the joint spacing and orientation are taken from experimental test data and geophysical logs corresponding to the Climax Stock granitic outcrop, which is the geologic setting of the Source Physics Experiment (SPE). Agreement between simulation results and near field wave motion data from SPE enables newfound understanding of the origin and extent of non-spherical motions associated with underground explosions in fractured geologic media.« less

Melatonin: Free Radicals and Metabolites Resulting by Emission and Consumption of Solvated Electrons (eaq-): Reaction Mechanisms.

PubMed

Kneidinger, Herbert; Mitulovic, Goran; Hartmann, Johannes; Quint, Ruth Maria; Getoff, Nikola

2015-01-01

Melatonin not only regulates circadian rhythm, but also induces apoptosis in tumor cells. Hence, elucidation of the basic reaction mechanisms of melatonin and its metabolites is a matter of interest. Melatonin dissolved in a mixture of water/ethanol=40/60 form associates (unstable complexes). For simulation of biological processes, melatonin was excited by UV light into the singlet state. By using monochromatic UV light (λ=254 nm) melatonin ejects solvated electrons (eaq (-)), a part of which is scavenged by melatonin in ground state contained in the associates. Consequently, with increase of melatonin concentration a decrease of the determined quantum yield of emitted eaq (-), Q(eaq (-)), is obtained. The complex molecular structure of melatonin contains functional groups which can emit eaq (-), as well such consuming eaq (-). As a succession of these processes various types of metabolites are generated, as well as degradation products, with lower molecular weight, are formed. Not melatonin per se, but the ejected eaq (-) and thereby resulting various metabolites are responsible for different biological properties of melatonin. Copyright © 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Research advances on microbial genetics in China in 2015.

PubMed

Xie, Jian-ping; Han, Yu-bo; Liu, Gang; Bai, Lin-quan

2016-09-01

In 2015, there are significant progresses in many aspects of the microbial genetics in China. To showcase the contribution of Chinese scientists in microbial genetics, this review surveys several notable progresses in microbial genetics made largely by Chinese scientists, and some key findings are highlighted. For the basic microbial genetics, the components, structures and functions of many macromolecule complexes involved in gene expression regulation have been elucidated. Moreover, the molecular basis underlying the recognition of foreign nucleic acids by microbial immune systems was unveiled. We also illustrated the biosynthetic pathways and regulators of multiple microbial compounds, novel enzyme reactions, and new mechanisms regulating microbial gene expression. And new findings were obtained in the microbial development, evolution and population genetics. For the industrial microbiology, more understanding on the molecular basis of the microbial factory has been gained. For the pathogenic microbiology, the genetic circuits of several pathogens were depicted, and significant progresses were achieved for understanding the pathogen-host interaction and revealing the genetic mechanisms underlying antimicrobial resistance, emerging pathogens and environmental microorganisms at the genomic level. In future, the genetic diversity of microbes can be used to obtain specific products, while gut microbiome is gathering momentum.

Basics of Radiation Biology When Treating Hyperproliferative Benign Diseases.

PubMed

Rödel, Franz; Fournier, Claudia; Wiedemann, Julia; Merz, Felicitas; Gaipl, Udo S; Frey, Benjamin; Keilholz, Ludwig; Seegenschmiedt, M Heinrich; Rödel, Claus; Hehlgans, Stephanie

2017-01-01

For decades, low- and moderate-dose radiation therapy (RT) has been shown to exert a beneficial therapeutic effect in a multitude of non-malignant conditions including painful degenerative muscoloskeletal and hyperproliferative disorders. Dupuytren and Ledderhose diseases are benign fibroproliferative diseases of the hand/foot with fibrotic nodules and fascial cords, which determine debilitating contractures and deformities of fingers/toes, while keloids are exuberant scar formations following burn damage, surgery, and trauma. Although RT has become an established and effective option in the management of these diseases, experimental studies to illustrate cellular composites and factors involved remain to be elucidated. More recent findings, however, indicate the involvement of radiation-sensitive targets like mitotic fibroblasts/myofibroblasts as well as inflammatory cells. Radiation-related molecular mechanisms affecting these target cells include the production of free radicals to hamper proliferative activity and interference with growth factors and cytokines. Moreover, an impairment of activated immune cells involved in both myofibroblast proliferative and inflammatory processes may further contribute to the clinical effects. We here aim at briefly describing mechanisms contributing to a modulation of proliferative and inflammatory processes and to summarize current concepts of treating hyperproliferative diseases by low and moderate doses of ionizing radiation.

Copyright Renewal for Libraries: Seven Steps toward a User-Friendly Law

ERIC Educational Resources Information Center

Smith, Kevin L.

2010-01-01

Copyright law is a source of a great deal of bewilderment and frustration to academic librarians. Beyond the basics of copyright protection and fair use, most librarians struggle to grasp the complexity of the law and the roadblocks it presents to access and use. This article attempts to elucidate some of those complexities by suggesting seven…

Exploring the Efficacy of Behavioral Skills Training to Teach Basic Behavior Analytic Techniques to Oral Care Providers

ERIC Educational Resources Information Center

Graudins, Maija M.; Rehfeldt, Ruth Anne; DeMattei, Ronda; Baker, Jonathan C.; Scaglia, Fiorella

2012-01-01

Performing oral care procedures with children with autism who exhibit noncompliance can be challenging for oral care professionals. Previous research has elucidated a number of effective behavior analytic procedures for increasing compliance, but some procedures are likely to be too time consuming and expensive for community-based oral care…

Spatial distribrrtion of soil carbon in southern New England hardwood forest landscapes

Treesearch

Aletta A. Davis; Mark H. Stolt; Jana E. Compton

2004-01-01

Understanding soil organic C (SOC) spatial variability is critical when developing C budgets, explaining the cause and effects of climate change, and for basic ecosystem characterization. We investigated delineations of four soil series to elucidate teh factors that affect the size, distribution, and varibility of SOC pools from horizon to landscape scales. These soils...

Different Action Patterns for Cooperative and Competitive Behaviour

ERIC Educational Resources Information Center

Georgiou, Ioanna; Becchio, Cristina; Glover, Scott; Castiello, Umberto

2007-01-01

The aim of the present study is to elucidate the influence of context on the kinematics of the reach-to-grasp movement. In particular, we consider two basic modes of social cognition, namely cooperation and competition. In two experiments kinematics of the very same action--reaching-to-grasp a wooden block--were analyzed in two different contexts…

Thermophilic Beta-Glycosidase

NASA Technical Reports Server (NTRS)

Grogan, Dennis W.

1992-01-01

Report describes identification of thermophilic Beta-glycosidase enzyme from isolate of Sulfolobus solfataricus, sulfur-metabolizing archaebacteria growing aerobically and heterotrophically to relatively high cell yields. Enzyme useful in enzymatic conversion of cellulose to D-glucose and important in recycling of biomass. Used for removal of lactose from milk products. Offers promise as model substance for elucidation of basic principles of structural stabilization of proteins.

Analyzing Public Discourse: Using Media Content Analysis to Understand the Policy Process

ERIC Educational Resources Information Center

Saraisky, Nancy Green

2016-01-01

One of the most basic and obvious sources of data for education policy analysis is text. This article discusses content analysis as an important part of the methodological toolbox for elucidating patterns and trends about education policy. Focusing specifically on media, I show how media content analysis can produce nuanced insights about the ways…

A Neuro-Mechanical Model Explaining the Physiological Role of Fast and Slow Muscle Fibres at Stop and Start of Stepping of an Insect Leg

PubMed Central

Toth, Tibor Istvan; Grabowska, Martyna; Schmidt, Joachim; Büschges, Ansgar; Daun-Gruhn, Silvia

2013-01-01

Stop and start of stepping are two basic actions of the musculo-skeletal system of a leg. Although they are basic phenomena, they require the coordinated activities of the leg muscles. However, little is known of the details of how these activities are generated by the interactions between the local neuronal networks controlling the fast and slow muscle fibres at the individual leg joints. In the present work, we aim at uncovering some of those details using a suitable neuro-mechanical model. It is an extension of the model in the accompanying paper and now includes all three antagonistic muscle pairs of the main joints of an insect leg, together with their dedicated neuronal control, as well as common inhibitory motoneurons and the residual stiffness of the slow muscles. This model enabled us to study putative processes of intra-leg coordination during stop and start of stepping. We also made use of the effects of sensory signals encoding the position and velocity of the leg joints. Where experimental observations are available, the corresponding simulation results are in good agreement with them. Our model makes detailed predictions as to the coordination processes of the individual muscle systems both at stop and start of stepping. In particular, it reveals a possible role of the slow muscle fibres at stop in accelerating the convergence of the leg to its steady-state position. These findings lend our model physiological relevance and can therefore be used to elucidate details of the stop and start of stepping in insects, and perhaps in other animals, too. PMID:24278108

Impairment of interferon regulatory factor-3 activation by hepatitis C virus core protein basic amino acid region 1.

PubMed

Inoue, Kazuaki; Tsukiyama-Kohara, Kyoko; Matsuda, Chiho; Yoneyama, Mitsutoshi; Fujita, Takashi; Kuge, Shusuke; Yoshiba, Makoto; Kohara, Michinori

2012-11-30

Interferon regulatory factor-3 (IRF-3), a key transcriptional factor in the type I interferon system, is frequently impaired by hepatitis C virus (HCV), in order to establish persistent infection. However, the exact mechanism by which the virus establishes persistent infection has not been fully understood yet. The present study aimed to investigate the effects of various HCV proteins on IRF-3 activation, and elucidate the underlying mechanisms. To achieve this, full-length HCV and HCV subgenomic constructs corresponding to structural and each of the nonstructural proteins were transiently transfected into HepG2 cells. IFN-β induction, plaque formation, and IRF-3 dimerization were elicited by Newcastle disease virus (NDV) infection. The expressions of IRF-3 homodimer and its monomer, Ser386-phosphorylated IRF-3, and HCV core protein were detected by immunofluorescence and western blotting. IFN-β mRNA expression was quantified by real-time PCR (RT-PCR), and IRF-3 activity was measured by the levels of IRF-3 dimerization and phosphorylation, induced by NDV infection or polyriboinosinic:polyribocytidylic acid [poly(I:C)]. Switching of the expression of the complete HCV genome as well as the core proteins, E1, E2, and NS2, suppressed IFN-β mRNA levels and IRF-3 dimerization, induced by NDV infection. Our study revealed a crucial region of the HCV core protein, basic amino acid region 1 (BR1), to inhibit IRF-3 dimerization as well as its phosphorylation induced by NDV infection and poly (I:C), thus interfering with IRF-3 activation. Therefore, our study suggests that rescue of the IRF-3 pathway impairment may be an effective treatment for HCV infection. Copyright © 2012 Elsevier Inc. All rights reserved.

Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

PubMed

Suda, Kenichi; Mizuuchi, Hiroshi; Maehara, Yoshihiko; Mitsudomi, Tetsuya

2012-12-01

Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.

Elucidating Mechanisms of Molecular Recognition Between Human Argonaute and miRNA Using Computational Approaches.

PubMed

Jiang, Hanlun; Zhu, Lizhe; Héliou, Amélie; Gao, Xin; Bernauer, Julie; Huang, Xuhui

2017-01-01

MicroRNA (miRNA) and Argonaute (AGO) protein together form the RNA-induced silencing complex (RISC) that plays an essential role in the regulation of gene expression. Elucidating the underlying mechanism of AGO-miRNA recognition is thus of great importance not only for the in-depth understanding of miRNA function but also for inspiring new drugs targeting miRNAs. In this chapter we introduce a combined computational approach of molecular dynamics (MD) simulations, Markov state models (MSMs), and protein-RNA docking to investigate AGO-miRNA recognition. Constructed from MD simulations, MSMs can elucidate the conformational dynamics of AGO at biologically relevant timescales. Protein-RNA docking can then efficiently identify the AGO conformations that are geometrically accessible to miRNA. Using our recent work on human AGO2 as an example, we explain the rationale and the workflow of our method in details. This combined approach holds great promise to complement experiments in unraveling the mechanisms of molecular recognition between large, flexible, and complex biomolecules.

Tissue fluid pressures - From basic research tools to clinical applications

NASA Technical Reports Server (NTRS)

Hargens, Alan R.; Akeson, Wayne H.; Mubarak, Scott J.; Owen, Charles A.; Gershuni, David H.

1989-01-01

This paper describes clinical applications of two basic research tools developed and refined in the past 20 years: the wick catheter (for measuring tissue fluid pressure) and the colloid osmometer (for measuring osmotic pressure). Applications of the osmometer include estimations of the reduced osmotic pressure of sickle-cell hemoglobin with deoxygenation, and of reduced swelling pressure of human nucleus pulposus with hydration or upon action of certain enzymes. Clinical uses of the wick-catheter technique include an improvement of diagnosis and treatment of acute and chronic compartment syndromes, the elucidation of the tissue pressure thresholds for neuromuscular dysfunction, and the development of a better tourniquet for orthopedics.

Natural pigments: carotenoids, anthocyanins, and betalains--characteristics, biosynthesis, processing, and stability.

PubMed

Delgado-Vargas, F; Jiménez, A R; Paredes-López, O

2000-05-01

Pigments are present in all living matter and provide attractive colors and play basic roles in the development of organisms. Human beings, like most animals, come in contact with their surroundings through color, and things can or cannot be acceptable based on their color characteristics. This review presents the basic information about pigments focusing attention on the natural ones; it emphasizes the principal plant pigments: carotenoids, anthocyanins, and betalains. Special considerations are given to their salient characteristics; to their biosynthesis, taking into account the biochemical and molecular biology information generated in their elucidation; and to the processing and stability properties of these compounds as food colorants.

Molecular and Cellular Designs of Insect Taste Receptor System

PubMed Central

Isono, Kunio; Morita, Hiromi

2010-01-01

The insect gustatory receptors (GRs) are members of a large G-protein coupled receptor family distantly related to the insect olfactory receptors. They are phylogenetically different from taste receptors of most other animals. GRs are often coexpressed with other GRs in single receptor neurons. Taste receptors other than GRs are also expressed in some neurons. Recent molecular studies in the fruitfly Drosophila revealed that the insect taste receptor system not only covers a wide ligand spectrum of sugars, bitter substances or salts that are common to mammals but also includes reception of pheromone and somatosensory stimulants. However, the central mechanism to perceive and discriminate taste information is not yet elucidated. Analysis of the primary projection of taste neurons to the brain shows that the projection profiles depend basically on the peripheral locations of the neurons as well as the GRs that they express. These results suggest that both peripheral and central design principles of insect taste perception are different from those of olfactory perception. PMID:20617187

Nanotechnology applications in hematological malignancies (Review).

PubMed

Samir, Ahmed; Elgamal, Basma M; Gabr, Hala; Sabaawy, Hatem E

2015-09-01

A major limitation to current cancer therapies is the development of therapy-related side-effects and dose limiting complications. Moreover, a better understanding of the biology of cancer cells and the mechanisms of resistance to therapy is rapidly developing. The translation of advanced knowledge and discoveries achieved at the molecular level must be supported by advanced diagnostic, therapeutic and delivery technologies to translate these discoveries into useful tools that are essential in achieving progress in the war against cancer. Nanotechnology can play an essential role in this aspect providing a transforming technology that can translate the basic and clinical findings into novel diagnostic, therapeutic and preventive tools useful in different types of cancer. Hematological malignancies represent a specific class of cancer, which attracts special attention in the applications of nanotechnology for cancer diagnosis and treatment. The aim of the present review is to elucidate the emerging applications of nanotechnology in cancer management and describe the potentials of nanotechnology in changing the key fundamental aspects of hematological malignancy diagnosis, treatment and follow-up.

Anomalous evolution of Ar metastable density with electron density in high density Ar discharge

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

Park, Min; Chang, Hong-Young; You, Shin-Jae

2011-10-15

Recently, an anomalous evolution of argon metastable density with plasma discharge power (electron density) was reported [A. M. Daltrini, S. A. Moshkalev, T. J. Morgan, R. B. Piejak, and W. G. Graham, Appl. Phys. Lett. 92, 061504 (2008)]. Although the importance of the metastable atom and its density has been reported in a lot of literature, however, a basic physics behind the anomalous evolution of metastable density has not been clearly understood yet. In this study, we investigated a simple global model to elucidate the underlying physics of the anomalous evolution of argon metastable density with the electron density. Onmore » the basis of the proposed simple model, we reproduced the anomalous evolution of the metastable density and disclosed the detailed physics for the anomalous result. Drastic changes of dominant mechanisms for the population and depopulation processes of Ar metastable atoms with electron density, which take place even in relatively low electron density regime, is the clue to understand the result.« less

An RNA-Binding Multimer Specifies Nematode Sperm Fate.

PubMed

Aoki, Scott T; Porter, Douglas F; Prasad, Aman; Wickens, Marvin; Bingman, Craig A; Kimble, Judith

2018-06-26

FOG-3 is a master regulator of sperm fate in Caenorhabditis elegans and homologous to Tob/BTG proteins, which in mammals are monomeric adaptors that recruit enzymes to RNA binding proteins. Here, we determine the FOG-3 crystal structure and in vitro demonstrate that FOG-3 forms dimers that can multimerize. The FOG-3 multimeric structure has a basic surface potential, suggestive of binding nucleic acid. Consistent with that prediction, FOG-3 binds directly to nearly 1,000 RNAs in nematode spermatogenic germ cells. Most binding is to the 3' UTR, and most targets (94%) are oogenic mRNAs, even though assayed in spermatogenic cells. When tethered to a reporter mRNA, FOG-3 represses its expression. Together these findings elucidate the molecular mechanism of sperm fate specification and reveal the evolution of a protein from monomeric to multimeric form with acquisition of a distinct mode of mRNA repression. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Psychological stressors as interventions: good out of the evil.

PubMed

Sood, Parul; Priyadarshini, Sushri; Aich, Palok

2012-01-01

Stress in general can be defined as a state of threatened balance, equilibrium or harmony that tends to disturb the homeostasis of the body. Stress can be of many kinds viz. psychological, physiological, social, emotional, and nutritional. Albeit the distinct kinds of stress stated in the aforementioned stress list, it is hard to bring out a clear distinction between them since each stress may precede or succeed the manifestation of any other. The studies discussed in the review elucidate effects of psychological stressors (PS) on diseases such as cancer, AIDS, epidermal abnormalities, obesity, and various inflammatory diseases like colonic inflammations, Coronary Artery Disease (CAD), Coronary Heart Disease (CHD), asthma. From these studies, further attempt was made to establish the basic mechanisms which come into play during a stressor stimulus and consequently modulate the physiology of the body. In this review we have highlighted effects of PS on diseases while simultaneously building on the modes of operation of PS to alter physiology and its further implications in developing potential psychotherapeutic methods for disease treatment.

Development of a carbazole-based fluorescence probe for G-quadruplex DNA: The importance of side-group effect on binding specificity

NASA Astrophysics Data System (ADS)

Wang, Ming-Qi; Ren, Gui-Ying; Zhao, Shuang; Lian, Guang-Chang; Chen, Ting-Ting; Ci, Yang; Li, Hong-Yao

2018-06-01

G-quadruplex DNAs are highly prevalent in the human genome and involved in many important biological processes. However, many aspects of their biological mechanism and significance still need to be elucidated. Therefore, the development of fluorescent probes for G-quadruplex detection is important for the basic research. We report here on the development of small molecular dyes designed on the basis of carbazole scaffold by introducing styrene-like substituents at its 9-position, for the purpose of G-quadruplex recognition. Results revealed that the side group on the carbazole scaffold was very important for their ability to selectively recognize G-quadruplex DNA structures. 1a with the pyridine side group displayed excellent fluorescence signal turn-on property for the specific discrimination of G-quadruplex DNAs against other nucleic acids. The characteristics of 1a were further investigated with UV-vis spectrophotometry, fluorescence, circular dichroism, FID assay and molecular docking to validate the selectivity, sensitivity and detailed binding mode toward G-quadruplex DNAs.

Intersections of lung progenitor cells, lung disease and lung cancer.

PubMed

Kim, Carla F

2017-06-30

The use of stem cell biology approaches to study adult lung progenitor cells and lung cancer has brought a variety of new techniques to the field of lung biology and has elucidated new pathways that may be therapeutic targets in lung cancer. Recent results have begun to identify the ways in which different cell populations interact to regulate progenitor activity, and this has implications for the interventions that are possible in cancer and in a variety of lung diseases. Today's better understanding of the mechanisms that regulate lung progenitor cell self-renewal and differentiation, including understanding how multiple epigenetic factors affect lung injury repair, holds the promise for future better treatments for lung cancer and for optimising the response to therapy in lung cancer. Working between platforms in sophisticated organoid culture techniques, genetically engineered mouse models of injury and cancer, and human cell lines and specimens, lung progenitor cell studies can begin with basic biology, progress to translational research and finally lead to the beginnings of clinical trials. Copyright ©ERS 2017.

Nanotechnology applications in hematological malignancies (Review)

PubMed Central

SAMIR, AHMED; ELGAMAL, BASMA M; GABR, HALA; SABAAWY, HATEM E

2015-01-01

A major limitation to current cancer therapies is the development of therapy-related side-effects and dose limiting complications. Moreover, a better understanding of the biology of cancer cells and the mechanisms of resistance to therapy is rapidly developing. The translation of advanced knowledge and discoveries achieved at the molecular level must be supported by advanced diagnostic, therapeutic and delivery technologies to translate these discoveries into useful tools that are essential in achieving progress in the war against cancer. Nanotechnology can play an essential role in this aspect providing a transforming technology that can translate the basic and clinical findings into novel diagnostic, therapeutic and preventive tools useful in different types of cancer. Hematological malignancies represent a specific class of cancer, which attracts special attention in the applications of nanotechnology for cancer diagnosis and treatment. The aim of the present review is to elucidate the emerging applications of nanotechnology in cancer management and describe the potentials of nanotechnology in changing the key fundamental aspects of hematological malignancy diagnosis, treatment and follow-up. PMID:26134389

Genetic architecture of retinal and macular degenerative diseases: the promise and challenges of next-generation sequencing

PubMed Central

2013-01-01

Inherited retinal degenerative diseases (RDDs) display wide variation in their mode of inheritance, underlying genetic defects, age of onset, and phenotypic severity. Molecular mechanisms have not been delineated for many retinal diseases, and treatment options are limited. In most instances, genotype-phenotype correlations have not been elucidated because of extensive clinical and genetic heterogeneity. Next-generation sequencing (NGS) methods, including exome, genome, transcriptome and epigenome sequencing, provide novel avenues towards achieving comprehensive understanding of the genetic architecture of RDDs. Whole-exome sequencing (WES) has already revealed several new RDD genes, whereas RNA-Seq and ChIP-Seq analyses are expected to uncover novel aspects of gene regulation and biological networks that are involved in retinal development, aging and disease. In this review, we focus on the genetic characterization of retinal and macular degeneration using NGS technology and discuss the basic framework for further investigations. We also examine the challenges of NGS application in clinical diagnosis and management. PMID:24112618

4D Origami by Smart Embroidery.

PubMed

Stoychev, Georgi; Razavi, Mir Jalil; Wang, Xianqiao; Ionov, Leonid

2017-09-01

There exist many methods for processing of materials: extrusion, injection molding, fibers spinning, 3D printing, to name a few. In most cases, materials with a static, fixed shape are produced. However, numerous advanced applications require customized elements with reconfigurable shape. The few available techniques capable of overcoming this problem are expensive and/or time-consuming. Here, the use of one of the most ancient technologies for structuring, embroidering, is proposed to generate sophisticated patterns of active materials, and, in this way, to achieve complex actuation. By combining experiments and computational modeling, the fundamental rules that can predict the folding behavior of sheets with a variety of stitch-patterns are elucidated. It is demonstrated that theoretical mechanics analysis is only suitable to predict the behavior of the simplest experimental setups, whereas computer modeling gives better predictions for more complex cases. Finally, the applicability of the rules by designing basic origami structures and wrinkling substrates with controlled thermal insulation properties is shown. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Vertical propagation of information in a middle atmosphere data assimilation system by gravity-wave drag feedbacks

NASA Astrophysics Data System (ADS)

Ren, Shuzhan; Polavarapu, Saroja M.; Shepherd, Theodore G.

2008-03-01

The mesospheric response to the 2002 Antarctic Stratospheric Sudden Warming (SSW) is analysed using the Canadian Middle Atmosphere Model Data Assimilation System (CMAM-DAS), where it represents a vertical propagation of information from the observations into the data-free mesosphere. The CMAM-DAS simulates a cooling in the lowest part of the mesosphere which is accomplished by resolved motions, but which is extended to the mid- to upper mesosphere by the response of the model's non-orographic gravity-wave drag parameterization to the change in zonal winds. The basic mechanism is that elucidated by Holton consisting of a net eastward wave-drag anomaly in the mesosphere during the SSW, although in this case there is a net upwelling in the polar mesosphere. Since the zonal-mean mesospheric response is shown to be predictable, this demonstrates that variations in the mesospheric state can be slaved to the lower atmosphere through gravity-wave drag.

[Dream in the land of paradoxical sleep].

PubMed

Pire, E; Herman, G; Cambron, L; Maquet, P; Poirrier, R

2008-01-01

Paradoxical sleep (PS or REM sleep) is traditionally a matter for neurophysiology, a science of the brain. Dream is associated with neuropsychology and sciences of the mind. The relationships between sleep and dream are better understood in the light of new methodologies in both domains, particularly those of basic neurosciences which elucidate the mechanisms underlying SP and functional imaging techniques. Data from these approaches are placed here in the perspective of rather old clinical observations in human cerebral lesions and in the phylogeny of vertebrates, in order to support a theory of dream. Dreams may be seen as a living marker of a cognitivo-emotional process, called here "eidictic process", involving posterior brain and limbic structures, keeping up during wakefulness, but subjected, at that time, to the leading role of a cognitivo-rational process, called here "thought process". The last one is of instrumental origin in human beings. It involves prefrontal cortices (executive tasks) and frontal/parietal cortices (attention) in the brain. Some clinical implications of the theory are illustrated.

Load redistribution in walking and trotting Beagles with induced forelimb lameness.

PubMed

Abdelhadi, Jalal; Wefstaedt, Patrick; Galindo-Zamora, Vladimir; Anders, Alexandra; Nolte, Ingo; Schilling, Nadja

2013-01-01

To evaluate the load redistribution mechanisms in walking and trotting dogs with induced forelimb lameness. 7 healthy adult Beagles. Dogs walked and trotted on an instrumented treadmill to determine control values for peak and mean vertical force as well as vertical impulse for all 4 limbs. A small sphere was attached to the ventral pad of the right forelimb paw to induce a reversible lameness, and recordings were repeated for both gaits. Additionally, footfall patterns were assessed to test for changes in temporal gait variables. During walking and trotting, peak and mean vertical force as well as vertical impulse were decreased in the ipsilateral forelimb, increased in the contralateral hind limb, and remained unchanged in the ipsilateral hind limb after lameness was induced. All 3 variables were increased in the contralateral forelimb during trotting, whereas only mean vertical force and vertical impulse were increased during walking. Stance phase duration increased in the contralateral forelimb and hind limb during walking but not during trotting. Analysis of the results suggested that compensatory load redistribution mechanisms in dogs depend on the gait. All 4 limbs should be evaluated in basic research and clinical studies to determine the effects of lameness on the entire body. Further studies are necessary to elucidate specific mechanisms for unloading of the affected limb and to determine the long-term effects of load changes in animals with chronic lameness.

Brain network dysfunction in youth with obsessive-compulsive disorder induced by simple uni-manual behavior: The role of the dorsal anterior cingulate cortex

PubMed Central

Friedman, Amy L.; Burgess, Ashley; Ramaseshan, Karthik; Easter, Phil; Khatib, Dalal; Chowdury, Asadur; Arnold, Paul D.; Hanna, Gregory L.; Rosenberg, David R.; Diwadkar, Vaibhav A.

2017-01-01

In an effort to elucidate differences in functioning brain networks between youth with obsessive-compulsive disorder and controls, we used fMRI signals to analyze brain network interactions of the dorsal anterior cingulate cortex (dACC) during visually coordinated motor responses. Subjects made a uni-manual response to briefly presented probes, at periodic (allowing participants to maintain a “motor set”) or random intervals (demanding reactive responses). Network interactions were assessed using psycho-physiological interaction (PPI), a basic model of functional connectivity evaluating modulatory effects of the dACC in the context of each task condition. Across conditions, OCD were characterized by hyper-modulation by the dACC, with loci alternatively observed as both condition-general and condition-specific. Thus, dynamically driven task demands during simple uni-manual motor control induce compensatory network interactions in cortical-thalamic regions in OCD. These findings support previous research in OCD showing compensatory network interactions during complex memory tasks, but establish that these network effects are observed during basic sensorimotor processing. Thus, these patterns of network dysfunction may in fact be independent of the complexity of tasks used to induce brain network activity. Hypothesis-driven approaches coupled with sophisticated network analyses are a highly valuable approach in using fMRI to uncover mechanisms in disorders like OCD. PMID:27992792

Molecular aspects of magnetic resonance imaging and spectroscopy.

PubMed

Boesch, C

1999-01-01

Magnetic resonance imaging (MRI) is a well known diagnostic tool in radiology that produces unsurpassed images of the human body, in particular of soft tissue. However, the medical community is often not aware that MRI is an important yet limited segment of magnetic resonance (MR) or nuclear magnetic resonance (NMR) as this method is called in basic science. The tremendous morphological information of MR images sometimes conceal the fact that MR signals in general contain much more information, especially on processes on the molecular level. NMR is successfully used in physics, chemistry, and biology to explore and characterize chemical reactions, molecular conformations, biochemical pathways, solid state material, and many other applications that elucidate invisible characteristics of matter and tissue. In medical applications, knowledge of the molecular background of MRI and in particular MR spectroscopy (MRS) is an inevitable basis to understand molecular phenomenon leading to macroscopic effects visible in diagnostic images or spectra. This review shall provide the necessary background to comprehend molecular aspects of magnetic resonance applications in medicine. An introduction into the physical basics aims at an understanding of some of the molecular mechanisms without extended mathematical treatment. The MR typical terminology is explained such that reading of original MR publications could be facilitated for non-MR experts. Applications in MRI and MRS are intended to illustrate the consequences of molecular effects on images and spectra.

Proinflammatory cytokines: a link between chorioamnionitis and fetal brain injury.

PubMed

Patrick, Lindsay A; Smith, Graeme N

2002-09-01

To review the etiology of impaired fetal neurodevelopment - in particular, the relationship between chorioamnionitis, cytokines, and cerebral palsy. A MEDLINE search was performed for all clinical and basic science studies published in the English literature from 1966 to 2002. Key words or phrases used were chorioamnionitis, cerebral palsy, fetal brain damage, fetal CNS injury, infection in pregnancy, proinflammatory cytokines in pregnancy, proinflammatory cytokines in infection, and preterm labour or birth. All relevant human and animal studies were included. Fetal brain injury remains a major cause of lifelong morbidity, incurring significant societal and health care costs. It has been postulated that chorioamnionitis stimulates maternal/fetal proinflammatory cytokine release, which is damaging to the developing fetal nervous system. Elevated cytokine concentrations may interfere with glial cell development and proliferation in the late second trimester of pregnancy, when the central nervous system is most vulnerable. Increasing numbers of epidemiological and basic science studies found through MEDLINE searches support this hypothesis. Treatment options aimed at etiologic factors may lead to improved neurodevelopmental outcomes. Clearly, some relationship exists between chorioamnionitis, cytokines, and the development of cerebral palsy, but the severity and duration of exposure required to produce fetal damage remains unknown. Future research addressing these issues may aid in clinical decision-making. As well, the elucidation of mechanisms of cytokine action may aid in early treatment options to prevent or limit development of fetal brain injury.

Studies on the chemical constituents of the fruits of Cordia latifolia.

PubMed

Siddiqui, Bina S; Perwaiz, Sobiya; Begum, Sabira

2006-02-01

Four new aromatic compounds have been isolated from the fruits of Cordia latifolia (Boreginaceae) bearing a common basic skeleton but differing in the side chain. Their structures were elucidated using spectrometric methods including 1D- (1H and 13C) and 2D-NMR experiments, (1H, 1H-COSY, NOESY, HMQC and HMBC) and chemical transformations.

HIV/AIDS Information Needs of Sexually Transmitted Infection Clinic Patients: Content Analysis of Questions Asked during Prevention Counseling

ERIC Educational Resources Information Center

Kalichman, Seth C.; Cain, Demetria; Knecht, Joanna; Hill, Justin

2008-01-01

Basic factual information about disease is the cornerstone of health promotion and disease prevention interventions. Previous studies have shown that content analysis of the questions asked of service providers can elucidate the information needs of service consumers. Questions asked by individuals at known high risk for HIV infection have not…

Identifying Students' Misconceptions about Nuclear Chemistry: A Study of Turkish High School Students

ERIC Educational Resources Information Center

Nakiboglu, Canan; Tekin, Berna Bulbul

2006-01-01

This study represents the first attempt to elucidate and detail the types of misconceptions high school students hold relating to basic concepts and topics of nuclear chemistry. A diagnostic multiple-choice test was administered to 157 tenth-grade students (15-16 years old) and the data were analyzed. The results show that high school students…

History of drugs for thrombotic disease. Discovery, development, and directions for the future.

PubMed

Mueller, R L; Scheidt, S

1994-01-01

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.

Stiffness, working stroke, and force of single-myosin molecules in skeletal muscle: elucidation of these mechanical properties via nonlinear elasticity evaluation.

PubMed

Kaya, Motoshi; Higuchi, Hideo

2013-11-01

In muscles, the arrays of skeletal myosin molecules interact with actin filaments and continuously generate force at various contraction speeds. Therefore, it is crucial for myosin molecules to generate force collectively and minimize the interference between individual myosin molecules. Knowledge of the elasticity of myosin molecules is crucial for understanding the molecular mechanisms of muscle contractions because elasticity directly affects the working and drag (resistance) force generation when myosin molecules are positively or negatively strained. The working stroke distance is also an important mechanical property necessary for elucidation of the thermodynamic efficiency of muscle contractions at the molecular level. In this review, we focus on these mechanical properties obtained from single-fiber and single-molecule studies and discuss recent findings associated with these mechanical properties. We also discuss the potential molecular mechanisms associated with reduction of the drag effect caused by negatively strained myosin molecules.

Synthesis, dynamics and photophysics of nanoscale systems

NASA Astrophysics Data System (ADS)

Mirkovic, Tihana

The emerging field of nanotechnology, which spans diverse areas such as nanoelectronics, medicine, chemical and pharmaceutical industries, biotechnology and computation, focuses on the development of devices whose improved performance is based on the utilization of self-assembled nanoscale components exhibiting unique properties owing to their miniaturized dimensions. The first phase in the conception of such multifunctional devices based on integrated technologies requires the study of basic principles behind the functional mechanism of nanoscale components, which could originate from individual nanoobjects or result as a collective behaviour of miniaturized unit structures. The comprehensive studies presented in this thesis encompass the mechanical, dynamical and photophysical aspects of three nanoscale systems. A newly developed europium sulfide nanocrystalline material is introduced. Advances in synthetic methods allowed for shape control of surface-functionalized EuS nanocrystals and the fabrication of multifunctional EuS-CdSe hybrid particles, whose unique structural and optical properties hold promise as useful attributes of integrated materials in developing technologies. A comprehensive study based on a new class of multifunctional nanomaterials, derived from the basic unit of barcoded metal nanorods is presented. Their chemical composition affords them the ability to undergo autonomous motion in the presence of a suitable fuel. The nature of their chemically powered self-propulsion locomotion was investigated, and plausible mechanisms for various motility modes were presented. Furthermore functionalization of striped metallic nanorods has been realized through the incorporation of chemically controlled flexible hinges displaying bendable properties. The structural aspect of the light harvesting machinery of a photosynthetic cryptophyte alga, Rhodomonas CS24, and the mobility of the antenna protein, PE545, in vivo were investigated. Information obtained through a combination of steady-state and time-resolved spectroscopy in conjunction with quantum chemical calculations aided in the elucidation of the dynamics and the mechanism of light harvesting in the multichromophoric phycobiliprotein phycocyanin PC645 in vitro. Investigation of the light-harvesting efficiency and optimization of energy transfer with respect to the structural organization of light-harvesting chromophores on the nanoscale, can provide us with fundamental information necessary for the development of synthetic light-harvesting devices capable of mimicking the efficiency of the natural system.

Tradeoffs between hydraulic and mechanical stress responses of mature Norway spruce trunk wood.

PubMed

Rosner, Sabine; Klein, Andrea; Müller, Ulrich; Karlsson, Bo

2008-08-01

We tested the effects of growth characteristics and basic density on hydraulic and mechanical properties of mature Norway spruce (Picea abies (L.) Karst.) wood from six 24-year-old clones, grown on two sites in southern Sweden differing in water availability. Hydraulic parameters assessed were specific hydraulic conductivity at full saturation (ks100) and vulnerability to cavitation (Psi50), mechanical parameters included bending strength (sigma b), modulus of elasticity (MOE), compression strength (sigma a) and Young's modulus (E). Basic density, diameter at breast height, tree height, and hydraulic and mechanical parameters varied considerably among clones. Clonal means of hydraulic and mechanical properties were strongly related to basic density and to growth parameters across sites, especially to diameter at breast height. Compared with stem wood of slower growing clones, stem wood of rapidly growing clones had significantly lower basic density, lower sigma b, MOE, sigma a and E, was more vulnerable to cavitation, but had higher ks100. Basic density was negatively correlated to Psi50 and ks100. We therefore found a tradeoff between Psi50 and ks100. Clones with high basic density had significantly lower hydraulic vulnerability, but also lower hydraulic conductivity at full saturation and thus less rapid growth than clones with low basic density. This tradeoff involved a negative relationship between Psi50 and sigma b as well as MOE, and between ks100 and sigma b, MOE and sigma a. Basic density and Psi50 showed no site-specific differences, but tree height, diameter at breast height, ks100 and mechanical strength and stiffness were significantly lower at the drier site. Basic density had no influence on the site-dependent differences in hydraulic and mechanical properties, but was strongly negatively related to diameter at breast height. Selecting for growth may thus lead not only to a reduction in mechanical strength and stiffness but also to a reduction in hydraulic safety.

Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin

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

Muramatsu, Aya; Enomoto, Atsushi, E-mail: enomoto@iar.nagoya-u.ac.jp; Kato, Takuya

Girdin is an actin-binding protein that has multiple functions in postnatal neural development and cancer progression. We previously showed that Girdin is a regulator of migration for neuroblasts born from neural stem cells in the subventricular zone (SVZ) and the dentate gyrus of the hippocampus in the postnatal brain. Despite a growing list of Girdin-interacting proteins, the mechanism of Girdin-mediated migration has not been fully elucidated. Girdin interacts with Disrupted-In-Schizophrenia 1 and partitioning-defective 3, both of which have been shown to interact with the kinesin microtubule motor proteins. Based on this, we have identified that Girdin also interacts with kinesin-1,more » a member of neuronal kinesin proteins. Although a direct interaction of Girdin and kinesin-1 has not been determined, it is of interest to find that Girdin loss-of-function mutant mice with the mutation of a basic amino acid residue-rich region (Basic mut mice) exhibit limited interaction with kinesin-1. Furthermore, expression of a kinesin-1 mutant with motor defects, leads to Girdin mislocalization. Finally, consistent with previous studies on the role of kinesin proteins in trafficking a cell–cell adhesion molecule N-cadherin, Basic mut mice showed an aberrant expression pattern of N-cadherin in migrating SVZ neuroblasts. These findings suggest a potential role of Girdin/kinesin-1 interaction in the regulation of neuroblast migration in the postnatal brain. - Highlights: • Girdin is a regulator of migration for neuroblasts in the postnatal brain. • Girdin interacts with kinesin-1, a member of neuronal kinesin proteins. • Girdin mutant mice showed an aberrant expression of N-cadherin in neuroblasts.« less

Simulations of cellulose translocation in the bacterial cellulose synthase suggest a regulatory mechanism for the dimeric structure of cellulose

DOE PAGES

Knott, Brandon C.; Crowley, Michael F.; Himmel, Michael E.; ...

2016-01-29

The processive cycle of the bacterial cellulose synthase (Bcs) includes the addition of a single glucose moiety to the end of a growing cellulose chain followed by the translocation of the nascent chain across the plasma membrane. The mechanism of this translocation and its precise location within the processive cycle are not well understood. In particular, the molecular details of how a polymer (cellulose) whose basic structural unit is a dimer (cellobiose) can be constructed by adding one monomer (glucose) at a time are yet to be elucidated. Here, we have utilized molecular dynamics simulations and free energy calculations tomore » the shed light on these questions. We find that translocation forward by one glucose unit is quite favorable energetically, giving a free energy stabilization of greater than 10 kcal mol-1. In addition, there is only a small barrier to translocation, implying that translocation is not rate limiting within the Bcs processive cycle (given experimental rates for cellulose synthesis in vitro). Perhaps most significantly, our results also indicate that steric constraints at the transmembrane tunnel entrance regulate the dimeric structure of cellulose. Namely, when a glucose molecule is added to the cellulose chain in the same orientation as the acceptor glucose, the terminal glucose freely rotates upon forward motion, thus suggesting a regulatory mechanism for the dimeric structure of cellulose. We characterize both the conserved and non-conserved enzyme-polysaccharide interactions that drive translocation, and find that 20 of the 25 residues that strongly interact with the translocating cellulose chain in the simulations are well conserved, mostly with polar or aromatic side chains. Our results also allow for a dynamical analysis of the role of the so-called 'finger helix' in cellulose translocation that has been observed structurally. Taken together, these findings aid in the elucidation of the translocation steps of the Bcs processive cycle and may be widely relevant to polysaccharide synthesizing or degrading enzymes that couple catalysis with chain translocation.« less

Pseudouridine: Still mysterious, but never a fake (uridine)!

PubMed Central

Spenkuch, Felix; Motorin, Yuri; Helm, Mark

2014-01-01

Pseudouridine (Ψ) is the most abundant of >150 nucleoside modifications in RNA. Although Ψ was discovered as the first modified nucleoside more than half a century ago, neither the enzymatic mechanism of its formation, nor the function of this modification are fully elucidated. We present the consistent picture of Ψ synthases, their substrates and their substrate positions in model organisms of all domains of life as it has emerged to date and point out the challenges that remain concerning higher eukaryotes and the elucidation of the enzymatic mechanism. PMID:25616362

[Pharmacokinetic research strategies of compatibilities and synergistic effects of classical Danshen herb pairs based on pharmacokinetics of "Danshen-Bingpian" and "Danshen-Honghua"].

PubMed

Zhang, Cui-Ying; Ren, Wei-Guang

2017-06-01

Herb pairs are usual clinical compatibility forms and one of compound prescription sources in Chinese medicine. Pharmacokinetic research in vivo is one of the important items in elucidating the mechanism for synergistic and attenuated mechanisms of herb pairs. The paper comprehensively summarized and systemized the pharmacokinetic researches of marker-ingredients about Danshen-Honghua and Danshen-Bingpian in order to elucidate the rationality and scientificity of herb pairs and provide some feasible suggestions on the pharmacokinetics of drugs in the future. In view of complicated system of Traditional Chinese medicines and a chemical system that is not separated from its natural state, comparative pharmacokinetic researches on marker-ingredients from the herb pairs are reasonable to elucidate the synergistic and attenuated mechanisms of monarch-subjects compatible herbs and monarch-guide compatible herbs. Such pharmacokinetic research can better explain the mechanism of drug compatibility, while the pharmacokinetic researches based on the monomer chemical compositions and marker-ingredients that have been separated from complex chemical environment of traditional Chinese Medicine are still unreasonable and should be discussed deeply. Copyright© by the Chinese Pharmaceutical Association.

Pathophysiology of priapism: dysregulatory erection physiology thesis.

PubMed

Burnett, Arthur L

2003-07-01

While a modest amount of medical literature has been written on the topic of priapism, reports heretofore have focused predominantly on diagnostic and management related aspects of the disorder, providing meager information in regard to its pathophysiology. Accordingly the intent of this review was to explore the etiological and pathogenic factors involved in priapism. The review entailed an overview of traditional and modern concepts that have been applied to the pathophysiology of priapism and an evaluation of assorted observational and experimental data relating to this field of study. The basic exercise consisted of a literature search using the National Library of Medicine PubMed Services, index referencing provided through the Historical Collection of the Institute of Medicine of The Johns Hopkins University and a survey of abstract proceedings from national meetings relevant to priapism. Insight into the pathophysiology of priapism was derived from a synthesis of evolutionary clinical experiences, mythical beliefs, clinical variants and scientific advances associated with the field of priapism. The results can be summarized. 1) Clinicopathological manifestations of priapism support its basic classification into low flow (ischemic) and high flow (nonischemic) hemodynamic categories, commonly attributed to venous outflow occlusion and unregulated arterial overflow of the penis, respectively. 2) Factual information is insufficient to substantiate etiological roles for urethral infection, bladder distention, failed ejaculation, satyriasis and sleep apnea in priapism. 3) Features of the variant forms of priapism invoke changes in nervous system control of erection and penile vascular homeostasis as having pathogenic roles in the disorder. 4) Clinical therapeutic and basic science investigative studies have revealed various effector mechanisms of the erectile tissue response that may act in dysregulated fashion to subserve priapism. This exercise suggested that, while priapism is commonly defined in terms of adverse mechanical contexts affecting penile circulation, it may also be viewed at least in some situations as an unbalanced erectile response involving derangements in possibly diverse systems of regulatory control. An integrative scientific approach that encompasses tissular, cellular and molecular levels of investigation may allow further understanding of the pathophysiology of the disorder. Ongoing elucidation of this pathophysiology can be expected to promote the development of new priapism therapies.

Achievement Test Program.

ERIC Educational Resources Information Center

Ohio State Dept. of Education, Columbus. Trade and Industrial Education Service.

The Ohio Trade and Industrial Education Achievement Test battery is comprised of seven basic achievement tests: Machine Trades, Automotive Mechanics, Basic Electricity, Basic Electronics, Mechanical Drafting, Printing, and Sheet Metal. The tests were developed by subject matter committees and specialists in testing and research. The Ohio Trade and…

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

Knott, Brandon C.; Crowley, Michael F.; Himmel, Michael E.

The processive cycle of the bacterial cellulose synthase (Bcs) includes the addition of a single glucose moiety to the end of a growing cellulose chain followed by the translocation of the nascent chain across the plasma membrane. The mechanism of this translocation and its precise location within the processive cycle are not well understood. In particular, the molecular details of how a polymer (cellulose) whose basic structural unit is a dimer (cellobiose) can be constructed by adding one monomer (glucose) at a time are yet to be elucidated. Here, we have utilized molecular dynamics simulations and free energy calculations tomore » the shed light on these questions. We find that translocation forward by one glucose unit is quite favorable energetically, giving a free energy stabilization of greater than 10 kcal mol-1. In addition, there is only a small barrier to translocation, implying that translocation is not rate limiting within the Bcs processive cycle (given experimental rates for cellulose synthesis in vitro). Perhaps most significantly, our results also indicate that steric constraints at the transmembrane tunnel entrance regulate the dimeric structure of cellulose. Namely, when a glucose molecule is added to the cellulose chain in the same orientation as the acceptor glucose, the terminal glucose freely rotates upon forward motion, thus suggesting a regulatory mechanism for the dimeric structure of cellulose. We characterize both the conserved and non-conserved enzyme-polysaccharide interactions that drive translocation, and find that 20 of the 25 residues that strongly interact with the translocating cellulose chain in the simulations are well conserved, mostly with polar or aromatic side chains. Our results also allow for a dynamical analysis of the role of the so-called 'finger helix' in cellulose translocation that has been observed structurally. Taken together, these findings aid in the elucidation of the translocation steps of the Bcs processive cycle and may be widely relevant to polysaccharide synthesizing or degrading enzymes that couple catalysis with chain translocation.« less

Animal Models for the Study of Female Sexual Dysfunction

PubMed Central

Marson, Lesley; Giamberardino, Maria Adele; Costantini, Raffaele; Czakanski, Peter; Wesselmann, Ursula

2017-01-01

Introduction Significant progress has been made in elucidating the physiological and pharmacological mechanisms of female sexual function through preclinical animal research. The continued development of animal models is vital for the understanding and treatment of the many diverse disorders that occur in women. Aim To provide an updated review of the experimental models evaluating female sexual function that may be useful for clinical translation. Methods Review of English written, peer-reviewed literature, primarily from 2000 to 2012, that described studies on female sexual behavior related to motivation, arousal, physiological monitoring of genital function and urogenital pain. Main Outcomes Measures Analysis of supporting evidence for the suitability of the animal model to provide measurable indices related to desire, arousal, reward, orgasm, and pelvic pain. Results The development of female animal models has provided important insights in the peripheral and central processes regulating sexual function. Behavioral models of sexual desire, motivation, and reward are well developed. Central arousal and orgasmic responses are less well understood, compared with the physiological changes associated with genital arousal. Models of nociception are useful for replicating symptoms and identifying the neurobiological pathways involved. While in some cases translation to women correlates with the findings in animals, the requirement of circulating hormones for sexual receptivity in rodents and the multifactorial nature of women’s sexual function requires better designed studies and careful analysis. The current models have studied sexual dysfunction or pelvic pain in isolation; combining these aspects would help to elucidate interactions of the pathophysiology of pain and sexual dysfunction. Conclusions Basic research in animals has been vital for understanding the anatomy, neurobiology, and physiological mechanisms underlying sexual function and urogenital pain. These models are important for understanding the etiology of female sexual function and for future development of pharmacological treatments for sexual dysfunctions with or without pain. PMID:27784584

Bioglass promotes wound healing by affecting gap junction connexin 43 mediated endothelial cell behavior.

PubMed

Li, Haiyan; He, Jin; Yu, Hongfei; Green, Colin R; Chang, Jiang

2016-04-01

It is well known that gap junctions play an important role in wound healing, and bioactive glass (BG) has been shown to help healing when applied as a wound dressing. However, the effects of BG on gap junctional communication between cells involved in wound healing is not well understood. We hypothesized that BG may be able to affect gap junction mediated cell behavior to enhance wound healing. Therefore, we set out to investigate the effects of BG on gap junction related behavior of endothelial cells in order to elucidate the mechanisms through which BG is operating. In in vitro studies, BG ion extracts prevented death of human umbilical vein endothelial cells (HUVEC) following hypoxia in a dose dependent manner, possibly through connexin hemichannel modulation. In addition, BG showed stimulatory effects on gap junction communication between HUVECs and upregulated connexin43 (Cx43) expression. Furthermore, BG prompted expression of vascular endothelial growth factor and basic fibroblast growth factor as well as their receptors, and vascular endothelial cadherin in HUVECs, all of which are beneficial for vascularization. In vivo wound healing results showed that the wound closure of full-thickness excisional wounds of rats was accelerated by BG with reduced inflammation during initial stages of healing and stimulated angiogenesis during the proliferation stage. Therefore, BG can stimulate wound healing through affecting gap junctions and gap junction related endothelial cell behaviors, including prevention of endothelial cell death following hypoxia, stimulation of gap junction communication and upregulation of critical vascular growth factors, which contributes to the enhancement of angiogenesis in the wound bed and finally to accelerate wound healing. Although many studies have reported that BG stimulates angiogenesis and wound healing, this work reveals the relationship between BG and gap junction connexin 43 mediated endothelial cell behavior and elucidates one of the possible mechanisms through which BG stimulates wound healing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Acoustic and higher-level representations of naturalistic auditory scenes in human auditory and frontal cortex.

PubMed

Hausfeld, Lars; Riecke, Lars; Formisano, Elia

2018-06-01

Often, in everyday life, we encounter auditory scenes comprising multiple simultaneous sounds and succeed to selectively attend to only one sound, typically the most relevant for ongoing behavior. Studies using basic sounds and two-talker stimuli have shown that auditory selective attention aids this by enhancing the neural representations of the attended sound in auditory cortex. It remains unknown, however, whether and how this selective attention mechanism operates on representations of auditory scenes containing natural sounds of different categories. In this high-field fMRI study we presented participants with simultaneous voices and musical instruments while manipulating their focus of attention. We found an attentional enhancement of neural sound representations in temporal cortex - as defined by spatial activation patterns - at locations that depended on the attended category (i.e., voices or instruments). In contrast, we found that in frontal cortex the site of enhancement was independent of the attended category and the same regions could flexibly represent any attended sound regardless of its category. These results are relevant to elucidate the interacting mechanisms of bottom-up and top-down processing when listening to real-life scenes comprised of multiple sound categories. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Translocator protein (TSPO) ligands for the diagnosis or treatment of neurodegenerative diseases: a patent review (2010-2015; part 1).

PubMed

Kim, TaeHun; Pae, Ae Nim

2016-11-01

The translocator protein (TSPO) is an emerging target in diverse neurodegenerative diseases. Up-regulated TSPO in the central nervous system (CNS) appears to be involved in neuroinflammatory processes; therefore, the development of potent TSPO ligands is a promising method for alleviating or imaging patients with neurodegenerative diseases. Areas covered: This review will provide an overview of recently developed TSPO ligands patented from 2010 to 2015. Part 1 will present a summary focusing on TSPO ligands other than indole-based or cholesterol-like compounds, which will be discussed in part 2. Part 1 covers diverse benzodiazepine-derived analogues such as isoquinoline carboxamides and aryloxyanilides. Moreover, bicyclic ring structures such as imidazopyridine, pyrazolopyrimidine, and phenylpurine will be highlighted as promising scaffolds for TSPO ligands. A brief analysis of currently reported TSPO structures will also be covered in part 1. Expert opinion: Although the underlying pharmacological mechanism of TSPO remains to be elucidated, several TSPO ligands have shown therapeutic efficacy in experimental animal models of neurodegenerative diseases. In addition, radioactive TSPO ligands have been extensively studied for the diagnosis of neurodegenerative processes. Thus, further studies on both the basic and applied mechanisms of TSPO are warranted in the pursuit of successful pharmacological applications of TSPO ligands.

The origin of life: a problem of history, chemistry, and evolution.

PubMed

Ma, Wentao

2014-12-01

The origin of life is a field full of controversies, not only because of our vague understanding concerning the relevant issues, but also, perhaps more often, owing to our dim conceptual framework throughout the whole field. To improve this situation, an in-depth conceptual dissection is presented here. It is elucidated that, at its core, the origin of life has three aspects. The facts involved in the process are taken as the historical aspect, which is destined to be uncertain and often irrelevant to debate regarding details. The rules involved include two distinct aspects: chemical mechanisms operated in the whole process, while evolutionary mechanisms joined in only after the emergence of the first Darwinian entities - and then accounted for the subsequent buildup of complexity (this cannot be explained solely by natural selection). Basically, we can ask about the possibility of any assumed event in the origin of life: 'Is it evolutionarily plausible, chemically feasible, and historically likely?' Clues from any of the three aspects may be quite valuable in directing our explorations on the other two. This conceptual dissection provides a clearer context for the field, which may even be more useful than any sort of specific research. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

β-Escin Effectively Modulates HUVECS Proliferation and Tube Formation.

PubMed

Varinská, Lenka; Fáber, Lenka; Kello, Martin; Petrovová, Eva; Balážová, Ľudmila; Solár, Peter; Čoma, Matúš; Urdzík, Peter; Mojžiš, Ján; Švajdlenka, Emil; Mučaji, Pavel; Gál, Peter

2018-01-17

In the present study we evaluated the anti-angiogenic activities of β-escin (the major active compound of Aesculus hippocastanum L. seeds). Human umbilical-vein endothelial cells (HUVECs) were used as an in vitro model for studying the molecular mechanism underlying the anti-angiogenic effect of β-escin. We investigated the in vitro effects on proliferation, migration, and tube formation of HUVECs and in vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) angiogenesis assay. Moreover, the effect on gene expressions was determined by the RT2 ProfilerTM human angiogenesis PCR Array. It was found that β-escin exerts inhibitory effect on the basic fibroblast growth factor (bFGF)-induced proliferation, migration and tube formation, as well as CAM angiogenesis in vivo. The inhibition of critical steps of angiogenic process observed with β-escin could be partially explained by suppression of Akt activation in response to bFGF. Moreover, the anti-angiogenic effects of β-escin could also be mediated via inhibition of EFNB2 and FGF-1 gene expressions in endothelial cells. In conclusion, β-escin affects endothelial cells as a negative mediator of angiogenesis in vitro and in vivo and may therefore be considered as a promising candidate for further research elucidating its underlying mechanism of action.

Elucidation of the mechanism of enzymatic browning inhibition by sodium chlorite.

PubMed

He, Qiang; Luo, Yaguang; Chen, Pei

2008-10-15

Sodium chlorite (SC) is a well known anti-microbial agent and its strong inhibitory effect on enzymatic browning of fresh-cut produce has recently been identified. We investigated the effect of SC on polyphenol oxidase (PPO) and its substrate, chlorogenic acid (CA), as it relates to the mechanisms of browning inhibition by SC. Results indicate that the browning reaction of CA (1.0mM) catalyzed by PPO (33U/mL) was significantly inhibited by 1.0mM SC at pH 4.6. Two PPO isoforms were identified by native polyacrylamide gel electrophoresis, and both were inactivated by SC (3.0mM). This suggests that SC serves as a PPO inhibitor to prevent enzymatic browning. Furthermore, the effect of SC on the stability of CA in both acidic (pH 4.5) and basic conditions (pH 8.3) was studied by UV-Vis scan and LC-MS analysis. The results showed that at the presence of SC (3.0mM), CA (0.1mM) degraded to quinic acid and caffeic acid as well as other intermediates. Hence, the anti-browning property of SC can be attributed to the two modes of action: the inactivation of polyphenol oxidase directly and the oxidative degradation of phenolic substrates. Published by Elsevier Ltd.

Basic Engineer Equipment Mechanic.

ERIC Educational Resources Information Center

Marine Corps Inst., Washington, DC.

This student guide, one of a series of correspondence training courses designed to improve the job performance of members of the Marine Corps, deals with the skills needed by basic engineer equipment mechanics. Addressed in the four individual units of the course are the following topics: mechanics and their tools (mechanics, hand tools, and power…

MECHANISM OF ALPHA-SYNUCLEIN OLIGOMERIZATION AND MEMBRANE INTERACTION: THEORETICAL APPROACH TO UNSTRUCTURED PROTEINS STUDIES

PubMed Central

Tsigelny, Igor F.; Sharikov, Yuriy; Miller, Mark A.; Masliah, Eliezer

2008-01-01

Misfolding and oligomerization of unstructured proteins is involved in the pathogenesis of Parkinson’s (PD), Alzheimer’s (AD), Huntington’s, and other neurodegenerative disorders. Elucidation of possible conformations of these proteins and their interactions with the membrane is necessary to understand the molecular mechanisms of neurodegeneration. We developed a strategy that makes it possible to elucidate the molecular mechanisms of of alpha-synuclein aggregation- a key molecular event in the pathogenesis of PD. This strategy can be also useful for the study of other unstructured proteins involved in neurodegeneration. The results of these theoretical studies have been confirmed with biochemical and electrophysiological studies. Our studies provide insights into the molecular mechanism for PD initiation and progression, and provide a useful paradigm for identifying possible therapeutic interventions through computational modeling. PMID:18640077

14 CFR 147.23 - Instructor requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... mechanic certificates and ratings that the Administrator determines necessary to provide adequate... mechanics, to teach mathematics, physics, basic electricity, basic hydraulics, drawing, and similar subjects...

14 CFR 147.23 - Instructor requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... mechanic certificates and ratings that the Administrator determines necessary to provide adequate... mechanics, to teach mathematics, physics, basic electricity, basic hydraulics, drawing, and similar subjects...

14 CFR 147.23 - Instructor requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... mechanic certificates and ratings that the Administrator determines necessary to provide adequate... mechanics, to teach mathematics, physics, basic electricity, basic hydraulics, drawing, and similar subjects...

14 CFR 147.23 - Instructor requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... mechanic certificates and ratings that the Administrator determines necessary to provide adequate... mechanics, to teach mathematics, physics, basic electricity, basic hydraulics, drawing, and similar subjects...

14 CFR 147.23 - Instructor requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... mechanic certificates and ratings that the Administrator determines necessary to provide adequate... mechanics, to teach mathematics, physics, basic electricity, basic hydraulics, drawing, and similar subjects...

Auto Mechanics. Performance Objectives. Basic Course.

ERIC Educational Resources Information Center

Carter, Thomas G., Sr.

Several intermediate performance objectives and corresponding criterion measures are listed for each of 14 terminal objectives for a basic automotive mechanics course. The materials were developed for a two-semester course (2 hours daily) designed to provide training in the basic fundamentals in diagnosis and repair including cooling system and…

Elucidation of reaction mechanism for m -cresol hydrodeoxygenation over Fe based catalysts: A kinetic study

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

Hong, Yongchun; Wang, Yong

Fe based catalysts are promising for hydrodeoxygenation (HDO) of lignin derived phenolics due to their high selectivity for aromatics. In this work, the reaction mechanism of m-cresol HDO on Fe catalysts and the kinetic consequence with Pd addition were elucidated by examining the effect of H2, H2O and m-cresol pressures on toluene formation rate on Fe and PdFe catalysts. A direct CO bond cleavage mechanism is proposed for HDO catalysis on both Fe and PdFe catalysts, while Pd provides a facilitated reaction pathway at the PdFe interface and therefore promotes the catalysis on Fe without changing the high selectivity towardsmore » aromatics.« less

Homeostasis of exercise hyperpnea and optimal sensorimotor integration: the internal model paradigm.

PubMed

Poon, Chi-Sang; Tin, Chung; Yu, Yunguo

2007-10-15

Homeostasis is a basic tenet of biomedicine and an open problem for many physiological control systems. Among them, none has been more extensively studied and intensely debated than the dilemma of exercise hyperpnea - a paradoxical homeostatic increase of respiratory ventilation that is geared to metabolic demands instead of the normal chemoreflex mechanism. Classical control theory has led to a plethora of "feedback/feedforward control" or "set point" hypotheses for homeostatic regulation, yet so far none of them has proved satisfactory in explaining exercise hyperpnea and its interactions with other respiratory inputs. Instead, the available evidence points to a far more sophisticated respiratory controller capable of integrating multiple afferent and efferent signals in adapting the ventilatory pattern toward optimality relative to conflicting homeostatic, energetic and other objectives. This optimality principle parsimoniously mimics exercise hyperpnea, chemoreflex and a host of characteristic respiratory responses to abnormal gas exchange or mechanical loading/unloading in health and in cardiopulmonary diseases - all without resorting to a feedforward "exercise stimulus". Rather, an emergent controller signal encoding the projected metabolic level is predicted by the principle as an exercise-induced 'mental percept' or 'internal model', presumably engendered by associative learning (operant conditioning or classical conditioning) which achieves optimality through continuous identification of, and adaptation to, the causal relationship between respiratory motor output and resultant chemical-mechanical afferent feedbacks. This internal model self-tuning adaptive control paradigm opens a new challenge and exciting opportunity for experimental and theoretical elucidations of the mechanisms of respiratory control - and of homeostatic regulation and sensorimotor integration in general.

Utility of surface enhanced Raman spectroscopy (SERS) for elucidation and simultaneous determination of some penicillins and penicilloic acid using hydroxylamine silver nanoparticles.

PubMed

El-Zahry, Marwa R; Refaat, Ibrahim H; Mohamed, Horria A; Rosenberg, Erwin; Lendl, Bernhard

2015-11-01

Elucidation and quantitative determination of some of commonly used penicillins (ampicillin, penicillin G and carbenicillin) in the presence of their main degradation product (penicilloic acid) were developed. Forced acidic and basic degradation processes were applied at different time intervals. The formed degradation products were elucidated and quantified using surface enhanced Raman spectroscopy (SERS). Silver nanoparticles (AgNPs) prepared by reduction of silver nitrate using hydroxylamine-HCl in alkaline medium were used as SERS substrate. The results obtained in SERS were confirmed by the application of LC/MS method. The concentration range was 100-600 ng/ml in case of the studied penicillins and 100-700 ng/ml in case of penicilloic acid. An excellent correlation coefficient was found in case of ampicillin (r=0.9993) and in the case of penicilloic acid (r=0.9997). Validation procedures were carried out including precision, robustness and accuracy by comparing F- and t-values of both the proposed and reported methods. Copyright © 2015 Elsevier B.V. All rights reserved.

Deformation-mechanism map for nanocrystalline metals by molecular-dynamics simulation.

PubMed

Yamakov, V; Wolf, D; Phillpot, S R; Mukherjee, A K; Gleiter, H

2004-01-01

Molecular-dynamics simulations have recently been used to elucidate the transition with decreasing grain size from a dislocation-based to a grain-boundary-based deformation mechanism in nanocrystalline f.c.c. metals. This transition in the deformation mechanism results in a maximum yield strength at a grain size (the 'strongest size') that depends strongly on the stacking-fault energy, the elastic properties of the metal, and the magnitude of the applied stress. Here, by exploring the role of the stacking-fault energy in this crossover, we elucidate how the size of the extended dislocations nucleated from the grain boundaries affects the mechanical behaviour. Building on the fundamental physics of deformation as exposed by these simulations, we propose a two-dimensional stress-grain size deformation-mechanism map for the mechanical behaviour of nanocrystalline f.c.c. metals at low temperature. The map captures this transition in both the deformation mechanism and the related mechanical behaviour with decreasing grain size, as well as its dependence on the stacking-fault energy, the elastic properties of the material, and the applied stress level.

14 CFR 147.36 - Maintenance of instructor requirements.

Code of Federal Regulations, 2010 CFR

2010-01-01

... holding appropriate mechanic certificates and ratings that the Administrator determines necessary to... certificated mechanics to teach mathematics, physics, drawing, basic electricity, basic hydraulics, and similar...

14 CFR 147.36 - Maintenance of instructor requirements.

Code of Federal Regulations, 2013 CFR

2013-01-01

... holding appropriate mechanic certificates and ratings that the Administrator determines necessary to... certificated mechanics to teach mathematics, physics, drawing, basic electricity, basic hydraulics, and similar...

14 CFR 147.36 - Maintenance of instructor requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... holding appropriate mechanic certificates and ratings that the Administrator determines necessary to... certificated mechanics to teach mathematics, physics, drawing, basic electricity, basic hydraulics, and similar...

14 CFR 147.36 - Maintenance of instructor requirements.

Code of Federal Regulations, 2012 CFR

2012-01-01

... holding appropriate mechanic certificates and ratings that the Administrator determines necessary to... certificated mechanics to teach mathematics, physics, drawing, basic electricity, basic hydraulics, and similar...

14 CFR 147.36 - Maintenance of instructor requirements.

Code of Federal Regulations, 2014 CFR

2014-01-01

... holding appropriate mechanic certificates and ratings that the Administrator determines necessary to... certificated mechanics to teach mathematics, physics, drawing, basic electricity, basic hydraulics, and similar...

Novel glutamatergic drugs for the treatment of mood disorders

PubMed Central

Lapidus, Kyle AB; Soleimani, Laili; Murrough, James W

2013-01-01

Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing antidepressant agents (eg, those who suffer from treatment-resistant depression [TRD]) require innovative therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of antidepressant action, most antidepressant drugs target monoaminergic mechanisms identified decades ago. Glutamate, the major excitatory neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in mood disorders. These data provide a rationale for the pursuit of glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of glutamatergic agents in mood disorders with a focus on depression. We begin with discussion of evidence for the rapid antidepressant effects of ketamine, followed by studies of the antidepressant efficacy of the currently marketed drugs riluzole and lamotrigine. Promising novel agents currently in development, including N-methyl-D-aspartate (NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptor modulators, and drugs with activity at the metabotropic glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the glutamate system as novel therapeutic agents in mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting therapeutics can be developed for patients suffering from these disabling disorders. PMID:23976856

Immunological mechanisms of sublingual allergen-specific immunotherapy.

PubMed

Novak, Natalija; Bieber, T; Allam, J-P

2011-06-01

Within the last 100 years of allergen-specific immunotherapy, many clinical and scientific efforts have been made to establish alternative noninvasive allergen application strategies. Thus, intra-oral allergen delivery to the sublingual mucosa has been proven to be safe and effective. As a consequence, to date, sublingual immunotherapy (SLIT) is widely accepted by most allergists as an alternative to conventional subcutaneous immunotherapy. Although immunological mechanisms remain to be elucidated in detail, several studies in mice and humans within recent years provided deeper insights into local as well as systemic immunological features in response to SLIT. First of all, it was shown that the target organ, the oral mucosa, harbours a sophisticated immunological network as an important prerequisite for SLIT, which contains among other cells, local antigen-presenting cells (APC), such as dendritic cells (DCs), with a constitutive disposition to enforce tolerogenic mechanisms. Further on, basic research on local DCs within the oral mucosa gave rise to possible alternative strategies to deliver the allergens to other mucosal regions than sublingual tissue, such as the vestibulum oris. Moreover, characterization of oral DCs led to the identification of target structures for both allergens as well as adjuvants, which could be applied during SLIT. Altogether, SLIT came a long way since its very beginning in the last century and some, but not all questions about SLIT could be answered so far. However, recent research efforts as well as clinical approaches paved the way for another exciting 100 years of SLIT. © 2011 John Wiley & Sons A/S.

Emotion Regulation and Depressive Symptoms: Close Relationships as Social Context and Influence

PubMed Central

Marroquín, Brett; Nolen-Hoeksema, Susan

2015-01-01

Depression is associated with social dysfunction and maladaptive social environments, but mechanisms through which social relationships affect depressive psychopathology are unclear. We hypothesized that emotion regulation (ER) is such a mechanism, with outcomes of individuals’ ER efforts sensitive to the social context, and individuals’ ER strategy repertoire and use sensitive to social influence. In Study 1, a longitudinal study of community adults (N = 1,319), associations of individuals’ ER strategies with depressive symptoms depended on social connectedness and romantic relationship status (social context hypothesis). Moreover, associations of social connectedness and relationship status with symptoms were accounted for by maladaptive ER concurrently and, for social connectedness, prospectively over 1 year (social influence hypothesis). Study 2a, using a national sample (N = 772), replicated and extended these findings with a broader array of ER strategies, and ruled out alternative explanations regarding social skills and psychological wellbeing. Among participants in romantic relationships (Study 2b; N = 558), intimacy and trust buffered associations of maladaptive ER strategies with symptoms (context), and maladaptive and adaptive ER mediated links between relationship variables and symptoms (influence). Findings suggest that close relationships—and variation in underlying relational processes within relationships— influence the ER strategies people use, and also affect whether individuals’ own ER repertoires contribute to depression when deployed. Results elucidate core social mechanisms of ER in terms of both basic processes and depressive psychopathology, suggest ER is a channel through which social factors affect internal functioning and mental health, and inform relationship pathways for clinical intervention. PMID:26479366

Computational studies of adsorption in metal organic frameworks and interaction of nanoparticles in condensed phases

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

Annapureddy, Harsha V.; Motkuri, Radha K.; Nguyen, Phuong T.

In this review, we describe recent efforts in which computer simulations were used to systematically study nano-structured metal organic frameworks, with particular emphasis on their application in heating and cooling processes. These materials also are known as metal organic heat carriers. We used both molecular dynamics and Grand Canonical Monte Carlo simulation techniques to gain a molecular-level understanding of the adsorption mechanism of gases in these porous materials. We investigated the uptake of various gases such as refrigerants R12 and R143a and also the elemental gases Xe and Rn by the metal organic framework (i.e., Ni2(dhtp)). We also evaluated themore » effects of temperature and pressure on the uptake mechanism. Our computed results compared reasonably well with available experimental measurements, thus validating our potential models and approaches. In addition, we also investigated the structural, diffusive, and adsorption properties of different hydrocarbons in Ni2(dhtp). To elucidate the mechanism of nanoparticle dispersion in condensed phases, we also studied the interactions among nanoparticles in various liquids, such as n-hexane, water and methanol. This work was performed at Pacific Northwest National Laboratory (PNNL) and was supported by the Division of Chemical Sciences, Geosciences and Biosciences, Office of Basic Energy Sciences, U.S. Department of Energy (DOE). PNNL is operated by Battelle for the DOE. The authors also gratefully acknowledge support received from the National Energy Technology Laboratory of DOE's Office of Fossil Energy.« less

Mechanisms and Effects of Transcranial Direct Current Stimulation

PubMed Central

Giordano, James; Bikson, Marom; Kappenman, Emily S.; Clark, Vincent P.; Coslett, H. Branch; Hamblin, Michael R.; Hamilton, Roy; Jankord, Ryan; Kozumbo, Walter J.; McKinley, R. Andrew; Nitsche, Michael A.; Reilly, J. Patrick; Richardson, Jessica; Wurzman, Rachel

2017-01-01

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose–response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged. PMID:28210202

Basic Science Evidence for the Link Between Erectile Dysfunction and Cardiometabolic Dysfunction

PubMed Central

Musicki, Biljana; Bella, Anthony J.; Bivalacqua, Trinity J.; Davies, Kelvin P.; DiSanto, Michael E.; Gonzalez-Cadavid, Nestor F.; Hannan, Johanna L.; Kim, Noel N.; Podlasek, Carol A.; Wingard, Christopher J.; Burnett, Arthur L.

2016-01-01

Introduction Although clinical evidence supports an association between cardiovascular/metabolic diseases (CVMD) and erectile dysfunction (ED), scientific evidence for this link is incompletely elucidated. Aim This study aims to provide scientific evidence for the link between CVMD and ED. Methods In this White Paper, the Basic Science Committee of the Sexual Medicine Society of North America assessed the current literature on basic scientific support for a mechanistic link between ED and CVMD, and deficiencies in this regard with a critical assessment of current preclinical models of disease. Results A link exists between ED and CVMD on several grounds: the endothelium (endothelium-derived nitric oxide and oxidative stress imbalance); smooth muscle (SM) (SM abundance and altered molecular regulation of SM contractility); autonomic innervation (autonomic neuropathy and decreased neuronal-derived nitric oxide); hormones (impaired testosterone release and actions); and metabolics (hyperlipidemia, advanced glycation end product formation). Conclusion Basic science evidence supports the link between ED and CVMD. The Committee also highlighted gaps in knowledge and provided recommendations for guiding further scientific study defining this risk relationship. This endeavor serves to develop novel strategic directions for therapeutic interventions. PMID:26646025

Preventing a Relapse or Setting Goals? Elucidating the Impact of Post-Training Transfer Interventions on Training Transfer Performance

ERIC Educational Resources Information Center

Rahyuda, Agoes Ganesha; Soltani, Ebrahim; Syed, Jawad

2018-01-01

Based on a review of the literature on post-training transfer interventions, this paper offers a conceptual model that elucidates potential mechanisms through which two types of post-training transfer intervention (relapse prevention and proximal plus distal goal setting) influence the transfer of training. We explain how the application of…

Evaluating the oxidative, photothermal and electrical stability of colloidal nanocrystal solids

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

Law, Matt

2016-02-16

IV-VI quantum dot (QD) solids are a novel class of granular electronic materials with great technological potential (e.g., in photodetectors, field-effect transistors (FETs), and solar cells), but their oxidative and thermal instability present a barrier to practical applications [1]. Poor stability is a fundamental issue facing many nanoscale materials due to high surface area and surface energy. Basic studies are needed to elucidate the most important mechanisms of degradation and develop robust countermeasures if QD materials are to become technologically important. This project determined the degradation mechanisms of IV-VI QD solids (primarily PbSe and PbS) and introduced new chemical strategiesmore » to drastically improve their performance, stability, and operating lifetimes [2-5]. Our approach was based on (1) detailed testing of QD thin film materials (principally FETs and solar cells) as a function of oxidative and thermal stress, and (2) the use of organic and inorganic approaches to link the QDs into strongly electronically coupled, high-mobility films, prevent their oxidation, and eliminate internal degrees of freedom that lead to film instability and degradation in response to electrical and thermal stress. Stability against oxidation and thermal degradation was the major focus of this project. We have evaluated the stability of QD thin films and interfaces at temperatures less than 100°C (the regime most relevant to solar and transistor applications). Low-temperature oxidation and sintering of QD films have been investigated using optical absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), current-voltage scanning of transistors and solar cells, X-ray photoelectron spectroscopy, and scanning Kelvin probe microscopy (SKPM). SKPM was used to map the potential profiles of operating QD FETs and solar cells as a function of bias and illumination, which provides detailed information on how the work functions, potential drops and electric field within these devices determine device operation, and set the stage for future studies targeted at understanding and preventing device failure. We pursued two strategies to fabricate QD films with stable electrical characteristics: (1) the use of robust molecular surface ligands [2], and (2) “matrix engineering,” i.e., infilling the QD solid with metal oxide or metal sulfide matrices by low-temperature atomic layer deposition (ALD) to passivate surface states, prevent oxidation, lock the QDs into position, inhibit diffusion, and tune the height and width of the inter-QD potential barriers that govern charge transport [5,6]. Poor stability is a common feature of nanoscale electronic materials, yet stability is all too rarely the focus of basic research. Fundamental studies are therefore needed to elucidate the most important mechanisms of degradation and develop simple yet effective countermeasures. By revealing both how QD solids degrade in response to environmental stresses (oxidative, photothermal, and electric) and how to prevent this degradation, the project has greatly improved our ability to develop stable, high-performance QD materials for real-world applications.« less

Primary blast-induced traumatic brain injury: lessons from lithotripsy

NASA Astrophysics Data System (ADS)

Nakagawa, A.; Ohtani, K.; Armonda, R.; Tomita, H.; Sakuma, A.; Mugikura, S.; Takayama, K.; Kushimoto, S.; Tominaga, T.

2017-11-01

Traumatic injury caused by explosive or blast events is traditionally divided into four mechanisms: primary, secondary, tertiary, and quaternary blast injury. The mechanisms of blast-induced traumatic brain injury (bTBI) are biomechanically distinct and can be modeled in both in vivo and in vitro systems. The primary bTBI injury mechanism is associated with the response of brain tissue to the initial blast wave. Among the four mechanisms of bTBI, there is a remarkable lack of information regarding the mechanism of primary bTBI. On the other hand, 30 years of research on the medical application of shock waves (SWs) has given us insight into the mechanisms of tissue and cellular damage in bTBI, including both air-mediated and underwater SW sources. From a basic physics perspective, the typical blast wave consists of a lead SW followed by shock-accelerated flow. The resultant tissue injury includes several features observed in primary bTBI, such as hemorrhage, edema, pseudo-aneurysm formation, vasoconstriction, and induction of apoptosis. These are well-described pathological findings within the SW literature. Acoustic impedance mismatch, penetration of tissue by shock/bubble interaction, geometry of the skull, shear stress, tensile stress, and subsequent cavitation formation are all important factors in determining the extent of SW-induced tissue and cellular injury. In addition, neuropsychiatric aspects of blast events need to be taken into account, as evidenced by reports of comorbidity and of some similar symptoms between physical injury resulting in bTBI and the psychiatric sequelae of post-traumatic stress. Research into blast injury biophysics is important to elucidate specific pathophysiologic mechanisms of blast injury, which enable accurate differential diagnosis, as well as development of effective treatments. Herein we describe the requirements for an adequate experimental setup when investigating blast-induced tissue and cellular injury; review SW physics, research, and the importance of engineering validation (visualization/pressure measurement/numerical simulation); and, based upon our findings of SW-induced injury, discuss the potential underlying mechanisms of primary bTBI.

[Proceedings of clinical pharmacy research with the cooperation of community and hospital pharmacist and pharmacy school].

PubMed

Hirotani, Yoshihiko

2007-11-01

The new pharmaceutical education system starts in Japan, those constructions are performed at a lot of universities aiming at the execution of a common examination and the clinical training, and the workshop for directive pharmacists have been held actively since last year. Moreover, various educational lectures, open lectures, and the training lectures for on-site pharmacist's upskilling are carried out. However, a technical training and the lecture for research approach that supports the pharmacist in a pharmaceutical clinical research are little at the chance to learn the research methods. Now, many joint researches with university initiative or a university is performed, and the institution of presentation inexperience at academic society also exists in terms of a regional element, a staff arrangement side, etc, and also when the continuation is difficult, it looks mostly. It is necessary that the teacher of pharmacy school almost arranged in the whole country support positively a clinical research by the nearby pharmacist, and also it seems that a clinical teacher's role is large in the cooperation of pharmacy school and the medical institution. Moreover, in order to elucidate the scientific basis (mechanism) of a problem suggestion in the clinical spot, basic research in a pharmacy school is also required. We always need to advance a pharmaceutical clinical research by considering the basic research by pharmacy school in medical institution, considering clinical research by medical institution in pharmacy school, while cooperating mutually. In this article, I show how to advance pharmaceutical clinical research.

Basic Fibroblast Growth Factor Influences Epidermal Homeostasis of Living Skin Equivalents through Affecting Fibroblast Phenotypes and Functions.

PubMed

Yang, Lujun; Zhang, Dangui; Wu, Hongjuan; Xie, Sitian; Zhang, Mingjun; Zhang, Bingna; Tang, Shijie

2018-05-30

To elucidate the possible mechanisms of how basic fibroblast growth factor (bFGF) influences epidermal homeostasis in a living skin equivalent (LSE) model. Several wound healing-related growth factors were analyzed at protein and mRNA levels for dermal fibroblasts of induced alpha-smooth muscle actin (α-SMA)-positive or α-SMA-negative phenotypes. During culturing an LSE model by seeding normal human keratinocytes on a fibroblast-populated type I collagen gel, bFGF or neutralizing antibody for keratinocyte growth factor (KGF) was added to investigate its effects on fibroblast phenotypes and, subsequently, epidermal homeostasis by histology and immunohistochemistry. The α-SMA-positive phenotype of fibroblasts induced by transforming growth factor beta-1 (TGF-β1) markedly suppressed the expression of KGF and hepatocyte growth factor (HGF), and slightly upregulated vascular endothelial growth factor (VEGF) and TGF-β1 at mRNA and protein levels, compared with α-SMA-negative fibroblasts treated with bFGF. α-SMA expression of fibroblasts at the epidermal-mesenchymal junction of the LSEs was suppressed by the addition of bFGF, and a better-differentiated epidermis was presented. The abrogation of KGF from fibroblasts by the addition of the KGF neutralizing antibody disenabled the LSE culturing system to develop an epidermis. bFGF, through affecting the phenotypes and functions of fibroblasts, especially KGF expression, influenced epidermal homeostasis in an LSE model. © 2018 S. Karger AG, Basel.

Molecular Engineering for Mechanically Resilient and Stretchable Electronic Polymers and Composites

DTIC Science & Technology

2016-06-08

conjugated polymers and composites by analysis of the structural determinants of the mechanical properties. We developed coarse-grained molecular...dynamics simulations that predicted the mechanical properties of conjugated polymers and polymer -fullerene composites. We elucidated the mechanical...We also determined the effect of cyclic stretching on the microstructure and mechanical properties of conjugated polymers . We used many of

Photoredox Catalysis: The Need to Elucidate the Photochemical Mechanism.

PubMed

Marchini, Marianna; Bergamini, Giacomo; Cozzi, Pier Giorgio; Ceroni, Paola; Balzani, Vincenzo

2017-10-09

The photocatalytic mechanism reported in a recent Communication to produce the radical anion of pyrenes postulates a highly endergonic electron transfer process. An analysis of the thermodynamics is reported together with the proposal of an alternative thermodynamically feasible mechanism. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bone grafts, bone substitutes and orthobiologics

PubMed Central

Roberts, Timothy T.; Rosenbaum, Andrew J.

2012-01-01

The biology of fracture healing is better understood than ever before, with advancements such as the locking screw leading to more predictable and less eventful osseous healing. However, at times one’s intrinsic biological response, and even concurrent surgical stabilization, is inadequate. In hopes of facilitating osseous union, bone grafts, bone substitutes and orthobiologics are being relied on more than ever before. The osteoinductive, osteoconductive and osteogenic properties of these substrates have been elucidated in the basic science literature and validated in clinical orthopaedic practice. Furthermore, an industry built around these items is more successful and in demand than ever before. This review provides a comprehensive overview of the basic science, clinical utility and economics of bone grafts, bone substitutes and orthobiologics. PMID:23247591

Standardized Curriculum for Diesel Engine Mechanics.

ERIC Educational Resources Information Center

Mississippi State Dept. of Education, Jackson. Office of Vocational, Technical and Adult Education.

Standardized curricula are provided for two courses for the secondary vocational education program in Mississippi: diesel engine mechanics I and II. The eight units in diesel engine mechanics I are as follows: orientation; shop safety; basic shop tools; fasteners; measurement; engine operating principles; engine components; and basic auxiliary…

Combination Drug Therapy for Pain following Chronic Spinal Cord Injury

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2012-01-01

A number of mechanisms have been elucidated that maintain neuropathic pain due to spinal cord injury (SCI). While target-based therapeutics are being developed based on elucidation of these mechanisms, treatment for neuropathic SCI pain has not been entirely satisfactory due in part to the significant convergence of neurological and inflammatory processes that maintain the neuropathic pain state. Thus, a combination drug treatment strategy, wherein several pain-related mechanism are simultaneously engaged, could be more efficacious than treatment against individual mechanisms alone. Also, by engaging several targets at once, it may be possible to reduce the doses of the individual drugs, thereby minimizing the potential for adverse side effects. Positive preclinical and clinical studies have demonstrated improved efficacy of combination drug treatment over single drug treatment in neuropathic pain of peripheral origin, and perhaps such combinations could be utilized for neuropathic SCI pain. At the same time, there are mechanisms that distinguish SCI from peripheral neuropathic pain, so novel combination therapies will be needed. PMID:22550581

Advances in neuroimmunology

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

Raine, C.S.

1988-01-01

This volume presents the proceedings of the Second International Congress of Neuroimmunology. It brought together basic researchers and clinicians involved in the application of immunologic methodologies to the elucidation of problems related to nervous system development and disease. Neuroimmunology as a discipline is still in its infancy although its roots date back more than 50 years when it was realized that certain neurologic disorders were related to allergic reactions. Since then, it has been shown that immunological mechanisms are involved not only in a growing number of disease processes of the nervous system, but also in the development of nervousmore » tissue. It is now widely accepted that the nervous system shares a unique relationship with the immune system, sometimes through shared receptors, and possesses a large repertoire of specific antigens. Thus, with the continuing and intensive application of immunologic techniques to the neurologic sciences, the specialty of neuroimmunology has evolved. The major diseases that now fall into its realm include multiple sclerosis, myasthenia gravis, peripheral neuropathy, systemic lupus erythematosus, AIDS, leprosy, narcolepsy, tumors, viral encephalitis, and their experimental counterparts.« less

Direct single-molecule dynamic detection of chemical reactions.

PubMed

Guan, Jianxin; Jia, Chuancheng; Li, Yanwei; Liu, Zitong; Wang, Jinying; Yang, Zhongyue; Gu, Chunhui; Su, Dingkai; Houk, Kendall N; Zhang, Deqing; Guo, Xuefeng

2018-02-01

Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry.

Antimicrobial blue light: a drug-free approach for inactivating pathogenic microbes

NASA Astrophysics Data System (ADS)

Wang, Ying; Dai, Tianhong

2018-02-01

Due to the growing global threat of antibiotic resistance, there is a critical need for the development of alternative therapeutics for infectious diseases. Antimicrobial blue light (aBL), as an innovative non-antibiotic approach, has attracted increasing attention. This paper discussed the basic concepts of aBL and recent findings in the studies of aBL. It is commonly hypothesized that the antimicrobial property of aBL is attributed to the presence of endogenous photosensitizing chromophores in microbial cells, which produce cytotoxic reactive oxygen species upon light irradiation. A wide range of important microbes are found to be susceptible to aBL inactivation. Studies have also shown there exist therapeutic windows where microbes are selectively inactivated by aBL while host cells are preserved. The combination of aBL with some other agents result in synergistically improved antimicrobial efficacy. Future efforts should be exerted on the standardization of study design for evaluating aBL efficacy, further elucidation of the mechanism of action, optimization of the technical parameters, and translation of this technique to clinic.

A Hybrid Methacrylate-Sodium Carboxymethylcellulose Interpolyelectrolyte Complex: Rheometry and in Silico Disposition for Controlled Drug Release

PubMed Central

Ngwuluka, Ndidi Chinyelu; Choonara, Yahya Essop; Kumar, Pradeep; Modi, Girish; du Toit, Lisa Claire; Pillay, Viness

2013-01-01

The rheological behavioral changes that occurred during the synthesis of an interpolyelectrolyte complex (IPEC) of methacrylate copolymer and sodium carboxymethylcellulose were assessed. These changes were compared with the rheological behavior of the individual polymers employing basic viscosity, yield stress, stress sweep, frequency sweep, temperature ramp as well as creep and recovery testing. The rheological studies demonstrated that the end-product of the complexation of low viscous methacrylate copolymer and entangled solution of sodium carboxymethylcellulose generated a polymer, which exhibited a solid-like behavior with a three-dimensional network. Additionally, the rheological profile of the sodium carboxymethylcellulose and methacrylate copolymer with respect to the effect of various concentrations of acetic acid on the synthesis of the IPEC was elucidated using molecular mechanics energy relationships (MMER) by exploring the spatial disposition of carboxymethylcellulose and methacrylate copolymer with respect to each other and acetic acid. The computational results corroborated well with the experimental in vitro drug release data. Results have shown that the IPEC may be suitable polymeric material for achieving controlled zero-order drug delivery. PMID:28788332

Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection.

PubMed

Rivas-Ortiz, Claudia I; Lopez-Vidal, Yolanda; Arredondo-Hernandez, Luis Jose Rene; Castillo-Rojas, Gonzalo

2017-01-01

Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2) have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.

Development of a carbazole-based fluorescence probe for G-quadruplex DNA: The importance of side-group effect on binding specificity.

PubMed

Wang, Ming-Qi; Ren, Gui-Ying; Zhao, Shuang; Lian, Guang-Chang; Chen, Ting-Ting; Ci, Yang; Li, Hong-Yao

2018-06-15

G-quadruplex DNAs are highly prevalent in the human genome and involved in many important biological processes. However, many aspects of their biological mechanism and significance still need to be elucidated. Therefore, the development of fluorescent probes for G-quadruplex detection is important for the basic research. We report here on the development of small molecular dyes designed on the basis of carbazole scaffold by introducing styrene-like substituents at its 9-position, for the purpose of G-quadruplex recognition. Results revealed that the side group on the carbazole scaffold was very important for their ability to selectively recognize G-quadruplex DNA structures. 1a with the pyridine side group displayed excellent fluorescence signal turn-on property for the specific discrimination of G-quadruplex DNAs against other nucleic acids. The characteristics of 1a were further investigated with UV-vis spectrophotometry, fluorescence, circular dichroism, FID assay and molecular docking to validate the selectivity, sensitivity and detailed binding mode toward G-quadruplex DNAs. Copyright © 2018 Elsevier B.V. All rights reserved.

Linear solvation energy relationship (LSER) characterization of the normal phase retention mechanism on hypercrosslinked polystyrenes.

PubMed

Wu, Di; Jiang, Ping; Lucy, Charles A

2018-03-30

Linear solvation energy relationships (LSERs) were applied to retention on hypercrosslinked polystyrene on silica (HC-Tol) to elucidate the type and relative importance of molecular interactions between model solutes and the HC-Tol stationary phase. Classical amino phase and another hypercrosslinked phase (5-HGN) were used as reference columns. On both the HC-Tol and amino, polar interactions predominate and contribute to retention. Solute volume V has no impact on retention on the amino column, while V has a slightly negative influence on retention for the HC-Tol column. The differences in coefficient v between the amino and the HC-Tol columns might explain why the HC-Tol is capable of group-type separations. 5-HGN phase has smaller a and b values compared to HC-Tol, which means that 5-HGN is not as basic or acidic in terms of hydrogen bonds as is HC-Tol. This suggests that the hydrogen bonding character of the HC-Tol phase arises from its silica substrate. Copyright © 2018 Elsevier B.V. All rights reserved.

Transient lattice contraction in the solid to plasma transition of x-ray heated xenon clusters

NASA Astrophysics Data System (ADS)

Bostedt, C.; Ferguson, K.; Gorkhover, T.; Bucksbaum, P. H.; Boutet, S.; Koglin, J. E.; Lutman, A.; Marinelli, A.; Turner, J.; Bucher, M.; Ho, P.; Knight, C.; Young, L.; Fukuzawa, H.; Kumagai, Y.; Ueda, K.; Nagaya, K.; Messerschmidt, M.; Williams, G.

2016-05-01

Any sample in the focus of intense x-ray pulses will be transformed into a nanoplasma within femtoseconds. We have employed the novel two-color two-pulse mode available at the Linac Coherent Light Source free-electron laser to investigate the structural dynamics in nanoparticles upon x-ray exposure. We find that the nanoparticle transiently contracts within the first 80 fs following x-ray irradiation before ultimately disintegrating in a rapid hydrodynamic expansion. The contraction can be attributed to the massive x-ray induced electronic excitation that induces a collective change in the bond character of the nanoparticles. Alternative explanations for the contraction include a compression wave stemming from a rapid surface explosion of the nanoparticle. Computer simulations under way can elucidate the dominant contraction mechanism and yield further insight into the complex x-ray induced dynamics in nanoscale samples. This work is funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences, and Biosciences, under Contract No. DE-AC02-06CH11357.

Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection

PubMed Central

Rivas-Ortiz, Claudia I.; Lopez-Vidal, Yolanda; Arredondo-Hernandez, Luis Jose Rene; Castillo-Rojas, Gonzalo

2017-01-01

Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2) have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease. PMID:28512631

Basic Gravitational Reflexes in the Larval Frog

NASA Technical Reports Server (NTRS)

Cochran, Stephen L.

1996-01-01

This investigation was designed to determine how a primitive vertebrate, the bullfrog tadpole, is able to sense and process gravitational stimuli. Because of the phylogenetic similarities of the vestibular systems in all vertebrates, the understanding of the gravitational reflexes in this relatively simple vertebrate should elucidate a skeletal framework on a elementary level, upon which the more elaborate reflexes of higher vertebrates may be constructed. The purpose of this study was to understand how the nervous system of the larval amphibian processes gravitational information. This study involved predominantly electrophysiological investigations of the isolated, alert (forebrain removed) bullfrog tadpole head. The focus of these experiments is threefold: (1) to understand from whole extraocular nerve recordings the signals sent to the eye following static gravitational tilt of the head; (2) to localize neuronal centers responsible for generating these signals through reversible pharmacological ablation of these centers; and (3) to record intracellularly from neurons within these centers in order to determine the single neuron's role in the overall processing of the center. This study has provided information on the mechanisms by which a primitive vertebrate processes gravitational reflexes.

Advances in Monitoring Cell-Based Therapies with Magnetic Resonance Imaging: Future Perspectives

PubMed Central

Ngen, Ethel J.; Artemov, Dmitri

2017-01-01

Cell-based therapies are currently being developed for applications in both regenerative medicine and in oncology. Preclinical, translational, and clinical research on cell-based therapies will benefit tremendously from novel imaging approaches that enable the effective monitoring of the delivery, survival, migration, biodistribution, and integration of transplanted cells. Magnetic resonance imaging (MRI) offers several advantages over other imaging modalities for elucidating the fate of transplanted cells both preclinically and clinically. These advantages include the ability to image transplanted cells longitudinally at high spatial resolution without exposure to ionizing radiation, and the possibility to co-register anatomical structures with molecular processes and functional changes. However, since cellular MRI is still in its infancy, it currently faces a number of challenges, which provide avenues for future research and development. In this review, we describe the basic principle of cell-tracking with MRI; explain the different approaches currently used to monitor cell-based therapies; describe currently available MRI contrast generation mechanisms and strategies for monitoring transplanted cells; discuss some of the challenges in tracking transplanted cells; and suggest future research directions. PMID:28106829

Sleep and dietary habits in the urban environment: the role of chrono-nutrition.

PubMed

Pot, Gerda K

2017-10-25

The urban environment has changed vastly over past decades, which also has had an impact on our sleep and dietary patterns and possibly health outcomes. Some studies have shown that sleep duration and sleep quality has declined over past decades, especially in children. In parallel, our lifestyle and dietary patterns have also changed including more shift work, more meals outside the home or family setting and more irregular eating patterns, including breakfast skipping and late-night eating. This new area of research in nutritional sciences studying the impact of the timing of eating on health outcomes is called chrono-nutrition, and combines elements from nutritional research with chrono-biology. The objectives of this paper were to discuss secular trends in sleep patterns and related dietary patterns, introduce basic concepts and mechanisms of chrono-nutrition and discuss the evidence for the importance of sleep and chrono-nutrition in relation to health outcomes. Overall, chrono-nutrition could mediate the effects between sleep, diet and urbanisation, and more research is needed to elucidate the importance of chrono-nutrition for metabolic health and its impact on public health.

Principles that Govern the Performance of Molecular Motors

NASA Astrophysics Data System (ADS)

Eide, Jon; Chakraborty, Arup; Oster, George

2003-03-01

We have created a two dimensional polymeric coarse-grained model to simulate the power stroke from the F0F1 ATP synthase class of molecular motors. There has been much work to understand the structure and dynamics of this type of molecular motor using both constrained molecular dynamics and general Markov models but neither of them have been able to elucidate in a qualitative manner how a constant force is created and transferred in the motor at a nearly 100efficiency. Our model is a modified Rouse system using Brownian and Monte Carlo (with solvent) Dynamics, concentrating only on the catalytic site and protein structures that we think are important for motor motion and energy transfer. While modeling the real system as closely as possible, we have determined the optimum characteristics for maximum efficiency. The efficiency depends on the load against the polymer, the polymer flexibility, polymer and surface matching, and solvent interactions. Insight into the basic principles behind the mechanical motion of this system may have implications for many other molecular motors driven by nucleotide hydrolysis and help design synthetic devices that can carry out biomimetic tasks.

Genomewide screens for Escherichia coli genes affecting growth of T7 bacteriophage

PubMed Central

Qimron, Udi; Marintcheva, Boriana; Tabor, Stanley; Richardson, Charles C.

2006-01-01

Use of bacteriophages as a therapy for bacterial infection has been attempted over the last century. Such an endeavor requires the elucidation of basic aspects of the host–virus interactions and the resistance mechanisms of the host. Two recently developed bacterial collections now enable a genomewide search of the genetic interactions between Escherichia coli and bacteriophages. We have screened >85% of the E. coli genes for their ability to inhibit growth of T7 phage and >90% of the host genes for their ability to be used by the virus. In addition to identifying all of the known interactions, several other interactions have been identified. E. coli CMP kinase is essential for T7 growth, whereas overexpression of the E. coli uridine/cytidine kinase inhibits T7 growth. Mutations in any one of nine genes that encode enzymes for the synthesis of the E. coli lipopolysaccharide receptor for T7 adsorption leads to T7 resistance. Selection of T7 phage that can recognize these altered receptors has enabled the construction of phage to which the host is 100-fold less resistant. PMID:17135349

Oleoylethanolamide: A fat ally in the fight against obesity.

PubMed

Brown, Jacob D; Karimian Azari, Elnaz; Ayala, Julio E

2017-07-01

Obesity is a pandemic, gateway disease that has thrived in modern, sedentary, high calorie-eating societies. Left unchecked, obesity and obesity-related diseases will continue to plague future generations with heavy burdens on economies, healthcare systems, and the quality of life of billions. There is a significant need to elucidate basic physiological mechanisms and therapies that address this global health care crisis. Oleoylethanolamide (OEA) is an endocannabinoid-like lipid that induces hypophagia and reduces fat mass in rodents. For over a decade, PPAR-α has been the most widely accepted mediator of the hypophagic action of OEA via signaling to homeostatic brain centers. Recent evidence suggests that OEA may also reduce food intake via effects on dopamine and endocannabinoid signaling within hedonic brain centers. Limited study of OEA supplementation in humans has provided some encouraging insight into OEA-based weight loss therapy, but more thorough, controlled investigations are needed. As a potential link between homeostatic and hedonic regulation of food intake, OEA is a prime starting point for the development of more effective obesity therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Modelling ADHD: A review of ADHD theories through their predictions for computational models of decision-making and reinforcement learning.

PubMed

Ziegler, Sigurd; Pedersen, Mads L; Mowinckel, Athanasia M; Biele, Guido

2016-12-01

Attention deficit hyperactivity disorder (ADHD) is characterized by altered decision-making (DM) and reinforcement learning (RL), for which competing theories propose alternative explanations. Computational modelling contributes to understanding DM and RL by integrating behavioural and neurobiological findings, and could elucidate pathogenic mechanisms behind ADHD. This review of neurobiological theories of ADHD describes predictions for the effect of ADHD on DM and RL as described by the drift-diffusion model of DM (DDM) and a basic RL model. Empirical studies employing these models are also reviewed. While theories often agree on how ADHD should be reflected in model parameters, each theory implies a unique combination of predictions. Empirical studies agree with the theories' assumptions of a lowered DDM drift rate in ADHD, while findings are less conclusive for boundary separation. The few studies employing RL models support a lower choice sensitivity in ADHD, but not an altered learning rate. The discussion outlines research areas for further theoretical refinement in the ADHD field. Copyright © 2016 Elsevier Ltd. All rights reserved.

Label-Free in Situ Discrimination of Live and Dead Bacteria by Surface-Enhanced Raman Scattering.

PubMed

Zhou, Haibo; Yang, Danting; Ivleva, Natalia P; Mircescu, Nicoleta E; Schubert, Sören; Niessner, Reinhard; Wieser, Andreas; Haisch, Christoph

2015-07-07

Techniques to distinguish between live and dead bacteria in a quantitative manner are in high demand in numerous fields including medical care, food safety, and public security as well as basic science research. This work demonstrates new nanostructures (silver nanoparticles coating bacteria structure, Bacteria@AgNPs) and their utility for rapid counting of live and dead bacteria by surface-enhanced Raman scattering (SERS). We found that suspensions containing Gram-negative organisms as well as AgNPs give strong SERS signals of live bacteria when generated selectively on the particle surface. However, almost no SERS signals can be detected from Bacteria@AgNPs suspensions containing dead bacteria. We demonstrate successful quantification of different percentages of dead bacteria both in bulk liquid and on glass surfaces by using SERS mapping on a single cell basis. Furthermore, different chemicals have been used to elucidate the mechanism involved in this observation. Finally, we used the Bacteria@AgNPs method to detect antibiotic resistance of E. coli strains against several antibiotics used in human medicine.

Experimental and Theoretical Study of Molecular Response of Amine Bases in Organic Solvents

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

Kathmann, Shawn M.; Cho, Herman M.; Chang, Tsun-Mei

2014-05-08

Reorientational correlation times of various amine bases (viz., pyridine, 2,6-lutidene, 2,2,6,6-tetramethylpiperidine) and organic solvents (dichloromethane, toluene) were determined by solution-state NMR relaxation time measurements and compared with predictions from molecular dynamics (MD) simulations. The bases and solvents are reagents in complex reactions involving Frustrated Lewis Pairs (FLP), which display remarkable catalytic activity in metal-free H2 scission. The comparison of measured and simulated correlation times is a key test of the ability of recent MD and quantum electronic structure calculations to elucidate the mechanism of FLP activity. Correla- tion times were found to be in the range 1.4-3.4 ps (NMR) andmore » 1.23-5.28 ps (MD) for the amines, and 0.9-2.3 ps (NMR) and 0.2-1.7 ps (MD) for the solvent molecules. This work was supported by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences. Pacic Northwest National Laboratory (PNNL) is a multiprogram national laboratory operated for DOE by Battelle.« less

Decoupling Polymer Properties to Elucidate Mechanisms Governing Cell Behavior

PubMed Central

Wang, Xintong; Boire, Timothy C.; Bronikowski, Christine; Zachman, Angela L.; Crowder, Spencer W.

2012-01-01

Determining how a biomaterial interacts with cells (“structure-function relationship”) reflects its eventual clinical applicability. Therefore, a fundamental understanding of how individual material properties modulate cell-biomaterial interactions is pivotal to improving the efficacy and safety of clinically translatable biomaterial systems. However, due to the coupled nature of material properties, their individual effects on cellular responses are difficult to understand. Structure-function relationships can be more clearly understood by the effective decoupling of each individual parameter. In this article, we discuss three basic decoupling strategies: (1) surface modification, (2) cross-linking, and (3) combinatorial approaches (i.e., copolymerization and polymer blending). Relevant examples of coupled material properties are briefly reviewed in each section to highlight the need for improved decoupling methods. This follows with examples of more effective decoupling techniques, mainly from the perspective of three primary classes of synthetic materials: polyesters, polyethylene glycol, and polyacrylamide. Recent strides in decoupling methodologies, especially surface-patterning and combinatorial techniques, offer much promise in further understanding the structure-function relationships that largely govern the success of future advancements in biomaterials, tissue engineering, and drug delivery. PMID:22536977

Non-compact Groups, Coherent States, Relativistic Wave Equations and the Harmonic Oscillator II: Physical and Geometrical Considerations

NASA Astrophysics Data System (ADS)

Cirilo-Lombardo, Diego Julio

2009-04-01

The physical meaning of the particularly simple non-degenerate supermetric, introduced in the previous part by the authors, is elucidated and the possible connection with processes of topological origin in high energy physics is analyzed and discussed. New possible mechanism of the localization of the fields in a particular sector of the supermanifold is proposed and the similarity and differences with a 5-dimensional warped model are shown. The relation with gauge theories of supergravity based in the OSP(1/4) group is explicitly given and the possible original action is presented. We also show that in this non-degenerate super-model the physic states, in contrast with the basic states, are observables and can be interpreted as tomographic projections or generalized representations of operators belonging to the metaplectic group Mp(2). The advantage of geometrical formulations based on non-degenerate super-manifolds over degenerate ones is pointed out and the description and the analysis of some interesting aspects of the simplest Riemannian superspaces are presented from the point of view of the possible vacuum solutions.

Thickness-controlled electronic structure and thermoelectric performance of ultrathin SnS2 nanosheets.

PubMed

Li, Jun; Shen, Jinni; Ma, Zuju; Wu, Kechen

2017-08-21

The thermoelectric conversion efficiency of a material relies on a dimensionless parameter (ZT = S 2 σT/κ). It is a great challenge in enhancing the ZT value basically due to that the related transport factors of most of the bulk materials are inter-conditioned to each other, making it very difficult to simultaneously optimize these parameters. In this report, the negative correlation between power factor and thermal conductivity of nano-scaled SnS 2 multilayers is predicted by high-level first-principle computations combined with Boltzmann transport theory. By diminishing the thickness of SnS 2 nanosheet to about 3 L, the S and σ along a direction simultaneously increase whereas κ decreases, achieving a high ZT value of 1.87 at 800 K. The microscopic mechanisms for this unusual negative correlation in nano-scaled two dimensional (2D) material are elucidated and attributed to the quantum confinement effect. The results may open a way to explore the high ZT thermoelectric nano-devices for the practical thermoelectric applications.

Elucidating the Key Role of a Lewis Base Solvent in the Formation of Perovskite Films Fabricated from the Lewis Adduct Approach.

PubMed

Cao, Xiaobing; Zhi, Lili; Li, Yahui; Fang, Fei; Cui, Xian; Yao, Youwei; Ci, Lijie; Ding, Kongxian; Wei, Jinquan

2017-09-27

High-quality perovskite films can be fabricated from Lewis acid-base adducts through molecule exchange. Substantial work is needed to fully understand the formation mechanism of the perovskite films, which helps to further improve their quality. Here, we study the formation of CH 3 NH 3 PbI 3 perovskite films by introducing some dimethylacetamide into the PbI 2 /N,N-dimethylformamide solution. We reveal that there are three key processes during the formation of perovskite films through the Lewis acid-base adduct approach: molecule intercalation of solvent into the PbI 2 lattice, molecule exchange between the solvent and CH 3 NH 3 I, and dissolution-recrystallization of the perovskite grains during annealing. The Lewis base solvents play multiple functions in the above processes. The properties of the solvent, including Lewis basicity and boiling point, play key roles in forming smooth perovskite films with large grains. We also provide some rules for choosing Lewis base additives to prepare high-quality perovskite films through the Lewis adduct approach.

Direct single-molecule dynamic detection of chemical reactions

PubMed Central

Guan, Jianxin; Jia, Chuancheng; Li, Yanwei; Liu, Zitong; Wang, Jinying; Yang, Zhongyue; Gu, Chunhui; Su, Dingkai; Houk, Kendall N.; Zhang, Deqing; Guo, Xuefeng

2018-01-01

Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry. PMID:29487914

Teaching Experiment to Elucidate a Cation-Pi Effect in an Alkyne Cycloaddition Reaction and Illustrate Hypothesis-Driven Design of Experiments

ERIC Educational Resources Information Center

St.Germain, Elijah J.; Horowitz, Andrew S.; Rucco, Dominic; Rezler, Evonne M.; Lepore, Salvatore D.

2017-01-01

An organic chemistry experiment is described that is based on recent research to elucidate a novel cation-pi interaction between tetraalkammonium cations and propargyl hydrazines. This nonbonded interaction is a key component of the mechanism of ammonium-catalyzed intramolecular cycloaddition of nitrogen to the terminal carbon of a C-C triple bond…

The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis.

PubMed

Heijman, Jordi; Algalarrondo, Vincent; Voigt, Niels; Melka, Jonathan; Wehrens, Xander H T; Dobrev, Dobromir; Nattel, Stanley

2016-04-01

Atrial fibrillation (AF) is an extremely common clinical problem associated with increased morbidity and mortality. Current antiarrhythmic options include pharmacological, ablation, and surgical therapies, and have significantly improved clinical outcomes. However, their efficacy remains suboptimal, and their use is limited by a variety of potentially serious adverse effects. There is a clear need for improved therapeutic options. Several decades of research have substantially expanded our understanding of the basic mechanisms of AF. Ectopic firing and re-entrant activity have been identified as the predominant mechanisms for arrhythmia initiation and maintenance. However, it has become clear that the clinical factors predisposing to AF and the cellular and molecular mechanisms involved are extremely complex. Moreover, all AF-promoting and maintaining mechanisms are dynamically regulated and subject to remodelling caused by both AF and cardiovascular disease. Accordingly, the initial presentation and clinical progression of AF patients are enormously heterogeneous. An understanding of arrhythmia mechanisms is widely assumed to be the basis of therapeutic innovation, but while this assumption seems self-evident, we are not aware of any papers that have critically examined the practical contributions of basic research into AF mechanisms to arrhythmia management. Here, we review recent insights into the basic mechanisms of AF, critically analyse the role of basic research insights in the development of presently used anti-AF therapeutic options and assess the potential value of contemporary experimental discoveries for future therapeutic innovation. Finally, we highlight some of the important challenges to the translation of basic science findings to clinical application. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Auto-Mechanics Course. Bilingual Vocational Instructional Materials.

ERIC Educational Resources Information Center

Lopez-Cox, Guadalupe

This auto-mechanics course, one of a series of bilingual English-Spanish vocational education courses, is designed to introduce the basic skills that an automotive mechanics student should know. It is geared to teach the student basic manipulative skills, safety judgments, proper work habits, desirable attitudes, and proper behavior for initial…

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

PubMed Central

Greenwood-Van Meerveld, Beverley; Johnson, Anthony C.

2017-01-01

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing. PMID:29213232

Young’s modulus calculations for cellulose Iß by MM3 and quantum mechanics

USDA-ARS?s Scientific Manuscript database

Quantum mechanics (QM) and molecular mechanics (MM) calculations were performed to elucidate Young’s moduli for a series of cellulose Iß models. Computations using the second generation empirical force field MM3 with a disaccharide cellulose model, 1,4'-O-dimethyl-ß-cellobioside (DMCB), and an analo...

Drosophila Courtship Conditioning As a Measure of Learning and Memory.

PubMed

Koemans, Tom S; Oppitz, Cornelia; Donders, Rogier A T; van Bokhoven, Hans; Schenck, Annette; Keleman, Krystyna; Kramer, Jamie M

2017-06-05

Many insights into the molecular mechanisms underlying learning and memory have been elucidated through the use of simple behavioral assays in model organisms such as the fruit fly, Drosophila melanogaster. Drosophila is useful for understanding the basic neurobiology underlying cognitive deficits resulting from mutations in genes associated with human cognitive disorders, such as intellectual disability (ID) and autism. This work describes a methodology for testing learning and memory using a classic paradigm in Drosophila known as courtship conditioning. Male flies court females using a distinct pattern of easily recognizable behaviors. Premated females are not receptive to mating and will reject the male's copulation attempts. In response to this rejection, male flies reduce their courtship behavior. This learned reduction in courtship behavior is measured over time, serving as an indicator of learning and memory. The basic numerical output of this assay is the courtship index (CI), which is defined as the percentage of time that a male spends courting during a 10 min interval. The learning index (LI) is the relative reduction of CI in flies that have been exposed to a premated female compared to naïve flies with no previous social encounters. For the statistical comparison of LIs between genotypes, a randomization test with bootstrapping is used. To illustrate how the assay can be used to address the role of a gene relating to learning and memory, the pan-neuronal knockdown of Dihydroxyacetone phosphate acyltransferase (Dhap-at) was characterized here. The human ortholog of Dhap-at, glyceronephosphate O-acyltransferase (GNPT), is involved in rhizomelic chondrodysplasia punctata type 2, an autosomal-recessive syndrome characterized by severe ID. Using the courtship conditioning assay, it was determined that Dhap-at is required for long-term memory, but not for short-term memory. This result serves as a basis for further investigation of the underlying molecular mechanisms.

Optimization of a 3D Dynamic Culturing System for In Vitro Modeling of Frontotemporal Neurodegeneration-Relevant Pathologic Features

PubMed Central

Tunesi, Marta; Fusco, Federica; Fiordaliso, Fabio; Corbelli, Alessandro; Biella, Gloria; Raimondi, Manuela T.

2016-01-01

Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative disorder that is diagnosed with increasing frequency in clinical setting. Currently, no therapy is available and in addition the molecular basis of the disease are far from being elucidated. Consequently, it is of pivotal importance to develop reliable and cost-effective in vitro models for basic research purposes and drug screening. To this respect, recent results in the field of Alzheimer’s disease have suggested that a tridimensional (3D) environment is an added value to better model key pathologic features of the disease. Here, we have tried to add complexity to the 3D cell culturing concept by using a microfluidic bioreactor, where cells are cultured under a continuous flow of medium, thus mimicking the interstitial fluid movement that actually perfuses the body tissues, including the brain. We have implemented this model using a neuronal-like cell line (SH-SY5Y), a widely exploited cell model for neurodegenerative disorders that shows some basic features relevant for FTLD modeling, such as the release of the FTLD-related protein progranulin (PRGN) in specific vesicles (exosomes). We have efficiently seeded the cells on 3D scaffolds, optimized a disease-relevant oxidative stress experiment (by targeting mitochondrial function that is one of the possible FTLD-involved pathological mechanisms) and evaluated cell metabolic activity in dynamic culture in comparison to static conditions, finding that SH-SY5Y cells cultured in 3D scaffold are susceptible to the oxidative damage triggered by a mitochondrial-targeting toxin (6-OHDA) and that the same cells cultured in dynamic conditions kept their basic capacity to secrete PRGN in exosomes once recovered from the bioreactor and plated in standard 2D conditions. We think that a further improvement of our microfluidic system may help in providing a full device where assessing basic FTLD-related features (including PRGN dynamic secretion) that may be useful for monitoring disease progression over time or evaluating therapeutic interventions. PMID:27445790

75 FR 61219 - Entergy Operations, Inc.; River Bend Station, Unit 1; Environmental Assessment and Finding of No...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-04

... Emergencies,'' for repair and corrective actions states that two individuals, one Mechanical Maintenance... actions will be taken to ensure basic electrical/l&C tasks can be performed by Mechanical Maintenance personnel. Mechanical Maintenance personnel will receive training in basic electrical and I&C tasks to...

Kuhn's Paradigm and Example-Based Teaching of Newtonian Mechanics.

ERIC Educational Resources Information Center

Whitaker, M. A. B.

1980-01-01

Makes a recommendation for more direct teaching of the basic principles of mechanics. Contends that students currently learn mechanics in terms of standard examples. This causes difficulty when the student is confronted with a problem that can be solved from basic principles, but which does not fit a standard category. (GS)

Diesel Mechanics. Performance Objectives. Basic Course.

ERIC Educational Resources Information Center

Tidwell, Joseph

Several intermediate performance objectives and corresponding criterion measures are listed for each of 12 terminal objectives for a basic diesel mechanics course. The course is designed as a two-semester (2 hour daily) course for 10th graders interested in being diesel service and repair mechanics; it would serve as the first year of a 3-year…

Elucidation of Small RNAs that Activate Transcription in Bacteria

DTIC Science & Technology

2012-03-01

bacterial sRNAs that activate transcription of a target gene in E. coli to varying degrees. Mutation of the strongest activator modified its...identified RNA- based transcriptional activators in yeast (Buskirk et al., 2003) although the underlying mechanism was not elucidated. We show that the...previous yeast two-hybrid (Buskirk et al., 2003) and three-hybrid studies (Bernstein et al., 2002). Colonies were observed from co-transformations of pBT

Elucidating the alkaline oxygen evolution reaction mechanism on platinum

DOE PAGES

Favaro, M.; Valero-Vidal, C.; Eichhorn, J.; ...

2017-03-07

Understanding the interplay between surface chemistry, electronic structure, and reaction mechanism of the catalyst at the electrified solid/liquid interface will enable the design of more efficient materials systems for sustainable energy production. The substantial progress in operando characterization, particularly using synchrotron based X-ray spectroscopies, provides the unprecedented opportunity to uncover surface chemical and structural transformations under various (electro)chemical reaction environments. In this work, we study a polycrystalline platinum surface under oxygen evolution conditions in an alkaline electrolyte by means of ambient pressure X-ray photoelectron spectroscopy performed at the electrified solid/liquid interface. We elucidate previously inaccessible aspects of the surface chemistrymore » and structure as a function of the applied potential, allowing us to propose a reaction mechanism for oxygen evolution on a platinum electrode in alkaline solutions.« less

Elucidating Neuronal Mechanisms Using Intracellular Recordings during Behavior.

PubMed

Lee, Albert K; Brecht, Michael

2018-06-01

Intracellular recording allows measurement and perturbation of the membrane potential of identified neurons with sub-millisecond and sub-millivolt precision. This gives intracellular recordings a unique capacity to provide rich information about individual cells (e.g., high-resolution characterization of inputs, outputs, excitability, and structure). Hence, such recordings can elucidate the mechanisms that underlie fundamental phenomena, such as brain state, sparse coding, gating, gain modulation, and learning. Technical developments have increased the range of behaviors during which intracellular recording methods can be employed, such as in freely moving animals and head-fixed animals actively performing tasks, including in virtual environments. Such advances, and the combination of intracellular recordings with genetic and imaging techniques, have enabled investigation of the mechanisms that underlie neural computations during natural and trained behaviors. Copyright © 2018 Elsevier Ltd. All rights reserved.

Elucidating reaction mechanisms on quantum computers.

PubMed

Reiher, Markus; Wiebe, Nathan; Svore, Krysta M; Wecker, Dave; Troyer, Matthias

2017-07-18

With rapid recent advances in quantum technology, we are close to the threshold of quantum devices whose computational powers can exceed those of classical supercomputers. Here, we show that a quantum computer can be used to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical computer simulations used to probe these reaction mechanisms, to significantly increase their accuracy and enable hitherto intractable simulations. Our resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. Our results demonstrate that quantum computers will be able to tackle important problems in chemistry without requiring exorbitant resources.

Elucidating reaction mechanisms on quantum computers

PubMed Central

Reiher, Markus; Wiebe, Nathan; Svore, Krysta M.; Wecker, Dave; Troyer, Matthias

2017-01-01

With rapid recent advances in quantum technology, we are close to the threshold of quantum devices whose computational powers can exceed those of classical supercomputers. Here, we show that a quantum computer can be used to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical computer simulations used to probe these reaction mechanisms, to significantly increase their accuracy and enable hitherto intractable simulations. Our resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. Our results demonstrate that quantum computers will be able to tackle important problems in chemistry without requiring exorbitant resources. PMID:28674011

Elucidating reaction mechanisms on quantum computers

NASA Astrophysics Data System (ADS)

Reiher, Markus; Wiebe, Nathan; Svore, Krysta M.; Wecker, Dave; Troyer, Matthias

2017-07-01

With rapid recent advances in quantum technology, we are close to the threshold of quantum devices whose computational powers can exceed those of classical supercomputers. Here, we show that a quantum computer can be used to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical computer simulations used to probe these reaction mechanisms, to significantly increase their accuracy and enable hitherto intractable simulations. Our resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. Our results demonstrate that quantum computers will be able to tackle important problems in chemistry without requiring exorbitant resources.

Elucidation of reaction mechanism involved in the formation of LaNiO3 from XRD and TG analysis

NASA Astrophysics Data System (ADS)

Dharmadhikari, Dipti V.; Athawale, Anjali A.

2013-06-01

The present work is focused on the synthesis and elucidation of reaction mechanism involved in the formation of LaNiO3 with the help of X-ray diffraction (XRD) and thermogravimetric (TG) analysis. LaNiO3 was synthesized by hydrothermal method by heating at 160°C under autogenous pressure for 6h. Pure phase product was obtained after calcining the hydrothermally activated product for 6h at 700°C. The various phases of the product obtained after hydrothermal treatment and calcination followed by the formation of pure phase nanocrystalline lanthanum nickel oxide could be determined from XRD analysis of the samples. The reaction mechanism and phase formation temperature has been interpreted by thermogravimetric analysis of the hydrothermally synthesized product and XRD analysis.

Research progress on Drosophila visual cognition in China.

PubMed

Guo, AiKe; Zhang, Ke; Peng, YueQin; Xi, Wang

2010-03-01

Visual cognition, as one of the fundamental aspects of cognitive neuroscience, is generally associated with high-order brain functions in animals and human. Drosophila, as a model organism, shares certain features of visual cognition in common with mammals at the genetic, molecular, cellular, and even higher behavioral levels. From learning and memory to decision making, Drosophila covers a broad spectrum of higher cognitive behaviors beyond what we had expected. Armed with powerful tools of genetic manipulation in Drosophila, an increasing number of studies have been conducted in order to elucidate the neural circuit mechanisms underlying these cognitive behaviors from a genes-brain-behavior perspective. The goal of this review is to integrate the most important studies on visual cognition in Drosophila carried out in mainland China during the last decade into a body of knowledge encompassing both the basic neural operations and circuitry of higher brain function in Drosophila. Here, we consider a series of the higher cognitive behaviors beyond learning and memory, such as visual pattern recognition, feature and context generalization, different feature memory traces, salience-based decision, attention-like behavior, and cross-modal leaning and memory. We discuss the possible general gain-gating mechanism implementing by dopamine - mushroom body circuit in fly's visual cognition. We hope that our brief review on this aspect will inspire further study on visual cognition in flies, or even beyond.

Cellular Responses to Mechanical Stress Selected Contribution: A Three-Dimensional Model for Assessment of in Vitro Toxicity in Balaena Mysticetus Renal Tissue

NASA Technical Reports Server (NTRS)

Goodwin, T. J.; Coate-Li, L.; Linnehan, R. M.; Hammond, T. G.

2000-01-01

This study established two- and three-dimensional renal proximal tubular cell cultures of the endangered species bowhead whale (Balaena mysticetus), developed SV40-transfected cultures, and cloned the 61-amino acid open reading frame for the metallothionein protein, the primary binding site for heavy metal contamination in mammals. Microgravity research, modulations in mechanical culture conditions (modeled microgravity), and shear stress have spawned innovative approaches to understanding the dynamics of cellular interactions, gene expression, and differentiation in several cellular systems. These investigations have led to the creation of ex vivo tissue models capable of serving as physiological research analogs for three-dimensional cellular interactions. These models are enabling studies in immune function, tissue modeling for basic research, and neoplasia. Three-dimensional cellular models emulate aspects of in vivo cellular architecture and physiology and may facilitate environmental toxicological studies aimed at elucidating biological functions and responses at the cellular level. Marine mammals occupy a significant ecological niche (72% of the Earth's surface is water) in terms of the potential for information on bioaccumulation and transport of terrestrial and marine environmental toxins in high-order vertebrates. Few ex vivo models of marine mammal physiology exist in vitro to accomplish the aforementioned studies. Techniques developed in this investigation, based on previous tissue modeling successes, may serve to facilitate similar research in other marine mammals.

Experimental and Numerical Evaluation of the Mechanical Behavior of Strongly Anisotropic Light-Weight Metallic Fiber Structures under Static and Dynamic Compressive Loading

PubMed Central

Andersen, Olaf; Vesenjak, Matej; Fiedler, Thomas; Jehring, Ulrike; Krstulović-Opara, Lovre

2016-01-01

Rigid metallic fiber structures made from a variety of different metals and alloys have been investigated mainly with regard to their functional properties such as heat transfer, pressure drop, or filtration characteristics. With the recent advent of aluminum and magnesium-based fiber structures, the application of such structures in light-weight crash absorbers has become conceivable. The present paper therefore elucidates the mechanical behavior of rigid sintered fiber structures under quasi-static and dynamic loading. Special attention is paid to the strongly anisotropic properties observed for different directions of loading in relation to the main fiber orientation. Basically, the structures show an orthotropic behavior; however, a finite thickness of the fiber slabs results in moderate deviations from a purely orthotropic behavior. The morphology of the tested specimens is examined by computed tomography, and experimental results for different directions of loading as well as different relative densities are presented. Numerical calculations were carried out using real structural data derived from the computed tomography data. Depending on the direction of loading, the fiber structures show a distinctively different deformation behavior both experimentally and numerically. Based on these results, the prevalent modes of deformation are discussed and a first comparison with an established polymer foam and an assessment of the applicability of aluminum fiber structures in crash protection devices is attempted. PMID:28773522

Inquiry into chemotherapy-induced p53 activation in cancer cells as a model for teaching signal transduction.

PubMed

Srougi, Melissa C; Carson, Susan

2013-01-01

Intracellular and extracellular communication is conducted through an intricate and interwoven network of signal transduction pathways. The mechanisms for how cells speak with one another are of significant biological importance to both basic and industrial scientists from a number of different disciplines. We have therefore developed and implemented a new laboratory-intensive course that teaches students the theory and techniques used to study cell signaling pathways. Students learn these methodologies as they conduct a hypothesis-driven research project where they elucidate the mechanism of breast cancer cell death caused by a cancer chemotherapeutic agent. While each lab experiment can be conducted independently, the findings build upon one another to form the beginnings of a signaling pathway. In the lecture component of the course, students investigate different signaling pathways and the methods employed to study them. In addition, students actively participate in journal article discussions where they assess the primary scientific literature. We evaluated the course over two semesters and found that in both semesters learning outcomes were met by both undergraduate and graduate students. The evaluation of the course was based on a number of instructor assessments of student work, including lab reports, experimental results, journal article discussions, and a final cumulative exam. Furthermore, students' self-assessments revealed gains in perceived confidence in both conceptual knowledge and technical skills Copyright © 2013 Wiley-Liss, Inc.

Experimental and Numerical Evaluation of the Mechanical Behavior of Strongly Anisotropic Light-Weight Metallic Fiber Structures under Static and Dynamic Compressive Loading.

PubMed

Andersen, Olaf; Vesenjak, Matej; Fiedler, Thomas; Jehring, Ulrike; Krstulović-Opara, Lovre

2016-05-21

Rigid metallic fiber structures made from a variety of different metals and alloys have been investigated mainly with regard to their functional properties such as heat transfer, pressure drop, or filtration characteristics. With the recent advent of aluminum and magnesium-based fiber structures, the application of such structures in light-weight crash absorbers has become conceivable. The present paper therefore elucidates the mechanical behavior of rigid sintered fiber structures under quasi-static and dynamic loading. Special attention is paid to the strongly anisotropic properties observed for different directions of loading in relation to the main fiber orientation. Basically, the structures show an orthotropic behavior; however, a finite thickness of the fiber slabs results in moderate deviations from a purely orthotropic behavior. The morphology of the tested specimens is examined by computed tomography, and experimental results for different directions of loading as well as different relative densities are presented. Numerical calculations were carried out using real structural data derived from the computed tomography data. Depending on the direction of loading, the fiber structures show a distinctively different deformation behavior both experimentally and numerically. Based on these results, the prevalent modes of deformation are discussed and a first comparison with an established polymer foam and an assessment of the applicability of aluminum fiber structures in crash protection devices is attempted.

Severe Delayed Cutaneous and Systemic Reactions to Drugs: A Global Perspective on the Science and Art of Current Practice.

PubMed

Peter, Jonathan Grant; Lehloenya, Rannakoe; Dlamini, Sipho; Risma, Kimberly; White, Katie D; Konvinse, Katherine C; Phillips, Elizabeth J

Most immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCARs) are an uncommon, potentially life-threatening, and challenging subgroup of IM-ADRs with diverse clinical phenotypes, mechanisms, and offending drugs. T-cell-mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson syndrome/toxic epidermal necrolysis, although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short- and long-term morbidity/mortality and the potential need to treat ongoing comorbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive, diagnostic, treatment, and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying comorbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice

PubMed Central

Peter, Jonathan Grant; Lehloenya, Rannakoe; Dlamini, Sipho; Risma, Kimberly; White, Katie D.; Konvinse, Katherine C.; Phillips, Elizabeth J.

2017-01-01

The majority of immune-mediated adverse drug reactions (IM-ADRs) involve the skin, and many have additional systemic features. Severe cutaneous adverse drug reactions (SCAR) are an uncommon, potentially life-threatening and challenging sub-group of IM-ADRs with diverse clinical phenotypes, mechanisms and offending drugs. T-cell mediated immunopathology is central to these severe delayed reactions, but effector cells and cytokines differ by clinical phenotype. Strong HLA-gene associations have been elucidated for specific drug-SCAR IM-ADRs such as Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN); although the mechanisms by which carriage of a specific HLA allele is necessary but not sufficient for the development of many IM-ADRs is still being defined. SCAR management is complicated by substantial short and long-term morbidity/ mortality and the potential need to treat ongoing co-morbid disease with related medications. Multidisciplinary specialist teams at experienced units should care for patients. In the setting of SCAR, patient outcomes as well as preventive,diagnostic, treatment and management approaches are often not generalizable, but rather context specific, driven by population HLA-genetics, the pharmacology and genetic risk factors of the implicated drug, severity of underlying co-morbid disease necessitating ongoing treatments, and cost considerations. In this review, we update the basic and clinical science of SCAR diagnosis and management. PMID:28483310

The imperative for controlled mechanical stresses in unraveling cellular mechanisms of mechanotransduction

PubMed Central

Anderson, Eric J; Falls, Thomas D; Sorkin, Adam M; Tate, Melissa L Knothe

2006-01-01

Background In vitro mechanotransduction studies are designed to elucidate cell behavior in response to a well-defined mechanical signal that is imparted to cultured cells, e.g. through fluid flow. Typically, flow rates are calculated based on a parallel plate flow assumption, to achieve a targeted cellular shear stress. This study evaluates the performance of specific flow/perfusion chambers in imparting the targeted stress at the cellular level. Methods To evaluate how well actual flow chambers meet their target stresses (set for 1 and 10 dyn/cm2 for this study) at a cellular level, computational models were developed to calculate flow velocity components and imparted shear stresses for a given pressure gradient. Computational predictions were validated with micro-particle image velocimetry (μPIV) experiments. Results Based on these computational and experimental studies, as few as 66% of cells seeded along the midplane of commonly implemented flow/perfusion chambers are subjected to stresses within ±10% of the target stress. In addition, flow velocities and shear stresses imparted through fluid drag vary as a function of location within each chamber. Hence, not only a limited number of cells are exposed to target stress levels within each chamber, but also neighboring cells may experience different flow regimes. Finally, flow regimes are highly dependent on flow chamber geometry, resulting in significant variation in magnitudes and spatial distributions of stress between chambers. Conclusion The results of this study challenge the basic premise of in vitro mechanotransduction studies, i.e. that a controlled flow regime is applied to impart a defined mechanical stimulus to cells. These results also underscore the fact that data from studies in which different chambers are utilized can not be compared, even if the target stress regimes are comparable. PMID:16672051

Microdialysis Sampling Techniques Applied to Studies of the Foreign Body Reaction

PubMed Central

Sides, Cynthia R.; Stenken, Julie A.

2014-01-01

Implanted materials including drug delivery devices and chemical sensors undergo what is termed the foreign body reaction (FBR). Depending on the device and its intended application, the FBR can have differing consequences. An extensive scientific research effort has been devoted to elucidating the cellular and molecular mechanisms that drive the FBR. Important, yet relatively unexplored, research includes the localized tissue biochemistry and the chemical signaling events that occur throughout the FBR. This review provides an overview of the mechanisms of the FBR, describes how the FBR affects different implanted devices, and illustrates the role that microdialysis sampling can play in further elucidating the chemical communication processes that drive FBR outcomes. PMID:24269987

Elucidating Reaction Mechanisms on Quantum Computers

NASA Astrophysics Data System (ADS)

Wiebe, Nathan; Reiher, Markus; Svore, Krysta; Wecker, Dave; Troyer, Matthias

We show how a quantum computer can be employed to elucidate reaction mechanisms in complex chemical systems, using the open problem of biological nitrogen fixation in nitrogenase as an example. We discuss how quantum computers can augment classical-computer simulations for such problems, to significantly increase their accuracy and enable hitherto intractable simulations. Detailed resource estimates show that, even when taking into account the substantial overhead of quantum error correction, and the need to compile into discrete gate sets, the necessary computations can be performed in reasonable time on small quantum computers. This demonstrates that quantum computers will realistically be able to tackle important problems in chemistry that are both scientifically and economically significant.

Mechanisms for Electron Transfer Through Pili to Fe(III) Oxide in Geobacter

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

Lovley, Derek R.

The purpose of these studies was to aid the Department of Energy in its goal of understanding how microorganisms involved in the bioremediation of metals and radionuclides sustain their activity in the subsurface. This information is required in order to incorporate biological processes into decision making for environmental remediation and long-term stewardship of contaminated sites. The proposed research was designed to elucidate the mechanisms for electron transfer to Fe(III) oxides in Geobacter species because Geobacter species are abundant dissimilatory metal-reducing microorganisms in a diversity of sites in which uranium is undergoing natural attenuation via the reduction of soluble U(VI) tomore » insoluble U(IV) or when this process is artificially stimulated with the addition of organic electron donors. This study investigated the novel, but highly controversial, concept that the final conduit for electron transfer to Fe(III) oxides are electrically conductive pili. The specific objectives were to: 1) further evaluate the conductivity along the pili of Geobacter sulfurreducens and related organisms; 2) determine the mechanisms for pili conductivity; and 3) investigate the role of pili in Fe(III) oxide reduction. The studies demonstrated that the pili of G. sulfurreducens are conductive along their length. Surprisingly, the pili possess a metallic-like conductivity similar to that observed in synthetic organic conducting polymers such as polyaniline. Detailed physical analysis of the pili, as well as studies in which the structure of the pili was genetically modified, demonstrated that the metallic-like conductivity of the pili could be attributed to overlapping pi-pi orbitals of aromatic amino acids. Other potential mechanisms for conductivity, such as electron hopping between cytochromes associated with the pili were definitively ruled out. Pili were also found to be essential for Fe(III) oxide reduction in G. metallireducens. Ecological studies demonstrated that electron conduction along pili is a better strategy for Fe(III) oxide reduction under conditions found in the subsurface than producing an electron shuttle. The role of pili in uranium reduction was also elucidated. Our results are the first example of metallic-like conductivity in a biological protein and represent a paradigm shift in the understanding of long-range biological electron transport. The results are of importance not only for understanding subsurface microbial processes involved in the mobility of metal contaminants and carbon cycling, but also make a basic contribution to microbiology and the emerging field of bioelectronics.« less

Study on Formation Mechanism of CaO-SiO2-Based Inclusions in Saw Wire Steel

NASA Astrophysics Data System (ADS)

Wang, Kun-Peng; Jiang, Min; Wang, Xin-Hua; Wang, Ying; Zhao, Hao-Qian; Cao, Zhan-Min

2017-12-01

Attempts were made to elucidate the formation mechanism of CaO-SiO2-based inclusions in saw wires by both laboratory experiments and industrial trials. The key point was to make clear the origin of CaO in such oxide inclusions. Probable origins of [Ca] in steel were first discussed, which can be taken into steel from the steel-slag reaction or ferrous alloy. As a result, slag-steel chemical reaction equilibrium was carefully evaluated at 1873 K (1600 °C) to classify the changes of dissolved aluminum ([Al]), total magnesium (Mg), and total calcium (Ca) in steel and the caused composition variations of inclusions. With the rise of slag basicity from 0.5 to 1.8, [Al] was remarkably increased from 0.00045 to 0.00139 mass pct, whereas Mg varied in the range of 0.00038 to 0.00048 mass pct. By contrast, Ca was constantly kept below 0.00003 mass pct. Accordingly, Al2O3 and MgO in inclusions witnessed obvious rises from 5 to 23 mass pct and from 2 to 8 mass pct, respectively. By contrast, inclusions were free of CaO when slag basicity was below 1.5. With slag basicity further increased to 1.8, CaO witnessed a negligible rise to only 1.0 mass pct on average. This phenomenon agreed well with thermodynamic calculations, which revealed that chemical reaction between steel and CaO in slag (for example, between [Si] and CaO) was weak to hardly supplying sufficient [Ca] to steel to increase CaO in inclusions. Ca contained in ferrous alloys as contaminations was not the cause of CaO-SiO2-based inclusions, either. The industrial trial results indicated that CaO-SiO2-based inclusions have been readily produced in short time just after BOF tapping. Also, a percentage of them changed slightly with the proceeding of refining. Based on the good agreement of laboratory, industrial, and thermodynamics calculations results, it can be reasonably concluded that CaO-SiO2-based inclusions in saw wire were exogenous particles from entrapped/emulsified top slag, but not products of slag-steel-inclusion chemical reactions.

Frequency sensitive mechanism in low-intensity ultrasound enhanced bioeffects

PubMed Central

Chama, Abdoulkadri; Subramanian, Anuradha; Viljoen, Hendrik J.

2017-01-01

This study presents two novel theoretical models to elucidate frequency sensitive nuclear mechanisms in low-intensity ultrasound enhanced bioeffects. In contrast to the typical 1.5 MHz pulsed ultrasound regime, our group previously experimentally confirmed that ultrasound stimulation of anchored chondrocytes at resonant frequency maximized gene expression of load inducible genes which are regulatory markers for cellular response to external stimuli. However, ERK phosphorylation displayed no frequency dependency, suggesting that the biochemical mechanisms involved in enhanced gene expression is downstream of ERK phosphorylation. To elucidate such underlying mechanisms, this study presents a theoretical model of an anchored cell, representing an in vitro chondrocyte, in an ultrasound field. The model results showed that the mechanical energy storage is maximized at the chondrocyte’s resonant frequency and the energy density in the nucleus is almost twice as high as in the cytoplasm. Next, a mechanochemical model was developed to link the mechanical stimulation of ultrasound and the increased mechanical energy density in the nucleus to the downstream targets of the ERK pathway. This study showed for the first time that ultrasound stimulation induces frequency dependent gene expression as a result of altered rates of transcription factors binding to chromatin. PMID:28763448

Computational mass spectrometry for small molecules

PubMed Central

2013-01-01

The identification of small molecules from mass spectrometry (MS) data remains a major challenge in the interpretation of MS data. This review covers the computational aspects of identifying small molecules, from the identification of a compound searching a reference spectral library, to the structural elucidation of unknowns. In detail, we describe the basic principles and pitfalls of searching mass spectral reference libraries. Determining the molecular formula of the compound can serve as a basis for subsequent structural elucidation; consequently, we cover different methods for molecular formula identification, focussing on isotope pattern analysis. We then discuss automated methods to deal with mass spectra of compounds that are not present in spectral libraries, and provide an insight into de novo analysis of fragmentation spectra using fragmentation trees. In addition, this review shortly covers the reconstruction of metabolic networks using MS data. Finally, we list available software for different steps of the analysis pipeline. PMID:23453222

The Past Achievements and Future Promises of Developmental Psychopathology: The Coming of Age of a Discipline

PubMed Central

Cicchetti, Dante; Toth, Sheree L.

2012-01-01

Over the past decades, developmental psychopathology has coalesced into a discipline that has made significant contributions toward the understanding of risk, psychopathology, and resilience in individuals across the life course. The overarching goal of the discipline has been to elucidate the interplay among biological, psychological, and social-contextual aspects of normal and abnormal development. In addition to directing efforts toward bridging fields of study and aiding in elucidating important truths about the processes underlying adaptation and maladaptation, investigators in developmental psychopathology have been equally devoted to developing and evaluating methods for preventing and ameliorating maladaptive and psychopathological outcomes. Increasingly, efforts are being made to conduct investigations at multiple levels of analysis and to translate basic research knowledge into real world contexts. In this article, the contributions, challenges, and future directions of the field are highlighted. PMID:19175810

Protein–protein interactions and selection: yeast-based approaches that exploit guanine nucleotide-binding protein signaling.

PubMed

Ishii, Jun; Fukuda, Nobuo; Tanaka, Tsutomu; Ogino, Chiaki; Kondo, Akihiko

2010-05-01

For elucidating protein–protein interactions, many methodologies have been developed during the past two decades. For investigation of interactions inside cells under physiological conditions, yeast is an attractive organism with which to quickly screen for hopeful candidates using versatile genetic technologies, and various types of approaches are now available.Among them, a variety of unique systems using the guanine nucleotide-binding protein (G-protein) signaling pathway in yeast have been established to investigate the interactions of proteins for biological study and pharmaceutical research. G-proteins involved in various cellular processes are mainly divided into two groups: small monomeric G-proteins,and heterotrimeric G-proteins. In this minireview, we summarize the basic principles and applications of yeast-based screening systems, using these two types of G-protein, which are typically used for elucidating biological protein interactions but are differentiated from traditional yeast two-hybrid systems.

Thermodynamic models to elucidate the enantioseparation of drugs with two stereogenic centers by micellar electrokinetic chromatography.

PubMed

Guo, Xuming; Liu, Qiuxia; Hu, Shaoqiang; Guo, Wenbo; Yang, Zhuo; Zhang, Yonghua

2017-08-25

An equilibrium model depicting the simultaneous protonation of chiral drugs and partitioning of protonated ions and neutral molecules into chiral micelles in micellar electrokinetic chromatography (MEKC) has been introduced. It was used for the prediction and elucidation of complex changes in migration order patterns with experimental conditions in the enantioseparation of drugs with two stereogenic centers. Palonosetron hydrochloride (PALO), a weakly basic drug with two stereogenic centers, was selected as a model drug. Its four stereoisomers were separated by MEKC using sodium cholate (SC) as chiral selector and surfactant. Based on the equilibrium model, equations were derived for a calculation of the effective mobility and migration time of each stereoisomer at a certain pH. The migration times of four stereoisomers at different pHs were calculated and then the migration order patterns were constructed with derived equations. The results were in accord with the experiment. And the contribution of each mechanism to the separation and its influence on the migration order pattern was analyzed separately by introducing virtual isomers, i.e., hypothetical stereoisomers with only one parameter changed relative to a real PALO stereoisomer. A thermodynamic model for a judgment of the correlation of interactions between two stereogenic centers of stereoisomers and chiral selector was also proposed. According to this model, the interactions of two stereogenic centers of PALO stereoisomers in both neutral molecules and protonated ions with chiral selector are not independent, so the chiral recognition in each pair of enantiomers as well as the recognition for diastereomers is not simply the algebraic sum of the contributions of two stereogenic centers due to their correlation. Copyright © 2017 Elsevier B.V. All rights reserved.

Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

PubMed

Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

2016-09-01

Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

Shock and Impact Response of Naval Composite Structures

DTIC Science & Technology

2010-08-09

elucidating physical mechanisms that control the survivability of composite structures under blast and impact. TECHNICAL APPROACH The Principal...the Proceedings of the 16th International Conference on Composite Structures , Kyoto, Japan, July 8-13, 2007. D. ONR Solid Mechanics Program...ONR Solid Mechanics Program Review, Marine Composites and Sandwich Structures , University of Maryland University College, Adelphi, MD, September 21

Illustrating the Basic Functioning of Mass Analyzers in Mass Spectrometers with Ball-Rolling Mechanisms

ERIC Educational Resources Information Center

Horikoshi, Ryo; Takeiri, Fumitaka; Mikita, Riho; Kobayashi, Yoji; Kageyama, Hiroshi

2017-01-01

A unique demonstration with ball-rolling mechanisms has been developed to illustrate the basic principles of mass analyzers as components of mass spectrometers. Three ball-rolling mechanisms mimicking the currently used mass analyzers (i.e., a quadrupole mass filter, a magnetic sector, and a time-of- flight) have been constructed. Each mechanism…

The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration

PubMed Central

2013-01-01

Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration. PMID:23829673

Cranial Radiation Therapy and Damage to Hippocampal Neurogenesis

ERIC Educational Resources Information Center

Monje, Michelle

2008-01-01

Cranial radiation therapy is associated with a progressive decline in cognitive function, prominently memory function. Impairment of hippocampal neurogenesis is thought to be an important mechanism underlying this cognitive decline. Recent work has elucidated the mechanisms of radiation-induced failure of neurogenesis. Potential therapeutic…

TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS IN RAT LIVERS ACCURATELY CATEGORIZES CHEMICALS AND IDENTIFIES MECHANISMS OF TOXICITY

EPA Science Inventory

Toxicogenomic analysis of five environmental chemicals was performed to investigate the ability of genomics to predict toxicity, categorize chemicals, and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole, and triadimefon) and two perfluori...

Studying mechanism of radical reactions: From radiation to nitroxides as research tools

NASA Astrophysics Data System (ADS)

Maimon, Eric; Samuni, Uri; Goldstein, Sara

2018-02-01

Radicals are part of the chemistry of life, and ionizing radiation chemistry serves as an indispensable research tool for elucidation of the mechanism(s) underlying their reactions. The ever-increasing understanding of their involvement in diverse physiological and pathological processes has expanded the search for compounds that can diminish radical-induced damage. This review surveys the areas of research focusing on radical reactions and particularly with stable cyclic nitroxide radicals, which demonstrate unique antioxidative activities. Unlike common antioxidants that are progressively depleted under oxidative stress and yield secondary radicals, nitroxides are efficient radical scavengers yielding in most cases their respective oxoammonium cations, which are readily reduced back in the tissue to the nitroxide thus continuously being recycled. Nitroxides, which not only protect enzymes, cells, and laboratory animals from diverse kinds of biological injury, but also modify the catalytic activity of heme enzymes, could be utilized in chemical and biological systems serving as a research tool for elucidating mechanisms underlying complex chemical and biochemical processes.

Early T-cell activation biophysics

PubMed Central

Henry, Nelly; Hivroz, Claire

2009-01-01

The T-cell is one of the main players in the mammalian immune response. It ensures antigen recognition at the surface of antigen-presenting cells in a complex and highly sensitive and specific process, in which the encounter of the T-cell receptor with the agonist peptide associated with the major histocompatibility complex triggers T-cell activation. While signaling pathways have been elucidated in increasing detail, the mechanism of TCR triggering remains highly controversial despite active research published in the past 10 years. In this paper, we present a short overview of pending questions on critical initial events associated with T-cell triggering. In particular, we examine biophysical approaches already in use, as well as future directions. We suggest that the most recent advances in fluorescence super-resolution imaging, coupled with the new classes of genetic fluorescent probes, will play an important role in elucidation of the T-cell triggering mechanism. Beyond this aspect, we predict that exploration of mechanical cues in the triggering process will provide new clues leading to clarification of the entire mechanism. PMID:20514131

Advanced research technology for discovery of new effective compounds from Chinese herbal medicine and their molecular targets.

PubMed

Wong, Vincent Kam-Wai; Law, Betty Yuen-Kwan; Yao, Xiao-Jun; Chen, Xi; Xu, Su Wei; Liu, Liang; Leung, Elaine Lai-Han

2016-09-01

Traditional biotechnology has been utilized by human civilization for long in wide aspects of our daily life, such as wine and vinegar production, which can generate new phytochemicals from natural products using micro-organism. Today, with advanced biotechnology, diverse applications and advantages have been exhibited not only in bringing benefits to increase the diversity and composition of herbal phytochemicals, but also helping to elucidate the treatment mechanism and accelerate new drug discovery from Chinese herbal medicine (CHM). Applications on phytochemical biotechnologies and microbial biotechnologies have been promoted to enhance phytochemical diversity. Cell labeling and imaging technology and -omics technology have been utilized to elucidate CHM treatment mechanism. Application of computational methods, such as chemoinformatics and bioinformatics provide new insights on direct target of CHM. Overall, these technologies provide efficient ways to overcome the bottleneck of CHM, such as helping to increase the phytochemical diversity, match their molecular targets and elucidate the treatment mechanism. Potentially, new oriented herbal phytochemicals and their corresponding drug targets can be identified. In perspective, tighter integration of multi-disciplinary biotechnology and computational technology will be the cornerstone to accelerate new arena formation, advancement and revolution in the fields of CHM and world pharmaceutical industry. Copyright © 2016 Elsevier Ltd. All rights reserved.

A tribute to Ulrich Heber (1930-2016) for his contribution to photosynthesis research: understanding the interplay between photosynthetic primary reactions, metabolism and the environment.

PubMed

Dietz, Karl-Josef; Krause, G Heinrich; Siebke, Katharina; Krieger-Liszkay, Anja

2018-07-01

The dynamic and efficient coordination of primary photosynthetic reactions with leaf energization and metabolism under a wide range of environmental conditions is a fundamental property of plants involving processes at all functional levels. The present historical perspective covers 60 years of research aiming to understand the underlying mechanisms, linking major breakthroughs to current progress. It centers on the contributions of Ulrich Heber who had pioneered novel concepts, fundamental methods, and mechanistic understanding of photosynthesis. An important first step was the development of non-aqueous preparation of chloroplasts allowing the investigation of chloroplast metabolites ex vivo (meaning that the obtained results reflect the in vivo situation). Later on, intact chloroplasts, retaining their functional envelope membranes, were isolated in aqueous media to investigate compartmentation and exchange of metabolites between chloroplasts and external medium. These studies elucidated metabolic interaction between chloroplasts and cytoplasm during photosynthesis. Experiments with isolated intact chloroplasts clarified that oxygenation of ribulose-1.5-bisphosphate generates glycolate in photorespiration. The development of non-invasive optical methods enabled researchers identifying mechanisms that balance electron flow in the photosynthetic electron transport system avoiding its over-reduction. Recording chlorophyll a (Chl a) fluorescence allowed one to monitor, among other parameters, thermal energy dissipation by means of 'nonphotochemical quenching' of the excited state of Chl a. Furthermore, studies both in vivo and in vitro led to basic understanding of the biochemical mechanisms of freezing damage and frost tolerance of plant leaves, to SO 2 tolerance of tree leaves and dehydrating lichens and mosses.

Circadian Rhythm Connections to Oxidative Stress: Implications for Human Health

PubMed Central

Wilking, Melissa; Ndiaye, Mary; Mukhtar, Hasan

2013-01-01

Abstract Significance: Oxygen and circadian rhythmicity are essential in a myriad of physiological processes to maintain homeostasis, from blood pressure and sleep/wake cycles, down to cellular signaling pathways that play critical roles in health and disease. If the human body or cells experience significant stress, their ability to regulate internal systems, including redox levels and circadian rhythms, may become impaired. At cellular as well as organismal levels, impairment in redox regulation and circadian rhythms may lead to a number of adverse effects, including the manifestation of a variety of diseases such as heart diseases, neurodegenerative conditions, and cancer. Recent Advances: Researchers have come to an understanding as to the basics of the circadian rhythm mechanism, as well as the importance of the numerous species of oxidative stress components. The effects of oxidative stress and dysregulated circadian rhythms have been a subject of intense investigations since they were first discovered, and recent investigations into the molecular mechanisms linking the two have started to elucidate the bases of their connection. Critical Issues: While much is known about the mechanics and importance of oxidative stress systems and circadian rhythms, the front where they interact has had very little research focused on it. This review discusses the idea that these two systems are together intricately involved in the healthy body, as well as in disease. Future Directions: We believe that for a more efficacious management of diseases that have both circadian rhythm and oxidative stress components in their pathogenesis, targeting both systems in tandem would be far more successful. Antioxid. Redox Signal. 19, 192–208 PMID:23198849

Halophilic mechanism of the enzymatic function of a moderately halophilic dihydrofolate reductase from Haloarcula japonica strain TR-1.

PubMed

Miyashita, Yurina; Ohmae, Eiji; Ikura, Teikichi; Nakasone, Kaoru; Katayanagi, Katsuo

2017-05-01

Dihydrofolate (DHF) reductase coded by a plasmid of the extremely halophilic archaeon Haloarcula japonica strain TR-1 (HjDHFR P1) shows moderate halophilicity on enzymatic activity at pH 6.0, although there is no significant effect of NaCl on its secondary structure. To elucidate the salt-activation and -inactivation mechanisms of this enzyme, we investigated the effects of pH and salt concentration, deuterium isotope effect, steady-state kinetics, and rapid-phase ligand-binding kinetics. Enzyme activity was increased eightfold by the addition of 500 mM NaCl at pH 6.0, fourfold by 250 mM at pH 8.0, and became independent of salt concentration at pH 10.0. Full isotope effects observed at pH 10.0 under 0-1000 mM NaCl indicated that the rate of hydride transfer, which was the rate-determining step at the basic pH region, was independent of salt concentration. Conversely, rapid-phase ligand-binding experiments showed that the amplitude of the DHF-binding reaction increased and the tetrahydrofolate (THF)-releasing rate decreased with increasing NaCl concentration. These results suggested that the salt-activation mechanism of HjDHFR P1 is via the population change of the anion-unbound and anion-bound conformers, which are binding-incompetent and -competent conformations for DHF, respectively, while that of salt inactivation is via deceleration of the THF-releasing rate, which is the rate-determining step at the neutral pH region.

Massage therapy: understanding the mechanisms of action on blood pressure. A scoping review.

PubMed

Nelson, Nicole L

2015-10-01

Massage therapy (MT) has shown potential in reducing blood pressure (BP); however, the psychophysiological pathways and structures involved in this outcome are unclear. The aims of this scoping review were twofold. (1) To summarize the current knowledge of the mechanisms of action of MT on BP. (2) To highlight the research gaps and challenges that researchers must overcome to further elucidate how MT attenuates BP. A scoping review was conducted to examine the evidence regarding the mechanisms of action of MT on BP. This review included the thematic analysis of 27 publications that considered the influence of MT on BP. Based on this analysis, six potential BP mediating pathways were identified Current theories suggest that MT exerts sympatholytic effects through physiologic and psychological mechanisms, improves hypothalamus-pituitary-adrenocortical axis function, and increases in blood flow, which, in turn, may improve endothelial function. Future study is needed, using more scientifically rigorous methodology, to fully elucidate the mechanism of action of MT. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

Study of the Stereochemistry and Oxidation Mechanism of Plant Polyphenols, Assisted by Computational Chemistry.

PubMed

Matsuo, Yosuke

2017-01-01

In recent years, plant polyphenols have attracted great attention due to their wide range of biological activities. Certain kinds of polyphenols have complex structures; therefore, it is difficult to elucidate their total structure, including stereochemistry. In this study, we reinvestigated the stereostructures of two major C-glycosidic ellagitannins contained in Quercus plants, vescalagin and castalagin, and revised their stereostructures based on theoretical calculations of spectroscopic data. We also determined the structures of quercusnins A and B, isolated from the sapwood of Quercus crispula, based on theoretical calculations of NMR data. The oxidation mechanism of polyphenols has not been entirely elucidated. Therefore, we have also studied the oxidation mechanism of tea catechins during black tea production. Our investigation of the oxidation mechanism of black tea pigment theaflavins revealed that the difference in the position of the galloyl ester affords different oxidation products of theaflavins. In addition, oxidation products of pyrogallol-type catechins could be classified into three types-dehydrotheasinensins, theacitrins, and proepitheaflagallins; their detailed production and degradation mechanisms were also examined.

Journey of a molecular biologist.

PubMed

Nomura, Masayasu

2011-01-01

My journey into a research career began in fermentation biochemistry in an applied science department during the difficult post-World War II time in Japan. Subsequently, my desire to do research in basic science developed. I was fortunate to be a postdoctoral fellow in the United States during the early days of molecular biology. From 1957 to 1960, I worked with three pioneers of molecular biology, Sol Spiegelman, James Watson, and Seymour Benzer. These experiences helped me develop into a basic research scientist. My initial research projects at Osaka University, and subsequently at the University of Wisconsin, Madison, were on the mode of action of colicins as well as on mRNA and ribosomes. Following success in the reconstitution of ribosomal subunits, my efforts focused more on ribosomes, initially on the aspects of structure, function, and in vitro assembly, such as the construction of the 30S subunit assembly map. After this, my laboratory studied the regulation of the synthesis of ribosomes and ribosomal components in Escherichia coli. Our achievements included the discovery of translational feedback regulation of ribosomal protein synthesis and the identification of several repressor ribosomal proteins used in this regulation. In 1984, I moved to the University of California, Irvine, and initiated research on rRNA transcription by RNA polymerase I in the yeast Saccharomyces cerevisiae. The use of yeast genetics combined with biochemistry allowed us to identify genes uniquely involved in rRNA synthesis and to elucidate the mechanism of initiation of transcription. This essay is a reflection on my life as a research scientist.

An overview of plant volatile metabolomics, sample treatment and reporting considerations with emphasis on mechanical damage and biological control of weeds.

PubMed

Beck, John J; Smith, Lincoln; Baig, Nausheena

2014-01-01

The technology for the collection and analysis of plant-emitted volatiles for understanding chemical cues of plant-plant, plant-insect or plant-microbe interactions has increased over the years. Consequently, the in situ collection, analysis and identification of volatiles are considered integral to elucidation of complex plant communications. Due to the complexity and range of emissions the conditions for consistent emission of volatiles are difficult to standardise. To discuss: evaluation of emitted volatile metabolites as a means of screening potential target- and non-target weeds/plants for insect biological control agents; plant volatile metabolomics to analyse resultant data; importance of considering volatiles from damaged plants; and use of a database for reporting experimental conditions and results. Recent literature relating to plant volatiles and plant volatile metabolomics are summarised to provide a basic understanding of how metabolomics can be applied to the study of plant volatiles. An overview of plant secondary metabolites, plant volatile metabolomics, analysis of plant volatile metabolomics data and the subsequent input into a database, the roles of plant volatiles, volatile emission as a function of treatment, and the application of plant volatile metabolomics to biological control of invasive weeds. It is recommended that in addition to a non-damaged treatment, plants be damaged prior to collecting volatiles to provide the greatest diversity of odours. For the model system provided, optimal volatile emission occurred when the leaf was punctured with a needle. Results stored in a database should include basic environmental conditions or treatments. Copyright © 2013 John Wiley & Sons, Ltd.

Nanometer-scale mapping of irreversible electrochemical nucleation processes on solid Li-ion electrolytes

NASA Astrophysics Data System (ADS)

Kumar, Amit; Arruda, Thomas M.; Tselev, Alexander; Ivanov, Ilia N.; Lawton, Jamie S.; Zawodzinski, Thomas A.; Butyaev, Oleg; Zayats, Sergey; Jesse, Stephen; Kalinin, Sergei V.

2013-04-01

Electrochemical processes associated with changes in structure, connectivity or composition typically proceed via new phase nucleation with subsequent growth of nuclei. Understanding and controlling reactions requires the elucidation and control of nucleation mechanisms. However, factors controlling nucleation kinetics, including the interplay between local mechanical conditions, microstructure and local ionic profile remain inaccessible. Furthermore, the tendency of current probing techniques to interfere with the original microstructure prevents a systematic evaluation of the correlation between the microstructure and local electrochemical reactivity. In this work, the spatial variability of irreversible nucleation processes of Li on a Li-ion conductive glass-ceramics surface is studied with ~30 nm resolution. An increased nucleation rate at the boundaries between the crystalline AlPO4 phase and amorphous matrix is observed and attributed to Li segregation. This study opens a pathway for probing mechanisms at the level of single structural defects and elucidation of electrochemical activities in nanoscale volumes.

Operating Mechanisms of Mesoscopic Perovskite Solar Cells through Impedance Spectroscopy and J-V Modeling.

PubMed

Zarazúa, Isaac; Sidhik, Siraj; Lopéz-Luke, Tzarara; Esparza, Diego; De la Rosa, Elder; Reyes-Gomez, Juan; Mora-Seró, Iván; Garcia-Belmonte, Germà

2017-12-21

The performance of perovskite solar cell (PSC) is highly sensitive to deposition conditions, the substrate, humidity, and the efficiency of solvent extraction. However, the physical mechanism involved in the observed changes of efficiency with different deposition conditions has not been elucidated yet. In this work, PSCs were fabricated by the antisolvent deposition (AD) and recently proposed air-extraction antisolvent (AAD) process. Impedance analysis and J-V curve fitting were used to analyze the photogeneration, charge transportation, recombination, and leakage properties of PSCs. It can be elucidated that the improvement in morphology of perovskite film promoted by AAD method leads to increase in light absorption, reduction in recombination sites, and interstitial defects, thus enhancing the short-circuit current density, open-circuit voltage, and fill factor. This study will open up doors for further improvement of device and help in understanding its physical mechanism and its relation to the deposition methods.

Nanometer-scale mapping of irreversible electrochemical nucleation processes on solid Li-ion electrolytes.

PubMed

Kumar, Amit; Arruda, Thomas M; Tselev, Alexander; Ivanov, Ilia N; Lawton, Jamie S; Zawodzinski, Thomas A; Butyaev, Oleg; Zayats, Sergey; Jesse, Stephen; Kalinin, Sergei V

2013-01-01

Electrochemical processes associated with changes in structure, connectivity or composition typically proceed via new phase nucleation with subsequent growth of nuclei. Understanding and controlling reactions requires the elucidation and control of nucleation mechanisms. However, factors controlling nucleation kinetics, including the interplay between local mechanical conditions, microstructure and local ionic profile remain inaccessible. Furthermore, the tendency of current probing techniques to interfere with the original microstructure prevents a systematic evaluation of the correlation between the microstructure and local electrochemical reactivity. In this work, the spatial variability of irreversible nucleation processes of Li on a Li-ion conductive glass-ceramics surface is studied with ~30 nm resolution. An increased nucleation rate at the boundaries between the crystalline AlPO4 phase and amorphous matrix is observed and attributed to Li segregation. This study opens a pathway for probing mechanisms at the level of single structural defects and elucidation of electrochemical activities in nanoscale volumes.

Nanometer-scale mapping of irreversible electrochemical nucleation processes on solid Li-ion electrolytes

PubMed Central

Kumar, Amit; Arruda, Thomas M.; Tselev, Alexander; Ivanov, Ilia N.; Lawton, Jamie S.; Zawodzinski, Thomas A.; Butyaev, Oleg; Zayats, Sergey; Jesse, Stephen; Kalinin, Sergei V.

2013-01-01

Electrochemical processes associated with changes in structure, connectivity or composition typically proceed via new phase nucleation with subsequent growth of nuclei. Understanding and controlling reactions requires the elucidation and control of nucleation mechanisms. However, factors controlling nucleation kinetics, including the interplay between local mechanical conditions, microstructure and local ionic profile remain inaccessible. Furthermore, the tendency of current probing techniques to interfere with the original microstructure prevents a systematic evaluation of the correlation between the microstructure and local electrochemical reactivity. In this work, the spatial variability of irreversible nucleation processes of Li on a Li-ion conductive glass-ceramics surface is studied with ~30 nm resolution. An increased nucleation rate at the boundaries between the crystalline AlPO4 phase and amorphous matrix is observed and attributed to Li segregation. This study opens a pathway for probing mechanisms at the level of single structural defects and elucidation of electrochemical activities in nanoscale volumes. PMID:23563856

English: Basic Mechanics Modules 4 and 5.

ERIC Educational Resources Information Center

Pipeline, 1983

1983-01-01

"English: Basic Mechanics" is a series of computer-based lessons for the Apple II that allow students to practice applying the fundamentals of English grammar and punctuation. The two newest modules covering use of subordinate clauses and use of subordinate phrases are described. (JN)

Basic mechanisms governing solar-cell efficiency

NASA Technical Reports Server (NTRS)

Lindholm, F. A.; Neugroschel, A.; Sah, C. T.

1976-01-01

The efficiency of a solar cell depends on the material parameters appearing in the set of differential equations that describe the transport, recombination, and generation of electrons and holes. This paper describes the many basic mechanisms occurring in semiconductors that can control these material parameters.

Ductilisation of tungsten (W): Tungsten laminated composites

DOE PAGES

Reiser, Jens; Garrison, Lauren M.; Greuner, Henri; ...

2017-08-02

Here we elucidate the mechanisms of plastic deformation and fracture of tungsten laminated composites. Furthermore our results suggest that the mechanical response of the laminates is governed by the plastic deformation of the tungsten plies. In most cases, the impact of the interlayer is of secondary importance.

Cooperative Effects in Models of Steady-State Transport across Membranes

PubMed Central

Hill, Terrell L.; Chen, Yi-Der

1971-01-01

Several different one-site, two-site, and multisite models of steady-state ion transport across a membrane are investigated. The basic features, including cooperative interactions between channels, are the same as in earlier papers in this series. In particular, the present paper represents a considerable elaboration of part III. The models might apply to artificial or possibly to biological membranes, but particular applications must await further elucidation of the molecular structure and operation of these membranes. PMID:5132496

Reliability training

NASA Technical Reports Server (NTRS)

Lalli, Vincent R. (Editor); Malec, Henry A. (Editor); Dillard, Richard B.; Wong, Kam L.; Barber, Frank J.; Barina, Frank J.

1992-01-01

Discussed here is failure physics, the study of how products, hardware, software, and systems fail and what can be done about it. The intent is to impart useful information, to extend the limits of production capability, and to assist in achieving low cost reliable products. A review of reliability for the years 1940 to 2000 is given. Next, a review of mathematics is given as well as a description of what elements contribute to product failures. Basic reliability theory and the disciplines that allow us to control and eliminate failures are elucidated.

Virtual laboratory learning media development to improve science literacy skills of mechanical engineering students on basic physics concept of material measurement

NASA Astrophysics Data System (ADS)

Jannati, E. D.; Setiawan, A.; Siahaan, P.; Rochman, C.

2018-05-01

This study aims to determine the description of virtual laboratory learning media development to improve science literacy skills of Mechanical Engineering students on the concept of basic Physics. Quasi experimental method was employed in this research. The participants of this research were first semester students of mechanical engineering in Majalengka University. The research instrument was readability test of instructional media. The results of virtual laboratory learning media readability test show that the average score is 78.5%. It indicates that virtual laboratory learning media development are feasible to be used in improving science literacy skill of Mechanical Engineering students in Majalengka University, specifically on basic Physics concepts of material measurement.

Mechanism of Selenium Chemoprevention and Therapy in Prostate Cancer

DTIC Science & Technology

2010-11-01

06-1-0006 TITLE: Mechanism of Selenium Chemoprevention and Therapy in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Allen Gao...Introduction The goal of this application is to elucidate the importance of down regulation of AR signaling by multiple selenium compounds and...select the best leading selenium compound for prostate cancer chemoprevention and therapy. In this application, we will further study the mechanisms of

Neutrino-Induced Hydrogen Burning

NASA Astrophysics Data System (ADS)

Kishimoto, Chad T.; Fuller, George M.

2006-07-01

The principal hydrogen burning mechanisms that take place in stars have been elucidated and explored for many decades. However, the introduction of a prodigious flux of electron anti-neutrinos would significantly accelerate these mechanisms and change the path toward the production of an α particle. We discuss the nature of such changes in the hydrogen burning mechanisms, and the side effects spawned from such alterations.

Basic Automotive Mechanics. Florida Vocational Program Guide.

ERIC Educational Resources Information Center

University of South Florida, Tampa. Dept. of Adult and Vocational Education.

This program guide identifies primary concerns in the organization, operation, and evaluation of a basic automotive mechanics program. It is designed for local school district and community college administrators, instructors, program advisory committees, and regional coordinating councils. The guide begins with the Dictionary of Occupational…

Two new phenylpropanoid glycosides with interesterification from Scrophularia dentata Royle ex Benth

NASA Astrophysics Data System (ADS)

Zhang, Liuqiang; Yang, Zhuo; Jia, Qi; Dorje, Gaawe; Zhao, Zhili; Guo, Fujiang; Li, Yiming

2013-10-01

Two new phenylpropanoid glycosides (1-2), along with seven known ones (3-9), were isolated from the whole plant of Scrophularia dentata Royle ex Benth. Their structures were elucidated by spectroscopic methods. Among them, compounds 1 and 2 failed to separated, because they can easily transform into each other by acyl migrant reaction. In this paper, the interesterification mechanism was discussed firstly and the rule can be used in the similar structure elucidation in future.

[100] Directed Cu-doped h-CoO nanorods: elucidation of the growth mechanism and application to lithium-ion batteries.

PubMed

Nam, Ki Min; Choi, Young Cheol; Jung, Sung Chul; Kim, Yong-Il; Jo, Mi Ru; Park, Se Ho; Kang, Yong-Mook; Han, Young-Kyu; Park, Joon T

2012-01-21

Thermal decomposition of Co(acac)(3) and Cu(acac)(2) in benzylamine leads to the formation of [100] directed Cu-doped h-CoO nanorods, which are very stable in an aqueous solution. The formation mechanism of the [100] directed Cu-doped h-CoO nanorods is fully elucidated by using first-principles calculations, demonstrating that Cu-doping not only changes the growth direction but also enhances the stability of the nanorods significantly. Evaluation of the electrochemical performance of Cu-doped h-CoO nanorods shows high initial Coulombic efficiency and ultrahigh capacity with excellent cycling performance, indicating their suitability as an anode material for next generation lithium-ion batteries.

Mechanical design of deformation compensated flexural pivots structured for linear nanopositioning stages

DOEpatents

Shu, Deming; Kearney, Steven P.; Preissner, Curt A.

2015-02-17

A method and deformation compensated flexural pivots structured for precision linear nanopositioning stages are provided. A deformation-compensated flexural linear guiding mechanism includes a basic parallel mechanism including a U-shaped member and a pair of parallel bars linked to respective pairs of I-link bars and each of the I-bars coupled by a respective pair of flexural pivots. The basic parallel mechanism includes substantially evenly distributed flexural pivots minimizing center shift dynamic errors.

DNAPL REMOVAL MECHANISMS AND MASS TRANSFER CHARACTERISTICS DURING COSOLVENT-AIR FLOODING

EPA Science Inventory

The concurrent injection of cosolvent and air, a cosolvent-air (CA) flood was recently suggested for a dense nonaqueous phase liquid (DNAPL) remediation technology. The objectives of this study were to elucidate the DNAPL removal mechanisms of the CA flood and to quantify mass t...

Degradation Mechanism of Cyanobacterial Toxin Cylindrospermopsin by Hydroxyl Radicals in Homogeneous UV/H2O2 Process

EPA Science Inventory

The degradation of cylindrospermopsin (CYN), a widely distributed and highly toxic cyanobacterial toxin (cyanotoxin), remains poorly elucidated. In this study, the mechanism of CYN destruction by UV-254 nm/H2O2 advanced oxidation process (AOP) was investigated by mass spectrometr...

[The development of molecular human genetics and its significance for perspectives of modern medicine].

PubMed

Coutelle, C; Speer, A; Grade, K; Rosenthal, A; Hunger, H D

1989-01-01

The introduction of molecular human genetics has become a paradigma for the application of genetic engineering in medicine. The main principles of this technology are the isolation of molecular probes, their application in hybridization reactions, specific gene-amplification by the polymerase chain reaction, and DNA sequencing reactions. These methods are used for the analysis of monogenic diseases by linkage studies and the elucidation of the molecular defect causing these conditions, respectively. They are also the basis for genomic diagnosis of monogenic diseases, introduced into the health care system of the GDR by a national project on Duchenne/Becker muscular dystrophy, Cystic Fibrosis and Phenylketonuria. The rapid development of basic research on the molecular analysis of the human genome and genomic diagnosis indicates, that human molecular genetics is becoming a decisive basic discipline of modern medicine.

More similar than you think: Frog metamorphosis as a model of human perinatal endocrinology.

PubMed

Buchholz, Daniel R

2015-12-15

Hormonal control of development during the human perinatal period is critically important and complex with multiple hormones regulating fetal growth, brain development, and organ maturation in preparation for birth. Genetic and environmental perturbations of such hormonal control may cause irreversible morphological and physiological impairments and may also predispose individuals to diseases of adulthood, including diabetes and cardiovascular disease. Endocrine and molecular mechanisms that regulate perinatal development and that underlie the connections between early life events and adult diseases are not well elucidated. Such mechanisms are difficult to study in uterus-enclosed mammalian embryos because of confounding maternal effects. To elucidate mechanisms of developmental endocrinology in the perinatal period, Xenopus laevis the African clawed frog is a valuable vertebrate model. Frogs and humans have identical hormones which peak at birth and metamorphosis, have conserved hormone receptors and mechanisms of gene regulation, and have comparable roles for hormones in many target organs. Study of molecular and endocrine mechanisms of hormone-dependent development in frogs is advantageous because an extended free-living larval period followed by metamorphosis (1) is independent of maternal endocrine influence, (2) exhibits dramatic yet conserved developmental effects induced by thyroid and glucocorticoid hormones, and (3) begins at a developmental stage with naturally undetectable hormone levels, thereby facilitating endocrine manipulation and interpretation of results. This review highlights the utility of frog metamorphosis to elucidate molecular and endocrine actions, hormone interactions, and endocrine disruption, especially with respect to thyroid hormone. Knowledge from the frog model is expected to provide fundamental insights to aid medical understanding of endocrine disease, stress, and endocrine disruption affecting the perinatal period in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

Mechanism of three-component collision to produce ultrastable pRNA three-way junction of Phi29 DNA-packaging motor by kinetic assessment

PubMed Central

Binzel, Daniel W.; Khisamutdinov, Emil; Vieweger, Mario; Ortega, Janice; Li, Jingyuan; Guo, Peixuan

2016-01-01

RNA nanotechnology is rapidly emerging. Due to advantageous pharmacokinetics and favorable in vivo biodistribution, RNA nanoparticles have shown promise in targeted delivery of therapeutics. RNA nanotechnology applies bottom-up assembly, thus elucidation of the mechanism of interaction between multiple components is of fundamental importance. The tendency of diminishing concern about RNA instability has accelerated by the finding of the novel thermostable three-way junction (3WJ) motif of the phi29 DNA-packaging motor. The kinetics of these three components, each averaging 18 nucleotides (nt), was investigated to elucidate the mechanism for producing the stable 3WJ. The three fragments coassembled into the 3WJ with extraordinary speed and affinity via a two-step reaction mechanism, 3WJb + 3WJc ↔ 3WJbc + 3WJa ↔ 3WJabc. The first step of reaction between 3WJb and 3WJc is highly dynamic since these two fragments only contain 8 nt for complementation. In the second step, the 3WJa, which contains 17 nt complementary to the 3WJbc complex, locks the unstable 3WJbc complex into a highly stable 3WJ. The resulting pRNA-3WJ is more stable than any of the dimer species as shown in the much more rapid association rates and slowest dissociation rate constant. The second step occurs at a very high association rate that is difficult to quantify, resulting in a rapid formation of a stable 3WJ. Elucidation of the mechanism of three-component collision in producing the ultrastable 3WJ proves a promising platform for bottom-up assembly of RNA nanoparticles as a new class of anion polymers for material science, electronic elements, or therapeutic reagents. PMID:27672132

Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/MM) modelling.

PubMed

Lodola, Alessio; Mor, Marco; Sirirak, Jitnapa; Mulholland, Adrian J

2009-04-01

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the carbamoylating compound URB524. These are potentially crucial insights for designing new covalent inhibitors of this drug target.

Preventing Cartilage Degeneration in Warfighters by Elucidating Novel Mechanisms Regulating Osteocyte-Mediated Perilacunar Bone Remodeling

DTIC Science & Technology

2015-10-01

quality, and cartilage health in post-traumatic osteoarthritis (PTOA). Few molecular details are known about the regulation of PLR or bone quality...degeneration. 15. SUBJECT TERMS Osteocyte, remodeling, bone, bone quality, post-traumatic osteoarthritis , TGF-beta, mechanical load, matrix...joint health, and their contribution to post-traumatic osteoarthritis (PTOA). Osteocytes sense and respond to mechanical loads, and they are also

Investigation of wear phenomena by microscopy

NASA Technical Reports Server (NTRS)

Buckley, D. H.

1982-01-01

The various wear mechanisms involved in the loss of material from metallic and nonmetallic surfaces are discussed. The results presented indicate how various microscopy techniques used in conjunction with other analytical tools can assist in the elucidation of a wear mechanism. Without question, microscopy is the single most important tool for the study of the wear of surfaces, to assess and address inherent mechanisms of the material removal process.

Validation and Interrogation of Differentially Expressed and Alternately Spliced Genes in African American Prostate Cancer

DTIC Science & Technology

2017-10-01

aggressive disease. 15. SUBJECT TERMS Prostate cancer, health disparities among racial groups, molecular mechanisms, differential gene expression...identify molecular mechanisms of tumor aggressiveness. The studies proposed here address the urgent need to elucidate the molecular mechanisms underlying... genetic /epigenetic/post-transcriptional factors in AA prostate cancer and Gleason grade and 2) manipulate splicing using novel splice-switching

Diesel Mechanics: Fundamentals.

ERIC Educational Resources Information Center

Foutes, William; And Others

This publication is the first in a series of three texts for a diesel mechanics curriculum. Its purpose is to teach the basic concepts related to employment in a diesel trade. Six sections contain 29 units. Each instructional unit includes some or all of these basic components: unit and specific (performance) objectives, suggested activities for…

Basic Gasoline Engine Mechanics. Florida Vocational Program Guide.

ERIC Educational Resources Information Center

University of South Florida, Tampa. Dept. of Adult and Vocational Education.

This packet contains a program guide and Career Merit Achievement Plan (Career MAP) for the implementation of a basic gasoline engine mechanics program in Florida secondary and postsecondary schools. The program guide describes the program content and structure, provides a program description, lists job titles under the program, and includes a…

Teaching Basic Quantum Mechanics in Secondary School Using Concepts of Feynman Path Integrals Method

ERIC Educational Resources Information Center

Fanaro, Maria de los Angeles; Otero, Maria Rita; Arlego, Marcelo

2012-01-01

This paper discusses the teaching of basic quantum mechanics in high school. Rather than following the usual formalism, our approach is based on Feynman's path integral method. Our presentation makes use of simulation software and avoids sophisticated mathematical formalism. (Contains 3 figures.)

Air Pollution.

ERIC Educational Resources Information Center

Scorer, Richard S.

The purpose of this book is to describe the basic mechanisms whereby pollution is transported and diffused in the atmosphere. It is designed to give practitioners an understanding of basic mechanics and physics so they may have a correct basis on which to formulate their decisions related to practical air pollution control problems. Since many…

Quantitative aspects of vibratory mobilization and break-up of non-wetting fluids in porous media

NASA Astrophysics Data System (ADS)

Deng, Wen

Seismic stimulation is a promising technology aimed to mobilize the entrapped non-wetting fluids in the subsurface. The applications include enhanced oil recovery or, alternatively, facilitation of movement of immiscible/partly-miscible gases far into porous media, for example, for CO2 sequestration. This work is devoted to detailed quantitative studies of the two basic pore-scale mechanisms standing behind seismic stimulation: the mobilization of bubbles or drops entrapped in pore constrictions by capillary forces and the break-up of continuous long bubbles or drops. In typical oil-production operations, oil is produced by the natural reservoir-pressure drive during the primary stage and by artificial water flooding at the secondary stage. Capillary forces act to retain a substantial residual fraction of reservoir oil even after water flooding. The seismic stimulation is an unconventional technology that serves to overcome capillary barriers in individual pores and liberate the entrapped oil by adding an oscillatory inertial forcing to the external pressure gradient. According to our study, the effect of seismic stimulation on oil mobilization is highly dependent on the frequencies and amplitudes of the seismic waves. Generally, the lower the frequency and the larger the amplitude, more effective is the mobilization. To describe the mobilization process, we developed two theoretical hydrodynamics-based models and justified both using computational fluid dynamics (CFD). Our theoretical models have a significant advantage over CFD in that they reduce the computational time significantly, while providing correct practical guidance regarding the required field parameters of vibroseismic stimulation, such as the amplitude and frequency of the seismic field. The models also provide important insights into the basic mechanisms governing the vibration-driven two-phase flow in constricted capillaries. In a waterflooded reservoir, oil can be recovered most efficiently by forming continuous streams from isolated droplets. The longer the continuous oil phase under a certain pressure gradient, the more easily it overcomes its capillary barrier. However, surface tension between water and oil causes the typically non-wetting oil, constituting the core phase in the channels, to break up at the pore constriction into isolated beads, which inhibits further motion. The break-up thus counteracts the mobilization. We developed a theoretical model that provides an exact quantitative description of the dynamics of the oil-snap-off process. It also formulates a purely geometric criterion that controls, based on pore geometry only, whether the oil core phase stays continuous or disintegrates into droplets. Both the theoretical model and the break-criterion have been validated against CFD simulations. The work completed elucidates the basic physical mechanisms behind the enhanced oil recovery by seismic waves and vibrations. This creates a theoretical foundation for the further development of corresponding field technologies.

Organization and integration of biomedical knowledge with concept maps for key peroxisomal pathways.

PubMed

Willemsen, A M; Jansen, G A; Komen, J C; van Hooff, S; Waterham, H R; Brites, P M T; Wanders, R J A; van Kampen, A H C

2008-08-15

One important area of clinical genomics research involves the elucidation of molecular mechanisms underlying (complex) disorders which eventually may lead to new diagnostic or drug targets. To further advance this area of clinical genomics one of the main challenges is the acquisition and integration of data, information and expert knowledge for specific biomedical domains and diseases. Currently the required information is not very well organized but scattered over biological and biomedical databases, basic text books, scientific literature and experts' minds and may be highly specific, heterogeneous, complex and voluminous. We present a new framework to construct knowledge bases with concept maps for presentation of information and the web ontology language OWL for the representation of information. We demonstrate this framework through the construction of a peroxisomal knowledge base, which focuses on four key peroxisomal pathways and several related genetic disorders. All 155 concept maps in our knowledge base are linked to at least one other concept map, which allows the visualization of one big network of related pieces of information. The peroxisome knowledge base is available from www.bioinformaticslaboratory.nl (Support-->Web applications). Supplementary data is available from www.bioinformaticslaboratory.nl (Research-->Output--> Publications--> KB_SuppInfo)

Selective influences of oxytocin on the evaluative processing of social stimuli

PubMed Central

Norman, Greg J; Cacioppo, John T; Morris, John S; Karelina, Kate; Malarkey, William B; DeVries, A Courtney; Berntson, Gary G

2013-01-01

The neuropeptide oxytocin has been implicated in a wide range of social processes, such as pair bonding, affiliation, and social judgments that may contribute to normal adjustment and psychiatric states. The present experimental study sought to elucidate potential underlying mechanisms by which oxytocin may impact social processes by examining the effects of intranasal oxytocin on basic evaluative processes. Subjects rated slide stimuli from the International Affective Picture System, varying across multiple categories (pleasant, neutral, unpleasant) and social content. Separate ratings for arousal and for the positive and negative components of valence were obtained in the context of a bivariate evaluative space model. Oxytocin did not have an independent significant effect on positivity or negativity ratings, but instead oxytocin treatment altered the interaction between these component processes for social, relative to non-social stimuli regardless of valence conditions. Specifically, oxytocin, relative to vehicle, significantly decreased arousal ratings to threatening human stimuli without altering ratings of threatening animal stimuli. These results indicate that oxytocin may exert its effects through dynamic alterations in the partially separable neural substrates mediating arousal as well as positive and negative evaluations of social stimuli. PMID:20498133

Magnetogenetics: Remote Control of Cellular Signaling with Magnetic Fields

NASA Astrophysics Data System (ADS)

Sauer, Jeremy P.

Means for temporally regulating gene expression and cellular activity are invaluable for elucidating the underlying physiological processes and have therapeutic implications. Here we report the development of a system for remote regulation of gene expression by low frequency radiowaves (RF) or by a static magnetic field. We accomplished this by first adding iron oxide nanoparticles - either exogenously or as genetically encoded ferritin/ferric oxyhydroxide particle. These particles have been designed with affinity to the plasma membrane ion channel Transient Receptor Potential Vanilloid 1 (TRPV1) by a conjugated antibody. Application of a magnetic field stimulates the particle to gate the ion channel and this, in turn, initiates calcium-dependent transgene expression. We first demonstrated in vitro that TRPV1 can be actuated to cause calcium flux into the cell by directly applying a localized magnetic field. In mice expressing these genetically encoded components, application of external magnetic field caused remote stimulation of insulin transgene expression and significantly lowered blood glucose. In addition, we are investigating mechanisms by which iron oxide nanoparticles can absorb RF, and transduce this energy to cause channel opening. This robust, repeatable method for remote cellular regulation in vivo may ultimately have applications in basic science, as well as in technology and therapeutics.

Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise.

PubMed

Giudicessi, John R; Ackerman, Michael J

2013-01-01

In this review, we summarize the basic principles governing rare variant interpretation in the heritable cardiac arrhythmia syndromes, focusing on recent advances that have led to disease-specific approaches to the interpretation of positive genetic testing results. Elucidation of the genetic substrates underlying heritable cardiac arrhythmia syndromes has unearthed new arrhythmogenic mechanisms and given rise to a number of clinically meaningful genotype-phenotype correlations. As such, genetic testing for these disorders now carries important diagnostic, prognostic, and therapeutic implications. Recent large-scale systematic studies designed to explore the background genetic 'noise' rate associated with these genetic tests have provided important insights and enhanced how positive genetic testing results are interpreted for these potentially lethal, yet highly treatable, cardiovascular disorders. Clinically available genetic tests for heritable cardiac arrhythmia syndromes allow the identification of potentially at-risk family members and contribute to the risk-stratification and selection of therapeutic interventions in affected individuals. The systematic evaluation of the 'signal-to-noise' ratio associated with these genetic tests has proven critical and essential to assessing the probability that a given variant represents a rare pathogenic mutation or an equally rare, yet innocuous, genetic bystander.

Phosphodiester models for cleavage of nucleic acids

PubMed Central

2018-01-01

Nucleic acids that store and transfer biological information are polymeric diesters of phosphoric acid. Cleavage of the phosphodiester linkages by protein enzymes, nucleases, is one of the underlying biological processes. The remarkable catalytic efficiency of nucleases, together with the ability of ribonucleic acids to serve sometimes as nucleases, has made the cleavage of phosphodiesters a subject of intensive mechanistic studies. In addition to studies of nucleases by pH-rate dependency, X-ray crystallography, amino acid/nucleotide substitution and computational approaches, experimental and theoretical studies with small molecular model compounds still play a role. With small molecules, the importance of various elementary processes, such as proton transfer and metal ion binding, for stabilization of transition states may be elucidated and systematic variation of the basicity of the entering or departing nucleophile enables determination of the position of the transition state on the reaction coordinate. Such data is important on analyzing enzyme mechanisms based on synergistic participation of several catalytic entities. Many nucleases are metalloenzymes and small molecular models offer an excellent tool to construct models for their catalytic centers. The present review tends to be an up to date summary of what has been achieved by mechanistic studies with small molecular phosphodiesters. PMID:29719577

Site-specific identification of heparan and chondroitin sulfate glycosaminoglycans in hybrid proteoglycans.

PubMed

Noborn, Fredrik; Gomez Toledo, Alejandro; Green, Anders; Nasir, Waqas; Sihlbom, Carina; Nilsson, Jonas; Larson, Göran

2016-10-03

Heparan sulfate (HS) and chondroitin sulfate (CS) are complex polysaccharides that regulate important biological pathways in virtually all metazoan organisms. The polysaccharides often display opposite effects on cell functions with HS and CS structural motifs presenting unique binding sites for specific ligands. Still, the mechanisms by which glycan biosynthesis generates complex HS and CS polysaccharides required for the regulation of mammalian physiology remain elusive. Here we present a glycoproteomic approach that identifies and differentiates between HS and CS attachment sites and provides identity to the core proteins. Glycopeptides were prepared from perlecan, a complex proteoglycan known to be substituted with both HS and CS chains, further digested with heparinase or chondroitinase ABC to reduce the HS and CS chain lengths respectively, and thereafter analyzed by nLC-MS/MS. This protocol enabled the identification of three consensus HS sites and one hybrid site, carrying either a HS or a CS chain. Inspection of the amino acid sequence at the hybrid attachment locus indicates that certain peptide motifs may encode for the chain type selection process. This analytical approach will become useful when addressing fundamental questions in basic biology specifically in elucidating the functional roles of site-specific glycosylations of proteoglycans.

Development of a novel artificial medium based on utilization of algal photosynthetic metabolites by symbiotic heterotrophs.

PubMed

Watanabe, K; Imase, M; Aoyagi, H; Ohmura, N; Saiki, H; Tanaka, H

2008-09-01

(i) Quantitative and qualitative analyses of photosynthetic metabolites of Chlorella sorokiniana and elucidation of the mechanism of their utilization by algal symbionts. (ii) Development of artificial medium that imitates photoautotroph-heterotroph interaction and investigation of its suitability for isolation of novel microbes from the environment. Various components, including free dissolved carbohydrates, nitrogenous compounds and vitamin, were detected and together contributed 11.1% (as carbon content) of the total photosynthetic metabolites in the medium. Utilization of these photosynthetic metabolites in algal culture broth by algal symbionts was studied. Many symbionts showed specific utilization patterns. A novel artificial extracellular released organic carbon medium, which imitated the nutritional conditions surrounding algae, was developed based on the pattern of utilization of the algal metabolites by the symbiotic heterotrophs. About 42.9% of the isolates were closely related to photoautotrophic-dependent and oligotrophic bacteria. With the novel artificial medium, it was possible to selectively isolate some bacterial strains. Synthetic bacterial growth medium is an important and basic tool for bacterial isolation from environmental samples. The current study shows that preferential separation of typical bacterial subset can be achieved by using artificial medium that mimics photosynthetic metabolites.

Predicting seizure by modeling synaptic plasticity based on EEG signals - a case study of inherited epilepsy

NASA Astrophysics Data System (ADS)

Zhang, Honghui; Su, Jianzhong; Wang, Qingyun; Liu, Yueming; Good, Levi; Pascual, Juan M.

2018-03-01

This paper explores the internal dynamical mechanisms of epileptic seizures through quantitative modeling based on full brain electroencephalogram (EEG) signals. Our goal is to provide seizure prediction and facilitate treatment for epileptic patients. Motivated by an earlier mathematical model with incorporated synaptic plasticity, we studied the nonlinear dynamics of inherited seizures through a differential equation model. First, driven by a set of clinical inherited electroencephalogram data recorded from a patient with diagnosed Glucose Transporter Deficiency, we developed a dynamic seizure model on a system of ordinary differential equations. The model was reduced in complexity after considering and removing redundancy of each EEG channel. Then we verified that the proposed model produces qualitatively relevant behavior which matches the basic experimental observations of inherited seizure, including synchronization index and frequency. Meanwhile, the rationality of the connectivity structure hypothesis in the modeling process was verified. Further, through varying the threshold condition and excitation strength of synaptic plasticity, we elucidated the effect of synaptic plasticity to our seizure model. Results suggest that synaptic plasticity has great effect on the duration of seizure activities, which support the plausibility of therapeutic interventions for seizure control.

The effects of incretins on energy homeostasis: physiology and implications for the treatment of type 2 diabetes mellitus and obesity.

PubMed

Karras, Spyridon; Goulis, Dimitrios G; Mintziori, Gesthimani; Katsiki, Niki; Tzotzas, Themistoklis

2012-11-01

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.

[Biochemical basis of tolerance to osmotic stress in phytopathogenic fungus: The case of Macrophomina phaseolina (Tassi) Goid.

PubMed

Martínez-Villarreal, Rodolfo; Garza-Romero, Tamar S; Moreno-Medina, Víctor R; Hernández-Delgado, Sanjuana; Mayek-Pérez, Netzahualcoyotl

Fungus Macrophomina phaseolina (Tassi) Goid. is the causative agent of charcoal rot disease which causes significant yield losses in major crops such as maize, sorghum, soybean and common beans in Mexico. This fungus is a facultative parasite which shows broad ability to adapt itself to stressed environments where water deficits and/or high temperature stresses commonly occur. These environmental conditions are common for most cultivable lands throughout Mexico. Here we describe some basic facts related to the etiology and epidemiology of the fungus as well as to the importance of responses to stressed environments, particularly to water deficits, based on morphology and growth traits, as well as on physiology, biochemistry and pathogenicity of fungus M. phaseolina. To conclude, we show some perspectives related to future research into the genus, which emphasize the increasing need to improve the knowledge based on the application of both traditional and biotechnological tools in order to elucidate the mechanisms of resistance to environmental stress which can be extrapolated to other useful organisms to man. Copyright © 2016 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Identifying pathological biomarkers: histochemistry still ranks high in the omics era

PubMed Central

Pellicciari, C.; Malatesta, M.

2011-01-01

In recent years, omic analyses have been proposed as possible approaches to diagnosis, in particular for tumours, as they should be able to provide quantitative tools to detect and measure abnormalities in gene and protein expression, through the evaluation of transcription and translation products in the abnormal vs normal tissues. Unfortunately, this approach proved to be much less powerful than expected, due to both intrinsic technical limits and the nature itself of the pathological tissues to be investigated, the heterogeneity deriving from polyclonality and tissue phenotype variability between patients being a major limiting factor in the search for unique omic biomarkers. Especially in the last few years, the application of refined techniques for investigating gene expression in situ has greatly increased the diagnostic/prognostic potential of histochemistry, while the progress in light microscopy technology and in the methods for imaging molecules in vivo have provided valuable tools for elucidating the molecular events and the basic mechanisms leading to a pathological condition. Histochemical techniques thus remain irreplaceable in pathologist's armamentarium, and it may be expected that even in the future histochemistry will keep a leading position among the methodological approaches for clinical pathology. PMID:22297448

Inner ear test battery in guinea pig models - a review.

PubMed

Young, Yi-Ho

2018-06-01

This study reviewed the development of the inner ear test battery comprising auditory brainstem response (ABR), and caloric, ocular vestibular-evoked myogenic potential (oVEMP), and cervical vestibular-evoked myogenic potential (cVEMP) tests in guinea pig models at our laboratory over the last 20 years. Detailed description of the methodology for testing the small animals is also included. Inner ear disorders, i.e. ototoxicity, noise exposure, or perilymph fistula were established in guinea pig models first. One to four weeks after operation, each animal underwent ABR, oVEMP, cVEMP, and caloric tests. Then, animals were sacrificed for morphological study in the temporal bones. Inner ear endorgans can be comprehensively evaluated in guinea pig models via an inner ear test battery, which provides thorough information on the cochlea, saccule, utricle, and semicircular canal function of guinea pigs. Coupled with morphological study in the temporal bones of the animals may help elucidate the mechanism of inner ear disorders in humans. The inner ear test battery in guinea pig models may encourage young researchers to perform basic study in animals and stimulate the progress of experimental otology which is in evolution.

Laboratory Investigation of Organic Aerosol Formation from Aromatic Hydrocarbons

DOE R&D Accomplishments Database

Molina, Luisa T.; Molina, Mario J.; Zhang, Renyi

2006-08-23

Our work for this DOE funded project includes: (1) measurements of the kinetics and mechanism of the gas-phase oxidation reactions of the aromatic hydrocarbons initiated by OH; (2) measurements of aerosol formation from the aromatic hydrocarbons; and (3) theoretical studies to elucidate the OH-toluene reaction mechanism using quantum-chemical and rate theories.

Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin

USDA-ARS?s Scientific Manuscript database

The mechanism(s) by which fatty acids are sequestered and transported in muscle have not been fully elucidated. A potential key player in this process is the protein myoglobin (Mb). Indeed, there is a catalogue of empirical evidence supporting direct interaction of globins with fatty acid metabolite...

Assessment of optimal control mechanism complexity by experimental landscape Hessian analysis: fragmentation of CH2BrI

NASA Astrophysics Data System (ADS)

Xing, Xi; Rey-de-Castro, Roberto; Rabitz, Herschel

2014-12-01

Optimally shaped femtosecond laser pulses can often be effectively identified in adaptive feedback quantum control experiments, but elucidating the underlying control mechanism can be a difficult task requiring significant additional analysis. We introduce landscape Hessian analysis (LHA) as a practical experimental tool to aid in elucidating control mechanism insights. This technique is applied to the dissociative ionization of CH2BrI using shaped fs laser pulses for optimization of the absolute yields of ionic fragments as well as their ratios for the competing processes of breaking the C-Br and C-I bonds. The experimental results suggest that these nominally complex problems can be reduced to a low-dimensional control space with insights into the control mechanisms. While the optimal yield for some fragments is dominated by a non-resonant intensity-driven process, the optimal generation of other fragments maa difficult task requiring significant additionaly be explained by a non-resonant process coupled to few level resonant dynamics. Theoretical analysis and modeling is consistent with the experimental observations.

Gene expression of the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in the regulation of hematopoietic stem cell aging by ginsenoside Rg1.

PubMed

Yue, Z; Rong, J; Ping, W; Bing, Y; Xin, Y; Feng, L D; Yaping, W

2014-12-04

The elucidation of the molecular mechanisms underlying the effects of traditional Chinese medicines in clinical practice is a key step toward their worldwide application, and this topic is currently a subject of intense research interest. Rg1, a component of ginsenoside, has recently been shown to perform several pharmacological functions; however, the underlying mechanisms of these effects remain unclear. In the present study, we investigated whether Rg1 has an anti-senescence effect on hematopoietic stem cells (HSCs) and the possible molecular mechanisms driving any effects. The results showed that Rg1 could effectively delay tert-butyl hydroperoxide (t-BHP)-induced senescence and inhibit gene expression in the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in HSCs. Our study suggested that these two signaling pathways might be potential targets for elucidating the molecular mechanisms of the Rg1 anti-senescence effect.

Badminton--Teaching Concepts.

ERIC Educational Resources Information Center

Gibbs, Marilyn J.

1988-01-01

Teaching four basic badminton concepts along with the usual basic skill shots allows players to develop game strategy awareness as well as mechanical skills. These four basic concepts are: (1) ready position, (2) flight trajectory, (3) early shuttle contact, and (4) camouflage. (IAH)

The molecular mechanism of plant gravitropism.

PubMed

Wu, Di; Huang, Lin-zhou; Gao, Jin; Wang, Yong-hong

2016-07-20

Gravity is an important environmental factor that regulates plant growth and morphogenesis. In response to gravity stimulus, plants can set the optimum angle between the organs and the gravity vector. Plant gravitropism is divided into four sequential steps, including gravity perception, signal transduction, asymmetrical distribution of auxin, and organ curvature. In recent years, large numbers of mutants with defective gravitropism have been identified and genes involved in the regulation of gravitropism have been functionally characterized. In particular, progress has been achieved on elucidating the molecular mechanisms of gravity perception and asymmetrical distribution of auxin. As one of the most important strategies for plant to adapt environmental changes, gravitropism is also involved in the regulation of rice plant architecture and grain yield through modulating rice tiller angle. Therefore, the investigation of plant gravitropism not only contributes to decipher the regulatory mechanisms of plant growth and development, but also helps to guide the genetic improvement of crop architecture. However, the molecular mechanisms and regulatory network of gravitropism remain to be elusive. In this review, we focus on recent progress on elucidating molecular mechanisms underlying gravitropism and its involvement in regulating rice tiller angle, which is an important agronomic trait that determines rice plant architecture and thus grain yields.

Silver nanoparticles: A new view on mechanistic aspects on antimicrobial activity.

PubMed

Durán, Nelson; Durán, Marcela; de Jesus, Marcelo Bispo; Seabra, Amedea B; Fávaro, Wagner J; Nakazato, Gerson

2016-04-01

Silver nanoparticles are well known potent antimicrobial agents. Although significant progresses have been achieved on the elucidation of antimicrobial mechanism of silver nanoparticles, the exact mechanism of action is still not completely known. This overview incorporates a retrospective of previous reviews published and recent original contributions on the progress of research on antimicrobial mechanisms of silver nanoparticles. The main topics discussed include release of silver nanoparticles and silver ions, cell membrane damage, DNA interaction, free radical generation, bacterial resistance and the relationship of resistance to silver ions versus resistance to silver nanoparticles. The focus of the overview is to summarize the current knowledge in the field of antibacterial activity of silver nanoparticles. The possibility that pathogenic microbes may develop resistance to silver nanoparticles is also discussed. Antibacterial effect of nanoscopic silver generated a lot of interest both in research projects and in practical applications. However, the exact mechanism is still will have to be elucidated. This overview incorporates a retrospective of previous reviews published from 2007 to 2013 and recent original contributions on the progress of research on antimicrobial mechanisms to summarize our current knowledge in the field of antibacterial activity of silver nanoparticles. Copyright © 2015 Elsevier Inc. All rights reserved.

Voice Rest versus Exercise: A Review of the Literature

PubMed Central

Ishikawa, Keiko; Thibeault, Susan

2010-01-01

Voice rest is commonly prescribed after vocal fold surgery to promote wound healing of the vocal fold. Currently, there is no standard protocol that is established based on biological evidence. In orthopedic rehabilitation, long-term rest is found to be less effective for connective tissue healing than exercise. Connective tissue healing is also an important factor for successful voice rehabilitation; however, whether this concept can be extrapolated to voice rehabilitation is unknown. The purpose of this article is to review current clinical and basic science literature to examine the effect of voice rest in post-surgical rehabilitation. First, we present a summary of clinical literature that pertains to voice rest. Second, description of connective tissue that are involved in orthopedic and voice rehabilitation, specifically, ligament and lamina propria, respectively, and their wound healing process are offered. Third, a summary of the literature from orthopedic research on the effect of rest versus exercise is presented. Lastly, it summarizes in vitro and in vivo studies that examined the effect of mechanical stress on vocal fold tissue. Current literature suggests that there is a lack of clinical evidence that supports a specific type and duration of voice rest, and extrapolation of the findings from orthopedic research may be unreasonable due to the morphological and biochemical difference between the tissues. In order to determine the effect of voice rest, further elucidation of vocal fold wound healing process and the effect of mechanical stress on vocal fold tissue remodeling are needed. PMID:19660903

A biomimetic bioelectronic tongue: A switch for On- and Off- response of acid sensations.

PubMed

Zhang, Wei; Chen, Peihua; Zhou, Lianqun; Qin, Zhen; Gao, Keqiang; Yao, Jia; Li, Chuanyu; Wang, Ping

2017-06-15

The perception of sour taste in mammals is important for its basic modality properties and avoiding toxic substances. We explore a biomimetic bioelectronic tongue, which integrate MEA (microelectrode array) and taste receptor cell for acid detection as a switch. However, the acid-sensing mechanism and coding of the taste receptor cells in the periphery is not well understood, with long-standing debate. Therefore, we firstly construct a Hodgkin-Huxley type mathematical model of whole-cell acid-sensing taste receptor cells based on the electrophysiologic patch clamp recordings with different acid sensitive receptor expressing and different acidic stimulations. ASICs and PKDL channels are two most promising candidates for acidic sensation. ASICs channels contribute to the On response, and PKDL channels coding the Offset stimulations respectively, which function as a pair for switch. Therefore, with the advantage of effective and noninvasive detection for MEA, a sour taste biosensor based on MEA and taste receptor cells was designed and established to detect sour response from the elementary acid sensitive taste receptor cells during and after stimulus. From simulation and extracelluar potential recordings, we found the biomimetic bioelectronic tongue was acid-sensitive, as acid stimulation pH decrease, the firing frequency significantly increase. Furthermore, this reliable and effective MEA based bioelectronic tongue functioned as a switch for stimulation On and Off. This study provided a powerful platform to recognize sour stimulation and help elucidate the sour taste sensation and coding mechanism. Copyright © 2016 Elsevier B.V. All rights reserved.

Myofilament properties comprise the rate-limiting step for cardiac relaxation at body temperature in the rat.

PubMed

Janssen, Paul M L; Stull, Linda B; Marbán, Eduardo

2002-02-01

The majority of studies aimed at characterizing basic contractile mechanisms have been conducted at room temperature. To elucidate the mechanism of cardiac relaxation under more physiological conditions, we investigated contractile function and calcium handling in ultrathin rat cardiac trabeculae. Active developed tension was unaltered between 22.5 and 30.0 degrees C (from 89 +/- 10 to 86 +/- 11 mN/mm(2), P = not significant) but steeply declined at 37.5 degrees C (30 +/- 5 mN/mm(2)). Meanwhile, the speed of relaxation (time from peak force to 50% relaxation) declined from 22.5 to 30.0 degrees C (from 360 +/- 40 to 157 +/- 17 ms) and further declined at 37.5 degrees C to 76 +/- 13 ms. Phase-plane analysis of calcium versus force revealed that, with increasing temperature, the relaxation phase is shifted rightward, indicating that the rate-limiting step of relaxation tends to depend more on calcium kinetics as temperature rises. The force-frequency relationship, which was slightly negative at 22.5 degrees C (0.1 vs. 1 Hz: 77 +/- 12 vs. 66 +/- 7 mN/mm(2)), became clearly positive at 37.5 degrees C (1 vs. 10 Hz: 30 +/- 5 vs. 69 +/- 9 mN/mm(2)). Phase-plane analyses indicated that, with increasing frequency, the relaxation phase is shifted leftward. We conclude that temperature independently affects contraction and relaxation, and cross-bridge cycling kinetics become rate limiting for cardiac relaxation under experimental conditions closest to those in vivo.

Development and Application of Computational/In Vitro Toxicological Methods for Chemical Hazard Risk Reduction of New Materials for Advanced Weapon Systems

NASA Technical Reports Server (NTRS)

Frazier, John M.; Mattie, D. R.; Hussain, Saber; Pachter, Ruth; Boatz, Jerry; Hawkins, T. W.

2000-01-01

The development of quantitative structure-activity relationship (QSAR) is essential for reducing the chemical hazards of new weapon systems. The current collaboration between HEST (toxicology research and testing), MLPJ (computational chemistry) and PRS (computational chemistry, new propellant synthesis) is focusing R&D efforts on basic research goals that will rapidly transition to useful products for propellant development. Computational methods are being investigated that will assist in forecasting cellular toxicological end-points. Models developed from these chemical structure-toxicity relationships are useful for the prediction of the toxicological endpoints of new related compounds. Research is focusing on the evaluation tools to be used for the discovery of such relationships and the development of models of the mechanisms of action. Combinations of computational chemistry techniques, in vitro toxicity methods, and statistical correlations, will be employed to develop and explore potential predictive relationships; results for series of molecular systems that demonstrate the viability of this approach are reported. A number of hydrazine salts have been synthesized for evaluation. Computational chemistry methods are being used to elucidate the mechanism of action of these salts. Toxicity endpoints such as viability (LDH) and changes in enzyme activity (glutahoione peroxidase and catalase) are being experimentally measured as indicators of cellular damage. Extrapolation from computational/in vitro studies to human toxicity, is the ultimate goal. The product of this program will be a predictive tool to assist in the development of new, less toxic propellants.

Effect of botulinum toxin type A on transforming growth factor beta1 in fibroblasts derived from hypertrophic scar: a preliminary report.

PubMed

Xiao, Zhibo; Zhang, Fengmin; Lin, Weibin; Zhang, Miaobo; Liu, Ying

2010-08-01

Hypertrophic scar is a common dermal disease. Numerous treatments are currently available but they do not always yield excellent therapeutic results. Hence, alternatives are needed. Recent basic and clinical research has shown that botulinum toxin type A (BTXA) has antihypertrophic scar properties but the molecular mechanism for this action is unknown. The aim of this study was to explore the effect of BTXA on transforming growth factor beta1 (TGF-beta1) in fibroblasts derived from hypertrophic scar and further elucidate its actual mechanism. Fibroblasts were isolated from tissue specimens of hypertrophic scar. Fibroblasts were treated with BTXA and the difference in proliferation between treated and nontreated cells was analyzed through the MTT method from the first to the fifth day after treatment. Proteins of TGF-beta1 were checked using ELISA in fibroblasts with BTXA and without BTXA from the first to the fifth day. The growth of the fibroblast treated with BTXA was obviously slower than that of the fibroblast without BTXA treatment (p < 0.01), which showed that BTXA effectively inhibited the growth of fibroblasts. Proteins of TGF-beta1 between fibroblasts with BTXA and fibroblasts without BTXA are statistically significant (p < 0.01). These results suggest that BTXA effectively inhibited the growth of fibroblasts derived from hypertrophic scar and in turn caused a decrease in TGF-beta1 protein, indicating that BTXA-based therapies for hypertrophic scar are promising and worth investigating further.

Orientation, Sketching, Mechanical Drawing, Drafting--Basic: 9253.01.

ERIC Educational Resources Information Center

Dade County Public Schools, Miami, FL.

The course introduces the student to the drafting trade, freehand sketching, and basic mechanical drawing. The course has no prerequisites and will guide the student into drafting concepts and serve as a foundation for further study in vocational drafting. Requiring a total of 45 class hours, eight hours are utilized in orientation, 15 hours are…

Gasoline Engine Mechanics. Performance Objectives. Basic Course.

ERIC Educational Resources Information Center

Jones, Marion

Several intermediate performance objectives and corresponding criterion measures are listed for each of five terminal objectives presented in this curriculum guide for a basic gasoline engine mechanics course at the secondary level. (For the intermediate course guide see CE 010 946.) The materials were developed for a two semester (2 hours daily)…

Quantum Social Science

NASA Astrophysics Data System (ADS)

Haven, Emmanuel; Khrennikov, Andrei

2013-01-01

Preface; Part I. Physics Concepts in Social Science? A Discussion: 1. Classical, statistical and quantum mechanics: all in one; 2. Econophysics: statistical physics and social science; 3. Quantum social science: a non-mathematical motivation; Part II. Mathematics and Physics Preliminaries: 4. Vector calculus and other mathematical preliminaries; 5. Basic elements of quantum mechanics; 6. Basic elements of Bohmian mechanics; Part III. Quantum Probabilistic Effects in Psychology: Basic Questions and Answers: 7. A brief overview; 8. Interference effects in psychology - an introduction; 9. A quantum-like model of decision making; Part IV. Other Quantum Probabilistic Effects in Economics, Finance and Brain Sciences: 10. Financial/economic theory in crisis; 11. Bohmian mechanics in finance and economics; 12. The Bohm-Vigier Model and path simulation; 13. Other applications to economic/financial theory; 14. The neurophysiological sources of quantum-like processing in the brain; Conclusion; Glossary; Index.

Hysteresis, phase transitions, and dangerous transients in electrical power distribution systems

NASA Astrophysics Data System (ADS)

Duclut, Charlie; Backhaus, Scott; Chertkov, Michael

2013-06-01

The majority of dynamical studies in power systems focus on the high-voltage transmission grids where models consider large generators interacting with crude aggregations of individual small loads. However, new phenomena have been observed indicating that the spatial distribution of collective, nonlinear contribution of these small loads in the low-voltage distribution grid is crucial to the outcome of these dynamical transients. To elucidate the phenomenon, we study the dynamics of voltage and power flows in a spatially extended distribution feeder (circuit) connecting many asynchronous induction motors and discover that this relatively simple 1+1 (space+time) dimensional system exhibits a plethora of nontrivial spatiotemporal effects, some of which may be dangerous for power system stability. Long-range motor-motor interactions mediated by circuit voltage and electrical power flows result in coexistence and segregation of spatially extended phases defined by individual motor states, a “normal” state where the motors’ mechanical (rotation) frequency is slightly smaller than the nominal frequency of the basic ac flows and a “stalled” state where the mechanical frequency is small. Transitions between the two states can be initiated by a perturbation of the voltage or base frequency at the head of the distribution feeder. Such behavior is typical of first-order phase transitions in physics, and this 1+1 dimensional model shows many other properties of a first-order phase transition with the spatial distribution of the motors’ mechanical frequency playing the role of the order parameter. In particular, we observe (a) propagation of the phase-transition front with the constant speed (in very long feeders) and (b) hysteresis in transitions between the normal and stalled (or partially stalled) phases.

VPLS: an effective technology for building scalable transparent LAN services

NASA Astrophysics Data System (ADS)

Dong, Ximing; Yu, Shaohua

2005-02-01

Virtual Private LAN Service (VPLS) is generating considerable interest with enterprises and service providers as it offers multipoint transparent LAN service (TLS) over MPLS networks. This paper describes an effective technology - VPLS, which links virtual switch instances (VSIs) through MPLS to form an emulated Ethernet switch and build Scalable Transparent Lan Services. It first focuses on the architecture of VPLS with Ethernet bridging technique at the edge and MPLS at the core, then it tries to elucidate the data forwarding mechanism within VPLS domain, including learning and aging MAC addresses on a per LSP basis, flooding of unknown frames and replication for unknown, multicast, and broadcast frames. The loop-avoidance mechanism, known as split horizon forwarding, is also analyzed. Another important aspect of VPLS service is its basic operation, including autodiscovery and signaling, is discussed. From the perspective of efficiency and scalability the paper compares two important signaling mechanism, BGP and LDP, which are used to set up a PW between the PEs and bind the PWs to a particular VSI. With the extension of VPLS and the increase of full mesh of PWs between PE devices (n*(n-1)/2 PWs in all, a n2 complete problem), VPLS instance could have a large number of remote PE associations, resulting in an inefficient use of network bandwidth and system resources as the ingress PE has to replicate each frame and append MPLS labels for remote PE. So the latter part of this paper focuses on the scalability issue: the Hierarchical VPLS. Within the architecture of HVPLS, this paper addresses two ways to cope with a possibly large number of MAC addresses, which make VPLS operate more efficiently.

Micromechanisms of brittle fracture: STM, TEM and electron channeling analysis. Final report

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

Gerberich, W.W.

1997-01-01

The original thrust of this grant was to apply newly developed techniques in scanning tunneling and transmission electron microscopy to elucidate the mechanism of brittle fracture. This grant spun-off several new directions in that some of the findings on bulk structural materials could be utilized on thin films or intermetallic single crystals. Modeling and material evaluation efforts in this grant are represented in a figure. Out of this grant evolved the field the author has designated as Contact Fracture Mechanics. By appropriate modeling of stress and strain distribution fields around normal indentations or scratch tracks, various measures of thin filmmore » fracture or decohesion and brittle fracture of low ductility intermetallics is possible. These measures of fracture resistance in small volumes are still evolving and as such no standard technique or analysis has been uniformly accepted. For brittle ceramics and ceramic films, there are a number of acceptable analyses such as those published by Lawn, Evans and Hutchinson. For more dissipative systems involving metallic or polymeric films and/or substrates, there is still much to be accomplished as can be surmised from some of the findings in the present grant. In Section 2 the author reviews the funding history and accomplishments associated mostly with bulk brittle fracture. This is followed by Section 3 which covers more recent work on using novel techniques to evaluate fracture in low ductility single crystals or thin films using micromechanical probes. Basically Section 3 outlines how the recent work fits in with the goals of defining contact fracture mechanics and gives an overview of how the several examples in Section 4 (the Appendices) fit into this framework.« less

Myelin damage and repair in pathologic CNS: challenges and prospects

PubMed Central

Alizadeh, Arsalan; Dyck, Scott M.; Karimi-Abdolrezaee, Soheila

2015-01-01

Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for CNS repair. PMID:26283909

Hysteresis, phase transitions, and dangerous transients in electrical power distribution systems.

PubMed

Duclut, Charlie; Backhaus, Scott; Chertkov, Michael

2013-06-01

The majority of dynamical studies in power systems focus on the high-voltage transmission grids where models consider large generators interacting with crude aggregations of individual small loads. However, new phenomena have been observed indicating that the spatial distribution of collective, nonlinear contribution of these small loads in the low-voltage distribution grid is crucial to the outcome of these dynamical transients. To elucidate the phenomenon, we study the dynamics of voltage and power flows in a spatially extended distribution feeder (circuit) connecting many asynchronous induction motors and discover that this relatively simple 1+1 (space+time) dimensional system exhibits a plethora of nontrivial spatiotemporal effects, some of which may be dangerous for power system stability. Long-range motor-motor interactions mediated by circuit voltage and electrical power flows result in coexistence and segregation of spatially extended phases defined by individual motor states, a "normal" state where the motors' mechanical (rotation) frequency is slightly smaller than the nominal frequency of the basic ac flows and a "stalled" state where the mechanical frequency is small. Transitions between the two states can be initiated by a perturbation of the voltage or base frequency at the head of the distribution feeder. Such behavior is typical of first-order phase transitions in physics, and this 1+1 dimensional model shows many other properties of a first-order phase transition with the spatial distribution of the motors' mechanical frequency playing the role of the order parameter. In particular, we observe (a) propagation of the phase-transition front with the constant speed (in very long feeders) and (b) hysteresis in transitions between the normal and stalled (or partially stalled) phases.

Detectable states, cycle fluxes, and motility scaling of molecular motor kinesin: An integrative kinetic graph theory analysis

NASA Astrophysics Data System (ADS)

Ren, Jie

2017-12-01

The process by which a kinesin motor couples its ATPase activity with concerted mechanical hand-over-hand steps is a foremost topic of molecular motor physics. Two major routes toward elucidating kinesin mechanisms are the motility performance characterization of velocity and run length, and single-molecular state detection experiments. However, these two sets of experimental approaches are largely uncoupled to date. Here, we introduce an integrative motility state analysis based on a theorized kinetic graph theory for kinesin, which, on one hand, is validated by a wealth of accumulated motility data, and, on the other hand, allows for rigorous quantification of state occurrences and chemomechanical cycling probabilities. An interesting linear scaling for kinesin motility performance across species is discussed as well. An integrative kinetic graph theory analysis provides a powerful tool to bridge motility and state characterization experiments, so as to forge a unified effort for the elucidation of the working mechanisms of molecular motors.

Long-lived polarization protected by symmetry

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

Feng, Yesu; Theis, Thomas; Wu, Tung-Lin

2014-10-07

In this paper we elucidate, theoretically and experimentally, molecular motifs which permit Long-Lived Polarization Protected by Symmetry (LOLIPOPS). The basic assembly principle starts from a pair of chemically equivalent nuclei supporting a long-lived singlet state and is completed by coupling to additional pairs of spins. LOLIPOPS can be created in various sizes; here we review four-spin systems, introduce a group theory analysis of six-spin systems, and explore eight-spin systems by simulation. The focus is on AA′X{sub n}X′{sub n} spin systems, where typically the A spins are {sup 15}N or {sup 13}C and X spins are protons. We describe the symmetrymore » of the accessed states, we detail the pulse sequences used to access these states, we quantify the fraction of polarization that can be stored as LOLIPOPS, we elucidate how to access the protected states from A or from X polarization and we examine the behavior of these spin systems upon introduction of a small chemical shift difference.« less

Epidermal cell turnover across tight junctions based on Kelvin's tetrakaidecahedron cell shape

PubMed Central

Yokouchi, Mariko; Atsugi, Toru; van Logtestijn, Mark; Tanaka, Reiko J; Kajimura, Mayumi; Suematsu, Makoto; Furuse, Mikio; Amagai, Masayuki; Kubo, Akiharu

2016-01-01

In multicellular organisms, cells adopt various shapes, from flattened sheets of endothelium to dendritic neurons, that allow the cells to function effectively. Here, we elucidated the unique shape of cells in the cornified stratified epithelia of the mammalian epidermis that allows them to achieve homeostasis of the tight junction (TJ) barrier. Using intimate in vivo 3D imaging, we found that the basic shape of TJ-bearing cells is a flattened Kelvin's tetrakaidecahedron (f-TKD), an optimal shape for filling space. In vivo live imaging further elucidated the dynamic replacement of TJs on the edges of f-TKD cells that enables the TJ-bearing cells to translocate across the TJ barrier. We propose a spatiotemporal orchestration model of f-TKD cell turnover, where in the classic context of 'form follows function', cell shape provides a fundamental basis for the barrier homeostasis and physical strength of cornified stratified epithelia. DOI: http://dx.doi.org/10.7554/eLife.19593.001 PMID:27894419

Technical aspects of gel-based proteomics designed for elucidating an aryl hydrocarbon receptor complex.

PubMed

Wada, Yoshinao; Nakano, Norihiko

2004-01-01

The identification of proteins by mass spectrometry has revolutionalized the basic method of identifying proteins constituting an intracellular unit or network for certain biological functions. The gel-based strategy following immunoprecipitation was applied to elucidating proteins associated with the aryl hydrocarbon receptor (AhR). Two hundred femtomoles of AhR was recovered from approximately 2 x 10(7) HepG2 cells by immunoprecipitation and was sufficient for identification by peptide mass fingerprinting. Possible candidates for the AhR-associated proteins were also identified. Improvements of the current strategy to increase the overall sensitivity tenfold are required to clarify the AhR complex in full detail. For example, a combination of trypsin and Achromobacter protease I for in-gel digestion allows the number of missed cleavage sites to be set at zero for database searching, thereby reducing random matches and facilitating identification. There is also room for improvement in each step of sample preparation prior to mass spectrometry.

Tagging insulin in microgravity

NASA Technical Reports Server (NTRS)

Dobeck, Michael; Nelson, Ronald S.

1992-01-01

Knowing the exact subcellular sites of action of insulin in the body has the potential to give basic science investigators a basis from which a cause and cure for this disease can be approached. The goal of this project is to create a test reagent that can be used to visualize these subcellular sites. The unique microgravity environment of the Shuttle will allow the creation of a reagent that has the possibility of elucidating the subcellular sites of action of insulin. Several techniques have been used in an attempt to isolate the sites of action of items such as insulin. One of these is autoradiography in which the test item is obtained from animals fed radioactive materials. What is clearly needed is to visualize individual insulin molecules at their sites of action. The insulin tagging process to be used on G-399 involves the conjugation of insulin molecules with ferritin molecules to create a reagent that will be used back on Earth in an attempt to elucidate the sites of action of insulin.

Long-lived polarization protected by symmetry

NASA Astrophysics Data System (ADS)

Feng, Yesu; Theis, Thomas; Wu, Tung-Lin; Claytor, Kevin; Warren, Warren S.

2014-10-01

In this paper we elucidate, theoretically and experimentally, molecular motifs which permit Long-Lived Polarization Protected by Symmetry (LOLIPOPS). The basic assembly principle starts from a pair of chemically equivalent nuclei supporting a long-lived singlet state and is completed by coupling to additional pairs of spins. LOLIPOPS can be created in various sizes; here we review four-spin systems, introduce a group theory analysis of six-spin systems, and explore eight-spin systems by simulation. The focus is on AA'XnX'n spin systems, where typically the A spins are 15N or 13C and X spins are protons. We describe the symmetry of the accessed states, we detail the pulse sequences used to access these states, we quantify the fraction of polarization that can be stored as LOLIPOPS, we elucidate how to access the protected states from A or from X polarization and we examine the behavior of these spin systems upon introduction of a small chemical shift difference.

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

Caberoy, Nora B.; Zhou, Yixiong; Alvarado, Gabriela

To efficiently elucidate the biological roles of phosphatidylserine (PS), we developed open-reading-frame (ORF) phage display to identify PS-binding proteins. The procedure of phage panning was optimized with a phage clone expressing MFG-E8, a well-known PS-binding protein. Three rounds of phage panning with ORF phage display cDNA library resulted in {approx}300-fold enrichment in PS-binding activity. A total of 17 PS-binding phage clones were identified. Unlike phage display with conventional cDNA libraries, all 17 PS-binding clones were ORFs encoding 13 real proteins. Sequence analysis revealed that all identified PS-specific phage clones had dimeric basic amino acid residues. GST fusion proteins were expressedmore » for 3 PS-binding proteins and verified for their binding activity to PS liposomes, but not phosphatidylcholine liposomes. These results elucidated previously unknown PS-binding proteins and demonstrated that ORF phage display is a versatile technology capable of efficiently identifying binding proteins for non-protein molecules like PS.« less

Proofreading using an assistive software homophone tool: compensatory and remedial effects on the literacy skills of students with reading difficulties.

PubMed

Lange, Alissa A; Mulhern, Gerry; Wylie, Judith

2009-01-01

The present study investigated the effects of using an assistive software homophone tool on the assisted proofreading performance and unassisted basic skills of secondary-level students with reading difficulties. Students aged 13 to 15 years proofread passages for homophonic errors under three conditions: with the homophone tool, with homophones highlighted only, or with no help. The group using the homophone tool significantly outperformed the other two groups on assisted proofreading and outperformed the others on unassisted spelling, although not significantly. Remedial (unassisted) improvements in automaticity of word recognition, homophone proofreading, and basic reading were found over all groups. Results elucidate the differential contributions of each function of the homophone tool and suggest that with the proper training, assistive software can help not only students with diagnosed disabilities but also those with generally weak reading skills.

Basic research for the geodynamics program

NASA Technical Reports Server (NTRS)

1986-01-01

Further development of utility program software for analyzing final results of Earth rotation parameter determination from different space geodetic systems was completed. Main simulation experiments were performed. Results and conclusions were compiled. The utilization of range-difference observations in geodynamics is also examined. A method based on the Bayesian philosophy and entropy measure of information is given for the elucidation of time-dependent models of crustal motions as part of a proposed algorithm. The strategy of model discrimination and design of measurements is illustrated in an example for the case of crustal deformation models.

Impact of socioeconomic status on the use of inhaled corticosteroids in young adult asthmatics.

PubMed

Davidsen, Jesper Rømhild; Søndergaard, Jens; Hallas, Jesper; Siersted, Hans Christian; Knudsen, Thomas Bøllingtoft; Lykkegaard, Jesper; Andersen, Morten

2011-05-01

The aim of this population-based longitudinal study was to examine the associations between socioeconomic status (SES) and anti-asthmatic treatment with inhaled corticosteroids (ICS) among young Danish adult asthmatics, and to investigate whether these associations were consistent over time. We extracted data on prescription drug use, education, and income in 97 665 users of anti-asthmatic drugs, aged 18-44 years, identified in Statistics Denmark during 1997-2005. Individual information on education and income was used as measures of SES. Education was categorised into basic school/high school, vocational training, and higher education, and income was categorised into low, middle, and high income. Associations between ICS use and SES were estimated by logistic regression models. High levels of education and income were independently associated with ICS use, education demonstrating the strongest association. Using basic school/high school and low income as baselines, the adjusted odds ratios (ORs) of ICS use for higher education were 1.46 (95% CI 1.40-1.51) and 1.10 (95% CI 1.06-1.14) for high income. Higher education was a nearly constant factor associated with ICS use throughout the observation period, but high income did not demonstrate any association before 2001 with increasing ORs observed each year hereafter. All associations became more pronounced when restricting to 35-44 year-olds. High levels of SES were positively associated with ICS use in young adult asthmatics. To encourage ICS use, special attention should be paid to asthmatics with low educational level and low income. Further studies are needed to elucidate underlying mechanisms for this socioeconomic inequality. Copyright © 2010 Elsevier Ltd. All rights reserved.

Composition of the organic components in polyxometalate (POM) liquors from kraft pulp bleaching

Treesearch

Biljana Bujanovic; Kolby C. Hirth; Sally A. Ralph; Richard S. Reiner; Rajai H. Atalla

2007-01-01

Promising results from the selective oxidative delignification of kraft pulp with polyoxometalates (POMs) prompted interest in elucidating the lignin oxidation mechanism. The degradation of lignin model compounds and residual lignin in kraft pulps, upon treatment with POMs was studied and differences in the reaction mechanisms between guaiacyl (G-) and syringyl (S-)...

Molecular and Cellular Mechanisms Elucidating Neurocognitive Basis of Functional Impairments Associated with Intellectual Disability in Down Syndrome

ERIC Educational Resources Information Center

Rachidi, Mohammed; Lopes, Carmela

2010-01-01

Down syndrome, the most common genetic cause of intellectual disability, is associated with brain disorders due to chromosome 21 gene overdosage. Molecular and cellular mechanisms involved in the neuromorphological alterations and cognitive impairments are reported herein in a global model. Recent advances in Down syndrome research have lead to…

5 CFR 772.101 - Basic authority.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Basic authority. 772.101 Section 772.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) INTERIM RELIEF General § 772.101 Basic authority. This part establishes a mechanism for agencies to provide...

5 CFR 772.101 - Basic authority.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Basic authority. 772.101 Section 772.101 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE REGULATIONS (CONTINUED) INTERIM RELIEF General § 772.101 Basic authority. This part establishes a mechanism for agencies to provide...

LC MS analysis in the e-beam and gamma radiolysis of metoprolol tartrate in aqueous solution: Structure elucidation and formation mechanism of radiolytic products

NASA Astrophysics Data System (ADS)

Slegers, Catherine; Maquille, Aubert; Deridder, Véronique; Sonveaux, Etienne; Habib Jiwan, Jean-Louis; Tilquin, Bernard

2006-09-01

E-beam and gamma products from the radiolysis of aqueous solutions of (±)-metoprolol tartrate, saturated in nitrogen, are analyzed by HPLC with on-line mass and UV detectors. The structures of 10 radiolytic products common to e-beam and gamma irradiations are elucidated by comparing their fragmentation pattern to that of (±)-metoprolol. Two of the radiolytic products are also metabolites. Different routes for the formation of the radiolytic products are proposed.

The Application of Physical Organic Chemistry to Biochemical Problems.

ERIC Educational Resources Information Center

Westheimer, Frank

1986-01-01

Presents the synthesis of the science of enzymology from application of the concepts of physical organic chemistry from a historical perspective. Summarizes enzyme and coenzyme mechanisms elucidated prior to 1963. (JM)

Biomass accessibility analysis using electron tomography

DOE PAGES

Hinkle, Jacob D.; Ciesielski, Peter N.; Gruchalla, Kenny; ...

2015-12-25

Substrate accessibility to catalysts has been a dominant theme in theories of biomass deconstruction. Furthermore, current methods of quantifying accessibility do not elucidate mechanisms for increased accessibility due to changes in microstructure following pretreatment.

TOXICOGENOMIC STUDY OF TRIAZOLE FUNGICIDES AND PERFLUOROALKYL ACIDS

EPA Science Inventory

Toxicogenomic analysis of five environmental contaminants was performed to investigate the ability of genomics to categorize chemicals and elucidate mechanisms of toxicity. Three triazole antifungals (myclobutanil, propiconazole and triadimefon) and two perfluorinated compounds (...

Development of dielectrophoresis MEMS device for PC12 cell patterning to elucidate nerve-network generation

NASA Astrophysics Data System (ADS)

Nakamachi, Eiji; Koga, Hirotaka; Morita, Yusuke; Yamamoto, Koji; Sakamoto, Hidetoshi

2018-01-01

We developed a PC12 cell trapping and patterning device by combining the dielectrophoresis (DEP) methodology and the micro electro mechanical systems (MEMS) technology for time-lapse observation of morphological change of nerve network to elucidate the generation mechanism of neural network. We succeeded a neural network generation, which consisted of cell body, axon and dendrites by using tetragonal and hexagonal cell patterning. Further, the time laps observations was carried out to evaluate the axonal extension rate. The axon extended in the channel and reached to the target cell body. We found that the shorter the PC12 cell distance, the less the axonal connection time in both tetragonal and hexagonal structures. After 48 hours culture, a maximum success rate of network formation was 85% in the case of 40 μm distance tetragonal structure.

Purification, crystallization and preliminary X-ray analysis of the regulatory subunit of aspartate kinase from Thermus thermophilus

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

Yoshida, Ayako; Tomita, Takeo; Kuzuyama, Tomohisa

2007-02-01

To elucidate the mechanism of regulation of aspartate kinase, the regulatory subunit (the β subunit of T. thermophilus aspartate kinase) was crystallized in the presence of the inhibitor threonine. Aspartate kinase (AK) from Thermus thermophilus, which catalyzes the first step of threonine and methionine biosynthesis, is regulated via feedback inhibition by the end product threonine. To elucidate the mechanism of regulation of AK, the regulatory subunit (the β subunit of T. thermophilus AK) was crystallized in the presence of the inhibitor threonine. Diffraction data were collected to 2.15 Å at a synchrotron source. The crystal belongs to the cubic spacemore » group P4{sub 3}32 or P4{sub 1}32, with unit-cell parameters a = b = c = 141.8 Å.« less

[Functional targets of Chinese herbal medicine].

PubMed

Xiao, Bin; Wang, Yun

2010-12-01

In order to elucidate the mechanisms of Chinese herbal medicine, much work has been done based on chemical constituent-target in the molecular system. It cannot comply with the holistic efficacy of Chinese herbal medicine. Thus, the authors of this paper proposed to study the functional target adopted from Western medicine. The data of Chinese herbal function were collected from 2005 edition of The People's Republic of China Pharmacopoeia. A total of 135 functional targets were found, and a network about functional target and mode of action was built. The authors also explored the applications of functional target and the network combined with Sijunzi Decoction and Mahuang Decoction. The results, reflecting the feature of Chinese herbal medicine, will not only be helpful to elucidate the holistic mechanisms of Chinese herbal medicine, but also beneficial to studying the theory of Chinese formulas and developing new formulas.

Compliant leg behaviour explains basic dynamics of walking and running

PubMed Central

Geyer, Hartmut; Seyfarth, Andre; Blickhan, Reinhard

2006-01-01

The basic mechanics of human locomotion are associated with vaulting over stiff legs in walking and rebounding on compliant legs in running. However, while rebounding legs well explain the stance dynamics of running, stiff legs cannot reproduce that of walking. With a simple bipedal spring–mass model, we show that not stiff but compliant legs are essential to obtain the basic walking mechanics; incorporating the double support as an essential part of the walking motion, the model reproduces the characteristic stance dynamics that result in the observed small vertical oscillation of the body and the observed out-of-phase changes in forward kinetic and gravitational potential energies. Exploring the parameter space of this model, we further show that it not only combines the basic dynamics of walking and running in one mechanical system, but also reveals these gaits to be just two out of the many solutions to legged locomotion offered by compliant leg behaviour and accessed by energy or speed. PMID:17015312

Quantum mechanical calculations suggest that lytic polysaccharide monooxygenases use a copper-oxyl, oxygen-rebound mechanism

PubMed Central

Kim, Seonah; Ståhlberg, Jerry; Sandgren, Mats; Paton, Robert S.; Beckham, Gregg T.

2014-01-01

Lytic polysaccharide monooxygenases (LPMOs) exhibit a mononuclear copper-containing active site and use dioxygen and a reducing agent to oxidatively cleave glycosidic linkages in polysaccharides. LPMOs represent a unique paradigm in carbohydrate turnover and exhibit synergy with hydrolytic enzymes in biomass depolymerization. To date, several features of copper binding to LPMOs have been elucidated, but the identity of the reactive oxygen species and the key steps in the oxidative mechanism have not been elucidated. Here, density functional theory calculations are used with an enzyme active site model to identify the reactive oxygen species and compare two hypothesized reaction pathways in LPMOs for hydrogen abstraction and polysaccharide hydroxylation; namely, a mechanism that employs a η1-superoxo intermediate, which abstracts a substrate hydrogen and a hydroperoxo species is responsible for substrate hydroxylation, and a mechanism wherein a copper-oxyl radical abstracts a hydrogen and subsequently hydroxylates the substrate via an oxygen-rebound mechanism. The results predict that oxygen binds end-on (η1) to copper, and that a copper-oxyl–mediated, oxygen-rebound mechanism is energetically preferred. The N-terminal histidine methylation is also examined, which is thought to modify the structure and reactivity of the enzyme. Density functional theory calculations suggest that this posttranslational modification has only a minor effect on the LPMO active site structure or reactivity for the examined steps. Overall, this study suggests the steps in the LPMO mechanism for oxidative cleavage of glycosidic bonds. PMID:24344312

On the Acquisition of Some Basic Word Spelling Mechanisms in a Deep (French) and a Shallow (Spanish) System

ERIC Educational Resources Information Center

Carrillo, Maria Soledad; Alegria, Jesus; Marin, Javier

2013-01-01

An experiment was carried out to compare the time course of the acquisition of two basic spelling mechanisms in Spanish, a shallow system, and French, a deep system. The first was lexical. It relies on the orthographic lexicon, a hypothetical structure containing the orthographic representations of words accessible for word spelling. To evaluate…

29 CFR 5.24 - The basic hourly rate of pay.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 29 Labor 1 2012-07-01 2012-07-01 false The basic hourly rate of pay. 5.24 Section 5.24 Labor... Provisions of the Davis-Bacon Act § 5.24 The basic hourly rate of pay. “The basic hourly rate of pay” is that part of a laborer's or mechanic's wages which the Secretary of Labor would have found and included in...

29 CFR 5.24 - The basic hourly rate of pay.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 1 2010-07-01 2010-07-01 true The basic hourly rate of pay. 5.24 Section 5.24 Labor Office... Provisions of the Davis-Bacon Act § 5.24 The basic hourly rate of pay. “The basic hourly rate of pay” is that part of a laborer's or mechanic's wages which the Secretary of Labor would have found and included in...

29 CFR 5.24 - The basic hourly rate of pay.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 29 Labor 1 2011-07-01 2011-07-01 false The basic hourly rate of pay. 5.24 Section 5.24 Labor... Provisions of the Davis-Bacon Act § 5.24 The basic hourly rate of pay. “The basic hourly rate of pay” is that part of a laborer's or mechanic's wages which the Secretary of Labor would have found and included in...

29 CFR 5.24 - The basic hourly rate of pay.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 29 Labor 1 2014-07-01 2013-07-01 true The basic hourly rate of pay. 5.24 Section 5.24 Labor Office... Provisions of the Davis-Bacon Act § 5.24 The basic hourly rate of pay. “The basic hourly rate of pay” is that part of a laborer's or mechanic's wages which the Secretary of Labor would have found and included in...

29 CFR 5.24 - The basic hourly rate of pay.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 29 Labor 1 2013-07-01 2013-07-01 false The basic hourly rate of pay. 5.24 Section 5.24 Labor... Provisions of the Davis-Bacon Act § 5.24 The basic hourly rate of pay. “The basic hourly rate of pay” is that part of a laborer's or mechanic's wages which the Secretary of Labor would have found and included in...

Development of a Mechanism and Standards for the Assessment of Adult Basic Education Students as They Relate to Post-Secondary Vocational Education Programs. Final Report.

ERIC Educational Resources Information Center

Grosskoph, Arlys; And Others

The purpose of this project was to develop a process that would reduce the attrition rate of adult basic education students entering occupational programs. To accomplish this goal, adult basic education students in occupational programs, adult basic education students who had dropped out of occupational programs, and their instructors were…

[Mechanism Causing Abnormal Laboratory Data--Significance of Electrophoresis and Information Transmission--Chairmen's Introductory Remarks].

PubMed

Maekawa, Masato; Fujita, Kiyotaka

2014-11-01

Abnormal laboratory data are observed due to some kinds of modification as well as pathological conditions of patients. Elucidation of the causal mechanism is very important for clinical laboratories. This symposium was planned to highlight the significance of electrophoresis. Electrophoresis is one of the most important tools to provide clinicians with information for medical diagnosis and care.

Crystal structure of an EfPDF complex with Met-Ala-Ser based on crystallographic packing.

PubMed

Nam, Ki Hyun; Kim, Kook-Han; Kim, Eunice Eun Kyeong; Hwang, Kwang Yeon

2009-04-17

PDF (peptide deformylase) plays a critical role in the production of mature proteins by removing the N-formyl polypeptide of nascent proteins in the prokaryote cell system. This protein is essential for bacterial growth, making it an attractive target for the design of new antibiotics. Accordingly, PDF has been evaluated as a drug target; however, architectural mechanism studies of PDF have not yet fully elucidated its molecular function. We recently reported the crystal structure of PDF produced by Enterococcus faecium [K.H. Nam, J.I. Ham, A. Priyadarshi, E.E. Kim, N. Chung, K.Y. Hwang, "Insight into the antibacterial drug design and architectural mechanism of peptide recognition from the E. faecium peptide deformylase structure", Proteins 74 (2009) 261-265]. Here, we present the crystal structure of the EfPDF complex with MAS (Met-Ser-Ala), thereby not only delineating the architectural mechanism for the recognition of mimic-peptides by N-terminal cleaved expression peptide, but also suggesting possible targets for rational design of antibacterial drugs. In addition to their implications for drug design, these structural studies will facilitate elucidation of the architectural mechanism responsible for the peptide recognition of PDF.

Elucidating the Mechanism of p27 Inactivation by the Bcr-Abl Tyrosine Kinase

DTIC Science & Technology

2005-10-01

Grants 2002- Leukemia Research Fund Membership in Scientific Committees 2000- Molecular diagnostics (German competence network acute...transplantation, including reduced intensity conditioning. Hematological Diagnostics Standard morphology. Supervised molecular diagnostics in the

Effect of mechanical denaturation on surface free energy of protein powders.

PubMed

Mohammad, Mohammad Amin; Grimsey, Ian M; Forbes, Robert T; Blagbrough, Ian S; Conway, Barbara R

2016-10-01

Globular proteins are important both as therapeutic agents and excipients. However, their fragile native conformations can be denatured during pharmaceutical processing, which leads to modification of the surface energy of their powders and hence their performance. Lyophilized powders of hen egg-white lysozyme and β-galactosidase from Aspergillus oryzae were used as models to study the effects of mechanical denaturation on the surface energies of basic and acidic protein powders, respectively. Their mechanical denaturation upon milling was confirmed by the absence of their thermal unfolding transition phases and by the changes in their secondary and tertiary structures. Inverse gas chromatography detected differences between both unprocessed protein powders and the changes induced by their mechanical denaturation. The surfaces of the acidic and basic protein powders were relatively basic, however the surface acidity of β-galactosidase was higher than that of lysozyme. Also, the surface of β-galactosidase powder had a higher dispersive energy compared to lysozyme. The mechanical denaturation decreased the dispersive energy and the basicity of the surfaces of both protein powders. The amino acid composition and molecular conformation of the proteins explained the surface energy data measured by inverse gas chromatography. The biological activity of mechanically denatured protein powders can either be reversible (lysozyme) or irreversible (β-galactosidase) upon hydration. Our surface data can be exploited to understand and predict the performance of protein powders within pharmaceutical dosage forms. Copyright © 2016 Elsevier B.V. All rights reserved.

Osteoarthritis year in review 2014: mechanics--basic and clinical studies in osteoarthritis.

PubMed

Moyer, R F; Ratneswaran, A; Beier, F; Birmingham, T B

2014-12-01

The purpose of this review was to highlight recent research in mechanics and osteoarthritis (OA) by summarizing results from selected studies spanning basic and clinical research methods. Databases were searched from January 2013 through to March 2014. Working in pairs, reviewers selected 67 studies categorized into four themes--mechanobiology, ambulatory mechanics, biomechanical interventions and mechanical risk factors. Novel developments in mechanobiology included the identification of cell signaling pathways that mediated cellular responses to loading of articular cartilage. Studies in ambulatory mechanics included an increased focus on instrumented knee implants and progress in computational models, both emphasizing the importance of muscular contributions to load. Several proposed biomechanical interventions (e.g., shoe insoles and knee braces) produced variable changes in external knee joint moments during walking, while meta-analysis of randomized clinical trials did not support the use of lateral wedge insoles for decreasing pain. Results from high quality randomized trials suggested diet with or without exercise decreased indicators of knee joint load during walking, whereas similar effects from exercise alone were not detected with the measures used. Data from longitudinal cohorts suggested mechanical alignment was a risk factor for incidence and progression of OA, with the mechanism involving damage to the meniscus. In combination, the basic and clinical studies highlight the importance of considering multiple contributors to joint loading that can evoke both protective and damaging responses. Although challenges clearly exist, future studies should strive to integrate basic and clinical research methods to gain a greater understanding of the interactions among mechanical factors in OA and to develop improved preventive and therapeutic strategies. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Exploring cognitive integration of basic science and its effect on diagnostic reasoning in novices.

PubMed

Lisk, Kristina; Agur, Anne M R; Woods, Nicole N

2016-06-01

Integration of basic and clinical science knowledge is increasingly being recognized as important for practice in the health professions. The concept of 'cognitive integration' places emphasis on the value of basic science in providing critical connections to clinical signs and symptoms while accounting for the fact that clinicians may not spontaneously articulate their use of basic science knowledge in clinical reasoning. In this study we used a diagnostic justification test to explore the impact of integrated basic science instruction on novices' diagnostic reasoning process. Participants were allocated to an integrated basic science or clinical science training group. The integrated basic science group was taught the clinical features along with the underlying causal mechanisms of four musculoskeletal pathologies while the clinical science group was taught only the clinical features. Participants completed a diagnostic accuracy test immediately after initial learning, and one week later a diagnostic accuracy and justification test. The results showed that novices who learned the integrated causal mechanisms had superior diagnostic accuracy and better understanding of the relative importance of key clinical features. These findings further our understanding of cognitive integration by providing evidence of the specific changes in clinical reasoning when basic and clinical sciences are integrated during learning.

Non-Natural Linker Configuration in 2,6-Dipeptidyl-Anthraquinones Enhances the Inhibition of TAR RNA Binding/Annealing Activities by HIV-1 NC and Tat Proteins.

PubMed

Sosic, Alice; Saccone, Irene; Carraro, Caterina; Kenderdine, Thomas; Gamba, Elia; Caliendo, Giuseppe; Corvino, Angela; Di Vaio, Paola; Fiorino, Ferdinando; Magli, Elisa; Perissutti, Elisa; Santagada, Vincenzo; Severino, Beatrice; Spada, Valentina; Fabris, Dan; Frecentese, Francesco; Gatto, Barbara

2018-06-12

The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.

Soil chemical insights provided through vibrational spectroscopy

USDA-ARS?s Scientific Manuscript database

Vibrational spectroscopy techniques provide a powerful approach to study environmental materials and processes. These multifunctional analysis tools can be used to probe molecular vibrations of solid, liquid, and gaseous samples for characterizing materials, elucidating reaction mechanisms, and exam...

Learning Genetics with Paper Pets

ERIC Educational Resources Information Center

Finnerty, Valerie Raunig

2006-01-01

By the end of the eighth grade, students are expected to have a basic understanding of the mechanism of basic genetic inheritance. However, these concepts can be difficult to teach. In this article, the author introduces a new learning tool that will help facilitate student learning and enthusiasm to the basic concepts of genetic inheritance. This…

Specific interactions between DNA and regulatory protein controlled by ligand-binding: Ab initio molecular simulation

NASA Astrophysics Data System (ADS)

Matsushita, Y.; Murakawa, T.; Shimamura, K.; Oishi, M.; Ohyama, T.; Kurita, N.

2015-02-01

The catabolite activator protein (CAP) is one of the regulatory proteins controlling the transcription mechanism of gene. Biochemical experiments elucidated that the complex of CAP with cyclic AMP (cAMP) is indispensable for controlling the mechanism, while previous molecular simulations for the monomer of CAP+cAMP complex revealed the specific interactions between CAP and cAMP. However, the effect of cAMP-binding to CAP on the specific interactions between CAP and DNA is not elucidated at atomic and electronic levels. We here considered the ternary complex of CAP, cAMP and DNA in solvating water molecules and investigated the specific interactions between them at atomic and electronic levels using ab initio molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital methods. The results highlight the important amino acid residues of CAP for the interactions between CAP and cAMP and between CAP and DNA.

Monte Carlo modeling of light-tissue interactions in narrow band imaging.

PubMed

Le, Du V N; Wang, Quanzeng; Ramella-Roman, Jessica C; Pfefer, T Joshua

2013-01-01

Light-tissue interactions that influence vascular contrast enhancement in narrow band imaging (NBI) have not been the subject of extensive theoretical study. In order to elucidate relevant mechanisms in a systematic and quantitative manner we have developed and validated a Monte Carlo model of NBI and used it to study the effect of device and tissue parameters, specifically, imaging wavelength (415 versus 540 nm) and vessel diameter and depth. Simulations provided quantitative predictions of contrast-including up to 125% improvement in small, superficial vessel contrast for 415 over 540 nm. Our findings indicated that absorption rather than scattering-the mechanism often cited in prior studies-was the dominant factor behind spectral variations in vessel depth-selectivity. Narrow-band images of a tissue-simulating phantom showed good agreement in terms of trends and quantitative values. Numerical modeling represents a powerful tool for elucidating the factors that affect the performance of spectral imaging approaches such as NBI.

Elucidating the reaction pathways in the synthesis of organolead trihalide perovskite for high-performance solar cells.

PubMed

Wang, Baohua; Young Wong, King; Xiao, Xudong; Chen, Tao

2015-05-28

The past two years have witnessed unprecedentedly rapid development of organic-inorganic halide perovskite-based solar cells. The solution-processability and high efficiency make this technology extraordinarily attractive. The intensive investigations have accumulated rich experiences in the perovskite fabrication; while the mechanism of the chemical synthesis still remains unresolved. Here, we set up the chemical equation of the synthesis and elucidate the reactions from both thermodynamic and kinetic perspectives. Our study shows that gaseous products thermodynamically favour the reaction, while the activation energy and "collision" probability synergistically determine the reaction rate. These understandings enable us to finely tune the crystal size for high-quality perovskite film, leading to a record fill factor among similar device structures in the literature. This investigation provides a general strategy to explore the mechanism of perovskite synthesis and benefits the fabrication of high-efficiency perovskite photoactive layer.

Lessons from rare diseases of cartilage and bone.

PubMed

Gallagher, James A; Ranganath, Lakshminarayan R; Boyde, Alan

2015-06-01

Studying severe phenotypes of rare syndromes can elucidate disease mechanisms of more common disorders and identify potential therapeutic targets. Lessons from rare bone diseases contributed to the development of the most successful class of bone active agents, the bisphosphonates. More recent research on rare bone diseases has helped elucidate key pathways and identify new targets in bone resorption and bone formation including cathepsin K and sclerostin, for which drugs are now in clinical trials. By contrast, there has been much less focus on rare cartilage diseases and osteoarthritis (OA) remains a common disease with no effective therapy. Investigation of rare cartilage syndromes is identifying new potential targets in OA including GDF5 and lubricin. Research on the arthropathy of the ultra-rare disease alkaptonuria has identified several new features of the OA phenotype, including high density mineralized protrusions (HDMPs) which constitute a newly identified mechanism of joint destruction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Morphological elucidation of basal ganglia circuits contributing reward prediction

PubMed Central

Fujiyama, Fumino; Takahashi, Susumu; Karube, Fuyuki

2015-01-01

Electrophysiological studies in monkeys have shown that dopaminergic neurons respond to the reward prediction error. In addition, striatal neurons alter their responsiveness to cortical or thalamic inputs in response to the dopamine signal, via the mechanism of dopamine-regulated synaptic plasticity. These findings have led to the hypothesis that the striatum exhibits synaptic plasticity under the influence of the reward prediction error and conduct reinforcement learning throughout the basal ganglia circuits. The reinforcement learning model is useful; however, the mechanism by which such a process emerges in the basal ganglia needs to be anatomically explained. The actor–critic model has been previously proposed and extended by the existence of role sharing within the striatum, focusing on the striosome/matrix compartments. However, this hypothesis has been difficult to confirm morphologically, partly because of the complex structure of the striosome/matrix compartments. Here, we review recent morphological studies that elucidate the input/output organization of the striatal compartments. PMID:25698913

Interactions of structurally modified surfactants with reservoir minerals: Calorimetric, spectroscopic and electrokinetic study

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

Somasundaran, P.; Sivakumar, A.; Xu, Q.

1991-03-01

The objective of this project is to elucidate mechanisms of adsorption of structurally modified surfactants on reservoir minerals and to develop a full understanding of the effect of the surfactant structure on the nature of the adsorbed layers at the molecular level. An additional aim is to study the adsorption of surfactant mixtures on simple well-characterized minerals and on complex minerals representing real conditions. The practical goal of these studies is the identification of the optimum surfactant structures and their combinations for micellar flooding. In this work, the experiments on adsorption were focussed on the position of sulfonate and methylmore » groups on the aromatic ring of alkyl xylene sulfonates. A multi-pronged approach consisting of calorimetry, electrokinetics, wettability and spectroscopy is planned to elucidate the adsorption mechanism of surfactants and their mixtures on minerals such as alumina and kaolinite. 32 refs., 15 figs., 7 tabs.« less

Elucidation of salt stress defense and tolerance mechanisms of crop plants using proteomics--current achievements and perspectives.

PubMed

Barkla, Bronwyn J; Castellanos-Cervantes, Thelma; de León, José L Diaz; Matros, Andrea; Mock, Hans-Peter; Perez-Alfocea, Francisco; Salekdeh, Ghasem H; Witzel, Katja; Zörb, Christian

2013-06-01

Salinity is a major threat limiting the productivity of crop plants. A clear demand for improving the salinity tolerance of the major crop plants is imposed by the rapidly growing world population. This review summarizes the achievements of proteomic studies to elucidate the response mechanisms of selected model and crop plants to cope with salinity stress. We also aim at identifying research areas, which deserve increased attention in future proteome studies, as a prerequisite to identify novel targets for breeding strategies. Such areas include the impact of plant-microbial communities on the salinity tolerance of crops under field conditions, the importance of hormone signaling in abiotic stress tolerance, and the significance of control mechanisms underlying the observed changes in the proteome patterns. We briefly highlight the impact of novel tools for future proteome studies and argue for the use of integrated approaches. The evaluation of genetic resources by means of novel automated phenotyping facilities will have a large impact on the application of proteomics especially in combination with metabolomics or transcriptomics. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Elucidation of the mechanisms of optical clearing in collagen tissue with multiphoton imaging

NASA Astrophysics Data System (ADS)

Hovhannisyan, Vladimir; Hu, Po-Sheng; Chen, Shean-Jen; Kim, Chang-Seok; Dong, Chen-Yuan

2013-04-01

Optical clearing (OC) is a promising method to overcome limitations in biomedical depth-resolved optical studies. Mechanisms of OC in purified bovine Achilles tendon, chicken skin, and chicken tendon were studied using time-lapsed, three-dimensional second harmonic generation (SHG) and two-photon fluorescence microscopic imaging. Quantified nonlinear optical measurements allowed temporal separation of two processes in collagen OC with glycerol. The first one is a fast process of tissue dehydration accompanied with collagen shrinkage and the second relatively slow process is glycerol penetration into the interfibrillar space of collagen alongside with CF swelling. The use of 50% glycerol induced less-expressed OC via partial substitution of water molecules with glycerol molecules. We also found that phosphate-buffered saline- and glycerol-treatments were reversible, and fiber morphology and SHG signal intensity were recovered after the removal of immersion agents. It was shown that tissue OC was a dynamic process and elucidation of its physical mechanisms may help choose optimal diagnostic, treatment, and modification regimes for collagen-based as well as other types of biomaterials.

Electron Transfer Mechanisms of DNA Repair by Photolyase

NASA Astrophysics Data System (ADS)

Zhong, Dongping

2015-04-01

Photolyase is a flavin photoenzyme that repairs two DNA base damage products induced by ultraviolet (UV) light: cyclobutane pyrimidine dimers and 6-4 photoproducts. With femtosecond spectroscopy and site-directed mutagenesis, investigators have recently made significant advances in our understanding of UV-damaged DNA repair, and the entire enzymatic dynamics can now be mapped out in real time. For dimer repair, six elementary steps have been characterized, including three electron transfer reactions and two bond-breaking processes, and their reaction times have been determined. A unique electron-tunneling pathway was identified, and the critical residues in modulating the repair function at the active site were determined. The dynamic synergy between the elementary reactions for maintaining high repair efficiency was elucidated, and the biological nature of the flavin active state was uncovered. For 6-4 photoproduct repair, a proton-coupled electron transfer repair mechanism has been revealed. The elucidation of electron transfer mechanisms and two repair photocycles is significant and provides a molecular basis for future practical applications, such as in rational drug design for curing skin cancer.

Intracellular imaging of docosanol in living cells by coherent anti-Stokes Raman scattering microscopy

NASA Astrophysics Data System (ADS)

You, Sixian; Liu, Yuan; Arp, Zane; Zhao, Youbo; Chaney, Eric J.; Marjanovic, Marina; Boppart, Stephen A.

2017-07-01

Docosanol is an over-the-counter topical agent that has proved to be one of the most effective therapies for treating herpes simplex labialis. However, the mechanism by which docosanol suppresses lesion formation remains poorly understood. To elucidate its mechanism of action, we investigated the uptake of docosanol in living cells using coherent anti-Stokes Raman scattering microscopy. Based on direct visualization of the deuterated docosanol, we observed highly concentrated docosanol inside living cells 24 h after drug treatment. In addition, different spatial patterns of drug accumulation were observed in different cell lines. In keratinocytes, which are the targeted cells of docosanol, the drug molecules appeared to be docking at the periphery of the cell membrane. In contrast, the drug molecules in fibroblasts appeared to accumulate in densely packed punctate regions throughout the cytoplasm. These results suggest that this molecular imaging approach is suitable for the longitudinal tracking of drug molecules in living cells to identify cell-specific trafficking and may also have implications for elucidating the mechanism by which docosanol suppresses lesion formation.

Ensemble cryo-EM elucidates the mechanism of translation fidelity

PubMed Central

Loveland, Anna B.; Demo, Gabriel; Grigorieff, Nikolaus; Korostelev, Andrei A.

2017-01-01

SUMMARY Faithful gene translation depends on accurate decoding, whose structural mechanism remains a matter of debate. Ribosomes decode mRNA codons by selecting cognate aminoacyl-tRNAs delivered by EF-Tu. We present high-resolution structural ensembles of ribosomes with cognate or near-cognate aminoacyl-tRNAs delivered by EF-Tu. Both cognate and near-cognate tRNA anticodons explore the A site of an open 30S subunit, while inactive EF-Tu is separated from the 50S subunit. A transient conformation of decoding-center nucleotide G530 stabilizes the cognate codon-anticodon helix, initiating step-wise “latching” of the decoding center. The resulting 30S domain closure docks EF-Tu at the sarcin-ricin loop of the 50S subunit, activating EF-Tu for GTP hydrolysis and ensuing aminoacyl-tRNA accommodation. By contrast, near-cognate complexes fail to induce the G530 latch, thus favoring open 30S pre-accommodation intermediates with inactive EF-Tu. This work unveils long-sought structural differences between the pre-accommodation of cognate and near-cognate tRNA that elucidate the mechanism of accurate decoding. PMID:28538735

Preparation and characterization of polyclonal antibodies against human chaperonin 10

PubMed Central

Somodevilla-Torres, Maria J.; Hillyard, Narelle C.; Morton, Halle; Alewood, Dianne; Halliday, Judy A.; Alewood, Paul F.; Vesey, David A.; Walsh, Michael D.; Cavanagh, Alice C.

2000-01-01

Abstract Early pregnancy factor (EPF) has been identified as an extracellular homologue of chaperonin 10 (Cpn10), a heat shock protein that functions within the cell as a molecular chaperone. Here, we report the production of polyclonal antibodies directed against several different regions of the human Cpn10 molecule and their application to specific protein quantitation and localization techniques. These antibodies will be valuable tools in further studies to elucidate the mechanisms underlying the differential spatial and temporal localization of EPF and Cpn10 and in studies to elucidate structure and function. PMID:10701835

Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders

PubMed Central

Fine, Rebecca; Zhang, Jie; Stevens, Hanna E.

2014-01-01

Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that elucidates how this early, developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders. PMID:24751963

Bending nanowire growth in solution by mechanical disturbance.

PubMed

Wang, Chao; Wei, Yujie; Jiang, Hongyuan; Sun, Shouheng

2010-06-09

The effect of mechanical disturbance on one-dimensional nanocrystal growth in solution phase is investigated by controlled growth of Au nanowires with and without stirring. While a static growth leads to straight, single-crystal Au nanowires, the mechanic disturbance by stirring tends to bend the nanowire growth, yielding nanowire kinks abundant in various types of crystal defects including dislocations, twin boundaries, and grain boundaries. Mechanical modeling and analysis is introduced to elucidate the nanowire growth mechanisms in these two conditions. The provided fundamental understanding of crystal defect formation at nanoscale could be applied to guide the development of advanced nanomaterials with shape control and unique mechanical properties.

Selenium and selenocysteine: roles in cancer, health and development

PubMed Central

Hatfield, Dolph L.; Tsuji, Petra A.; Carlson, Bradley A.; Gladyshev, Vadim N.

2014-01-01

The many biological and biomedical effects of selenium are relatively unknown outside the selenium field. This fascinating element, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid 1990s, selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results. However, basic research on selenium continued to move at a rapid pace elucidating its many roles in health, development, and cancer prevention and promotion. Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions. PMID:24485058

Automated measurement of zebrafish larval movement

PubMed Central

Cario, Clinton L; Farrell, Thomas C; Milanese, Chiara; Burton, Edward A

2011-01-01

Abstract The zebrafish is a powerful vertebrate model that is readily amenable to genetic, pharmacological and environmental manipulations to elucidate the molecular and cellular basis of movement and behaviour. We report software enabling automated analysis of zebrafish movement from video recordings captured with cameras ranging from a basic camcorder to more specialized equipment. The software, which is provided as open-source MATLAB functions, can be freely modified and distributed, and is compatible with multiwell plates under a wide range of experimental conditions. Automated measurement of zebrafish movement using this technique will be useful for multiple applications in neuroscience, pharmacology and neuropsychiatry. PMID:21646414

Automated measurement of zebrafish larval movement.

PubMed

Cario, Clinton L; Farrell, Thomas C; Milanese, Chiara; Burton, Edward A

2011-08-01

The zebrafish is a powerful vertebrate model that is readily amenable to genetic, pharmacological and environmental manipulations to elucidate the molecular and cellular basis of movement and behaviour. We report software enabling automated analysis of zebrafish movement from video recordings captured with cameras ranging from a basic camcorder to more specialized equipment. The software, which is provided as open-source MATLAB functions, can be freely modified and distributed, and is compatible with multiwell plates under a wide range of experimental conditions. Automated measurement of zebrafish movement using this technique will be useful for multiple applications in neuroscience, pharmacology and neuropsychiatry.

The hatching larva of the priapulid worm Halicryptus spinulosus

PubMed Central

Janssen, Ralf; Wennberg, Sofia A; Budd, Graham E

2009-01-01

Despite their increasing evolutionary importance, basic knowledge about the priapulid worms remains limited. In particular, priapulid development has only been partially documented. Following previous description of hatching and the earliest larval stages of Priapulus caudatus, we here describe the hatching larva of Halicryptus spinulosus. Comparison of the P. caudatus and the H. spinulosus hatching larvae allows us to attempt to reconstruct the ground pattern of priapulid development. These findings may further help unravelling the phylogenetic position of the Priapulida within the Scalidophora and hence contribute to the elucidation of the nature of the ecdysozoan ancestor. PMID:19470151

Theoretical ecology as etiological from the start.

PubMed

Donhauser, Justin

2016-12-01

The world's leading environmental advisory institutions look to ecological theory and research as an objective guide for policy and resource management decision-making. In addition to the theoretical and broadly philosophical merits of doing so, it is therefore practically significant to clear up confusions about ecology's conceptual foundations and to clarify the basic workings of inferential methods used in the science. Through discussion of key moments in the genesis of the theoretical branch of ecology, this essay elucidates a general heuristic role of teleological metaphors in ecological research and defuses certain enduring confusions about work in ecology. Copyright © 2016. Published by Elsevier Ltd.

The hatching larva of the priapulid worm Halicryptus spinulosus.

PubMed

Janssen, Ralf; Wennberg, Sofia A; Budd, Graham E

2009-05-26

Despite their increasing evolutionary importance, basic knowledge about the priapulid worms remains limited. In particular, priapulid development has only been partially documented. Following previous description of hatching and the earliest larval stages of Priapulus caudatus, we here describe the hatching larva of Halicryptus spinulosus. Comparison of the P. caudatus and the H. spinulosus hatching larvae allows us to attempt to reconstruct the ground pattern of priapulid development. These findings may further help unravelling the phylogenetic position of the Priapulida within the Scalidophora and hence contribute to the elucidation of the nature of the ecdysozoan ancestor.

OBPR Product Lines, Human Research Initiative, and Physics Roadmap for Exploration

NASA Technical Reports Server (NTRS)

Israelsson, Ulf

2004-01-01

The pace of change has increased at NASA. OBPR s focus is now on the Human interface as it relates to the new Exploration vision. The fundamental physics community must demonstrate how we can contribute. Many opportunities exist for physicists to participate in addressing NASA's cross-disciplinary exploration challenges: a) Physicists can contribute to elucidating basic operating principles for complex biological systems; b) Physics technologies can contribute to developing miniature sensors and systems required for manned missions to Mars. NASA Codes other than OBPR may be viable sources of funding for physics research.

Diversity of the human intestinal microbial flora.

PubMed

Eckburg, Paul B; Bik, Elisabeth M; Bernstein, Charles N; Purdom, Elizabeth; Dethlefsen, Les; Sargent, Michael; Gill, Steven R; Nelson, Karen E; Relman, David A

2005-06-10

The human endogenous intestinal microflora is an essential "organ" in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.

ACOG Technology Assessment No. 11: Genetics and molecular diagnostic testing.

PubMed

2014-02-01

Human genetics and molecular testing are playing an increasingly important role in medicine, including obstetric and gynecologic practice. As the genetic basis for reproductive disorders, common diseases, and cancer is elucidated with improved molecular technology, genetic testing opportunities are expanding and influencing treatment options and prevention strategies. It is essential that obstetrician-gynecologists be aware of advances in the understanding of genetic disease and the fundamental principles of genetic screening and molecular testing as genetics becomes a more integral part of routine medical practice. This document reviews the basics of genetic transmission and genetic technologies in current use.

Convergent evolution of gene networks by single-gene duplications in higher eukaryotes.

PubMed

Amoutzias, Gregory D; Robertson, David L; Oliver, Stephen G; Bornberg-Bauer, Erich

2004-03-01

By combining phylogenetic, proteomic and structural information, we have elucidated the evolutionary driving forces for the gene-regulatory interaction networks of basic helix-loop-helix transcription factors. We infer that recurrent events of single-gene duplication and domain rearrangement repeatedly gave rise to distinct networks with almost identical hub-based topologies, and multiple activators and repressors. We thus provide the first empirical evidence for scale-free protein networks emerging through single-gene duplications, the dominant importance of molecular modularity in the bottom-up construction of complex biological entities, and the convergent evolution of networks.

Endocytosis of glycosylphosphatidylinositol-anchored proteins

PubMed Central

2009-01-01

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) represent an interesting amalgamation of the three basic kinds of cellular macromolecules viz. proteins, carbohydrates and lipids. An unusually hybrid moiety, the GPI-anchor is expressed in a diverse range of organisms from parasites to mammalian cells and serves to anchor a large number of functionally diverse proteins and has been the center of attention in scientific debate for some time now. Membrane organization of GPI-APs into laterally-organized cholesterol-sphingolipid ordered membrane domains or "rafts" and endocytosis of GPI-APs has been intensely debated. Inclusion into or exclusion from these membrane domains seems to be the critical factor in determining the endocytic mechanisms and intracellular destinations of GPI-APs. The intracellular signaling as well as endocytic trafficking of GPI-APs is critically dependent upon the cell surface organization of GPI-APs, and the associations with these lipid rafts play a vital role during these processes. The mechanism of endocytosis for GPI-APs may differ from other cellular endocytic pathways, such as those mediated by clathrin-coated pits (caveolae), and is necessary for unique biological functions. Numerous intracellular factors are involved in and regulate the endocytosis of GPI-APs, and these may be variably dependent on cell-type. The central focus of this article is to describe the significance of the endocytosis of GPI-APs on a multitude of biological processes, ranging from nutrient-uptake to more complex immune responses. Ultimately, a thorough elucidation of GPI-AP mediated signaling pathways and their regulatory elements will enhance our understanding of essential biological processes and benefit as components of disease intervention strategies. PMID:19832981

Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned

PubMed Central

Gudi, Viktoria; Gingele, Stefan; Skripuletz, Thomas; Stangel, Martin

2014-01-01

Although astrogliosis and microglia activation are characteristic features of multiple sclerosis (MS) and other central nervous system (CNS) lesions the exact functions of these events are not fully understood. Animal models help to understand the complex interplay between the different cell types of the CNS and uncover general mechanisms of damage and repair of myelin sheaths. The so called cuprizone model is a toxic model of demyelination in the CNS white and gray matter, which lacks an autoimmune component. Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions. Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells. Phagocytosis and removal of damaged myelin seems to be one of the major roles of microglia in this model and it is well known that removal of myelin debris is a prerequisite of successful remyelination. Furthermore, microglia provide several signals that support remyelination. The role of astrocytes during de- and remyelination is not well defined. Both supportive and destructive functions have been suggested. Using the cuprizone model we could demonstrate that there is an important crosstalk between astrocytes and microglia. In this review we focus on the role of glial reactions and interaction in the cuprizone model. Advantages and limitations of as well as its potential therapeutic relevance for the human disease MS are critically discussed in comparison to other animal models. PMID:24659953

Characterizing genes with distinct methylation patterns in the context of protein-protein interaction network: application to human brain tissues.

PubMed

Li, Yongsheng; Xu, Juan; Chen, Hong; Zhao, Zheng; Li, Shengli; Bai, Jing; Wu, Aiwei; Jiang, Chunjie; Wang, Yuan; Su, Bin; Li, Xia

2013-01-01

DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery. In the present study, we systematically dissected the characterization of genes with different methylation patterns in the PPIN. A negative association was detected between the methylation levels in the brain tissues and topological centralities. By focusing on two classes of genes with considerably different methylation levels in the brain tissues, namely the low methylated genes (LMGs) and high methylated genes (HMGs), we found that their organizing principles in the PPIN are distinct. The LMGs tend to be the center of the PPIN, and attacking them causes a more deleterious effect on the network integrity. Furthermore, the LMGs express their functions in a modular pattern and substantial differences in functions are observed between the two types of genes. The LMGs are enriched in the basic biological functions, such as binding activity and regulation of transcription. More importantly, cancer genes, especially recessive cancer genes, essential genes, and aging-related genes were all found more often in the LMGs. Additionally, our analysis presented that the intra-classes communications are enhanced, but inter-classes communications are repressed. Finally, a functional complementation was revealed between methylation and miRNA regulation in the human genome. We have elucidated the assembling principles of genes with different methylation levels in the context of the PPIN, providing key insights into the complex epigenetic regulation mechanisms.

Characterizing Genes with Distinct Methylation Patterns in the Context of Protein-Protein Interaction Network: Application to Human Brain Tissues

PubMed Central

Zhao, Zheng; Li, Shengli; Bai, Jing; Wu, Aiwei; Jiang, Chunjie; Wang, Yuan; Su, Bin; Li, Xia

2013-01-01

Background DNA methylation is an essential epigenetic mechanism involved in transcriptional control. However, how genes with different methylation patterns are assembled in the protein-protein interaction network (PPIN) remains a mystery. Results In the present study, we systematically dissected the characterization of genes with different methylation patterns in the PPIN. A negative association was detected between the methylation levels in the brain tissues and topological centralities. By focusing on two classes of genes with considerably different methylation levels in the brain tissues, namely the low methylated genes (LMGs) and high methylated genes (HMGs), we found that their organizing principles in the PPIN are distinct. The LMGs tend to be the center of the PPIN, and attacking them causes a more deleterious effect on the network integrity. Furthermore, the LMGs express their functions in a modular pattern and substantial differences in functions are observed between the two types of genes. The LMGs are enriched in the basic biological functions, such as binding activity and regulation of transcription. More importantly, cancer genes, especially recessive cancer genes, essential genes, and aging-related genes were all found more often in the LMGs. Additionally, our analysis presented that the intra-classes communications are enhanced, but inter-classes communications are repressed. Finally, a functional complementation was revealed between methylation and miRNA regulation in the human genome. Conclusions We have elucidated the assembling principles of genes with different methylation levels in the context of the PPIN, providing key insights into the complex epigenetic regulation mechanisms. PMID:23776563

Rheumatoid Arthritis-Associated Interstitial Lung Disease and Idiopathic Pulmonary Fibrosis: Shared Mechanistic and Phenotypic Traits Suggest Overlapping Disease Mechanisms.

PubMed

Paulin, Francisco; Doyle, Tracy J; Fletcher, Elaine A; Ascherman, Dana P; Rosas, Ivan O

2015-01-01

The prevalence of clinically evident interstitial lung disease in patients with rheumatoid arthritis is approximately 10%. An additional 33% of undiagnosed patients have interstitial lung abnormalities that can be detected with high-resolution computed tomography. Rheumatoid arthritis-interstitial lung disease patients have three times the risk of death compared to those with rheumatoid arthritis occurring in the absence of interstitial lung disease, and the mortality related to interstitial lung disease is rising. Rheumatoid arthritis-interstitial lung disease is most commonly classified as the usual interstitial pneumonia pattern, overlapping mechanistically and phenotypically with idiopathic pulmonary fibrosis, but can occur in a non-usual interstitial pneumonia pattern, mainly nonspecific interstitial pneumonia. Based on this, we propose two possible pathways to explain the coexistence of rheumatoid arthritis and interstitial lung disease: (i) Rheumatoid arthritis-interstitial lung disease with a non-usual interstitial pneumonia pattern may come about when an immune response against citrullinated peptides taking place in another site (e.g. the joints) subsequently affects the lungs; (ii) Rheumatoid arthritis-interstitial lung disease with a usual interstitial pneumonia pattern may represent a disease process in which idiopathic pulmonary fibrosis-like pathology triggers an immune response against citrullinated proteins that promotes articular disease indicative of rheumatoid arthritis. More studies focused on elucidating the basic mechanisms leading to different sub-phenotypes of rheumatoid arthritis-interstitial lung disease and the overlap with idiopathic pulmonary fibrosis are necessary to improve our understanding of the disease process and to define new therapeutic targets.

Modulation of attention network activation under antidepressant agents in healthy subjects.

PubMed

Graf, Heiko; Abler, Birgit; Hartmann, Antonie; Metzger, Coraline D; Walter, Martin

2013-07-01

While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

Mechanism and Catalytic Diversity of Rieske Non-Heme Iron-Dependent Oxygenases

PubMed Central

Barry, Sarah M.; Challis, Gregory L.

2013-01-01

Rieske non-heme iron-dependent oxygenases are important enzymes that catalyze a wide variety of reactions in the biodegradation of xenobiotics and the biosynthesis of bioactive natural products. In this perspective article, we summarize recent efforts to elucidate the catalytic mechanisms of Rieske oxygenases and highlight the diverse range of reactions now known to be catalyzed by such enzymes. PMID:24244885

Ketogenic Diets: New Advances for Metabolism-Based Therapies

PubMed Central

Kossoff, Eric H.; Hartman, Adam L.

2014-01-01

Purpose of review Despite myriad anticonvulsants available and in various stages of development, there are thousands of children and adults with epilepsy worldwide still refractory to treatment and not candidates for epilepsy surgery. Many of these patients will now turn to dietary therapies such as the ketogenic diet, medium-chain triglyceride (MCT) diet, modified Atkins diet, and low glycemic index treatment. Recent Findings In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome). Adults are also one of the most rapidly growing populations being treated nowadays; a group of patients previously not typically offered these treatments. In 2009, two controlled trials of the ketogenic diet were published as well as an International Expert Consensus Statement on dietary treatment of epilepsy. Ketogenic diets are also now being increasingly studied for neurologic conditions other than epilepsy, including Alzheimer disease and cancer. Insights from basic science research have helped elucidate the mechanisms by which metabolism-based therapy may be helpful, both in terms of an anticonvulsant and possibly neuroprotective effect. Summary Dietary therapy for epilepsy continues to grow in popularity worldwide, with expanding use for adults and conditions other than epilepsy. PMID:22322415

Predictors of proximal tibia anterior shear force during a vertical stop-jump.

PubMed

Sell, Timothy C; Ferris, Cheryl M; Abt, John P; Tsai, Yung-Shen; Myers, Joseph B; Fu, Freddie H; Lephart, Scott M

2007-12-01

Anterior cruciate ligament (ACL) continues to be a significant medical issue for athletes participating in sports and recreational activities. Biomechanical analyses have determined that anterior shear force is the most direct loading mechanism of the ACL and a probable component of noncontact ACL injury. The purpose of this study was to examine the biomechanical predictors of proximal tibia anterior shear force during a stop-jump task. A biomechanical and electromyographic (EMG) analysis of the knee was conducted while subjects performed a vertical stop-jump task. The task was chosen to simulate an athletic maneuver that included a landing with a sharp deceleration and a change in direction. The final regression model indicated that posterior ground reaction force, external knee flexion moment, knee flexion angle, integrated EMG activity of the vastus lateralis, and sex (female) would significantly predict proximal tibia anterior shear force (p < 0.0001, R2 = 0.8609). Knee flexion moment had the greatest influence on proximal tibia anterior shear force. The mathematical relationships elucidated in the current study support previous clinical and basic science research examining noncontact ACL injuries. This data provides important evidence for clinicians who are examining the risk factors for these injuries and developing/validating training programs to reduce the incidence of injury. Copyright 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

CCAAT/enhancer-binding protein beta promotes osteoblast differentiation by enhancing Runx2 activity with ATF4.

PubMed

Tominaga, Hiroyuki; Maeda, Shingo; Hayashi, Makoto; Takeda, Shu; Akira, Shizuo; Komiya, Setsuro; Nakamura, Takashi; Akiyama, Haruhiko; Imamura, Takeshi

2008-12-01

Although CCAAT/enhancer-binding protein beta (C/EBPbeta) is involved in osteocalcin gene expression in osteoblast in vitro, the physiological importance of and molecular mechanisms governing C/EBPbeta in bone formation remain to be elucidated. In particular, it remains unclear whether C/EBPbeta acts as a homodimer or a heterodimer with other proteins during osteoblast differentiation. Here, deletion of the C/EBPbeta gene from mice resulted in delayed bone formation with concurrent suppression of chondrocyte maturation and osteoblast differentiation. The expression of type X collagen as well as chondrocyte hypertrophy were suppressed in mutant bone, providing new insight into the possible roles of C/EBPbeta in chondrocyte maturation. In osteoblasts, luciferase reporter, gel shift, DNAP, and ChIP assays demonstrated that C/EBPbeta heterodimerized with activating transcription factor 4 (ATF4), another basic leucine zipper transcription factor crucial for osteoblast maturation. This complex interacted and transactivated osteocalcin-specific element 1 (OSE1) of the osteocalcin promoter. C/EBPbeta also enhanced the synergistic effect of ATF4 and Runx2 on osteocalcin promoter transactivation by enhancing their interaction. Thus, our results provide evidence that C/EBPbeta is a crucial cofactor in the promotion of osteoblast maturation by Runx2 and ATF4.

Three-Dimensional Rotating Wall Vessel-Derived Cell Culture Models for Studying Virus-Host Interactions

PubMed Central

Gardner, Jameson K.; Herbst-Kralovetz, Melissa M.

2016-01-01

The key to better understanding complex virus-host interactions is the utilization of robust three-dimensional (3D) human cell cultures that effectively recapitulate native tissue architecture and model the microenvironment. A lack of physiologically-relevant animal models for many viruses has limited the elucidation of factors that influence viral pathogenesis and of complex host immune mechanisms. Conventional monolayer cell cultures may support viral infection, but are unable to form the tissue structures and complex microenvironments that mimic host physiology and, therefore, limiting their translational utility. The rotating wall vessel (RWV) bioreactor was designed by the National Aeronautics and Space Administration (NASA) to model microgravity and was later found to more accurately reproduce features of human tissue in vivo. Cells grown in RWV bioreactors develop in a low fluid-shear environment, which enables cells to form complex 3D tissue-like aggregates. A wide variety of human tissues (from neuronal to vaginal tissue) have been grown in RWV bioreactors and have been shown to support productive viral infection and physiological meaningful host responses. The in vivo-like characteristics and cellular features of the human 3D RWV-derived aggregates make them ideal model systems to effectively recapitulate pathophysiology and host responses necessary to conduct rigorous basic science, preclinical and translational studies. PMID:27834891

Toll-Like Receptors: New Players in Myocardial Ischemia/Reperfusion Injury

PubMed Central

Ha, Tuanzhu; Liu, Li; Kelley, Jim; Kao, Race; Williams, David

2011-01-01

Abstract Innate immune and inflammatory responses have been implicated in myocardial ischemia/reperfusion (I/R) injury. However, the mechanisms by which innate immunity and inflammatory response are involved in myocardial I/R have not been elucidated completely. Recent studies highlight the role of Toll-like receptors (TLRs) in the induction of innate immune and inflammatory responses. Growing evidence has demonstrated that TLRs play a critical role in myocardial I/R injury. Specifically, deficiency of TLR4 protects the myocardium from ischemic injury, whereas modulation of TLR2 induces cardioprotection against ischemic insult. Importantly, cardioprotection induced by modulation of TLRs involves activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, suggesting that there is a crosstalk between TLRs and PI3K/Akt signaling pathways. In addition, TLRs also associate with other coreceptors, such as macrophage scavenger receptors in the recognition of their ligands. TLRs are also involved in the induction of angiogenesis, modulation of stem cell function, and expression of microRNA, which are currently important topic areas in myocardial I/R. Understanding how TLRs contribute to myocardial I/R injury could provide basic scientific knowledge for the development of new therapeutic approaches for the treatment and management of patients with heart attack. Antioxid. Redox Signal. 15, 1875–1893. PMID:21091074

Masquelier's grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefits.

PubMed

Weseler, Antje R; Bast, Aalt

2017-01-19

Careful characterization and standardization of the composition of plant-derived food supplements is essential to establish a cause-effect relationship between the intake of that product and its health effect. In this review we follow a specific grape seed extract containing monomeric and oligomeric flavan-3-ols from its creation by Jack Masquelier in 1947 towards a botanical remedy and nutraceutical with proven health benefits. The preparation's research history parallels the advancing insights in the fields of molecular biology, medicine, plant and nutritional sciences during the last 70 years. Analysis of the extract's flavanol composition emerged from unspecific colorimetric assays to precise high performance liquid chromatography - mass spectrometry and proton nuclear magnetic resonance fingerprinting techniques. The early recognition of the preparation's auspicious effects on the permeability of vascular capillaries directed research to unravel the underlying cellular and molecular mechanisms. Recent clinical data revealed a multitude of favorable alterations in the vasculature upon an 8 weeks supplementation which summed up in a health benefit of the extract in healthy humans. Changes in gene expression of inflammatory pathways in the volunteers' leukocytes were suggested to be involved in this benefit. The historically grown scientific evidence for the preparation's health effects paves the way to further elucidate its metabolic fate and molecular action in humans.

Amino acids--a life between metabolism and signaling.

PubMed

Häusler, Rainer E; Ludewig, Frank; Krueger, Stephan

2014-12-01

Amino acids serve as constituents of proteins, precursors for anabolism, and, in some cases, as signaling molecules in mammalians and plants. This review is focused on new insights, or speculations, on signaling functions of serine, γ-aminobutyric acid (GABA) and phenylalanine-derived phenylpropanoids. Serine acts as signal in brain tissue and mammalian cancer cells. In plants, de novo serine biosynthesis is also highly active in fast growing tissues such as meristems, suggesting a similar role of serine as in mammalians. GABA functions as inhibitory neurotransmitter in the brain. In plants, GABA is also abundant and seems to be involved in sexual reproduction, cell elongation, patterning and cell identity. The aromatic amino acids phenylalanine, tyrosine, and tryptophan are precursors for the production of secondary plant products. Besides their pharmaceutical value, lignans, neolignans and hydroxycinnamic acid amides (HCAA) deriving from phenylpropanoid metabolism and, in the case of HCAA, also from arginine have been shown to fulfill signaling functions or are involved in the response to biotic and abiotic stress. Although some basics on phenylpropanoid-derived signaling have been described, little is known on recognition- or signal transduction mechanisms. In general, mutant- and transgenic approaches will be helpful to elucidate the mechanistic basis of metabolite signaling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Microbial nitrilases: versatile, spiral forming, industrial enzymes.

PubMed

Thuku, R N; Brady, D; Benedik, M J; Sewell, B T

2009-03-01

The nitrilases are enzymes that convert nitriles to the corresponding acid and ammonia. They are members of a superfamily, which includes amidases and occur in both prokaryotes and eukaryotes. The superfamily is characterized by having a homodimeric building block with a alpha beta beta alpha-alpha beta beta alpha sandwich fold and an active site containing four positionally conserved residues: cys, glu, glu and lys. Their high chemical specificity and frequent enantioselectivity makes them attractive biocatalysts for the production of fine chemicals and pharmaceutical intermediates. Nitrilases are also used in the treatment of toxic industrial effluent and cyanide remediation. The superfamily enzymes have been visualized as dimers, tetramers, hexamers, octamers, tetradecamers, octadecamers and variable length helices, but all nitrilase oligomers have the same basic dimer interface. Moreover, in the case of the octamers, tetradecamers, octadecamers and the helices, common principles of subunit association apply. While the range of industrially interesting reactions catalysed by this enzyme class continues to increase, research efforts are still hampered by the lack of a high resolution microbial nitrilase structure which can provide insights into their specificity, enantioselectivity and the mechanism of catalysis. This review provides an overview of the current progress in elucidation of structure and function in this enzyme class and emphasizes insights that may lead to further biotechnological applications.

Possible Involvement of Insulin Resistance in the Progression of Cancer Cachexia in Mice.

PubMed

Ohsawa, Masahiro; Murakami, Tomoyasu; Kume, Kazuhiko

2016-01-01

Malnutrition is a common problem among cancer patients, affecting up to 85% of patients with certain cancers. In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterized by loss of lean body mass and muscle wasting. Although this muscle wasting might be a product of enhanced protein degradation, the precise mechanisms of cancer cachexia are not fully elucidated. Based on basic and clinical research, glucose intolerance and insulin resistance have been postulated to be associated with cancer cachexia. Since insulin in the skeletal muscle inhibits protein degradation and promotes protein synthesis, insulin resistance could be a possible cause of cancer cachexia. Therefore, we investigated the involvement of insulin resistance in the development of cancer cachexia in tumor-bearing mice. The signaling protein in the insulin cascade was attenuated in the skeletal muscle and hypothalamus from tumor-bearing mice. We identified Chrysanthemum morifolium RAMAT., known as Kikuka, as a peroxisome proliferator-activated receptor γ (PPARγ) ligand. Treatment with Kikuka attenuates the skeletal muscle changes in tumor-bearing mice. These results suggest that this natural PPARγ activator might be an attractive candidate for the treatment of cancer cachexia. In the symposium, we presented the PPARγ activator-induced improvement of cancer cachexia.

Inoculation Stress Hypothesis of Environmental Enrichment

PubMed Central

Crofton, Elizabeth J.; Zhang, Yafang; Green, Thomas A.

2014-01-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. PMID:25449533

Inoculation stress hypothesis of environmental enrichment.

PubMed

Crofton, Elizabeth J; Zhang, Yafang; Green, Thomas A

2015-02-01

One hallmark of psychiatric conditions is the vast continuum of individual differences in susceptibility vs. resilience resulting from the interaction of genetic and environmental factors. The environmental enrichment paradigm is an animal model that is useful for studying a range of psychiatric conditions, including protective phenotypes in addiction and depression models. The major question is how environmental enrichment, a non-drug and non-surgical manipulation, can produce such robust individual differences in such a wide range of behaviors. This paper draws from a variety of published sources to outline a coherent hypothesis of inoculation stress as a factor producing the protective enrichment phenotypes. The basic tenet suggests that chronic mild stress from living in a complex environment and interacting non-aggressively with conspecifics can inoculate enriched rats against subsequent stressors and/or drugs of abuse. This paper reviews the enrichment phenotypes, mulls the fundamental nature of environmental enrichment vs. isolation, discusses the most appropriate control for environmental enrichment, and challenges the idea that cortisol/corticosterone equals stress. The intent of the inoculation stress hypothesis of environmental enrichment is to provide a scaffold with which to build testable hypotheses for the elucidation of the molecular mechanisms underlying these protective phenotypes and thus provide new therapeutic targets to treat psychiatric/neurological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Cognition-Emotion Interactions and Psychopathic Personality: Distinct Pathways to Antisocial and Violent Behavior].

PubMed

Verona, Edelyn

Researchers have long acknowledged heterogeneity among persons who exhibit antisocial and violent behaviours. The study of psychopathic personality or psychopathy can help elucidate this heterogeneity through examination of the different facets that constitute this disorder. In particular, the distinct correlates of the interpersonal-affective traits (Factor 1) and the impulsive-antisocial traits (Factor 2) of psychopathy suggest at least two possible pathways to antisocial behaviours. Building on basic studies in cognitive and affective neuroscience, we provide a focused, non-comprehensive review of work identifying the biopsychological mechanisms involved in these two pathways, with special attention to studies using event-related potential (ERP) methods. In specific, a series of studies are discussed which examined affective and cognitive processes that may distinguish offenders high on psychopathic traits from other offenders, with emphasis on alterations in emotion-cognition interactions related to each factor of psychopathy. The set of findings reviewed highlight a central conclusion: Factor 1 represents a pathway involving reduced emotional responding, exacerbated by attentional abnormalities, that make for a more deliberate and emotionally insensitive offender profile. In contrast, Factor 2 characterizes a pathway marked by emotional and behavioural dysregulation and cognitive control dysfunctions, particularly in emotional contexts. Implications for identifying etiological processes and the further understanding of antisocial and violent behaviours are discussed.

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

PubMed Central

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

2011-01-01

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

The relevance of α-KLOTHO to the central nervous system: Some key questions.

PubMed

Cararo-Lopes, Marina Minto; Mazucanti, Caio Henrique Yokoyama; Scavone, Cristoforo; Kawamoto, Elisa Mitiko; Berwick, Daniel Charles

2017-07-01

α-Klotho is well described as an anti-aging protein, with critical roles in kidney function as a transmembrane co-receptor for FGF23, and as a soluble factor in serum. α-Klotho is also expressed in the choroid plexus, where it is released into the cerebrospinal fluid. Nonetheless, α-Klotho is also expressed in the brain parenchyma. Accumulating evidence indicates that this pool of α-Klotho, which we define as brain α-Klotho, may play important roles as a neuroprotective factor and in promoting myelination, thereby supporting healthy brain aging. Here we summarize what is known about brain α-Klotho before focusing on the outstanding scientific questions related to its function. We believe there is a need for in vitro studies designed to distinguish between brain α-Klotho and other pools of α-Klotho, and for a greater understanding of the basic function of soluble α-Klotho. The mechanism by which the human KL-VS variant affects cognition also requires further elucidation. To help address these questions we suggest some experimental approaches that other laboratories might consider. In short, we hope to stimulate fresh ideas and encourage new research approaches that will allow the importance of α-Klotho for the aging brain to become clear. Copyright © 2017. Published by Elsevier B.V.

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

PubMed Central

Pamenter, Matthew E.; Powell, Frank L.

2016-01-01

Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields. PMID:27347896

The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches

PubMed Central

Pramstaller, Peter P.; Hicks, Andrew A.; Rossini, Alessandra

2017-01-01

Genome-editing technology has emerged as a powerful method that enables the generation of genetically modified cells and organisms necessary to elucidate gene function and mechanisms of human diseases. The clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system has rapidly become one of the most popular approaches for genome editing in basic biomedical research over recent years because of its simplicity and adaptability. CRISPR/Cas9 genome editing has been used to correct DNA mutations ranging from a single base pair to large deletions in both in vitro and in vivo model systems. CRISPR/Cas9 has been used to increase the understanding of many aspects of cardiovascular disorders, including lipid metabolism, electrophysiology and genetic inheritance. The CRISPR/Cas9 technology has been proven to be effective in creating gene knockout (KO) or knockin in human cells and is particularly useful for editing induced pluripotent stem cells (iPSCs). Despite these progresses, some biological, technical, and ethical issues are limiting the therapeutic potential of genome editing in cardiovascular diseases. This review will focus on various applications of CRISPR/Cas9 genome editing in the cardiovascular field, for both disease research and the prospect of in vivo genome-editing therapies in the future. PMID:29434642

Conserved Role of bFGF and a Divergent Role of LIF for Pluripotency Maintenance and Survival in Canine Pluripotent Stem Cells.

PubMed

Luo, Jiesi; Cibelli, Jose B

2016-09-19

Dogs have been widely used as a preclinical model for human disease. With the successful generation of canine induced pluripotent stem cells (ciPSCs), the biomedical community has a unique opportunity to study therapeutic interventions using autologous stem cells that can benefit dogs and humans. Unlike mice and human pluripotent cells, which are leukemia inhibitory factor (LIF)- and basic fibroblast growth factor (bFGF)-dependent, respectively, dog iPSCs require both growth factors simultaneously. In an effort to elucidate the role of each factor in the control of ciPSC self-renewal, we performed a series of experiments aiming at understanding the signaling pathways activated by them. We found that bFGF regulates pluripotency by indirectly activating the SMAD2/3 pathway in the presence of feeder cells, exclusively targeting NANOG expression, and inhibiting spontaneous differentiation toward ectoderm and mesoderm. LIF activates the JAK-STAT3 pathway but does not function in the typical manner described in mouse naïve embryonic stem cells. These results show that a unique mechanism for maintenance of pluripotency is present in ciPSC. These findings should be taken into account when establishing stem cell differentiation protocols and may provide more insight into pluripotency regulation in species other than mice and humans.

Evaluation of oxygen radical absorbance capacity in kampo medicine.

PubMed

Nishimura, Ko; Osawa, Toshihiko; Watanabe, Kenji

2011-01-01

Antioxidant capacity of food has come to be shown in terms of oxygen radical absorbance capacity (ORAC) mainly on vegetables or fruit. However, the evaluation of Kampo in terms of ORAC has not yet been accomplished. It is important that such an investigation is also conducted for Kampo medicine. We measured the ORAC value of almost all the available Kampo formulas used in the Japanese National health insurance system and examined the ORAC value both for the daily prescription, and also the crude herb ingredients. The ORAC value of Kampo medicine ranged 4.65-5913 units/day. The ORAC value was high in Kampo formulas including Rhei Rhizoma, and was relatively high in Kampo formulas including anti-inflammatory herbs other than Rhei Rhizoma. The ORAC value was also high in Kampo formulas including crude herbs that have relaxation effects. The ORAC value of a crude herb would seem to not be fixed but be dependent on combination with other crude herbs from the comparison of different herbs added to the basic Kampo medicine. These results suggest variability and complexity of the antioxidant capacity of Kampo medicine within the similar range of food. On the other hand, investigation of the compound changes of various crude herbs with ORAC may lead to the elucidation of the action mechanism of Kampo medicine.

Temporal and fluoride control of secondary metabolism regulates cellular organofluorine biosynthesis

PubMed Central

Walker, Mark C.; Wen, Miao; Weeks, Amy M.; Chang, Michelle C. Y.

2018-01-01

Elucidating mechanisms of natural organofluorine biosynthesis is essential for a basic understanding of fluorine biochemistry in living systems as well as for expanding biological methods for fluorine incorporation into probe or therapeutic molecules. To meet this goal we have combined massively parallel sequencing technologies, genetic knockout, and in vitro biochemical approaches to investigate the fluoride response of the only known genetic host of an organofluorine producing pathway, Streptomyces cattleya. Interestingly, we have discovered that the major mode of S. cattleya’s resistance to the fluorinated toxin it produces, fluoroacetate, may be due to temporal control of production rather than the ability of the host’s metabolic machinery to discriminate between fluorinated and non–fluorinated molecules. Indeed, neither the acetate kinase/phosphotransacetylase acetate assimilation pathway nor the TCA cycle enzymes (citrate synthase and aconitase) exclude fluorinated substrates based on in vitro biochemical characterization. Furthermore, disruption of the fluoroacetate resistance gene encoding a fluoroacetyl–CoA thioesterase (FlK) does not appear to lead to an observable growth defect related to organofluorine production. By showing that a switch in central metabolism can mediate and control molecular fluorine incorporation, our findings reveal a new potential strategy toward diversifying simple fluorinated building blocks into more complex products. PMID:22769062

Carcinogenicity of consumption of red meat and processed meat: A review of scientific news since the IARC decision.

PubMed

Domingo, José L; Nadal, Martí

2017-07-01

In October 2015, the International Agency for Research on Cancer (IARC) issued a press release on the results of the evaluation of the carcinogenicity of red and processed meat. Based on the accumulated scientific literature, the consumption of red meat was classified as "probably carcinogenic to humans" and processed meat as "carcinogenic to humans". Given the importance of this topic, this review was aimed at revising the current state-of-the-art on the carcinogenicity of red and processed meat, some time after the IARC decision. Some new epidemiological studies and new reviews clearly supporting the IARC decision have been published during these months. However, a number of gaps still exist. It is basic to establish the mechanisms leading to the increased risk of colorectal cancer (CRC) and other cancers arising from red and processed meat consumption. Another important pending issue is to establish the role of known/suspected carcinogens contained in uncooked or unprocessed meats, as well as the influence of cooking. Finally, it would be highly recommended to conduct new epidemiological studies to elucidate whether the consumption of white meat, such as pork and/or poultry, are -positively or inversely-associated with an increased risk of CRC and other types of cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mean-field dynamos: The old concept and some recent developments. Karl Schwarzschild Award Lecture 2013

NASA Astrophysics Data System (ADS)

Rädler, K.-H.

This article elucidates the basic ideas of electrodynamics and magnetohydrodynamics of mean fields in turbulently moving conducting fluids. It is stressed that the connection of the mean electromotive force with the mean magnetic field and its first spatial derivatives is in general neither local nor instantaneous and that quite a few claims concerning pretended failures of the mean-field concept result from ignoring this aspect. In addition to the mean-field dynamo mechanisms of α2 and α Ω type several others are considered. Much progress in mean-field electrodynamics and magnetohydrodynamics results from the test-field method for calculating the coefficients that determine the connection of the mean electromotive force with the mean magnetic field. As an important example the memory effect in homogeneous isotropic turbulence is explained. In magnetohydrodynamic turbulence there is the possibility of a mean electromotive force that is primarily independent of the mean magnetic field and labeled as Yoshizawa effect. Despite of many efforts there is so far no convincing comprehensive theory of α quenching, that is, the reduction of the α effect with growing mean magnetic field, and of the saturation of mean-field dynamos. Steps toward such a theory are explained. Finally, some remarks on laboratory experiments with dynamos are made.

NDE1 and NDEL1: twin neurodevelopmental proteins with similar ‘nature’ but different ‘nurture’

PubMed Central

Bradshaw, Nicholas J.; Hennah, William; Soares, Dinesh C.

2013-01-01

Nuclear distribution element 1 (NDE1, also known as NudE) and NDE-like 1 (NDEL1, also known as Nudel) are paralogous proteins essential for mitosis and neurodevelopment that have been implicated in psychiatric and neurodevelopmental disorders. The two proteins possess high sequence similarity and have been shown to physically interact with one another. Numerous lines of experimental evidence in vivo and in cell culture have demonstrated that these proteins share common functions, although instances of differing functions between the two have recently emerged. We review the key aspects of NDE1 and NDEL1 in terms of recent advances in structure elucidation and cellular function, with an emphasis on their differing mechanisms of post-translational modification. Based on a review of the literature and bioinformatics assessment, we advance the concept that the twin proteins NDE1 and NDEL1, while sharing a similar ‘nature’ in terms of their structure and basic functions, appear to be different in their ‘nurture’, the manner in which they are regulated both in terms of expression and of post-translational modification within the cell. These differences are likely to be of significant importance in understanding the specific roles of NDE1 and NDEL1 in neurodevelopment and disease. PMID:24093049

Mechanism of Stabilization of Labile Compounds by Silk Fibroin Proteins

DTIC Science & Technology

2017-04-05

AFRL-AFOSR-VA-TR-2017-0076 Mechanism of Stabilization of Labile Compounds by Silk Fibroin Proteins David Kaplan TRUSTEES OF TUFTS COLEGE INC 169... Proteins 5a.  CONTRACT NUMBER 5b.  GRANT NUMBER FA9550-14-1-0015 5c.  PROGRAM ELEMENT NUMBER 61102F 6. AUTHOR(S) David Kaplan 5d.  PROJECT NUMBER 5e...objective of this research was to elucidate the fundamental mechanisms by which labile compounds are entrapped and stabilized by silk fibroin protein . The

Finding, Conducting, and Nurturing Science: A Virologist's Memoir.

PubMed

Skalka, Anna Marie Ann

2017-09-29

My laboratory investigations have been driven by an abiding interest in understanding the consequences of genetic rearrangement in evolution and disease, and in using viruses to elucidate fundamental mechanisms in biology. Starting with bacteriophages and moving to the retroviruses, my use of the tools of genetics, molecular biology, biochemistry, and biophysics has spanned more than half a century-from the time when DNA structure was just discovered to the present day of big data and epigenetics. Both riding and contributing to the successive waves of technology, my laboratory has elucidated fundamental mechanisms in DNA replication, repair, and recombination. We have made substantial contributions in the area of retroviral oncogenesis, delineated mechanisms that control retroviral gene expression, and elucidated critical details of the structure and function of the retroviral enzymes-reverse transcriptase, protease, and integrase-and have had the satisfaction of knowing that the fundamental knowledge gained from these studies contributed important groundwork for the eventual development of antiviral drugs to treat AIDS. While pursuing laboratory research as a principal investigator, I have also been a science administrator-moving from laboratory head to department chair and, finally, to institute director. In addition, I have undertaken a number of community service, science-related "extracurricular" activities during this time. Filling all of these roles, while being a wife and mother, has required family love and support, creative management, and, above all, personal flexibility-with not too much long-term planning. I hope that this description of my journey, with various roles, obstacles, and successes, will be both interesting and informative, especially to young female scientists.

ELUCIDATING THE MECHANISMS BEHIND SUCCESSFUL INDICATORS OF BIODIVERSITY

EPA Science Inventory

Groups of species have been proposed as indicators of biodiversity for use in conservation planning. Different tests of indicator groups have produced divergent results varying with taxonomy, methodology, scale, and location. At large scales, successful indicator groups should b...

Mechanical Stimulation of Adipose-Derived Stem Cells for Functional Tissue Engineering of the Musculoskeletal System via Cyclic Hydrostatic Pressure, Simulated Microgravity, and Cyclic Tensile Strain.

PubMed

Nordberg, Rachel C; Bodle, Josie C; Loboa, Elizabeth G

2018-01-01

It is critical that human adipose stem cell (hASC) tissue-engineering therapies possess appropriate mechanical properties in order to restore function of the load bearing tissues of the musculoskeletal system. In an effort to elucidate the hASC response to mechanical stimulation and develop mechanically robust tissue engineered constructs, recent research has utilized a variety of mechanical loading paradigms including cyclic tensile strain, cyclic hydrostatic pressure, and mechanical unloading in simulated microgravity. This chapter describes methods for applying these mechanical stimuli to hASC to direct differentiation for functional tissue engineering of the musculoskeletal system.

29 CFR 5.32 - Overtime payments.

Code of Federal Regulations, 2014 CFR

2014-07-01

....25 an hour to a mechanic as his basic cash wage plus 50 cents an hour as a contribution to a welfare... prevailing wage statutes. It is clear from the legislative history that in no event can the regular or basic... less than the amount determined by the Secretary of Labor as the basic hourly rate (i.e. cash rate...

29 CFR 5.32 - Overtime payments.

Code of Federal Regulations, 2013 CFR

2013-07-01

....25 an hour to a mechanic as his basic cash wage plus 50 cents an hour as a contribution to a welfare... prevailing wage statutes. It is clear from the legislative history that in no event can the regular or basic... less than the amount determined by the Secretary of Labor as the basic hourly rate (i.e. cash rate...

29 CFR 5.32 - Overtime payments.

Code of Federal Regulations, 2012 CFR

2012-07-01

....25 an hour to a mechanic as his basic cash wage plus 50 cents an hour as a contribution to a welfare... prevailing wage statutes. It is clear from the legislative history that in no event can the regular or basic... less than the amount determined by the Secretary of Labor as the basic hourly rate (i.e. cash rate...

Object Categorization: Reversals and Explanations of the Basic-Level Advantage

ERIC Educational Resources Information Center

Rogers, Timothy T.; Patterson, Karalyn

2007-01-01

People are generally faster and more accurate to name or categorize objects at the basic level (e.g., dog) relative to more general (animal) or specific (collie) levels, an effect replicated in Experiment 1 for categorization of object pictures. To some, this pattern suggests a dual-process mechanism, in which objects first activate basic-level…

Elucidation of Enzymatic Mechanism of Phenazine Biosynthetic Protein PhzF Using QM/MM and MD Simulations

PubMed Central

Liu, Fei; Zhao, Yi-Lei; Wang, Xiaolei; Hu, Hongbo; Peng, Huasong; Wang, Wei; Wang, Jing-Fang; Zhang, Xuehong

2015-01-01

The phenazine biosynthetic pathway is of considerable importance for the pharmaceutical industry. The pathway produces two products: phenazine-1,6-dicarboxylic acid and phenazine-1-carboxylic acid. PhzF is an isomerase that catalyzes trans-2,3-dihydro-3-hydroxyanthranilic acid isomerization and plays an essential role in the phenazine biosynthetic pathway. Although the PhzF crystal structure has been determined recently, an understanding of the detailed catalytic mechanism and the roles of key catalytic residues are still lacking. In this study, a computational strategy using a combination of molecular modeling, molecular dynamics simulations, and quantum mechanics/molecular mechanics simulations was used to elucidate these important issues. The Apo enzyme, enzyme–substrate complexes with negatively charged Glu45, enzyme–transition state analog inhibitor complexes with neutral Glu45, and enzyme–product complexes with negatively charged Glu45 structures were optimized and modeled using a 200 ns molecular dynamics simulation. Residues such as Gly73, His74, Asp208, Gly212, Ser213, and water, which play important roles in ligand binding and the isomerization reaction, were comprehensively investigated. Our results suggest that the Glu45 residue at the active site of PhzF acts as a general base/acid catalyst during proton transfer. This study provides new insights into the detailed catalytic mechanism of PhzF and the results have important implications for PhzF modification. PMID:26414009

Ratio

NASA Astrophysics Data System (ADS)

Webster, Nathan A. S.; Pownceby, Mark I.; Madsen, Ian C.; Studer, Andrew J.; Manuel, James R.; Kimpton, Justin A.

2014-12-01

Effects of basicity, B (CaO:SiO2 ratio) on the thermal range, concentration, and formation mechanisms of silico-ferrite of calcium and aluminum (SFCA) and SFCA-I iron ore sinter bonding phases have been investigated using an in situ synchrotron X-ray diffraction-based methodology with subsequent Rietveld refinement-based quantitative phase analysis. SFCA and SFCA-I phases are the key bonding materials in iron ore sinter, and improved understanding of the effects of processing parameters such as basicity on their formation and decomposition may assist in improving efficiency of industrial iron ore sintering operations. Increasing basicity significantly increased the thermal range of SFCA-I, from 1363 K to 1533 K (1090 °C to 1260 °C) for a mixture with B = 2.48, to ~1339 K to 1535 K (1066 °C to 1262 °C) for a mixture with B = 3.96, and to ~1323 K to 1593 K (1050 °C to 1320 °C) at B = 4.94. Increasing basicity also increased the amount of SFCA-I formed, from 18 wt pct for the mixture with B = 2.48 to 25 wt pct for the B = 4.94 mixture. Higher basicity of the starting sinter mixture will, therefore, increase the amount of SFCA-I, considered to be more desirable of the two phases. Basicity did not appear to significantly influence the formation mechanism of SFCA-I. It did, however, affect the formation mechanism of SFCA, with the decomposition of SFCA-I coinciding with the formation of a significant amount of additional SFCA in the B = 2.48 and 3.96 mixtures but only a minor amount in the highest basicity mixture. In situ neutron diffraction enabled characterization of the behavior of magnetite after melting of SFCA produced a magnetite plus melt phase assemblage.

International involvement and national health governance: the basic benefit package in Tajikistan.

PubMed

Rechel, Bernd; Khodjamurodov, Ghafur

2010-06-01

Tajikistan, a Central Asian state of 7.4 million inhabitants, is facing particular health policy challenges: not only is the country the poorest of the former Soviet republics, but its capacity to deal with post-communist transition and economic crisis has been further undermined through civil war and large-scale migration. This paper, examining the introduction of the basic benefit package and formal co-payments, elucidates how international involvement in Tajikistan's health sector has impacted on national health governance. Based on documentary sources and information provided by key informants, we find that external agencies have both strengthened and weakened national health governance. Although they have played a major part in supporting Tajikistan's health sector, these efforts have often been fragmented, as donor coordination was at times less than optimal. A key challenge for national health governance is the limited technical and institutional capacity of the Ministry of Health and further efforts are needed to build national capacity. Copyright 2010 Elsevier Ltd. All rights reserved.

Acido-basic control of the thermoelectric properties of poly(3,4-ethylenedioxythiophene)tosylate (PEDOT-Tos) thin films.

PubMed

Khan, Zia Ullah; Bubnova, Olga; Jafari, Mohammad Javad; Brooke, Robert; Liu, Xianjie; Gabrielsson, Roger; Ederth, Thomas; Evans, Drew R; Andreasen, Jens W; Fahlman, Mats; Crispin, Xavier

2015-10-28

PEDOT-Tos is one of the conducting polymers that displays the most promising thermoelectric properties. Until now, it has been utterly difficult to control all the synthesis parameters and the morphology governing the thermoelectric properties. To improve our understanding of this material, we study the variation in the thermoelectric properties by a simple acido-basic treatment. The emphasis of this study is to elucidate the chemical changes induced by acid (HCl) or base (NaOH) treatment in PEDOT-Tos thin films using various spectroscopic and structural techniques. We could identify changes in the nanoscale morphology due to anion exchange between tosylate and Cl - or OH - . But, we identified that changing the pH leads to a tuning of the oxidation level of the polymer, which can explain the changes in thermoelectric properties. Hence, a simple acid-base treatment allows finding the optimum for the power factor in PEDOT-Tos thin films.

A magnetic and electronic circular dichroism study of azurin, plastocyanin, cucumber basic protein, and nitrite reductase based on time-dependent density functional theory calculations.

PubMed

Zhekova, Hristina R; Seth, Michael; Ziegler, Tom

2010-06-03

The excitation, circular dichroism, magnetic circular dichroism (MCD) and electron paramagnetic resonance (EPR) spectra of small models of four blue copper proteins are simulated on the TDDFT/BP86 level. X-Ray diffraction geometries are used for the modeling of the blue copper sites in azurin, plastocyanin, cucumber basic protein, and nitrite reductase. Comparison with experimental data reveals that the calculations reproduce most of the qualitative trends of the observed experimental spectra with some discrepancies in the orbital decompositions and the values of the excitation energies, the g( parallel) components of the g tensor, and the components of the A tensor. These discrepancies are discussed relative to deficiencies in the time-dependent density functional theory (TDDFT) methodology, as opposed to previous studies which address them as a result of insufficient model size or poor performance of the BP86 functional. In addition, attempts are made to elucidate the correlation between the MCD and EPR signals.

Biological characters of bats in relation to natural reservoir of emerging viruses.

PubMed

Omatsu, Tsutomu; Watanabe, Shumpei; Akashi, Hiroomi; Yoshikawa, Yasuhiro

2007-09-01

Many investigators focused on bats (Chiroptera) for their specific character, i.e. echolocation system, phylogenic tree, food practice and unique reproduction. However, most of basic information about the vital functions related to anti-viral activity has been unclear. For evaluating some animals as a natural reservoir or host of infectious pathogens, it is necessary that not only their immune system but also their biology, the environment of their living, food habits and physiological features should be clarified and they should be analyzed from these multi-view points. The majority of current studies on infectious diseases have been conducted for the elucidation of viral virulence using experimental animals or viral gene function in vitro, but in a few case, researchers focused on wild animal itself. In this paper, we described basic information about bats as follows; genetic background, character of the immunological factors, histological character of immune organs, the physiological function and sensitivity of bat cells to viral infection.

Preloaded joint analysis methodology for space flight systems

NASA Technical Reports Server (NTRS)

Chambers, Jeffrey A.

1995-01-01

This report contains a compilation of some of the most basic equations governing simple preloaded joint systems and discusses the more common modes of failure associated with such hardware. It is intended to provide the mechanical designer with the tools necessary for designing a basic bolted joint. Although the information presented is intended to aid in the engineering of space flight structures, the fundamentals are equally applicable to other forms of mechanical design.

Some important considerations in the development of stress corrosion cracking test methods.

NASA Technical Reports Server (NTRS)

Wei, R. P.; Novak, S. R.; Williams, D. P.

1972-01-01

Discussion of some of the precaution needs the development of fracture-mechanics based test methods for studying stress corrosion cracking involves. Following a review of pertinent analytical fracture mechanics considerations and of basic test methods, the implications for test corrosion cracking studies of the time-to-failure determining kinetics of crack growth and life are examined. It is shown that the basic assumption of the linear-elastic fracture mechanics analyses must be clearly recognized and satisfied in experimentation and that the effects of incubation and nonsteady-state crack growth must also be properly taken into account in determining the crack growth kinetics, if valid data are to be obtained from fracture-mechanics based test methods.

Exposure to Air Pollution Enhances the Generation of Vascular Microparticles

EPA Science Inventory

Epidemiological studies associate exposure to ambient levels of particulate matter (PM) with cardiovascular morbidity and mortality. The biological mechanisms by which PM exposure induces cardiovascular effects remain to be elucidated. One important limitation is the lack of sens...

Carrie Farberow | NREL

Science.gov Websites

important in addressing energy and environmental challenges Elucidating reaction mechanisms using combined selectivity under reaction conditions Developing improved models to bridge the pressure gap and materials gap Identity," ACS Catalysis (2016) "Density Functional Theory Calculations and Analysis of Reaction

CARDIOVASCULAR TOXICITY OF PM: SOLUBLE COMPONENTS OR SOLID PARTICLES?

EPA Science Inventory

Since strong suggestion of cardiac-related deaths has arisen from epidemiological studies of ambient PM, a major effort is required to identify PM components and mechanisms responsible for observed cardiac impairments. Unfortunately, it has been difficult to elucidate causality w...

Evidence for the Absence of Gluon Orbital Angular Momentum in the Nucleon

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

Brodsky, S.J.; Gardner, S.

2006-08-23

The Sivers mechanism for the single-spin asymmetry in unpolarized lepton scattering from a transversely polarized nucleon is driven by the orbital angular momentum carried by its quark and gluon constituents, combined with QCD final-state interactions. Both quark and gluon mechanisms can generate such a single-spin asymmetry, though only the quark mechanism can explain the small single-spin asymmetry measured by the COMPASS collaboration on the deuteron, suggesting the gluon mechanism is small relative to the quark mechanism. We detail empirical studies through which the gluon and quark orbital angular momentum contributions, quark-flavor by quark-flavor, can be elucidated.

Oxygen Sensing and Homeostasis

PubMed Central

Semenza, Gregg L.

2015-01-01

The discovery of carotid bodies as sensory receptors for detecting arterial blood oxygen levels, and the identification and elucidation of the roles of hypoxia-inducible factors (HIFs) in oxygen homeostasis have propelled the field of oxygen biology. This review highlights the gas-messenger signaling mechanisms associated with oxygen sensing, as well as transcriptional and non-transcriptional mechanisms underlying the maintenance of oxygen homeostasis by HIFs and their relevance to physiology and pathology. PMID:26328879

Genetic alterations in hepatocellular carcinoma: An update

PubMed Central

Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

2016-01-01

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

Tributyltin interacts with mitochondria and induces cytochrome c release.

PubMed Central

Nishikimi, A; Kira, Y; Kasahara, E; Sato, E F; Kanno, T; Utsumi, K; Inoue, M

2001-01-01

Although triorganotins are potent inducers of apoptosis in various cell types, the critical targets of these compounds and the mechanisms by which they lead to cell death remain to be elucidated. There are two major pathways by which apoptotic cell death occurs: one is triggered by a cytokine mediator and the other is by a mitochondrion-dependent mechanism. To elucidate the mechanism of triorganotin-induced apoptosis, we studied the effect of tributyltin on mitochondrial function. We found that moderately low doses of tributyltin decrease mitochondrial membrane potential and induce cytochrome c release by a mechanism inhibited by cyclosporine A and bongkrekic acid. Tributyltin-induced cytochrome c release is also prevented by dithiols such as dithiothreitol and 2,3-dimercaptopropanol but not by monothiols such as GSH, N-acetyl-L-cysteine, L-cysteine and 2-mercaptoethanol. Further studies with phenylarsine oxide agarose revealed that tributyltin interacts with the adenine nucleotide translocator, a functional constituent of the mitochondrial permeability transition pore, which is selectively inhibited by dithiothreitol. These results suggest that, at low doses, tributyltin interacts selectively with critical thiol residues in the adenine nucleotide translocator and opens the permeability transition pore, thereby decreasing membrane potential and releasing cytochrome c from mitochondria, a series of events consistent with established mechanistic models of apoptosis. PMID:11368793

Biophysical Approaches for Oral Wound Healing: Emphasis on Photobiomodulation

PubMed Central

Khan, Imran; Arany, Praveen

2015-01-01

Significance: Oral wounds can lead to significant pain and discomfort as well as affect overall general health due to poor diet and inadequate nutrition. Besides many biological and pharmaceutical methods being investigated, there is growing interest in exploring various biophysical devices that utilize electric, magnetic, ultrasound, pressure, and light energy. Recent Advances: Significant insight into mechanisms of these biophysical devices could provide a clear rationale for their clinical use. Preclinical studies are essential precursors in determining physiological mechanisms and elucidation of causal pathways. This will lead to development of safe and effective therapeutic protocols for clinical wound management. Critical Issues: Identification of precise events initiated by biophysical devices, specifically photobiomodulation—the major focus of this review, offers promising avenues in improving oral wound management. The primary phase responses initiated by the interventions that distinctly contribute to the therapeutic response must be clearly delineated from secondary phase responses. The latter events are a consequence of the wound healing process and must not be confused with causal mechanisms. Future Direction: Clinical adoption of these biophysical devices needs robust and efficacious protocols that can be developed by well-designed preclinical and clinical studies. Elucidation of the precise molecular mechanisms of these biophysical approaches could determine optimization of their applications for predictive oral wound care. PMID:26634185

Mechanical modeling for magnetorheological elastomer isolators based on constitutive equations and electromagnetic analysis

NASA Astrophysics Data System (ADS)

Wang, Qi; Dong, Xufeng; Li, Luyu; Ou, Jinping

2018-06-01

As constitutive models are too complicated and existing mechanical models lack universality, these models are beyond satisfaction for magnetorheological elastomer (MRE) devices. In this article, a novel universal method is proposed to build concise mechanical models. Constitutive model and electromagnetic analysis were applied in this method to ensure universality, while a series of derivations and simplifications were carried out to obtain a concise formulation. To illustrate the proposed modeling method, a conical MRE isolator was introduced. Its basic mechanical equations were built based on equilibrium, deformation compatibility, constitutive equations and electromagnetic analysis. An iteration model and a highly efficient differential equation editor based model were then derived to solve the basic mechanical equations. The final simplified mechanical equations were obtained by re-fitting the simulations with a novel optimal algorithm. In the end, verification test of the isolator has proved the accuracy of the derived mechanical model and the modeling method.

Strong activation of bile acid-sensitive ion channel (BASIC) by ursodeoxycholic acid

PubMed Central

Wiemuth, Dominik; Sahin, Hacer; Lefèvre, Cathérine M.T.; Wasmuth, Hermann E.; Gründer, Stefan

2013-01-01

Bile acid-sensitive ion channel (BASIC) is a member of the DEG/ENaC gene family of unknown function. Rat BASIC (rBASIC) is inactive at rest. We have recently shown that cholangiocytes, the epithelial cells lining the bile ducts, are the main site of BASIC expression in the liver and identified bile acids, in particular hyo- and chenodeoxycholic acid, as agonists of rBASIC. Moreover, it seems that extracellular divalent cations stabilize the resting state of rBASIC, because removal of extracellular divalent cations opens the channel. In this addendum, we demonstrate that removal of extracellular divalent cations potentiates the activation of rBASIC by bile acids, suggesting an allosteric mechanism. Furthermore, we show that rBASIC is strongly activated by the anticholestatic bile acid ursodeoxycholic acid (UDCA), suggesting that BASIC might mediate part of the therapeutic effects of UDCA. PMID:23064163